Case Reports

In 1960, Gorlin and Goltz¹ first described nevoid basal cell carcinoma syndrome (NBCCS) as a distinct clinical entity with multiple basal cell carcinomas (BCCs), jaw cysts, and bifid ribs. This rare autosomal-dominant genodermatosis has a minimal prevalence of 1 case per 57,000 individuals² and no sexual predilection.³ Nevoid basal cell carcinoma syndrome is caused by a mutation in the human homolog of a Drosophila gene, patched 1 (PTCH1), which is located on chromosome 9q22.^3.4,5 The major clinical diagnostic criteria includes multiple BCCs, odontogenic keratocysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and a family history of NBCCS.⁶ Basal cell carcinoma formation is affected by both skin pigmentation and sun exposure; 80% of white patients with NBCCS will develop at least 1 BCC compared to only 40% of black patients with NBCCS.⁷ Goldstein et al⁸ postulated that this disparity is associated with increased skin pigmentation providing UV radiation protection, thus decreasing the tumor burden. We report a case of an 11-year-old black boy with NBCCS to highlight the treatment considerations in pediatric cases of NBCCS.

Case Report

An 11-year-old boy with Fitzpatrick skin type V presented with a history of multiple facial lesions after undergoing excision of large keratocysts from the right maxilla, left maxilla, and right mandible. Physical examination revealed multiple light to dark brown facial papules (Figure 1), palmar and plantar pitting (Figure 2), and frontal bossing.

He was previously diagnosed with autism and his surgical history was notable only for excision of the keratocysts. The patient was not taking any medications and did not have any drug allergies. There was no maternal family history of skin cancer or related syndromes; his paternal family history was unknown. A shave biopsy was performed on a facial papule from the right nasolabial fold. Histopathologic evaluation revealed findings consistent with a pigmented nodular BCC (Figure 3). The patient was subsequently sent for magnetic resonance imaging of the brain, which demonstrated calcifications along the tentorium. Genetic consultation confirmed a heterozygous mutation of the PTCH1 gene.

Over the next 12 months, the patient had multiple biopsy-proven pigmented BCCs. Initial management of these carcinomas located on cosmetically sensitive areas, including the upper eyelid and penis, were excised by a pediatric plastic surgeon. A truncal carcinoma was treated with electrodesiccation and curettage, which resulted in keloid formation. Early suspicious lesions were treated with imiquimod cream 5% 5 times weekly in combination with the prophylactic use of tretinoin cream 0.1%. Despite this treatment regimen, the patient continued to demonstrate multiple small clinical pigmented BCCs along the malar surfaces of the cheeks and dorsum of the nose. The patient’s mother deferred chemoprevention with an oral retinoid due to the extensive side-effect profile and long-term necessity of administration.

Management also encompassed BCC surveillance every 4 months; annual digital panorex of the jaw; routine dental screening; routine developmental screening; annual follow-up with a geneticist to ensure multidisciplinary care; and annual vision, hearing, and speech-screening examinations. Strict sun-protective measures were encouraged, including wearing a hat during physical education class.

Comment

Classification and Clinical Presentation
Nevoid basal cell carcinoma syndrome is a multisystem disorder that requires close monitoring under multidisciplinary care. Evans et al⁶ defined the diagnostic criteria of NBCCS to require the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria include multiple BCCs, an odontogenic keratocyst or polyostotic bone cyst, palmar or plantar pits, ectopic calcification of the falx cerebri, and family history of NBCCS. The minor criteria are defined as congenital skeletal anomalies; macrocephaly with frontal bossing; cardiac or ovarian fibromas; medulloblastoma; lymphomesenteric cysts; and congenital malformations such as cleft lip or palate, polydactyly, or eye anomalies.⁶ The mean age of initial BCC diagnosis is 21 years, with proliferation of cancers between puberty and 35 years of age.^7,9 Our case is unique due to the patient’s young age at the time of diagnosis as well as his presentation with multiple BCCs with a darker skin type. Kimonis et al⁷ reported that approximately 20% of black patients develop their first BCC by the age of 21 years and 40% by 35 years. The presence of multiple BCCs is complicated by the limited treatment options in a pediatric patient. The patient’s inability to withstand multiple procedures contributed to our clinical decision to have multiple lesions removed under general anesthesia by a pediatric plastic surgeon.

Due to the patient’s young age of onset, we placed a great emphasis on close surveillance and management. A management protocol for pediatric patients with NBCCS was described by Bree and Shah; BCNS Colloquium Group¹⁰ (eTable). We closely followed this protocol for surveillance; however, we scheduled dermatologic examinations every 4 months due to his extensive history of BCCs.

Management
Our case presents a challenging therapeutic and management dilemma. The management of NBCCS utilizes a multitude of treatment modalities, but many of them posed cosmetic challenges in our patient such as postinflammatory hypopigmentation and the propensity for keloid formation. Although surgical excision or Mohs micrographic surgery is the standard of treatment of nodular BCCs, we were limited due to the patient’s inability to tolerate multiple surgical procedures without the use of general anesthesia.

Case reports have discussed the use of CO₂ laser resurfacing for management of multiple facial BCCs in patients with NBCCS. Doctoroff et al¹¹ treated a patient with 45 facial BCCs with full-face CO₂ laser resurfacing, and in a 10-month follow-up period the patient developed 6 new BCCs on the face. Nouri et al¹² described 3 cases of multiple BCCs on the face, trunk, and extremities treated with ultrapulse CO₂ laser with postoperative Mohs sections verifying complete histologic clearance of tumors. All 3 patients had Fitzpatrick skin type IV; their ages were 2, 16, and 35 years. Local anesthesia was used in the 2-year-old patient and intravenous sedation in the 16-year-old patient.¹² Although CO₂ laser therapy may be a practical treatment option, it posed too many cosmetic concerns in our patient.

Photodynamic therapy (PDT) is an emerging treatment option for NBCCS patients. Itkin and Gilchrest¹³ treated 2 NBCCS patients with δ-aminolevulinic acid for 1 to 5 hours prior to treatment with blue light therapy. Complete clearance was documented in 89% (8/9) of superficial BCCs and 31% (5/16) of nodular BCCs on the face, indicating that blue light treatment may reduce the cutaneous tumor burden.¹³ Oseroff et al¹⁴ reported similar success in treating 3 children with NBCCS with 20% δ-aminolevulinic acid for 24 hours under occlusion followed by red light treatment. After 1 to 3 treatments, the children had 85% to 98% total clearance, demonstrating it as a viable treatment option in young patients that yields excellent cosmetic results and is well tolerated.¹⁴ Photodynamic therapy is reported to have a low risk of carcinogenicity¹⁵; however, there has been 1 reported case of melanoma developing at the site of multiple PDT treatments.¹⁶ Thus, the risk of carcinogenicity is increasingly bothersome in NBCCS patients due to their sensitivity to exposure. The limited number of studies using topical PDT on pediatric patients, the lack of treatment protocols for pediatric patients, and the need to use general anesthesia for pediatric patients all posed limitations to the use of PDT in our case.

Imiquimod cream 5% was shown in randomized, vehicle-controlled studies to be a safe and effective treatment of superficial BCCs when used 5 days weekly for 6 weeks.¹⁷ These studies excluded patients with NBCCS; however, other studies have been completed in patients with NBCCS. Kagy and Amonette¹⁸ successfully treated 3 nonfacial BCCs in a patient with NBCCS with imiquimod cream 5% daily for 18 weeks, with complete histologic resolution of the tumors. Micali et al¹⁹ also treated 4 patients with NBCCS using imiquimod cream 5% 3 to 5 times weekly for 8 to 14 weeks. Thirteen of 17 BCCs resolved, as confirmed with histologic evaluation.¹⁹ One case report revealed a child with NBCCS who was successfully managed with topical fluorouracil and topical tretinoin for more than 10 years.²⁰ Our patient used imiquimod cream 5% 5 times weekly, which inhibited the growth of existing lesions but did not clear them entirely, as they were nodular in nature.

Chemoprevention with oral retinoids breaches a controversial treatment topic. In 1989, a case study of an NBCCS patient treated with surgical excision and oral etretinate for 12 months documented reduction of large tumors.²¹ A multicenter clinical trial reported that low-dose isotretinoin (10 mg daily) is ineffective in preventing the occurrence of new BCC formation in patients with a history of 2 or more sporadic BCCs.²² Chemoprevention with oral retinoids is well known for being effective for squamous cell carcinomas and actinic keratosis; however, the treatment is less effective for BCCs.²² Most importantly, the extensive side-effect profile and toxicity associated with long-term administration of oral retinoids prohibits many practitioners from routinely using them in pediatric NBCCS patients.

Nevoid basal cell carcinoma syndrome patients are exquisitely sensitive to ionizing radiation and the effects of UV exposure. Therefore, it is essential to emphasize the importance of sun-protective measures such as sun avoidance, broad-spectrum sunscreen use, and sun-protective clothing.

Conclusion

Nevoid basal cell carcinoma syndrome is a multisystem disorder with a notable predisposition for skin cancer. Our case demonstrates the treatment considerations in a pediatric patient with Fitzpatrick skin type V. Pediatric NBCCS patients develop BCCs at a young age and will continue to develop additional lesions throughout life; therefore, skin preservation is an important consideration when choosing the appropriate treatment regimen. Particularly in our patient, utilizing multiple strategic treatment modalities in combination with chemoprevention moving forward will be a continued management challenge. Strict adherence to a surveillance protocol is encouraged to closely monitor the systemic manifestations of the disorder.

In 1960, Gorlin and Goltz¹ first described nevoid basal cell carcinoma syndrome (NBCCS) as a distinct clinical entity with multiple basal cell carcinomas (BCCs), jaw cysts, and bifid ribs. This rare autosomal-dominant genodermatosis has a minimal prevalence of 1 case per 57,000 individuals² and no sexual predilection.³ Nevoid basal cell carcinoma syndrome is caused by a mutation in the human homolog of a Drosophila gene, patched 1 (PTCH1), which is located on chromosome 9q22.^3.4,5 The major clinical diagnostic criteria includes multiple BCCs, odontogenic keratocysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and a family history of NBCCS.⁶ Basal cell carcinoma formation is affected by both skin pigmentation and sun exposure; 80% of white patients with NBCCS will develop at least 1 BCC compared to only 40% of black patients with NBCCS.⁷ Goldstein et al⁸ postulated that this disparity is associated with increased skin pigmentation providing UV radiation protection, thus decreasing the tumor burden. We report a case of an 11-year-old black boy with NBCCS to highlight the treatment considerations in pediatric cases of NBCCS.

Case Report

An 11-year-old boy with Fitzpatrick skin type V presented with a history of multiple facial lesions after undergoing excision of large keratocysts from the right maxilla, left maxilla, and right mandible. Physical examination revealed multiple light to dark brown facial papules (Figure 1), palmar and plantar pitting (Figure 2), and frontal bossing.

He was previously diagnosed with autism and his surgical history was notable only for excision of the keratocysts. The patient was not taking any medications and did not have any drug allergies. There was no maternal family history of skin cancer or related syndromes; his paternal family history was unknown. A shave biopsy was performed on a facial papule from the right nasolabial fold. Histopathologic evaluation revealed findings consistent with a pigmented nodular BCC (Figure 3). The patient was subsequently sent for magnetic resonance imaging of the brain, which demonstrated calcifications along the tentorium. Genetic consultation confirmed a heterozygous mutation of the PTCH1 gene.

Over the next 12 months, the patient had multiple biopsy-proven pigmented BCCs. Initial management of these carcinomas located on cosmetically sensitive areas, including the upper eyelid and penis, were excised by a pediatric plastic surgeon. A truncal carcinoma was treated with electrodesiccation and curettage, which resulted in keloid formation. Early suspicious lesions were treated with imiquimod cream 5% 5 times weekly in combination with the prophylactic use of tretinoin cream 0.1%. Despite this treatment regimen, the patient continued to demonstrate multiple small clinical pigmented BCCs along the malar surfaces of the cheeks and dorsum of the nose. The patient’s mother deferred chemoprevention with an oral retinoid due to the extensive side-effect profile and long-term necessity of administration.

Management also encompassed BCC surveillance every 4 months; annual digital panorex of the jaw; routine dental screening; routine developmental screening; annual follow-up with a geneticist to ensure multidisciplinary care; and annual vision, hearing, and speech-screening examinations. Strict sun-protective measures were encouraged, including wearing a hat during physical education class.

Comment

Classification and Clinical Presentation
Nevoid basal cell carcinoma syndrome is a multisystem disorder that requires close monitoring under multidisciplinary care. Evans et al⁶ defined the diagnostic criteria of NBCCS to require the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria include multiple BCCs, an odontogenic keratocyst or polyostotic bone cyst, palmar or plantar pits, ectopic calcification of the falx cerebri, and family history of NBCCS. The minor criteria are defined as congenital skeletal anomalies; macrocephaly with frontal bossing; cardiac or ovarian fibromas; medulloblastoma; lymphomesenteric cysts; and congenital malformations such as cleft lip or palate, polydactyly, or eye anomalies.⁶ The mean age of initial BCC diagnosis is 21 years, with proliferation of cancers between puberty and 35 years of age.^7,9 Our case is unique due to the patient’s young age at the time of diagnosis as well as his presentation with multiple BCCs with a darker skin type. Kimonis et al⁷ reported that approximately 20% of black patients develop their first BCC by the age of 21 years and 40% by 35 years. The presence of multiple BCCs is complicated by the limited treatment options in a pediatric patient. The patient’s inability to withstand multiple procedures contributed to our clinical decision to have multiple lesions removed under general anesthesia by a pediatric plastic surgeon.

Due to the patient’s young age of onset, we placed a great emphasis on close surveillance and management. A management protocol for pediatric patients with NBCCS was described by Bree and Shah; BCNS Colloquium Group¹⁰ (eTable). We closely followed this protocol for surveillance; however, we scheduled dermatologic examinations every 4 months due to his extensive history of BCCs.

Management
Our case presents a challenging therapeutic and management dilemma. The management of NBCCS utilizes a multitude of treatment modalities, but many of them posed cosmetic challenges in our patient such as postinflammatory hypopigmentation and the propensity for keloid formation. Although surgical excision or Mohs micrographic surgery is the standard of treatment of nodular BCCs, we were limited due to the patient’s inability to tolerate multiple surgical procedures without the use of general anesthesia.

Case reports have discussed the use of CO₂ laser resurfacing for management of multiple facial BCCs in patients with NBCCS. Doctoroff et al¹¹ treated a patient with 45 facial BCCs with full-face CO₂ laser resurfacing, and in a 10-month follow-up period the patient developed 6 new BCCs on the face. Nouri et al¹² described 3 cases of multiple BCCs on the face, trunk, and extremities treated with ultrapulse CO₂ laser with postoperative Mohs sections verifying complete histologic clearance of tumors. All 3 patients had Fitzpatrick skin type IV; their ages were 2, 16, and 35 years. Local anesthesia was used in the 2-year-old patient and intravenous sedation in the 16-year-old patient.¹² Although CO₂ laser therapy may be a practical treatment option, it posed too many cosmetic concerns in our patient.

Photodynamic therapy (PDT) is an emerging treatment option for NBCCS patients. Itkin and Gilchrest¹³ treated 2 NBCCS patients with δ-aminolevulinic acid for 1 to 5 hours prior to treatment with blue light therapy. Complete clearance was documented in 89% (8/9) of superficial BCCs and 31% (5/16) of nodular BCCs on the face, indicating that blue light treatment may reduce the cutaneous tumor burden.¹³ Oseroff et al¹⁴ reported similar success in treating 3 children with NBCCS with 20% δ-aminolevulinic acid for 24 hours under occlusion followed by red light treatment. After 1 to 3 treatments, the children had 85% to 98% total clearance, demonstrating it as a viable treatment option in young patients that yields excellent cosmetic results and is well tolerated.¹⁴ Photodynamic therapy is reported to have a low risk of carcinogenicity¹⁵; however, there has been 1 reported case of melanoma developing at the site of multiple PDT treatments.¹⁶ Thus, the risk of carcinogenicity is increasingly bothersome in NBCCS patients due to their sensitivity to exposure. The limited number of studies using topical PDT on pediatric patients, the lack of treatment protocols for pediatric patients, and the need to use general anesthesia for pediatric patients all posed limitations to the use of PDT in our case.

Imiquimod cream 5% was shown in randomized, vehicle-controlled studies to be a safe and effective treatment of superficial BCCs when used 5 days weekly for 6 weeks.¹⁷ These studies excluded patients with NBCCS; however, other studies have been completed in patients with NBCCS. Kagy and Amonette¹⁸ successfully treated 3 nonfacial BCCs in a patient with NBCCS with imiquimod cream 5% daily for 18 weeks, with complete histologic resolution of the tumors. Micali et al¹⁹ also treated 4 patients with NBCCS using imiquimod cream 5% 3 to 5 times weekly for 8 to 14 weeks. Thirteen of 17 BCCs resolved, as confirmed with histologic evaluation.¹⁹ One case report revealed a child with NBCCS who was successfully managed with topical fluorouracil and topical tretinoin for more than 10 years.²⁰ Our patient used imiquimod cream 5% 5 times weekly, which inhibited the growth of existing lesions but did not clear them entirely, as they were nodular in nature.

Chemoprevention with oral retinoids breaches a controversial treatment topic. In 1989, a case study of an NBCCS patient treated with surgical excision and oral etretinate for 12 months documented reduction of large tumors.²¹ A multicenter clinical trial reported that low-dose isotretinoin (10 mg daily) is ineffective in preventing the occurrence of new BCC formation in patients with a history of 2 or more sporadic BCCs.²² Chemoprevention with oral retinoids is well known for being effective for squamous cell carcinomas and actinic keratosis; however, the treatment is less effective for BCCs.²² Most importantly, the extensive side-effect profile and toxicity associated with long-term administration of oral retinoids prohibits many practitioners from routinely using them in pediatric NBCCS patients.

Nevoid basal cell carcinoma syndrome patients are exquisitely sensitive to ionizing radiation and the effects of UV exposure. Therefore, it is essential to emphasize the importance of sun-protective measures such as sun avoidance, broad-spectrum sunscreen use, and sun-protective clothing.

Conclusion

Nevoid basal cell carcinoma syndrome is a multisystem disorder with a notable predisposition for skin cancer. Our case demonstrates the treatment considerations in a pediatric patient with Fitzpatrick skin type V. Pediatric NBCCS patients develop BCCs at a young age and will continue to develop additional lesions throughout life; therefore, skin preservation is an important consideration when choosing the appropriate treatment regimen. Particularly in our patient, utilizing multiple strategic treatment modalities in combination with chemoprevention moving forward will be a continued management challenge. Strict adherence to a surveillance protocol is encouraged to closely monitor the systemic manifestations of the disorder.

In 1960, Gorlin and Goltz¹ first described nevoid basal cell carcinoma syndrome (NBCCS) as a distinct clinical entity with multiple basal cell carcinomas (BCCs), jaw cysts, and bifid ribs. This rare autosomal-dominant genodermatosis has a minimal prevalence of 1 case per 57,000 individuals² and no sexual predilection.³ Nevoid basal cell carcinoma syndrome is caused by a mutation in the human homolog of a Drosophila gene, patched 1 (PTCH1), which is located on chromosome 9q22.^3.4,5 The major clinical diagnostic criteria includes multiple BCCs, odontogenic keratocysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and a family history of NBCCS.⁶ Basal cell carcinoma formation is affected by both skin pigmentation and sun exposure; 80% of white patients with NBCCS will develop at least 1 BCC compared to only 40% of black patients with NBCCS.⁷ Goldstein et al⁸ postulated that this disparity is associated with increased skin pigmentation providing UV radiation protection, thus decreasing the tumor burden. We report a case of an 11-year-old black boy with NBCCS to highlight the treatment considerations in pediatric cases of NBCCS.

Case Report

An 11-year-old boy with Fitzpatrick skin type V presented with a history of multiple facial lesions after undergoing excision of large keratocysts from the right maxilla, left maxilla, and right mandible. Physical examination revealed multiple light to dark brown facial papules (Figure 1), palmar and plantar pitting (Figure 2), and frontal bossing.

He was previously diagnosed with autism and his surgical history was notable only for excision of the keratocysts. The patient was not taking any medications and did not have any drug allergies. There was no maternal family history of skin cancer or related syndromes; his paternal family history was unknown. A shave biopsy was performed on a facial papule from the right nasolabial fold. Histopathologic evaluation revealed findings consistent with a pigmented nodular BCC (Figure 3). The patient was subsequently sent for magnetic resonance imaging of the brain, which demonstrated calcifications along the tentorium. Genetic consultation confirmed a heterozygous mutation of the PTCH1 gene.

Over the next 12 months, the patient had multiple biopsy-proven pigmented BCCs. Initial management of these carcinomas located on cosmetically sensitive areas, including the upper eyelid and penis, were excised by a pediatric plastic surgeon. A truncal carcinoma was treated with electrodesiccation and curettage, which resulted in keloid formation. Early suspicious lesions were treated with imiquimod cream 5% 5 times weekly in combination with the prophylactic use of tretinoin cream 0.1%. Despite this treatment regimen, the patient continued to demonstrate multiple small clinical pigmented BCCs along the malar surfaces of the cheeks and dorsum of the nose. The patient’s mother deferred chemoprevention with an oral retinoid due to the extensive side-effect profile and long-term necessity of administration.

Management also encompassed BCC surveillance every 4 months; annual digital panorex of the jaw; routine dental screening; routine developmental screening; annual follow-up with a geneticist to ensure multidisciplinary care; and annual vision, hearing, and speech-screening examinations. Strict sun-protective measures were encouraged, including wearing a hat during physical education class.

Comment

Classification and Clinical Presentation
Nevoid basal cell carcinoma syndrome is a multisystem disorder that requires close monitoring under multidisciplinary care. Evans et al⁶ defined the diagnostic criteria of NBCCS to require the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria include multiple BCCs, an odontogenic keratocyst or polyostotic bone cyst, palmar or plantar pits, ectopic calcification of the falx cerebri, and family history of NBCCS. The minor criteria are defined as congenital skeletal anomalies; macrocephaly with frontal bossing; cardiac or ovarian fibromas; medulloblastoma; lymphomesenteric cysts; and congenital malformations such as cleft lip or palate, polydactyly, or eye anomalies.⁶ The mean age of initial BCC diagnosis is 21 years, with proliferation of cancers between puberty and 35 years of age.^7,9 Our case is unique due to the patient’s young age at the time of diagnosis as well as his presentation with multiple BCCs with a darker skin type. Kimonis et al⁷ reported that approximately 20% of black patients develop their first BCC by the age of 21 years and 40% by 35 years. The presence of multiple BCCs is complicated by the limited treatment options in a pediatric patient. The patient’s inability to withstand multiple procedures contributed to our clinical decision to have multiple lesions removed under general anesthesia by a pediatric plastic surgeon.

Due to the patient’s young age of onset, we placed a great emphasis on close surveillance and management. A management protocol for pediatric patients with NBCCS was described by Bree and Shah; BCNS Colloquium Group¹⁰ (eTable). We closely followed this protocol for surveillance; however, we scheduled dermatologic examinations every 4 months due to his extensive history of BCCs.

Management
Our case presents a challenging therapeutic and management dilemma. The management of NBCCS utilizes a multitude of treatment modalities, but many of them posed cosmetic challenges in our patient such as postinflammatory hypopigmentation and the propensity for keloid formation. Although surgical excision or Mohs micrographic surgery is the standard of treatment of nodular BCCs, we were limited due to the patient’s inability to tolerate multiple surgical procedures without the use of general anesthesia.

Case reports have discussed the use of CO₂ laser resurfacing for management of multiple facial BCCs in patients with NBCCS. Doctoroff et al¹¹ treated a patient with 45 facial BCCs with full-face CO₂ laser resurfacing, and in a 10-month follow-up period the patient developed 6 new BCCs on the face. Nouri et al¹² described 3 cases of multiple BCCs on the face, trunk, and extremities treated with ultrapulse CO₂ laser with postoperative Mohs sections verifying complete histologic clearance of tumors. All 3 patients had Fitzpatrick skin type IV; their ages were 2, 16, and 35 years. Local anesthesia was used in the 2-year-old patient and intravenous sedation in the 16-year-old patient.¹² Although CO₂ laser therapy may be a practical treatment option, it posed too many cosmetic concerns in our patient.

Photodynamic therapy (PDT) is an emerging treatment option for NBCCS patients. Itkin and Gilchrest¹³ treated 2 NBCCS patients with δ-aminolevulinic acid for 1 to 5 hours prior to treatment with blue light therapy. Complete clearance was documented in 89% (8/9) of superficial BCCs and 31% (5/16) of nodular BCCs on the face, indicating that blue light treatment may reduce the cutaneous tumor burden.¹³ Oseroff et al¹⁴ reported similar success in treating 3 children with NBCCS with 20% δ-aminolevulinic acid for 24 hours under occlusion followed by red light treatment. After 1 to 3 treatments, the children had 85% to 98% total clearance, demonstrating it as a viable treatment option in young patients that yields excellent cosmetic results and is well tolerated.¹⁴ Photodynamic therapy is reported to have a low risk of carcinogenicity¹⁵; however, there has been 1 reported case of melanoma developing at the site of multiple PDT treatments.¹⁶ Thus, the risk of carcinogenicity is increasingly bothersome in NBCCS patients due to their sensitivity to exposure. The limited number of studies using topical PDT on pediatric patients, the lack of treatment protocols for pediatric patients, and the need to use general anesthesia for pediatric patients all posed limitations to the use of PDT in our case.

Imiquimod cream 5% was shown in randomized, vehicle-controlled studies to be a safe and effective treatment of superficial BCCs when used 5 days weekly for 6 weeks.¹⁷ These studies excluded patients with NBCCS; however, other studies have been completed in patients with NBCCS. Kagy and Amonette¹⁸ successfully treated 3 nonfacial BCCs in a patient with NBCCS with imiquimod cream 5% daily for 18 weeks, with complete histologic resolution of the tumors. Micali et al¹⁹ also treated 4 patients with NBCCS using imiquimod cream 5% 3 to 5 times weekly for 8 to 14 weeks. Thirteen of 17 BCCs resolved, as confirmed with histologic evaluation.¹⁹ One case report revealed a child with NBCCS who was successfully managed with topical fluorouracil and topical tretinoin for more than 10 years.²⁰ Our patient used imiquimod cream 5% 5 times weekly, which inhibited the growth of existing lesions but did not clear them entirely, as they were nodular in nature.

Chemoprevention with oral retinoids breaches a controversial treatment topic. In 1989, a case study of an NBCCS patient treated with surgical excision and oral etretinate for 12 months documented reduction of large tumors.²¹ A multicenter clinical trial reported that low-dose isotretinoin (10 mg daily) is ineffective in preventing the occurrence of new BCC formation in patients with a history of 2 or more sporadic BCCs.²² Chemoprevention with oral retinoids is well known for being effective for squamous cell carcinomas and actinic keratosis; however, the treatment is less effective for BCCs.²² Most importantly, the extensive side-effect profile and toxicity associated with long-term administration of oral retinoids prohibits many practitioners from routinely using them in pediatric NBCCS patients.

Nevoid basal cell carcinoma syndrome patients are exquisitely sensitive to ionizing radiation and the effects of UV exposure. Therefore, it is essential to emphasize the importance of sun-protective measures such as sun avoidance, broad-spectrum sunscreen use, and sun-protective clothing.

