Nonmelanoma Skin Cancer

To the Editor:

A 61-year-old man with a medical history of type 2 diabetes mellitus presented to us with a 2.5×3.0-cm erythematous, ulcerated, and exophytic tumor on the right dorsal forearm that had rapidly developed over 2 weeks. A tangential biopsy was performed followed by treatment with electrodesiccation and curettage (ED&C). Histology revealed a squamous cell carcinoma (SCC), keratoacanthoma (KA) type. Over the next 11 days the lesion rapidly recurred and the patient returned with his own daily photodocumentation of the KA’s progression (Figure). The lesion was re-excised with 5-mm margins; histology again revealed SCC, KA type, with deep margin involvement. Chest radiograph revealed findings suspicious for metastatic lesions in the right lung. He was referred to oncology for metastatic workup; positron emission tomography was negative and ultimately the lung lesion was found to be benign. The patient underwent adjuvant radia-tion to the KA resection bed and lymph nodes with minimal side effects. The patient has remained cancer free to date.

Keratoacanthomas are rapidly growing, typically painless, cutaneous neoplasms that often develop on sun-exposed areas. They can occur spontaneously or following trauma and have the propensity to regress with time.^1-3 They are described as progressing through 3 clinical stages: rapid proliferation, mature/stable, and involution. However, KAs can be aggressive, becoming locally destructive; therefore, KAs are typically treated to avoid further morbidity. Keratoacanthomas may be considered a subtype of SCC, as some have the potential to become locally destructive and metastasize.^3-5 There are reports of spontaneous resolution of KAs over weeks to months, though surgical excision is the gold standard of treatment.^3,5

Reactive KA is a subtype that is thought to develop at the site of prior trauma, representing a sort of Köbner phenomenon.^3,4 We demonstrated a case of a recurrent KA in the setting of recent ED&C. Several reports describe KAs developing after dermatologic surgery, including Mohs micrographic surgery, laser resurfacing, radiation therapy, and after skin grafting.^3,4,6 Trauma-induced epidermal injury and dermal inflammation may play a role in postoperative KA formation or recurrence.⁶

Keratoacanthoma recurrence has been reported in 3% to 8% of cases within a few weeks after treatment, as seen in our current patient.^3,5 In our case, the patient photodocumented the regrowth of his lesion (Figure). Treatment of reactive KAs may be therapeutically challenging, as they can form or worsen with repeated surgeries and may require several treatment modalities to eradicate them.⁴ Treatment options include observation, ED&C, excision, Mohs micrographic surgery, radiation, cryosurgery, laser, isotretinoin, acitretin, imiquimod, 5-fluorouracil, methotrexate, interferon alfa-2b, or bleomycin, to name a few.^3,4,7

Keratoacanthoma recurrence at day 1 (A), day 3 (B), day 5 (C),day 6 (D), day 7 (E), and day 9 (F) following electrodesiccation and curettage.

Combination therapy should be considered in the presence of recurrent and/or aggressive KAs, such as in our case. Our patient has remained disease free after a combination of surgical excision with radiation therapy.

To the Editor:

A 61-year-old man with a medical history of type 2 diabetes mellitus presented to us with a 2.5×3.0-cm erythematous, ulcerated, and exophytic tumor on the right dorsal forearm that had rapidly developed over 2 weeks. A tangential biopsy was performed followed by treatment with electrodesiccation and curettage (ED&C). Histology revealed a squamous cell carcinoma (SCC), keratoacanthoma (KA) type. Over the next 11 days the lesion rapidly recurred and the patient returned with his own daily photodocumentation of the KA’s progression (Figure). The lesion was re-excised with 5-mm margins; histology again revealed SCC, KA type, with deep margin involvement. Chest radiograph revealed findings suspicious for metastatic lesions in the right lung. He was referred to oncology for metastatic workup; positron emission tomography was negative and ultimately the lung lesion was found to be benign. The patient underwent adjuvant radia-tion to the KA resection bed and lymph nodes with minimal side effects. The patient has remained cancer free to date.

Keratoacanthomas are rapidly growing, typically painless, cutaneous neoplasms that often develop on sun-exposed areas. They can occur spontaneously or following trauma and have the propensity to regress with time.^1-3 They are described as progressing through 3 clinical stages: rapid proliferation, mature/stable, and involution. However, KAs can be aggressive, becoming locally destructive; therefore, KAs are typically treated to avoid further morbidity. Keratoacanthomas may be considered a subtype of SCC, as some have the potential to become locally destructive and metastasize.^3-5 There are reports of spontaneous resolution of KAs over weeks to months, though surgical excision is the gold standard of treatment.^3,5

Reactive KA is a subtype that is thought to develop at the site of prior trauma, representing a sort of Köbner phenomenon.^3,4 We demonstrated a case of a recurrent KA in the setting of recent ED&C. Several reports describe KAs developing after dermatologic surgery, including Mohs micrographic surgery, laser resurfacing, radiation therapy, and after skin grafting.^3,4,6 Trauma-induced epidermal injury and dermal inflammation may play a role in postoperative KA formation or recurrence.⁶

Keratoacanthoma recurrence has been reported in 3% to 8% of cases within a few weeks after treatment, as seen in our current patient.^3,5 In our case, the patient photodocumented the regrowth of his lesion (Figure). Treatment of reactive KAs may be therapeutically challenging, as they can form or worsen with repeated surgeries and may require several treatment modalities to eradicate them.⁴ Treatment options include observation, ED&C, excision, Mohs micrographic surgery, radiation, cryosurgery, laser, isotretinoin, acitretin, imiquimod, 5-fluorouracil, methotrexate, interferon alfa-2b, or bleomycin, to name a few.^3,4,7

Keratoacanthoma recurrence at day 1 (A), day 3 (B), day 5 (C),day 6 (D), day 7 (E), and day 9 (F) following electrodesiccation and curettage.

Combination therapy should be considered in the presence of recurrent and/or aggressive KAs, such as in our case. Our patient has remained disease free after a combination of surgical excision with radiation therapy.

To the Editor:

A 61-year-old man with a medical history of type 2 diabetes mellitus presented to us with a 2.5×3.0-cm erythematous, ulcerated, and exophytic tumor on the right dorsal forearm that had rapidly developed over 2 weeks. A tangential biopsy was performed followed by treatment with electrodesiccation and curettage (ED&C). Histology revealed a squamous cell carcinoma (SCC), keratoacanthoma (KA) type. Over the next 11 days the lesion rapidly recurred and the patient returned with his own daily photodocumentation of the KA’s progression (Figure). The lesion was re-excised with 5-mm margins; histology again revealed SCC, KA type, with deep margin involvement. Chest radiograph revealed findings suspicious for metastatic lesions in the right lung. He was referred to oncology for metastatic workup; positron emission tomography was negative and ultimately the lung lesion was found to be benign. The patient underwent adjuvant radia-tion to the KA resection bed and lymph nodes with minimal side effects. The patient has remained cancer free to date.

Keratoacanthomas are rapidly growing, typically painless, cutaneous neoplasms that often develop on sun-exposed areas. They can occur spontaneously or following trauma and have the propensity to regress with time.^1-3 They are described as progressing through 3 clinical stages: rapid proliferation, mature/stable, and involution. However, KAs can be aggressive, becoming locally destructive; therefore, KAs are typically treated to avoid further morbidity. Keratoacanthomas may be considered a subtype of SCC, as some have the potential to become locally destructive and metastasize.^3-5 There are reports of spontaneous resolution of KAs over weeks to months, though surgical excision is the gold standard of treatment.^3,5

Reactive KA is a subtype that is thought to develop at the site of prior trauma, representing a sort of Köbner phenomenon.^3,4 We demonstrated a case of a recurrent KA in the setting of recent ED&C. Several reports describe KAs developing after dermatologic surgery, including Mohs micrographic surgery, laser resurfacing, radiation therapy, and after skin grafting.^3,4,6 Trauma-induced epidermal injury and dermal inflammation may play a role in postoperative KA formation or recurrence.⁶

Keratoacanthoma recurrence has been reported in 3% to 8% of cases within a few weeks after treatment, as seen in our current patient.^3,5 In our case, the patient photodocumented the regrowth of his lesion (Figure). Treatment of reactive KAs may be therapeutically challenging, as they can form or worsen with repeated surgeries and may require several treatment modalities to eradicate them.⁴ Treatment options include observation, ED&C, excision, Mohs micrographic surgery, radiation, cryosurgery, laser, isotretinoin, acitretin, imiquimod, 5-fluorouracil, methotrexate, interferon alfa-2b, or bleomycin, to name a few.^3,4,7

Keratoacanthoma recurrence at day 1 (A), day 3 (B), day 5 (C),day 6 (D), day 7 (E), and day 9 (F) following electrodesiccation and curettage.

Combination therapy should be considered in the presence of recurrent and/or aggressive KAs, such as in our case. Our patient has remained disease free after a combination of surgical excision with radiation therapy.

Nail matrix biopsies are performed to confirm a diagnosis or surgically remove a skin lesion that is affecting the growth of the nail plate. The procedure may be used to identify:

Nail biopsy can lead to complications such as bleeding, infection, or scarring. Postoperative scarring can cause permanent nail splitting, dystrophy, or both.

In a Cosmetic Dermatology article, “Matrix Biopsy of Longitudinal Melanonychia and Longitudinal Erythronychia: A Step-by-Step Approach,” Drs. Siobhan C. Collins and Nathaniel J. Jellinek review 6 techniques used to biopsy the nail matrix.

Techniques used to biopsy the nail matrix. From Cosmet Dermatol. 2009;22:130-136.

In the setting of longitudinal melanonychia (to diagnose nail melanoma or SCC) and longitudinal erythronychia (to diagnose SCC and rarely amelanotic melanoma or basal cell carcinoma), the techniques they describe accomplish 3 fundamental goals of nail surgery:

Dermatologists must be confident when performing nail biopsies and the techniques discussed by the authors will help approach nail surgery with more certainty.

At the 73rd Annual Meeting of the American Academy of Dermatology, Dr. Jellinek provides a hands-on approach to nail surgery. On Saturday, March 21, he will provide tips for nail surgeries at the “Medical and Surgical Management of Nail Disorders” lecture.

For more information, read the Collins and Jellinek article from Cosmetic Dermatology.

Nail matrix biopsies are performed to confirm a diagnosis or surgically remove a skin lesion that is affecting the growth of the nail plate. The procedure may be used to identify:

Nail biopsy can lead to complications such as bleeding, infection, or scarring. Postoperative scarring can cause permanent nail splitting, dystrophy, or both.

In a Cosmetic Dermatology article, “Matrix Biopsy of Longitudinal Melanonychia and Longitudinal Erythronychia: A Step-by-Step Approach,” Drs. Siobhan C. Collins and Nathaniel J. Jellinek review 6 techniques used to biopsy the nail matrix.

