Case Letter

To the Editor:

Papulonecrotic tuberculid (PNT) is a cutaneous hypersensitivity reaction to antigenic components of Mycobacterium species, most commonly Mycobacterium tuberculosis. According to a PubMed search of articles indexed for MEDLINE using the terms papulonecrotic tuberculid, Mycobacterium avium complex, and Mycobacterium, only 1 case of PNT secondary to infection with Mycobacterium avium complex (MAC) has been reported.^1,2 Papulonecrotic tuberculid classically presents with symmetrical, dusky red papules with necrosis on the extremities.³ Patients may or may not have associated symptoms of fever and weight loss. It is diagnosed through skin biopsy as well as identification of a distant source of mycobacterial infection. Papulonecrotic tuberculid is considered a reactive process to a distant site of mycobacterial infection, and skin lesions contain few, if any, mycobacteria.⁴

A 65-year-old man was admitted to the hospital for expedited workup of chronic fevers, 20-lb weight loss, and night sweats of 8 months’ duration. He had a medical history of myelodysplastic syndrome and autoimmune hemolytic anemia. During hospitalization, positron emission tomography revealed multilevel vertebral lytic and sclerotic lesions. Subsequent T10 vertebral biopsy showed necrotizing granulomatous inflammation with extensive necrosis and acid-fast bacilli–positive organisms. The patient was empirically started on rifampicin, isoniazid, pyrazinamide, ethambutol, and pyridoxine for presumed M tuberculosis and placed on respiratory isolation.

Dermatology was consulted for a recurrent tender rash on the bilateral upper and lower extremities of 5 years’ duration. Physical examination revealed numerous erythematous papulonecrotic lesions in various states of healing on the bilateral upper and lower extremities (Figure 1). Three years prior to the current presentation, 2 lesions were biopsied and demonstrated leukocytoclastic vasculitis with neutrophilic panniculitis and vasculopathy. A presumptive diagnosis of Sweet syndrome was made given the history of myelodysplastic syndrome, though an infectious etiology could not be ruled out at that time. Concurrently, the patient was diagnosed with autoimmune hemolytic anemia and was started on prednisone. Initially, the skin lesions improved with prednisone but never fully resolved; however, as the dosage of oral steroids decreased, the skin lesions worsened and presented in larger numbers with more frequency. The patient was titrated down to prednisone 5 mg daily with no additional treatment of the skin lesions at that time.

Disseminated MAC infection also was on the differential for our patient; however, we felt it was less likely than PNT for several reasons. First, disseminated infection rarely presents with cutaneous involvement and is associated with pulmonary involvement in 90% of cases.^7-9 Second, the granuloma formation noted on our patient’s skin biopsy was not typical for disseminated MAC but is well described in cases of PNT.^4,8,9 Finally, in the rare cases in which cutaneous involvement has occurred with disseminated mycobacterial infections, skin biopsies typically revealed numerous Mycobacterium organisms.^8,10 In contrast, skin lesions associated with PNT usually reveal few, if any, organisms, as was seen with our patient.²

The patient’s initial biopsies also supported a diagnosis of PNT, as early lesions of PNT typically show leukocytoclastic vasculitis. His response to low and high doses of prednisone also fit well with a PNT diagnosis. In fact, a case of PNT secondary to Mycobacterium bovis similarly showed an improvement in the rash with high-dose steroids but progression with lower doses.¹¹ It is possible that our patient’s response to steroids complicated the diagnosis of his rash.

The treatment of PNT is clearance of the underlying infection. Macrolide antibiotics, such as clarithromycin and azithromycin, have the best efficacy against MAC, in combination with ethambutol and/or rifabutin.^6,12 Treatment duration should be 1 year. Amikacin or streptomycin may be added to this regimen during early treatment.⁶ Mycobacterium avium complex is resistant to many antibiotics, including typical antituberculosis drugs, and sensitivities should be identified at the onset of treatment.^11,12

Albeit rare, clinicians should be aware of PNT secondary to MAC or other mycobacterial infections. Because this condition is difficult to diagnose with varying histologic findings and often negative tissue cultures, a high index of suspicion is necessary when a patient presents with recurrent papulonecrotic lesions, especially in immunocompromised hosts and patients with exposure to mycobacteria.

To the Editor:

Papulonecrotic tuberculid (PNT) is a cutaneous hypersensitivity reaction to antigenic components of Mycobacterium species, most commonly Mycobacterium tuberculosis. According to a PubMed search of articles indexed for MEDLINE using the terms papulonecrotic tuberculid, Mycobacterium avium complex, and Mycobacterium, only 1 case of PNT secondary to infection with Mycobacterium avium complex (MAC) has been reported.^1,2 Papulonecrotic tuberculid classically presents with symmetrical, dusky red papules with necrosis on the extremities.³ Patients may or may not have associated symptoms of fever and weight loss. It is diagnosed through skin biopsy as well as identification of a distant source of mycobacterial infection. Papulonecrotic tuberculid is considered a reactive process to a distant site of mycobacterial infection, and skin lesions contain few, if any, mycobacteria.⁴

A 65-year-old man was admitted to the hospital for expedited workup of chronic fevers, 20-lb weight loss, and night sweats of 8 months’ duration. He had a medical history of myelodysplastic syndrome and autoimmune hemolytic anemia. During hospitalization, positron emission tomography revealed multilevel vertebral lytic and sclerotic lesions. Subsequent T10 vertebral biopsy showed necrotizing granulomatous inflammation with extensive necrosis and acid-fast bacilli–positive organisms. The patient was empirically started on rifampicin, isoniazid, pyrazinamide, ethambutol, and pyridoxine for presumed M tuberculosis and placed on respiratory isolation.

Dermatology was consulted for a recurrent tender rash on the bilateral upper and lower extremities of 5 years’ duration. Physical examination revealed numerous erythematous papulonecrotic lesions in various states of healing on the bilateral upper and lower extremities (Figure 1). Three years prior to the current presentation, 2 lesions were biopsied and demonstrated leukocytoclastic vasculitis with neutrophilic panniculitis and vasculopathy. A presumptive diagnosis of Sweet syndrome was made given the history of myelodysplastic syndrome, though an infectious etiology could not be ruled out at that time. Concurrently, the patient was diagnosed with autoimmune hemolytic anemia and was started on prednisone. Initially, the skin lesions improved with prednisone but never fully resolved; however, as the dosage of oral steroids decreased, the skin lesions worsened and presented in larger numbers with more frequency. The patient was titrated down to prednisone 5 mg daily with no additional treatment of the skin lesions at that time.

Disseminated MAC infection also was on the differential for our patient; however, we felt it was less likely than PNT for several reasons. First, disseminated infection rarely presents with cutaneous involvement and is associated with pulmonary involvement in 90% of cases.^7-9 Second, the granuloma formation noted on our patient’s skin biopsy was not typical for disseminated MAC but is well described in cases of PNT.^4,8,9 Finally, in the rare cases in which cutaneous involvement has occurred with disseminated mycobacterial infections, skin biopsies typically revealed numerous Mycobacterium organisms.^8,10 In contrast, skin lesions associated with PNT usually reveal few, if any, organisms, as was seen with our patient.²

The patient’s initial biopsies also supported a diagnosis of PNT, as early lesions of PNT typically show leukocytoclastic vasculitis. His response to low and high doses of prednisone also fit well with a PNT diagnosis. In fact, a case of PNT secondary to Mycobacterium bovis similarly showed an improvement in the rash with high-dose steroids but progression with lower doses.¹¹ It is possible that our patient’s response to steroids complicated the diagnosis of his rash.

The treatment of PNT is clearance of the underlying infection. Macrolide antibiotics, such as clarithromycin and azithromycin, have the best efficacy against MAC, in combination with ethambutol and/or rifabutin.^6,12 Treatment duration should be 1 year. Amikacin or streptomycin may be added to this regimen during early treatment.⁶ Mycobacterium avium complex is resistant to many antibiotics, including typical antituberculosis drugs, and sensitivities should be identified at the onset of treatment.^11,12

Albeit rare, clinicians should be aware of PNT secondary to MAC or other mycobacterial infections. Because this condition is difficult to diagnose with varying histologic findings and often negative tissue cultures, a high index of suspicion is necessary when a patient presents with recurrent papulonecrotic lesions, especially in immunocompromised hosts and patients with exposure to mycobacteria.

To the Editor:

Papulonecrotic tuberculid (PNT) is a cutaneous hypersensitivity reaction to antigenic components of Mycobacterium species, most commonly Mycobacterium tuberculosis. According to a PubMed search of articles indexed for MEDLINE using the terms papulonecrotic tuberculid, Mycobacterium avium complex, and Mycobacterium, only 1 case of PNT secondary to infection with Mycobacterium avium complex (MAC) has been reported.^1,2 Papulonecrotic tuberculid classically presents with symmetrical, dusky red papules with necrosis on the extremities.³ Patients may or may not have associated symptoms of fever and weight loss. It is diagnosed through skin biopsy as well as identification of a distant source of mycobacterial infection. Papulonecrotic tuberculid is considered a reactive process to a distant site of mycobacterial infection, and skin lesions contain few, if any, mycobacteria.⁴

A 65-year-old man was admitted to the hospital for expedited workup of chronic fevers, 20-lb weight loss, and night sweats of 8 months’ duration. He had a medical history of myelodysplastic syndrome and autoimmune hemolytic anemia. During hospitalization, positron emission tomography revealed multilevel vertebral lytic and sclerotic lesions. Subsequent T10 vertebral biopsy showed necrotizing granulomatous inflammation with extensive necrosis and acid-fast bacilli–positive organisms. The patient was empirically started on rifampicin, isoniazid, pyrazinamide, ethambutol, and pyridoxine for presumed M tuberculosis and placed on respiratory isolation.

Dermatology was consulted for a recurrent tender rash on the bilateral upper and lower extremities of 5 years’ duration. Physical examination revealed numerous erythematous papulonecrotic lesions in various states of healing on the bilateral upper and lower extremities (Figure 1). Three years prior to the current presentation, 2 lesions were biopsied and demonstrated leukocytoclastic vasculitis with neutrophilic panniculitis and vasculopathy. A presumptive diagnosis of Sweet syndrome was made given the history of myelodysplastic syndrome, though an infectious etiology could not be ruled out at that time. Concurrently, the patient was diagnosed with autoimmune hemolytic anemia and was started on prednisone. Initially, the skin lesions improved with prednisone but never fully resolved; however, as the dosage of oral steroids decreased, the skin lesions worsened and presented in larger numbers with more frequency. The patient was titrated down to prednisone 5 mg daily with no additional treatment of the skin lesions at that time.

Disseminated MAC infection also was on the differential for our patient; however, we felt it was less likely than PNT for several reasons. First, disseminated infection rarely presents with cutaneous involvement and is associated with pulmonary involvement in 90% of cases.^7-9 Second, the granuloma formation noted on our patient’s skin biopsy was not typical for disseminated MAC but is well described in cases of PNT.^4,8,9 Finally, in the rare cases in which cutaneous involvement has occurred with disseminated mycobacterial infections, skin biopsies typically revealed numerous Mycobacterium organisms.^8,10 In contrast, skin lesions associated with PNT usually reveal few, if any, organisms, as was seen with our patient.²

The patient’s initial biopsies also supported a diagnosis of PNT, as early lesions of PNT typically show leukocytoclastic vasculitis. His response to low and high doses of prednisone also fit well with a PNT diagnosis. In fact, a case of PNT secondary to Mycobacterium bovis similarly showed an improvement in the rash with high-dose steroids but progression with lower doses.¹¹ It is possible that our patient’s response to steroids complicated the diagnosis of his rash.

The treatment of PNT is clearance of the underlying infection. Macrolide antibiotics, such as clarithromycin and azithromycin, have the best efficacy against MAC, in combination with ethambutol and/or rifabutin.^6,12 Treatment duration should be 1 year. Amikacin or streptomycin may be added to this regimen during early treatment.⁶ Mycobacterium avium complex is resistant to many antibiotics, including typical antituberculosis drugs, and sensitivities should be identified at the onset of treatment.^11,12

Albeit rare, clinicians should be aware of PNT secondary to MAC or other mycobacterial infections. Because this condition is difficult to diagnose with varying histologic findings and often negative tissue cultures, a high index of suspicion is necessary when a patient presents with recurrent papulonecrotic lesions, especially in immunocompromised hosts and patients with exposure to mycobacteria.

To the Editor:

Mycosis fungoides (MF) is the most common form of primary cutaneous T-cell lymphoma. It has been associated with increased risk for other visceral and hematologic malignancies.¹ Chronic lymphocytic leukemia (CLL) is one of the most common hematologic malignancies. In the United States, a patient’s lifetime risk for CLL is 0.6%. Chronic lymphocytic leukemia often is diagnosed as an incidental finding and typically is not detrimental to a patient’s health. Six cases of MF with antecedent or concomitant CLL were identified in a cohort of patients treated at the University of Minnesota (Minneapolis, Minnesota) from 2005 to 2017 (Table).

All 6 patients were male, with a mean age of 80.5 years. The mean age at CLL diagnosis was 62.5 years, while the mean age at MF diagnosis was 75.3 years. Three patients were younger than 60 years when their CLL was diagnosed: 49, 55, and 57 years. Notably, 4 patients had more aggressive types of MF: 3 with tumor-stage disease, and 1 with folliculotropic MF. Five patients were diagnosed with CLL before their MF was diagnosed (mean, 13.4 years prior; range, 3–31 years), and 1 was diagnosed as part of the initial MF workup.

Given the frequency of both MF and CLL, the co-occurrence of these diseases is not surprising, as other case reports and a larger case series have described the relationship between MF and malignancy.² It is possible that CLL patients are more likely to be diagnosed with MF because of their regular hematology/oncology follow-up; however, none of our patients were referred from hematology/oncology to dermatology. Alternatively, patients with MF may be more likely to be diagnosed with CLL because of repeated bloodwork performed for diagnosis and screening, which occurred in only 1 of 6 cases. Most of the other patients were diagnosed with MF more than a decade after being diagnosed with CLL.

Does having CLL make patients more likely to develop MF? It is known that patients with CLL may experience immunodeficiency secondary to immune dysregulation, making them more susceptible to infection and secondary malignancies.³ Of our 6 cases, 4 had aggressive or advanced forms of MF, which is similar to the findings of Chang et al.² In their report, of 8 patients with MF, 2 had tumor-stage disease and 2 had erythrodermic MF. They determined that these patients had worse overall survival.² Our data corroborate the finding that patients with CLL may develop more severe MF, which leads to the conclusion that patients diagnosed with CLL before, concomitantly, or after their diagnosis of MF should be closely monitored. It is notable that patients with more advanced disease tend to be older at the time of diagnosis and that patients who are diagnosed at 57 years or older have been found to have worse disease-specific survival.^4,5

This report is limited by the small sample size (6 cases), but it serves to draw attention to the phenomenon of co-occurrence of MF and CLL, and the concern that patients with CLL may develop more aggressive MF.

To the Editor:

Mycosis fungoides (MF) is the most common form of primary cutaneous T-cell lymphoma. It has been associated with increased risk for other visceral and hematologic malignancies.¹ Chronic lymphocytic leukemia (CLL) is one of the most common hematologic malignancies. In the United States, a patient’s lifetime risk for CLL is 0.6%. Chronic lymphocytic leukemia often is diagnosed as an incidental finding and typically is not detrimental to a patient’s health. Six cases of MF with antecedent or concomitant CLL were identified in a cohort of patients treated at the University of Minnesota (Minneapolis, Minnesota) from 2005 to 2017 (Table).

All 6 patients were male, with a mean age of 80.5 years. The mean age at CLL diagnosis was 62.5 years, while the mean age at MF diagnosis was 75.3 years. Three patients were younger than 60 years when their CLL was diagnosed: 49, 55, and 57 years. Notably, 4 patients had more aggressive types of MF: 3 with tumor-stage disease, and 1 with folliculotropic MF. Five patients were diagnosed with CLL before their MF was diagnosed (mean, 13.4 years prior; range, 3–31 years), and 1 was diagnosed as part of the initial MF workup.

Given the frequency of both MF and CLL, the co-occurrence of these diseases is not surprising, as other case reports and a larger case series have described the relationship between MF and malignancy.² It is possible that CLL patients are more likely to be diagnosed with MF because of their regular hematology/oncology follow-up; however, none of our patients were referred from hematology/oncology to dermatology. Alternatively, patients with MF may be more likely to be diagnosed with CLL because of repeated bloodwork performed for diagnosis and screening, which occurred in only 1 of 6 cases. Most of the other patients were diagnosed with MF more than a decade after being diagnosed with CLL.

Does having CLL make patients more likely to develop MF? It is known that patients with CLL may experience immunodeficiency secondary to immune dysregulation, making them more susceptible to infection and secondary malignancies.³ Of our 6 cases, 4 had aggressive or advanced forms of MF, which is similar to the findings of Chang et al.² In their report, of 8 patients with MF, 2 had tumor-stage disease and 2 had erythrodermic MF. They determined that these patients had worse overall survival.² Our data corroborate the finding that patients with CLL may develop more severe MF, which leads to the conclusion that patients diagnosed with CLL before, concomitantly, or after their diagnosis of MF should be closely monitored. It is notable that patients with more advanced disease tend to be older at the time of diagnosis and that patients who are diagnosed at 57 years or older have been found to have worse disease-specific survival.^4,5

This report is limited by the small sample size (6 cases), but it serves to draw attention to the phenomenon of co-occurrence of MF and CLL, and the concern that patients with CLL may develop more aggressive MF.