Conclusion

Nevoid basal cell carcinoma syndrome is a multisystem disorder with a notable predisposition for skin cancer. Our case demonstrates the treatment considerations in a pediatric patient with Fitzpatrick skin type V. Pediatric NBCCS patients develop BCCs at a young age and will continue to develop additional lesions throughout life; therefore, skin preservation is an important consideration when choosing the appropriate treatment regimen. Particularly in our patient, utilizing multiple strategic treatment modalities in combination with chemoprevention moving forward will be a continued management challenge. Strict adherence to a surveillance protocol is encouraged to closely monitor the systemic manifestations of the disorder.

Case Report

A 71-year-old woman presented with pink to violaceous, flat-topped, polygonal papules consistent with lichen planus (LP) on the volar wrists, extensor elbows, and bilateral lower legs of 3 years’ duration. She also had erythematous, violaceous, infiltrated plaques with microvesiculation on the bilateral thighs of several months’ duration (Figure 1). She reported pruritus, burning, and discomfort. Her medical history included type 2 diabetes mellitus, hypertension, and asthma with no history of skin rashes. A complete physical examination was performed. Age-appropriate screening for malignancy was negative. Hepatitis B and C antibody serologies were negative. Her medications at the time included risedronate and atenolol, which she had been taking for several years.

Punch biopsies from perilesional skin were submitted for hematoxylin and eosin staining and direct immunofluorescence (DIF). Histopathology showed a subepidermal blistering disease with tissue eosinophilia consistent with lichen planus pemphigoides (LPP)(Figure 2); direct immunofluorescence was positive for IgG, C3, and type IV collagen at the dermoepidermal junction. Serum BP180 was positive at 51 U/mL (reference range, <14 U/mL) and BP230 was negative. She was then started on tetracycline (500 mg twice daily), nicotinamide (500 mg twice daily), prednisone (5 mg daily), and dapsone (100 mg daily).

After 3 months without improvement, tetracycline and nicotinamide were discontinued, prednisone was increased to 10 mg daily, and dapsone was continued. A repeat biopsy was taken from a new area of involvement on the left lower leg, which revealed a psoriasiform dermatitis with interface changes. The DIF was positive for IgG and C3 along the basement membrane. A serum indirect immunofluorescence for BP180 also was positive.

The patient developed mild hemolytic anemia on dapsone; the medication was eventually discontinued. Subsequent treatments included adequate trials of azathioprine, mycophenolate mofetil, and hydroxychloroquine. Azathioprine (150 mg daily) and hydroxychloroquine (400 mg daily) treatment failed. She initially improved on mycophenolate mofetil (500 mg in the morning and 1000 mg in the evening) with flattening of the papules on the arms and legs and decreased erythema. However, mycophenolate mofetil eventually lost its efficacy and was discontinued.

Because several medications failed (ie, tetracycline, nicotinamide, prednisone, dapsone, azathioprine, mycophenolate mofetil, hydroxychloroquine), she was started on ustekinumab (45 mg) initial loading dose by subcutaneous injection (patient’s weight, 63 kg). At 4 weeks, the patient was given the second subcutaneous injection of ustekinumab (45 mg). She experienced marked improvement with no new lesions. The prior lesions also had decreased in size and were only slightly pink. The prednisone dose was tapered to 5 mg daily.

She had near-complete resolution of the skin lesions 12 weeks after the second dose of ustekinumab. Since then, she has had some recrudescence of the papulosquamous lesions but no vesicles or bullae. With the exception of occasional scattered pink papules on the forearms, her condition greatly improved on ustekinumab. She is no longer taking any of the other medications with the exception of prednisone (down to 1 mg daily) with a plan to gradually taper completely off of it.

Comment

Clinical Presentation
Lichen planus pemphigoides is a rare autoimmune subepidermal blistering disease with few cases reported in the literature. It is considered a clinical variation of bullous pemphigoid (BP) or a coexistence of LP and BP.^1,2 It is characterized by bullous lesions developing on LP papules as well as on clinically uninvolved areas of the skin. It has been reported that LPP is provoked by several medications including cinnarizine, captopril, ramipril, simvastatin, psoralen plus UVA, and antituberculous medications (eg, isoniazid, rifampin, ethambutol, pyrazinamide).¹ Risedronate or atenolol have not been reported to cause LPP, LP, or BP; however, according to Litt,³ a lichenoid drug eruption has been associated with atenolol. Furthermore, some cases of LPP demonstrate overlapping characteristics with paraneoplastic pemphigus and have been associated with internal malignancy. Hamada et al⁴ described a case of LPP coupled with colon adenocarcinoma and numerous keratoacanthomas. The earliest depiction of the coexistence of a case of mainstream LP complicated by an extensive bullous eruption was by Kaposi⁵ in 1892. He coined the term lichen ruber pemphigoides.⁵

Compared to BP, LPP is believed to affect a younger age group and have a less serious clinical course. The mean age of onset of LPP is in the third to fourth decades of life, while BP typically presents in the sixth decade. When comparing the location of bullae in LPP versus BP, the lesions of LPP tend to occur on the limbs, while BP tends to occur on the trunk.⁶

Clinically, LPP is distinguished by the existence of bullous lesions developing atop of the lesions of LP as well as on normal skin, with the latter being more commonplace. A classic example of LPP is characterized by an initial episode of traditional LP lesions often having severe pruritus, with or without patches of erythema, with the sudden eruption of tense bullae. These bullae commonly appear on the extremities and can appear over the normal skin, erythematous patches, or preexisting papules.⁷ In the atypical clinical presentations of this dubious skin condition, the bullae may only be seen on the lesions of LP.⁸ There also could be a lichenoid erythrodermic manifestation of a bullous eruption.⁹

Oral lesions of LPP have been described but had not been studied immunopathologically until Allen et al¹⁰ portrayed a 59-year-old man with cutaneous and oral lesions of LPP. They performed biopsies on the oral lesions and examined them by routine light microscopy and immunofluorescent techniques. The fine keratotic striae on the anterior buccal mucosal lesions were clinically consistent with oral LP. Perilesional tissue in conjunction with ulceration of the posterior buccal mucosa demonstrated histologic and immunopathologic alterations consistent with BP.¹⁰

Histopathology
Histopathologically, the lesions of LP show a bandlike lymphohistiocytic infiltrate, colloid bodies in the dermis, irregular acanthosis with saw-toothed rete ridges, orthokeratosis, wedge-shaped hypergranulosis, and liquefaction degeneration of the basal layer. Direct immunofluorescence shows mainly IgM and C3 deposited on colloid bodies, fibrin, and fibrinogen.¹¹ The histopathology of the bullous lesion of LPP depicts a subepidermal bulla with variable diffuse or sparse lymphohistiocytic infiltrate and frequent eosinophils with or without neutrophils in the upper dermis. The existence of C3 alone or with IgG along the dermoepidermal junction gives confirmation on DIF.⁷

Autoantibodies
The expression of IgG autoantibodies directed against the basement membrane zone distinguishes LPP from bullous LP.² IgG autoantibodies to either one or both the 230-kDa and 180-kDa BP (type XVII collagen) antigens has been demonstrated with LPP.^4,12-14 Hamada et al⁴ described a histologic pattern more consistent with paraneoplastic pemphigus. It has been suggested that injury to the basal cells in LP or damage due to other courses of therapy such as psoralen plus UVA unveil suppressed antigenic determinants or produce new antigens, leading to antibody development and production of BP.^12,15

Zillikens et al² performed a study to identify the target antigen of LPP autoantibodies. They used sera from patients with LPP (n=4) and stained the epidermal side of salt-split human skin in a configuration identical to BP sera. In BP, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. They demonstrated that sera from BP patients largely reacted with a set of 4 epitopes (MCW-0 through MCW-3) grouped within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, LPP sera also were compellingly reactive with recombinant BP180 NC16A. Lichen planus pemphigoides epitopes were additionally mapped using a series of overlapping recombinant segments of the NC16A domain. The authors demonstrated that all LPP sera reacted with amino acids 46 through 59 of domain NC16A, a protein portion that was previously shown to be unreactive with BP sera. In addition, they showed that 2 LPP sera reacted with the immunodominant antigenic region related to BP. Furthermore, they identified a unique epitope within the BP180 NC16A domain—MCW-4—which was distinctively recognized by sera from patients with LPP.²

Pathogenesis
The pathogenesis of both LP and BP has been linked to multiple cytokines that induce apoptosis in basal keratinocytes. Implicated cytokines include IFN-γ, tumor necrosis factor α (TNF-α), IL-1, IL-6, and IL-8, as well as other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2 in LP.^16-18 Soluble E-selectin, vascular endothelial growth factor, IL-1β, IL-8, IL-5, transforming growth factor β1, and TNF-α were found to be elevated in either blister fluid or sera of BP patients.^15-17

Management
Lichen planus pemphigoides usually responds well to traditional therapies, with systemic steroids being the most efficacious treatment of extensive disease.^12,13 Other options include tetracycline and nicotinamide, isotretinoin, dapsone, and immunosuppressive drugs such as systemic cortico-steroids.¹² Demirçay et al¹² described a patient with skin lesions that rapidly cleared after the administration of oral methylprednisolone (48 mg/d) and oral dapsone (100 mg/d). The methylprednisolone and dapsone were withdrawn after 12 and 16 weeks, respectively. There was no recurrence during the 1-year follow-up period.¹²Kolb-Mäurer et al¹⁹ described a patient who was treated with pulsed intravenous corticosteroids and continued to develop new papular and vesicular skin lesions. However, when oral acitretin was added to the patient’s regimen, the skin lesions cleared.¹⁹ There are several case reports of the successful use of hydroxychloroquine in LP.^20,21

Cutaneous, nail, and oral LP also can be treated with TNF-α inhibitors (eg, adalimumab, etanercept) with resolution of lesions.^22-25 However, we have not been able to find any reports of treating LPP with biologic medications in a search of PubMed articles indexed for MEDLINE using the terms lichen planus pemphigoides and biologic treatments/therapies. Given the fact that TNF-α and other inflammatory cytokines are involved in the pathogenesis of BP and LP, it is feasible that they also may be involved in the pathogenesis of LPP.

In our patient with cutaneous LPP, we chose to use ustekinumab instead of a primary TNF-α inhibitor because ustekinumab indirectly blocks TNF-α, as well as other proinflammatory cytokines such as IFN-γ, IL-17, and IL-22, which also could have played a role in the patient’s disease. Our goal was to use ustekinumab as a potential corticosteroid-sparing agent. Ustekinumab greatly improved her skin condition and allowed us to discontinue other medications.

Case Report

A 71-year-old woman presented with pink to violaceous, flat-topped, polygonal papules consistent with lichen planus (LP) on the volar wrists, extensor elbows, and bilateral lower legs of 3 years’ duration. She also had erythematous, violaceous, infiltrated plaques with microvesiculation on the bilateral thighs of several months’ duration (Figure 1). She reported pruritus, burning, and discomfort. Her medical history included type 2 diabetes mellitus, hypertension, and asthma with no history of skin rashes. A complete physical examination was performed. Age-appropriate screening for malignancy was negative. Hepatitis B and C antibody serologies were negative. Her medications at the time included risedronate and atenolol, which she had been taking for several years.

Punch biopsies from perilesional skin were submitted for hematoxylin and eosin staining and direct immunofluorescence (DIF). Histopathology showed a subepidermal blistering disease with tissue eosinophilia consistent with lichen planus pemphigoides (LPP)(Figure 2); direct immunofluorescence was positive for IgG, C3, and type IV collagen at the dermoepidermal junction. Serum BP180 was positive at 51 U/mL (reference range, <14 U/mL) and BP230 was negative. She was then started on tetracycline (500 mg twice daily), nicotinamide (500 mg twice daily), prednisone (5 mg daily), and dapsone (100 mg daily).

After 3 months without improvement, tetracycline and nicotinamide were discontinued, prednisone was increased to 10 mg daily, and dapsone was continued. A repeat biopsy was taken from a new area of involvement on the left lower leg, which revealed a psoriasiform dermatitis with interface changes. The DIF was positive for IgG and C3 along the basement membrane. A serum indirect immunofluorescence for BP180 also was positive.

The patient developed mild hemolytic anemia on dapsone; the medication was eventually discontinued. Subsequent treatments included adequate trials of azathioprine, mycophenolate mofetil, and hydroxychloroquine. Azathioprine (150 mg daily) and hydroxychloroquine (400 mg daily) treatment failed. She initially improved on mycophenolate mofetil (500 mg in the morning and 1000 mg in the evening) with flattening of the papules on the arms and legs and decreased erythema. However, mycophenolate mofetil eventually lost its efficacy and was discontinued.

Because several medications failed (ie, tetracycline, nicotinamide, prednisone, dapsone, azathioprine, mycophenolate mofetil, hydroxychloroquine), she was started on ustekinumab (45 mg) initial loading dose by subcutaneous injection (patient’s weight, 63 kg). At 4 weeks, the patient was given the second subcutaneous injection of ustekinumab (45 mg). She experienced marked improvement with no new lesions. The prior lesions also had decreased in size and were only slightly pink. The prednisone dose was tapered to 5 mg daily.

She had near-complete resolution of the skin lesions 12 weeks after the second dose of ustekinumab. Since then, she has had some recrudescence of the papulosquamous lesions but no vesicles or bullae. With the exception of occasional scattered pink papules on the forearms, her condition greatly improved on ustekinumab. She is no longer taking any of the other medications with the exception of prednisone (down to 1 mg daily) with a plan to gradually taper completely off of it.

Comment

Clinical Presentation
Lichen planus pemphigoides is a rare autoimmune subepidermal blistering disease with few cases reported in the literature. It is considered a clinical variation of bullous pemphigoid (BP) or a coexistence of LP and BP.^1,2 It is characterized by bullous lesions developing on LP papules as well as on clinically uninvolved areas of the skin. It has been reported that LPP is provoked by several medications including cinnarizine, captopril, ramipril, simvastatin, psoralen plus UVA, and antituberculous medications (eg, isoniazid, rifampin, ethambutol, pyrazinamide).¹ Risedronate or atenolol have not been reported to cause LPP, LP, or BP; however, according to Litt,³ a lichenoid drug eruption has been associated with atenolol. Furthermore, some cases of LPP demonstrate overlapping characteristics with paraneoplastic pemphigus and have been associated with internal malignancy. Hamada et al⁴ described a case of LPP coupled with colon adenocarcinoma and numerous keratoacanthomas. The earliest depiction of the coexistence of a case of mainstream LP complicated by an extensive bullous eruption was by Kaposi⁵ in 1892. He coined the term lichen ruber pemphigoides.⁵

Compared to BP, LPP is believed to affect a younger age group and have a less serious clinical course. The mean age of onset of LPP is in the third to fourth decades of life, while BP typically presents in the sixth decade. When comparing the location of bullae in LPP versus BP, the lesions of LPP tend to occur on the limbs, while BP tends to occur on the trunk.⁶

Clinically, LPP is distinguished by the existence of bullous lesions developing atop of the lesions of LP as well as on normal skin, with the latter being more commonplace. A classic example of LPP is characterized by an initial episode of traditional LP lesions often having severe pruritus, with or without patches of erythema, with the sudden eruption of tense bullae. These bullae commonly appear on the extremities and can appear over the normal skin, erythematous patches, or preexisting papules.⁷ In the atypical clinical presentations of this dubious skin condition, the bullae may only be seen on the lesions of LP.⁸ There also could be a lichenoid erythrodermic manifestation of a bullous eruption.⁹

Oral lesions of LPP have been described but had not been studied immunopathologically until Allen et al¹⁰ portrayed a 59-year-old man with cutaneous and oral lesions of LPP. They performed biopsies on the oral lesions and examined them by routine light microscopy and immunofluorescent techniques. The fine keratotic striae on the anterior buccal mucosal lesions were clinically consistent with oral LP. Perilesional tissue in conjunction with ulceration of the posterior buccal mucosa demonstrated histologic and immunopathologic alterations consistent with BP.¹⁰

Histopathology
Histopathologically, the lesions of LP show a bandlike lymphohistiocytic infiltrate, colloid bodies in the dermis, irregular acanthosis with saw-toothed rete ridges, orthokeratosis, wedge-shaped hypergranulosis, and liquefaction degeneration of the basal layer. Direct immunofluorescence shows mainly IgM and C3 deposited on colloid bodies, fibrin, and fibrinogen.¹¹ The histopathology of the bullous lesion of LPP depicts a subepidermal bulla with variable diffuse or sparse lymphohistiocytic infiltrate and frequent eosinophils with or without neutrophils in the upper dermis. The existence of C3 alone or with IgG along the dermoepidermal junction gives confirmation on DIF.⁷

Autoantibodies
The expression of IgG autoantibodies directed against the basement membrane zone distinguishes LPP from bullous LP.² IgG autoantibodies to either one or both the 230-kDa and 180-kDa BP (type XVII collagen) antigens has been demonstrated with LPP.^4,12-14 Hamada et al⁴ described a histologic pattern more consistent with paraneoplastic pemphigus. It has been suggested that injury to the basal cells in LP or damage due to other courses of therapy such as psoralen plus UVA unveil suppressed antigenic determinants or produce new antigens, leading to antibody development and production of BP.^12,15

Zillikens et al² performed a study to identify the target antigen of LPP autoantibodies. They used sera from patients with LPP (n=4) and stained the epidermal side of salt-split human skin in a configuration identical to BP sera. In BP, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. They demonstrated that sera from BP patients largely reacted with a set of 4 epitopes (MCW-0 through MCW-3) grouped within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, LPP sera also were compellingly reactive with recombinant BP180 NC16A. Lichen planus pemphigoides epitopes were additionally mapped using a series of overlapping recombinant segments of the NC16A domain. The authors demonstrated that all LPP sera reacted with amino acids 46 through 59 of domain NC16A, a protein portion that was previously shown to be unreactive with BP sera. In addition, they showed that 2 LPP sera reacted with the immunodominant antigenic region related to BP. Furthermore, they identified a unique epitope within the BP180 NC16A domain—MCW-4—which was distinctively recognized by sera from patients with LPP.²

Pathogenesis
The pathogenesis of both LP and BP has been linked to multiple cytokines that induce apoptosis in basal keratinocytes. Implicated cytokines include IFN-γ, tumor necrosis factor α (TNF-α), IL-1, IL-6, and IL-8, as well as other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2 in LP.^16-18 Soluble E-selectin, vascular endothelial growth factor, IL-1β, IL-8, IL-5, transforming growth factor β1, and TNF-α were found to be elevated in either blister fluid or sera of BP patients.^15-17

Management
Lichen planus pemphigoides usually responds well to traditional therapies, with systemic steroids being the most efficacious treatment of extensive disease.^12,13 Other options include tetracycline and nicotinamide, isotretinoin, dapsone, and immunosuppressive drugs such as systemic cortico-steroids.¹² Demirçay et al¹² described a patient with skin lesions that rapidly cleared after the administration of oral methylprednisolone (48 mg/d) and oral dapsone (100 mg/d). The methylprednisolone and dapsone were withdrawn after 12 and 16 weeks, respectively. There was no recurrence during the 1-year follow-up period.¹²Kolb-Mäurer et al¹⁹ described a patient who was treated with pulsed intravenous corticosteroids and continued to develop new papular and vesicular skin lesions. However, when oral acitretin was added to the patient’s regimen, the skin lesions cleared.¹⁹ There are several case reports of the successful use of hydroxychloroquine in LP.^20,21

Cutaneous, nail, and oral LP also can be treated with TNF-α inhibitors (eg, adalimumab, etanercept) with resolution of lesions.^22-25 However, we have not been able to find any reports of treating LPP with biologic medications in a search of PubMed articles indexed for MEDLINE using the terms lichen planus pemphigoides and biologic treatments/therapies. Given the fact that TNF-α and other inflammatory cytokines are involved in the pathogenesis of BP and LP, it is feasible that they also may be involved in the pathogenesis of LPP.

In our patient with cutaneous LPP, we chose to use ustekinumab instead of a primary TNF-α inhibitor because ustekinumab indirectly blocks TNF-α, as well as other proinflammatory cytokines such as IFN-γ, IL-17, and IL-22, which also could have played a role in the patient’s disease. Our goal was to use ustekinumab as a potential corticosteroid-sparing agent. Ustekinumab greatly improved her skin condition and allowed us to discontinue other medications.

Case Report

A 71-year-old woman presented with pink to violaceous, flat-topped, polygonal papules consistent with lichen planus (LP) on the volar wrists, extensor elbows, and bilateral lower legs of 3 years’ duration. She also had erythematous, violaceous, infiltrated plaques with microvesiculation on the bilateral thighs of several months’ duration (Figure 1). She reported pruritus, burning, and discomfort. Her medical history included type 2 diabetes mellitus, hypertension, and asthma with no history of skin rashes. A complete physical examination was performed. Age-appropriate screening for malignancy was negative. Hepatitis B and C antibody serologies were negative. Her medications at the time included risedronate and atenolol, which she had been taking for several years.

Punch biopsies from perilesional skin were submitted for hematoxylin and eosin staining and direct immunofluorescence (DIF). Histopathology showed a subepidermal blistering disease with tissue eosinophilia consistent with lichen planus pemphigoides (LPP)(Figure 2); direct immunofluorescence was positive for IgG, C3, and type IV collagen at the dermoepidermal junction. Serum BP180 was positive at 51 U/mL (reference range, <14 U/mL) and BP230 was negative. She was then started on tetracycline (500 mg twice daily), nicotinamide (500 mg twice daily), prednisone (5 mg daily), and dapsone (100 mg daily).

After 3 months without improvement, tetracycline and nicotinamide were discontinued, prednisone was increased to 10 mg daily, and dapsone was continued. A repeat biopsy was taken from a new area of involvement on the left lower leg, which revealed a psoriasiform dermatitis with interface changes. The DIF was positive for IgG and C3 along the basement membrane. A serum indirect immunofluorescence for BP180 also was positive.

The patient developed mild hemolytic anemia on dapsone; the medication was eventually discontinued. Subsequent treatments included adequate trials of azathioprine, mycophenolate mofetil, and hydroxychloroquine. Azathioprine (150 mg daily) and hydroxychloroquine (400 mg daily) treatment failed. She initially improved on mycophenolate mofetil (500 mg in the morning and 1000 mg in the evening) with flattening of the papules on the arms and legs and decreased erythema. However, mycophenolate mofetil eventually lost its efficacy and was discontinued.

Because several medications failed (ie, tetracycline, nicotinamide, prednisone, dapsone, azathioprine, mycophenolate mofetil, hydroxychloroquine), she was started on ustekinumab (45 mg) initial loading dose by subcutaneous injection (patient’s weight, 63 kg). At 4 weeks, the patient was given the second subcutaneous injection of ustekinumab (45 mg). She experienced marked improvement with no new lesions. The prior lesions also had decreased in size and were only slightly pink. The prednisone dose was tapered to 5 mg daily.

She had near-complete resolution of the skin lesions 12 weeks after the second dose of ustekinumab. Since then, she has had some recrudescence of the papulosquamous lesions but no vesicles or bullae. With the exception of occasional scattered pink papules on the forearms, her condition greatly improved on ustekinumab. She is no longer taking any of the other medications with the exception of prednisone (down to 1 mg daily) with a plan to gradually taper completely off of it.

Comment

Clinical Presentation
Lichen planus pemphigoides is a rare autoimmune subepidermal blistering disease with few cases reported in the literature. It is considered a clinical variation of bullous pemphigoid (BP) or a coexistence of LP and BP.^1,2 It is characterized by bullous lesions developing on LP papules as well as on clinically uninvolved areas of the skin. It has been reported that LPP is provoked by several medications including cinnarizine, captopril, ramipril, simvastatin, psoralen plus UVA, and antituberculous medications (eg, isoniazid, rifampin, ethambutol, pyrazinamide).¹ Risedronate or atenolol have not been reported to cause LPP, LP, or BP; however, according to Litt,³ a lichenoid drug eruption has been associated with atenolol. Furthermore, some cases of LPP demonstrate overlapping characteristics with paraneoplastic pemphigus and have been associated with internal malignancy. Hamada et al⁴ described a case of LPP coupled with colon adenocarcinoma and numerous keratoacanthomas. The earliest depiction of the coexistence of a case of mainstream LP complicated by an extensive bullous eruption was by Kaposi⁵ in 1892. He coined the term lichen ruber pemphigoides.⁵

Compared to BP, LPP is believed to affect a younger age group and have a less serious clinical course. The mean age of onset of LPP is in the third to fourth decades of life, while BP typically presents in the sixth decade. When comparing the location of bullae in LPP versus BP, the lesions of LPP tend to occur on the limbs, while BP tends to occur on the trunk.⁶

Clinically, LPP is distinguished by the existence of bullous lesions developing atop of the lesions of LP as well as on normal skin, with the latter being more commonplace. A classic example of LPP is characterized by an initial episode of traditional LP lesions often having severe pruritus, with or without patches of erythema, with the sudden eruption of tense bullae. These bullae commonly appear on the extremities and can appear over the normal skin, erythematous patches, or preexisting papules.⁷ In the atypical clinical presentations of this dubious skin condition, the bullae may only be seen on the lesions of LP.⁸ There also could be a lichenoid erythrodermic manifestation of a bullous eruption.⁹

Oral lesions of LPP have been described but had not been studied immunopathologically until Allen et al¹⁰ portrayed a 59-year-old man with cutaneous and oral lesions of LPP. They performed biopsies on the oral lesions and examined them by routine light microscopy and immunofluorescent techniques. The fine keratotic striae on the anterior buccal mucosal lesions were clinically consistent with oral LP. Perilesional tissue in conjunction with ulceration of the posterior buccal mucosa demonstrated histologic and immunopathologic alterations consistent with BP.¹⁰

Histopathology
Histopathologically, the lesions of LP show a bandlike lymphohistiocytic infiltrate, colloid bodies in the dermis, irregular acanthosis with saw-toothed rete ridges, orthokeratosis, wedge-shaped hypergranulosis, and liquefaction degeneration of the basal layer. Direct immunofluorescence shows mainly IgM and C3 deposited on colloid bodies, fibrin, and fibrinogen.¹¹ The histopathology of the bullous lesion of LPP depicts a subepidermal bulla with variable diffuse or sparse lymphohistiocytic infiltrate and frequent eosinophils with or without neutrophils in the upper dermis. The existence of C3 alone or with IgG along the dermoepidermal junction gives confirmation on DIF.⁷

Autoantibodies
The expression of IgG autoantibodies directed against the basement membrane zone distinguishes LPP from bullous LP.² IgG autoantibodies to either one or both the 230-kDa and 180-kDa BP (type XVII collagen) antigens has been demonstrated with LPP.^4,12-14 Hamada et al⁴ described a histologic pattern more consistent with paraneoplastic pemphigus. It has been suggested that injury to the basal cells in LP or damage due to other courses of therapy such as psoralen plus UVA unveil suppressed antigenic determinants or produce new antigens, leading to antibody development and production of BP.^12,15

Zillikens et al² performed a study to identify the target antigen of LPP autoantibodies. They used sera from patients with LPP (n=4) and stained the epidermal side of salt-split human skin in a configuration identical to BP sera. In BP, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. They demonstrated that sera from BP patients largely reacted with a set of 4 epitopes (MCW-0 through MCW-3) grouped within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, LPP sera also were compellingly reactive with recombinant BP180 NC16A. Lichen planus pemphigoides epitopes were additionally mapped using a series of overlapping recombinant segments of the NC16A domain. The authors demonstrated that all LPP sera reacted with amino acids 46 through 59 of domain NC16A, a protein portion that was previously shown to be unreactive with BP sera. In addition, they showed that 2 LPP sera reacted with the immunodominant antigenic region related to BP. Furthermore, they identified a unique epitope within the BP180 NC16A domain—MCW-4—which was distinctively recognized by sera from patients with LPP.²

Pathogenesis
The pathogenesis of both LP and BP has been linked to multiple cytokines that induce apoptosis in basal keratinocytes. Implicated cytokines include IFN-γ, tumor necrosis factor α (TNF-α), IL-1, IL-6, and IL-8, as well as other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2 in LP.^16-18 Soluble E-selectin, vascular endothelial growth factor, IL-1β, IL-8, IL-5, transforming growth factor β1, and TNF-α were found to be elevated in either blister fluid or sera of BP patients.^15-17

Management
Lichen planus pemphigoides usually responds well to traditional therapies, with systemic steroids being the most efficacious treatment of extensive disease.^12,13 Other options include tetracycline and nicotinamide, isotretinoin, dapsone, and immunosuppressive drugs such as systemic cortico-steroids.¹² Demirçay et al¹² described a patient with skin lesions that rapidly cleared after the administration of oral methylprednisolone (48 mg/d) and oral dapsone (100 mg/d). The methylprednisolone and dapsone were withdrawn after 12 and 16 weeks, respectively. There was no recurrence during the 1-year follow-up period.¹²Kolb-Mäurer et al¹⁹ described a patient who was treated with pulsed intravenous corticosteroids and continued to develop new papular and vesicular skin lesions. However, when oral acitretin was added to the patient’s regimen, the skin lesions cleared.¹⁹ There are several case reports of the successful use of hydroxychloroquine in LP.^20,21

Cutaneous, nail, and oral LP also can be treated with TNF-α inhibitors (eg, adalimumab, etanercept) with resolution of lesions.^22-25 However, we have not been able to find any reports of treating LPP with biologic medications in a search of PubMed articles indexed for MEDLINE using the terms lichen planus pemphigoides and biologic treatments/therapies. Given the fact that TNF-α and other inflammatory cytokines are involved in the pathogenesis of BP and LP, it is feasible that they also may be involved in the pathogenesis of LPP.