Techniques used to biopsy the nail matrix. From Cosmet Dermatol. 2009;22:130-136.

In the setting of longitudinal melanonychia (to diagnose nail melanoma or SCC) and longitudinal erythronychia (to diagnose SCC and rarely amelanotic melanoma or basal cell carcinoma), the techniques they describe accomplish 3 fundamental goals of nail surgery:

Dermatologists must be confident when performing nail biopsies and the techniques discussed by the authors will help approach nail surgery with more certainty.

At the 73rd Annual Meeting of the American Academy of Dermatology, Dr. Jellinek provides a hands-on approach to nail surgery. On Saturday, March 21, he will provide tips for nail surgeries at the “Medical and Surgical Management of Nail Disorders” lecture.

For more information, read the Collins and Jellinek article from Cosmetic Dermatology.

Nail matrix biopsies are performed to confirm a diagnosis or surgically remove a skin lesion that is affecting the growth of the nail plate. The procedure may be used to identify:

Nail biopsy can lead to complications such as bleeding, infection, or scarring. Postoperative scarring can cause permanent nail splitting, dystrophy, or both.

In a Cosmetic Dermatology article, “Matrix Biopsy of Longitudinal Melanonychia and Longitudinal Erythronychia: A Step-by-Step Approach,” Drs. Siobhan C. Collins and Nathaniel J. Jellinek review 6 techniques used to biopsy the nail matrix.

Techniques used to biopsy the nail matrix. From Cosmet Dermatol. 2009;22:130-136.

In the setting of longitudinal melanonychia (to diagnose nail melanoma or SCC) and longitudinal erythronychia (to diagnose SCC and rarely amelanotic melanoma or basal cell carcinoma), the techniques they describe accomplish 3 fundamental goals of nail surgery:

Dermatologists must be confident when performing nail biopsies and the techniques discussed by the authors will help approach nail surgery with more certainty.

At the 73rd Annual Meeting of the American Academy of Dermatology, Dr. Jellinek provides a hands-on approach to nail surgery. On Saturday, March 21, he will provide tips for nail surgeries at the “Medical and Surgical Management of Nail Disorders” lecture.

For more information, read the Collins and Jellinek article from Cosmetic Dermatology.

Sun damage and chronic exposure to UV radiation have been recognized as causative factors for the development of squamous cell carcinoma (SCC), its precursor actinic keratosis (AK), and basal cell carcinoma (BCC). Although surgical treatment is necessary for most advanced cases of skin cancer, several other therapeutic approaches have been described including the use of topical chemotherapy agents such as 5-fluorouracil (5-FU) and topical immunomodulators such as imiquimod. Unlike surgery, these agents provide the added benefit of treating larger fields of photodamaged skin. With the increasing prevalence of nonmelanoma skin cancers (NMSCs), the use of multiple topical agents for treatment will continue to become more common.

We present the case of a patient who underwent field therapy with topical 5-FU for diffuse actinic damage and AKs. There was no subsequent inflammatory response within the perimeter of a BCC that had been treated with imiquimod 10 years prior.

Case Report

An otherwise healthy 58-year-old man with a history of long-standing diffuse sun damage and multiple prior NMSCs presented for treatment of a recurrent BCC on the right cheek. The patient reported that the BCC had initially been biopsied and excised by his primary care physician. Two months later local recurrence was noted by the primary care physician and the patient was subsequently referred to our dermatology office. A 2-month treatment course with daily imiquimod cream 5% was initiated. This treatment caused extensive inflammation of the right cheek but was otherwise well tolerated (Figure 1).

Figure 1. Extensive inflammation following application of imiquimod cream 5% for treatment of basal cell carcinoma. Figure 2. Right side of the patient’s face on day 1 (A) and day 30 (B) of treatment with 5-fluorouracil cream 0.5% as well as 15 days posttreatment (C), with no inflammatory response on the area that was previously treated with imiquimod.

During a routine skin cancer screening 10 years later, no recurrence of the BCC was noted on the right cheek; however, the patient had developed multiple AKs on the face. Therapeutic options were discussed with the patient; he agreed to topical field therapy with 5-FU cream 0.5%. The patient applied the 5-FU cream to the entire face nightly for 1 month. During this time he experienced a brisk inflammatory response with painful cracking and redness of the skin. On follow-up, it was noted that the area on the right cheek that had been treated with imiquimod 10 years prior showed no inflammatory response despite nightly application of 5-FU cream to the area (Figure 2). The patient denied any routine use of sunscreen or other sun-protective practices.

Comment

Basal cell carcinoma is the most common skin cancer in the United States with an incidence of 1.4% to 2% per year. It has become more prevalent in recent decades, likely due to genetic predisposition and increasing cumulative sun exposure.^1-4 A variety of treatment options are available. Surgical interventions include destruction via electrodesiccation and curettage, local excision, and Mohs micrographic surgery. One of the challenges in the management of BCC, as was the case in our patient, is the treatment of tumors that arise in cosmetically or functionally sensitive areas. Approaches that minimize the amount of tissue removed while ensuring the highest possible cure rate are favorable. In addition to surgery, topical imiquimod has been established as a potential treatment of BCC. Imiquimod, a nucleoside analogue of the imidazoquinoline family, is an agonist of toll-like receptors 7 and 8 that promotes cytokine-induced cell death via nuclear factor kB and a helper T cell T_H1-weighted antitumor inflammatory response.^5,6 Although clearance rates with imiquimod vary by drug regimen, success rates of 43% to 100% for superficial BCCs, 42% to 100% for nodular BCCs, and 56% to 63% for infiltrative BCCs have been reported.⁷ In a 2007 randomized study of imiquimod cream 5%, 5-FU ointment 5%, or cryosurgery for the treatment of AK, imiquimod resulted in superior and more reliable clearance with lower recurrence rates.⁸

Similar to BCC, AK is closely linked to lifetime cumulative sun exposure.⁹ Actinic keratoses have been well established as precursors to SCC, and some researchers advocate for their reclassification as early SCC in situ.¹⁰ The incidence of malignant conversion of AK to SCC has been estimated at 0.025% to 16% annually, with an estimated lifetime risk for malignant transformation of 8% per individual AK.^11,12 Cryotherapy has been a mainstay for the treatment of isolated AK, and alternative therapies including curettage, photodynamic therapy, and laser therapy have been employed. Field-directed therapy has become a popular alternative that targets multiple lesions and field cancerization.^8,13,14 Field cancerization implies that if one cell in the patient’s epidermis has been exposed to enough UV radiation to develop into a precancerous lesion or early skin cancer, then many other cells in the same environment likely have some degree of UV radiation–induced atypia.¹⁵ 5-Fluorouacil is a pyrimidine analogue chemotherapeutic agent that inhibits thymidylate synthase and interferes with DNA synthesis.¹⁶ This mechanism of 5-FU commonly causes an inflammatory response characterized by burning, dryness, and redness, but these effects rarely force early discontinuation of treatment. A randomized controlled trial comparing 5-FU cream 0.5% to a placebo found that complete clearance rates at 4 weeks posttreatment were significantly higher in the treatment group (47.5%) versus placebo (3.4%)(P<.001).¹³ Additional trials have established no significant superiority of 5-FU cream 5% over 5-FU cream 0.5%, with a decrease in side effects noted in patients treated with the lower concentration.¹⁷

Our patient had a history of a recurrent BCC and was previously treated with imiquimod. He showed no inflammatory response to field therapy with 5-FU within the perimeter of prior immunomodulatory therapy. Although no frank scaling or crusting papules consistent with AK were observed in the previously treated area prior to 5-FU therapy, subclinical field damage in that area was expected because 10 years of additional sun exposure had accumulated since imiquimod therapy was completed. Several conclusions can be drawn from this observation. Primarily, no new clinically significant actinic lesions occurred on the previously treated skin. This observation is consistent with 12-month follow-up data on AKs treated with either 5-FU, imiquimod, or cryosurgery that identified imiquimod as having the lowest recurrence rate.⁸ Thus, a photoprotective effect may be ascribed to imiquimod therapy that extends beyond its drug effects on atypical keratinocytes. It has been one author’s personal experience (M.Q.) that patients treated with 5-FU experience recurrence of AKs within 3 to 5 years versus 10 years of remission with imiquimod. In our patient, imiquimod therapy seemed to reset the patient’s skin at the location of the prior BCC and surrounding field cancerization.

Studies with long-term follow-up are needed to investigate the need for re-treatment with imiquimod or 5-FU. The longevity of imiquimod treatment may be of importance beyond the treatment of AKs or NMSCs. For instance, during the treatment of lentigo maligna with imiquimod, Metcalf et al¹⁸ found a significant reduction in solar elastosis (P=.0036), normalization of epidermal thickness (P=.0073), and increased papillary dermal fibroplasia in pre- and posttreatment biopsies (P<.0001), which have been described as antiaging effects in the laypress. Some of these mechanisms appear to be implicated in the observations noted in our patient. The 10-year period between the 2 courses of therapy in our patient suggests that imiquimod may cause sustained healing of skin that was previously classified both clinically and microscopically as UV damaged.

Conclusion

Both topical immunomodulators such as imiquimod and topical chemotherapeutic agents such as 5-FU have a role in the field treatment of AK and the focal treatment of superficial BCC and SCC. As multiple topical immunomodulators continue to be evaluated, long-term studies assessing the need for re-treatment as well as the degree of sustained remission of sun damage will be necessary. We expect that their individual roles will continue to become more precisely defined and distinct in the coming years.

Sun damage and chronic exposure to UV radiation have been recognized as causative factors for the development of squamous cell carcinoma (SCC), its precursor actinic keratosis (AK), and basal cell carcinoma (BCC). Although surgical treatment is necessary for most advanced cases of skin cancer, several other therapeutic approaches have been described including the use of topical chemotherapy agents such as 5-fluorouracil (5-FU) and topical immunomodulators such as imiquimod. Unlike surgery, these agents provide the added benefit of treating larger fields of photodamaged skin. With the increasing prevalence of nonmelanoma skin cancers (NMSCs), the use of multiple topical agents for treatment will continue to become more common.

We present the case of a patient who underwent field therapy with topical 5-FU for diffuse actinic damage and AKs. There was no subsequent inflammatory response within the perimeter of a BCC that had been treated with imiquimod 10 years prior.

Case Report

An otherwise healthy 58-year-old man with a history of long-standing diffuse sun damage and multiple prior NMSCs presented for treatment of a recurrent BCC on the right cheek. The patient reported that the BCC had initially been biopsied and excised by his primary care physician. Two months later local recurrence was noted by the primary care physician and the patient was subsequently referred to our dermatology office. A 2-month treatment course with daily imiquimod cream 5% was initiated. This treatment caused extensive inflammation of the right cheek but was otherwise well tolerated (Figure 1).