To the Editor:

Mycosis fungoides (MF) is the most common form of primary cutaneous T-cell lymphoma. It has been associated with increased risk for other visceral and hematologic malignancies.¹ Chronic lymphocytic leukemia (CLL) is one of the most common hematologic malignancies. In the United States, a patient’s lifetime risk for CLL is 0.6%. Chronic lymphocytic leukemia often is diagnosed as an incidental finding and typically is not detrimental to a patient’s health. Six cases of MF with antecedent or concomitant CLL were identified in a cohort of patients treated at the University of Minnesota (Minneapolis, Minnesota) from 2005 to 2017 (Table).

All 6 patients were male, with a mean age of 80.5 years. The mean age at CLL diagnosis was 62.5 years, while the mean age at MF diagnosis was 75.3 years. Three patients were younger than 60 years when their CLL was diagnosed: 49, 55, and 57 years. Notably, 4 patients had more aggressive types of MF: 3 with tumor-stage disease, and 1 with folliculotropic MF. Five patients were diagnosed with CLL before their MF was diagnosed (mean, 13.4 years prior; range, 3–31 years), and 1 was diagnosed as part of the initial MF workup.

Given the frequency of both MF and CLL, the co-occurrence of these diseases is not surprising, as other case reports and a larger case series have described the relationship between MF and malignancy.² It is possible that CLL patients are more likely to be diagnosed with MF because of their regular hematology/oncology follow-up; however, none of our patients were referred from hematology/oncology to dermatology. Alternatively, patients with MF may be more likely to be diagnosed with CLL because of repeated bloodwork performed for diagnosis and screening, which occurred in only 1 of 6 cases. Most of the other patients were diagnosed with MF more than a decade after being diagnosed with CLL.

Does having CLL make patients more likely to develop MF? It is known that patients with CLL may experience immunodeficiency secondary to immune dysregulation, making them more susceptible to infection and secondary malignancies.³ Of our 6 cases, 4 had aggressive or advanced forms of MF, which is similar to the findings of Chang et al.² In their report, of 8 patients with MF, 2 had tumor-stage disease and 2 had erythrodermic MF. They determined that these patients had worse overall survival.² Our data corroborate the finding that patients with CLL may develop more severe MF, which leads to the conclusion that patients diagnosed with CLL before, concomitantly, or after their diagnosis of MF should be closely monitored. It is notable that patients with more advanced disease tend to be older at the time of diagnosis and that patients who are diagnosed at 57 years or older have been found to have worse disease-specific survival.^4,5

This report is limited by the small sample size (6 cases), but it serves to draw attention to the phenomenon of co-occurrence of MF and CLL, and the concern that patients with CLL may develop more aggressive MF.

To the Editor:

Nevus sebaceous of Jadassohn (or nevus sebaceous [NS]) is a congenital hamartomatous disorder initially described by Jadassohn¹ in 1895. Nevus sebaceous occurs in 0.3% of newborns² and is most commonly identified on the face and scalp.^3,4 Mehregan and Pinkus⁵ characterized NS as an organoid tumor containing multiple skin components with 3 life stages. The first stage—occurring during infancy—consists of immature hair follicles and sebaceous glands. The second stage—beginning at puberty—shows development of sebaceous glands, epidermal hyperplasia, and maturation of apocrine glands. The final stage involves formation of secondary benign and malignant neoplasms.

Historically, basal cell carcinoma (BCC) was thought to be the most common neoplasm arising in NS.^5-8 In 1993, Ackerman et al⁹ introduced a new definition of trichoblastoma (TB), expanding the definition to encompass previously excluded benign follicular neoplasms. Large studies conducted after this new definition was proposed suggested that syringocystadenoma papilliferum and TB develop more frequently than does BCC.^3,4,10-15 Furthermore, Cribier et al⁴ and Merrot et al¹⁵ reviewed prior cases of NS using the new definition and asserted that the majority of previously diagnosed cases of BCC were considered to be TB under the new criteria. With the advent of modern diagnostic testing, the rate of secondary benign neoplasm growth is now thought to be between 7% and 19%, with syringocystadenoma papilliferum arising in 2% to 13% of cases and TB in 1.5% to 7%.^3,4,10-14 Malignant neoplasms are observed much less frequently, with BCC arising in 0% to 1% of NS cases.

Nevus sebaceous lesions typically enlarge during puberty, while malignant neoplasms occur almost exclusively in adulthood,^4,10-12 suggesting that hormones contribute to NS stage progression. We present the case of a woman who developed BCC in a previously asymptomatic NS during pregnancy.

A 32-year-old woman who was otherwise healthy presented to our dermatology clinic with a pink-yellow verrucous plaque on the right temporal hairline extending to the preauricular area of the face. The patient had no personal or family history of skin cancer and no history of tanning bed use. She reported that the lesion had been present since birth. A diagnosis of NS was made.

Two years later, she presented with a new bleeding growth atop the previously diagnosed NS that had been present for approximately 4 months (Figure). At this visit she was pregnant (30 weeks’ gestation). Physical examination revealed a 4-mm, brown, pearly papule at the inferior margin of the previously noted pink verrucous plaque on the right temporal hairline. A biopsy was performed and histopathology displayed aggregates of basaloid cells with a high nuclear to cytoplasmic ratio, peripheral palisading, and abundant melanin, consistent with pigmented BCC. The patient was referred for Mohs micrographic surgery; the lesion was removed with clear margins. The patient had no recurrence of BCC at 36-month follow-up.

Similarly, cases of rapid growth of NS lesions during pregnancy, a state of increased testosterone production,²⁷ have been reported.²⁸ We present a case of a BCC arising in a previously asymptomatic NS during pregnancy. To our knowledge, no large studies have assessed the effect of hormone level changes during pregnancy on NS growth and secondary malignant transformation. Prior to the 1990s, prophylactic excision of NS during childhood was recommended to prevent malignant neoplasm formation.^29,30 More recently, a more conservative approach has been advocated because of a lower rate of malignant transformation than previously thought; some dermatologists recommend close monitoring as an alternative to early removal.^{4,13,14,29,31} This case report proposes that pregnancy may be a time of increased risk for malignant transformation and that NS lesions might require close monitoring during pregnancy.

To the Editor:

Nevus sebaceous of Jadassohn (or nevus sebaceous [NS]) is a congenital hamartomatous disorder initially described by Jadassohn¹ in 1895. Nevus sebaceous occurs in 0.3% of newborns² and is most commonly identified on the face and scalp.^3,4 Mehregan and Pinkus⁵ characterized NS as an organoid tumor containing multiple skin components with 3 life stages. The first stage—occurring during infancy—consists of immature hair follicles and sebaceous glands. The second stage—beginning at puberty—shows development of sebaceous glands, epidermal hyperplasia, and maturation of apocrine glands. The final stage involves formation of secondary benign and malignant neoplasms.

Historically, basal cell carcinoma (BCC) was thought to be the most common neoplasm arising in NS.^5-8 In 1993, Ackerman et al⁹ introduced a new definition of trichoblastoma (TB), expanding the definition to encompass previously excluded benign follicular neoplasms. Large studies conducted after this new definition was proposed suggested that syringocystadenoma papilliferum and TB develop more frequently than does BCC.^3,4,10-15 Furthermore, Cribier et al⁴ and Merrot et al¹⁵ reviewed prior cases of NS using the new definition and asserted that the majority of previously diagnosed cases of BCC were considered to be TB under the new criteria. With the advent of modern diagnostic testing, the rate of secondary benign neoplasm growth is now thought to be between 7% and 19%, with syringocystadenoma papilliferum arising in 2% to 13% of cases and TB in 1.5% to 7%.^3,4,10-14 Malignant neoplasms are observed much less frequently, with BCC arising in 0% to 1% of NS cases.

Nevus sebaceous lesions typically enlarge during puberty, while malignant neoplasms occur almost exclusively in adulthood,^4,10-12 suggesting that hormones contribute to NS stage progression. We present the case of a woman who developed BCC in a previously asymptomatic NS during pregnancy.

A 32-year-old woman who was otherwise healthy presented to our dermatology clinic with a pink-yellow verrucous plaque on the right temporal hairline extending to the preauricular area of the face. The patient had no personal or family history of skin cancer and no history of tanning bed use. She reported that the lesion had been present since birth. A diagnosis of NS was made.

Two years later, she presented with a new bleeding growth atop the previously diagnosed NS that had been present for approximately 4 months (Figure). At this visit she was pregnant (30 weeks’ gestation). Physical examination revealed a 4-mm, brown, pearly papule at the inferior margin of the previously noted pink verrucous plaque on the right temporal hairline. A biopsy was performed and histopathology displayed aggregates of basaloid cells with a high nuclear to cytoplasmic ratio, peripheral palisading, and abundant melanin, consistent with pigmented BCC. The patient was referred for Mohs micrographic surgery; the lesion was removed with clear margins. The patient had no recurrence of BCC at 36-month follow-up.

Similarly, cases of rapid growth of NS lesions during pregnancy, a state of increased testosterone production,²⁷ have been reported.²⁸ We present a case of a BCC arising in a previously asymptomatic NS during pregnancy. To our knowledge, no large studies have assessed the effect of hormone level changes during pregnancy on NS growth and secondary malignant transformation. Prior to the 1990s, prophylactic excision of NS during childhood was recommended to prevent malignant neoplasm formation.^29,30 More recently, a more conservative approach has been advocated because of a lower rate of malignant transformation than previously thought; some dermatologists recommend close monitoring as an alternative to early removal.^{4,13,14,29,31} This case report proposes that pregnancy may be a time of increased risk for malignant transformation and that NS lesions might require close monitoring during pregnancy.

To the Editor:

Nevus sebaceous of Jadassohn (or nevus sebaceous [NS]) is a congenital hamartomatous disorder initially described by Jadassohn¹ in 1895. Nevus sebaceous occurs in 0.3% of newborns² and is most commonly identified on the face and scalp.^3,4 Mehregan and Pinkus⁵ characterized NS as an organoid tumor containing multiple skin components with 3 life stages. The first stage—occurring during infancy—consists of immature hair follicles and sebaceous glands. The second stage—beginning at puberty—shows development of sebaceous glands, epidermal hyperplasia, and maturation of apocrine glands. The final stage involves formation of secondary benign and malignant neoplasms.

Historically, basal cell carcinoma (BCC) was thought to be the most common neoplasm arising in NS.^5-8 In 1993, Ackerman et al⁹ introduced a new definition of trichoblastoma (TB), expanding the definition to encompass previously excluded benign follicular neoplasms. Large studies conducted after this new definition was proposed suggested that syringocystadenoma papilliferum and TB develop more frequently than does BCC.^3,4,10-15 Furthermore, Cribier et al⁴ and Merrot et al¹⁵ reviewed prior cases of NS using the new definition and asserted that the majority of previously diagnosed cases of BCC were considered to be TB under the new criteria. With the advent of modern diagnostic testing, the rate of secondary benign neoplasm growth is now thought to be between 7% and 19%, with syringocystadenoma papilliferum arising in 2% to 13% of cases and TB in 1.5% to 7%.^3,4,10-14 Malignant neoplasms are observed much less frequently, with BCC arising in 0% to 1% of NS cases.

Nevus sebaceous lesions typically enlarge during puberty, while malignant neoplasms occur almost exclusively in adulthood,^4,10-12 suggesting that hormones contribute to NS stage progression. We present the case of a woman who developed BCC in a previously asymptomatic NS during pregnancy.

A 32-year-old woman who was otherwise healthy presented to our dermatology clinic with a pink-yellow verrucous plaque on the right temporal hairline extending to the preauricular area of the face. The patient had no personal or family history of skin cancer and no history of tanning bed use. She reported that the lesion had been present since birth. A diagnosis of NS was made.

Two years later, she presented with a new bleeding growth atop the previously diagnosed NS that had been present for approximately 4 months (Figure). At this visit she was pregnant (30 weeks’ gestation). Physical examination revealed a 4-mm, brown, pearly papule at the inferior margin of the previously noted pink verrucous plaque on the right temporal hairline. A biopsy was performed and histopathology displayed aggregates of basaloid cells with a high nuclear to cytoplasmic ratio, peripheral palisading, and abundant melanin, consistent with pigmented BCC. The patient was referred for Mohs micrographic surgery; the lesion was removed with clear margins. The patient had no recurrence of BCC at 36-month follow-up.

Similarly, cases of rapid growth of NS lesions during pregnancy, a state of increased testosterone production,²⁷ have been reported.²⁸ We present a case of a BCC arising in a previously asymptomatic NS during pregnancy. To our knowledge, no large studies have assessed the effect of hormone level changes during pregnancy on NS growth and secondary malignant transformation. Prior to the 1990s, prophylactic excision of NS during childhood was recommended to prevent malignant neoplasm formation.^29,30 More recently, a more conservative approach has been advocated because of a lower rate of malignant transformation than previously thought; some dermatologists recommend close monitoring as an alternative to early removal.^{4,13,14,29,31} This case report proposes that pregnancy may be a time of increased risk for malignant transformation and that NS lesions might require close monitoring during pregnancy.

To the Editor:

Keratoacanthoma (KA)–type squamous cell carcinomas (SCCs) are rapidly evolving neoplasms of the epithelium that often spontaneously regress but rarely metastasize.^1,2 Keratoacanthomas are thought to ascend from the hair follicle,¹ and they clinically present as an enlarging solitary crateriform nodule with a keratin-filled center. Multiple KAs are rare²; histologically, KAs can be difficult to distinguish from conventional SCCs and are frequently treated by standard surgical excision.¹ Reactive KAs are a subtype of KA that are induced by trauma including UV exposure, electromagnetic radiation, surgical procedures, chemical peels, laser treatments, and rarely tattoos.^3-5

A 56-year-old man presented to the clinic with 3 asymptomatic enlarging papulonodules within a multicolored tattoo along the right forearm and elbow of 5 months’ duration (Figure 1). The lesions developed 1 month after the tattoo was placed and were localized to the areas of red pigment. The patient had several other tattoos. Histologic examination of the lesions revealed a well-differentiated squamous neoplasm with a crateriform invagination consistent with the superficial portion of a KA (Figures 2A–C). The specimen also revealed exogenous red pigment that was consistent with the background tattoo (Figure 2D). The patient underwent excisions of all 3 KAs, and free surgical margins were obtained.

Cipollaro¹⁰ reported the first case of a KA in a tattoo in 1973. Although there have been reports of melanoma and basal cell carcinoma occurring within tattoos, KAs and conventional SCCs are the most common cutaneous neoplasms arising in tattoos.

The pathogenesis underlying the development of malignancies in tattoos is unclear. It has been hypothesized that trauma from tattooing may play a role given the temporal relationship between tattoo placement and malignancy development.¹¹ Another theory is that tattoo pigment causes a chronic inflammatory foreign body reaction that triggers carcinogenesis.¹² Lastly, it has been postulated that tattoo pigment may alter UV light absorption in the skin that could potentially impact mutagenesis.¹¹

The most common treatment of KAs is standard surgical excision.⁴ Mohs micrographic surgery is an option if the KA is located in a cosmetically sensitive area. Although there are no reports of recurrence after excision of tattoo-related KAs, new KAs forming adjacent to a previously excised KA have been reported.¹³

Currently, tattoos are not regulated by the US Food and Drug Administration before going to market. Although many states regulate the practice of tattooing, few regulate the contents of tattoo ink, and ink is only investigated when safety issues arise.¹⁴ This case provides further evidence of an association between KAs, tattooing, and potentially carcinogenic pigments, especially in red dye, supporting the need for further research on the safety of pigment components and more regulation of tattoo ink.

To the Editor:

Keratoacanthoma (KA)–type squamous cell carcinomas (SCCs) are rapidly evolving neoplasms of the epithelium that often spontaneously regress but rarely metastasize.^1,2 Keratoacanthomas are thought to ascend from the hair follicle,¹ and they clinically present as an enlarging solitary crateriform nodule with a keratin-filled center. Multiple KAs are rare²; histologically, KAs can be difficult to distinguish from conventional SCCs and are frequently treated by standard surgical excision.¹ Reactive KAs are a subtype of KA that are induced by trauma including UV exposure, electromagnetic radiation, surgical procedures, chemical peels, laser treatments, and rarely tattoos.^3-5

A 56-year-old man presented to the clinic with 3 asymptomatic enlarging papulonodules within a multicolored tattoo along the right forearm and elbow of 5 months’ duration (Figure 1). The lesions developed 1 month after the tattoo was placed and were localized to the areas of red pigment. The patient had several other tattoos. Histologic examination of the lesions revealed a well-differentiated squamous neoplasm with a crateriform invagination consistent with the superficial portion of a KA (Figures 2A–C). The specimen also revealed exogenous red pigment that was consistent with the background tattoo (Figure 2D). The patient underwent excisions of all 3 KAs, and free surgical margins were obtained.

Cipollaro¹⁰ reported the first case of a KA in a tattoo in 1973. Although there have been reports of melanoma and basal cell carcinoma occurring within tattoos, KAs and conventional SCCs are the most common cutaneous neoplasms arising in tattoos.