In our patient with cutaneous LPP, we chose to use ustekinumab instead of a primary TNF-α inhibitor because ustekinumab indirectly blocks TNF-α, as well as other proinflammatory cytokines such as IFN-γ, IL-17, and IL-22, which also could have played a role in the patient’s disease. Our goal was to use ustekinumab as a potential corticosteroid-sparing agent. Ustekinumab greatly improved her skin condition and allowed us to discontinue other medications.

Multinucleate cell angiohistiocytoma (MCAH) is a rare benign, soft-tissue tumor first described in 1985 by Smith and Jones¹ that presents clinically as erythematous to violaceous papules most commonly affecting females on the dorsal aspect of the hands and face.² Multinucleate cell angiohistiocytoma is histologically characterized by vascular and histiocytic proliferations with dermal fibrosis. Few cases have been reported of lesions affecting the lower extremities. We report a case of MCAH affecting the legs.

Case Report

An 83-year-old white man with a history of basal cell carcinoma presented for evaluation of grouped, well-circumscribed, soft, red-violet, painless papules on the right anterior thigh that had been present for 8 months (Figure 1A). A review of symptoms was negative for immunologic, respiratory, and hematologic changes. The patient’s medical history also was remarkable for prostate cancer treated with radiation 18 years prior as well as right hip and left knee implants. The initial clinical impression was Kaposi sarcoma or a granulomatous disorder.

Histopathologic evaluation of a deep shave biopsy initially determined the lesion to be scar tissue without other pathologic findings. The patient returned to the clinic 12 months later for a complete skin examination given his history of skin cancer. Compared to clinical photographs taken a year prior, new violaceous papules were noted on the right thigh (Figure 1B) and left calf. Furthermore, there was no recurrence of the lesion at the prior biopsy site. Shave biopsies of the papules on the right thigh and left calf demonstrated similar histologic findings to each other. There was a mild increase in the number of small blood vessels in the superficial dermis (Figure 2A). A mild perivascular lymphocytic infiltrate surrounded some of these blood vessels. The endothelial cells had small nuclei with no evidence of nuclear pleomorphism. Careful examination of the interstitial dermis revealed scattered multinucleate cells with angulated cytoplasm (Figure 2B). Immunostaining for CD31 and human herpesvirus 8 were negative, excluding an infiltrative vascular tumor and Kaposi sarcoma, respectively. The diagnosis of MCAH was made based on the histopathologic findings.

At 1-year follow-up, the condition was stable with no gross changes in the lesions based on prior photographs. Once again, there was no recurrence of the excised lesions at both biopsy sites.

Comment

Presentation
A systematic review of published reports determined that 79% of MCAH cases occur in females, with an average age of onset of 50.1 years.² However, MCAH likely is underreported due to the overall lack of knowledge regarding this condition by physicians and pathologists. The hands and face are the most commonly affected areas, though other sites of involvement have been reported, including the lower extremities,^3,4 oral mucosa and upper lip,^5,6 and trunk,^7,8 as well as generalized distribution.^9-12 Additionally, 1 case presented as a single plaque on the trunk rather than having papular or nodular morphology.⁸ Multinucleate cell angiohistiocytoma lesions generally are asymptomatic, though pruritus may be present.¹³ The condition is regarded as benign, though a minority of cases have exhibited spontaneous resolution.^14-16

Histopathology
Multinucleate cell angiohistiocytoma histology demonstrates full-thickness dermal microvessel proliferation and fibrosis with characteristic multinucleate giant cells.^2,3 Vascular endothelial cells stained positive for CD68 in 60% of cases² as well as the normal endothelial markers (ie, factor VIII, CD31, CD34). The multinucleate giant cells exhibit immunoreactivity for macrophage/histiocytic markers factor XIIIa and CD68.

Etiology
The pathogenesis of MCAH is not yet fully understood, but it is considered to be a benign vascular or fibrohistiocytic neoplasm.¹⁷ Calderaro et al¹⁸ described a series of 8 patients who developed MCAH either within a cutaneous neoplastic process or in conjunction with various cutaneous reactive conditions, including hidradenitis suppurativa and chronic radiation dermatitis, as well as overlying a bone prosthesis placed due to degenerative arthritis. These cases suggest that MCAH, or possibly a subset of the disease, is a reactive process. Suggested inciting events include cancer with stromal inflammatory reaction, chronic inflammation (as seen in hidradenitis suppurativa), chronic radiation dermatitis, scarring, and vascular injury.¹⁸ Retrospective immunohistochemical evaluation of a series of MCAH cases demonstrated intralesional spindle cells to strongly express estrogen receptor alpha and factor XIIIa. Additionally, these cells sparsely expressed progesterone receptor and demonstrated no vascular endothelial growth factor immunoreactivity.¹⁹ This immunohistochemical profile supports MCAH as a distinct entity from dermatofibromas. These findings also suggest a role of hormone signaling, namely estrogen receptor alpha, in MCAH tumor biology and may offer an explanation for the predilection of MCAH in females. Furthermore, estrogen receptor positivity offers a possible mechanism for the highly vascular nature of the lesions, considering the angiogenic properties of estrogen signaling.²⁰ In a systematic review of 142 published cases of MCAH, CD68 positivity on multinucleate cells in MCAH lesions suggested a fibrohistiocytic origin.² However, a number of these cases exhibited CD34 positivity, thus a macrophage origin may not be excluded.

Differential Diagnosis
The differential diagnosis for MCAH includes Kaposi sarcoma clinically and dermatofibroma and fibrous papules histologically. Sass et al²¹ determined the in vitro behavior of cultured MCAH cells to contrast markedly with Kaposi sarcoma–derived cells. Although Kaposi sarcoma–derived cells exhibited invasive behavior, cells isolated from MCAH lesions were less elongated and were unable to traverse basement membranes.

Treatment
Surgical excision or cryotherapy appear to be definitive treatments of MCAH; however, a number of cases have reported light and laser modalities as successful alternatives to excision. One case of MCAH affecting the face was treated with pulsed dye laser monotherapy.²² This modality allowed selective coagulation of the vascular structures in MCAH. At 8-month follow-up, the initial lesion was noted to be completely cleared, though similar lesions had recently appeared elsewhere on the face.²² Another case of MCAH affecting the leg was treated with pulsed dye laser and both topical and intralesional corticosteroid combination therapy. In this case, the lesion failed to respond to treatment, which may suggest that facial localization could influence response in pulsed dye laser treatment.³

Intense pulsed light also has been reported as a definitive treatment in 2 cases.^2,13 Slight erythema and transient pruritus have been reported immediately following treatment. In this case, complete resolution with only residual hyperpigmentation was reported at 2-month follow-up, with no recurrence during 12 months of follow-up.¹³

Argon laser therapy has been used in 2 cases. After a single session, lesions were no longer palpable, with no scarring noted at 8 weeks follow-up.²³ Lastly, 2 cases of MCAH have been successfully treated with the CO₂ laser, with no relapse noted at 2.5- or 5-month follow-up, respectively.²⁴

Conclusion

Multinucleate cell angiohistiocytoma is a rare and likely underdiagnosed dermatologic condition that is believed to be a reactive process. Characteristic histology of MCAH demonstrates microvascular proliferations of the dermis with multinucleate giant cells amidst a fibrous background. Although surgical excision is curative, there are reports in which laser and light therapies were used to effectively treat MCAH.

Multinucleate cell angiohistiocytoma (MCAH) is a rare benign, soft-tissue tumor first described in 1985 by Smith and Jones¹ that presents clinically as erythematous to violaceous papules most commonly affecting females on the dorsal aspect of the hands and face.² Multinucleate cell angiohistiocytoma is histologically characterized by vascular and histiocytic proliferations with dermal fibrosis. Few cases have been reported of lesions affecting the lower extremities. We report a case of MCAH affecting the legs.

Case Report

An 83-year-old white man with a history of basal cell carcinoma presented for evaluation of grouped, well-circumscribed, soft, red-violet, painless papules on the right anterior thigh that had been present for 8 months (Figure 1A). A review of symptoms was negative for immunologic, respiratory, and hematologic changes. The patient’s medical history also was remarkable for prostate cancer treated with radiation 18 years prior as well as right hip and left knee implants. The initial clinical impression was Kaposi sarcoma or a granulomatous disorder.

Histopathologic evaluation of a deep shave biopsy initially determined the lesion to be scar tissue without other pathologic findings. The patient returned to the clinic 12 months later for a complete skin examination given his history of skin cancer. Compared to clinical photographs taken a year prior, new violaceous papules were noted on the right thigh (Figure 1B) and left calf. Furthermore, there was no recurrence of the lesion at the prior biopsy site. Shave biopsies of the papules on the right thigh and left calf demonstrated similar histologic findings to each other. There was a mild increase in the number of small blood vessels in the superficial dermis (Figure 2A). A mild perivascular lymphocytic infiltrate surrounded some of these blood vessels. The endothelial cells had small nuclei with no evidence of nuclear pleomorphism. Careful examination of the interstitial dermis revealed scattered multinucleate cells with angulated cytoplasm (Figure 2B). Immunostaining for CD31 and human herpesvirus 8 were negative, excluding an infiltrative vascular tumor and Kaposi sarcoma, respectively. The diagnosis of MCAH was made based on the histopathologic findings.

At 1-year follow-up, the condition was stable with no gross changes in the lesions based on prior photographs. Once again, there was no recurrence of the excised lesions at both biopsy sites.

Comment

Presentation
A systematic review of published reports determined that 79% of MCAH cases occur in females, with an average age of onset of 50.1 years.² However, MCAH likely is underreported due to the overall lack of knowledge regarding this condition by physicians and pathologists. The hands and face are the most commonly affected areas, though other sites of involvement have been reported, including the lower extremities,^3,4 oral mucosa and upper lip,^5,6 and trunk,^7,8 as well as generalized distribution.^9-12 Additionally, 1 case presented as a single plaque on the trunk rather than having papular or nodular morphology.⁸ Multinucleate cell angiohistiocytoma lesions generally are asymptomatic, though pruritus may be present.¹³ The condition is regarded as benign, though a minority of cases have exhibited spontaneous resolution.^14-16

Histopathology
Multinucleate cell angiohistiocytoma histology demonstrates full-thickness dermal microvessel proliferation and fibrosis with characteristic multinucleate giant cells.^2,3 Vascular endothelial cells stained positive for CD68 in 60% of cases² as well as the normal endothelial markers (ie, factor VIII, CD31, CD34). The multinucleate giant cells exhibit immunoreactivity for macrophage/histiocytic markers factor XIIIa and CD68.

Etiology
The pathogenesis of MCAH is not yet fully understood, but it is considered to be a benign vascular or fibrohistiocytic neoplasm.¹⁷ Calderaro et al¹⁸ described a series of 8 patients who developed MCAH either within a cutaneous neoplastic process or in conjunction with various cutaneous reactive conditions, including hidradenitis suppurativa and chronic radiation dermatitis, as well as overlying a bone prosthesis placed due to degenerative arthritis. These cases suggest that MCAH, or possibly a subset of the disease, is a reactive process. Suggested inciting events include cancer with stromal inflammatory reaction, chronic inflammation (as seen in hidradenitis suppurativa), chronic radiation dermatitis, scarring, and vascular injury.¹⁸ Retrospective immunohistochemical evaluation of a series of MCAH cases demonstrated intralesional spindle cells to strongly express estrogen receptor alpha and factor XIIIa. Additionally, these cells sparsely expressed progesterone receptor and demonstrated no vascular endothelial growth factor immunoreactivity.¹⁹ This immunohistochemical profile supports MCAH as a distinct entity from dermatofibromas. These findings also suggest a role of hormone signaling, namely estrogen receptor alpha, in MCAH tumor biology and may offer an explanation for the predilection of MCAH in females. Furthermore, estrogen receptor positivity offers a possible mechanism for the highly vascular nature of the lesions, considering the angiogenic properties of estrogen signaling.²⁰ In a systematic review of 142 published cases of MCAH, CD68 positivity on multinucleate cells in MCAH lesions suggested a fibrohistiocytic origin.² However, a number of these cases exhibited CD34 positivity, thus a macrophage origin may not be excluded.

Differential Diagnosis
The differential diagnosis for MCAH includes Kaposi sarcoma clinically and dermatofibroma and fibrous papules histologically. Sass et al²¹ determined the in vitro behavior of cultured MCAH cells to contrast markedly with Kaposi sarcoma–derived cells. Although Kaposi sarcoma–derived cells exhibited invasive behavior, cells isolated from MCAH lesions were less elongated and were unable to traverse basement membranes.

Treatment
Surgical excision or cryotherapy appear to be definitive treatments of MCAH; however, a number of cases have reported light and laser modalities as successful alternatives to excision. One case of MCAH affecting the face was treated with pulsed dye laser monotherapy.²² This modality allowed selective coagulation of the vascular structures in MCAH. At 8-month follow-up, the initial lesion was noted to be completely cleared, though similar lesions had recently appeared elsewhere on the face.²² Another case of MCAH affecting the leg was treated with pulsed dye laser and both topical and intralesional corticosteroid combination therapy. In this case, the lesion failed to respond to treatment, which may suggest that facial localization could influence response in pulsed dye laser treatment.³

Intense pulsed light also has been reported as a definitive treatment in 2 cases.^2,13 Slight erythema and transient pruritus have been reported immediately following treatment. In this case, complete resolution with only residual hyperpigmentation was reported at 2-month follow-up, with no recurrence during 12 months of follow-up.¹³

Argon laser therapy has been used in 2 cases. After a single session, lesions were no longer palpable, with no scarring noted at 8 weeks follow-up.²³ Lastly, 2 cases of MCAH have been successfully treated with the CO₂ laser, with no relapse noted at 2.5- or 5-month follow-up, respectively.²⁴

Conclusion

Multinucleate cell angiohistiocytoma is a rare and likely underdiagnosed dermatologic condition that is believed to be a reactive process. Characteristic histology of MCAH demonstrates microvascular proliferations of the dermis with multinucleate giant cells amidst a fibrous background. Although surgical excision is curative, there are reports in which laser and light therapies were used to effectively treat MCAH.

Multinucleate cell angiohistiocytoma (MCAH) is a rare benign, soft-tissue tumor first described in 1985 by Smith and Jones¹ that presents clinically as erythematous to violaceous papules most commonly affecting females on the dorsal aspect of the hands and face.² Multinucleate cell angiohistiocytoma is histologically characterized by vascular and histiocytic proliferations with dermal fibrosis. Few cases have been reported of lesions affecting the lower extremities. We report a case of MCAH affecting the legs.

Case Report

An 83-year-old white man with a history of basal cell carcinoma presented for evaluation of grouped, well-circumscribed, soft, red-violet, painless papules on the right anterior thigh that had been present for 8 months (Figure 1A). A review of symptoms was negative for immunologic, respiratory, and hematologic changes. The patient’s medical history also was remarkable for prostate cancer treated with radiation 18 years prior as well as right hip and left knee implants. The initial clinical impression was Kaposi sarcoma or a granulomatous disorder.

Histopathologic evaluation of a deep shave biopsy initially determined the lesion to be scar tissue without other pathologic findings. The patient returned to the clinic 12 months later for a complete skin examination given his history of skin cancer. Compared to clinical photographs taken a year prior, new violaceous papules were noted on the right thigh (Figure 1B) and left calf. Furthermore, there was no recurrence of the lesion at the prior biopsy site. Shave biopsies of the papules on the right thigh and left calf demonstrated similar histologic findings to each other. There was a mild increase in the number of small blood vessels in the superficial dermis (Figure 2A). A mild perivascular lymphocytic infiltrate surrounded some of these blood vessels. The endothelial cells had small nuclei with no evidence of nuclear pleomorphism. Careful examination of the interstitial dermis revealed scattered multinucleate cells with angulated cytoplasm (Figure 2B). Immunostaining for CD31 and human herpesvirus 8 were negative, excluding an infiltrative vascular tumor and Kaposi sarcoma, respectively. The diagnosis of MCAH was made based on the histopathologic findings.

At 1-year follow-up, the condition was stable with no gross changes in the lesions based on prior photographs. Once again, there was no recurrence of the excised lesions at both biopsy sites.

Comment

Presentation
A systematic review of published reports determined that 79% of MCAH cases occur in females, with an average age of onset of 50.1 years.² However, MCAH likely is underreported due to the overall lack of knowledge regarding this condition by physicians and pathologists. The hands and face are the most commonly affected areas, though other sites of involvement have been reported, including the lower extremities,^3,4 oral mucosa and upper lip,^5,6 and trunk,^7,8 as well as generalized distribution.^9-12 Additionally, 1 case presented as a single plaque on the trunk rather than having papular or nodular morphology.⁸ Multinucleate cell angiohistiocytoma lesions generally are asymptomatic, though pruritus may be present.¹³ The condition is regarded as benign, though a minority of cases have exhibited spontaneous resolution.^14-16

Histopathology
Multinucleate cell angiohistiocytoma histology demonstrates full-thickness dermal microvessel proliferation and fibrosis with characteristic multinucleate giant cells.^2,3 Vascular endothelial cells stained positive for CD68 in 60% of cases² as well as the normal endothelial markers (ie, factor VIII, CD31, CD34). The multinucleate giant cells exhibit immunoreactivity for macrophage/histiocytic markers factor XIIIa and CD68.

Etiology
The pathogenesis of MCAH is not yet fully understood, but it is considered to be a benign vascular or fibrohistiocytic neoplasm.¹⁷ Calderaro et al¹⁸ described a series of 8 patients who developed MCAH either within a cutaneous neoplastic process or in conjunction with various cutaneous reactive conditions, including hidradenitis suppurativa and chronic radiation dermatitis, as well as overlying a bone prosthesis placed due to degenerative arthritis. These cases suggest that MCAH, or possibly a subset of the disease, is a reactive process. Suggested inciting events include cancer with stromal inflammatory reaction, chronic inflammation (as seen in hidradenitis suppurativa), chronic radiation dermatitis, scarring, and vascular injury.¹⁸ Retrospective immunohistochemical evaluation of a series of MCAH cases demonstrated intralesional spindle cells to strongly express estrogen receptor alpha and factor XIIIa. Additionally, these cells sparsely expressed progesterone receptor and demonstrated no vascular endothelial growth factor immunoreactivity.¹⁹ This immunohistochemical profile supports MCAH as a distinct entity from dermatofibromas. These findings also suggest a role of hormone signaling, namely estrogen receptor alpha, in MCAH tumor biology and may offer an explanation for the predilection of MCAH in females. Furthermore, estrogen receptor positivity offers a possible mechanism for the highly vascular nature of the lesions, considering the angiogenic properties of estrogen signaling.²⁰ In a systematic review of 142 published cases of MCAH, CD68 positivity on multinucleate cells in MCAH lesions suggested a fibrohistiocytic origin.² However, a number of these cases exhibited CD34 positivity, thus a macrophage origin may not be excluded.

Differential Diagnosis
The differential diagnosis for MCAH includes Kaposi sarcoma clinically and dermatofibroma and fibrous papules histologically. Sass et al²¹ determined the in vitro behavior of cultured MCAH cells to contrast markedly with Kaposi sarcoma–derived cells. Although Kaposi sarcoma–derived cells exhibited invasive behavior, cells isolated from MCAH lesions were less elongated and were unable to traverse basement membranes.

Treatment
Surgical excision or cryotherapy appear to be definitive treatments of MCAH; however, a number of cases have reported light and laser modalities as successful alternatives to excision. One case of MCAH affecting the face was treated with pulsed dye laser monotherapy.²² This modality allowed selective coagulation of the vascular structures in MCAH. At 8-month follow-up, the initial lesion was noted to be completely cleared, though similar lesions had recently appeared elsewhere on the face.²² Another case of MCAH affecting the leg was treated with pulsed dye laser and both topical and intralesional corticosteroid combination therapy. In this case, the lesion failed to respond to treatment, which may suggest that facial localization could influence response in pulsed dye laser treatment.³

Intense pulsed light also has been reported as a definitive treatment in 2 cases.^2,13 Slight erythema and transient pruritus have been reported immediately following treatment. In this case, complete resolution with only residual hyperpigmentation was reported at 2-month follow-up, with no recurrence during 12 months of follow-up.¹³

Argon laser therapy has been used in 2 cases. After a single session, lesions were no longer palpable, with no scarring noted at 8 weeks follow-up.²³ Lastly, 2 cases of MCAH have been successfully treated with the CO₂ laser, with no relapse noted at 2.5- or 5-month follow-up, respectively.²⁴

Conclusion

Multinucleate cell angiohistiocytoma is a rare and likely underdiagnosed dermatologic condition that is believed to be a reactive process. Characteristic histology of MCAH demonstrates microvascular proliferations of the dermis with multinucleate giant cells amidst a fibrous background. Although surgical excision is curative, there are reports in which laser and light therapies were used to effectively treat MCAH.

Pulmonary sarcomatoid carcinoma (PSC) is a rare histological subtype that has an aggressive course with average survival of 11-13 months.¹ In clinical practice, the possible presentations of this rare cancer are not widely known, resulting in a misdiagnosis. That is what happened with our patient, who presented with necrotizing cavitary lung lesion and soft tissue necrotizing lymphadenitis. The clinical picture was reminiscent of tuberculosis or granulomatosis with polyangiitis and was further confounded by negative computed-tomography (CT)-guided biopsy and bronchoscopy findings, which added to the delay in diagnosis. With the currently available knowledge, the diagnosis of PSC depends largely on evaluation of the surgically resected specimen, which in most cases is avoided until there is a high suspicion of PSC. Biopsy is not useful due to extensive necrosis, as will be seen in our case. Consequently, most of the data in the literature is based on case series of autopsy specimen, and the clinical characteristics of PSC remain unclear. The rarity of PSC has prevented its characterization in literature. We report here a rare presentation of PSC with necrotizing lung lesion, to add to the paucity of the current data.

Case presentation and summary

A 58-year-old homeless man presented to the Upstate University Hospital, Syracuse, New York, with a 25-pound weight loss during the previous month and associated productive cough and hemoptysis for a week and a painful mass in the nape of his neck. He denied any fever, chest pain, sick contacts, or joint pain. He had a history of about 40 pack-years of smoking, and his brother had recently been diagnosed with lung cancer. A tender fluctuant mass was detected in the nape of his neck on examination (Figure 1).

The patient had presented 9 months earlier with persistent cough and hemoptysis, and at that visit was found to have a cavitary lesion in the right lung measuring 2 cm (0.8 in). He had undergone a computed-tomograpghy (CT)-guided biopsy of the lesion, which had shown acute and chronic inflammation with fibrosis, and he had negative bronchoscopy findings. The patient tested negative for tuberculosis during the first visit but he left the hospital against the medical advice of the physicians and he was lost to follow-up until his re-presentation.

On physical examination at his re-presentation, the patient seemed cachectic, with a blood pressure of 94/62 mm of Hg. The mass in the nape of his neck was about 3 cm (1.2 in) long, with erythema of the surrounding skin (Figure 1). Bronchial breath sounds were heard in the right upper lobe of the lung, likely due to the underlying cavitary lesion (Figure 2B). Relevant lab findings included a negative HIV test and repeat AFB (acid-fast bacilli) sputum cultures. A CT-guided biopsy with contrast of the thorax showed an interval increase in the size of the cavitary lesion in the patient’s right upper lobe, now measuring about 10 cm (4 in). Also seen were multiple nodules elsewhere in both lungs, with the largest measuring 8 mm (0.3 in). A CT scan of the neck showed 3 cm cystic mass within the posterior subcutaneous soft tissue of the C3 level, confirming the examination finding of the neck mass (Figure 2A) with peripheral enhancement and surrounding infiltrative changes, likely abscess or malignant lymph node versus necrotic infection. He underwent bronchoscopy, which again failed to reveal any endobronchial lesions. Bronchoalveolar lavage was sent for microbiological analysis, including AFB and fungus, but came back negative. Transbronchial biopsy cytology revealed fragments of tumor composed of large pleomorphic cells without glandular or squamous differentiation, within large areas of necrosis (Figure 3). Immunohistochemical studies showed strong reactivity with cytokeratin CAM5.2 (Figure 4), weak and focal reactivity with cytokeratin AE1/AE3 (Figure 5), and lack of reactivity with CD20, CD3, CD30, S-100, MART-1, TTF-1 and p63, all findings consistent with sarcomatoid carcinoma.

The patient underwent fine-needle aspiration and drainage of the neck lesion and the culture grew mixed organisms The results of a bone scan, which was done within a week, showed multiple foci of uptake in the ribs and cervical spine. Given the patient’s advanced disease, he was started on palliative radiotherapy with radiosensitizing chemotherapy with carboplatin (target AUC 6) and paclitaxel (135 mg/m2 over 24 hours). His symptoms of hemoptysis improved transiently after the first cycle, but he became hypotensive and drowsy during the second cycle of therapy, and the family decided to make the patient comfort care and withdraw all further treatment. He was discharged to hospice.

Discussion

PSC is a rare variant of non-small-cell carcinoma lung cancer, accounting for up to 0.4% of lung malignancy.1  It was

recently subtyped by the World Health Organization as a non-small cell lung carcinoma with certain amount of differentiation resembling sarcoma or containing elements of sarcoma.^2-4  It is not known why both elements co-exist in the tumor, but Franks and colleagues some theories have been postulated in the literature, including possible origin from a single, aberrant stem cell with progenies differentiating in two separate pathways.³

Sarcomatoid carcinoma consists of spectrum of tumors including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and blastoma.3,4 It usually shows male preponderance, and association with smoking.3  The diagnosis commonly occurs in the sixth decade of life, except for pulmonary blastoma, which is more common in the fourth decade andnwith equal gender distribution.⁴

The presenting symptoms can be variable and nonspecific, but predominantly include chest pain, cough, hemoptysis, and/or weight loss.⁵  Radiologically, pulmonary sarcomatoid cancer presenting as a necrotizing cavitary lesion in the lung is a rare finding, seldom reported in the past.^6,7  The presentation in our case, with necrotizing lymphadenitis, was reminiscent of an infectious or autoimmune etiology such as tuberculosis or granulomatosis with polyangiitis. The presence of extensive necrosis in the lesion and the characteristic heterogeneity of the tumor had resulted in inconclusive biopsy findings during the previous presentation. In clinical practice, there is over-reliance on biopsy findings to make the distinction between cancer and other mimicking conditions. This is especially true for rare tumors such as PSC, which often results in misdiagnosis and a delay in administering the proper treatment. Transbronchial biopsy in cases such as the present case, carries little benefit because the diagnosis depends on the site from which the biopsy is taken and whether the biopsied tissue is representative of the entire mass. The diagnosis can be suspected based on the clinical and radiological findings but confirmation requires a surgical resection to delineate the accurate cytology and architecture.5,6,8 Huang and colleagues showed a misdiagnosis rate of PSC of >70% preoperatively.4 Resective surgery is feasible only in patients with high index of suspicion for a malignancy, which in most cases requires previous confirmation with a biopsy. The rarity of this cancer, its unusual presentations, and the lack of specific testing preclude early diagnosis and timely treatment of this fatal condition.