Figure 1. Extensive inflammation following application of imiquimod cream 5% for treatment of basal cell carcinoma. Figure 2. Right side of the patient’s face on day 1 (A) and day 30 (B) of treatment with 5-fluorouracil cream 0.5% as well as 15 days posttreatment (C), with no inflammatory response on the area that was previously treated with imiquimod.

During a routine skin cancer screening 10 years later, no recurrence of the BCC was noted on the right cheek; however, the patient had developed multiple AKs on the face. Therapeutic options were discussed with the patient; he agreed to topical field therapy with 5-FU cream 0.5%. The patient applied the 5-FU cream to the entire face nightly for 1 month. During this time he experienced a brisk inflammatory response with painful cracking and redness of the skin. On follow-up, it was noted that the area on the right cheek that had been treated with imiquimod 10 years prior showed no inflammatory response despite nightly application of 5-FU cream to the area (Figure 2). The patient denied any routine use of sunscreen or other sun-protective practices.

Comment

Basal cell carcinoma is the most common skin cancer in the United States with an incidence of 1.4% to 2% per year. It has become more prevalent in recent decades, likely due to genetic predisposition and increasing cumulative sun exposure.^1-4 A variety of treatment options are available. Surgical interventions include destruction via electrodesiccation and curettage, local excision, and Mohs micrographic surgery. One of the challenges in the management of BCC, as was the case in our patient, is the treatment of tumors that arise in cosmetically or functionally sensitive areas. Approaches that minimize the amount of tissue removed while ensuring the highest possible cure rate are favorable. In addition to surgery, topical imiquimod has been established as a potential treatment of BCC. Imiquimod, a nucleoside analogue of the imidazoquinoline family, is an agonist of toll-like receptors 7 and 8 that promotes cytokine-induced cell death via nuclear factor kB and a helper T cell T_H1-weighted antitumor inflammatory response.^5,6 Although clearance rates with imiquimod vary by drug regimen, success rates of 43% to 100% for superficial BCCs, 42% to 100% for nodular BCCs, and 56% to 63% for infiltrative BCCs have been reported.⁷ In a 2007 randomized study of imiquimod cream 5%, 5-FU ointment 5%, or cryosurgery for the treatment of AK, imiquimod resulted in superior and more reliable clearance with lower recurrence rates.⁸

Similar to BCC, AK is closely linked to lifetime cumulative sun exposure.⁹ Actinic keratoses have been well established as precursors to SCC, and some researchers advocate for their reclassification as early SCC in situ.¹⁰ The incidence of malignant conversion of AK to SCC has been estimated at 0.025% to 16% annually, with an estimated lifetime risk for malignant transformation of 8% per individual AK.^11,12 Cryotherapy has been a mainstay for the treatment of isolated AK, and alternative therapies including curettage, photodynamic therapy, and laser therapy have been employed. Field-directed therapy has become a popular alternative that targets multiple lesions and field cancerization.^8,13,14 Field cancerization implies that if one cell in the patient’s epidermis has been exposed to enough UV radiation to develop into a precancerous lesion or early skin cancer, then many other cells in the same environment likely have some degree of UV radiation–induced atypia.¹⁵ 5-Fluorouacil is a pyrimidine analogue chemotherapeutic agent that inhibits thymidylate synthase and interferes with DNA synthesis.¹⁶ This mechanism of 5-FU commonly causes an inflammatory response characterized by burning, dryness, and redness, but these effects rarely force early discontinuation of treatment. A randomized controlled trial comparing 5-FU cream 0.5% to a placebo found that complete clearance rates at 4 weeks posttreatment were significantly higher in the treatment group (47.5%) versus placebo (3.4%)(P<.001).¹³ Additional trials have established no significant superiority of 5-FU cream 5% over 5-FU cream 0.5%, with a decrease in side effects noted in patients treated with the lower concentration.¹⁷

Our patient had a history of a recurrent BCC and was previously treated with imiquimod. He showed no inflammatory response to field therapy with 5-FU within the perimeter of prior immunomodulatory therapy. Although no frank scaling or crusting papules consistent with AK were observed in the previously treated area prior to 5-FU therapy, subclinical field damage in that area was expected because 10 years of additional sun exposure had accumulated since imiquimod therapy was completed. Several conclusions can be drawn from this observation. Primarily, no new clinically significant actinic lesions occurred on the previously treated skin. This observation is consistent with 12-month follow-up data on AKs treated with either 5-FU, imiquimod, or cryosurgery that identified imiquimod as having the lowest recurrence rate.⁸ Thus, a photoprotective effect may be ascribed to imiquimod therapy that extends beyond its drug effects on atypical keratinocytes. It has been one author’s personal experience (M.Q.) that patients treated with 5-FU experience recurrence of AKs within 3 to 5 years versus 10 years of remission with imiquimod. In our patient, imiquimod therapy seemed to reset the patient’s skin at the location of the prior BCC and surrounding field cancerization.

Studies with long-term follow-up are needed to investigate the need for re-treatment with imiquimod or 5-FU. The longevity of imiquimod treatment may be of importance beyond the treatment of AKs or NMSCs. For instance, during the treatment of lentigo maligna with imiquimod, Metcalf et al¹⁸ found a significant reduction in solar elastosis (P=.0036), normalization of epidermal thickness (P=.0073), and increased papillary dermal fibroplasia in pre- and posttreatment biopsies (P<.0001), which have been described as antiaging effects in the laypress. Some of these mechanisms appear to be implicated in the observations noted in our patient. The 10-year period between the 2 courses of therapy in our patient suggests that imiquimod may cause sustained healing of skin that was previously classified both clinically and microscopically as UV damaged.

Conclusion

Both topical immunomodulators such as imiquimod and topical chemotherapeutic agents such as 5-FU have a role in the field treatment of AK and the focal treatment of superficial BCC and SCC. As multiple topical immunomodulators continue to be evaluated, long-term studies assessing the need for re-treatment as well as the degree of sustained remission of sun damage will be necessary. We expect that their individual roles will continue to become more precisely defined and distinct in the coming years.

Sun damage and chronic exposure to UV radiation have been recognized as causative factors for the development of squamous cell carcinoma (SCC), its precursor actinic keratosis (AK), and basal cell carcinoma (BCC). Although surgical treatment is necessary for most advanced cases of skin cancer, several other therapeutic approaches have been described including the use of topical chemotherapy agents such as 5-fluorouracil (5-FU) and topical immunomodulators such as imiquimod. Unlike surgery, these agents provide the added benefit of treating larger fields of photodamaged skin. With the increasing prevalence of nonmelanoma skin cancers (NMSCs), the use of multiple topical agents for treatment will continue to become more common.

We present the case of a patient who underwent field therapy with topical 5-FU for diffuse actinic damage and AKs. There was no subsequent inflammatory response within the perimeter of a BCC that had been treated with imiquimod 10 years prior.

Case Report

An otherwise healthy 58-year-old man with a history of long-standing diffuse sun damage and multiple prior NMSCs presented for treatment of a recurrent BCC on the right cheek. The patient reported that the BCC had initially been biopsied and excised by his primary care physician. Two months later local recurrence was noted by the primary care physician and the patient was subsequently referred to our dermatology office. A 2-month treatment course with daily imiquimod cream 5% was initiated. This treatment caused extensive inflammation of the right cheek but was otherwise well tolerated (Figure 1).

Figure 1. Extensive inflammation following application of imiquimod cream 5% for treatment of basal cell carcinoma. Figure 2. Right side of the patient’s face on day 1 (A) and day 30 (B) of treatment with 5-fluorouracil cream 0.5% as well as 15 days posttreatment (C), with no inflammatory response on the area that was previously treated with imiquimod.

During a routine skin cancer screening 10 years later, no recurrence of the BCC was noted on the right cheek; however, the patient had developed multiple AKs on the face. Therapeutic options were discussed with the patient; he agreed to topical field therapy with 5-FU cream 0.5%. The patient applied the 5-FU cream to the entire face nightly for 1 month. During this time he experienced a brisk inflammatory response with painful cracking and redness of the skin. On follow-up, it was noted that the area on the right cheek that had been treated with imiquimod 10 years prior showed no inflammatory response despite nightly application of 5-FU cream to the area (Figure 2). The patient denied any routine use of sunscreen or other sun-protective practices.

Comment

Basal cell carcinoma is the most common skin cancer in the United States with an incidence of 1.4% to 2% per year. It has become more prevalent in recent decades, likely due to genetic predisposition and increasing cumulative sun exposure.^1-4 A variety of treatment options are available. Surgical interventions include destruction via electrodesiccation and curettage, local excision, and Mohs micrographic surgery. One of the challenges in the management of BCC, as was the case in our patient, is the treatment of tumors that arise in cosmetically or functionally sensitive areas. Approaches that minimize the amount of tissue removed while ensuring the highest possible cure rate are favorable. In addition to surgery, topical imiquimod has been established as a potential treatment of BCC. Imiquimod, a nucleoside analogue of the imidazoquinoline family, is an agonist of toll-like receptors 7 and 8 that promotes cytokine-induced cell death via nuclear factor kB and a helper T cell T_H1-weighted antitumor inflammatory response.^5,6 Although clearance rates with imiquimod vary by drug regimen, success rates of 43% to 100% for superficial BCCs, 42% to 100% for nodular BCCs, and 56% to 63% for infiltrative BCCs have been reported.⁷ In a 2007 randomized study of imiquimod cream 5%, 5-FU ointment 5%, or cryosurgery for the treatment of AK, imiquimod resulted in superior and more reliable clearance with lower recurrence rates.⁸

Similar to BCC, AK is closely linked to lifetime cumulative sun exposure.⁹ Actinic keratoses have been well established as precursors to SCC, and some researchers advocate for their reclassification as early SCC in situ.¹⁰ The incidence of malignant conversion of AK to SCC has been estimated at 0.025% to 16% annually, with an estimated lifetime risk for malignant transformation of 8% per individual AK.^11,12 Cryotherapy has been a mainstay for the treatment of isolated AK, and alternative therapies including curettage, photodynamic therapy, and laser therapy have been employed. Field-directed therapy has become a popular alternative that targets multiple lesions and field cancerization.^8,13,14 Field cancerization implies that if one cell in the patient’s epidermis has been exposed to enough UV radiation to develop into a precancerous lesion or early skin cancer, then many other cells in the same environment likely have some degree of UV radiation–induced atypia.¹⁵ 5-Fluorouacil is a pyrimidine analogue chemotherapeutic agent that inhibits thymidylate synthase and interferes with DNA synthesis.¹⁶ This mechanism of 5-FU commonly causes an inflammatory response characterized by burning, dryness, and redness, but these effects rarely force early discontinuation of treatment. A randomized controlled trial comparing 5-FU cream 0.5% to a placebo found that complete clearance rates at 4 weeks posttreatment were significantly higher in the treatment group (47.5%) versus placebo (3.4%)(P<.001).¹³ Additional trials have established no significant superiority of 5-FU cream 5% over 5-FU cream 0.5%, with a decrease in side effects noted in patients treated with the lower concentration.¹⁷

Our patient had a history of a recurrent BCC and was previously treated with imiquimod. He showed no inflammatory response to field therapy with 5-FU within the perimeter of prior immunomodulatory therapy. Although no frank scaling or crusting papules consistent with AK were observed in the previously treated area prior to 5-FU therapy, subclinical field damage in that area was expected because 10 years of additional sun exposure had accumulated since imiquimod therapy was completed. Several conclusions can be drawn from this observation. Primarily, no new clinically significant actinic lesions occurred on the previously treated skin. This observation is consistent with 12-month follow-up data on AKs treated with either 5-FU, imiquimod, or cryosurgery that identified imiquimod as having the lowest recurrence rate.⁸ Thus, a photoprotective effect may be ascribed to imiquimod therapy that extends beyond its drug effects on atypical keratinocytes. It has been one author’s personal experience (M.Q.) that patients treated with 5-FU experience recurrence of AKs within 3 to 5 years versus 10 years of remission with imiquimod. In our patient, imiquimod therapy seemed to reset the patient’s skin at the location of the prior BCC and surrounding field cancerization.