The pathogenesis underlying the development of malignancies in tattoos is unclear. It has been hypothesized that trauma from tattooing may play a role given the temporal relationship between tattoo placement and malignancy development.¹¹ Another theory is that tattoo pigment causes a chronic inflammatory foreign body reaction that triggers carcinogenesis.¹² Lastly, it has been postulated that tattoo pigment may alter UV light absorption in the skin that could potentially impact mutagenesis.¹¹

The most common treatment of KAs is standard surgical excision.⁴ Mohs micrographic surgery is an option if the KA is located in a cosmetically sensitive area. Although there are no reports of recurrence after excision of tattoo-related KAs, new KAs forming adjacent to a previously excised KA have been reported.¹³

Currently, tattoos are not regulated by the US Food and Drug Administration before going to market. Although many states regulate the practice of tattooing, few regulate the contents of tattoo ink, and ink is only investigated when safety issues arise.¹⁴ This case provides further evidence of an association between KAs, tattooing, and potentially carcinogenic pigments, especially in red dye, supporting the need for further research on the safety of pigment components and more regulation of tattoo ink.

To the Editor:

Keratoacanthoma (KA)–type squamous cell carcinomas (SCCs) are rapidly evolving neoplasms of the epithelium that often spontaneously regress but rarely metastasize.^1,2 Keratoacanthomas are thought to ascend from the hair follicle,¹ and they clinically present as an enlarging solitary crateriform nodule with a keratin-filled center. Multiple KAs are rare²; histologically, KAs can be difficult to distinguish from conventional SCCs and are frequently treated by standard surgical excision.¹ Reactive KAs are a subtype of KA that are induced by trauma including UV exposure, electromagnetic radiation, surgical procedures, chemical peels, laser treatments, and rarely tattoos.^3-5

A 56-year-old man presented to the clinic with 3 asymptomatic enlarging papulonodules within a multicolored tattoo along the right forearm and elbow of 5 months’ duration (Figure 1). The lesions developed 1 month after the tattoo was placed and were localized to the areas of red pigment. The patient had several other tattoos. Histologic examination of the lesions revealed a well-differentiated squamous neoplasm with a crateriform invagination consistent with the superficial portion of a KA (Figures 2A–C). The specimen also revealed exogenous red pigment that was consistent with the background tattoo (Figure 2D). The patient underwent excisions of all 3 KAs, and free surgical margins were obtained.

Cipollaro¹⁰ reported the first case of a KA in a tattoo in 1973. Although there have been reports of melanoma and basal cell carcinoma occurring within tattoos, KAs and conventional SCCs are the most common cutaneous neoplasms arising in tattoos.

The pathogenesis underlying the development of malignancies in tattoos is unclear. It has been hypothesized that trauma from tattooing may play a role given the temporal relationship between tattoo placement and malignancy development.¹¹ Another theory is that tattoo pigment causes a chronic inflammatory foreign body reaction that triggers carcinogenesis.¹² Lastly, it has been postulated that tattoo pigment may alter UV light absorption in the skin that could potentially impact mutagenesis.¹¹

The most common treatment of KAs is standard surgical excision.⁴ Mohs micrographic surgery is an option if the KA is located in a cosmetically sensitive area. Although there are no reports of recurrence after excision of tattoo-related KAs, new KAs forming adjacent to a previously excised KA have been reported.¹³

Currently, tattoos are not regulated by the US Food and Drug Administration before going to market. Although many states regulate the practice of tattooing, few regulate the contents of tattoo ink, and ink is only investigated when safety issues arise.¹⁴ This case provides further evidence of an association between KAs, tattooing, and potentially carcinogenic pigments, especially in red dye, supporting the need for further research on the safety of pigment components and more regulation of tattoo ink.

To the Editor:

Kaposi sarcoma (KS) is an angioproliferative tumor of endothelial origin associated with human herpesvirus 8 infection. It is one of the most prevalent opportunistic infections associated with AIDS and is considered an AIDS-defining illness. In the general population, the incidence of KS is 1 in 100,000 worldwide.¹ At the onset of the human immunodeficiency virus (HIV) epidemic in the early 1980s, 25% of individuals with AIDS were found to have KS at the time of AIDS diagnosis. Beginning in the mid-1980s and early 1990s with the introduction of highly active antiretroviral therapy (HAART), the incidence of KS declined to 2% to 4%,² likely secondary to restoration of immune response.³

The clinical course of KS ranges from benign to severe, involving both cutaneous and visceral forms of disease. Cutaneous KS is the most common form of disease and typically characterizes the initial presentation. It is classically described as violaceous patches, papules, or plaques that can become confluent, forming larger tumors over time. Biopsy of cutaneous lesions may vary based on the clinical morphology. The patch stage typically is characterized by abnormal proliferating vessels surrounding larger ectatic vessels.⁴ Vascular spaces are more jagged and lined by thin endothelial cells extending into the dermis, forming the classic promontory sign.⁵ In the plaque stage, the vascular infiltrate becomes more diffuse, involving the dermis and subcutis, and there is proliferation of spindle cells.⁴ In the nodular stage, spindle-shaped tumor cells form fascicles and vascular spaces become more dilated.^4,5 Advanced lesions are further associated with hyaline globules staining positive with periodic acid–Schiff.⁴ Lymphocytes, plasma cells, and hemosiderin-laden macrophages are admixed within this pathologic architecture.^4,5

Visceral KS most commonly occurs in the oropharynx, respiratory tract, and gastrointestinal tract, and rarely is the initial presentation of disease. Classically, visceral KS is an aggressive, potentially life-threatening form of disease and has been found to have a much worse prognosis than cutaneous KS alone. Pulmonary involvement is the second most common site of extracutaneous KS and is known as the most severely life-threatening form of disease.¹ Interestingly, since the advent of HAART, the incidence of KS with involvement of the visceral organs has declined at a more dramatic rate than cutaneous KS alone.³ Therefore, although more aggressive in nature, KS with visceral features has become increasingly rare and should be largely preventable given advances in AIDS therapy. We present a case of advanced AIDS-related KS with pulmonary involvement that is rarely seen after the advent of HAART.

A 39-year-old man with HIV diagnosed 8 years prior presented with fever, chest pain, progressive dyspnea, and hemoptysis of 5 months’ duration. At the time, he was nonadherent to medications and had poor follow-up with primary care physicians. At presentation he was tachycardic (149 beats per minute), tachypneic (26 breaths per minute), and his oxygen saturation was 80% on room air. Physical examination of the skin revealed asymptomatic violaceous penile lesions that the patient reported had been present for the last 8 months (Figure 1). Pertinent laboratory values included an HIV-1 viral load of 480,135 copies/mL (reference range, <20 copies/mL) and CD4 count of 14 cells/mm³ (reference range, 480–1700 cells/mm³). A chest radiograph was obtained and revealed bibasilar opacities compatible with a pleural and/or parenchymal process. Bronchoscopy was then performed and revealed bloody secretions throughout the tracheobronchial tree.

Histologic examination of biopsies of the penile lesions revealed spindle cell proliferation with hemorrhage (Figure 2A) that stained positively for HHV-8 (Figure 2B), consistent with KS. Biopsies taken during bronchoscopy similarly revealed spindle cells with hemorrhage (Figure 3). The patient was diagnosed with AIDS-related KS with visceral involvement of the lung parenchyma and tracheobronchial tree. The patient was then admitted to the medical intensive care unit and intubated. Therapy with HAART and paclitaxel was initiated. After 7 days of poor response to therapy, the family opted for terminal extubation and comfort care measures. The patient died hours later.

It is evident that treatment of AIDS patients with HAART is not only first-line therapy for the disease but also the best preventative measure against development of KS. Management of KS also centers around the initiation of HAART if the patient is not already maintained on the proper therapy.⁸ In addition to HAART, treatment options for visceral KS include a variety of chemotherapeutic agents, including but not limited to the use of single-agent adriamycin, vinblastine, paclitaxel, and thalidomide, or combination therapies.

Although notable advances have been made in the management of AIDS patients, this case highlights the need for clinicians to be aware of the risk for KS in the context of immunocompromise. Specifically, patients with advanced AIDS who are not adherent to HAART or who have a poor response to therapy have an amplified risk for developing KS in general as well as an increased risk for developing more severe visceral KS. Maintenance of patients with HAART is shown to greatly reduce the risk for both cutaneous and visceral KS; therefore, patient adherence with therapy is of utmost importance in preventing the occurrence of this deadly disease and its complications. Appropriate follow-up should be made, ensuring that these patients at high risk are adherent to therapy and have proper access to medical care to allow for prevention and early identification of potential complications.

To the Editor:

Kaposi sarcoma (KS) is an angioproliferative tumor of endothelial origin associated with human herpesvirus 8 infection. It is one of the most prevalent opportunistic infections associated with AIDS and is considered an AIDS-defining illness. In the general population, the incidence of KS is 1 in 100,000 worldwide.¹ At the onset of the human immunodeficiency virus (HIV) epidemic in the early 1980s, 25% of individuals with AIDS were found to have KS at the time of AIDS diagnosis. Beginning in the mid-1980s and early 1990s with the introduction of highly active antiretroviral therapy (HAART), the incidence of KS declined to 2% to 4%,² likely secondary to restoration of immune response.³

The clinical course of KS ranges from benign to severe, involving both cutaneous and visceral forms of disease. Cutaneous KS is the most common form of disease and typically characterizes the initial presentation. It is classically described as violaceous patches, papules, or plaques that can become confluent, forming larger tumors over time. Biopsy of cutaneous lesions may vary based on the clinical morphology. The patch stage typically is characterized by abnormal proliferating vessels surrounding larger ectatic vessels.⁴ Vascular spaces are more jagged and lined by thin endothelial cells extending into the dermis, forming the classic promontory sign.⁵ In the plaque stage, the vascular infiltrate becomes more diffuse, involving the dermis and subcutis, and there is proliferation of spindle cells.⁴ In the nodular stage, spindle-shaped tumor cells form fascicles and vascular spaces become more dilated.^4,5 Advanced lesions are further associated with hyaline globules staining positive with periodic acid–Schiff.⁴ Lymphocytes, plasma cells, and hemosiderin-laden macrophages are admixed within this pathologic architecture.^4,5

Visceral KS most commonly occurs in the oropharynx, respiratory tract, and gastrointestinal tract, and rarely is the initial presentation of disease. Classically, visceral KS is an aggressive, potentially life-threatening form of disease and has been found to have a much worse prognosis than cutaneous KS alone. Pulmonary involvement is the second most common site of extracutaneous KS and is known as the most severely life-threatening form of disease.¹ Interestingly, since the advent of HAART, the incidence of KS with involvement of the visceral organs has declined at a more dramatic rate than cutaneous KS alone.³ Therefore, although more aggressive in nature, KS with visceral features has become increasingly rare and should be largely preventable given advances in AIDS therapy. We present a case of advanced AIDS-related KS with pulmonary involvement that is rarely seen after the advent of HAART.

A 39-year-old man with HIV diagnosed 8 years prior presented with fever, chest pain, progressive dyspnea, and hemoptysis of 5 months’ duration. At the time, he was nonadherent to medications and had poor follow-up with primary care physicians. At presentation he was tachycardic (149 beats per minute), tachypneic (26 breaths per minute), and his oxygen saturation was 80% on room air. Physical examination of the skin revealed asymptomatic violaceous penile lesions that the patient reported had been present for the last 8 months (Figure 1). Pertinent laboratory values included an HIV-1 viral load of 480,135 copies/mL (reference range, <20 copies/mL) and CD4 count of 14 cells/mm³ (reference range, 480–1700 cells/mm³). A chest radiograph was obtained and revealed bibasilar opacities compatible with a pleural and/or parenchymal process. Bronchoscopy was then performed and revealed bloody secretions throughout the tracheobronchial tree.

Histologic examination of biopsies of the penile lesions revealed spindle cell proliferation with hemorrhage (Figure 2A) that stained positively for HHV-8 (Figure 2B), consistent with KS. Biopsies taken during bronchoscopy similarly revealed spindle cells with hemorrhage (Figure 3). The patient was diagnosed with AIDS-related KS with visceral involvement of the lung parenchyma and tracheobronchial tree. The patient was then admitted to the medical intensive care unit and intubated. Therapy with HAART and paclitaxel was initiated. After 7 days of poor response to therapy, the family opted for terminal extubation and comfort care measures. The patient died hours later.

It is evident that treatment of AIDS patients with HAART is not only first-line therapy for the disease but also the best preventative measure against development of KS. Management of KS also centers around the initiation of HAART if the patient is not already maintained on the proper therapy.⁸ In addition to HAART, treatment options for visceral KS include a variety of chemotherapeutic agents, including but not limited to the use of single-agent adriamycin, vinblastine, paclitaxel, and thalidomide, or combination therapies.

Although notable advances have been made in the management of AIDS patients, this case highlights the need for clinicians to be aware of the risk for KS in the context of immunocompromise. Specifically, patients with advanced AIDS who are not adherent to HAART or who have a poor response to therapy have an amplified risk for developing KS in general as well as an increased risk for developing more severe visceral KS. Maintenance of patients with HAART is shown to greatly reduce the risk for both cutaneous and visceral KS; therefore, patient adherence with therapy is of utmost importance in preventing the occurrence of this deadly disease and its complications. Appropriate follow-up should be made, ensuring that these patients at high risk are adherent to therapy and have proper access to medical care to allow for prevention and early identification of potential complications.

To the Editor:

Kaposi sarcoma (KS) is an angioproliferative tumor of endothelial origin associated with human herpesvirus 8 infection. It is one of the most prevalent opportunistic infections associated with AIDS and is considered an AIDS-defining illness. In the general population, the incidence of KS is 1 in 100,000 worldwide.¹ At the onset of the human immunodeficiency virus (HIV) epidemic in the early 1980s, 25% of individuals with AIDS were found to have KS at the time of AIDS diagnosis. Beginning in the mid-1980s and early 1990s with the introduction of highly active antiretroviral therapy (HAART), the incidence of KS declined to 2% to 4%,² likely secondary to restoration of immune response.³

The clinical course of KS ranges from benign to severe, involving both cutaneous and visceral forms of disease. Cutaneous KS is the most common form of disease and typically characterizes the initial presentation. It is classically described as violaceous patches, papules, or plaques that can become confluent, forming larger tumors over time. Biopsy of cutaneous lesions may vary based on the clinical morphology. The patch stage typically is characterized by abnormal proliferating vessels surrounding larger ectatic vessels.⁴ Vascular spaces are more jagged and lined by thin endothelial cells extending into the dermis, forming the classic promontory sign.⁵ In the plaque stage, the vascular infiltrate becomes more diffuse, involving the dermis and subcutis, and there is proliferation of spindle cells.⁴ In the nodular stage, spindle-shaped tumor cells form fascicles and vascular spaces become more dilated.^4,5 Advanced lesions are further associated with hyaline globules staining positive with periodic acid–Schiff.⁴ Lymphocytes, plasma cells, and hemosiderin-laden macrophages are admixed within this pathologic architecture.^4,5

Visceral KS most commonly occurs in the oropharynx, respiratory tract, and gastrointestinal tract, and rarely is the initial presentation of disease. Classically, visceral KS is an aggressive, potentially life-threatening form of disease and has been found to have a much worse prognosis than cutaneous KS alone. Pulmonary involvement is the second most common site of extracutaneous KS and is known as the most severely life-threatening form of disease.¹ Interestingly, since the advent of HAART, the incidence of KS with involvement of the visceral organs has declined at a more dramatic rate than cutaneous KS alone.³ Therefore, although more aggressive in nature, KS with visceral features has become increasingly rare and should be largely preventable given advances in AIDS therapy. We present a case of advanced AIDS-related KS with pulmonary involvement that is rarely seen after the advent of HAART.

A 39-year-old man with HIV diagnosed 8 years prior presented with fever, chest pain, progressive dyspnea, and hemoptysis of 5 months’ duration. At the time, he was nonadherent to medications and had poor follow-up with primary care physicians. At presentation he was tachycardic (149 beats per minute), tachypneic (26 breaths per minute), and his oxygen saturation was 80% on room air. Physical examination of the skin revealed asymptomatic violaceous penile lesions that the patient reported had been present for the last 8 months (Figure 1). Pertinent laboratory values included an HIV-1 viral load of 480,135 copies/mL (reference range, <20 copies/mL) and CD4 count of 14 cells/mm³ (reference range, 480–1700 cells/mm³). A chest radiograph was obtained and revealed bibasilar opacities compatible with a pleural and/or parenchymal process. Bronchoscopy was then performed and revealed bloody secretions throughout the tracheobronchial tree.

Histologic examination of biopsies of the penile lesions revealed spindle cell proliferation with hemorrhage (Figure 2A) that stained positively for HHV-8 (Figure 2B), consistent with KS. Biopsies taken during bronchoscopy similarly revealed spindle cells with hemorrhage (Figure 3). The patient was diagnosed with AIDS-related KS with visceral involvement of the lung parenchyma and tracheobronchial tree. The patient was then admitted to the medical intensive care unit and intubated. Therapy with HAART and paclitaxel was initiated. After 7 days of poor response to therapy, the family opted for terminal extubation and comfort care measures. The patient died hours later.