Initial treatment options for localized or with limited spread disease is resective surgery. The role of chemo- or radiation therapy is not known, but they have not previously shown promising results,6,8 except in some cases when they are used as postoperative adjuvant chemotherapy4 or in bulky, locally invasive tumors.1 The recurrence rate after surgery is very high, resulting in a poor 5-year survival rate.1,8 Experimental therapies, such as antibodies that target epidermal growth factor receptor mutations, have not shown much success either.8 In conclusion, the outlook for patients with PSC with the current available knowledge and treatment protocols, is dismal.

Most of the current knowledge and data in the literature is based on cases from autopsy or early-stage surgical resections rather than on patients with advanced cancer.5 Moreover, the role of surgical resection in PSC is questionable, given the high recurrence rate. Subsequently, the clinical and pathological manifestations have yet to be well characterized.⁴ There has been advance with the publication of more studies recently. Cytokeratin markers such as CAM 5.2 and AE1/AE3 are commonly useful to support the diagnosis when suspected.³ Other markers, including the carcinoembryonic antigen, CD15, and thyroid transcription factor-1 may be variably positive, based on the differentiation of the cancer. Other exciting prospects in the study of PSC include the suggestion of a modified vimentin histologic score for better characterization of the cancer and the discovery of high plateletderived growth factor receptor beta immunohistochemistry expression in PSC as a potential target for future therapy.

Conclusion

Pulmonary sarcomatoid lung cancer can present with a predominant necrotizing picture that mimics diseases such as tuberculosis. In such case, transbronchial biopsy carries little benefit because the diagnosis depends on whether the biopsied tissue is representative of the entire mass, often confounded by the extensive necrosis. More data is needed to determine prognostic factors and appropriate therapeutic strategies. TSJ

Correspondence

Gaurang Nandkishor Vaidya, MD

References

1. Martin LW, Correa AM, Ordonez NG, et al. Sarcomatoid carcinoma of the lung: a predictor of poor prognosis. Ann Thorac Surg. 2007;84(3):973-980.

2. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001;18(6):1059-1068.

3. Franks TJ, Galvin JR. Sarcomatoid carcinoma of the lung: histologic criteria and common lesions in the differential diagnosis. Arch Pathol Lab Med. 2010;134(1):49-54.

4. Huang SY, Shen SJ, Li XY. Pulmonary sarcomatoid carcinoma: a clinicopathologic study and prognostic analysis of 51 cases. http://wjso. biomedcentral.com/articles/10.1186/1477-7819-11-252. Published 2013. Accessed March 12, 2017.

5. Travis WD. Sarcomatoid neoplasms of the lung and pleura. Arch Pathol Lab Med. 2010;134(11):1645-1658.

6. Pelosi G, Sonzogni A, De Pas T, et al. Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol. 2010;18(2):103-120.

7. Chang YL, Lee YC, Shih JY, Wu CT. Pulmonary pleomorphic (spindle) cell carcinoma: peculiar clinicopathologic manifestations different from ordinary non-small cell carcinoma. Lung Cancer. 2001;34(1):91-97.

8. Park JS, Lee Y, Han J, et al. Clinicopathologic outcomes of curative resection for sarcomatoid carcinoma of the lung. Oncology. 2011;81(3-4):206-213.

Pulmonary sarcomatoid carcinoma (PSC) is a rare histological subtype that has an aggressive course with average survival of 11-13 months.¹ In clinical practice, the possible presentations of this rare cancer are not widely known, resulting in a misdiagnosis. That is what happened with our patient, who presented with necrotizing cavitary lung lesion and soft tissue necrotizing lymphadenitis. The clinical picture was reminiscent of tuberculosis or granulomatosis with polyangiitis and was further confounded by negative computed-tomography (CT)-guided biopsy and bronchoscopy findings, which added to the delay in diagnosis. With the currently available knowledge, the diagnosis of PSC depends largely on evaluation of the surgically resected specimen, which in most cases is avoided until there is a high suspicion of PSC. Biopsy is not useful due to extensive necrosis, as will be seen in our case. Consequently, most of the data in the literature is based on case series of autopsy specimen, and the clinical characteristics of PSC remain unclear. The rarity of PSC has prevented its characterization in literature. We report here a rare presentation of PSC with necrotizing lung lesion, to add to the paucity of the current data.

Case presentation and summary

A 58-year-old homeless man presented to the Upstate University Hospital, Syracuse, New York, with a 25-pound weight loss during the previous month and associated productive cough and hemoptysis for a week and a painful mass in the nape of his neck. He denied any fever, chest pain, sick contacts, or joint pain. He had a history of about 40 pack-years of smoking, and his brother had recently been diagnosed with lung cancer. A tender fluctuant mass was detected in the nape of his neck on examination (Figure 1).

The patient had presented 9 months earlier with persistent cough and hemoptysis, and at that visit was found to have a cavitary lesion in the right lung measuring 2 cm (0.8 in). He had undergone a computed-tomograpghy (CT)-guided biopsy of the lesion, which had shown acute and chronic inflammation with fibrosis, and he had negative bronchoscopy findings. The patient tested negative for tuberculosis during the first visit but he left the hospital against the medical advice of the physicians and he was lost to follow-up until his re-presentation.

On physical examination at his re-presentation, the patient seemed cachectic, with a blood pressure of 94/62 mm of Hg. The mass in the nape of his neck was about 3 cm (1.2 in) long, with erythema of the surrounding skin (Figure 1). Bronchial breath sounds were heard in the right upper lobe of the lung, likely due to the underlying cavitary lesion (Figure 2B). Relevant lab findings included a negative HIV test and repeat AFB (acid-fast bacilli) sputum cultures. A CT-guided biopsy with contrast of the thorax showed an interval increase in the size of the cavitary lesion in the patient’s right upper lobe, now measuring about 10 cm (4 in). Also seen were multiple nodules elsewhere in both lungs, with the largest measuring 8 mm (0.3 in). A CT scan of the neck showed 3 cm cystic mass within the posterior subcutaneous soft tissue of the C3 level, confirming the examination finding of the neck mass (Figure 2A) with peripheral enhancement and surrounding infiltrative changes, likely abscess or malignant lymph node versus necrotic infection. He underwent bronchoscopy, which again failed to reveal any endobronchial lesions. Bronchoalveolar lavage was sent for microbiological analysis, including AFB and fungus, but came back negative. Transbronchial biopsy cytology revealed fragments of tumor composed of large pleomorphic cells without glandular or squamous differentiation, within large areas of necrosis (Figure 3). Immunohistochemical studies showed strong reactivity with cytokeratin CAM5.2 (Figure 4), weak and focal reactivity with cytokeratin AE1/AE3 (Figure 5), and lack of reactivity with CD20, CD3, CD30, S-100, MART-1, TTF-1 and p63, all findings consistent with sarcomatoid carcinoma.

The patient underwent fine-needle aspiration and drainage of the neck lesion and the culture grew mixed organisms The results of a bone scan, which was done within a week, showed multiple foci of uptake in the ribs and cervical spine. Given the patient’s advanced disease, he was started on palliative radiotherapy with radiosensitizing chemotherapy with carboplatin (target AUC 6) and paclitaxel (135 mg/m2 over 24 hours). His symptoms of hemoptysis improved transiently after the first cycle, but he became hypotensive and drowsy during the second cycle of therapy, and the family decided to make the patient comfort care and withdraw all further treatment. He was discharged to hospice.

Discussion

PSC is a rare variant of non-small-cell carcinoma lung cancer, accounting for up to 0.4% of lung malignancy.1  It was

recently subtyped by the World Health Organization as a non-small cell lung carcinoma with certain amount of differentiation resembling sarcoma or containing elements of sarcoma.^2-4  It is not known why both elements co-exist in the tumor, but Franks and colleagues some theories have been postulated in the literature, including possible origin from a single, aberrant stem cell with progenies differentiating in two separate pathways.³

Sarcomatoid carcinoma consists of spectrum of tumors including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and blastoma.3,4 It usually shows male preponderance, and association with smoking.3  The diagnosis commonly occurs in the sixth decade of life, except for pulmonary blastoma, which is more common in the fourth decade andnwith equal gender distribution.⁴

The presenting symptoms can be variable and nonspecific, but predominantly include chest pain, cough, hemoptysis, and/or weight loss.⁵  Radiologically, pulmonary sarcomatoid cancer presenting as a necrotizing cavitary lesion in the lung is a rare finding, seldom reported in the past.^6,7  The presentation in our case, with necrotizing lymphadenitis, was reminiscent of an infectious or autoimmune etiology such as tuberculosis or granulomatosis with polyangiitis. The presence of extensive necrosis in the lesion and the characteristic heterogeneity of the tumor had resulted in inconclusive biopsy findings during the previous presentation. In clinical practice, there is over-reliance on biopsy findings to make the distinction between cancer and other mimicking conditions. This is especially true for rare tumors such as PSC, which often results in misdiagnosis and a delay in administering the proper treatment. Transbronchial biopsy in cases such as the present case, carries little benefit because the diagnosis depends on the site from which the biopsy is taken and whether the biopsied tissue is representative of the entire mass. The diagnosis can be suspected based on the clinical and radiological findings but confirmation requires a surgical resection to delineate the accurate cytology and architecture.5,6,8 Huang and colleagues showed a misdiagnosis rate of PSC of >70% preoperatively.4 Resective surgery is feasible only in patients with high index of suspicion for a malignancy, which in most cases requires previous confirmation with a biopsy. The rarity of this cancer, its unusual presentations, and the lack of specific testing preclude early diagnosis and timely treatment of this fatal condition.

Initial treatment options for localized or with limited spread disease is resective surgery. The role of chemo- or radiation therapy is not known, but they have not previously shown promising results,6,8 except in some cases when they are used as postoperative adjuvant chemotherapy4 or in bulky, locally invasive tumors.1 The recurrence rate after surgery is very high, resulting in a poor 5-year survival rate.1,8 Experimental therapies, such as antibodies that target epidermal growth factor receptor mutations, have not shown much success either.8 In conclusion, the outlook for patients with PSC with the current available knowledge and treatment protocols, is dismal.

Most of the current knowledge and data in the literature is based on cases from autopsy or early-stage surgical resections rather than on patients with advanced cancer.5 Moreover, the role of surgical resection in PSC is questionable, given the high recurrence rate. Subsequently, the clinical and pathological manifestations have yet to be well characterized.⁴ There has been advance with the publication of more studies recently. Cytokeratin markers such as CAM 5.2 and AE1/AE3 are commonly useful to support the diagnosis when suspected.³ Other markers, including the carcinoembryonic antigen, CD15, and thyroid transcription factor-1 may be variably positive, based on the differentiation of the cancer. Other exciting prospects in the study of PSC include the suggestion of a modified vimentin histologic score for better characterization of the cancer and the discovery of high plateletderived growth factor receptor beta immunohistochemistry expression in PSC as a potential target for future therapy.

Conclusion

Pulmonary sarcomatoid lung cancer can present with a predominant necrotizing picture that mimics diseases such as tuberculosis. In such case, transbronchial biopsy carries little benefit because the diagnosis depends on whether the biopsied tissue is representative of the entire mass, often confounded by the extensive necrosis. More data is needed to determine prognostic factors and appropriate therapeutic strategies. TSJ

Correspondence

Gaurang Nandkishor Vaidya, MD

References

1. Martin LW, Correa AM, Ordonez NG, et al. Sarcomatoid carcinoma of the lung: a predictor of poor prognosis. Ann Thorac Surg. 2007;84(3):973-980.

2. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001;18(6):1059-1068.

3. Franks TJ, Galvin JR. Sarcomatoid carcinoma of the lung: histologic criteria and common lesions in the differential diagnosis. Arch Pathol Lab Med. 2010;134(1):49-54.

4. Huang SY, Shen SJ, Li XY. Pulmonary sarcomatoid carcinoma: a clinicopathologic study and prognostic analysis of 51 cases. http://wjso. biomedcentral.com/articles/10.1186/1477-7819-11-252. Published 2013. Accessed March 12, 2017.

5. Travis WD. Sarcomatoid neoplasms of the lung and pleura. Arch Pathol Lab Med. 2010;134(11):1645-1658.

6. Pelosi G, Sonzogni A, De Pas T, et al. Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol. 2010;18(2):103-120.

7. Chang YL, Lee YC, Shih JY, Wu CT. Pulmonary pleomorphic (spindle) cell carcinoma: peculiar clinicopathologic manifestations different from ordinary non-small cell carcinoma. Lung Cancer. 2001;34(1):91-97.

8. Park JS, Lee Y, Han J, et al. Clinicopathologic outcomes of curative resection for sarcomatoid carcinoma of the lung. Oncology. 2011;81(3-4):206-213.

Pulmonary sarcomatoid carcinoma (PSC) is a rare histological subtype that has an aggressive course with average survival of 11-13 months.¹ In clinical practice, the possible presentations of this rare cancer are not widely known, resulting in a misdiagnosis. That is what happened with our patient, who presented with necrotizing cavitary lung lesion and soft tissue necrotizing lymphadenitis. The clinical picture was reminiscent of tuberculosis or granulomatosis with polyangiitis and was further confounded by negative computed-tomography (CT)-guided biopsy and bronchoscopy findings, which added to the delay in diagnosis. With the currently available knowledge, the diagnosis of PSC depends largely on evaluation of the surgically resected specimen, which in most cases is avoided until there is a high suspicion of PSC. Biopsy is not useful due to extensive necrosis, as will be seen in our case. Consequently, most of the data in the literature is based on case series of autopsy specimen, and the clinical characteristics of PSC remain unclear. The rarity of PSC has prevented its characterization in literature. We report here a rare presentation of PSC with necrotizing lung lesion, to add to the paucity of the current data.

Case presentation and summary

A 58-year-old homeless man presented to the Upstate University Hospital, Syracuse, New York, with a 25-pound weight loss during the previous month and associated productive cough and hemoptysis for a week and a painful mass in the nape of his neck. He denied any fever, chest pain, sick contacts, or joint pain. He had a history of about 40 pack-years of smoking, and his brother had recently been diagnosed with lung cancer. A tender fluctuant mass was detected in the nape of his neck on examination (Figure 1).

The patient had presented 9 months earlier with persistent cough and hemoptysis, and at that visit was found to have a cavitary lesion in the right lung measuring 2 cm (0.8 in). He had undergone a computed-tomograpghy (CT)-guided biopsy of the lesion, which had shown acute and chronic inflammation with fibrosis, and he had negative bronchoscopy findings. The patient tested negative for tuberculosis during the first visit but he left the hospital against the medical advice of the physicians and he was lost to follow-up until his re-presentation.

On physical examination at his re-presentation, the patient seemed cachectic, with a blood pressure of 94/62 mm of Hg. The mass in the nape of his neck was about 3 cm (1.2 in) long, with erythema of the surrounding skin (Figure 1). Bronchial breath sounds were heard in the right upper lobe of the lung, likely due to the underlying cavitary lesion (Figure 2B). Relevant lab findings included a negative HIV test and repeat AFB (acid-fast bacilli) sputum cultures. A CT-guided biopsy with contrast of the thorax showed an interval increase in the size of the cavitary lesion in the patient’s right upper lobe, now measuring about 10 cm (4 in). Also seen were multiple nodules elsewhere in both lungs, with the largest measuring 8 mm (0.3 in). A CT scan of the neck showed 3 cm cystic mass within the posterior subcutaneous soft tissue of the C3 level, confirming the examination finding of the neck mass (Figure 2A) with peripheral enhancement and surrounding infiltrative changes, likely abscess or malignant lymph node versus necrotic infection. He underwent bronchoscopy, which again failed to reveal any endobronchial lesions. Bronchoalveolar lavage was sent for microbiological analysis, including AFB and fungus, but came back negative. Transbronchial biopsy cytology revealed fragments of tumor composed of large pleomorphic cells without glandular or squamous differentiation, within large areas of necrosis (Figure 3). Immunohistochemical studies showed strong reactivity with cytokeratin CAM5.2 (Figure 4), weak and focal reactivity with cytokeratin AE1/AE3 (Figure 5), and lack of reactivity with CD20, CD3, CD30, S-100, MART-1, TTF-1 and p63, all findings consistent with sarcomatoid carcinoma.

The patient underwent fine-needle aspiration and drainage of the neck lesion and the culture grew mixed organisms The results of a bone scan, which was done within a week, showed multiple foci of uptake in the ribs and cervical spine. Given the patient’s advanced disease, he was started on palliative radiotherapy with radiosensitizing chemotherapy with carboplatin (target AUC 6) and paclitaxel (135 mg/m2 over 24 hours). His symptoms of hemoptysis improved transiently after the first cycle, but he became hypotensive and drowsy during the second cycle of therapy, and the family decided to make the patient comfort care and withdraw all further treatment. He was discharged to hospice.

Discussion

PSC is a rare variant of non-small-cell carcinoma lung cancer, accounting for up to 0.4% of lung malignancy.1  It was

recently subtyped by the World Health Organization as a non-small cell lung carcinoma with certain amount of differentiation resembling sarcoma or containing elements of sarcoma.^2-4  It is not known why both elements co-exist in the tumor, but Franks and colleagues some theories have been postulated in the literature, including possible origin from a single, aberrant stem cell with progenies differentiating in two separate pathways.³

Sarcomatoid carcinoma consists of spectrum of tumors including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and blastoma.3,4 It usually shows male preponderance, and association with smoking.3  The diagnosis commonly occurs in the sixth decade of life, except for pulmonary blastoma, which is more common in the fourth decade andnwith equal gender distribution.⁴

The presenting symptoms can be variable and nonspecific, but predominantly include chest pain, cough, hemoptysis, and/or weight loss.⁵  Radiologically, pulmonary sarcomatoid cancer presenting as a necrotizing cavitary lesion in the lung is a rare finding, seldom reported in the past.^6,7  The presentation in our case, with necrotizing lymphadenitis, was reminiscent of an infectious or autoimmune etiology such as tuberculosis or granulomatosis with polyangiitis. The presence of extensive necrosis in the lesion and the characteristic heterogeneity of the tumor had resulted in inconclusive biopsy findings during the previous presentation. In clinical practice, there is over-reliance on biopsy findings to make the distinction between cancer and other mimicking conditions. This is especially true for rare tumors such as PSC, which often results in misdiagnosis and a delay in administering the proper treatment. Transbronchial biopsy in cases such as the present case, carries little benefit because the diagnosis depends on the site from which the biopsy is taken and whether the biopsied tissue is representative of the entire mass. The diagnosis can be suspected based on the clinical and radiological findings but confirmation requires a surgical resection to delineate the accurate cytology and architecture.5,6,8 Huang and colleagues showed a misdiagnosis rate of PSC of >70% preoperatively.4 Resective surgery is feasible only in patients with high index of suspicion for a malignancy, which in most cases requires previous confirmation with a biopsy. The rarity of this cancer, its unusual presentations, and the lack of specific testing preclude early diagnosis and timely treatment of this fatal condition.

Initial treatment options for localized or with limited spread disease is resective surgery. The role of chemo- or radiation therapy is not known, but they have not previously shown promising results,6,8 except in some cases when they are used as postoperative adjuvant chemotherapy4 or in bulky, locally invasive tumors.1 The recurrence rate after surgery is very high, resulting in a poor 5-year survival rate.1,8 Experimental therapies, such as antibodies that target epidermal growth factor receptor mutations, have not shown much success either.8 In conclusion, the outlook for patients with PSC with the current available knowledge and treatment protocols, is dismal.

Most of the current knowledge and data in the literature is based on cases from autopsy or early-stage surgical resections rather than on patients with advanced cancer.5 Moreover, the role of surgical resection in PSC is questionable, given the high recurrence rate. Subsequently, the clinical and pathological manifestations have yet to be well characterized.⁴ There has been advance with the publication of more studies recently. Cytokeratin markers such as CAM 5.2 and AE1/AE3 are commonly useful to support the diagnosis when suspected.³ Other markers, including the carcinoembryonic antigen, CD15, and thyroid transcription factor-1 may be variably positive, based on the differentiation of the cancer. Other exciting prospects in the study of PSC include the suggestion of a modified vimentin histologic score for better characterization of the cancer and the discovery of high plateletderived growth factor receptor beta immunohistochemistry expression in PSC as a potential target for future therapy.

Conclusion

Pulmonary sarcomatoid lung cancer can present with a predominant necrotizing picture that mimics diseases such as tuberculosis. In such case, transbronchial biopsy carries little benefit because the diagnosis depends on whether the biopsied tissue is representative of the entire mass, often confounded by the extensive necrosis. More data is needed to determine prognostic factors and appropriate therapeutic strategies. TSJ

Correspondence

Gaurang Nandkishor Vaidya, MD

References

1. Martin LW, Correa AM, Ordonez NG, et al. Sarcomatoid carcinoma of the lung: a predictor of poor prognosis. Ann Thorac Surg. 2007;84(3):973-980.

2. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001;18(6):1059-1068.

3. Franks TJ, Galvin JR. Sarcomatoid carcinoma of the lung: histologic criteria and common lesions in the differential diagnosis. Arch Pathol Lab Med. 2010;134(1):49-54.

4. Huang SY, Shen SJ, Li XY. Pulmonary sarcomatoid carcinoma: a clinicopathologic study and prognostic analysis of 51 cases. http://wjso. biomedcentral.com/articles/10.1186/1477-7819-11-252. Published 2013. Accessed March 12, 2017.

5. Travis WD. Sarcomatoid neoplasms of the lung and pleura. Arch Pathol Lab Med. 2010;134(11):1645-1658.

6. Pelosi G, Sonzogni A, De Pas T, et al. Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol. 2010;18(2):103-120.

7. Chang YL, Lee YC, Shih JY, Wu CT. Pulmonary pleomorphic (spindle) cell carcinoma: peculiar clinicopathologic manifestations different from ordinary non-small cell carcinoma. Lung Cancer. 2001;34(1):91-97.

8. Park JS, Lee Y, Han J, et al. Clinicopathologic outcomes of curative resection for sarcomatoid carcinoma of the lung. Oncology. 2011;81(3-4):206-213.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-B (HIV-B). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremeties, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹  We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm3 ; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia.The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.²  Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.3  Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴  Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma. TSJ

Correspondence

Rebecca E Neril, MD; Department of Internal Medicine, SBH Health System, Bronx, New York.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-B (HIV-B). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremeties, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹  We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm3 ; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia.The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.²  Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.3  Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴  Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma. TSJ

Correspondence

Rebecca E Neril, MD; Department of Internal Medicine, SBH Health System, Bronx, New York.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-B (HIV-B). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremeties, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹  We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm3 ; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia.The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.²  Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.3  Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴  Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma. TSJ

Correspondence

Rebecca E Neril, MD; Department of Internal Medicine, SBH Health System, Bronx, New York.

Three myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are associated with an abnormal somatic mutation of the JAK2 gene. Essential thrombocythemia is considered when there is a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow. The manifestations of PV, ET, and PMF all typically occur within the sixth or seventh decade of life. A patient may present with an abnormal blood count but be asymptomatic at the time. Over the course and progression of the disease, increases in hematocrit or platelet counts along with symptoms such as headaches, blurred vision, and plethora may occur.¹ The JAK2 V617F mutation is responsible for the production of the JAK2 protein, which is continuously activated, promoting the growth and division of cells such as erythrocytes, granulocytes, and platelets. It has been reported that there is a nearly 100% incidence of the JAK2 mutation in patients with polycythemia vera, and a 50% incidence in patients with essential thrombocythemia and primary myelofibrosis.²

The discovery of the JAK2 mutation in PV, ET, and PMF was an important advancement in helping distinguish these disorders from other MPNs, including chronic myelogenous leukemia, but its presence does not explain why some individuals develop ET and others, PV or PMF.³ Although there have been familial cases proven of ET, the somatic JAK2 mutation is acquired and not inherited. In this report, we describe the unusual circumstance of JAK2 V617F mutation in a brother and a sister who were both diagnosed with essential thrombocythemia.

Case presentations and summaries

RS, a 69-year-old white man, was referred to our service in 2006 for continued care of previously diagnosed essential thrombocythemia. At the time of his initial visit to our clinic, his complete blood count was normal, the platelet count being adequately controlled by anagrelide at a daily dose of 4.0 mg. He complained of palpitations and peripheral neuropathy. A bone marrow biopsy was performed, revealing moderate hypercellularity, atypical megakaryocytosis, and a negative BCR-ABL mutation but a positive JAK2 V617F mutation. The patient is now treated with hydroxyurea 1,000 mg daily in divided doses, which better controls his counts and does not have the side effects of anagrelide.

SW, a 73-year-old woman, and brother of RS (they share the same biological mother and father), was noted to have a mild thrombocytosis in 2008. In 2013, her platelet count rose to 865,000 cells/uL (normal, 150,000-450,000 cells/uL, age and sex adjusted) and she was referred to our clinic. A bone marrow biopsy was performed, revealing borderline hypercellularity with atypical megakaryocytosis and the presence of a JAK2 V617F mutation. As with her brother, the BCR-ABL mutation was not present. She has also responded to treatment with hydroxyurea, but at a reduced dosage of 500 mg daily.

A third sibling, AS, again of the same biological mother and father, had died of multiple veno-occlusive cerebral vascular events long before the diagnoses on his younger siblings had been made. The suggestion of any underling hematologic pathology would be interesting, but speculative. Nothing is known about the parents’ medical history. None of the three siblings had children.