Studies with long-term follow-up are needed to investigate the need for re-treatment with imiquimod or 5-FU. The longevity of imiquimod treatment may be of importance beyond the treatment of AKs or NMSCs. For instance, during the treatment of lentigo maligna with imiquimod, Metcalf et al¹⁸ found a significant reduction in solar elastosis (P=.0036), normalization of epidermal thickness (P=.0073), and increased papillary dermal fibroplasia in pre- and posttreatment biopsies (P<.0001), which have been described as antiaging effects in the laypress. Some of these mechanisms appear to be implicated in the observations noted in our patient. The 10-year period between the 2 courses of therapy in our patient suggests that imiquimod may cause sustained healing of skin that was previously classified both clinically and microscopically as UV damaged.

Conclusion

Both topical immunomodulators such as imiquimod and topical chemotherapeutic agents such as 5-FU have a role in the field treatment of AK and the focal treatment of superficial BCC and SCC. As multiple topical immunomodulators continue to be evaluated, long-term studies assessing the need for re-treatment as well as the degree of sustained remission of sun damage will be necessary. We expect that their individual roles will continue to become more precisely defined and distinct in the coming years.

First described by Fetsch et al¹ in 2001, superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor that typically affects the fingers and toes with frequent involvement of the nail unit. It is not widely recognized and remains poorly understood. We describe a series of 3 cases of SAFM encountered at our institution and provide a review of the literature on this unique tumor.

Case Reports

Patient 1

A 35-year-old man presented for treatment of a “wart” on the right fifth toe that had increased in size over the last year. He reported that the lesion was mildly painful and occasionally bled or drained clear fluid. He also noted cracking of the nail plate on the same toe. Physical examination revealed a firm, flesh-colored, 3-mm dermal papule on the proximal nail fold of the right fifth toe with subtle flattening of the underlying nail plate (Figure 1). The patient underwent biopsy of the involved proximal nail fold. Histopathology revealed a proliferation of small oval and spindle cells arranged in fascicles and bundles in the dermis (Figure 2). There was extensive mucin deposition associated with the spindle cell proliferation. Additionally, spindle cells and mucin surrounded and entrapped collagen bundles on the periphery of the lesion. Lesional cells were diffusely positive for CD34 and extended to the deep surgical margin (Figure 3). S-100 and factor XIIIa stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Figure 1. Firm dermal papule on the proximal nail fold of the right fifth toe with associated nail plate dystrophy. Figure 2. Small oval and spindle cells arranged in fascicles and bundles in the dermis, with extensive mucin deposition and collagen trapping (H&E, original magnification ×100). Figure 3. Tumor cells were positive on CD34 staining (original magnification ×40). Figure 4. Dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition (H&E, original magnification ×400).

Patient 2

A 47-year-old man presented with an asymptomatic growth on the left fourth toe that had increased in size over the last year. Physical examination revealed an 8-mm, firm, fleshy, flesh-colored, smooth and slightly pedunculated papule on the distal aspect of the left fourth toe. The nail plate and periungual region were not involved. A shave biopsy of the papule was obtained. Histopathology demonstrated dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition throughout the dermis (Figure 4). Lesional cells were positive for CD34. An S-100 stain highlighted dermal dendritic cells, but lesional cells were negative. No further excision was undertaken, and there was no evidence of recurrence at 1-year follow-up. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Patient 3

A 45-year-old woman presented with asymptomatic distal onycholysis of the right thumbnail of 1 year’s duration. She denied any history of trauma, and no bleeding or pigmentary changes were noted. Physical examination revealed a 5-mm flesh-colored papule on the hyponychium of the right thumb with focal onycholysis (Figure 5). A wedge biopsy of the lesion was performed. Histopathology showed an intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (Figure 6). CD34 staining strongly highlighted lesional cells. S-100 and neurofilament stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Comment

Clinically, SAFM typically presents as a slow-growing solitary nodule on the distal fingers or toes. The great toe is the most commonly affected digit, and the tumor may be subungual in up to two-thirds of cases.¹ Unusual locations, such as the heel, also have been reported.² Onset typically occurs in the fifth or sixth decade, and there is an approximately 2-fold higher incidence in men than women.^1-3

Histopathologically, SAFM is a characteristically well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma.⁴ The tumor often occupies the entire dermis and may extend into the subcutis or occasionally the underlying fascia and bone.^4,5 Mast cells often are prominent, and microvascular accentuation also may be seen. Inflammatory infiltrates and multinucleated giant cells typically are not seen.⁶ Although 2 cases of atypical SAFM have been described,² cellular atypia is not a characteristic feature of SAFM.

The immunohistochemical profile of SAFM is characterized by diffuse or focal expression of CD34, focal expression of epithelial membrane antigen (EMA), CD99 expression, and varying numbers of factor XIIIa–positive histiocytes.^2,3 Positive staining for vimentin also is common. Staining typically is negative for S-100, human melanoma black 45, keratin, smooth muscle actin, and desmin.

The standard treatment of SAFM is complete local resection of the tumor, though some patients have been treated with partial excision or biopsy and partial or complete digital amputation.¹ Local recurrence may occur in up to 20% of cases; however, approximately two-thirds of the reported recurrences in the literature occurred after incomplete tumor excision.^1,2 It may be more appropriate to consider these cases as persistent rather than recurrent tumors. Superficial acral fibromyxoma is considered a benign tumor, with no known cases of metastases.⁴

Figure 5. A firm flesh-colored papule on the hyponychium of the right thumb prior to biopsy. Figure 6. Intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (H&E, original magnification ×40).

A broad differential diagnosis exists for SAFM and it can be difficult to differentiate it from a wide variety of benign and malignant tumors that may be seen on the nail unit and distal extremities (Table). Myxoid neurofibromas typically present as solitary lesions on the hands and feet. Similar to SAFM, myxoid neurofibromas are unencapsulated dermal tumors composed of spindle-shaped cells in which mast cells often are conspicuous.^2,7 However, tumor cells in myxoid neurofibromas are S-100 positive, and the lesions typically do not show vasculature accentuation.^4,7

Sclerosing perineuriomas are benign fibrous tumors of the fingers and palms. Histopathologically, bland spindle cells arranged in fascicles and whorls are observed in a hyalinized collagen matrix.⁸ Immunohistochemically, sclerosing perineuriomas are positive for EMA and negative for S-100, but unlike SAFM, these tumors usually are CD34 negative.⁸

Superficial angiomyxomas typically are located on the head and neck but also may be found in other locations such as the trunk. They present as cutaneous papules or polypoid lesions. Histopathologically, superficial angiomyxomas are poorly circumscribed with a lobular pattern. Spindle-shaped fibroblasts exist in a myxoid matrix with neutrophils and thin-walled capillaries. The fibroblasts are variably positive for CD34 but also are S-100 positive.^1,9

Myxoid dermatofibrosarcoma protuberans is a rare, locally aggressive, mesenchymal tumor of the skin and subcutis² that typically presents on the trunk, proximal extremities, or head and neck; occurrence on the fingers or toes is exceedingly rare.^2,10 Histopathologically, a myxoid stroma contains sheets of bland spindle-shaped cells with minimal to no atypia, sometimes arranged in a storiform pattern. The tumor characteristically invades deeply into the subcutaneous tissues. CD34 is characteristically positive and S-100 is negative.^2,10

Low-grade myxofibrosarcoma is a soft tissue sarcoma easily confused with other spindle cell tumors. It is one of the most common sarcomas in adults but rarely arises in acral areas.² It is characterized by a nodular growth pattern with marked nuclear atypia and perivascular clustering of tumor cells. CD34 staining may be positive in some cases.¹¹

Similar to SAFM, myxoinflammatory fibroblastic sarcoma has a predilection for the extremities.⁴ However, it typically presents as a subcutaneous mass and has no documented tendency for nail bed involvement. Also unlike SAFM, it has a remarkable inflammatory infiltrate and characteristic virocyte or Reed-Sternberg cells.¹²

Acquired digital fibrokeratomas are benign neoplasms that occur on fingers and toes; the classic clinical presentation is a solitary smooth nodule or dome, often with a characteristic projecting configuration and horn shape.¹ Histopathologically, these tumors are paucicellular with thick, vertically oriented, interwoven collagen bundles; cells may be positive for CD34 but are negative for EMA.^1,13 Related to acquired digital fibrokeratomas are Koenen tumors, which share a similar histology but are distinguished by their clinical characteristics. For example, Koenen tumors tend to be multifocal and are strongly associated with tuberous sclerosis. These tumors also have a tendency to recur.¹

Conclusion

Our report of 3 typical cases of SAFM highlights the need to keep this increasingly recognized and well-defined clinicopathological entity in the differential for slow-growing tumors in acral locations, particularly those in the periungual and subungual regions.

First described by Fetsch et al¹ in 2001, superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor that typically affects the fingers and toes with frequent involvement of the nail unit. It is not widely recognized and remains poorly understood. We describe a series of 3 cases of SAFM encountered at our institution and provide a review of the literature on this unique tumor.

Case Reports

Patient 1

A 35-year-old man presented for treatment of a “wart” on the right fifth toe that had increased in size over the last year. He reported that the lesion was mildly painful and occasionally bled or drained clear fluid. He also noted cracking of the nail plate on the same toe. Physical examination revealed a firm, flesh-colored, 3-mm dermal papule on the proximal nail fold of the right fifth toe with subtle flattening of the underlying nail plate (Figure 1). The patient underwent biopsy of the involved proximal nail fold. Histopathology revealed a proliferation of small oval and spindle cells arranged in fascicles and bundles in the dermis (Figure 2). There was extensive mucin deposition associated with the spindle cell proliferation. Additionally, spindle cells and mucin surrounded and entrapped collagen bundles on the periphery of the lesion. Lesional cells were diffusely positive for CD34 and extended to the deep surgical margin (Figure 3). S-100 and factor XIIIa stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Figure 1. Firm dermal papule on the proximal nail fold of the right fifth toe with associated nail plate dystrophy. Figure 2. Small oval and spindle cells arranged in fascicles and bundles in the dermis, with extensive mucin deposition and collagen trapping (H&E, original magnification ×100). Figure 3. Tumor cells were positive on CD34 staining (original magnification ×40). Figure 4. Dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition (H&E, original magnification ×400).