It is evident that treatment of AIDS patients with HAART is not only first-line therapy for the disease but also the best preventative measure against development of KS. Management of KS also centers around the initiation of HAART if the patient is not already maintained on the proper therapy.⁸ In addition to HAART, treatment options for visceral KS include a variety of chemotherapeutic agents, including but not limited to the use of single-agent adriamycin, vinblastine, paclitaxel, and thalidomide, or combination therapies.

Although notable advances have been made in the management of AIDS patients, this case highlights the need for clinicians to be aware of the risk for KS in the context of immunocompromise. Specifically, patients with advanced AIDS who are not adherent to HAART or who have a poor response to therapy have an amplified risk for developing KS in general as well as an increased risk for developing more severe visceral KS. Maintenance of patients with HAART is shown to greatly reduce the risk for both cutaneous and visceral KS; therefore, patient adherence with therapy is of utmost importance in preventing the occurrence of this deadly disease and its complications. Appropriate follow-up should be made, ensuring that these patients at high risk are adherent to therapy and have proper access to medical care to allow for prevention and early identification of potential complications.

To the Editor:

Demodicosis is an infection of humans caused by species of the genus of saprophytic mites Demodex (most commonly Demodex brevis and Demodex folliculorum) that feed on the pilosebaceous unit.¹Demodex mites are believed to be a commensal species in humans; an increase in mite concentration or mite penetration of the dermis, however, can cause a shift from a commensal to a pathologic form.² Demodicosis manifests in a variety of forms, including pityriasis folliculorum, rosacealike demodicosis, and demodicosis gravis. The likelihood of colonization increases with age; the mite rarely is observed in children but is found at a rate approaching 100% in the elderly population.³ It is hypothesized that manifestation of disease might be due to a decrease in immune function or an inherited HLA antigen that causes local immunosuppression.⁴

A 51-year-old man who was otherwise healthy presented to our clinic with a crusting rash on the face of 9 weeks’ duration. The rash began a few days after he demolished a rotting wooden shed in his backyard. Lesions began as pustules on the left cheek, which then developed notable crusting over the next 5 to 7 days and spread to involve the forehead, nose, and right cheek (Figure 1A).

At our initial evaluation, biopsy was performed; specimens were sent for histopathologic analysis and culture. Findings included a dermal neutrophilic inflammation, a dense perivascular and perifollicular lymphoplasmacytic infiltrate with foci of neutrophilic pustules within the follicles (Figure 2), numerous intrafollicular Demodex mites (Figure 3), perifollicular vague noncaseating granuloma, and mild sebaceous hyperplasia. Grocott methenamine-silver stain and acid-fast bacilli stain were negative.

The 2 species of Demodex that cause disease in humans each behave distinctively: D folliculorum, with a cigar-shaped body, favors superficial hair follicles; D brevis, a smaller form, burrows deeper into skin where it feeds on the pilosebaceous unit.¹ Colonization occurs through direct skin-skin contact that begins as early as infancy and becomes more common with age due to development of sebaceous glands, the main source of nourishment for the mites.²

Demodicosis is classified as primary and secondary. In a prospective study of patients with clinical findings of demodicosis, Akilov et al¹ discovered that the 2 forms can be differentiated by skin distribution, seasonality, mite species, and preexisting dermatoses. Primary demodicosis is categorized by sudden onset of symptoms on healthy skin, usually the face. Secondary demodicosis develops progressively in patients with preexisting skin disease, such as rosacea, and can have a broader distribution, involving the face and trunk.² Clinical manifestations of demodicosis are broad and include pruritic papulopustular, nodulocystic, crusted, and abscesslike lesions.⁵

Most cases of demodicosis reported in the literature are associated with either local or systemic immunosuppression.^6-8 In a case report, an otherwise immunocompetent child developed facial demodicosis after local immunosuppression from chronic use of 2 topical steroid agents.⁹

Demodex infestation can be diagnosed using a variety of methods, including standardized skin surface biopsy, punch biopsy, and potassium hydroxide analysis. Standardized skin surface biopsy is the preferred method to diagnose demodicosis because it is noninvasive and samples the superficial follicle where Demodex mites typically reside. Diagnosis is made by identifying 5 or more Demodex mites in a low-power field or more than 5 mites per square centimeter in standardized skin surface biopsy.² Other potential diagnostic tools reported in the literature include dermoscopy and confocal laser scanning microscopy.^10,11

There is no standard therapeutic regimen for demodicosis because evidence-based trials regarding the efficacy of treatments are lacking. Oral ivermectin 200 µg/kg in a single dose is considered the preferred treatment; it can be combined with oral erythromycin, topical permethrin, or topical metronidazole.^5-7,9

Our case is unique, as crusted demodicosis developed in an immunocompetent adult. Demodicosis usually causes severe eruptions in immunocompromised persons, with only 1 case report detailing a papulopustular rash in an immunocompetent adult.^12,13

The pathogenesis of demodicosis remains unclear. Many mechanisms have been hypothesized to play a role in its pathogenesis, including mechanical obstruction of hair follicles, hypersensitivity reaction to Demodex mites, immune dysregulation, and a foreign-body granulomatous reaction to the skeleton of the mite.^2,3 Our patient’s particular infestation could have been caused by an exuberant reaction to Demodex; however, it is likely that many factors played a role in his disease process to cause an increase in mite density and subsequent manifestations of disease.

To the Editor:

Demodicosis is an infection of humans caused by species of the genus of saprophytic mites Demodex (most commonly Demodex brevis and Demodex folliculorum) that feed on the pilosebaceous unit.¹Demodex mites are believed to be a commensal species in humans; an increase in mite concentration or mite penetration of the dermis, however, can cause a shift from a commensal to a pathologic form.² Demodicosis manifests in a variety of forms, including pityriasis folliculorum, rosacealike demodicosis, and demodicosis gravis. The likelihood of colonization increases with age; the mite rarely is observed in children but is found at a rate approaching 100% in the elderly population.³ It is hypothesized that manifestation of disease might be due to a decrease in immune function or an inherited HLA antigen that causes local immunosuppression.⁴

A 51-year-old man who was otherwise healthy presented to our clinic with a crusting rash on the face of 9 weeks’ duration. The rash began a few days after he demolished a rotting wooden shed in his backyard. Lesions began as pustules on the left cheek, which then developed notable crusting over the next 5 to 7 days and spread to involve the forehead, nose, and right cheek (Figure 1A).

At our initial evaluation, biopsy was performed; specimens were sent for histopathologic analysis and culture. Findings included a dermal neutrophilic inflammation, a dense perivascular and perifollicular lymphoplasmacytic infiltrate with foci of neutrophilic pustules within the follicles (Figure 2), numerous intrafollicular Demodex mites (Figure 3), perifollicular vague noncaseating granuloma, and mild sebaceous hyperplasia. Grocott methenamine-silver stain and acid-fast bacilli stain were negative.

The 2 species of Demodex that cause disease in humans each behave distinctively: D folliculorum, with a cigar-shaped body, favors superficial hair follicles; D brevis, a smaller form, burrows deeper into skin where it feeds on the pilosebaceous unit.¹ Colonization occurs through direct skin-skin contact that begins as early as infancy and becomes more common with age due to development of sebaceous glands, the main source of nourishment for the mites.²

Demodicosis is classified as primary and secondary. In a prospective study of patients with clinical findings of demodicosis, Akilov et al¹ discovered that the 2 forms can be differentiated by skin distribution, seasonality, mite species, and preexisting dermatoses. Primary demodicosis is categorized by sudden onset of symptoms on healthy skin, usually the face. Secondary demodicosis develops progressively in patients with preexisting skin disease, such as rosacea, and can have a broader distribution, involving the face and trunk.² Clinical manifestations of demodicosis are broad and include pruritic papulopustular, nodulocystic, crusted, and abscesslike lesions.⁵

Most cases of demodicosis reported in the literature are associated with either local or systemic immunosuppression.^6-8 In a case report, an otherwise immunocompetent child developed facial demodicosis after local immunosuppression from chronic use of 2 topical steroid agents.⁹

Demodex infestation can be diagnosed using a variety of methods, including standardized skin surface biopsy, punch biopsy, and potassium hydroxide analysis. Standardized skin surface biopsy is the preferred method to diagnose demodicosis because it is noninvasive and samples the superficial follicle where Demodex mites typically reside. Diagnosis is made by identifying 5 or more Demodex mites in a low-power field or more than 5 mites per square centimeter in standardized skin surface biopsy.² Other potential diagnostic tools reported in the literature include dermoscopy and confocal laser scanning microscopy.^10,11

There is no standard therapeutic regimen for demodicosis because evidence-based trials regarding the efficacy of treatments are lacking. Oral ivermectin 200 µg/kg in a single dose is considered the preferred treatment; it can be combined with oral erythromycin, topical permethrin, or topical metronidazole.^5-7,9

Our case is unique, as crusted demodicosis developed in an immunocompetent adult. Demodicosis usually causes severe eruptions in immunocompromised persons, with only 1 case report detailing a papulopustular rash in an immunocompetent adult.^12,13

The pathogenesis of demodicosis remains unclear. Many mechanisms have been hypothesized to play a role in its pathogenesis, including mechanical obstruction of hair follicles, hypersensitivity reaction to Demodex mites, immune dysregulation, and a foreign-body granulomatous reaction to the skeleton of the mite.^2,3 Our patient’s particular infestation could have been caused by an exuberant reaction to Demodex; however, it is likely that many factors played a role in his disease process to cause an increase in mite density and subsequent manifestations of disease.

To the Editor:

Demodicosis is an infection of humans caused by species of the genus of saprophytic mites Demodex (most commonly Demodex brevis and Demodex folliculorum) that feed on the pilosebaceous unit.¹Demodex mites are believed to be a commensal species in humans; an increase in mite concentration or mite penetration of the dermis, however, can cause a shift from a commensal to a pathologic form.² Demodicosis manifests in a variety of forms, including pityriasis folliculorum, rosacealike demodicosis, and demodicosis gravis. The likelihood of colonization increases with age; the mite rarely is observed in children but is found at a rate approaching 100% in the elderly population.³ It is hypothesized that manifestation of disease might be due to a decrease in immune function or an inherited HLA antigen that causes local immunosuppression.⁴

A 51-year-old man who was otherwise healthy presented to our clinic with a crusting rash on the face of 9 weeks’ duration. The rash began a few days after he demolished a rotting wooden shed in his backyard. Lesions began as pustules on the left cheek, which then developed notable crusting over the next 5 to 7 days and spread to involve the forehead, nose, and right cheek (Figure 1A).

At our initial evaluation, biopsy was performed; specimens were sent for histopathologic analysis and culture. Findings included a dermal neutrophilic inflammation, a dense perivascular and perifollicular lymphoplasmacytic infiltrate with foci of neutrophilic pustules within the follicles (Figure 2), numerous intrafollicular Demodex mites (Figure 3), perifollicular vague noncaseating granuloma, and mild sebaceous hyperplasia. Grocott methenamine-silver stain and acid-fast bacilli stain were negative.

The 2 species of Demodex that cause disease in humans each behave distinctively: D folliculorum, with a cigar-shaped body, favors superficial hair follicles; D brevis, a smaller form, burrows deeper into skin where it feeds on the pilosebaceous unit.¹ Colonization occurs through direct skin-skin contact that begins as early as infancy and becomes more common with age due to development of sebaceous glands, the main source of nourishment for the mites.²

Demodicosis is classified as primary and secondary. In a prospective study of patients with clinical findings of demodicosis, Akilov et al¹ discovered that the 2 forms can be differentiated by skin distribution, seasonality, mite species, and preexisting dermatoses. Primary demodicosis is categorized by sudden onset of symptoms on healthy skin, usually the face. Secondary demodicosis develops progressively in patients with preexisting skin disease, such as rosacea, and can have a broader distribution, involving the face and trunk.² Clinical manifestations of demodicosis are broad and include pruritic papulopustular, nodulocystic, crusted, and abscesslike lesions.⁵

Most cases of demodicosis reported in the literature are associated with either local or systemic immunosuppression.^6-8 In a case report, an otherwise immunocompetent child developed facial demodicosis after local immunosuppression from chronic use of 2 topical steroid agents.⁹

Demodex infestation can be diagnosed using a variety of methods, including standardized skin surface biopsy, punch biopsy, and potassium hydroxide analysis. Standardized skin surface biopsy is the preferred method to diagnose demodicosis because it is noninvasive and samples the superficial follicle where Demodex mites typically reside. Diagnosis is made by identifying 5 or more Demodex mites in a low-power field or more than 5 mites per square centimeter in standardized skin surface biopsy.² Other potential diagnostic tools reported in the literature include dermoscopy and confocal laser scanning microscopy.^10,11

There is no standard therapeutic regimen for demodicosis because evidence-based trials regarding the efficacy of treatments are lacking. Oral ivermectin 200 µg/kg in a single dose is considered the preferred treatment; it can be combined with oral erythromycin, topical permethrin, or topical metronidazole.^5-7,9

Our case is unique, as crusted demodicosis developed in an immunocompetent adult. Demodicosis usually causes severe eruptions in immunocompromised persons, with only 1 case report detailing a papulopustular rash in an immunocompetent adult.^12,13

The pathogenesis of demodicosis remains unclear. Many mechanisms have been hypothesized to play a role in its pathogenesis, including mechanical obstruction of hair follicles, hypersensitivity reaction to Demodex mites, immune dysregulation, and a foreign-body granulomatous reaction to the skeleton of the mite.^2,3 Our patient’s particular infestation could have been caused by an exuberant reaction to Demodex; however, it is likely that many factors played a role in his disease process to cause an increase in mite density and subsequent manifestations of disease.

To the Editor:

Extramammary Paget disease (EMPD) is a rare intraepidermal neoplasm with glandular differentiation that is classically known as a mimicker of Bowen disease (squamous cell carcinoma in situ of the skin) due to their histologic similarities.^1,2 However, acantholytic anaplastic EMPD (AAEMPD) is a rare variant that can pose a particularly difficult diagnostic challenge because of its histologic similarity to benign acantholytic disorders and other malignant neoplasms. Major histologic features suggestive of AAEMPD include full-thickness atypia of the epidermis, loss of nuclear polarity, marked cytologic anaplasia, intraepidermal acantholysis, and Paget cells.³ The differential diagnosis of EMPD typically includes Bowen disease and pagetoid Bowen disease, but the acantholytic anaplastic variant more often is confused with intraepidermal acantholytic lesions such as acantholytic dyskeratosis of the genitocrural area, familial benign pemphigus (Hailey-Hailey disease), pemphigus vulgaris, and acantholytic Bowen disease. Immunohistochemistry (IHC) studies to assist in the definitive diagnosis of AAEMPD are strongly advised because of these difficulties in diagnosis.⁴ Cases of EMPD with an acantholytic appearance have rarely been reported in the literature.^5-7

A 78-year-old man with a history of arthritis, heart disease, hypertension, and gastrointestinal disease presented for evaluation of a tender lesion of the right genitocrural crease of 5 years’ duration. He had no history of cutaneous or internal malignancy. Previously the lesion had been treated by dermatology with a variety of topical products including antifungal and antibiotic creams with no improvement. Physical examination revealed a well-defined, 7×5-cm, tender, erythematous, macerated plaque on the right upper inner thigh adjacent to the scrotum with an odor possibly due to secondary infection (Figure 1).

The biopsy specimen was examined grossly, serially sectioned, and submitted for routine processing with hematoxylin and eosin, periodic acid–Schiff, and Hale colloidal iron staining. Routine IHC was performed with antibodies to cytokeratin (CK) 7, CK20, carcinoembryonic antigen (CEA), pancytokeratin (CKAE1/AE3), and low- molecular-weight cytokeratin (LMWCK).

Pathologic examination of the biopsy showed prominent acanthosis of the epidermis composed of a proliferation of epithelial cells with associated full-thickness suprabasal acantholysis (Figure 2A). On inspection at higher magnification, the neoplastic cells demonstrated anaplasia as cytologic atypia with prominent and frequently multiple nucleoli, scant cytoplasm, and a high nuclear to cytoplasmic ratio (Figure 2B). There was a marked increase in mitotic activity with as many as 5 mitotic figures per high-power field. A fairly dense mixed inflammatory infiltrate comprised of lymphocytes, plasma cells, neutrophils, and eosinophils was present in the dermis. No fungal elements were observed on periodic acid–Schiff staining. The vast majority of tumor cells demonstrated moderate to abundant cytoplasmic mucin on Hale colloidal iron staining (Figure 3).

Immunohistochemistry staining of tumor cells was positive for CK7, CEA, pancytokeratin (CKAE1/AE3), and LMWCK. The tumor cells were negative for CK20. On the basis of the histopathologic and IHC findings, the patient was diagnosed with AAEMPD.