Discussion

Much research has been done to understand the pathogenesis of and find a cure for myeloproliferative disorders, but despite some progress, a cure remains elusive. However, there have been some advances that have contributed to partial cures for MPNs. One of the major breakthroughs in MPN research, about 50 years ago, was related to the “sporadic vs familial debate” around the Philadelphia chromosome.4 It led to the discovery of the reciprocal translocation between chromosomes 9 and 22, known as the BCR-ABL mutation, which is found in many CML patients. This discovery allowed researchers to focus their attention on other tyrosine kinase domains, such as the JAK2 V617F mutation, which is presented in the three other MPNs; PV, ET, and PMF. Both the JAK2 V617F and BCR-ABL mutations are active in signaling transcription, more commonly growth of cells.⁴

Since the discovery of the JAK2 V617F mutation in early 2005, it has become a leading diagnostic criteria for myeloproliferative diseases. The presence of the JAK2 V617F mutation and the measurement of its allele burden can be assessed by examination of either peripheral blood or bone marrow samples.⁵

The JAK2 V617F mutation is a result of a single change in the DNA nucleotide base pair that causes a substitution of a valine amino acid for a phenylalanine amino acid at the 617 position on exon 14 within the JAK2 kinase regulatory domain. This point mutation disrupts the regular control of the JAK2 by removing its ability to turn off, leading to uncontrolled blood cell growth.⁶ When the JAK2 V617F mutation cannot be demonstrated in a patient with the hallmarks of an MPN, the detection of other JAK2 and MPL proto-oncogene, thrombopoietin receptor mutations may be used as a diagnostic procedure for other MPNs.⁷

Other mutations incorporated in JAK2 domain can be detected in the coding portions of the DNA known as exons. One such mutation is the JAK2 exon 12, which is involved in JAK2 V617F-negative PV patients. This mutation is not detected in patients with ET or PMF and is 2%-5% present in patients with PV. There are other somatic mutations in the thrombopoietin receptors that work in accordance with thrombopoietin: MPL W515L and MPL W515K, which are found at chromosome 1p34, are identified in about 5% of PMF and 1% of ET patients, but are not present in PV patients.^8.9

Pikman and colleagues reported in 2009 that the JAK2 V617F mutation is not acquired randomly.⁹ Their findings showed that, only in white populations, does the JAK2 V617F mutation arise preferentially on a specific constitutional JAK2 46/1 haplotype. According to the authors, the preconceived notion a of randomly acquired JAK2 V617F mutation does not account for familial MPN’s. Familial MPNs are thought to be produced by sporadic and extremely penetrant substitutions in genes that still are not identified and the 46/1 haplotype does not explain for the phenotypic diversity correlated with the JAK2 V617F gene. The 46/1 haplotype, however, correlates more frequently with different MPN subtypes. There are two hypotheses that try to explain how an acquired mutation as prevailing as the JAK2 V617F mutation can be associated with certain inherited backgrounds. The first hypothesis asserts the V617F accumulates at a faster rate than other genes because of the fundamentally unstable genetics of the 46/1 haplotype. The second theory is that all the mutated genes, including the V617F, arise at equal rates, but 46/1 may grant a selective advantage to the V617F-positive clone or interacts in some way to increase the likelihood of abnormal blood counts. A study that examined both these hypotheses concluded that the 46/1 haplotype was present more frequently in patients with myeloproliferative disorders than in their control groups and even more so in cases that were proven to be V617F-positive.10

There are very few cases that have reported familial MPN’s, especially as the pedigrees of the familial MPN’s illustrate that inheritance patterns are notably heterogeneous, indicating that there may be a range of different germline mutations driving the susceptibility. With recent data, the JAK2 V617F mutation in tandem with MPL W515L/K and inactivating TET2 mutations still continue to be the most frequently acquired mutations involved in both familial and sporadic MPN. As far as we know, there have been no cases to prove that JAK2 V617F and MPL W515L/K mutations are inherited through the germline, but there are other alleles that may pass through the germline that can be associated with hereditary thrombocytosis.¹¹ Further cytogenetic studies will clarify the pathogenesis of these disorders and possibly lead to effective targeted therapies.

Three myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are associated with an abnormal somatic mutation of the JAK2 gene. Essential thrombocythemia is considered when there is a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow. The manifestations of PV, ET, and PMF all typically occur within the sixth or seventh decade of life. A patient may present with an abnormal blood count but be asymptomatic at the time. Over the course and progression of the disease, increases in hematocrit or platelet counts along with symptoms such as headaches, blurred vision, and plethora may occur.¹ The JAK2 V617F mutation is responsible for the production of the JAK2 protein, which is continuously activated, promoting the growth and division of cells such as erythrocytes, granulocytes, and platelets. It has been reported that there is a nearly 100% incidence of the JAK2 mutation in patients with polycythemia vera, and a 50% incidence in patients with essential thrombocythemia and primary myelofibrosis.²

The discovery of the JAK2 mutation in PV, ET, and PMF was an important advancement in helping distinguish these disorders from other MPNs, including chronic myelogenous leukemia, but its presence does not explain why some individuals develop ET and others, PV or PMF.³ Although there have been familial cases proven of ET, the somatic JAK2 mutation is acquired and not inherited. In this report, we describe the unusual circumstance of JAK2 V617F mutation in a brother and a sister who were both diagnosed with essential thrombocythemia.

Case presentations and summaries

RS, a 69-year-old white man, was referred to our service in 2006 for continued care of previously diagnosed essential thrombocythemia. At the time of his initial visit to our clinic, his complete blood count was normal, the platelet count being adequately controlled by anagrelide at a daily dose of 4.0 mg. He complained of palpitations and peripheral neuropathy. A bone marrow biopsy was performed, revealing moderate hypercellularity, atypical megakaryocytosis, and a negative BCR-ABL mutation but a positive JAK2 V617F mutation. The patient is now treated with hydroxyurea 1,000 mg daily in divided doses, which better controls his counts and does not have the side effects of anagrelide.

SW, a 73-year-old woman, and brother of RS (they share the same biological mother and father), was noted to have a mild thrombocytosis in 2008. In 2013, her platelet count rose to 865,000 cells/uL (normal, 150,000-450,000 cells/uL, age and sex adjusted) and she was referred to our clinic. A bone marrow biopsy was performed, revealing borderline hypercellularity with atypical megakaryocytosis and the presence of a JAK2 V617F mutation. As with her brother, the BCR-ABL mutation was not present. She has also responded to treatment with hydroxyurea, but at a reduced dosage of 500 mg daily.

A third sibling, AS, again of the same biological mother and father, had died of multiple veno-occlusive cerebral vascular events long before the diagnoses on his younger siblings had been made. The suggestion of any underling hematologic pathology would be interesting, but speculative. Nothing is known about the parents’ medical history. None of the three siblings had children.

Discussion

Much research has been done to understand the pathogenesis of and find a cure for myeloproliferative disorders, but despite some progress, a cure remains elusive. However, there have been some advances that have contributed to partial cures for MPNs. One of the major breakthroughs in MPN research, about 50 years ago, was related to the “sporadic vs familial debate” around the Philadelphia chromosome.4 It led to the discovery of the reciprocal translocation between chromosomes 9 and 22, known as the BCR-ABL mutation, which is found in many CML patients. This discovery allowed researchers to focus their attention on other tyrosine kinase domains, such as the JAK2 V617F mutation, which is presented in the three other MPNs; PV, ET, and PMF. Both the JAK2 V617F and BCR-ABL mutations are active in signaling transcription, more commonly growth of cells.⁴

Since the discovery of the JAK2 V617F mutation in early 2005, it has become a leading diagnostic criteria for myeloproliferative diseases. The presence of the JAK2 V617F mutation and the measurement of its allele burden can be assessed by examination of either peripheral blood or bone marrow samples.⁵

The JAK2 V617F mutation is a result of a single change in the DNA nucleotide base pair that causes a substitution of a valine amino acid for a phenylalanine amino acid at the 617 position on exon 14 within the JAK2 kinase regulatory domain. This point mutation disrupts the regular control of the JAK2 by removing its ability to turn off, leading to uncontrolled blood cell growth.⁶ When the JAK2 V617F mutation cannot be demonstrated in a patient with the hallmarks of an MPN, the detection of other JAK2 and MPL proto-oncogene, thrombopoietin receptor mutations may be used as a diagnostic procedure for other MPNs.⁷

Other mutations incorporated in JAK2 domain can be detected in the coding portions of the DNA known as exons. One such mutation is the JAK2 exon 12, which is involved in JAK2 V617F-negative PV patients. This mutation is not detected in patients with ET or PMF and is 2%-5% present in patients with PV. There are other somatic mutations in the thrombopoietin receptors that work in accordance with thrombopoietin: MPL W515L and MPL W515K, which are found at chromosome 1p34, are identified in about 5% of PMF and 1% of ET patients, but are not present in PV patients.^8.9

Pikman and colleagues reported in 2009 that the JAK2 V617F mutation is not acquired randomly.⁹ Their findings showed that, only in white populations, does the JAK2 V617F mutation arise preferentially on a specific constitutional JAK2 46/1 haplotype. According to the authors, the preconceived notion a of randomly acquired JAK2 V617F mutation does not account for familial MPN’s. Familial MPNs are thought to be produced by sporadic and extremely penetrant substitutions in genes that still are not identified and the 46/1 haplotype does not explain for the phenotypic diversity correlated with the JAK2 V617F gene. The 46/1 haplotype, however, correlates more frequently with different MPN subtypes. There are two hypotheses that try to explain how an acquired mutation as prevailing as the JAK2 V617F mutation can be associated with certain inherited backgrounds. The first hypothesis asserts the V617F accumulates at a faster rate than other genes because of the fundamentally unstable genetics of the 46/1 haplotype. The second theory is that all the mutated genes, including the V617F, arise at equal rates, but 46/1 may grant a selective advantage to the V617F-positive clone or interacts in some way to increase the likelihood of abnormal blood counts. A study that examined both these hypotheses concluded that the 46/1 haplotype was present more frequently in patients with myeloproliferative disorders than in their control groups and even more so in cases that were proven to be V617F-positive.10

There are very few cases that have reported familial MPN’s, especially as the pedigrees of the familial MPN’s illustrate that inheritance patterns are notably heterogeneous, indicating that there may be a range of different germline mutations driving the susceptibility. With recent data, the JAK2 V617F mutation in tandem with MPL W515L/K and inactivating TET2 mutations still continue to be the most frequently acquired mutations involved in both familial and sporadic MPN. As far as we know, there have been no cases to prove that JAK2 V617F and MPL W515L/K mutations are inherited through the germline, but there are other alleles that may pass through the germline that can be associated with hereditary thrombocytosis.¹¹ Further cytogenetic studies will clarify the pathogenesis of these disorders and possibly lead to effective targeted therapies.

Three myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are associated with an abnormal somatic mutation of the JAK2 gene. Essential thrombocythemia is considered when there is a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow. The manifestations of PV, ET, and PMF all typically occur within the sixth or seventh decade of life. A patient may present with an abnormal blood count but be asymptomatic at the time. Over the course and progression of the disease, increases in hematocrit or platelet counts along with symptoms such as headaches, blurred vision, and plethora may occur.¹ The JAK2 V617F mutation is responsible for the production of the JAK2 protein, which is continuously activated, promoting the growth and division of cells such as erythrocytes, granulocytes, and platelets. It has been reported that there is a nearly 100% incidence of the JAK2 mutation in patients with polycythemia vera, and a 50% incidence in patients with essential thrombocythemia and primary myelofibrosis.²

The discovery of the JAK2 mutation in PV, ET, and PMF was an important advancement in helping distinguish these disorders from other MPNs, including chronic myelogenous leukemia, but its presence does not explain why some individuals develop ET and others, PV or PMF.³ Although there have been familial cases proven of ET, the somatic JAK2 mutation is acquired and not inherited. In this report, we describe the unusual circumstance of JAK2 V617F mutation in a brother and a sister who were both diagnosed with essential thrombocythemia.

Case presentations and summaries

RS, a 69-year-old white man, was referred to our service in 2006 for continued care of previously diagnosed essential thrombocythemia. At the time of his initial visit to our clinic, his complete blood count was normal, the platelet count being adequately controlled by anagrelide at a daily dose of 4.0 mg. He complained of palpitations and peripheral neuropathy. A bone marrow biopsy was performed, revealing moderate hypercellularity, atypical megakaryocytosis, and a negative BCR-ABL mutation but a positive JAK2 V617F mutation. The patient is now treated with hydroxyurea 1,000 mg daily in divided doses, which better controls his counts and does not have the side effects of anagrelide.

SW, a 73-year-old woman, and brother of RS (they share the same biological mother and father), was noted to have a mild thrombocytosis in 2008. In 2013, her platelet count rose to 865,000 cells/uL (normal, 150,000-450,000 cells/uL, age and sex adjusted) and she was referred to our clinic. A bone marrow biopsy was performed, revealing borderline hypercellularity with atypical megakaryocytosis and the presence of a JAK2 V617F mutation. As with her brother, the BCR-ABL mutation was not present. She has also responded to treatment with hydroxyurea, but at a reduced dosage of 500 mg daily.

A third sibling, AS, again of the same biological mother and father, had died of multiple veno-occlusive cerebral vascular events long before the diagnoses on his younger siblings had been made. The suggestion of any underling hematologic pathology would be interesting, but speculative. Nothing is known about the parents’ medical history. None of the three siblings had children.

Discussion

Much research has been done to understand the pathogenesis of and find a cure for myeloproliferative disorders, but despite some progress, a cure remains elusive. However, there have been some advances that have contributed to partial cures for MPNs. One of the major breakthroughs in MPN research, about 50 years ago, was related to the “sporadic vs familial debate” around the Philadelphia chromosome.4 It led to the discovery of the reciprocal translocation between chromosomes 9 and 22, known as the BCR-ABL mutation, which is found in many CML patients. This discovery allowed researchers to focus their attention on other tyrosine kinase domains, such as the JAK2 V617F mutation, which is presented in the three other MPNs; PV, ET, and PMF. Both the JAK2 V617F and BCR-ABL mutations are active in signaling transcription, more commonly growth of cells.⁴

Since the discovery of the JAK2 V617F mutation in early 2005, it has become a leading diagnostic criteria for myeloproliferative diseases. The presence of the JAK2 V617F mutation and the measurement of its allele burden can be assessed by examination of either peripheral blood or bone marrow samples.⁵

The JAK2 V617F mutation is a result of a single change in the DNA nucleotide base pair that causes a substitution of a valine amino acid for a phenylalanine amino acid at the 617 position on exon 14 within the JAK2 kinase regulatory domain. This point mutation disrupts the regular control of the JAK2 by removing its ability to turn off, leading to uncontrolled blood cell growth.⁶ When the JAK2 V617F mutation cannot be demonstrated in a patient with the hallmarks of an MPN, the detection of other JAK2 and MPL proto-oncogene, thrombopoietin receptor mutations may be used as a diagnostic procedure for other MPNs.⁷

Other mutations incorporated in JAK2 domain can be detected in the coding portions of the DNA known as exons. One such mutation is the JAK2 exon 12, which is involved in JAK2 V617F-negative PV patients. This mutation is not detected in patients with ET or PMF and is 2%-5% present in patients with PV. There are other somatic mutations in the thrombopoietin receptors that work in accordance with thrombopoietin: MPL W515L and MPL W515K, which are found at chromosome 1p34, are identified in about 5% of PMF and 1% of ET patients, but are not present in PV patients.^8.9

Pikman and colleagues reported in 2009 that the JAK2 V617F mutation is not acquired randomly.⁹ Their findings showed that, only in white populations, does the JAK2 V617F mutation arise preferentially on a specific constitutional JAK2 46/1 haplotype. According to the authors, the preconceived notion a of randomly acquired JAK2 V617F mutation does not account for familial MPN’s. Familial MPNs are thought to be produced by sporadic and extremely penetrant substitutions in genes that still are not identified and the 46/1 haplotype does not explain for the phenotypic diversity correlated with the JAK2 V617F gene. The 46/1 haplotype, however, correlates more frequently with different MPN subtypes. There are two hypotheses that try to explain how an acquired mutation as prevailing as the JAK2 V617F mutation can be associated with certain inherited backgrounds. The first hypothesis asserts the V617F accumulates at a faster rate than other genes because of the fundamentally unstable genetics of the 46/1 haplotype. The second theory is that all the mutated genes, including the V617F, arise at equal rates, but 46/1 may grant a selective advantage to the V617F-positive clone or interacts in some way to increase the likelihood of abnormal blood counts. A study that examined both these hypotheses concluded that the 46/1 haplotype was present more frequently in patients with myeloproliferative disorders than in their control groups and even more so in cases that were proven to be V617F-positive.10

There are very few cases that have reported familial MPN’s, especially as the pedigrees of the familial MPN’s illustrate that inheritance patterns are notably heterogeneous, indicating that there may be a range of different germline mutations driving the susceptibility. With recent data, the JAK2 V617F mutation in tandem with MPL W515L/K and inactivating TET2 mutations still continue to be the most frequently acquired mutations involved in both familial and sporadic MPN. As far as we know, there have been no cases to prove that JAK2 V617F and MPL W515L/K mutations are inherited through the germline, but there are other alleles that may pass through the germline that can be associated with hereditary thrombocytosis.¹¹ Further cytogenetic studies will clarify the pathogenesis of these disorders and possibly lead to effective targeted therapies.

Tonsillar carcinoma is the most common of the oropharyngeal malignancies of the head and neck region after thyroid and laryngeal carcinoma. Squamous cell carcinoma is the most frequent histologic type of these tumors.¹ Tonsillar tumors may originate in the oral cavity, oropharynx, hypopharynx, or larynx. In the United States, more than 5,000 new cases of oropharynx cancer are diagnosed annually.² Men are affected three to four times more often than are women, and the rate of incidence increases after the 4th decade of life.³ Surveillance, Epidemiology, and End Results data from 1975-2004 show that tonsillar squamous cell carcinoma has had one of the largest increases in the male-to-female incidence rate ratios.⁴ The overall incidence of tonsillar carcinoma is increasing, especially in the younger population, and this may be attributed to increasing rates of human papilloma virus.^5,6

Squamous cell carcinoma in the head and neck originate from subsites within the oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx.⁷ Traditionally, alcohol consumption and tobacco use were considered the most significant risk factors for the development of tonsillar cancer.⁸ More recently, however, the high-risk oncogenic human papilloma virus has emerged as a clinical entity in the pathogenesis of squamous cell carcinoma in the head and neck. Other risk factors include poor oral hygiene, mechanical irritation, chewing of betel quid preparations, and a lack of vegetables and fruits in the diet.^9-11 Squamous cell carcinoma of the oropharynx often presents late with lymph node involvement at the time of diagnosis. Nonspecific symptoms such as a sore throat and dysphagia can allow head and neck cancer to evade early detection. Many patients with tonsillar carcinoma present with advanced disease because early lesions are generally asymptomatic when small. This absence of symptoms is responsible for 67%-77% of patients presenting with tumors larger than 2.0 cm and often with regional nodal metastasis. At presentation, 45% of anterior tonsillar pillar lesions and 76% of tonsillar fossa lesions have clinically positive necks.¹²

Despite significant treatment advances, the management of advanced squamous cell carcinoma of the tonsil remains challenging. Historically, surgery was considered the standard of care for patients with tonsillar carcinoma with or without postoperative adjuvant radiotherapy. In locally advanced tonsillar carcinoma, extensive surgery with major tissue reconstruction was necessary, leading to speech dysfunction, cosmetic deformities, and difficulties in swallowing, all of which are detrimental to patient quality of life.¹³ Given the critical role of the oropharynx in speech and swallowing, nonsurgical therapy with organ-preserving chemoradiation has gained a greater role in the treatment of tonsil carcinoma.¹³ Over the past decade, innovations in radiation therapy techniques have led to the introduction of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) for the treatment of various cancers including tonsillar carcinoma.^14,15 IMRT is an advanced mode of conformal high-precision radiotherapy that uses computer-controlled multiple small radiation beams of varying intensities to deliver precise radiation doses to the target tissues while sparing adjacent healthy tissues.¹⁴ By incorporating three-dimensional computed-tomography (CT) or positron-emission–tomography (PET) imaging technology, IMRT allows the radiation dose to conform more precisely to the three-dimensional shape of the tumor while modulating the intensity of the radiation beam and minimizing its dose to those adjacent sensitive and unaffected organs. IGRT uses a range of two-, three-, and four-dimensional imaging techniques that improve the precision and accuracy of the delivery of the radiation dose to the targeted tumor tissue while minimizing the dose to the surrounding normal tissue during the course of radiation therapy (Figure 1). In this report, we present challenging cases of advanced tonsillar carcinoma and describe our experience in managing the disease using a hyperfractionated IMRT-IGRT based three-dimensional conformal radiation therapy protocol with concurrent chemotherapy.

Case presentations and summaries

Case 1

A 52-year-old white, nonsmoking man who worked in a research chemical laboratory, presented with complaints of throat pain and difficulty in swallowing. The patient had a history of asthma and allergies and had been seen by an ear, nose, and throat (ENT) specialist prior to his visit to our oncology center. A biopsy was performed on a right tonsillar mass measuring 2.7 x 3.6 cm. A computed-tomography (CT) scan showed 2 enlarged inhomogeneous lymph nodes measuring 2.9 cm and 1.7 cm. The nodes were well defined with no soft tissue edema. Neoplasm was favored as a diagnosis and biopsy of the mass was carried out. A biopsy specimen measuring 1.0 x 0.4 x 0.3 cm revealed a moderately differentiated infiltrating squamous cell carcinoma, which extended to the edge of the biopsy specimen. The patient’s Karnofsky performance status was 90% (ie, able to carry on normal activity; minor signs or symptoms of disease).

A CT scan of the chest was clear with no evidence of malignant involvement. A subsequent CT scan of the neck revealed a primary neoplasm of the right faucial tonsil measuring 3.3 x 3.0 cm and associated with right level II, level III, and level IV pathological lymphadenopathy. Positron-emission tomography (PET) imaging of the neck revealed a right tonsillar lesion of 2.7 x 3.0 cm involving the right parapharyngeal space (Figure 2, Case 1). The standardized uptake value (SUV) of the PET scan of the primary lesion was measured at 7.3. A cluster of right level II cervical nodes measuring 3.2 x 2.5 cm had an SUV of 3.5. A 1.0-cm right level III jugular node was also seen with an SUV of 1.6, and a right level IV lymph node measuring 1.5 x 1.0 cm was seen with an SUV of 1.8. No other lesions were noted. The tumor stage was T2N2bM0, a stage IVa disease.

Case 2

A 49-year-old black male presented with throat pain and a mass seen initially by his family physician. The patient had a history of tobacco use (at least 1 cigar a day) periodically for about 10 years and had quit cigar smoking 15 years prior to developing his disease. An initial evaluation indicated that the patient had a hypopharyngeal mass in the left inferior pole of his tonsil with near occlusion of the hypopharyngeal airway. His larynx could not be visualized because of the obstructive mass. A neck lymph node measuring 3.0 cm in the left jugulodigastric region was also noted. The patient’s Karnofsky performance status was 90%. Subsequently, the patient underwent excision of the right tonsil and left tonsillar region.

The pathology of the right tonsil was found to be benign. Histology of the left tonsil revealed invasive squamous cell carcinoma. The resected tumor size measured 3.7 x 2.7 x 2.5 cm. The tumor was moderately differentiated involving the deep surgical margins. No lymphovascular invasion was seen. A PET scan revealed a mass arising from the left tonsillar pillar measuring 3.6 x 2.6 x 3.3 cm with deviation of the epiglottis posteriorly nearing the left vallecula. In addition, multiple large cervical nodal lesions in the left level II nodal chain were seen, with the largest measuring 3.1 x 3.0 x 4.5 cm with an SUV of 3.4. Displacement of the left submandibular gland with several further enlarged level II lymph nodes was observed. In the region of left vallecula, there was soft tissue thickening with increased activity measuring 2.7 x 1.5 cm, likely crossing the midline with an SUV of 5.5. The rest of the neck was negative for metastatic involvement (Figure 2, Case 2). The tumor stage was T3N2Mx, a stage IVa disease.

The patient had a Port-A-Cath placed, which caused a hemothorax after placement of the port and delayed initiating his treatment. A pretreatment MRI scan of the neck revealed multiple conglomerate hypodense peripherally enhancing nodular areas in the left neck posterior to the left submandibular gland deep to the parotid tail worrisome for necrotic lymphadenopathy. The patient underwent a course of hyperfractionated IMRT-IGRT in 67 fractions of 120 cGy twice daily for a total dose of 8,040 cGy to the primary tumor site.¹⁶ The patient had a port and PEG tube prior to initiating his radiation therapy. He received IMRT-IGRT with concurrent chemotherapy that was selected based on the recommendation of his genomic testing.^17,18 The chemotherapy regimen used included carboplatin (300 mg weekly) and docetaxel (400 mg weekly). The patient had a treatment break because he was hospitalized for anemia and pancytopenia from his chemotherapy and he received supportive cancer care with epoetin alfa.A post therapy PET scan was negative for evidence of hypermetabolic malignancy; however, a 3.3 x 2.7 cm calcified lesion representing likely level III jugular lymph node exhibited no measurable activity at that time. The follow-up after 40 months indicated that the patient had no reported recurrence of the disease (Figure 2, Case 2). The patient’s demographics, tumor characteristics, and the treatment details are summarized in the Table.
 

Case 3

A 53-year-old white man, who had no smoking or tobacco history but who was exposed to chemicals including sulfuric acid, hydrogen chloride gas, and glycols at work, presented initially with a sore throat that became more painful over time. His ENT specialist referred him for a CT scan of the neck, which revealed a left-sided neck mass measuring 2.5 cm in diameter posterior to the submandibular gland and lateral to carotid sheath and anterior to the triangle (Figure 2, Case 3). The mass appeared to be encapsulated. There was a lobulated spherical mass in the left supraglottic area with formation of the airway of the pyriform sinus and additional anterior vascular involvement was noted. The mass measured 3.6 cm in transverse diameter.

A left tonsillar biopsy specimen measuring 1.4 x 0.6 x 0.2 cm was obtained, and its pathology revealed that the patient had a metastatic squamous cell carcinoma. The left neck lymph node mass aspiration also revealed the presence of squamous cell carcinoma. A PET-CT scan staging showed a dominant tonsillar fossa mass extending from the soft palate down to the pyriform sinus measuring 4.2 x 3.8 cm, with an SUV uptake of 7.3. There was a dominant left level II necrotic lymph node presence measuring 5.0 x 3.7 cm, with an SUV of 3.0. The patient’s Karnofsky performance status was 90%. The tumor stage was T4N2M0, a stage IVa disease. The patient received a course of conformal hyperfractionated IMRT-IGRT delivered to the primary tumor in 67 fractions at 120 cGy twice daily for a total dose of 8,040 cGy¹⁶ and concurrent carboplatin chemotherapy at a weekly dose of 200 mg.

After completion of his radiation therapy, chemotherapy was changed based on genomic testing from single agent to doublet with carboplatin (area under the curve (AUC) dose of 2 or 200 mg, weekly) plus docetaxel (25 mg/m² weekly for 3 weeks and 1 week off ).^17,18 A PET scan after chemoradiation therapy revealed a marked anatomical improvement in the primary neoplastic disease seen in the faucial tonsil. The tonsillar mass noted previously had almost completely resolved over the interval, with only a mild persistent asymmetrical thickening of around 1.5 cm, with a peak SUV of 2.0. A lymph node of 2.8 x 2.0 cm was present anterior to the left sternocleidomastoid muscle exhibiting SUV of only 1.8. No other abnormal lesions were noted (Figure 2, Case 3). The patient continues to do extremely well without local recurrence of the disease 46 months after radiation therapy (see Table for patient demographics, tumor characteristics, and therapy details.)
 

Discussion

The management of patients with primary squamous cell carcinoma of the oropharyngeal remains controversial. Traditionally, early-stage tonsillar squamous cell carcinoma was managed by a single modality treatment, either by surgery or radiation therapy, each showing similar efficacy and outcomes.¹⁹ For late-stage disease, a combined approach using surgery and radiation therapy was found to be superior to single modality treatment. However, surgery in conjugation with radiation therapy has been associated with significant toxicities compared with the radiation therapy alone.¹³Therefore, the use of radiation therapy without surgery is becoming more common with increasingly sophisticated radiation therapy techniques and organ preservation approach in patients with squamous cell carcinoma of the tonsil.

Findings from several studies have shown that in stage I or II oropharyngeal cancer, single modality treatment with radiation therapy achieves 80%-90% of local control of the disease, but poorer outcomes are reported for locally advanced stages III/IV with a local control rate of 63%-74%.²⁰ These findings and others have led to a shift to evaluate the clinical benefits of radiation therapy given with concurrent chemotherapy for the primary treatment of advanced stage oropharyngeal squamous cell carcinoma.^20,21 Findings from a number of studies have since reported comparable efficacy and toxicity outcomes using this regimen with concurrent chemotherapy in patients with locally advanced head and neck squamous cell cancer.^22-24 Synchronous carboplatin chemotherapy was used effectively as an alternative to cisplatin with fewer potential adverse effects in the good prognosis group of patients with oropharyngeal squamous cell carcinoma.^25,26 For our 3 patients, we used carboplatin-based chemotherapy with concurrent advanced hyperfractionated radiation therapy techniques to successfully manage tonsillar squamous cell carcinoma and reduce renal toxicity and neuropathy.