Patient 2

A 47-year-old man presented with an asymptomatic growth on the left fourth toe that had increased in size over the last year. Physical examination revealed an 8-mm, firm, fleshy, flesh-colored, smooth and slightly pedunculated papule on the distal aspect of the left fourth toe. The nail plate and periungual region were not involved. A shave biopsy of the papule was obtained. Histopathology demonstrated dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition throughout the dermis (Figure 4). Lesional cells were positive for CD34. An S-100 stain highlighted dermal dendritic cells, but lesional cells were negative. No further excision was undertaken, and there was no evidence of recurrence at 1-year follow-up. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Patient 3

A 45-year-old woman presented with asymptomatic distal onycholysis of the right thumbnail of 1 year’s duration. She denied any history of trauma, and no bleeding or pigmentary changes were noted. Physical examination revealed a 5-mm flesh-colored papule on the hyponychium of the right thumb with focal onycholysis (Figure 5). A wedge biopsy of the lesion was performed. Histopathology showed an intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (Figure 6). CD34 staining strongly highlighted lesional cells. S-100 and neurofilament stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Comment

Clinically, SAFM typically presents as a slow-growing solitary nodule on the distal fingers or toes. The great toe is the most commonly affected digit, and the tumor may be subungual in up to two-thirds of cases.¹ Unusual locations, such as the heel, also have been reported.² Onset typically occurs in the fifth or sixth decade, and there is an approximately 2-fold higher incidence in men than women.^1-3

Histopathologically, SAFM is a characteristically well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma.⁴ The tumor often occupies the entire dermis and may extend into the subcutis or occasionally the underlying fascia and bone.^4,5 Mast cells often are prominent, and microvascular accentuation also may be seen. Inflammatory infiltrates and multinucleated giant cells typically are not seen.⁶ Although 2 cases of atypical SAFM have been described,² cellular atypia is not a characteristic feature of SAFM.

The immunohistochemical profile of SAFM is characterized by diffuse or focal expression of CD34, focal expression of epithelial membrane antigen (EMA), CD99 expression, and varying numbers of factor XIIIa–positive histiocytes.^2,3 Positive staining for vimentin also is common. Staining typically is negative for S-100, human melanoma black 45, keratin, smooth muscle actin, and desmin.

The standard treatment of SAFM is complete local resection of the tumor, though some patients have been treated with partial excision or biopsy and partial or complete digital amputation.¹ Local recurrence may occur in up to 20% of cases; however, approximately two-thirds of the reported recurrences in the literature occurred after incomplete tumor excision.^1,2 It may be more appropriate to consider these cases as persistent rather than recurrent tumors. Superficial acral fibromyxoma is considered a benign tumor, with no known cases of metastases.⁴

Figure 5. A firm flesh-colored papule on the hyponychium of the right thumb prior to biopsy. Figure 6. Intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (H&E, original magnification ×40).

A broad differential diagnosis exists for SAFM and it can be difficult to differentiate it from a wide variety of benign and malignant tumors that may be seen on the nail unit and distal extremities (Table). Myxoid neurofibromas typically present as solitary lesions on the hands and feet. Similar to SAFM, myxoid neurofibromas are unencapsulated dermal tumors composed of spindle-shaped cells in which mast cells often are conspicuous.^2,7 However, tumor cells in myxoid neurofibromas are S-100 positive, and the lesions typically do not show vasculature accentuation.^4,7

Sclerosing perineuriomas are benign fibrous tumors of the fingers and palms. Histopathologically, bland spindle cells arranged in fascicles and whorls are observed in a hyalinized collagen matrix.⁸ Immunohistochemically, sclerosing perineuriomas are positive for EMA and negative for S-100, but unlike SAFM, these tumors usually are CD34 negative.⁸

Superficial angiomyxomas typically are located on the head and neck but also may be found in other locations such as the trunk. They present as cutaneous papules or polypoid lesions. Histopathologically, superficial angiomyxomas are poorly circumscribed with a lobular pattern. Spindle-shaped fibroblasts exist in a myxoid matrix with neutrophils and thin-walled capillaries. The fibroblasts are variably positive for CD34 but also are S-100 positive.^1,9

Myxoid dermatofibrosarcoma protuberans is a rare, locally aggressive, mesenchymal tumor of the skin and subcutis² that typically presents on the trunk, proximal extremities, or head and neck; occurrence on the fingers or toes is exceedingly rare.^2,10 Histopathologically, a myxoid stroma contains sheets of bland spindle-shaped cells with minimal to no atypia, sometimes arranged in a storiform pattern. The tumor characteristically invades deeply into the subcutaneous tissues. CD34 is characteristically positive and S-100 is negative.^2,10

Low-grade myxofibrosarcoma is a soft tissue sarcoma easily confused with other spindle cell tumors. It is one of the most common sarcomas in adults but rarely arises in acral areas.² It is characterized by a nodular growth pattern with marked nuclear atypia and perivascular clustering of tumor cells. CD34 staining may be positive in some cases.¹¹

Similar to SAFM, myxoinflammatory fibroblastic sarcoma has a predilection for the extremities.⁴ However, it typically presents as a subcutaneous mass and has no documented tendency for nail bed involvement. Also unlike SAFM, it has a remarkable inflammatory infiltrate and characteristic virocyte or Reed-Sternberg cells.¹²

Acquired digital fibrokeratomas are benign neoplasms that occur on fingers and toes; the classic clinical presentation is a solitary smooth nodule or dome, often with a characteristic projecting configuration and horn shape.¹ Histopathologically, these tumors are paucicellular with thick, vertically oriented, interwoven collagen bundles; cells may be positive for CD34 but are negative for EMA.^1,13 Related to acquired digital fibrokeratomas are Koenen tumors, which share a similar histology but are distinguished by their clinical characteristics. For example, Koenen tumors tend to be multifocal and are strongly associated with tuberous sclerosis. These tumors also have a tendency to recur.¹

Conclusion

Our report of 3 typical cases of SAFM highlights the need to keep this increasingly recognized and well-defined clinicopathological entity in the differential for slow-growing tumors in acral locations, particularly those in the periungual and subungual regions.

First described by Fetsch et al¹ in 2001, superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor that typically affects the fingers and toes with frequent involvement of the nail unit. It is not widely recognized and remains poorly understood. We describe a series of 3 cases of SAFM encountered at our institution and provide a review of the literature on this unique tumor.

Case Reports

Patient 1

A 35-year-old man presented for treatment of a “wart” on the right fifth toe that had increased in size over the last year. He reported that the lesion was mildly painful and occasionally bled or drained clear fluid. He also noted cracking of the nail plate on the same toe. Physical examination revealed a firm, flesh-colored, 3-mm dermal papule on the proximal nail fold of the right fifth toe with subtle flattening of the underlying nail plate (Figure 1). The patient underwent biopsy of the involved proximal nail fold. Histopathology revealed a proliferation of small oval and spindle cells arranged in fascicles and bundles in the dermis (Figure 2). There was extensive mucin deposition associated with the spindle cell proliferation. Additionally, spindle cells and mucin surrounded and entrapped collagen bundles on the periphery of the lesion. Lesional cells were diffusely positive for CD34 and extended to the deep surgical margin (Figure 3). S-100 and factor XIIIa stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Figure 1. Firm dermal papule on the proximal nail fold of the right fifth toe with associated nail plate dystrophy. Figure 2. Small oval and spindle cells arranged in fascicles and bundles in the dermis, with extensive mucin deposition and collagen trapping (H&E, original magnification ×100). Figure 3. Tumor cells were positive on CD34 staining (original magnification ×40). Figure 4. Dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition (H&E, original magnification ×400).

Patient 2

A 47-year-old man presented with an asymptomatic growth on the left fourth toe that had increased in size over the last year. Physical examination revealed an 8-mm, firm, fleshy, flesh-colored, smooth and slightly pedunculated papule on the distal aspect of the left fourth toe. The nail plate and periungual region were not involved. A shave biopsy of the papule was obtained. Histopathology demonstrated dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition throughout the dermis (Figure 4). Lesional cells were positive for CD34. An S-100 stain highlighted dermal dendritic cells, but lesional cells were negative. No further excision was undertaken, and there was no evidence of recurrence at 1-year follow-up. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Patient 3

A 45-year-old woman presented with asymptomatic distal onycholysis of the right thumbnail of 1 year’s duration. She denied any history of trauma, and no bleeding or pigmentary changes were noted. Physical examination revealed a 5-mm flesh-colored papule on the hyponychium of the right thumb with focal onycholysis (Figure 5). A wedge biopsy of the lesion was performed. Histopathology showed an intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (Figure 6). CD34 staining strongly highlighted lesional cells. S-100 and neurofilament stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Comment

Clinically, SAFM typically presents as a slow-growing solitary nodule on the distal fingers or toes. The great toe is the most commonly affected digit, and the tumor may be subungual in up to two-thirds of cases.¹ Unusual locations, such as the heel, also have been reported.² Onset typically occurs in the fifth or sixth decade, and there is an approximately 2-fold higher incidence in men than women.^1-3

Histopathologically, SAFM is a characteristically well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma.⁴ The tumor often occupies the entire dermis and may extend into the subcutis or occasionally the underlying fascia and bone.^4,5 Mast cells often are prominent, and microvascular accentuation also may be seen. Inflammatory infiltrates and multinucleated giant cells typically are not seen.⁶ Although 2 cases of atypical SAFM have been described,² cellular atypia is not a characteristic feature of SAFM.

The immunohistochemical profile of SAFM is characterized by diffuse or focal expression of CD34, focal expression of epithelial membrane antigen (EMA), CD99 expression, and varying numbers of factor XIIIa–positive histiocytes.^2,3 Positive staining for vimentin also is common. Staining typically is negative for S-100, human melanoma black 45, keratin, smooth muscle actin, and desmin.

The standard treatment of SAFM is complete local resection of the tumor, though some patients have been treated with partial excision or biopsy and partial or complete digital amputation.¹ Local recurrence may occur in up to 20% of cases; however, approximately two-thirds of the reported recurrences in the literature occurred after incomplete tumor excision.^1,2 It may be more appropriate to consider these cases as persistent rather than recurrent tumors. Superficial acral fibromyxoma is considered a benign tumor, with no known cases of metastases.⁴

Figure 5. A firm flesh-colored papule on the hyponychium of the right thumb prior to biopsy. Figure 6. Intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (H&E, original magnification ×40).