Extramammary Paget disease is a rare intraepidermal neoplasm with glandular differentiation. The most commonly involved sites are the anogenital areas including the vulvar, perianal, perineal, scrotal, and penile regions, as well as other areas rich in apocrine glands such as the axillae.⁸ Extramammary Paget disease most commonly originates as a primary intraepidermal neoplasm (type 1 EMPD), but an underlying malignant neoplasm that spreads intraepithelially is seen in a minority of cases (types 2 and 3 EMPD). In the vulva, type 1a refers to cutaneous noninvasive Paget disease, type 1b refers to dermal invasion of Paget disease, type 1c refers to vulvar adenocarcinoma–associated Paget disease, type 2 refers to rectal/anal adenocarcinoma–associated Paget disease, and type 3 refers to urogenital neoplasia–associated Paget disease.⁹

The acantholytic anaplastic variant of EMPD can be challenging to diagnose because of its similarities to many other lesions, including acantholytic dyskeratosis of the genitocrural area, familial benign pemphigus (Hailey-Hailey disease), pemphigus vulgaris, Bowen disease, pagetoid Bowen disease, and acantholytic Bowen disease. Major histologic features of AAEMPD include full-thickness atypia of the epidermis, loss of nuclear polarity, marked cytologic anaplasia, intraepidermal acantholysis, and Paget cells.³ The acantholytic anaplastic variant of EMPD can be differentiated from other diagnoses using IHC studies, with findings indicative of AAEMPD outlined below.

The proliferative neoplastic cell in EMPD is the Paget cell, which can be identified as a large round cell located in the epidermis with pale-staining cytoplasm, a large nucleus, and sometimes a prominent nucleolus. Paget cells can be distributed singly or in clusters, nests, or glandular structures within the epidermis and adjacent to adnexal structures.¹⁰ Extramammary Paget disease can have many patterns, including glandular, acantholysis-like, upper nest, tall nest, budding, and sheetlike.¹¹

Immunohistochemically, Paget cells in EMPD typically express pancytokeratins (CKAE1/AE3), low-molecular-weight/simple epithelial type keratins (CK7, CAM 5.2), sweat gland antigens (epithelial membrane antigen, CEA, gross cystic disease fluid protein 15 [GCDFP15]), mucin 5AC (MUC5AC), and often androgen receptor.^12-18 Paget cells contain cytoplasmic mucin and demonstrate prominent cytoplasmic staining with Hale colloidal iron.¹⁷ Paget cells typically do not express high-molecular-weight cytokeratin (eg, CK5/6), melanocytic antigens, estrogen receptor, or progesterone receptor.^15,18

Immunohistochemical staining has been shown to differ between primary cutaneous (type 1) and secondary (types 2 and 3) EMPD. Primary cutaneous EMPD typically expresses sweat gland markers (CK7⁺, CK20⁻, GCDFP15⁺). Secondary EMPD typically expresses an endodermal phenotype (CK7⁺, CK20⁺, GCDFP15⁻).¹²

Acantholytic dyskeratosis of the genitocrural area is a rare lesion included in the spectrum of focal acantholytic dyskeratoses described by Ackerman.¹⁹ It also has been referred to as papular acantholytic dyskeratosis of the vulva, though histologically similar lesions also have been reported in men.^20-22 Histologically, acantholytic dyskeratosis of the genitocrural area has prominent acantholysis and dyskeratosis with corps ronds and grains.¹⁹ Familial benign pemphigus (Hailey-Hailey disease) is caused by mutations of the ATP2C1 gene, which encodes for a secretory pathway Ca²⁺/Mn²⁺-ATPase pump type 1 (SPCA1) in the Golgi apparatus in keratinocytes.²³ Familial benign pemphigus has a histologic appearance similar to acantholytic dyskeratosis of the genitocrural area, but a positive family history of familial benign pemphigus can be used to differentiate the 2 entities from each other due to the autosomal-dominant inheritance pattern of familial benign pemphigus. Both of these disorders can appear similar to AAEMPD because of their extensive intraepidermal acantholysis, but they differ in the lack of Paget cells, intraepidermal atypia, and increased mitotic activity.

Acantholytic Bowen disease is a histologic variant that can be difficult to distinguish from AAEMPD on hematoxylin and eosin–stained sections because of their similar histologic features but can be differentiated by IHC stains.⁵ Acantholytic Bowen disease expresses high-molecular-weight cytokeratin (eg, CK5/6) but is negative for CK7, CAM 5.2, and CEA. Extramammary Paget disease generally has the opposite pattern: positive staining for CK7, CAM 5.2, and CEA, but negative for high-molecular-weight cytokeratin.^13,14,24

Primary cutaneous adenosquamous carcinoma is a rare malignancy of squamous and glandular differentiation known for being locally aggressive and metastatic.²⁵ Histologically, cutaneous adenosquamous carcinoma shows infiltrating nests of neoplastic cells with both squamous and glandular features. It differs notably from AAEMPD in that cutaneous adenosquamous carcinomas tend to arise in the head and arm regions, and their histologic morphology is different. The IHC profiles are similar, with positive staining for CEA, CK7, and mucin; however, they differ in that AAEMPD is negative for high-molecular-weight keratin while cutaneous adenosquamous carcinoma is positive.²⁵

Verrucous carcinoma is an uncommon variant of squamous cell carcinoma with well-differentiated keratinocytes and a blunt pushing border.²⁴ Similar to AAEMPD, this neoplasm can arise in the genital and perineal areas; however, the 2 entities differ considerably in morphology on histologic examination.

Pemphigus vulgaris is an autoimmune intraepidermal blistering disorder of the skin and mucous membranes of which pemphigus vegetans is a subtype.^26,27 Pemphigus vulgaris is another diagnosis that can possibly be mimicked by AAEMPD.²⁸ Histologic features of pemphigus vulgaris include intraepidermal acantholysis of keratinocytes immediately above the basal layer of the epidermis. Pemphigus vegetans is similar with the addition of papillomatosis, hyperkeratosis, and an eosinophilic infiltrate.^26,27 Immunofluorescence typically demonstrates intercellular C3 and IgG deposits.²⁶ These diseases mimic AAEMPD histologically but differ in their relative lack of atypia and Paget cells.

In summary, we report a case of AAEMPD in a 78-year-old man in whom routine histologic specimens showed marked intraepidermal acantholysis and atypical tumor cells with increased mitoses. The latter finding prompted IHC studies that revealed positive CK7, CEA, pancytokeratin, and LMWCK staining with negative CK20 staining. Hale colloidal iron staining showed moderate to abundant cytoplasmic mucin. The patient was diagnosed with AAEMPD. It is imperative to maintain clinical suspicion for AAEMPD and to examine acantholytic disorders with scrutiny. When there is evidence of atypia or mitoses, use of IHC stains can assist in fully characterizing the lesion.

To the Editor:

Extramammary Paget disease (EMPD) is a rare intraepidermal neoplasm with glandular differentiation that is classically known as a mimicker of Bowen disease (squamous cell carcinoma in situ of the skin) due to their histologic similarities.^1,2 However, acantholytic anaplastic EMPD (AAEMPD) is a rare variant that can pose a particularly difficult diagnostic challenge because of its histologic similarity to benign acantholytic disorders and other malignant neoplasms. Major histologic features suggestive of AAEMPD include full-thickness atypia of the epidermis, loss of nuclear polarity, marked cytologic anaplasia, intraepidermal acantholysis, and Paget cells.³ The differential diagnosis of EMPD typically includes Bowen disease and pagetoid Bowen disease, but the acantholytic anaplastic variant more often is confused with intraepidermal acantholytic lesions such as acantholytic dyskeratosis of the genitocrural area, familial benign pemphigus (Hailey-Hailey disease), pemphigus vulgaris, and acantholytic Bowen disease. Immunohistochemistry (IHC) studies to assist in the definitive diagnosis of AAEMPD are strongly advised because of these difficulties in diagnosis.⁴ Cases of EMPD with an acantholytic appearance have rarely been reported in the literature.^5-7

A 78-year-old man with a history of arthritis, heart disease, hypertension, and gastrointestinal disease presented for evaluation of a tender lesion of the right genitocrural crease of 5 years’ duration. He had no history of cutaneous or internal malignancy. Previously the lesion had been treated by dermatology with a variety of topical products including antifungal and antibiotic creams with no improvement. Physical examination revealed a well-defined, 7×5-cm, tender, erythematous, macerated plaque on the right upper inner thigh adjacent to the scrotum with an odor possibly due to secondary infection (Figure 1).

The biopsy specimen was examined grossly, serially sectioned, and submitted for routine processing with hematoxylin and eosin, periodic acid–Schiff, and Hale colloidal iron staining. Routine IHC was performed with antibodies to cytokeratin (CK) 7, CK20, carcinoembryonic antigen (CEA), pancytokeratin (CKAE1/AE3), and low- molecular-weight cytokeratin (LMWCK).

Pathologic examination of the biopsy showed prominent acanthosis of the epidermis composed of a proliferation of epithelial cells with associated full-thickness suprabasal acantholysis (Figure 2A). On inspection at higher magnification, the neoplastic cells demonstrated anaplasia as cytologic atypia with prominent and frequently multiple nucleoli, scant cytoplasm, and a high nuclear to cytoplasmic ratio (Figure 2B). There was a marked increase in mitotic activity with as many as 5 mitotic figures per high-power field. A fairly dense mixed inflammatory infiltrate comprised of lymphocytes, plasma cells, neutrophils, and eosinophils was present in the dermis. No fungal elements were observed on periodic acid–Schiff staining. The vast majority of tumor cells demonstrated moderate to abundant cytoplasmic mucin on Hale colloidal iron staining (Figure 3).

Immunohistochemistry staining of tumor cells was positive for CK7, CEA, pancytokeratin (CKAE1/AE3), and LMWCK. The tumor cells were negative for CK20. On the basis of the histopathologic and IHC findings, the patient was diagnosed with AAEMPD.

Extramammary Paget disease is a rare intraepidermal neoplasm with glandular differentiation. The most commonly involved sites are the anogenital areas including the vulvar, perianal, perineal, scrotal, and penile regions, as well as other areas rich in apocrine glands such as the axillae.⁸ Extramammary Paget disease most commonly originates as a primary intraepidermal neoplasm (type 1 EMPD), but an underlying malignant neoplasm that spreads intraepithelially is seen in a minority of cases (types 2 and 3 EMPD). In the vulva, type 1a refers to cutaneous noninvasive Paget disease, type 1b refers to dermal invasion of Paget disease, type 1c refers to vulvar adenocarcinoma–associated Paget disease, type 2 refers to rectal/anal adenocarcinoma–associated Paget disease, and type 3 refers to urogenital neoplasia–associated Paget disease.⁹

The acantholytic anaplastic variant of EMPD can be challenging to diagnose because of its similarities to many other lesions, including acantholytic dyskeratosis of the genitocrural area, familial benign pemphigus (Hailey-Hailey disease), pemphigus vulgaris, Bowen disease, pagetoid Bowen disease, and acantholytic Bowen disease. Major histologic features of AAEMPD include full-thickness atypia of the epidermis, loss of nuclear polarity, marked cytologic anaplasia, intraepidermal acantholysis, and Paget cells.³ The acantholytic anaplastic variant of EMPD can be differentiated from other diagnoses using IHC studies, with findings indicative of AAEMPD outlined below.

The proliferative neoplastic cell in EMPD is the Paget cell, which can be identified as a large round cell located in the epidermis with pale-staining cytoplasm, a large nucleus, and sometimes a prominent nucleolus. Paget cells can be distributed singly or in clusters, nests, or glandular structures within the epidermis and adjacent to adnexal structures.¹⁰ Extramammary Paget disease can have many patterns, including glandular, acantholysis-like, upper nest, tall nest, budding, and sheetlike.¹¹

Immunohistochemically, Paget cells in EMPD typically express pancytokeratins (CKAE1/AE3), low-molecular-weight/simple epithelial type keratins (CK7, CAM 5.2), sweat gland antigens (epithelial membrane antigen, CEA, gross cystic disease fluid protein 15 [GCDFP15]), mucin 5AC (MUC5AC), and often androgen receptor.^12-18 Paget cells contain cytoplasmic mucin and demonstrate prominent cytoplasmic staining with Hale colloidal iron.¹⁷ Paget cells typically do not express high-molecular-weight cytokeratin (eg, CK5/6), melanocytic antigens, estrogen receptor, or progesterone receptor.^15,18

Immunohistochemical staining has been shown to differ between primary cutaneous (type 1) and secondary (types 2 and 3) EMPD. Primary cutaneous EMPD typically expresses sweat gland markers (CK7⁺, CK20⁻, GCDFP15⁺). Secondary EMPD typically expresses an endodermal phenotype (CK7⁺, CK20⁺, GCDFP15⁻).¹²

Acantholytic dyskeratosis of the genitocrural area is a rare lesion included in the spectrum of focal acantholytic dyskeratoses described by Ackerman.¹⁹ It also has been referred to as papular acantholytic dyskeratosis of the vulva, though histologically similar lesions also have been reported in men.^20-22 Histologically, acantholytic dyskeratosis of the genitocrural area has prominent acantholysis and dyskeratosis with corps ronds and grains.¹⁹ Familial benign pemphigus (Hailey-Hailey disease) is caused by mutations of the ATP2C1 gene, which encodes for a secretory pathway Ca²⁺/Mn²⁺-ATPase pump type 1 (SPCA1) in the Golgi apparatus in keratinocytes.²³ Familial benign pemphigus has a histologic appearance similar to acantholytic dyskeratosis of the genitocrural area, but a positive family history of familial benign pemphigus can be used to differentiate the 2 entities from each other due to the autosomal-dominant inheritance pattern of familial benign pemphigus. Both of these disorders can appear similar to AAEMPD because of their extensive intraepidermal acantholysis, but they differ in the lack of Paget cells, intraepidermal atypia, and increased mitotic activity.

Acantholytic Bowen disease is a histologic variant that can be difficult to distinguish from AAEMPD on hematoxylin and eosin–stained sections because of their similar histologic features but can be differentiated by IHC stains.⁵ Acantholytic Bowen disease expresses high-molecular-weight cytokeratin (eg, CK5/6) but is negative for CK7, CAM 5.2, and CEA. Extramammary Paget disease generally has the opposite pattern: positive staining for CK7, CAM 5.2, and CEA, but negative for high-molecular-weight cytokeratin.^13,14,24

Primary cutaneous adenosquamous carcinoma is a rare malignancy of squamous and glandular differentiation known for being locally aggressive and metastatic.²⁵ Histologically, cutaneous adenosquamous carcinoma shows infiltrating nests of neoplastic cells with both squamous and glandular features. It differs notably from AAEMPD in that cutaneous adenosquamous carcinomas tend to arise in the head and arm regions, and their histologic morphology is different. The IHC profiles are similar, with positive staining for CEA, CK7, and mucin; however, they differ in that AAEMPD is negative for high-molecular-weight keratin while cutaneous adenosquamous carcinoma is positive.²⁵

Verrucous carcinoma is an uncommon variant of squamous cell carcinoma with well-differentiated keratinocytes and a blunt pushing border.²⁴ Similar to AAEMPD, this neoplasm can arise in the genital and perineal areas; however, the 2 entities differ considerably in morphology on histologic examination.

Pemphigus vulgaris is an autoimmune intraepidermal blistering disorder of the skin and mucous membranes of which pemphigus vegetans is a subtype.^26,27 Pemphigus vulgaris is another diagnosis that can possibly be mimicked by AAEMPD.²⁸ Histologic features of pemphigus vulgaris include intraepidermal acantholysis of keratinocytes immediately above the basal layer of the epidermis. Pemphigus vegetans is similar with the addition of papillomatosis, hyperkeratosis, and an eosinophilic infiltrate.^26,27 Immunofluorescence typically demonstrates intercellular C3 and IgG deposits.²⁶ These diseases mimic AAEMPD histologically but differ in their relative lack of atypia and Paget cells.

In summary, we report a case of AAEMPD in a 78-year-old man in whom routine histologic specimens showed marked intraepidermal acantholysis and atypical tumor cells with increased mitoses. The latter finding prompted IHC studies that revealed positive CK7, CEA, pancytokeratin, and LMWCK staining with negative CK20 staining. Hale colloidal iron staining showed moderate to abundant cytoplasmic mucin. The patient was diagnosed with AAEMPD. It is imperative to maintain clinical suspicion for AAEMPD and to examine acantholytic disorders with scrutiny. When there is evidence of atypia or mitoses, use of IHC stains can assist in fully characterizing the lesion.

To the Editor:

Extramammary Paget disease (EMPD) is a rare intraepidermal neoplasm with glandular differentiation that is classically known as a mimicker of Bowen disease (squamous cell carcinoma in situ of the skin) due to their histologic similarities.^1,2 However, acantholytic anaplastic EMPD (AAEMPD) is a rare variant that can pose a particularly difficult diagnostic challenge because of its histologic similarity to benign acantholytic disorders and other malignant neoplasms. Major histologic features suggestive of AAEMPD include full-thickness atypia of the epidermis, loss of nuclear polarity, marked cytologic anaplasia, intraepidermal acantholysis, and Paget cells.³ The differential diagnosis of EMPD typically includes Bowen disease and pagetoid Bowen disease, but the acantholytic anaplastic variant more often is confused with intraepidermal acantholytic lesions such as acantholytic dyskeratosis of the genitocrural area, familial benign pemphigus (Hailey-Hailey disease), pemphigus vulgaris, and acantholytic Bowen disease. Immunohistochemistry (IHC) studies to assist in the definitive diagnosis of AAEMPD are strongly advised because of these difficulties in diagnosis.⁴ Cases of EMPD with an acantholytic appearance have rarely been reported in the literature.^5-7

A 78-year-old man with a history of arthritis, heart disease, hypertension, and gastrointestinal disease presented for evaluation of a tender lesion of the right genitocrural crease of 5 years’ duration. He had no history of cutaneous or internal malignancy. Previously the lesion had been treated by dermatology with a variety of topical products including antifungal and antibiotic creams with no improvement. Physical examination revealed a well-defined, 7×5-cm, tender, erythematous, macerated plaque on the right upper inner thigh adjacent to the scrotum with an odor possibly due to secondary infection (Figure 1).