Advanced radiation therapy techniques such as IMRT-IGRT are used routinely at the University Cancer and Diagnostic Centers in Houston, Texas, to manage a range of malignant cancers.²⁷ These innovative techniques have the potential to deliver highly conformal dose-intense radiation to targeted regions of disease, while sparing adjacent critical nonmalignant tissue. The improved shaping of high-dose distributions with IMRT-IGRT could mitigate treatment-related toxicities. For example, the use of advanced radiation therapy techniques has been associated with increased preservation of parotid salivary flow.^28-30 The use of advanced radiation therapy techniques in head and neck squamous cell carcinoma is growing, and early evidence confirms its ability to secure excellent local and regional disease control.^31,32 In this study, we have demonstrated that by using hyperfractionated conformal three-dimensional IMRT-IGRT we were able not only to manage advanced tonsillar squamous cell carcinoma and treat the malignant metastasis, but also spare adjacent critical organs that were not involved in the disease, thus reducing many of the detrimental side effects associated with hyperfractionated chemoradiation.

All 3 patients were followed for between 40 and 46 months. They continue to do extremely well without local recurrence of their disease, indicating a 100% disease control and overall survival rate. The disease control and survival outcomes for our patients with stage IVA disease compare favorably to other published reports in the literature.^33,34 Findings from a study by Prestwich and colleagues³³ of 41 patients with stage IV tonsillar carcinoma showed that the radiation therapy with concurrent chemotherapy achieved local and regional disease control in 91% of complete responders and an overall survival rate of 66% at 3 years. Similarly, Setton and colleagues³⁴ reported on 442 patients – 50% with tonsillar cancer, 46% with base-of-tongue cancer – who underwent IMRT and concurrent chemotherapy and who achieved a 3-year overall survival of 84.9%. Our study findings demonstrate that hyperfractionated conformal three-dimensional IMRT-IGRT with concurrent chemotherapy can be delivered safely and effectively to patients with advanced tonsillar squamous cell carcinoma.
 

Acknowledgment

The authors thank Ms June Lyliston, LVN, for editing and proofreading the manuscript.

Tonsillar carcinoma is the most common of the oropharyngeal malignancies of the head and neck region after thyroid and laryngeal carcinoma. Squamous cell carcinoma is the most frequent histologic type of these tumors.¹ Tonsillar tumors may originate in the oral cavity, oropharynx, hypopharynx, or larynx. In the United States, more than 5,000 new cases of oropharynx cancer are diagnosed annually.² Men are affected three to four times more often than are women, and the rate of incidence increases after the 4th decade of life.³ Surveillance, Epidemiology, and End Results data from 1975-2004 show that tonsillar squamous cell carcinoma has had one of the largest increases in the male-to-female incidence rate ratios.⁴ The overall incidence of tonsillar carcinoma is increasing, especially in the younger population, and this may be attributed to increasing rates of human papilloma virus.^5,6

Squamous cell carcinoma in the head and neck originate from subsites within the oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx.⁷ Traditionally, alcohol consumption and tobacco use were considered the most significant risk factors for the development of tonsillar cancer.⁸ More recently, however, the high-risk oncogenic human papilloma virus has emerged as a clinical entity in the pathogenesis of squamous cell carcinoma in the head and neck. Other risk factors include poor oral hygiene, mechanical irritation, chewing of betel quid preparations, and a lack of vegetables and fruits in the diet.^9-11 Squamous cell carcinoma of the oropharynx often presents late with lymph node involvement at the time of diagnosis. Nonspecific symptoms such as a sore throat and dysphagia can allow head and neck cancer to evade early detection. Many patients with tonsillar carcinoma present with advanced disease because early lesions are generally asymptomatic when small. This absence of symptoms is responsible for 67%-77% of patients presenting with tumors larger than 2.0 cm and often with regional nodal metastasis. At presentation, 45% of anterior tonsillar pillar lesions and 76% of tonsillar fossa lesions have clinically positive necks.¹²

Despite significant treatment advances, the management of advanced squamous cell carcinoma of the tonsil remains challenging. Historically, surgery was considered the standard of care for patients with tonsillar carcinoma with or without postoperative adjuvant radiotherapy. In locally advanced tonsillar carcinoma, extensive surgery with major tissue reconstruction was necessary, leading to speech dysfunction, cosmetic deformities, and difficulties in swallowing, all of which are detrimental to patient quality of life.¹³ Given the critical role of the oropharynx in speech and swallowing, nonsurgical therapy with organ-preserving chemoradiation has gained a greater role in the treatment of tonsil carcinoma.¹³ Over the past decade, innovations in radiation therapy techniques have led to the introduction of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) for the treatment of various cancers including tonsillar carcinoma.^14,15 IMRT is an advanced mode of conformal high-precision radiotherapy that uses computer-controlled multiple small radiation beams of varying intensities to deliver precise radiation doses to the target tissues while sparing adjacent healthy tissues.¹⁴ By incorporating three-dimensional computed-tomography (CT) or positron-emission–tomography (PET) imaging technology, IMRT allows the radiation dose to conform more precisely to the three-dimensional shape of the tumor while modulating the intensity of the radiation beam and minimizing its dose to those adjacent sensitive and unaffected organs. IGRT uses a range of two-, three-, and four-dimensional imaging techniques that improve the precision and accuracy of the delivery of the radiation dose to the targeted tumor tissue while minimizing the dose to the surrounding normal tissue during the course of radiation therapy (Figure 1). In this report, we present challenging cases of advanced tonsillar carcinoma and describe our experience in managing the disease using a hyperfractionated IMRT-IGRT based three-dimensional conformal radiation therapy protocol with concurrent chemotherapy.

Case presentations and summaries

Case 1

A 52-year-old white, nonsmoking man who worked in a research chemical laboratory, presented with complaints of throat pain and difficulty in swallowing. The patient had a history of asthma and allergies and had been seen by an ear, nose, and throat (ENT) specialist prior to his visit to our oncology center. A biopsy was performed on a right tonsillar mass measuring 2.7 x 3.6 cm. A computed-tomography (CT) scan showed 2 enlarged inhomogeneous lymph nodes measuring 2.9 cm and 1.7 cm. The nodes were well defined with no soft tissue edema. Neoplasm was favored as a diagnosis and biopsy of the mass was carried out. A biopsy specimen measuring 1.0 x 0.4 x 0.3 cm revealed a moderately differentiated infiltrating squamous cell carcinoma, which extended to the edge of the biopsy specimen. The patient’s Karnofsky performance status was 90% (ie, able to carry on normal activity; minor signs or symptoms of disease).

A CT scan of the chest was clear with no evidence of malignant involvement. A subsequent CT scan of the neck revealed a primary neoplasm of the right faucial tonsil measuring 3.3 x 3.0 cm and associated with right level II, level III, and level IV pathological lymphadenopathy. Positron-emission tomography (PET) imaging of the neck revealed a right tonsillar lesion of 2.7 x 3.0 cm involving the right parapharyngeal space (Figure 2, Case 1). The standardized uptake value (SUV) of the PET scan of the primary lesion was measured at 7.3. A cluster of right level II cervical nodes measuring 3.2 x 2.5 cm had an SUV of 3.5. A 1.0-cm right level III jugular node was also seen with an SUV of 1.6, and a right level IV lymph node measuring 1.5 x 1.0 cm was seen with an SUV of 1.8. No other lesions were noted. The tumor stage was T2N2bM0, a stage IVa disease.

Case 2

A 49-year-old black male presented with throat pain and a mass seen initially by his family physician. The patient had a history of tobacco use (at least 1 cigar a day) periodically for about 10 years and had quit cigar smoking 15 years prior to developing his disease. An initial evaluation indicated that the patient had a hypopharyngeal mass in the left inferior pole of his tonsil with near occlusion of the hypopharyngeal airway. His larynx could not be visualized because of the obstructive mass. A neck lymph node measuring 3.0 cm in the left jugulodigastric region was also noted. The patient’s Karnofsky performance status was 90%. Subsequently, the patient underwent excision of the right tonsil and left tonsillar region.

The pathology of the right tonsil was found to be benign. Histology of the left tonsil revealed invasive squamous cell carcinoma. The resected tumor size measured 3.7 x 2.7 x 2.5 cm. The tumor was moderately differentiated involving the deep surgical margins. No lymphovascular invasion was seen. A PET scan revealed a mass arising from the left tonsillar pillar measuring 3.6 x 2.6 x 3.3 cm with deviation of the epiglottis posteriorly nearing the left vallecula. In addition, multiple large cervical nodal lesions in the left level II nodal chain were seen, with the largest measuring 3.1 x 3.0 x 4.5 cm with an SUV of 3.4. Displacement of the left submandibular gland with several further enlarged level II lymph nodes was observed. In the region of left vallecula, there was soft tissue thickening with increased activity measuring 2.7 x 1.5 cm, likely crossing the midline with an SUV of 5.5. The rest of the neck was negative for metastatic involvement (Figure 2, Case 2). The tumor stage was T3N2Mx, a stage IVa disease.

The patient had a Port-A-Cath placed, which caused a hemothorax after placement of the port and delayed initiating his treatment. A pretreatment MRI scan of the neck revealed multiple conglomerate hypodense peripherally enhancing nodular areas in the left neck posterior to the left submandibular gland deep to the parotid tail worrisome for necrotic lymphadenopathy. The patient underwent a course of hyperfractionated IMRT-IGRT in 67 fractions of 120 cGy twice daily for a total dose of 8,040 cGy to the primary tumor site.¹⁶ The patient had a port and PEG tube prior to initiating his radiation therapy. He received IMRT-IGRT with concurrent chemotherapy that was selected based on the recommendation of his genomic testing.^17,18 The chemotherapy regimen used included carboplatin (300 mg weekly) and docetaxel (400 mg weekly). The patient had a treatment break because he was hospitalized for anemia and pancytopenia from his chemotherapy and he received supportive cancer care with epoetin alfa.A post therapy PET scan was negative for evidence of hypermetabolic malignancy; however, a 3.3 x 2.7 cm calcified lesion representing likely level III jugular lymph node exhibited no measurable activity at that time. The follow-up after 40 months indicated that the patient had no reported recurrence of the disease (Figure 2, Case 2). The patient’s demographics, tumor characteristics, and the treatment details are summarized in the Table.
 

Case 3

A 53-year-old white man, who had no smoking or tobacco history but who was exposed to chemicals including sulfuric acid, hydrogen chloride gas, and glycols at work, presented initially with a sore throat that became more painful over time. His ENT specialist referred him for a CT scan of the neck, which revealed a left-sided neck mass measuring 2.5 cm in diameter posterior to the submandibular gland and lateral to carotid sheath and anterior to the triangle (Figure 2, Case 3). The mass appeared to be encapsulated. There was a lobulated spherical mass in the left supraglottic area with formation of the airway of the pyriform sinus and additional anterior vascular involvement was noted. The mass measured 3.6 cm in transverse diameter.

A left tonsillar biopsy specimen measuring 1.4 x 0.6 x 0.2 cm was obtained, and its pathology revealed that the patient had a metastatic squamous cell carcinoma. The left neck lymph node mass aspiration also revealed the presence of squamous cell carcinoma. A PET-CT scan staging showed a dominant tonsillar fossa mass extending from the soft palate down to the pyriform sinus measuring 4.2 x 3.8 cm, with an SUV uptake of 7.3. There was a dominant left level II necrotic lymph node presence measuring 5.0 x 3.7 cm, with an SUV of 3.0. The patient’s Karnofsky performance status was 90%. The tumor stage was T4N2M0, a stage IVa disease. The patient received a course of conformal hyperfractionated IMRT-IGRT delivered to the primary tumor in 67 fractions at 120 cGy twice daily for a total dose of 8,040 cGy¹⁶ and concurrent carboplatin chemotherapy at a weekly dose of 200 mg.

After completion of his radiation therapy, chemotherapy was changed based on genomic testing from single agent to doublet with carboplatin (area under the curve (AUC) dose of 2 or 200 mg, weekly) plus docetaxel (25 mg/m² weekly for 3 weeks and 1 week off ).^17,18 A PET scan after chemoradiation therapy revealed a marked anatomical improvement in the primary neoplastic disease seen in the faucial tonsil. The tonsillar mass noted previously had almost completely resolved over the interval, with only a mild persistent asymmetrical thickening of around 1.5 cm, with a peak SUV of 2.0. A lymph node of 2.8 x 2.0 cm was present anterior to the left sternocleidomastoid muscle exhibiting SUV of only 1.8. No other abnormal lesions were noted (Figure 2, Case 3). The patient continues to do extremely well without local recurrence of the disease 46 months after radiation therapy (see Table for patient demographics, tumor characteristics, and therapy details.)
 

Discussion

The management of patients with primary squamous cell carcinoma of the oropharyngeal remains controversial. Traditionally, early-stage tonsillar squamous cell carcinoma was managed by a single modality treatment, either by surgery or radiation therapy, each showing similar efficacy and outcomes.¹⁹ For late-stage disease, a combined approach using surgery and radiation therapy was found to be superior to single modality treatment. However, surgery in conjugation with radiation therapy has been associated with significant toxicities compared with the radiation therapy alone.¹³Therefore, the use of radiation therapy without surgery is becoming more common with increasingly sophisticated radiation therapy techniques and organ preservation approach in patients with squamous cell carcinoma of the tonsil.

Findings from several studies have shown that in stage I or II oropharyngeal cancer, single modality treatment with radiation therapy achieves 80%-90% of local control of the disease, but poorer outcomes are reported for locally advanced stages III/IV with a local control rate of 63%-74%.²⁰ These findings and others have led to a shift to evaluate the clinical benefits of radiation therapy given with concurrent chemotherapy for the primary treatment of advanced stage oropharyngeal squamous cell carcinoma.^20,21 Findings from a number of studies have since reported comparable efficacy and toxicity outcomes using this regimen with concurrent chemotherapy in patients with locally advanced head and neck squamous cell cancer.^22-24 Synchronous carboplatin chemotherapy was used effectively as an alternative to cisplatin with fewer potential adverse effects in the good prognosis group of patients with oropharyngeal squamous cell carcinoma.^25,26 For our 3 patients, we used carboplatin-based chemotherapy with concurrent advanced hyperfractionated radiation therapy techniques to successfully manage tonsillar squamous cell carcinoma and reduce renal toxicity and neuropathy.

Advanced radiation therapy techniques such as IMRT-IGRT are used routinely at the University Cancer and Diagnostic Centers in Houston, Texas, to manage a range of malignant cancers.²⁷ These innovative techniques have the potential to deliver highly conformal dose-intense radiation to targeted regions of disease, while sparing adjacent critical nonmalignant tissue. The improved shaping of high-dose distributions with IMRT-IGRT could mitigate treatment-related toxicities. For example, the use of advanced radiation therapy techniques has been associated with increased preservation of parotid salivary flow.^28-30 The use of advanced radiation therapy techniques in head and neck squamous cell carcinoma is growing, and early evidence confirms its ability to secure excellent local and regional disease control.^31,32 In this study, we have demonstrated that by using hyperfractionated conformal three-dimensional IMRT-IGRT we were able not only to manage advanced tonsillar squamous cell carcinoma and treat the malignant metastasis, but also spare adjacent critical organs that were not involved in the disease, thus reducing many of the detrimental side effects associated with hyperfractionated chemoradiation.

All 3 patients were followed for between 40 and 46 months. They continue to do extremely well without local recurrence of their disease, indicating a 100% disease control and overall survival rate. The disease control and survival outcomes for our patients with stage IVA disease compare favorably to other published reports in the literature.^33,34 Findings from a study by Prestwich and colleagues³³ of 41 patients with stage IV tonsillar carcinoma showed that the radiation therapy with concurrent chemotherapy achieved local and regional disease control in 91% of complete responders and an overall survival rate of 66% at 3 years. Similarly, Setton and colleagues³⁴ reported on 442 patients – 50% with tonsillar cancer, 46% with base-of-tongue cancer – who underwent IMRT and concurrent chemotherapy and who achieved a 3-year overall survival of 84.9%. Our study findings demonstrate that hyperfractionated conformal three-dimensional IMRT-IGRT with concurrent chemotherapy can be delivered safely and effectively to patients with advanced tonsillar squamous cell carcinoma.
 

Acknowledgment

The authors thank Ms June Lyliston, LVN, for editing and proofreading the manuscript.

Tonsillar carcinoma is the most common of the oropharyngeal malignancies of the head and neck region after thyroid and laryngeal carcinoma. Squamous cell carcinoma is the most frequent histologic type of these tumors.¹ Tonsillar tumors may originate in the oral cavity, oropharynx, hypopharynx, or larynx. In the United States, more than 5,000 new cases of oropharynx cancer are diagnosed annually.² Men are affected three to four times more often than are women, and the rate of incidence increases after the 4th decade of life.³ Surveillance, Epidemiology, and End Results data from 1975-2004 show that tonsillar squamous cell carcinoma has had one of the largest increases in the male-to-female incidence rate ratios.⁴ The overall incidence of tonsillar carcinoma is increasing, especially in the younger population, and this may be attributed to increasing rates of human papilloma virus.^5,6

Squamous cell carcinoma in the head and neck originate from subsites within the oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx.⁷ Traditionally, alcohol consumption and tobacco use were considered the most significant risk factors for the development of tonsillar cancer.⁸ More recently, however, the high-risk oncogenic human papilloma virus has emerged as a clinical entity in the pathogenesis of squamous cell carcinoma in the head and neck. Other risk factors include poor oral hygiene, mechanical irritation, chewing of betel quid preparations, and a lack of vegetables and fruits in the diet.^9-11 Squamous cell carcinoma of the oropharynx often presents late with lymph node involvement at the time of diagnosis. Nonspecific symptoms such as a sore throat and dysphagia can allow head and neck cancer to evade early detection. Many patients with tonsillar carcinoma present with advanced disease because early lesions are generally asymptomatic when small. This absence of symptoms is responsible for 67%-77% of patients presenting with tumors larger than 2.0 cm and often with regional nodal metastasis. At presentation, 45% of anterior tonsillar pillar lesions and 76% of tonsillar fossa lesions have clinically positive necks.¹²

Despite significant treatment advances, the management of advanced squamous cell carcinoma of the tonsil remains challenging. Historically, surgery was considered the standard of care for patients with tonsillar carcinoma with or without postoperative adjuvant radiotherapy. In locally advanced tonsillar carcinoma, extensive surgery with major tissue reconstruction was necessary, leading to speech dysfunction, cosmetic deformities, and difficulties in swallowing, all of which are detrimental to patient quality of life.¹³ Given the critical role of the oropharynx in speech and swallowing, nonsurgical therapy with organ-preserving chemoradiation has gained a greater role in the treatment of tonsil carcinoma.¹³ Over the past decade, innovations in radiation therapy techniques have led to the introduction of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) for the treatment of various cancers including tonsillar carcinoma.^14,15 IMRT is an advanced mode of conformal high-precision radiotherapy that uses computer-controlled multiple small radiation beams of varying intensities to deliver precise radiation doses to the target tissues while sparing adjacent healthy tissues.¹⁴ By incorporating three-dimensional computed-tomography (CT) or positron-emission–tomography (PET) imaging technology, IMRT allows the radiation dose to conform more precisely to the three-dimensional shape of the tumor while modulating the intensity of the radiation beam and minimizing its dose to those adjacent sensitive and unaffected organs. IGRT uses a range of two-, three-, and four-dimensional imaging techniques that improve the precision and accuracy of the delivery of the radiation dose to the targeted tumor tissue while minimizing the dose to the surrounding normal tissue during the course of radiation therapy (Figure 1). In this report, we present challenging cases of advanced tonsillar carcinoma and describe our experience in managing the disease using a hyperfractionated IMRT-IGRT based three-dimensional conformal radiation therapy protocol with concurrent chemotherapy.

Case presentations and summaries

Case 1

A 52-year-old white, nonsmoking man who worked in a research chemical laboratory, presented with complaints of throat pain and difficulty in swallowing. The patient had a history of asthma and allergies and had been seen by an ear, nose, and throat (ENT) specialist prior to his visit to our oncology center. A biopsy was performed on a right tonsillar mass measuring 2.7 x 3.6 cm. A computed-tomography (CT) scan showed 2 enlarged inhomogeneous lymph nodes measuring 2.9 cm and 1.7 cm. The nodes were well defined with no soft tissue edema. Neoplasm was favored as a diagnosis and biopsy of the mass was carried out. A biopsy specimen measuring 1.0 x 0.4 x 0.3 cm revealed a moderately differentiated infiltrating squamous cell carcinoma, which extended to the edge of the biopsy specimen. The patient’s Karnofsky performance status was 90% (ie, able to carry on normal activity; minor signs or symptoms of disease).

A CT scan of the chest was clear with no evidence of malignant involvement. A subsequent CT scan of the neck revealed a primary neoplasm of the right faucial tonsil measuring 3.3 x 3.0 cm and associated with right level II, level III, and level IV pathological lymphadenopathy. Positron-emission tomography (PET) imaging of the neck revealed a right tonsillar lesion of 2.7 x 3.0 cm involving the right parapharyngeal space (Figure 2, Case 1). The standardized uptake value (SUV) of the PET scan of the primary lesion was measured at 7.3. A cluster of right level II cervical nodes measuring 3.2 x 2.5 cm had an SUV of 3.5. A 1.0-cm right level III jugular node was also seen with an SUV of 1.6, and a right level IV lymph node measuring 1.5 x 1.0 cm was seen with an SUV of 1.8. No other lesions were noted. The tumor stage was T2N2bM0, a stage IVa disease.

Case 2

A 49-year-old black male presented with throat pain and a mass seen initially by his family physician. The patient had a history of tobacco use (at least 1 cigar a day) periodically for about 10 years and had quit cigar smoking 15 years prior to developing his disease. An initial evaluation indicated that the patient had a hypopharyngeal mass in the left inferior pole of his tonsil with near occlusion of the hypopharyngeal airway. His larynx could not be visualized because of the obstructive mass. A neck lymph node measuring 3.0 cm in the left jugulodigastric region was also noted. The patient’s Karnofsky performance status was 90%. Subsequently, the patient underwent excision of the right tonsil and left tonsillar region.

The pathology of the right tonsil was found to be benign. Histology of the left tonsil revealed invasive squamous cell carcinoma. The resected tumor size measured 3.7 x 2.7 x 2.5 cm. The tumor was moderately differentiated involving the deep surgical margins. No lymphovascular invasion was seen. A PET scan revealed a mass arising from the left tonsillar pillar measuring 3.6 x 2.6 x 3.3 cm with deviation of the epiglottis posteriorly nearing the left vallecula. In addition, multiple large cervical nodal lesions in the left level II nodal chain were seen, with the largest measuring 3.1 x 3.0 x 4.5 cm with an SUV of 3.4. Displacement of the left submandibular gland with several further enlarged level II lymph nodes was observed. In the region of left vallecula, there was soft tissue thickening with increased activity measuring 2.7 x 1.5 cm, likely crossing the midline with an SUV of 5.5. The rest of the neck was negative for metastatic involvement (Figure 2, Case 2). The tumor stage was T3N2Mx, a stage IVa disease.

The patient had a Port-A-Cath placed, which caused a hemothorax after placement of the port and delayed initiating his treatment. A pretreatment MRI scan of the neck revealed multiple conglomerate hypodense peripherally enhancing nodular areas in the left neck posterior to the left submandibular gland deep to the parotid tail worrisome for necrotic lymphadenopathy. The patient underwent a course of hyperfractionated IMRT-IGRT in 67 fractions of 120 cGy twice daily for a total dose of 8,040 cGy to the primary tumor site.¹⁶ The patient had a port and PEG tube prior to initiating his radiation therapy. He received IMRT-IGRT with concurrent chemotherapy that was selected based on the recommendation of his genomic testing.^17,18 The chemotherapy regimen used included carboplatin (300 mg weekly) and docetaxel (400 mg weekly). The patient had a treatment break because he was hospitalized for anemia and pancytopenia from his chemotherapy and he received supportive cancer care with epoetin alfa.A post therapy PET scan was negative for evidence of hypermetabolic malignancy; however, a 3.3 x 2.7 cm calcified lesion representing likely level III jugular lymph node exhibited no measurable activity at that time. The follow-up after 40 months indicated that the patient had no reported recurrence of the disease (Figure 2, Case 2). The patient’s demographics, tumor characteristics, and the treatment details are summarized in the Table.
 

Case 3

A 53-year-old white man, who had no smoking or tobacco history but who was exposed to chemicals including sulfuric acid, hydrogen chloride gas, and glycols at work, presented initially with a sore throat that became more painful over time. His ENT specialist referred him for a CT scan of the neck, which revealed a left-sided neck mass measuring 2.5 cm in diameter posterior to the submandibular gland and lateral to carotid sheath and anterior to the triangle (Figure 2, Case 3). The mass appeared to be encapsulated. There was a lobulated spherical mass in the left supraglottic area with formation of the airway of the pyriform sinus and additional anterior vascular involvement was noted. The mass measured 3.6 cm in transverse diameter.

A left tonsillar biopsy specimen measuring 1.4 x 0.6 x 0.2 cm was obtained, and its pathology revealed that the patient had a metastatic squamous cell carcinoma. The left neck lymph node mass aspiration also revealed the presence of squamous cell carcinoma. A PET-CT scan staging showed a dominant tonsillar fossa mass extending from the soft palate down to the pyriform sinus measuring 4.2 x 3.8 cm, with an SUV uptake of 7.3. There was a dominant left level II necrotic lymph node presence measuring 5.0 x 3.7 cm, with an SUV of 3.0. The patient’s Karnofsky performance status was 90%. The tumor stage was T4N2M0, a stage IVa disease. The patient received a course of conformal hyperfractionated IMRT-IGRT delivered to the primary tumor in 67 fractions at 120 cGy twice daily for a total dose of 8,040 cGy¹⁶ and concurrent carboplatin chemotherapy at a weekly dose of 200 mg.

After completion of his radiation therapy, chemotherapy was changed based on genomic testing from single agent to doublet with carboplatin (area under the curve (AUC) dose of 2 or 200 mg, weekly) plus docetaxel (25 mg/m² weekly for 3 weeks and 1 week off ).^17,18 A PET scan after chemoradiation therapy revealed a marked anatomical improvement in the primary neoplastic disease seen in the faucial tonsil. The tonsillar mass noted previously had almost completely resolved over the interval, with only a mild persistent asymmetrical thickening of around 1.5 cm, with a peak SUV of 2.0. A lymph node of 2.8 x 2.0 cm was present anterior to the left sternocleidomastoid muscle exhibiting SUV of only 1.8. No other abnormal lesions were noted (Figure 2, Case 3). The patient continues to do extremely well without local recurrence of the disease 46 months after radiation therapy (see Table for patient demographics, tumor characteristics, and therapy details.)
 

Discussion

The management of patients with primary squamous cell carcinoma of the oropharyngeal remains controversial. Traditionally, early-stage tonsillar squamous cell carcinoma was managed by a single modality treatment, either by surgery or radiation therapy, each showing similar efficacy and outcomes.¹⁹ For late-stage disease, a combined approach using surgery and radiation therapy was found to be superior to single modality treatment. However, surgery in conjugation with radiation therapy has been associated with significant toxicities compared with the radiation therapy alone.¹³Therefore, the use of radiation therapy without surgery is becoming more common with increasingly sophisticated radiation therapy techniques and organ preservation approach in patients with squamous cell carcinoma of the tonsil.