A broad differential diagnosis exists for SAFM and it can be difficult to differentiate it from a wide variety of benign and malignant tumors that may be seen on the nail unit and distal extremities (Table). Myxoid neurofibromas typically present as solitary lesions on the hands and feet. Similar to SAFM, myxoid neurofibromas are unencapsulated dermal tumors composed of spindle-shaped cells in which mast cells often are conspicuous.^2,7 However, tumor cells in myxoid neurofibromas are S-100 positive, and the lesions typically do not show vasculature accentuation.^4,7

Sclerosing perineuriomas are benign fibrous tumors of the fingers and palms. Histopathologically, bland spindle cells arranged in fascicles and whorls are observed in a hyalinized collagen matrix.⁸ Immunohistochemically, sclerosing perineuriomas are positive for EMA and negative for S-100, but unlike SAFM, these tumors usually are CD34 negative.⁸

Superficial angiomyxomas typically are located on the head and neck but also may be found in other locations such as the trunk. They present as cutaneous papules or polypoid lesions. Histopathologically, superficial angiomyxomas are poorly circumscribed with a lobular pattern. Spindle-shaped fibroblasts exist in a myxoid matrix with neutrophils and thin-walled capillaries. The fibroblasts are variably positive for CD34 but also are S-100 positive.^1,9

Myxoid dermatofibrosarcoma protuberans is a rare, locally aggressive, mesenchymal tumor of the skin and subcutis² that typically presents on the trunk, proximal extremities, or head and neck; occurrence on the fingers or toes is exceedingly rare.^2,10 Histopathologically, a myxoid stroma contains sheets of bland spindle-shaped cells with minimal to no atypia, sometimes arranged in a storiform pattern. The tumor characteristically invades deeply into the subcutaneous tissues. CD34 is characteristically positive and S-100 is negative.^2,10

Low-grade myxofibrosarcoma is a soft tissue sarcoma easily confused with other spindle cell tumors. It is one of the most common sarcomas in adults but rarely arises in acral areas.² It is characterized by a nodular growth pattern with marked nuclear atypia and perivascular clustering of tumor cells. CD34 staining may be positive in some cases.¹¹

Similar to SAFM, myxoinflammatory fibroblastic sarcoma has a predilection for the extremities.⁴ However, it typically presents as a subcutaneous mass and has no documented tendency for nail bed involvement. Also unlike SAFM, it has a remarkable inflammatory infiltrate and characteristic virocyte or Reed-Sternberg cells.¹²

Acquired digital fibrokeratomas are benign neoplasms that occur on fingers and toes; the classic clinical presentation is a solitary smooth nodule or dome, often with a characteristic projecting configuration and horn shape.¹ Histopathologically, these tumors are paucicellular with thick, vertically oriented, interwoven collagen bundles; cells may be positive for CD34 but are negative for EMA.^1,13 Related to acquired digital fibrokeratomas are Koenen tumors, which share a similar histology but are distinguished by their clinical characteristics. For example, Koenen tumors tend to be multifocal and are strongly associated with tuberous sclerosis. These tumors also have a tendency to recur.¹

Conclusion

Our report of 3 typical cases of SAFM highlights the need to keep this increasingly recognized and well-defined clinicopathological entity in the differential for slow-growing tumors in acral locations, particularly those in the periungual and subungual regions.

To the Editor:

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCCS) is a rare, highly penetrant, autosomal-dominant disorder that has been reported in approximately 200 families worldwide.^1,2 More than 90% of patients with HLRCCS develop multiple cutaneous leiomyomata, frequently in a segmental distribution, that increase in number and size with age. The extent of skin lesions is variable, even within the same family. Approximately 90% of female family members also have symptomatic uterine leiomyomata; 10% to 16% of these patients develop aggressive renal cell carcinomas,³ with more than 50% dying of metastatic disease within 5 years of diagnosis. Clinical diagnosis is established by the presence of multiple cutaneous leiomyomata, at least 1 of which should be histologically confirmed, or by a single leiomyoma in the presence of a positive family history.⁴

Mutations of fumarate hydratase (FH), a Krebs cycle enzyme that interconverts fumarate and malate, have been implicated in this syndrome.⁵ The homotetrameric 50 kDa protein exists in the mitochondrial matrix and the cytoplasm. Diagnosis is confirmed by molecular genetic testing for FH mutations or rarely by demonstrating reduced activity of FH enzyme. So far, at least 155 variations in DNA sequence of FH have been identified in HLRCCS. However, no definite genotype-phenotype correlations have been established yet. We present the case of a sporadic form of HLRCCS, which is rare.

A 27-year-old man presented with multiple slowly growing, painful lesions on the chest and back of 11 years’ duration. Physical examination revealed approximately twenty 2- to 4-mm pink-tan papules on the left side of the chest and several 2- to 7-mm tan-pink papules on the upper back (Figure 1A). The lesions were tender to touch, pressure, and cold temperatures. Microscopic examination of one of the lesions on the back showed benign smooth muscle proliferation expanding the reticular dermis, consistent with a cutaneous leiomyoma (Figure 1B).

Figure 1. Cluster of slow-growing, 2- to 7-mm, slightly erythematous papules on the upper back (A). Shave biopsy showed an unencapsulated dermal proliferation composed of interlacing fascicles of smooth muscle bundles with bland morphology, cigar-shaped nuclei, and lack of mitotic activity, compatible with cutaneous leiomyoma (B)(H&E, original magnification ×40).

Based on the clinical presentation, the possibility of HLRCCS was raised. Subsequently, the FH gene was sequenced from the peripheral blood revealing a heterozygous 4-base pair frameshift deletion mutation (TGAA deleted at positions 1083 through 1086 [complementary DNA][c.1083_1086delTGAA]), confirming the diagnosis (Figure 2). There was no family history of leiomyomata of the skin or uterus or renal tumors. Therefore, this case represents sporadic HLRCCS. Magnetic resonance imaging revealed only a 0.4-cm renal cortical cyst for which he was monitored for approximately a year but was lost to follow-up.

Figure 2. Sequencing analysis of the fumarate hydratase gene. DNA chromatograms: top, wild-type (WT) control; middle, patient (PT); bottom, comparison of WT and mutant DNA and protein sequences. Each gene located on autosomes has 2 copies, both of which are amplified during DNA sequencing. The height of peaks in the chromatograms represents the sum of nucleotides from both the copies. In this case (PT), there is a heterozygous c.1083_1086delTGAA 4-base pair deletion (TGAA deleted at positions 1083 through 1086 [complementary DNA]) in one copy and therefore the respective peak heights are reduced by approximately half compared to the WT. This deletion (underlined in bottom panel) leads to a frameshift in the coding sequence, resulting in altered amino acid sequence and a premature stop codon 10 codons downstream of the deletion, and thus a truncated protein.

The molecular mechanism of tumorigenesis in HLRCCS is poorly understood.⁶ Under normal circumstances, hypoxia-inducible factor (HIF) is hydroxylated by HIF prolyl hydroxylase after which it is targeted for an ubiquitin-mediated degradation (Figure 3 [top panel]). In the absence of FH, there is accumulation of fumarate, an inhibitor of HIF prolyl hydroxylase, leading to an increase in intracellular levels of unhydroxylated and undegradable HIF (Figure 3 [bottom panel]). Because of insufficient malate levels, the glucose metabolism through Krebs cycle shifts toward anaerobic glycolysis, even when sufficient oxygen is present to support respiration, creating a pseudohypoxic milieu that is similar to the Warburg effect. This environment leads to further stabilization of HIF, which is a transcription factor, that upregulates the expression of angiogenic factors (eg, vascular endothelial growth factor), growth factors (eg, erythropoietin, transforming growth factor a, platelet-derived growth factor), glucose transporters (eg, glucose transporter 1), and glycolytic enzymes (eg, phosphokinase mutase 1, lactate dehydrogenase A). These alterations may favor tumor growth by increasing the availability of biosynthetic intermediates needed for cellular proliferation and survival.

Figure 3.  Proposed mechanism of tumorigenesis in hereditary leiomyomatosis and renal cell carcinoma syndrome. In the presence of functional fumarate hydratase (FH), hypoxia-inducible factor (HIF) is degraded, resulting in normoxia (top panel). In the absence of functional FH, there is accumulation of fumarate, while malate levels decrease, and the glucose metabolism through Krebs cycle shifts toward anaerobic glycolysis, even when sufficient oxygen is present to support respiration (bottom panel). Increased fumarate inhibits HIF prolyl hydroxylase (HPH), which leads to stabilization of HIF, a transcription factor, that enhances anaerobic glycolysis, cellular proliferation, and angiogenesis, leading to tumor growth.

Patients with renal tumor–associated hereditary syndromes may present initially to dermatologists; therefore, it is important to recognize the cutaneous manifestations of these conditions because early diagnosis of renal cancer may prove to be lifesaving.

To the Editor:

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCCS) is a rare, highly penetrant, autosomal-dominant disorder that has been reported in approximately 200 families worldwide.^1,2 More than 90% of patients with HLRCCS develop multiple cutaneous leiomyomata, frequently in a segmental distribution, that increase in number and size with age. The extent of skin lesions is variable, even within the same family. Approximately 90% of female family members also have symptomatic uterine leiomyomata; 10% to 16% of these patients develop aggressive renal cell carcinomas,³ with more than 50% dying of metastatic disease within 5 years of diagnosis. Clinical diagnosis is established by the presence of multiple cutaneous leiomyomata, at least 1 of which should be histologically confirmed, or by a single leiomyoma in the presence of a positive family history.⁴

Mutations of fumarate hydratase (FH), a Krebs cycle enzyme that interconverts fumarate and malate, have been implicated in this syndrome.⁵ The homotetrameric 50 kDa protein exists in the mitochondrial matrix and the cytoplasm. Diagnosis is confirmed by molecular genetic testing for FH mutations or rarely by demonstrating reduced activity of FH enzyme. So far, at least 155 variations in DNA sequence of FH have been identified in HLRCCS. However, no definite genotype-phenotype correlations have been established yet. We present the case of a sporadic form of HLRCCS, which is rare.

A 27-year-old man presented with multiple slowly growing, painful lesions on the chest and back of 11 years’ duration. Physical examination revealed approximately twenty 2- to 4-mm pink-tan papules on the left side of the chest and several 2- to 7-mm tan-pink papules on the upper back (Figure 1A). The lesions were tender to touch, pressure, and cold temperatures. Microscopic examination of one of the lesions on the back showed benign smooth muscle proliferation expanding the reticular dermis, consistent with a cutaneous leiomyoma (Figure 1B).

Figure 1. Cluster of slow-growing, 2- to 7-mm, slightly erythematous papules on the upper back (A). Shave biopsy showed an unencapsulated dermal proliferation composed of interlacing fascicles of smooth muscle bundles with bland morphology, cigar-shaped nuclei, and lack of mitotic activity, compatible with cutaneous leiomyoma (B)(H&E, original magnification ×40).