The biopsy specimen was examined grossly, serially sectioned, and submitted for routine processing with hematoxylin and eosin, periodic acid–Schiff, and Hale colloidal iron staining. Routine IHC was performed with antibodies to cytokeratin (CK) 7, CK20, carcinoembryonic antigen (CEA), pancytokeratin (CKAE1/AE3), and low- molecular-weight cytokeratin (LMWCK).

Pathologic examination of the biopsy showed prominent acanthosis of the epidermis composed of a proliferation of epithelial cells with associated full-thickness suprabasal acantholysis (Figure 2A). On inspection at higher magnification, the neoplastic cells demonstrated anaplasia as cytologic atypia with prominent and frequently multiple nucleoli, scant cytoplasm, and a high nuclear to cytoplasmic ratio (Figure 2B). There was a marked increase in mitotic activity with as many as 5 mitotic figures per high-power field. A fairly dense mixed inflammatory infiltrate comprised of lymphocytes, plasma cells, neutrophils, and eosinophils was present in the dermis. No fungal elements were observed on periodic acid–Schiff staining. The vast majority of tumor cells demonstrated moderate to abundant cytoplasmic mucin on Hale colloidal iron staining (Figure 3).

Immunohistochemistry staining of tumor cells was positive for CK7, CEA, pancytokeratin (CKAE1/AE3), and LMWCK. The tumor cells were negative for CK20. On the basis of the histopathologic and IHC findings, the patient was diagnosed with AAEMPD.

Extramammary Paget disease is a rare intraepidermal neoplasm with glandular differentiation. The most commonly involved sites are the anogenital areas including the vulvar, perianal, perineal, scrotal, and penile regions, as well as other areas rich in apocrine glands such as the axillae.⁸ Extramammary Paget disease most commonly originates as a primary intraepidermal neoplasm (type 1 EMPD), but an underlying malignant neoplasm that spreads intraepithelially is seen in a minority of cases (types 2 and 3 EMPD). In the vulva, type 1a refers to cutaneous noninvasive Paget disease, type 1b refers to dermal invasion of Paget disease, type 1c refers to vulvar adenocarcinoma–associated Paget disease, type 2 refers to rectal/anal adenocarcinoma–associated Paget disease, and type 3 refers to urogenital neoplasia–associated Paget disease.⁹

The acantholytic anaplastic variant of EMPD can be challenging to diagnose because of its similarities to many other lesions, including acantholytic dyskeratosis of the genitocrural area, familial benign pemphigus (Hailey-Hailey disease), pemphigus vulgaris, Bowen disease, pagetoid Bowen disease, and acantholytic Bowen disease. Major histologic features of AAEMPD include full-thickness atypia of the epidermis, loss of nuclear polarity, marked cytologic anaplasia, intraepidermal acantholysis, and Paget cells.³ The acantholytic anaplastic variant of EMPD can be differentiated from other diagnoses using IHC studies, with findings indicative of AAEMPD outlined below.

The proliferative neoplastic cell in EMPD is the Paget cell, which can be identified as a large round cell located in the epidermis with pale-staining cytoplasm, a large nucleus, and sometimes a prominent nucleolus. Paget cells can be distributed singly or in clusters, nests, or glandular structures within the epidermis and adjacent to adnexal structures.¹⁰ Extramammary Paget disease can have many patterns, including glandular, acantholysis-like, upper nest, tall nest, budding, and sheetlike.¹¹

Immunohistochemically, Paget cells in EMPD typically express pancytokeratins (CKAE1/AE3), low-molecular-weight/simple epithelial type keratins (CK7, CAM 5.2), sweat gland antigens (epithelial membrane antigen, CEA, gross cystic disease fluid protein 15 [GCDFP15]), mucin 5AC (MUC5AC), and often androgen receptor.^12-18 Paget cells contain cytoplasmic mucin and demonstrate prominent cytoplasmic staining with Hale colloidal iron.¹⁷ Paget cells typically do not express high-molecular-weight cytokeratin (eg, CK5/6), melanocytic antigens, estrogen receptor, or progesterone receptor.^15,18

Immunohistochemical staining has been shown to differ between primary cutaneous (type 1) and secondary (types 2 and 3) EMPD. Primary cutaneous EMPD typically expresses sweat gland markers (CK7⁺, CK20⁻, GCDFP15⁺). Secondary EMPD typically expresses an endodermal phenotype (CK7⁺, CK20⁺, GCDFP15⁻).¹²

Acantholytic dyskeratosis of the genitocrural area is a rare lesion included in the spectrum of focal acantholytic dyskeratoses described by Ackerman.¹⁹ It also has been referred to as papular acantholytic dyskeratosis of the vulva, though histologically similar lesions also have been reported in men.^20-22 Histologically, acantholytic dyskeratosis of the genitocrural area has prominent acantholysis and dyskeratosis with corps ronds and grains.¹⁹ Familial benign pemphigus (Hailey-Hailey disease) is caused by mutations of the ATP2C1 gene, which encodes for a secretory pathway Ca²⁺/Mn²⁺-ATPase pump type 1 (SPCA1) in the Golgi apparatus in keratinocytes.²³ Familial benign pemphigus has a histologic appearance similar to acantholytic dyskeratosis of the genitocrural area, but a positive family history of familial benign pemphigus can be used to differentiate the 2 entities from each other due to the autosomal-dominant inheritance pattern of familial benign pemphigus. Both of these disorders can appear similar to AAEMPD because of their extensive intraepidermal acantholysis, but they differ in the lack of Paget cells, intraepidermal atypia, and increased mitotic activity.

Acantholytic Bowen disease is a histologic variant that can be difficult to distinguish from AAEMPD on hematoxylin and eosin–stained sections because of their similar histologic features but can be differentiated by IHC stains.⁵ Acantholytic Bowen disease expresses high-molecular-weight cytokeratin (eg, CK5/6) but is negative for CK7, CAM 5.2, and CEA. Extramammary Paget disease generally has the opposite pattern: positive staining for CK7, CAM 5.2, and CEA, but negative for high-molecular-weight cytokeratin.^13,14,24

Primary cutaneous adenosquamous carcinoma is a rare malignancy of squamous and glandular differentiation known for being locally aggressive and metastatic.²⁵ Histologically, cutaneous adenosquamous carcinoma shows infiltrating nests of neoplastic cells with both squamous and glandular features. It differs notably from AAEMPD in that cutaneous adenosquamous carcinomas tend to arise in the head and arm regions, and their histologic morphology is different. The IHC profiles are similar, with positive staining for CEA, CK7, and mucin; however, they differ in that AAEMPD is negative for high-molecular-weight keratin while cutaneous adenosquamous carcinoma is positive.²⁵

Verrucous carcinoma is an uncommon variant of squamous cell carcinoma with well-differentiated keratinocytes and a blunt pushing border.²⁴ Similar to AAEMPD, this neoplasm can arise in the genital and perineal areas; however, the 2 entities differ considerably in morphology on histologic examination.

Pemphigus vulgaris is an autoimmune intraepidermal blistering disorder of the skin and mucous membranes of which pemphigus vegetans is a subtype.^26,27 Pemphigus vulgaris is another diagnosis that can possibly be mimicked by AAEMPD.²⁸ Histologic features of pemphigus vulgaris include intraepidermal acantholysis of keratinocytes immediately above the basal layer of the epidermis. Pemphigus vegetans is similar with the addition of papillomatosis, hyperkeratosis, and an eosinophilic infiltrate.^26,27 Immunofluorescence typically demonstrates intercellular C3 and IgG deposits.²⁶ These diseases mimic AAEMPD histologically but differ in their relative lack of atypia and Paget cells.

In summary, we report a case of AAEMPD in a 78-year-old man in whom routine histologic specimens showed marked intraepidermal acantholysis and atypical tumor cells with increased mitoses. The latter finding prompted IHC studies that revealed positive CK7, CEA, pancytokeratin, and LMWCK staining with negative CK20 staining. Hale colloidal iron staining showed moderate to abundant cytoplasmic mucin. The patient was diagnosed with AAEMPD. It is imperative to maintain clinical suspicion for AAEMPD and to examine acantholytic disorders with scrutiny. When there is evidence of atypia or mitoses, use of IHC stains can assist in fully characterizing the lesion.

To the Editor:

Barber’s sinus, or interdigital pilonidal sinus, is an occupational dermatosis with a pathognomonic clinical picture. Nearly all reports of barber’s sinus in the literature have involved the hands of male barbers and hairdressers. We present an uncommon case of barber’s sinus between the toes of a female hairdresser. If left untreated, potential complications of barber’s sinus include abscess formation, cellulitis, lymphangitis, and osteomyelitis. Clinicians should advise patients with an occupational risk of barber’s sinus to wear protective footwear and maintain hygiene in the interdigital spaces.

A 23-year-old female hairdresser was referred to our outpatient dermatology clinic by general surgery for evaluation of an asymptomatic interdigital toe lesion of several months’ duration. She was otherwise healthy. Physical examination revealed a 3-mm sinus in the interdigital web space between the fourth and fifth digits of the left foot, creating a partial fistula terminating in an umbilicated pink papule on the dorsal aspect of the interdigital space (Figure). While at work, the patient reported that she usually wore open-toed flip-flops. A diagnosis of barber’s sinus was made clinically. She returned for follow-up to the referring surgeon within 2 months and was offered surgical debridement, but the patient declined treatment, instead opting to wait and monitor for any potential complications. The lesion showed no change in clinical appearance and remained asymptomatic.

Barber’s sinus is caused by sharp fragments of clipped hair that penetrate the fragile interdigital skin and cause a foreign-body reaction. Males are almost exclusively contributory to the reported cases of barber’s sinus in the literature.^1,2

The clinical picture of barber’s sinus is pathognomonic, as demonstrated in our case. Other potential diagnoses to consider include atypical mycobacterial infection, deep fungal infection, other foreign-body granuloma, and erosio interdigitalis blastomycetica. Although thorough removal of embedded hair fragments may be curative, most cases require surgical excision, often by curette, and subsequent skin closure. Pathology shows a foreign-body granulomatous reaction to hair fragments. If left untreated, potential complications of barber’s sinus include abscess formation, cellulitis, lymphangitis, and osteomyelitis. This lesion is preventable by maintaining hygiene of the interdigital spaces, use of barrier creams, and wearing protective footwear.^3,4

To the Editor:

Barber’s sinus, or interdigital pilonidal sinus, is an occupational dermatosis with a pathognomonic clinical picture. Nearly all reports of barber’s sinus in the literature have involved the hands of male barbers and hairdressers. We present an uncommon case of barber’s sinus between the toes of a female hairdresser. If left untreated, potential complications of barber’s sinus include abscess formation, cellulitis, lymphangitis, and osteomyelitis. Clinicians should advise patients with an occupational risk of barber’s sinus to wear protective footwear and maintain hygiene in the interdigital spaces.

A 23-year-old female hairdresser was referred to our outpatient dermatology clinic by general surgery for evaluation of an asymptomatic interdigital toe lesion of several months’ duration. She was otherwise healthy. Physical examination revealed a 3-mm sinus in the interdigital web space between the fourth and fifth digits of the left foot, creating a partial fistula terminating in an umbilicated pink papule on the dorsal aspect of the interdigital space (Figure). While at work, the patient reported that she usually wore open-toed flip-flops. A diagnosis of barber’s sinus was made clinically. She returned for follow-up to the referring surgeon within 2 months and was offered surgical debridement, but the patient declined treatment, instead opting to wait and monitor for any potential complications. The lesion showed no change in clinical appearance and remained asymptomatic.

Barber’s sinus is caused by sharp fragments of clipped hair that penetrate the fragile interdigital skin and cause a foreign-body reaction. Males are almost exclusively contributory to the reported cases of barber’s sinus in the literature.^1,2

The clinical picture of barber’s sinus is pathognomonic, as demonstrated in our case. Other potential diagnoses to consider include atypical mycobacterial infection, deep fungal infection, other foreign-body granuloma, and erosio interdigitalis blastomycetica. Although thorough removal of embedded hair fragments may be curative, most cases require surgical excision, often by curette, and subsequent skin closure. Pathology shows a foreign-body granulomatous reaction to hair fragments. If left untreated, potential complications of barber’s sinus include abscess formation, cellulitis, lymphangitis, and osteomyelitis. This lesion is preventable by maintaining hygiene of the interdigital spaces, use of barrier creams, and wearing protective footwear.^3,4

To the Editor:

Barber’s sinus, or interdigital pilonidal sinus, is an occupational dermatosis with a pathognomonic clinical picture. Nearly all reports of barber’s sinus in the literature have involved the hands of male barbers and hairdressers. We present an uncommon case of barber’s sinus between the toes of a female hairdresser. If left untreated, potential complications of barber’s sinus include abscess formation, cellulitis, lymphangitis, and osteomyelitis. Clinicians should advise patients with an occupational risk of barber’s sinus to wear protective footwear and maintain hygiene in the interdigital spaces.

A 23-year-old female hairdresser was referred to our outpatient dermatology clinic by general surgery for evaluation of an asymptomatic interdigital toe lesion of several months’ duration. She was otherwise healthy. Physical examination revealed a 3-mm sinus in the interdigital web space between the fourth and fifth digits of the left foot, creating a partial fistula terminating in an umbilicated pink papule on the dorsal aspect of the interdigital space (Figure). While at work, the patient reported that she usually wore open-toed flip-flops. A diagnosis of barber’s sinus was made clinically. She returned for follow-up to the referring surgeon within 2 months and was offered surgical debridement, but the patient declined treatment, instead opting to wait and monitor for any potential complications. The lesion showed no change in clinical appearance and remained asymptomatic.

Barber’s sinus is caused by sharp fragments of clipped hair that penetrate the fragile interdigital skin and cause a foreign-body reaction. Males are almost exclusively contributory to the reported cases of barber’s sinus in the literature.^1,2

The clinical picture of barber’s sinus is pathognomonic, as demonstrated in our case. Other potential diagnoses to consider include atypical mycobacterial infection, deep fungal infection, other foreign-body granuloma, and erosio interdigitalis blastomycetica. Although thorough removal of embedded hair fragments may be curative, most cases require surgical excision, often by curette, and subsequent skin closure. Pathology shows a foreign-body granulomatous reaction to hair fragments. If left untreated, potential complications of barber’s sinus include abscess formation, cellulitis, lymphangitis, and osteomyelitis. This lesion is preventable by maintaining hygiene of the interdigital spaces, use of barrier creams, and wearing protective footwear.^3,4

To the Editor:

Leiomyomas are benign smooth muscle tumors. There are 3 types of cutaneous leiomyomas: (1) piloleiomyomas, arising from the arrector pili muscles; (2) angioleiomyomas, arising from the muscles surrounding dermal blood vessels; and (3) leiomyomas of the external genitalia, arising from the dartoic, vulvar, or mammary smooth muscles.¹ There is no gender predilection for cutaneous leiomyomas, and lesions present on average at approximately 40 to 45 years of age.²

Piloleiomyomas are the most common type of cutaneous leiomyomas and typically present as red-brown papules and nodules on the trunk, arms, and legs.³ Piloleiomyomas often are associated with spontaneous or induced pain (eg, with cold exposure). The pain associated with piloleiomyomas can be severely debilitating to patients and may have a considerable impact on their quality of life.

A 40-year-old woman presented to our clinic with numerous widespread, painful, red-brown papules and nodules on the head, neck, chest, abdomen, back, arms, and legs of 6 years’ duration that were increasing in number (Figure 1). She had a history of uterine leiomyomas and type 2 renal papillary carcinoma following a left nephrectomy at 38 years of age. The patient’s mother had a history of similar skin lesions as well as uterine cancer. Multiple excisional biopsies were performed, all of which showed piloleiomyomas on histopathology (Figure 2). The pain associated with the patient’s extensive cutaneous leiomyomas considerably impaired her quality of life. Although she experienced pain in all affected areas of the body, the pain was the worst in the upper arms. She reported having requested a nerve ablation procedure from an outside pain management clinic, which was denied for unknown reasons.

Two years prior to the current presentation, the patient had been treated by a pain management specialist with gabapentin 300 mg twice daily as needed for pain associated with leiomyomas. The patient followed this regimen approximately 3 times weekly for the preceding 1 to 2 years with reduction in her pain symptoms; however, the painful episodes became more frequent and severe over time. The patient reported being unable to further increase the gabapentin dosing frequency because it made her too drowsy and impacted her ability to work a job that required heavy lifting. Thus, the patient requested additional therapy and was subsequently treated at our clinic with numerous excisional biopsies of the most painful lesions during the 2 years prior to her current presentation.

When the patient re-presented to our clinic, she requested additional lesion excisions given that she had experienced some pain relief from this treatment modality in the past; however, these prior excisions only resulted in local pain relief limited to the site of the excision. Because of the extent of the lesions and the patient’s inability to tolerate pain from the lidocaine injections, we did not feel multiple excisions were a practical treatment option. The patient subsequently was offered a trial of cryotherapy for symptom relief based on a reported case in which this modality was successfully used.⁴ After discussing the risks and benefits associated with this treatment, cryotherapy was attempted on a few of the leiomyomas on the patient’s right shoulder; however, she experienced severe pain during cryotherapy treatment, and the procedure had to be aborted.