Findings from several studies have shown that in stage I or II oropharyngeal cancer, single modality treatment with radiation therapy achieves 80%-90% of local control of the disease, but poorer outcomes are reported for locally advanced stages III/IV with a local control rate of 63%-74%.²⁰ These findings and others have led to a shift to evaluate the clinical benefits of radiation therapy given with concurrent chemotherapy for the primary treatment of advanced stage oropharyngeal squamous cell carcinoma.^20,21 Findings from a number of studies have since reported comparable efficacy and toxicity outcomes using this regimen with concurrent chemotherapy in patients with locally advanced head and neck squamous cell cancer.^22-24 Synchronous carboplatin chemotherapy was used effectively as an alternative to cisplatin with fewer potential adverse effects in the good prognosis group of patients with oropharyngeal squamous cell carcinoma.^25,26 For our 3 patients, we used carboplatin-based chemotherapy with concurrent advanced hyperfractionated radiation therapy techniques to successfully manage tonsillar squamous cell carcinoma and reduce renal toxicity and neuropathy.

Advanced radiation therapy techniques such as IMRT-IGRT are used routinely at the University Cancer and Diagnostic Centers in Houston, Texas, to manage a range of malignant cancers.²⁷ These innovative techniques have the potential to deliver highly conformal dose-intense radiation to targeted regions of disease, while sparing adjacent critical nonmalignant tissue. The improved shaping of high-dose distributions with IMRT-IGRT could mitigate treatment-related toxicities. For example, the use of advanced radiation therapy techniques has been associated with increased preservation of parotid salivary flow.^28-30 The use of advanced radiation therapy techniques in head and neck squamous cell carcinoma is growing, and early evidence confirms its ability to secure excellent local and regional disease control.^31,32 In this study, we have demonstrated that by using hyperfractionated conformal three-dimensional IMRT-IGRT we were able not only to manage advanced tonsillar squamous cell carcinoma and treat the malignant metastasis, but also spare adjacent critical organs that were not involved in the disease, thus reducing many of the detrimental side effects associated with hyperfractionated chemoradiation.

All 3 patients were followed for between 40 and 46 months. They continue to do extremely well without local recurrence of their disease, indicating a 100% disease control and overall survival rate. The disease control and survival outcomes for our patients with stage IVA disease compare favorably to other published reports in the literature.^33,34 Findings from a study by Prestwich and colleagues³³ of 41 patients with stage IV tonsillar carcinoma showed that the radiation therapy with concurrent chemotherapy achieved local and regional disease control in 91% of complete responders and an overall survival rate of 66% at 3 years. Similarly, Setton and colleagues³⁴ reported on 442 patients – 50% with tonsillar cancer, 46% with base-of-tongue cancer – who underwent IMRT and concurrent chemotherapy and who achieved a 3-year overall survival of 84.9%. Our study findings demonstrate that hyperfractionated conformal three-dimensional IMRT-IGRT with concurrent chemotherapy can be delivered safely and effectively to patients with advanced tonsillar squamous cell carcinoma.
 

Acknowledgment

The authors thank Ms June Lyliston, LVN, for editing and proofreading the manuscript.

THE CASE

A 67-year-old man presented to the hospital with subacute loss of vision in his left eye. The visual changes began 2 weeks earlier, with a central area of visual loss that had since progressed to near complete vision loss in the left eye.

Physical examination revealed patchy alopecia, a scaling and hyperkeratotic rash of his hands and feet (FIGURE 1), and blanching, erythematous plaques with associated scaling on the scrotum and glans penis. Ophthalmologic examination revealed 1/200 vision in his left eye with a large plaque occupying a substantial portion of the superior quadrant, smaller perifoveal plaques in both of his eyes, and a small infiltrate above the left optic nerve head (FIGURE 2). The patient also described fatigue, loss of taste, and an unintentional weight loss of 7 to 10 kg over the previous 6 months. He had seen his primary care provider 3 months prior for a burning sensation and scaling rash on his feet and hands, and was prescribed a topical steroid.

The patient’s social history was relevant for intermittent condom use with 6 lifetime female partners, but it was negative for new sexual partners, sexual contact with men, intravenous drug use, tattoos, blood transfusions, or travel outside the state. His medical history was significant for hypertension.

Routine laboratory tests were remarkable for an elevated erythrocyte sedimentation rate of 53 mm/hr (normal: 0-15 mm/hr) and a C-reactive protein of 5.3 mg/dL (normal: <0.5 mg/dL). Lumbar puncture revealed a white blood cell count of 133 cells/mcL (normal: 0-5 cells/mcL) with 87% lymphocytes and protein elevated to 63 mg/dL (normal: 15-40 mg/dL).

Other tests were ordered and included a serum fourth-generation ELISA to screen for human immunodeficiency virus (HIV)-1 and HIV-2, a cerebrospinal fluid venereal disease research laboratory (CSF-VDRL) test, a syphilis IgG screen and reflexive rapid plasma reagin (RPR) quantitation, and tests for cytomegalovirus antibodies, antinuclear antibody, rheumatoid factor, and Toxoplasma antibodies. Punch biopsy of the patient’s palmar skin changes was also performed; Steiner stain and spirochete immunohistochemical stain were applied to the sample. Magnetic resonance imaging of the brain and orbit was unremarkable.

THE DIAGNOSIS

The patient’s HIV screening test came back positive and was followed by confirmation of HIV-1 antibody, with an HIV viral load of 61,000 copies/mL and a CD4 count of 383 cells/mm³. The CSF-VDRL test and serum syphilis IgG were also positive, and the RPR titer was 1:16. The Steiner and spirochete immunohistochemical stains confirmed the presence of treponemes in the epidermis (FIGURE 3). Taken together, these findings confirmed a unifying diagnosis of ocular syphilis and syphilitic keratoderma with concomitant HIV.

DISCUSSION

After reaching an all-time low in the mid-1990s, several recent reports indicate that the incidence of syphilis is again increasing in North America.^1-3 In the United States, annual incidence rates have increased from 2.1/100,000 in 2000 to 5.3/100,000 in 2013.³ The increase has been most notable in younger men, men who have sex with men (MSM), and those with HIV infection.¹

A 2015 Centers for Disease Control and Prevention advisory highlights an unusual collection of cases of ocular syphilis, predominantly in HIV-infected MSM, from California and Washington.⁴ Disease sequelae in this outbreak have resulted in blindness.

A recent increase of syphilis in the United States has been most notable in younger men, men who have sex with men, and those with HIV infection.

HIV coinfection has been reported in 27.5% of males and 12.4% of females with new diagnoses of syphilis.¹ Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.^1,5,6 Cutaneous findings such as malignant syphilis (characterized by ulcerating, pustular, or rupioid lesions), as well as other atypical rashes mimicking eczema, leprosy, mycosis fungoides, or keratoderma blenorrhagicum, may all be more common in those with HIV coinfection.⁶ Ageusia or dysgeusia is rare in syphilis, and to our knowledge has only been described with concomitant oral lesions.⁷

MANAGEMENT

Our patient was treated with a continuous daily infusion of 20 million units of penicillin G for 14 days, one drop of 1% ocular prednisolone in each eye 4 times daily for 4 weeks, one drop of 2% cyclopentoate in each eye 2 times daily for 4 weeks, and 60 mg/d of oral prednisone tapered over 3 months. For the HIV infection, he was started on antiretroviral therapy soon after diagnosis.

Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.

Within 48 hours of initiating penicillin, he reported a marked improvement in vision and regained the ability to taste. After one week of therapy, near resolution of the palmoplantar rash was noted and the patient was discharged on hospital Day 8. At a 3-month follow-up visit, he was asymptomatic, with return of normal sensation. Repeat ophthalmologic examination showed no evidence of disease.

THE TAKEAWAY

This case complements other sporadic reports of symptoms of ocular and cutaneous syphilis serving as the initial presentation of HIV infection.^5,8,9 Risk-factor based screening for HIV often leads to missed diagnoses, and early recognition of this constellation of symptoms may aid in prompt diagnosis and treatment of syphilis and HIV.¹⁰

THE CASE

A 67-year-old man presented to the hospital with subacute loss of vision in his left eye. The visual changes began 2 weeks earlier, with a central area of visual loss that had since progressed to near complete vision loss in the left eye.

Physical examination revealed patchy alopecia, a scaling and hyperkeratotic rash of his hands and feet (FIGURE 1), and blanching, erythematous plaques with associated scaling on the scrotum and glans penis. Ophthalmologic examination revealed 1/200 vision in his left eye with a large plaque occupying a substantial portion of the superior quadrant, smaller perifoveal plaques in both of his eyes, and a small infiltrate above the left optic nerve head (FIGURE 2). The patient also described fatigue, loss of taste, and an unintentional weight loss of 7 to 10 kg over the previous 6 months. He had seen his primary care provider 3 months prior for a burning sensation and scaling rash on his feet and hands, and was prescribed a topical steroid.

The patient’s social history was relevant for intermittent condom use with 6 lifetime female partners, but it was negative for new sexual partners, sexual contact with men, intravenous drug use, tattoos, blood transfusions, or travel outside the state. His medical history was significant for hypertension.

Routine laboratory tests were remarkable for an elevated erythrocyte sedimentation rate of 53 mm/hr (normal: 0-15 mm/hr) and a C-reactive protein of 5.3 mg/dL (normal: <0.5 mg/dL). Lumbar puncture revealed a white blood cell count of 133 cells/mcL (normal: 0-5 cells/mcL) with 87% lymphocytes and protein elevated to 63 mg/dL (normal: 15-40 mg/dL).

Other tests were ordered and included a serum fourth-generation ELISA to screen for human immunodeficiency virus (HIV)-1 and HIV-2, a cerebrospinal fluid venereal disease research laboratory (CSF-VDRL) test, a syphilis IgG screen and reflexive rapid plasma reagin (RPR) quantitation, and tests for cytomegalovirus antibodies, antinuclear antibody, rheumatoid factor, and Toxoplasma antibodies. Punch biopsy of the patient’s palmar skin changes was also performed; Steiner stain and spirochete immunohistochemical stain were applied to the sample. Magnetic resonance imaging of the brain and orbit was unremarkable.

THE DIAGNOSIS

The patient’s HIV screening test came back positive and was followed by confirmation of HIV-1 antibody, with an HIV viral load of 61,000 copies/mL and a CD4 count of 383 cells/mm³. The CSF-VDRL test and serum syphilis IgG were also positive, and the RPR titer was 1:16. The Steiner and spirochete immunohistochemical stains confirmed the presence of treponemes in the epidermis (FIGURE 3). Taken together, these findings confirmed a unifying diagnosis of ocular syphilis and syphilitic keratoderma with concomitant HIV.

DISCUSSION

After reaching an all-time low in the mid-1990s, several recent reports indicate that the incidence of syphilis is again increasing in North America.^1-3 In the United States, annual incidence rates have increased from 2.1/100,000 in 2000 to 5.3/100,000 in 2013.³ The increase has been most notable in younger men, men who have sex with men (MSM), and those with HIV infection.¹

A 2015 Centers for Disease Control and Prevention advisory highlights an unusual collection of cases of ocular syphilis, predominantly in HIV-infected MSM, from California and Washington.⁴ Disease sequelae in this outbreak have resulted in blindness.

A recent increase of syphilis in the United States has been most notable in younger men, men who have sex with men, and those with HIV infection.

HIV coinfection has been reported in 27.5% of males and 12.4% of females with new diagnoses of syphilis.¹ Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.^1,5,6 Cutaneous findings such as malignant syphilis (characterized by ulcerating, pustular, or rupioid lesions), as well as other atypical rashes mimicking eczema, leprosy, mycosis fungoides, or keratoderma blenorrhagicum, may all be more common in those with HIV coinfection.⁶ Ageusia or dysgeusia is rare in syphilis, and to our knowledge has only been described with concomitant oral lesions.⁷

MANAGEMENT

Our patient was treated with a continuous daily infusion of 20 million units of penicillin G for 14 days, one drop of 1% ocular prednisolone in each eye 4 times daily for 4 weeks, one drop of 2% cyclopentoate in each eye 2 times daily for 4 weeks, and 60 mg/d of oral prednisone tapered over 3 months. For the HIV infection, he was started on antiretroviral therapy soon after diagnosis.

Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.

Within 48 hours of initiating penicillin, he reported a marked improvement in vision and regained the ability to taste. After one week of therapy, near resolution of the palmoplantar rash was noted and the patient was discharged on hospital Day 8. At a 3-month follow-up visit, he was asymptomatic, with return of normal sensation. Repeat ophthalmologic examination showed no evidence of disease.

THE TAKEAWAY

This case complements other sporadic reports of symptoms of ocular and cutaneous syphilis serving as the initial presentation of HIV infection.^5,8,9 Risk-factor based screening for HIV often leads to missed diagnoses, and early recognition of this constellation of symptoms may aid in prompt diagnosis and treatment of syphilis and HIV.¹⁰

THE CASE

A 67-year-old man presented to the hospital with subacute loss of vision in his left eye. The visual changes began 2 weeks earlier, with a central area of visual loss that had since progressed to near complete vision loss in the left eye.

Physical examination revealed patchy alopecia, a scaling and hyperkeratotic rash of his hands and feet (FIGURE 1), and blanching, erythematous plaques with associated scaling on the scrotum and glans penis. Ophthalmologic examination revealed 1/200 vision in his left eye with a large plaque occupying a substantial portion of the superior quadrant, smaller perifoveal plaques in both of his eyes, and a small infiltrate above the left optic nerve head (FIGURE 2). The patient also described fatigue, loss of taste, and an unintentional weight loss of 7 to 10 kg over the previous 6 months. He had seen his primary care provider 3 months prior for a burning sensation and scaling rash on his feet and hands, and was prescribed a topical steroid.

The patient’s social history was relevant for intermittent condom use with 6 lifetime female partners, but it was negative for new sexual partners, sexual contact with men, intravenous drug use, tattoos, blood transfusions, or travel outside the state. His medical history was significant for hypertension.

Routine laboratory tests were remarkable for an elevated erythrocyte sedimentation rate of 53 mm/hr (normal: 0-15 mm/hr) and a C-reactive protein of 5.3 mg/dL (normal: <0.5 mg/dL). Lumbar puncture revealed a white blood cell count of 133 cells/mcL (normal: 0-5 cells/mcL) with 87% lymphocytes and protein elevated to 63 mg/dL (normal: 15-40 mg/dL).

Other tests were ordered and included a serum fourth-generation ELISA to screen for human immunodeficiency virus (HIV)-1 and HIV-2, a cerebrospinal fluid venereal disease research laboratory (CSF-VDRL) test, a syphilis IgG screen and reflexive rapid plasma reagin (RPR) quantitation, and tests for cytomegalovirus antibodies, antinuclear antibody, rheumatoid factor, and Toxoplasma antibodies. Punch biopsy of the patient’s palmar skin changes was also performed; Steiner stain and spirochete immunohistochemical stain were applied to the sample. Magnetic resonance imaging of the brain and orbit was unremarkable.

THE DIAGNOSIS

The patient’s HIV screening test came back positive and was followed by confirmation of HIV-1 antibody, with an HIV viral load of 61,000 copies/mL and a CD4 count of 383 cells/mm³. The CSF-VDRL test and serum syphilis IgG were also positive, and the RPR titer was 1:16. The Steiner and spirochete immunohistochemical stains confirmed the presence of treponemes in the epidermis (FIGURE 3). Taken together, these findings confirmed a unifying diagnosis of ocular syphilis and syphilitic keratoderma with concomitant HIV.

DISCUSSION

After reaching an all-time low in the mid-1990s, several recent reports indicate that the incidence of syphilis is again increasing in North America.^1-3 In the United States, annual incidence rates have increased from 2.1/100,000 in 2000 to 5.3/100,000 in 2013.³ The increase has been most notable in younger men, men who have sex with men (MSM), and those with HIV infection.¹

A 2015 Centers for Disease Control and Prevention advisory highlights an unusual collection of cases of ocular syphilis, predominantly in HIV-infected MSM, from California and Washington.⁴ Disease sequelae in this outbreak have resulted in blindness.

A recent increase of syphilis in the United States has been most notable in younger men, men who have sex with men, and those with HIV infection.

HIV coinfection has been reported in 27.5% of males and 12.4% of females with new diagnoses of syphilis.¹ Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.^1,5,6 Cutaneous findings such as malignant syphilis (characterized by ulcerating, pustular, or rupioid lesions), as well as other atypical rashes mimicking eczema, leprosy, mycosis fungoides, or keratoderma blenorrhagicum, may all be more common in those with HIV coinfection.⁶ Ageusia or dysgeusia is rare in syphilis, and to our knowledge has only been described with concomitant oral lesions.⁷

MANAGEMENT

Our patient was treated with a continuous daily infusion of 20 million units of penicillin G for 14 days, one drop of 1% ocular prednisolone in each eye 4 times daily for 4 weeks, one drop of 2% cyclopentoate in each eye 2 times daily for 4 weeks, and 60 mg/d of oral prednisone tapered over 3 months. For the HIV infection, he was started on antiretroviral therapy soon after diagnosis.

Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.

Within 48 hours of initiating penicillin, he reported a marked improvement in vision and regained the ability to taste. After one week of therapy, near resolution of the palmoplantar rash was noted and the patient was discharged on hospital Day 8. At a 3-month follow-up visit, he was asymptomatic, with return of normal sensation. Repeat ophthalmologic examination showed no evidence of disease.

THE TAKEAWAY

This case complements other sporadic reports of symptoms of ocular and cutaneous syphilis serving as the initial presentation of HIV infection.^5,8,9 Risk-factor based screening for HIV often leads to missed diagnoses, and early recognition of this constellation of symptoms may aid in prompt diagnosis and treatment of syphilis and HIV.¹⁰

THE CASE

A 34-year-old healthy woman presented to the breast surgical oncology clinic with skin changes to her left nipple after being referred by her primary care provider. She attributed the skin changes to shearing from breastfeeding her third child 5 years earlier. Physical examination revealed an erythematous and friable nipple with loss of protrusion (FIGURE 1). The patient reported routine bleeding from her nipple, but said the skin changes had remained stable and denied any breast masses. The patient’s last mammogram was 2.5 years earlier and had only been remarkable for bilateral benign calcifications.

THE DIAGNOSIS

A screening mammogram showed flattening and retraction of the left nipple, as well as suspicious left breast calcifications (BIRADS [Breast Imaging Reporting and Data System] 4 classification, FIGURE 2). A subsequent diagnostic mammogram showed a cluster of fine pleomorphic calcifications in the upper inner quadrant of the left breast (FIGURE 3). A stereotactic core needle biopsy was performed, and results confirmed a diagnosis of high-grade, estrogen receptor-negative, ductal carcinoma in situ (DCIS).

Subsequent work-up included a staging magnetic resonance imaging (MRI) and a left areola punch biopsy. MRI revealed an absence of a normal left nipple and extensive focal clumped non-mass enhancement in the area of the known DCIS (FIGURE 4). Biopsy results revealed enlarged atypical single cells within the epidermis. The cells stained positive for mucicarmine and cytokeratin 7 and negative for carcinoembryonic antigen and S-100 protein. This ruled out a pagetoid spread of melanoma and confirmed a diagnosis of Paget’s disease (PD) of the breast.

DISCUSSION

PD of the breast is a rare disorder (accounting for 0.5%-5% of all breast cancers) that is clinically characterized by erythematous, eczematous changes of the nipple-areolar complex (NAC).^1-7 PD is almost always unilateral and symptoms include pain, burning, and itching of the nipple, often with bloody nipple discharge.^1,3-8

PD can be mistaken for benign skin changes and diagnosed as dermatitis or eczema.^3,5 Because such changes often resolve temporarily with the use of topical corticosteroids or no treatment at all,² diagnosis is often delayed. PD of the breast is associated with underlying ductal carcinoma in 90% to 100% of cases,^1,2,5,8 so any skin pathology involving the nipple should be assumed to be PD until proven otherwise.

When no palpable mass is noted on physical exam, DCIS is usually found centrally behind the nipple.¹ In addition, lymph node involvement is noted in about 60% of cases.¹

Confirm the diagnosis with these tests

Diagnosis of PD of the breast is primarily clinical, with pathologic confirmation. All patients with clinically suspected PD should be evaluated using the following tests to determine the need for biopsy.

Mammography with magnification views of the NAC will show thickening, retraction, or flattening of the nipple, microcalcifications of the retroareolar region, and/or a subareolar mass.³ However, because breast tissue appears normal on mammography in 22% to 71% of patients,^1,5 the use of ultrasound and potentially MRI to delineate the extent of disease is warranted.

Ultrasound. While there are no characteristic findings on ultrasound, it can be used to detect dilation of the subareolar ducts, calcification, or a mass.⁴

MRI has a higher sensitivity for detection of occult disease.^2,5 MRI is also useful in the evaluation of axillary node asymmetry, which may indicate nodal involvement.²

Treatment is variable and has not been widely studied

Due to the rarity of PD, there are no randomized studies to point toward optimal treatment strategies.⁷ Treatment for PD is typically surgical and often involves mastectomy, with or without axillary node dissection.¹ Retrospective analyses have demonstrated that central lumpectomy (complete resection of the NAC and underlying disease) with radiation therapy has outcomes similar to mastectomy;² however, the cosmetic result is sometimes unfavorable.

In cases where there is no palpable mass nor mammographic findings of disease, breast conserving therapy may be considered. If chemotherapy is considered, it should be chosen based on the receptor profile of the disease and subsequent oncotype scoring.

The prognosis for patients with PD who are adequately treated and remain disease free after 5 years is excellent. These patients are likely to have achieved cure.²

Our patient underwent left simple mastectomy with sentinel node biopsy and tissue expander placement. Her postoperative course was uncomplicated, and she was discharged home on postoperative Day 1. On final pathology, the 2 sentinel nodes were disease free. The left mastectomy specimen was found to have high-grade DCIS with clear surgical margins. The area of involvement was found to be 3.5 cm × 3 cm in size and had clear skin margins. At follow-up one year later, the patient was doing well with no evidence of disease. She subsequently underwent implant insertion.

THE TAKEAWAY

This case highlights the unique progression of undiagnosed PD of the breast. It also highlights the importance of ruling out PD when skin changes involving the nipple are present, despite other possible explanations for those changes. This case in particular was complicated by a proximal history of breastfeeding, which erroneously provided an explanation and false reassurance for the primary care provider and patient.

Due to the common association of PD of the breast with underlying DCIS or invasive cancer, the most important aspect of care is early diagnostic work-up and appropriate referral. Primary care physicians have a unique role in obtaining appropriate early diagnostic tests (including mammogram and ultrasound) and making the necessary referral to a breast specialist in the presence of an abnormal physical exam involving the NAC, even in the absence of a palpable mass. In our patient’s case, punch biopsy of the NAC would have been appropriate at the first signs of friable, erythematous changes.

THE CASE

A 34-year-old healthy woman presented to the breast surgical oncology clinic with skin changes to her left nipple after being referred by her primary care provider. She attributed the skin changes to shearing from breastfeeding her third child 5 years earlier. Physical examination revealed an erythematous and friable nipple with loss of protrusion (FIGURE 1). The patient reported routine bleeding from her nipple, but said the skin changes had remained stable and denied any breast masses. The patient’s last mammogram was 2.5 years earlier and had only been remarkable for bilateral benign calcifications.

THE DIAGNOSIS

A screening mammogram showed flattening and retraction of the left nipple, as well as suspicious left breast calcifications (BIRADS [Breast Imaging Reporting and Data System] 4 classification, FIGURE 2). A subsequent diagnostic mammogram showed a cluster of fine pleomorphic calcifications in the upper inner quadrant of the left breast (FIGURE 3). A stereotactic core needle biopsy was performed, and results confirmed a diagnosis of high-grade, estrogen receptor-negative, ductal carcinoma in situ (DCIS).

Subsequent work-up included a staging magnetic resonance imaging (MRI) and a left areola punch biopsy. MRI revealed an absence of a normal left nipple and extensive focal clumped non-mass enhancement in the area of the known DCIS (FIGURE 4). Biopsy results revealed enlarged atypical single cells within the epidermis. The cells stained positive for mucicarmine and cytokeratin 7 and negative for carcinoembryonic antigen and S-100 protein. This ruled out a pagetoid spread of melanoma and confirmed a diagnosis of Paget’s disease (PD) of the breast.

DISCUSSION

PD of the breast is a rare disorder (accounting for 0.5%-5% of all breast cancers) that is clinically characterized by erythematous, eczematous changes of the nipple-areolar complex (NAC).^1-7 PD is almost always unilateral and symptoms include pain, burning, and itching of the nipple, often with bloody nipple discharge.^1,3-8

PD can be mistaken for benign skin changes and diagnosed as dermatitis or eczema.^3,5 Because such changes often resolve temporarily with the use of topical corticosteroids or no treatment at all,² diagnosis is often delayed. PD of the breast is associated with underlying ductal carcinoma in 90% to 100% of cases,^1,2,5,8 so any skin pathology involving the nipple should be assumed to be PD until proven otherwise.

When no palpable mass is noted on physical exam, DCIS is usually found centrally behind the nipple.¹ In addition, lymph node involvement is noted in about 60% of cases.¹

Confirm the diagnosis with these tests

Diagnosis of PD of the breast is primarily clinical, with pathologic confirmation. All patients with clinically suspected PD should be evaluated using the following tests to determine the need for biopsy.

Mammography with magnification views of the NAC will show thickening, retraction, or flattening of the nipple, microcalcifications of the retroareolar region, and/or a subareolar mass.³ However, because breast tissue appears normal on mammography in 22% to 71% of patients,^1,5 the use of ultrasound and potentially MRI to delineate the extent of disease is warranted.

Ultrasound. While there are no characteristic findings on ultrasound, it can be used to detect dilation of the subareolar ducts, calcification, or a mass.⁴

MRI has a higher sensitivity for detection of occult disease.^2,5 MRI is also useful in the evaluation of axillary node asymmetry, which may indicate nodal involvement.²

Treatment is variable and has not been widely studied

Due to the rarity of PD, there are no randomized studies to point toward optimal treatment strategies.⁷ Treatment for PD is typically surgical and often involves mastectomy, with or without axillary node dissection.¹ Retrospective analyses have demonstrated that central lumpectomy (complete resection of the NAC and underlying disease) with radiation therapy has outcomes similar to mastectomy;² however, the cosmetic result is sometimes unfavorable.

In cases where there is no palpable mass nor mammographic findings of disease, breast conserving therapy may be considered. If chemotherapy is considered, it should be chosen based on the receptor profile of the disease and subsequent oncotype scoring.

The prognosis for patients with PD who are adequately treated and remain disease free after 5 years is excellent. These patients are likely to have achieved cure.²

Our patient underwent left simple mastectomy with sentinel node biopsy and tissue expander placement. Her postoperative course was uncomplicated, and she was discharged home on postoperative Day 1. On final pathology, the 2 sentinel nodes were disease free. The left mastectomy specimen was found to have high-grade DCIS with clear surgical margins. The area of involvement was found to be 3.5 cm × 3 cm in size and had clear skin margins. At follow-up one year later, the patient was doing well with no evidence of disease. She subsequently underwent implant insertion.

THE TAKEAWAY

This case highlights the unique progression of undiagnosed PD of the breast. It also highlights the importance of ruling out PD when skin changes involving the nipple are present, despite other possible explanations for those changes. This case in particular was complicated by a proximal history of breastfeeding, which erroneously provided an explanation and false reassurance for the primary care provider and patient.

Due to the common association of PD of the breast with underlying DCIS or invasive cancer, the most important aspect of care is early diagnostic work-up and appropriate referral. Primary care physicians have a unique role in obtaining appropriate early diagnostic tests (including mammogram and ultrasound) and making the necessary referral to a breast specialist in the presence of an abnormal physical exam involving the NAC, even in the absence of a palpable mass. In our patient’s case, punch biopsy of the NAC would have been appropriate at the first signs of friable, erythematous changes.