Based on the clinical presentation, the possibility of HLRCCS was raised. Subsequently, the FH gene was sequenced from the peripheral blood revealing a heterozygous 4-base pair frameshift deletion mutation (TGAA deleted at positions 1083 through 1086 [complementary DNA][c.1083_1086delTGAA]), confirming the diagnosis (Figure 2). There was no family history of leiomyomata of the skin or uterus or renal tumors. Therefore, this case represents sporadic HLRCCS. Magnetic resonance imaging revealed only a 0.4-cm renal cortical cyst for which he was monitored for approximately a year but was lost to follow-up.

Figure 2. Sequencing analysis of the fumarate hydratase gene. DNA chromatograms: top, wild-type (WT) control; middle, patient (PT); bottom, comparison of WT and mutant DNA and protein sequences. Each gene located on autosomes has 2 copies, both of which are amplified during DNA sequencing. The height of peaks in the chromatograms represents the sum of nucleotides from both the copies. In this case (PT), there is a heterozygous c.1083_1086delTGAA 4-base pair deletion (TGAA deleted at positions 1083 through 1086 [complementary DNA]) in one copy and therefore the respective peak heights are reduced by approximately half compared to the WT. This deletion (underlined in bottom panel) leads to a frameshift in the coding sequence, resulting in altered amino acid sequence and a premature stop codon 10 codons downstream of the deletion, and thus a truncated protein.

The molecular mechanism of tumorigenesis in HLRCCS is poorly understood.⁶ Under normal circumstances, hypoxia-inducible factor (HIF) is hydroxylated by HIF prolyl hydroxylase after which it is targeted for an ubiquitin-mediated degradation (Figure 3 [top panel]). In the absence of FH, there is accumulation of fumarate, an inhibitor of HIF prolyl hydroxylase, leading to an increase in intracellular levels of unhydroxylated and undegradable HIF (Figure 3 [bottom panel]). Because of insufficient malate levels, the glucose metabolism through Krebs cycle shifts toward anaerobic glycolysis, even when sufficient oxygen is present to support respiration, creating a pseudohypoxic milieu that is similar to the Warburg effect. This environment leads to further stabilization of HIF, which is a transcription factor, that upregulates the expression of angiogenic factors (eg, vascular endothelial growth factor), growth factors (eg, erythropoietin, transforming growth factor a, platelet-derived growth factor), glucose transporters (eg, glucose transporter 1), and glycolytic enzymes (eg, phosphokinase mutase 1, lactate dehydrogenase A). These alterations may favor tumor growth by increasing the availability of biosynthetic intermediates needed for cellular proliferation and survival.

Figure 3.  Proposed mechanism of tumorigenesis in hereditary leiomyomatosis and renal cell carcinoma syndrome. In the presence of functional fumarate hydratase (FH), hypoxia-inducible factor (HIF) is degraded, resulting in normoxia (top panel). In the absence of functional FH, there is accumulation of fumarate, while malate levels decrease, and the glucose metabolism through Krebs cycle shifts toward anaerobic glycolysis, even when sufficient oxygen is present to support respiration (bottom panel). Increased fumarate inhibits HIF prolyl hydroxylase (HPH), which leads to stabilization of HIF, a transcription factor, that enhances anaerobic glycolysis, cellular proliferation, and angiogenesis, leading to tumor growth.

Patients with renal tumor–associated hereditary syndromes may present initially to dermatologists; therefore, it is important to recognize the cutaneous manifestations of these conditions because early diagnosis of renal cancer may prove to be lifesaving.

To the Editor:

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCCS) is a rare, highly penetrant, autosomal-dominant disorder that has been reported in approximately 200 families worldwide.^1,2 More than 90% of patients with HLRCCS develop multiple cutaneous leiomyomata, frequently in a segmental distribution, that increase in number and size with age. The extent of skin lesions is variable, even within the same family. Approximately 90% of female family members also have symptomatic uterine leiomyomata; 10% to 16% of these patients develop aggressive renal cell carcinomas,³ with more than 50% dying of metastatic disease within 5 years of diagnosis. Clinical diagnosis is established by the presence of multiple cutaneous leiomyomata, at least 1 of which should be histologically confirmed, or by a single leiomyoma in the presence of a positive family history.⁴

Mutations of fumarate hydratase (FH), a Krebs cycle enzyme that interconverts fumarate and malate, have been implicated in this syndrome.⁵ The homotetrameric 50 kDa protein exists in the mitochondrial matrix and the cytoplasm. Diagnosis is confirmed by molecular genetic testing for FH mutations or rarely by demonstrating reduced activity of FH enzyme. So far, at least 155 variations in DNA sequence of FH have been identified in HLRCCS. However, no definite genotype-phenotype correlations have been established yet. We present the case of a sporadic form of HLRCCS, which is rare.

A 27-year-old man presented with multiple slowly growing, painful lesions on the chest and back of 11 years’ duration. Physical examination revealed approximately twenty 2- to 4-mm pink-tan papules on the left side of the chest and several 2- to 7-mm tan-pink papules on the upper back (Figure 1A). The lesions were tender to touch, pressure, and cold temperatures. Microscopic examination of one of the lesions on the back showed benign smooth muscle proliferation expanding the reticular dermis, consistent with a cutaneous leiomyoma (Figure 1B).

Figure 1. Cluster of slow-growing, 2- to 7-mm, slightly erythematous papules on the upper back (A). Shave biopsy showed an unencapsulated dermal proliferation composed of interlacing fascicles of smooth muscle bundles with bland morphology, cigar-shaped nuclei, and lack of mitotic activity, compatible with cutaneous leiomyoma (B)(H&E, original magnification ×40).

Based on the clinical presentation, the possibility of HLRCCS was raised. Subsequently, the FH gene was sequenced from the peripheral blood revealing a heterozygous 4-base pair frameshift deletion mutation (TGAA deleted at positions 1083 through 1086 [complementary DNA][c.1083_1086delTGAA]), confirming the diagnosis (Figure 2). There was no family history of leiomyomata of the skin or uterus or renal tumors. Therefore, this case represents sporadic HLRCCS. Magnetic resonance imaging revealed only a 0.4-cm renal cortical cyst for which he was monitored for approximately a year but was lost to follow-up.

Figure 2. Sequencing analysis of the fumarate hydratase gene. DNA chromatograms: top, wild-type (WT) control; middle, patient (PT); bottom, comparison of WT and mutant DNA and protein sequences. Each gene located on autosomes has 2 copies, both of which are amplified during DNA sequencing. The height of peaks in the chromatograms represents the sum of nucleotides from both the copies. In this case (PT), there is a heterozygous c.1083_1086delTGAA 4-base pair deletion (TGAA deleted at positions 1083 through 1086 [complementary DNA]) in one copy and therefore the respective peak heights are reduced by approximately half compared to the WT. This deletion (underlined in bottom panel) leads to a frameshift in the coding sequence, resulting in altered amino acid sequence and a premature stop codon 10 codons downstream of the deletion, and thus a truncated protein.

The molecular mechanism of tumorigenesis in HLRCCS is poorly understood.⁶ Under normal circumstances, hypoxia-inducible factor (HIF) is hydroxylated by HIF prolyl hydroxylase after which it is targeted for an ubiquitin-mediated degradation (Figure 3 [top panel]). In the absence of FH, there is accumulation of fumarate, an inhibitor of HIF prolyl hydroxylase, leading to an increase in intracellular levels of unhydroxylated and undegradable HIF (Figure 3 [bottom panel]). Because of insufficient malate levels, the glucose metabolism through Krebs cycle shifts toward anaerobic glycolysis, even when sufficient oxygen is present to support respiration, creating a pseudohypoxic milieu that is similar to the Warburg effect. This environment leads to further stabilization of HIF, which is a transcription factor, that upregulates the expression of angiogenic factors (eg, vascular endothelial growth factor), growth factors (eg, erythropoietin, transforming growth factor a, platelet-derived growth factor), glucose transporters (eg, glucose transporter 1), and glycolytic enzymes (eg, phosphokinase mutase 1, lactate dehydrogenase A). These alterations may favor tumor growth by increasing the availability of biosynthetic intermediates needed for cellular proliferation and survival.

Figure 3.  Proposed mechanism of tumorigenesis in hereditary leiomyomatosis and renal cell carcinoma syndrome. In the presence of functional fumarate hydratase (FH), hypoxia-inducible factor (HIF) is degraded, resulting in normoxia (top panel). In the absence of functional FH, there is accumulation of fumarate, while malate levels decrease, and the glucose metabolism through Krebs cycle shifts toward anaerobic glycolysis, even when sufficient oxygen is present to support respiration (bottom panel). Increased fumarate inhibits HIF prolyl hydroxylase (HPH), which leads to stabilization of HIF, a transcription factor, that enhances anaerobic glycolysis, cellular proliferation, and angiogenesis, leading to tumor growth.

Patients with renal tumor–associated hereditary syndromes may present initially to dermatologists; therefore, it is important to recognize the cutaneous manifestations of these conditions because early diagnosis of renal cancer may prove to be lifesaving.

There are anecdotal reports of dogs detecting melanoma and studies of canines being able to not only detect but also distinguish cancer from noncancer. Analysis of volatile compounds or metabolites from exhaled human breath and excreted urine also has been shown to differentiate between patients with certain cancers and healthy individuals. In addition, investigators have demonstrated that melanoma tissue has a volatile profile that is distinct from healthy nonneoplastic skin and nevi.

Abaffy et al (Metabolomics. 2013;9:998-1008) conducted a study that gives further support to the potential for analyzing volatile organic compounds as biomarkers of melanoma. They used the headspace solid phase microextraction method followed by gas chromatography and mass spectrometry to compare the volatile metabolic profiles of melanoma and nonneoplastic healthy-appearing adjacent skin from the same patient. They discovered increased levels of lauric acid (C12:0) and palmitic acid (C16:0) in melanoma and they postulated that the increased levels of these fatty acids were due to cancer-associated upregulation of de novo lipid synthesis.

What’s the issue?

In the 1980s, nail fold capillary microscopy using an ophthalmoscope was occasionally performed to evaluate for disease-associated vascular changes in patients who were being evaluated for connective tissue disorders. Within 2 decades, a dermoscope to assist in the evaluation of not only nail folds but also pigmented and other lesions replaced the ophthalmoscope. The US Food and Drug Administration recently approved a software-driven optical imaging and data analysis device that can be used to obtain additional information to assist the clinician in making a decision whether to biopsy a pigmented lesion.

As our ability to develop more sensitive and specific methods to diagnose melanoma and differentiate it from benign lesions advances, our approach to the evaluation of patients with pigmented lesions shall continue to be modified. Based on the detection of melanoma-associated volatile organic compounds coupled with their potential use as readily accessible tumor-related biomarkers, it is reasonable to speculate: (1) that a handheld office-based device, a dermatoscenter, that can identify melanoma-induced volatile tumor markers shall be developed to evaluate whether pigmented lesions are malignant or benign, and (2) that this device will eventually become an integral component of the dermatologist’s diagnostic armamentarium. Does your dermatology center need a dermatoscenter?