We then increased the patient’s gabapentin regimen to 300 mg in the morning and 600 mg in the evening, as tolerated. The patient reported that she was better able to tolerate the sedating side effects of the increased dose of gabapentin because she had stopped working due to her severe pain episodes. We also added oral nifedipine 10 mg 3 times daily, as needed. Within 30 minutes of starting this treatment regimen, the pain associated with the lesions remarkably improved (10/10 severity before starting treatment vs 3/10 after starting treatment). Her pain levels remained stable (3/10 severity) during 3 weeks of treatment with this combination regimen, but unfortunately she developed headaches and malaise, which she associated with the nifedipine at the 3 times daily dose.

The patient was able to better tolerate the nifedipine after reducing the dose to once daily on an as-needed basis. On average, the patient took nifedipine once every 3 days; however, she reported that she had to periodically increase the frequency of the nifedipine to once daily for up to 2 weeks at a time for periods of more frequent pain flares. The patient reported a consistent pattern of the breakthrough symptoms rapidly improving with each dose of nifedipine, though she did feel that taking consistent gabapentin enhanced baseline symptom control. The patient also noticed on a few occasions when she did not have access to her nifedipine that her pain would flare to 10/10 severity and would decrease to 4/10 severity 30 minutes after restarting nifedipine at 10 mg once daily. She experienced breakthrough pain due to exacerbating factors including her menstrual cycle; exposure to the sun and cold temperatures or water; excessive physical activity; and mild trauma. Due to exacerbations from sun exposure, the patient often wore long-sleeved shirts, which helped reduce the severity of the pain episodes while she was outdoors.

The exact mechanism for the pain associated with cutaneous leiomyomas is unknown but is thought to be due to infringement of the lesion on the surrounding cutaneous nerves. In addition, norepinephrine activates alpha receptors on the smooth muscle to contract through an influx of ions such as calcium. When smooth muscle contracts, the compression of nerves likely is worsened.

There are a limited number of case reports in the literature that have demonstrated successful treatment of the pain associated with cutaneous leiomyomas. Previously reported treatment modalities have included phenoxybenzamine, an alpha-blocking agent that may reduce pain through its antiadrenergic effects²; nitroglycerin, a venous and arterial dilator that may reduce pain by decreasing muscle oxygen requirements²; gabapentin, an antiepileptic and analgesic medication with structural similarity to the gamma-aminobutyric acid neurotransmitter for which the exact mechanism of action is unknown³; botulinum toxin, a neuromuscular blocker that prevents the release of presynaptic acetylcholine and may decrease neuropathic pain by reducing hyperactive nerves^5,6; hyoscine butylbromide and topical hyoscine hydrobromide, both antispasmodics that may reduce pain through their anticholinergic effects, which relax smooth muscle^7,8; and the CO₂ laser, a treatment that has been utilized for its resurfacing, excisional, and ablative properties.^9,10

Calcium channel blockers such as amlodipine, verapamil, and nifedipine also have been used to treat the pain associated with piloleiomyomas.¹¹ Calcium ion channel antagonists inhibit the influx of calcium ions across the cell membrane; therefore, nifedipine and other calcium channel blockers may prevent the smooth muscle contraction that is hypothesized to cause pain in patients with cutaneous leiomyomas.¹²

Mean plasma concentration of nifedipine has been shown to reach maximum values of 160 +/− 49 µg/L after 30 to 60 minutes following oral administration of 10 mg of nifedipine.¹³ After 8 hours, the mean concentration drops to 3.4 +/− 1.2 µg/L. The clinical response in our patient appeared consistent with the reported pharmacokinetics of the drug, as she was able to consistently obtain considerable reduction in her pain symptoms within 30 minutes of starting nifedipine, coinciding with the period of time it takes for the nifedipine to reach maximum plasma concentrations.¹³

Interestingly, our patient had worsening pain episodes associated with sun exposure, which typically is not reported as one of the usual triggers for cutaneous leiomyomas. We are not aware of any described mechanisms that would explain this phenomenon.

Importantly, any patient presenting with multiple cutaneous and uterine (if female) leiomyomas should be screened for hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), an autosomal-dominant disorder linked to a mutation in the fumarate hydratase tumor suppressor gene. Clinically, HLRCC patients typically present with multiple cutaneous leiomyomas, uterine leiomyomas, and renal cell cancer (most often type 2 papillary renal cell carcinoma).¹⁴ Hereditary leiomyomatosis and renal cell carcinoma syndrome (also known as multiple cutaneous and uterine leiomyomatosis syndrome) previously was thought to be a separate disease entity from Reed syndrome; however, after the same mutation in the fumarate hydratase tumor suppressor gene was found to be responsible for both Reed syndrome and HLRCC, they are now thought to be the same disease process.¹⁵

Diagnosis of HLRCC is likely when the patient meets the major criterion of multiple cutaneous piloleiomyomas confirmed histopathologically. Clinical diagnosis of HLRCC is suspected if 2 or more of the following minor criteria are present: type 2 papillary renal cell carcinoma before 40 years of age; onset of severely symptomatic (requiring surgery) uterine fibroids before 40 years of age in females; and first-degree family member who meets 1 or more of these criteria.¹⁵ At the time of presentation, the patient met clinical criteria for HLRCC, including multiple cutaneous leiomyomas (major criterion) and type 2 papillary renal cell carcinoma before 40 years of age (minor criterion). The patient also had a history of uterine leiomyomas, but these lesions did not fulfill the criterion of being severely symptomatic requiring surgery. Furthermore, the patient’s mother had similar cutaneous leiomyomas and a history of uterine cancer, which fulfilled additional minor criterion, consistent with an autosomal-dominant inheritance pattern (with variable penetrance) seen in HLRCC. An important issue for counseling and monitoring patients is that premenopausal women with HLRCC are at an increased risk of developing uterine leiomyosarcoma.¹⁵ Our patient followed up with an oncologist for tumor surveillance and subsequently underwent genetic testing, which revealed a mutation in the fumarate hydratase gene.

Treatment of painful cutaneous leiomyomas, particularly in patients with HLRCC, remains a therapeutic challenge. Although surgical and/or destructive treatments can provide pain relief for patients who have a limited number of lesions, these options are impracticable when a patient has numerous widespread leiomyomas; therefore, systemic therapies may be more beneficial. Clinicians should be aware of nifedipine, which may be used in combination with gabapentin as a viable treatment option in the management of acute and breakthrough pain associated with cutaneous leiomyomas.

Acknowledgment
The authors thank Alejandra Encalada, MA, for her assistance in the care and follow-up of the patient.

To the Editor:

Leiomyomas are benign smooth muscle tumors. There are 3 types of cutaneous leiomyomas: (1) piloleiomyomas, arising from the arrector pili muscles; (2) angioleiomyomas, arising from the muscles surrounding dermal blood vessels; and (3) leiomyomas of the external genitalia, arising from the dartoic, vulvar, or mammary smooth muscles.¹ There is no gender predilection for cutaneous leiomyomas, and lesions present on average at approximately 40 to 45 years of age.²

Piloleiomyomas are the most common type of cutaneous leiomyomas and typically present as red-brown papules and nodules on the trunk, arms, and legs.³ Piloleiomyomas often are associated with spontaneous or induced pain (eg, with cold exposure). The pain associated with piloleiomyomas can be severely debilitating to patients and may have a considerable impact on their quality of life.

A 40-year-old woman presented to our clinic with numerous widespread, painful, red-brown papules and nodules on the head, neck, chest, abdomen, back, arms, and legs of 6 years’ duration that were increasing in number (Figure 1). She had a history of uterine leiomyomas and type 2 renal papillary carcinoma following a left nephrectomy at 38 years of age. The patient’s mother had a history of similar skin lesions as well as uterine cancer. Multiple excisional biopsies were performed, all of which showed piloleiomyomas on histopathology (Figure 2). The pain associated with the patient’s extensive cutaneous leiomyomas considerably impaired her quality of life. Although she experienced pain in all affected areas of the body, the pain was the worst in the upper arms. She reported having requested a nerve ablation procedure from an outside pain management clinic, which was denied for unknown reasons.

Two years prior to the current presentation, the patient had been treated by a pain management specialist with gabapentin 300 mg twice daily as needed for pain associated with leiomyomas. The patient followed this regimen approximately 3 times weekly for the preceding 1 to 2 years with reduction in her pain symptoms; however, the painful episodes became more frequent and severe over time. The patient reported being unable to further increase the gabapentin dosing frequency because it made her too drowsy and impacted her ability to work a job that required heavy lifting. Thus, the patient requested additional therapy and was subsequently treated at our clinic with numerous excisional biopsies of the most painful lesions during the 2 years prior to her current presentation.

When the patient re-presented to our clinic, she requested additional lesion excisions given that she had experienced some pain relief from this treatment modality in the past; however, these prior excisions only resulted in local pain relief limited to the site of the excision. Because of the extent of the lesions and the patient’s inability to tolerate pain from the lidocaine injections, we did not feel multiple excisions were a practical treatment option. The patient subsequently was offered a trial of cryotherapy for symptom relief based on a reported case in which this modality was successfully used.⁴ After discussing the risks and benefits associated with this treatment, cryotherapy was attempted on a few of the leiomyomas on the patient’s right shoulder; however, she experienced severe pain during cryotherapy treatment, and the procedure had to be aborted.

We then increased the patient’s gabapentin regimen to 300 mg in the morning and 600 mg in the evening, as tolerated. The patient reported that she was better able to tolerate the sedating side effects of the increased dose of gabapentin because she had stopped working due to her severe pain episodes. We also added oral nifedipine 10 mg 3 times daily, as needed. Within 30 minutes of starting this treatment regimen, the pain associated with the lesions remarkably improved (10/10 severity before starting treatment vs 3/10 after starting treatment). Her pain levels remained stable (3/10 severity) during 3 weeks of treatment with this combination regimen, but unfortunately she developed headaches and malaise, which she associated with the nifedipine at the 3 times daily dose.

The patient was able to better tolerate the nifedipine after reducing the dose to once daily on an as-needed basis. On average, the patient took nifedipine once every 3 days; however, she reported that she had to periodically increase the frequency of the nifedipine to once daily for up to 2 weeks at a time for periods of more frequent pain flares. The patient reported a consistent pattern of the breakthrough symptoms rapidly improving with each dose of nifedipine, though she did feel that taking consistent gabapentin enhanced baseline symptom control. The patient also noticed on a few occasions when she did not have access to her nifedipine that her pain would flare to 10/10 severity and would decrease to 4/10 severity 30 minutes after restarting nifedipine at 10 mg once daily. She experienced breakthrough pain due to exacerbating factors including her menstrual cycle; exposure to the sun and cold temperatures or water; excessive physical activity; and mild trauma. Due to exacerbations from sun exposure, the patient often wore long-sleeved shirts, which helped reduce the severity of the pain episodes while she was outdoors.

The exact mechanism for the pain associated with cutaneous leiomyomas is unknown but is thought to be due to infringement of the lesion on the surrounding cutaneous nerves. In addition, norepinephrine activates alpha receptors on the smooth muscle to contract through an influx of ions such as calcium. When smooth muscle contracts, the compression of nerves likely is worsened.

There are a limited number of case reports in the literature that have demonstrated successful treatment of the pain associated with cutaneous leiomyomas. Previously reported treatment modalities have included phenoxybenzamine, an alpha-blocking agent that may reduce pain through its antiadrenergic effects²; nitroglycerin, a venous and arterial dilator that may reduce pain by decreasing muscle oxygen requirements²; gabapentin, an antiepileptic and analgesic medication with structural similarity to the gamma-aminobutyric acid neurotransmitter for which the exact mechanism of action is unknown³; botulinum toxin, a neuromuscular blocker that prevents the release of presynaptic acetylcholine and may decrease neuropathic pain by reducing hyperactive nerves^5,6; hyoscine butylbromide and topical hyoscine hydrobromide, both antispasmodics that may reduce pain through their anticholinergic effects, which relax smooth muscle^7,8; and the CO₂ laser, a treatment that has been utilized for its resurfacing, excisional, and ablative properties.^9,10

Calcium channel blockers such as amlodipine, verapamil, and nifedipine also have been used to treat the pain associated with piloleiomyomas.¹¹ Calcium ion channel antagonists inhibit the influx of calcium ions across the cell membrane; therefore, nifedipine and other calcium channel blockers may prevent the smooth muscle contraction that is hypothesized to cause pain in patients with cutaneous leiomyomas.¹²

Mean plasma concentration of nifedipine has been shown to reach maximum values of 160 +/− 49 µg/L after 30 to 60 minutes following oral administration of 10 mg of nifedipine.¹³ After 8 hours, the mean concentration drops to 3.4 +/− 1.2 µg/L. The clinical response in our patient appeared consistent with the reported pharmacokinetics of the drug, as she was able to consistently obtain considerable reduction in her pain symptoms within 30 minutes of starting nifedipine, coinciding with the period of time it takes for the nifedipine to reach maximum plasma concentrations.¹³

Interestingly, our patient had worsening pain episodes associated with sun exposure, which typically is not reported as one of the usual triggers for cutaneous leiomyomas. We are not aware of any described mechanisms that would explain this phenomenon.

Importantly, any patient presenting with multiple cutaneous and uterine (if female) leiomyomas should be screened for hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), an autosomal-dominant disorder linked to a mutation in the fumarate hydratase tumor suppressor gene. Clinically, HLRCC patients typically present with multiple cutaneous leiomyomas, uterine leiomyomas, and renal cell cancer (most often type 2 papillary renal cell carcinoma).¹⁴ Hereditary leiomyomatosis and renal cell carcinoma syndrome (also known as multiple cutaneous and uterine leiomyomatosis syndrome) previously was thought to be a separate disease entity from Reed syndrome; however, after the same mutation in the fumarate hydratase tumor suppressor gene was found to be responsible for both Reed syndrome and HLRCC, they are now thought to be the same disease process.¹⁵

Diagnosis of HLRCC is likely when the patient meets the major criterion of multiple cutaneous piloleiomyomas confirmed histopathologically. Clinical diagnosis of HLRCC is suspected if 2 or more of the following minor criteria are present: type 2 papillary renal cell carcinoma before 40 years of age; onset of severely symptomatic (requiring surgery) uterine fibroids before 40 years of age in females; and first-degree family member who meets 1 or more of these criteria.¹⁵ At the time of presentation, the patient met clinical criteria for HLRCC, including multiple cutaneous leiomyomas (major criterion) and type 2 papillary renal cell carcinoma before 40 years of age (minor criterion). The patient also had a history of uterine leiomyomas, but these lesions did not fulfill the criterion of being severely symptomatic requiring surgery. Furthermore, the patient’s mother had similar cutaneous leiomyomas and a history of uterine cancer, which fulfilled additional minor criterion, consistent with an autosomal-dominant inheritance pattern (with variable penetrance) seen in HLRCC. An important issue for counseling and monitoring patients is that premenopausal women with HLRCC are at an increased risk of developing uterine leiomyosarcoma.¹⁵ Our patient followed up with an oncologist for tumor surveillance and subsequently underwent genetic testing, which revealed a mutation in the fumarate hydratase gene.

Treatment of painful cutaneous leiomyomas, particularly in patients with HLRCC, remains a therapeutic challenge. Although surgical and/or destructive treatments can provide pain relief for patients who have a limited number of lesions, these options are impracticable when a patient has numerous widespread leiomyomas; therefore, systemic therapies may be more beneficial. Clinicians should be aware of nifedipine, which may be used in combination with gabapentin as a viable treatment option in the management of acute and breakthrough pain associated with cutaneous leiomyomas.

Acknowledgment
The authors thank Alejandra Encalada, MA, for her assistance in the care and follow-up of the patient.

To the Editor:

Leiomyomas are benign smooth muscle tumors. There are 3 types of cutaneous leiomyomas: (1) piloleiomyomas, arising from the arrector pili muscles; (2) angioleiomyomas, arising from the muscles surrounding dermal blood vessels; and (3) leiomyomas of the external genitalia, arising from the dartoic, vulvar, or mammary smooth muscles.¹ There is no gender predilection for cutaneous leiomyomas, and lesions present on average at approximately 40 to 45 years of age.²

Piloleiomyomas are the most common type of cutaneous leiomyomas and typically present as red-brown papules and nodules on the trunk, arms, and legs.³ Piloleiomyomas often are associated with spontaneous or induced pain (eg, with cold exposure). The pain associated with piloleiomyomas can be severely debilitating to patients and may have a considerable impact on their quality of life.

A 40-year-old woman presented to our clinic with numerous widespread, painful, red-brown papules and nodules on the head, neck, chest, abdomen, back, arms, and legs of 6 years’ duration that were increasing in number (Figure 1). She had a history of uterine leiomyomas and type 2 renal papillary carcinoma following a left nephrectomy at 38 years of age. The patient’s mother had a history of similar skin lesions as well as uterine cancer. Multiple excisional biopsies were performed, all of which showed piloleiomyomas on histopathology (Figure 2). The pain associated with the patient’s extensive cutaneous leiomyomas considerably impaired her quality of life. Although she experienced pain in all affected areas of the body, the pain was the worst in the upper arms. She reported having requested a nerve ablation procedure from an outside pain management clinic, which was denied for unknown reasons.