THE CASE

A 34-year-old healthy woman presented to the breast surgical oncology clinic with skin changes to her left nipple after being referred by her primary care provider. She attributed the skin changes to shearing from breastfeeding her third child 5 years earlier. Physical examination revealed an erythematous and friable nipple with loss of protrusion (FIGURE 1). The patient reported routine bleeding from her nipple, but said the skin changes had remained stable and denied any breast masses. The patient’s last mammogram was 2.5 years earlier and had only been remarkable for bilateral benign calcifications.

THE DIAGNOSIS

A screening mammogram showed flattening and retraction of the left nipple, as well as suspicious left breast calcifications (BIRADS [Breast Imaging Reporting and Data System] 4 classification, FIGURE 2). A subsequent diagnostic mammogram showed a cluster of fine pleomorphic calcifications in the upper inner quadrant of the left breast (FIGURE 3). A stereotactic core needle biopsy was performed, and results confirmed a diagnosis of high-grade, estrogen receptor-negative, ductal carcinoma in situ (DCIS).

Subsequent work-up included a staging magnetic resonance imaging (MRI) and a left areola punch biopsy. MRI revealed an absence of a normal left nipple and extensive focal clumped non-mass enhancement in the area of the known DCIS (FIGURE 4). Biopsy results revealed enlarged atypical single cells within the epidermis. The cells stained positive for mucicarmine and cytokeratin 7 and negative for carcinoembryonic antigen and S-100 protein. This ruled out a pagetoid spread of melanoma and confirmed a diagnosis of Paget’s disease (PD) of the breast.

DISCUSSION

PD of the breast is a rare disorder (accounting for 0.5%-5% of all breast cancers) that is clinically characterized by erythematous, eczematous changes of the nipple-areolar complex (NAC).^1-7 PD is almost always unilateral and symptoms include pain, burning, and itching of the nipple, often with bloody nipple discharge.^1,3-8

PD can be mistaken for benign skin changes and diagnosed as dermatitis or eczema.^3,5 Because such changes often resolve temporarily with the use of topical corticosteroids or no treatment at all,² diagnosis is often delayed. PD of the breast is associated with underlying ductal carcinoma in 90% to 100% of cases,^1,2,5,8 so any skin pathology involving the nipple should be assumed to be PD until proven otherwise.

When no palpable mass is noted on physical exam, DCIS is usually found centrally behind the nipple.¹ In addition, lymph node involvement is noted in about 60% of cases.¹

Confirm the diagnosis with these tests

Diagnosis of PD of the breast is primarily clinical, with pathologic confirmation. All patients with clinically suspected PD should be evaluated using the following tests to determine the need for biopsy.

Mammography with magnification views of the NAC will show thickening, retraction, or flattening of the nipple, microcalcifications of the retroareolar region, and/or a subareolar mass.³ However, because breast tissue appears normal on mammography in 22% to 71% of patients,^1,5 the use of ultrasound and potentially MRI to delineate the extent of disease is warranted.

Ultrasound. While there are no characteristic findings on ultrasound, it can be used to detect dilation of the subareolar ducts, calcification, or a mass.⁴

MRI has a higher sensitivity for detection of occult disease.^2,5 MRI is also useful in the evaluation of axillary node asymmetry, which may indicate nodal involvement.²

Treatment is variable and has not been widely studied

Due to the rarity of PD, there are no randomized studies to point toward optimal treatment strategies.⁷ Treatment for PD is typically surgical and often involves mastectomy, with or without axillary node dissection.¹ Retrospective analyses have demonstrated that central lumpectomy (complete resection of the NAC and underlying disease) with radiation therapy has outcomes similar to mastectomy;² however, the cosmetic result is sometimes unfavorable.

In cases where there is no palpable mass nor mammographic findings of disease, breast conserving therapy may be considered. If chemotherapy is considered, it should be chosen based on the receptor profile of the disease and subsequent oncotype scoring.

The prognosis for patients with PD who are adequately treated and remain disease free after 5 years is excellent. These patients are likely to have achieved cure.²

Our patient underwent left simple mastectomy with sentinel node biopsy and tissue expander placement. Her postoperative course was uncomplicated, and she was discharged home on postoperative Day 1. On final pathology, the 2 sentinel nodes were disease free. The left mastectomy specimen was found to have high-grade DCIS with clear surgical margins. The area of involvement was found to be 3.5 cm × 3 cm in size and had clear skin margins. At follow-up one year later, the patient was doing well with no evidence of disease. She subsequently underwent implant insertion.

THE TAKEAWAY

This case highlights the unique progression of undiagnosed PD of the breast. It also highlights the importance of ruling out PD when skin changes involving the nipple are present, despite other possible explanations for those changes. This case in particular was complicated by a proximal history of breastfeeding, which erroneously provided an explanation and false reassurance for the primary care provider and patient.

Due to the common association of PD of the breast with underlying DCIS or invasive cancer, the most important aspect of care is early diagnostic work-up and appropriate referral. Primary care physicians have a unique role in obtaining appropriate early diagnostic tests (including mammogram and ultrasound) and making the necessary referral to a breast specialist in the presence of an abnormal physical exam involving the NAC, even in the absence of a palpable mass. In our patient’s case, punch biopsy of the NAC would have been appropriate at the first signs of friable, erythematous changes.

Lesions of porokeratosis are thought to arise from disordered keratinization, though the exact pathogenesis remains uncertain. At least 5 clinical subtypes of porokeratosis have been identified: porokeratosis of Mibelli, disseminated superficial porokeratosis and disseminated superficial actinic porokeratosis (DSAP), linear porokeratosis, punctuate porokeratosis, and porokeratosis palmaris et plantaris disseminata (PPPD).^1,2 Linear porokeratosis is a rare subtype with a clinical differential diagnosis that includes lichen striatus, linear lichen planus, linear verrucous epidermal nevus, segmental Darier disease, and incontinentia pigmenti.³ Definitive diagnosis of linear porokeratosis is made by histopathologic examination demonstrating a cornoid lamella, defined as a column of parakeratotic cells that lies at 45°to the surface of the epidermis and contains pyknotic basophilic nuclei.⁴ Patients with linear porokeratosis typically develop lesions along the lines of Blaschko in infancy or childhood.^5,6 Among the different subtypes of porokeratosis, linear porokeratosis demonstrates the highest rate of malignant transformation, therefore requiring close clinical observation.⁷

Case Report

An 83-year-old woman presented to the outpatient clinic with a large linear plaque on the right leg that had been present since birth. Ten years prior to presentation, a portion of the lesion started to bleed; biopsy of the area was performed by an outside provider demonstrating squamous cell carcinoma (SCC), which was treated with wide local excision. One year prior to presentation, a separate portion of the plaque was biopsied by an outside provider and another diagnosis of SCC was made.

On examination performed during the initial presentation to our clinic, there was a well-demarcated tan to violaceous linear plaque present at the lower buttock and extending along the posterior leg to the skin overlying the Achilles tendon and dorsal aspect of the right foot. Within the plaque, there were areas of atrophy and areas of inflammation, induration, and hyperkeratosis (Figures 1 and 2). Two punch biopsies were performed: one from the edge of the plaque and one from a hyperkeratotic region within the plaque. Histology from the edge of the plaque demonstrated a cornoid lamella, consistent with a porokeratosis (Figure 3), whereas the histology from the hyperkeratotic region demonstrated a lichenoid infiltrate (Figure 4).

Several treatment options directed at the entire lesion were offered to the patient, but she declined these therapies and opted to address only those areas with clinical features of SCC, such as hyperkeratosis, bleeding, and rapid growth. Although biopsies performed by an outside provider were consistent with SCC, it had not been detected on biopsy performed during her initial visit to our clinic.

The patient was educated on the risk associated with her condition and instructed to follow up every 6 months to monitor for the development of SCC.

Comment

Porokeratosis is a disorder of keratinization with at least 5 clinical subtypes that share histologic similarities: porokeratosis of Mibelli, disseminated superficial porokeratosis and DSAP, linear porokeratosis, punctate porokeratosis, and PPPD.^1,2 Other less common variants of porokeratosis include porokeratosis ptychotropica (a verrucous variant confined to the perianal area) and congenital unilateral linear porokeratosis.^8,9

Linear porokeratosis appears in infancy or childhood with plaques that follow the lines of Blaschko.^5,6 Most commonly, it presents unilaterally with annular plaques and linear hyperkeratotic papules that preferentially affect the extremities, though it also may present in a more generalized form or appear in a zosteriform pattern.^10,11 Linear porokeratosis affects fewer than 20,000 individuals in the United States and accounts for fewer than 13% of all porokeratosis cases.^12,13

Despite its relatively low prevalence, early identification of linear porokeratosis is important due to its high oncogenic potential, with malignant transformation to basal cell carcinoma or, more commonly, SCC reported in 19% of reported cases.^1,5,7,14 The malignant transformation rate of linear porokeratosis is reported to be higher than rates seen in other porokeratosis subtypes (9.5%, 7.6%, and 3.4% for PPPD, porokeratosis of Mibelli, and DSAP, respectively).⁷ The risk of malignant transformation from porokeratosis increases with exposure to ionizing radiation, duration of the lesion, larger or coalescing lesions, and advanced age.^7,15,16 Histologic studies have provided support for correlation between lesion size and oncogenic potential, with greater numbers of mitotic cells and more abnormal DNA ploidy seen in larger lesions.¹⁷

Histopathology
All subtypes of porokeratosis share certain histopathologic features that aid in the diagnosis of the disorder.¹⁸ Identification of the clinically observed hyperkeratotic ridged border or cornoid lamella is the primary means of definitively diagnosing porokeratosis; however, cornoid lamellae may be observed in other conditions, including verruca vulgaris and actinic keratosis.^4,14

The cornoid lamella appears as a skewed column of densely packed parakeratotic cells with pyknotic basophilic nuclei extending through the stratum corneum from an epidermal invagination.⁴ Directly beneath the cornoid lamella, the granular layer is markedly diminished or absent, and cells of the stratum spinosum may demonstrate vacuolar changes or dyskeratosis.^4,19 The superficial layer of the cornoid lamella may appear to be more centrifugally located and the cornoid lamella may be seen in several locations throughout the lesion.^2,20 The degree of epidermal invagination, which is present under the cornoid lamella, varies by porokeratosis subtype; the central portion of the lesion may contain epidermis that ranges from hyperplastic to atrophic.² Shumack et al²¹ noted that histologic changes under the cornoid lamella may include a lichenoid tissue reaction, papillary dermal lymphocytic infiltrate, vacuolar changes, dyskeratosis, and liquefaction degeneration of the basal layer. Because many of these histologic features also can be identified in lichen planus, a biopsy of the edge of lesions of porokeratosis is essential for making the correct diagnosis.

Heritability
Although linear porokeratosis has no identified pattern of inheritance and appears sporadic in onset, reports have described concomitant occurrence of linear porokeratosis and DSAP as well as linear porokeratosis arising in children of parents who have a diagnosis of DSAP.^5,18,22,23 Based on these findings, it has been hypothesized that linear porokeratosis may represent a mosaic or segmental form of autosomal-dominant inherited subtypes of porokeratosis, such as DSAP.⁵ According to this hypothesis, loss of heterozygosity in patients with a DSAP mutation during early embryogenesis leads to proliferation of cells that are homozygous or hemizygous for the underlying mutation along lines of Blaschko.²⁴ It has been suggested that the allelic loss implicated in the development of linear porokeratosis is the first step in a multistage process of carcinogenesis, which may help to explain the higher rates of malignant transformation that can be seen in linear porokeratosis.²⁴

Management
Several treatment options exist for porokeratosis, including cryotherapy, topical 5-fluorouracil with or without adjunctive retinoid treatment, topical imiquimod, CO₂ laser, shave and linear excision, curettage, dermabrasion, and oral acitretin for widespread lesions.^1,25-29 One case report detailed successful treatment of adult-onset linear porokeratosis with tacrolimus ointment 0.1%.³⁰ Treatments for porokeratosis demonstrate variable degrees of success, with the aim of eradicating the clonal population of mutant keratinocytes.² Additionally, protection from UV radiation should be encouraged, especially in patients who have lesions that occur in areas of high actinic damage.¹

Conclusion

We report of a case of linear porokeratosis with associated multiple SCCs that developed within the lesion. Definitive diagnosis of linear porokeratosis is important due to the higher rate of malignant transformation than the rate seen in other porokeratoses. In larger lesions, appropriate sampling and orientation of the pathology specimen is essential for identifying cornoid lamellae, thus allowing for appropriate follow-up and management. Several treatment options are available, though evidence for the effectiveness of any particular therapy is lacking. Research has shed light on possible genetic and molecular abnormalities in linear porokeratosis, but the exact pathogenesis of the disorder remains unclear.

Lesions of porokeratosis are thought to arise from disordered keratinization, though the exact pathogenesis remains uncertain. At least 5 clinical subtypes of porokeratosis have been identified: porokeratosis of Mibelli, disseminated superficial porokeratosis and disseminated superficial actinic porokeratosis (DSAP), linear porokeratosis, punctuate porokeratosis, and porokeratosis palmaris et plantaris disseminata (PPPD).^1,2 Linear porokeratosis is a rare subtype with a clinical differential diagnosis that includes lichen striatus, linear lichen planus, linear verrucous epidermal nevus, segmental Darier disease, and incontinentia pigmenti.³ Definitive diagnosis of linear porokeratosis is made by histopathologic examination demonstrating a cornoid lamella, defined as a column of parakeratotic cells that lies at 45°to the surface of the epidermis and contains pyknotic basophilic nuclei.⁴ Patients with linear porokeratosis typically develop lesions along the lines of Blaschko in infancy or childhood.^5,6 Among the different subtypes of porokeratosis, linear porokeratosis demonstrates the highest rate of malignant transformation, therefore requiring close clinical observation.⁷

Case Report

An 83-year-old woman presented to the outpatient clinic with a large linear plaque on the right leg that had been present since birth. Ten years prior to presentation, a portion of the lesion started to bleed; biopsy of the area was performed by an outside provider demonstrating squamous cell carcinoma (SCC), which was treated with wide local excision. One year prior to presentation, a separate portion of the plaque was biopsied by an outside provider and another diagnosis of SCC was made.

On examination performed during the initial presentation to our clinic, there was a well-demarcated tan to violaceous linear plaque present at the lower buttock and extending along the posterior leg to the skin overlying the Achilles tendon and dorsal aspect of the right foot. Within the plaque, there were areas of atrophy and areas of inflammation, induration, and hyperkeratosis (Figures 1 and 2). Two punch biopsies were performed: one from the edge of the plaque and one from a hyperkeratotic region within the plaque. Histology from the edge of the plaque demonstrated a cornoid lamella, consistent with a porokeratosis (Figure 3), whereas the histology from the hyperkeratotic region demonstrated a lichenoid infiltrate (Figure 4).

Several treatment options directed at the entire lesion were offered to the patient, but she declined these therapies and opted to address only those areas with clinical features of SCC, such as hyperkeratosis, bleeding, and rapid growth. Although biopsies performed by an outside provider were consistent with SCC, it had not been detected on biopsy performed during her initial visit to our clinic.

The patient was educated on the risk associated with her condition and instructed to follow up every 6 months to monitor for the development of SCC.

Comment

Porokeratosis is a disorder of keratinization with at least 5 clinical subtypes that share histologic similarities: porokeratosis of Mibelli, disseminated superficial porokeratosis and DSAP, linear porokeratosis, punctate porokeratosis, and PPPD.^1,2 Other less common variants of porokeratosis include porokeratosis ptychotropica (a verrucous variant confined to the perianal area) and congenital unilateral linear porokeratosis.^8,9

Linear porokeratosis appears in infancy or childhood with plaques that follow the lines of Blaschko.^5,6 Most commonly, it presents unilaterally with annular plaques and linear hyperkeratotic papules that preferentially affect the extremities, though it also may present in a more generalized form or appear in a zosteriform pattern.^10,11 Linear porokeratosis affects fewer than 20,000 individuals in the United States and accounts for fewer than 13% of all porokeratosis cases.^12,13

Despite its relatively low prevalence, early identification of linear porokeratosis is important due to its high oncogenic potential, with malignant transformation to basal cell carcinoma or, more commonly, SCC reported in 19% of reported cases.^1,5,7,14 The malignant transformation rate of linear porokeratosis is reported to be higher than rates seen in other porokeratosis subtypes (9.5%, 7.6%, and 3.4% for PPPD, porokeratosis of Mibelli, and DSAP, respectively).⁷ The risk of malignant transformation from porokeratosis increases with exposure to ionizing radiation, duration of the lesion, larger or coalescing lesions, and advanced age.^7,15,16 Histologic studies have provided support for correlation between lesion size and oncogenic potential, with greater numbers of mitotic cells and more abnormal DNA ploidy seen in larger lesions.¹⁷

Histopathology
All subtypes of porokeratosis share certain histopathologic features that aid in the diagnosis of the disorder.¹⁸ Identification of the clinically observed hyperkeratotic ridged border or cornoid lamella is the primary means of definitively diagnosing porokeratosis; however, cornoid lamellae may be observed in other conditions, including verruca vulgaris and actinic keratosis.^4,14

The cornoid lamella appears as a skewed column of densely packed parakeratotic cells with pyknotic basophilic nuclei extending through the stratum corneum from an epidermal invagination.⁴ Directly beneath the cornoid lamella, the granular layer is markedly diminished or absent, and cells of the stratum spinosum may demonstrate vacuolar changes or dyskeratosis.^4,19 The superficial layer of the cornoid lamella may appear to be more centrifugally located and the cornoid lamella may be seen in several locations throughout the lesion.^2,20 The degree of epidermal invagination, which is present under the cornoid lamella, varies by porokeratosis subtype; the central portion of the lesion may contain epidermis that ranges from hyperplastic to atrophic.² Shumack et al²¹ noted that histologic changes under the cornoid lamella may include a lichenoid tissue reaction, papillary dermal lymphocytic infiltrate, vacuolar changes, dyskeratosis, and liquefaction degeneration of the basal layer. Because many of these histologic features also can be identified in lichen planus, a biopsy of the edge of lesions of porokeratosis is essential for making the correct diagnosis.

Heritability
Although linear porokeratosis has no identified pattern of inheritance and appears sporadic in onset, reports have described concomitant occurrence of linear porokeratosis and DSAP as well as linear porokeratosis arising in children of parents who have a diagnosis of DSAP.^5,18,22,23 Based on these findings, it has been hypothesized that linear porokeratosis may represent a mosaic or segmental form of autosomal-dominant inherited subtypes of porokeratosis, such as DSAP.⁵ According to this hypothesis, loss of heterozygosity in patients with a DSAP mutation during early embryogenesis leads to proliferation of cells that are homozygous or hemizygous for the underlying mutation along lines of Blaschko.²⁴ It has been suggested that the allelic loss implicated in the development of linear porokeratosis is the first step in a multistage process of carcinogenesis, which may help to explain the higher rates of malignant transformation that can be seen in linear porokeratosis.²⁴

Management
Several treatment options exist for porokeratosis, including cryotherapy, topical 5-fluorouracil with or without adjunctive retinoid treatment, topical imiquimod, CO₂ laser, shave and linear excision, curettage, dermabrasion, and oral acitretin for widespread lesions.^1,25-29 One case report detailed successful treatment of adult-onset linear porokeratosis with tacrolimus ointment 0.1%.³⁰ Treatments for porokeratosis demonstrate variable degrees of success, with the aim of eradicating the clonal population of mutant keratinocytes.² Additionally, protection from UV radiation should be encouraged, especially in patients who have lesions that occur in areas of high actinic damage.¹

Conclusion

We report of a case of linear porokeratosis with associated multiple SCCs that developed within the lesion. Definitive diagnosis of linear porokeratosis is important due to the higher rate of malignant transformation than the rate seen in other porokeratoses. In larger lesions, appropriate sampling and orientation of the pathology specimen is essential for identifying cornoid lamellae, thus allowing for appropriate follow-up and management. Several treatment options are available, though evidence for the effectiveness of any particular therapy is lacking. Research has shed light on possible genetic and molecular abnormalities in linear porokeratosis, but the exact pathogenesis of the disorder remains unclear.

Lesions of porokeratosis are thought to arise from disordered keratinization, though the exact pathogenesis remains uncertain. At least 5 clinical subtypes of porokeratosis have been identified: porokeratosis of Mibelli, disseminated superficial porokeratosis and disseminated superficial actinic porokeratosis (DSAP), linear porokeratosis, punctuate porokeratosis, and porokeratosis palmaris et plantaris disseminata (PPPD).^1,2 Linear porokeratosis is a rare subtype with a clinical differential diagnosis that includes lichen striatus, linear lichen planus, linear verrucous epidermal nevus, segmental Darier disease, and incontinentia pigmenti.³ Definitive diagnosis of linear porokeratosis is made by histopathologic examination demonstrating a cornoid lamella, defined as a column of parakeratotic cells that lies at 45°to the surface of the epidermis and contains pyknotic basophilic nuclei.⁴ Patients with linear porokeratosis typically develop lesions along the lines of Blaschko in infancy or childhood.^5,6 Among the different subtypes of porokeratosis, linear porokeratosis demonstrates the highest rate of malignant transformation, therefore requiring close clinical observation.⁷

Case Report

An 83-year-old woman presented to the outpatient clinic with a large linear plaque on the right leg that had been present since birth. Ten years prior to presentation, a portion of the lesion started to bleed; biopsy of the area was performed by an outside provider demonstrating squamous cell carcinoma (SCC), which was treated with wide local excision. One year prior to presentation, a separate portion of the plaque was biopsied by an outside provider and another diagnosis of SCC was made.

On examination performed during the initial presentation to our clinic, there was a well-demarcated tan to violaceous linear plaque present at the lower buttock and extending along the posterior leg to the skin overlying the Achilles tendon and dorsal aspect of the right foot. Within the plaque, there were areas of atrophy and areas of inflammation, induration, and hyperkeratosis (Figures 1 and 2). Two punch biopsies were performed: one from the edge of the plaque and one from a hyperkeratotic region within the plaque. Histology from the edge of the plaque demonstrated a cornoid lamella, consistent with a porokeratosis (Figure 3), whereas the histology from the hyperkeratotic region demonstrated a lichenoid infiltrate (Figure 4).

Several treatment options directed at the entire lesion were offered to the patient, but she declined these therapies and opted to address only those areas with clinical features of SCC, such as hyperkeratosis, bleeding, and rapid growth. Although biopsies performed by an outside provider were consistent with SCC, it had not been detected on biopsy performed during her initial visit to our clinic.

The patient was educated on the risk associated with her condition and instructed to follow up every 6 months to monitor for the development of SCC.

Comment

Porokeratosis is a disorder of keratinization with at least 5 clinical subtypes that share histologic similarities: porokeratosis of Mibelli, disseminated superficial porokeratosis and DSAP, linear porokeratosis, punctate porokeratosis, and PPPD.^1,2 Other less common variants of porokeratosis include porokeratosis ptychotropica (a verrucous variant confined to the perianal area) and congenital unilateral linear porokeratosis.^8,9

Linear porokeratosis appears in infancy or childhood with plaques that follow the lines of Blaschko.^5,6 Most commonly, it presents unilaterally with annular plaques and linear hyperkeratotic papules that preferentially affect the extremities, though it also may present in a more generalized form or appear in a zosteriform pattern.^10,11 Linear porokeratosis affects fewer than 20,000 individuals in the United States and accounts for fewer than 13% of all porokeratosis cases.^12,13

Despite its relatively low prevalence, early identification of linear porokeratosis is important due to its high oncogenic potential, with malignant transformation to basal cell carcinoma or, more commonly, SCC reported in 19% of reported cases.^1,5,7,14 The malignant transformation rate of linear porokeratosis is reported to be higher than rates seen in other porokeratosis subtypes (9.5%, 7.6%, and 3.4% for PPPD, porokeratosis of Mibelli, and DSAP, respectively).⁷ The risk of malignant transformation from porokeratosis increases with exposure to ionizing radiation, duration of the lesion, larger or coalescing lesions, and advanced age.^7,15,16 Histologic studies have provided support for correlation between lesion size and oncogenic potential, with greater numbers of mitotic cells and more abnormal DNA ploidy seen in larger lesions.¹⁷

Histopathology
All subtypes of porokeratosis share certain histopathologic features that aid in the diagnosis of the disorder.¹⁸ Identification of the clinically observed hyperkeratotic ridged border or cornoid lamella is the primary means of definitively diagnosing porokeratosis; however, cornoid lamellae may be observed in other conditions, including verruca vulgaris and actinic keratosis.^4,14

The cornoid lamella appears as a skewed column of densely packed parakeratotic cells with pyknotic basophilic nuclei extending through the stratum corneum from an epidermal invagination.⁴ Directly beneath the cornoid lamella, the granular layer is markedly diminished or absent, and cells of the stratum spinosum may demonstrate vacuolar changes or dyskeratosis.^4,19 The superficial layer of the cornoid lamella may appear to be more centrifugally located and the cornoid lamella may be seen in several locations throughout the lesion.^2,20 The degree of epidermal invagination, which is present under the cornoid lamella, varies by porokeratosis subtype; the central portion of the lesion may contain epidermis that ranges from hyperplastic to atrophic.² Shumack et al²¹ noted that histologic changes under the cornoid lamella may include a lichenoid tissue reaction, papillary dermal lymphocytic infiltrate, vacuolar changes, dyskeratosis, and liquefaction degeneration of the basal layer. Because many of these histologic features also can be identified in lichen planus, a biopsy of the edge of lesions of porokeratosis is essential for making the correct diagnosis.

Heritability
Although linear porokeratosis has no identified pattern of inheritance and appears sporadic in onset, reports have described concomitant occurrence of linear porokeratosis and DSAP as well as linear porokeratosis arising in children of parents who have a diagnosis of DSAP.^5,18,22,23 Based on these findings, it has been hypothesized that linear porokeratosis may represent a mosaic or segmental form of autosomal-dominant inherited subtypes of porokeratosis, such as DSAP.⁵ According to this hypothesis, loss of heterozygosity in patients with a DSAP mutation during early embryogenesis leads to proliferation of cells that are homozygous or hemizygous for the underlying mutation along lines of Blaschko.²⁴ It has been suggested that the allelic loss implicated in the development of linear porokeratosis is the first step in a multistage process of carcinogenesis, which may help to explain the higher rates of malignant transformation that can be seen in linear porokeratosis.²⁴

Management
Several treatment options exist for porokeratosis, including cryotherapy, topical 5-fluorouracil with or without adjunctive retinoid treatment, topical imiquimod, CO₂ laser, shave and linear excision, curettage, dermabrasion, and oral acitretin for widespread lesions.^1,25-29 One case report detailed successful treatment of adult-onset linear porokeratosis with tacrolimus ointment 0.1%.³⁰ Treatments for porokeratosis demonstrate variable degrees of success, with the aim of eradicating the clonal population of mutant keratinocytes.² Additionally, protection from UV radiation should be encouraged, especially in patients who have lesions that occur in areas of high actinic damage.¹

Conclusion

We report of a case of linear porokeratosis with associated multiple SCCs that developed within the lesion. Definitive diagnosis of linear porokeratosis is important due to the higher rate of malignant transformation than the rate seen in other porokeratoses. In larger lesions, appropriate sampling and orientation of the pathology specimen is essential for identifying cornoid lamellae, thus allowing for appropriate follow-up and management. Several treatment options are available, though evidence for the effectiveness of any particular therapy is lacking. Research has shed light on possible genetic and molecular abnormalities in linear porokeratosis, but the exact pathogenesis of the disorder remains unclear.