We want to know your views! Tell us what you think.

There are anecdotal reports of dogs detecting melanoma and studies of canines being able to not only detect but also distinguish cancer from noncancer. Analysis of volatile compounds or metabolites from exhaled human breath and excreted urine also has been shown to differentiate between patients with certain cancers and healthy individuals. In addition, investigators have demonstrated that melanoma tissue has a volatile profile that is distinct from healthy nonneoplastic skin and nevi.

Abaffy et al (Metabolomics. 2013;9:998-1008) conducted a study that gives further support to the potential for analyzing volatile organic compounds as biomarkers of melanoma. They used the headspace solid phase microextraction method followed by gas chromatography and mass spectrometry to compare the volatile metabolic profiles of melanoma and nonneoplastic healthy-appearing adjacent skin from the same patient. They discovered increased levels of lauric acid (C12:0) and palmitic acid (C16:0) in melanoma and they postulated that the increased levels of these fatty acids were due to cancer-associated upregulation of de novo lipid synthesis.

What’s the issue?

In the 1980s, nail fold capillary microscopy using an ophthalmoscope was occasionally performed to evaluate for disease-associated vascular changes in patients who were being evaluated for connective tissue disorders. Within 2 decades, a dermoscope to assist in the evaluation of not only nail folds but also pigmented and other lesions replaced the ophthalmoscope. The US Food and Drug Administration recently approved a software-driven optical imaging and data analysis device that can be used to obtain additional information to assist the clinician in making a decision whether to biopsy a pigmented lesion.

As our ability to develop more sensitive and specific methods to diagnose melanoma and differentiate it from benign lesions advances, our approach to the evaluation of patients with pigmented lesions shall continue to be modified. Based on the detection of melanoma-associated volatile organic compounds coupled with their potential use as readily accessible tumor-related biomarkers, it is reasonable to speculate: (1) that a handheld office-based device, a dermatoscenter, that can identify melanoma-induced volatile tumor markers shall be developed to evaluate whether pigmented lesions are malignant or benign, and (2) that this device will eventually become an integral component of the dermatologist’s diagnostic armamentarium. Does your dermatology center need a dermatoscenter?

We want to know your views! Tell us what you think.

There are anecdotal reports of dogs detecting melanoma and studies of canines being able to not only detect but also distinguish cancer from noncancer. Analysis of volatile compounds or metabolites from exhaled human breath and excreted urine also has been shown to differentiate between patients with certain cancers and healthy individuals. In addition, investigators have demonstrated that melanoma tissue has a volatile profile that is distinct from healthy nonneoplastic skin and nevi.

Abaffy et al (Metabolomics. 2013;9:998-1008) conducted a study that gives further support to the potential for analyzing volatile organic compounds as biomarkers of melanoma. They used the headspace solid phase microextraction method followed by gas chromatography and mass spectrometry to compare the volatile metabolic profiles of melanoma and nonneoplastic healthy-appearing adjacent skin from the same patient. They discovered increased levels of lauric acid (C12:0) and palmitic acid (C16:0) in melanoma and they postulated that the increased levels of these fatty acids were due to cancer-associated upregulation of de novo lipid synthesis.

What’s the issue?

In the 1980s, nail fold capillary microscopy using an ophthalmoscope was occasionally performed to evaluate for disease-associated vascular changes in patients who were being evaluated for connective tissue disorders. Within 2 decades, a dermoscope to assist in the evaluation of not only nail folds but also pigmented and other lesions replaced the ophthalmoscope. The US Food and Drug Administration recently approved a software-driven optical imaging and data analysis device that can be used to obtain additional information to assist the clinician in making a decision whether to biopsy a pigmented lesion.

As our ability to develop more sensitive and specific methods to diagnose melanoma and differentiate it from benign lesions advances, our approach to the evaluation of patients with pigmented lesions shall continue to be modified. Based on the detection of melanoma-associated volatile organic compounds coupled with their potential use as readily accessible tumor-related biomarkers, it is reasonable to speculate: (1) that a handheld office-based device, a dermatoscenter, that can identify melanoma-induced volatile tumor markers shall be developed to evaluate whether pigmented lesions are malignant or benign, and (2) that this device will eventually become an integral component of the dermatologist’s diagnostic armamentarium. Does your dermatology center need a dermatoscenter?

We want to know your views! Tell us what you think.

To the Editor:

In a recent Cutis^® article, Cesaretti et al¹ reported a case of cutaneous metastasis from primary gastric cancer that appeared on a resection scar 6 years after remission and without any relapse of the primary tumor. We report a case of a 68-year-old man who was referred to the dermatology clinic with a 15×20-cm nonpruritic, nonscaly, bruiselike lesion on the right forearm of 1 month’s duration. Approximately 1.5 years prior to presentation, the patient was diagnosed with gastric adenocarcinoma (stage IV: T4N3M1) with hepatic and lung metastasis. Following 6 months of chemotherapy with cisplatin and 5-fluorouracil, a positron emission tomography–computed tomography scan was performed and showed a reduction in metastasis but growth of the primitive tumor. After 1 year of chemotherapy, the new positron emission tomography–computed tomography scan showed no metastases. However, the primitive tumor had increased in size.

One month prior to presentation to the dermatology department, a traumatic blood sample on the right forearm left the patient with a persistent ecchymosis. The lesion was thought to be a healing ecchymosis and no biopsy was performed. One month later, the skin lesion had become much thicker and more erythematous (Figure) but not larger. A skin biopsy of this well-defined plaque was performed. Histologic examination showed neovascularization, proliferative epithelial cells, and cytokeratin markers AE1/AE3 and CK20, leading to the diagnosis of skin metastasis of the gastric adenocarcinoma. Chemotherapy was discontinued because of the patient’s altered general status and palliative care was given until he died the following month (2 months after presentation).

Iatrogenic dissemination of cancer cells has been described often on scars of tumor surgery,² and in malignant melanoma, bruises and hematoma revealing preexisting metastases have been reported.^3,4 Our report of secondary metastasis on an ecchymosis suggests that the traumatic blood sample performed before the development of the metastasis caused circulating tumor cells in the skin, which led to their local proliferation. The skin metastasis was the first sign of relapse and was followed by alteration of the general status and death.

Our patient is an example of the “soil and seed”⁵ hypothesis. Our case illustrates the abilities of tumor cells to colonize the skin under favorable conditions and emphasizes the importance of minimizing bleeding events and iatrogenic seeding of internal neoplasms in daily practice.

To the Editor:

In a recent Cutis^® article, Cesaretti et al¹ reported a case of cutaneous metastasis from primary gastric cancer that appeared on a resection scar 6 years after remission and without any relapse of the primary tumor. We report a case of a 68-year-old man who was referred to the dermatology clinic with a 15×20-cm nonpruritic, nonscaly, bruiselike lesion on the right forearm of 1 month’s duration. Approximately 1.5 years prior to presentation, the patient was diagnosed with gastric adenocarcinoma (stage IV: T4N3M1) with hepatic and lung metastasis. Following 6 months of chemotherapy with cisplatin and 5-fluorouracil, a positron emission tomography–computed tomography scan was performed and showed a reduction in metastasis but growth of the primitive tumor. After 1 year of chemotherapy, the new positron emission tomography–computed tomography scan showed no metastases. However, the primitive tumor had increased in size.

One month prior to presentation to the dermatology department, a traumatic blood sample on the right forearm left the patient with a persistent ecchymosis. The lesion was thought to be a healing ecchymosis and no biopsy was performed. One month later, the skin lesion had become much thicker and more erythematous (Figure) but not larger. A skin biopsy of this well-defined plaque was performed. Histologic examination showed neovascularization, proliferative epithelial cells, and cytokeratin markers AE1/AE3 and CK20, leading to the diagnosis of skin metastasis of the gastric adenocarcinoma. Chemotherapy was discontinued because of the patient’s altered general status and palliative care was given until he died the following month (2 months after presentation).

Iatrogenic dissemination of cancer cells has been described often on scars of tumor surgery,² and in malignant melanoma, bruises and hematoma revealing preexisting metastases have been reported.^3,4 Our report of secondary metastasis on an ecchymosis suggests that the traumatic blood sample performed before the development of the metastasis caused circulating tumor cells in the skin, which led to their local proliferation. The skin metastasis was the first sign of relapse and was followed by alteration of the general status and death.

Our patient is an example of the “soil and seed”⁵ hypothesis. Our case illustrates the abilities of tumor cells to colonize the skin under favorable conditions and emphasizes the importance of minimizing bleeding events and iatrogenic seeding of internal neoplasms in daily practice.

To the Editor:

In a recent Cutis^® article, Cesaretti et al¹ reported a case of cutaneous metastasis from primary gastric cancer that appeared on a resection scar 6 years after remission and without any relapse of the primary tumor. We report a case of a 68-year-old man who was referred to the dermatology clinic with a 15×20-cm nonpruritic, nonscaly, bruiselike lesion on the right forearm of 1 month’s duration. Approximately 1.5 years prior to presentation, the patient was diagnosed with gastric adenocarcinoma (stage IV: T4N3M1) with hepatic and lung metastasis. Following 6 months of chemotherapy with cisplatin and 5-fluorouracil, a positron emission tomography–computed tomography scan was performed and showed a reduction in metastasis but growth of the primitive tumor. After 1 year of chemotherapy, the new positron emission tomography–computed tomography scan showed no metastases. However, the primitive tumor had increased in size.

One month prior to presentation to the dermatology department, a traumatic blood sample on the right forearm left the patient with a persistent ecchymosis. The lesion was thought to be a healing ecchymosis and no biopsy was performed. One month later, the skin lesion had become much thicker and more erythematous (Figure) but not larger. A skin biopsy of this well-defined plaque was performed. Histologic examination showed neovascularization, proliferative epithelial cells, and cytokeratin markers AE1/AE3 and CK20, leading to the diagnosis of skin metastasis of the gastric adenocarcinoma. Chemotherapy was discontinued because of the patient’s altered general status and palliative care was given until he died the following month (2 months after presentation).

Iatrogenic dissemination of cancer cells has been described often on scars of tumor surgery,² and in malignant melanoma, bruises and hematoma revealing preexisting metastases have been reported.^3,4 Our report of secondary metastasis on an ecchymosis suggests that the traumatic blood sample performed before the development of the metastasis caused circulating tumor cells in the skin, which led to their local proliferation. The skin metastasis was the first sign of relapse and was followed by alteration of the general status and death.

Our patient is an example of the “soil and seed”⁵ hypothesis. Our case illustrates the abilities of tumor cells to colonize the skin under favorable conditions and emphasizes the importance of minimizing bleeding events and iatrogenic seeding of internal neoplasms in daily practice.