Two years prior to the current presentation, the patient had been treated by a pain management specialist with gabapentin 300 mg twice daily as needed for pain associated with leiomyomas. The patient followed this regimen approximately 3 times weekly for the preceding 1 to 2 years with reduction in her pain symptoms; however, the painful episodes became more frequent and severe over time. The patient reported being unable to further increase the gabapentin dosing frequency because it made her too drowsy and impacted her ability to work a job that required heavy lifting. Thus, the patient requested additional therapy and was subsequently treated at our clinic with numerous excisional biopsies of the most painful lesions during the 2 years prior to her current presentation.

When the patient re-presented to our clinic, she requested additional lesion excisions given that she had experienced some pain relief from this treatment modality in the past; however, these prior excisions only resulted in local pain relief limited to the site of the excision. Because of the extent of the lesions and the patient’s inability to tolerate pain from the lidocaine injections, we did not feel multiple excisions were a practical treatment option. The patient subsequently was offered a trial of cryotherapy for symptom relief based on a reported case in which this modality was successfully used.⁴ After discussing the risks and benefits associated with this treatment, cryotherapy was attempted on a few of the leiomyomas on the patient’s right shoulder; however, she experienced severe pain during cryotherapy treatment, and the procedure had to be aborted.

We then increased the patient’s gabapentin regimen to 300 mg in the morning and 600 mg in the evening, as tolerated. The patient reported that she was better able to tolerate the sedating side effects of the increased dose of gabapentin because she had stopped working due to her severe pain episodes. We also added oral nifedipine 10 mg 3 times daily, as needed. Within 30 minutes of starting this treatment regimen, the pain associated with the lesions remarkably improved (10/10 severity before starting treatment vs 3/10 after starting treatment). Her pain levels remained stable (3/10 severity) during 3 weeks of treatment with this combination regimen, but unfortunately she developed headaches and malaise, which she associated with the nifedipine at the 3 times daily dose.

The patient was able to better tolerate the nifedipine after reducing the dose to once daily on an as-needed basis. On average, the patient took nifedipine once every 3 days; however, she reported that she had to periodically increase the frequency of the nifedipine to once daily for up to 2 weeks at a time for periods of more frequent pain flares. The patient reported a consistent pattern of the breakthrough symptoms rapidly improving with each dose of nifedipine, though she did feel that taking consistent gabapentin enhanced baseline symptom control. The patient also noticed on a few occasions when she did not have access to her nifedipine that her pain would flare to 10/10 severity and would decrease to 4/10 severity 30 minutes after restarting nifedipine at 10 mg once daily. She experienced breakthrough pain due to exacerbating factors including her menstrual cycle; exposure to the sun and cold temperatures or water; excessive physical activity; and mild trauma. Due to exacerbations from sun exposure, the patient often wore long-sleeved shirts, which helped reduce the severity of the pain episodes while she was outdoors.

The exact mechanism for the pain associated with cutaneous leiomyomas is unknown but is thought to be due to infringement of the lesion on the surrounding cutaneous nerves. In addition, norepinephrine activates alpha receptors on the smooth muscle to contract through an influx of ions such as calcium. When smooth muscle contracts, the compression of nerves likely is worsened.

There are a limited number of case reports in the literature that have demonstrated successful treatment of the pain associated with cutaneous leiomyomas. Previously reported treatment modalities have included phenoxybenzamine, an alpha-blocking agent that may reduce pain through its antiadrenergic effects²; nitroglycerin, a venous and arterial dilator that may reduce pain by decreasing muscle oxygen requirements²; gabapentin, an antiepileptic and analgesic medication with structural similarity to the gamma-aminobutyric acid neurotransmitter for which the exact mechanism of action is unknown³; botulinum toxin, a neuromuscular blocker that prevents the release of presynaptic acetylcholine and may decrease neuropathic pain by reducing hyperactive nerves^5,6; hyoscine butylbromide and topical hyoscine hydrobromide, both antispasmodics that may reduce pain through their anticholinergic effects, which relax smooth muscle^7,8; and the CO₂ laser, a treatment that has been utilized for its resurfacing, excisional, and ablative properties.^9,10

Calcium channel blockers such as amlodipine, verapamil, and nifedipine also have been used to treat the pain associated with piloleiomyomas.¹¹ Calcium ion channel antagonists inhibit the influx of calcium ions across the cell membrane; therefore, nifedipine and other calcium channel blockers may prevent the smooth muscle contraction that is hypothesized to cause pain in patients with cutaneous leiomyomas.¹²

Mean plasma concentration of nifedipine has been shown to reach maximum values of 160 +/− 49 µg/L after 30 to 60 minutes following oral administration of 10 mg of nifedipine.¹³ After 8 hours, the mean concentration drops to 3.4 +/− 1.2 µg/L. The clinical response in our patient appeared consistent with the reported pharmacokinetics of the drug, as she was able to consistently obtain considerable reduction in her pain symptoms within 30 minutes of starting nifedipine, coinciding with the period of time it takes for the nifedipine to reach maximum plasma concentrations.¹³

Interestingly, our patient had worsening pain episodes associated with sun exposure, which typically is not reported as one of the usual triggers for cutaneous leiomyomas. We are not aware of any described mechanisms that would explain this phenomenon.

Importantly, any patient presenting with multiple cutaneous and uterine (if female) leiomyomas should be screened for hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), an autosomal-dominant disorder linked to a mutation in the fumarate hydratase tumor suppressor gene. Clinically, HLRCC patients typically present with multiple cutaneous leiomyomas, uterine leiomyomas, and renal cell cancer (most often type 2 papillary renal cell carcinoma).¹⁴ Hereditary leiomyomatosis and renal cell carcinoma syndrome (also known as multiple cutaneous and uterine leiomyomatosis syndrome) previously was thought to be a separate disease entity from Reed syndrome; however, after the same mutation in the fumarate hydratase tumor suppressor gene was found to be responsible for both Reed syndrome and HLRCC, they are now thought to be the same disease process.¹⁵

Diagnosis of HLRCC is likely when the patient meets the major criterion of multiple cutaneous piloleiomyomas confirmed histopathologically. Clinical diagnosis of HLRCC is suspected if 2 or more of the following minor criteria are present: type 2 papillary renal cell carcinoma before 40 years of age; onset of severely symptomatic (requiring surgery) uterine fibroids before 40 years of age in females; and first-degree family member who meets 1 or more of these criteria.¹⁵ At the time of presentation, the patient met clinical criteria for HLRCC, including multiple cutaneous leiomyomas (major criterion) and type 2 papillary renal cell carcinoma before 40 years of age (minor criterion). The patient also had a history of uterine leiomyomas, but these lesions did not fulfill the criterion of being severely symptomatic requiring surgery. Furthermore, the patient’s mother had similar cutaneous leiomyomas and a history of uterine cancer, which fulfilled additional minor criterion, consistent with an autosomal-dominant inheritance pattern (with variable penetrance) seen in HLRCC. An important issue for counseling and monitoring patients is that premenopausal women with HLRCC are at an increased risk of developing uterine leiomyosarcoma.¹⁵ Our patient followed up with an oncologist for tumor surveillance and subsequently underwent genetic testing, which revealed a mutation in the fumarate hydratase gene.

Treatment of painful cutaneous leiomyomas, particularly in patients with HLRCC, remains a therapeutic challenge. Although surgical and/or destructive treatments can provide pain relief for patients who have a limited number of lesions, these options are impracticable when a patient has numerous widespread leiomyomas; therefore, systemic therapies may be more beneficial. Clinicians should be aware of nifedipine, which may be used in combination with gabapentin as a viable treatment option in the management of acute and breakthrough pain associated with cutaneous leiomyomas.

Acknowledgment
The authors thank Alejandra Encalada, MA, for her assistance in the care and follow-up of the patient.

To the Editor:

The increase in nontuberculous mycobacteria (NTM) infections over the last 3 decades likely is multifaceted, including increased clinical awareness, improved laboratory diagnostics, growing numbers of immunocompromised patients, and an aging population.^1,2 Historically, the majority of mycobacteria-related diseases are due to Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium leprae.³

Mycobacterium haemophilum is a slow-growing acid-fast bacillus (AFB) that differs from other Mycobacterium species in that it requires iron-supplemented media and incubation temperatures of 30°C to 32°C for culture. As these requirements for growth are not standard for AFB cultures, M haemophilum infection may be underrecognized and underreported.³Mycobacterium haemophilum infections largely are cutaneous and generally are seen in AIDS patients and bone marrow transplant recipients who are iatrogenically immunosuppressed.^4,5 No species-specific treatment guidelines exist²; however, triple-drug therapy combining a macrolide, rifamycin, and a quinolone for a minimum of 12 months often is recommended.

A 64-year-old man with a history of coronary artery disease, hypertension, hyperlipidemia, and acute myelogenous leukemia (AML) underwent allogenic stem cell transplantation. His posttransplant course was complicated by multiple deep vein thromboses, hypogammaglobulinemia, and graft-vs-host disease (GVHD) of the skin and gastrointestinal tract that manifested as chronic diarrhea, which was managed with chronic prednisone. Thirteen months after the transplant, the patient presented to his outpatient oncologist (M.K.) for evaluation of painless, nonpruritic, erythematous papules and nodules that had emerged on the right side of the chest, right arm, and left leg of approximately 2 weeks’ duration.

On review of systems by oncology, the patient denied any fevers, chills, or night sweats but noted chronic loose nonbloody stools without abdominal pain, likely related to the GVHD. The patient’s medications included prednisone 20 mg once daily, fluconazole, amitriptyline, atovaquone, budesonide, dabigatran, metoprolol, pantoprazole, rosuvastatin, senna glycoside, spironolactone, tramadol, and valacyclovir.

Physical examination revealed multiple singular erythematous nodules on the right side of the chest (Figure 1A), right arm (Figure 1B), and left leg. There was no regional lymphadenopathy. The patient was afebrile and hemodynamically stable. A biopsy of the arm performed to rule out leukemia cutis revealed a granulomatous dermatitis with numerous AFB (Figures 2A and 2B), which were confirmed on Ziehl-Neelsen staining (Figures 2C and 2D). The presence of AFB raised concern for a disseminated mycobacterial infection. The patient was admitted to our institution approximately 1 week after the outpatient biopsy was performed. He was evaluated by infectious diseases (B.H.) and was recommended for repeat biopsy with AFB culture and for initiation of intravenous antibiotics.

The patient was evaluated by the dermatology consultation service on hospital day 1. At the time of consultation, the lesions were still painless but had enlarged. Two new satellite lesions were noted on his other extremities. Due to the widespread distribution of the lesions, there was concern for disseminated disease. The relatively rapid onset of new lesions increased concern for infection with rapid-growing mycobacteria, including Mycobacterium abscessus, Mycobacterium fortuitum, and Mycobacterium chelonae. A detailed history revealed that the patient’s wife had a fish tank, which supported the inclusion of Mycobacterium marinum in the differential; however, further questioning revealed that the patient never came in contact with the aquarium water. The initial outpatient biopsy had not been sent for culture. Following inpatient biopsy, the patient was initiated on empiric antimycobacterials, including imipenem, amikacin, clarithromycin, and levofloxacin. Computed tomography of the head was negative for cerebral involvement.

Acid-fast bacilli blood cultures were drawn per the recommendation from infectious diseases in an attempt to confirm disseminated disease; however, blood cultures remained negative. Tissue biopsy from the right arm was sent for AFB staining and culture. Many AFB were identified on microscopy, and growth was observed in the mycobacterial growth indicator tube after 6 days of incubation. The DNA probe was negative for M tuberculosis complex or Mycobacterium avium complex.

The patient was discharged on hospital day 6 on empiric therapy for rapid-growing mycobacteria while cultures were pending. The empiric regimen included intravenous imipenem 1 g every 6 hours, intravenous amikacin 1 g once daily, clarithromycin 500 mg every 12 hours, and levofloxacin 750 mg once daily. All solid media cultures were negative at the time of discharge.

The biopsy specimen proved difficult to culture on solid media using traditional methods. Three weeks after the inpatient biopsy, the microbiology laboratory reported that growth was observed on solid media that was incubated at 30°C and supplemented with iron. These findings were not characteristic of a rapidly growing mycobacteria (eg, M fortuitum, M chelonae, M abscessus) or M marinum but raised concern for infectionwith M haemophilum. Antimycobacterial treatment was adjusted to amikacin, clarithromycin, levofloxacin, and rifabutin.

Six weeks after the inpatient skin biopsy, final speciation confirmed infection with M haemophilum. The isolate proved susceptible to amikacin (minimal inhibitory concentration [MIC], 16), clarithromycin (MIC, 0.12), linezolid (MIC, <1), moxifloxacin (MIC, 0.5), rifabutin (MIC, <0.25), and trimethoprim-sulfamethoxazole (MIC, 0.5/9.5). The isolate was resistant to ciprofloxacin (MIC, 4), ethambutol (MIC, >16), and rifampin (MIC, 2). Based on these findings, an infectious disease specialist modified the treatment regimen to azithromycin 600 mg once daily, moxifloxacin 400 mg once daily, and rifabutin 300 mg once daily. Azithromycin was substituted for clarithromycin in an attempt to minimize the gastrointestinal side effects of the antibiotics. The infectious disease specialist was concerned that the clarithromycin could exacerbate the patient’s chronic GVHD-associated diarrhea, which posed a challenge to the oncologist, who was attempting to manage the patient’s GVHD and minimize the use of additional prednisone. At the time of this change, the patient was doing well clinically and denied any active skin lesions.

Four months later, he developed new left-sided neck swelling. Computed tomography revealed nonspecific enhancement involving the skin and superficial subcutaneous tissues in the left anterior neck. He was referred to otolaryngology given concern for recurrent infection vs leukemia cutis. He underwent excisional biopsy. Pathology was negative for malignancy but demonstrated subcutaneous necrotizing granulomatous inflammation with a positive AFB stain. Tissue AFB cultures revealed moderate AFB on direct stain, but there was no AFB growth at 12 weeks. Clarithromycin was restarted in place of azithromycin to increase the potency of the antimycobacterial regimen. Cultures from this neck biopsy were negative after 12 weeks of incubation.

In addition to this change in antibiotic coverage, the patient’s medical oncologist tapered the patient’s immunosuppression considerably. The patient subsequently completed 12 months of therapy with clarithromycin, moxifloxacin, and rifabutin starting from the time of the neck biopsy. He remained free of recurrence of mycobacterial infection for nearly 2 years until he died from an unrelated illness.

Nontuberculous mycobacteria are an ubiquitous environmental group.² Sources include soil and natural water (M avium), fish tanks and swimming pools (M marinum), and tap water and occasionally domestic animals (Mycobacterium kansasii). Additionally, rapidly growing NTM such as M abscessus, M chelonae, and M fortuitum have been isolated from soil and natural water supplies.³

Mycobacterium haemophilum is a fastidious organism with a predilection for skin of the chest and extremities. Iatrogenically or inherently immunocompromised patients are most commonly affected^6-11; however, there also have been reports in healthy patients.^12,13 Infections typically present as painless erythematous papules or nodules that eventually suppurate, ulcerate, and become painful. Presentations involving Fitz-Hugh–Curtis syndrome,¹³ new B-cell lymphoma,¹⁰ and lymphadenitis¹² also have been described. Beyond cutaneous involvement, M haemophilum has been cultured from bone, the synovium, the lungs, and the central nervous system.^4,9 The majority of morbidities occur in patients with lung involvement.⁴ Therefore, even patients presenting with isolated cutaneous disease require close follow-up.

Mycobacterium haemophilum is a slowly proliferating organism that is unable to grow in standard egg-potato (Lowenstein-Jensen) medium or agar base (Middlebrook 7H10 or 7H11 agar) without iron supplementation (ferric ammonium citrate, hemin, or hemoglobin). It also requires temperatures of 30°C to 32°C for growth. Its iron requisite is unique, but species such as M marinum and Mycobacterium ulcerans also share reduced temperature requirements. Without a high index of suspicion, growth often is absent because standard Mycobacterium culture techniques will not foster organism growth. Our case demonstrated that special culture instructions must be relayed to the laboratory, even in the face of positive AFB smears. Failure to request hemin and modified incubation temperatures may have contributed to the negative AFB blood culture in our patient.

Due to the relatively rare incidence of M haemophilum infection, there are no known randomized controlled trials guiding antibiotic regimens. Infectious disease specialists often treat empirically with triple-drug therapy derived from locally reported species susceptibilities. The largest case series to date did not identify resistance to amikacin, ciprofloxacin, or clarithromycin.⁴ Our case identified a novel finding of ciprofloxacin and rifampin resistance, which may highlight the emergence of a newly resistant strain of M haemophilum. Of note, one case of rifampin resistance has been reported, but the culture was drawn from a postmortem specimen in the setting of previously rifampin-sensitive isolates.⁴ Empiric therapies should be guided by hospital susceptibility reports and expert consultation.

Coinfection with 2 or more NTM—including M tuberculosis, M leprae, and M fortuitum—has been reported.^8,14 Temporally distinct coinfections with M leprae and M haemophilum also have been described.¹⁵ Thus, practitioners should have a low threshold for repeat cultures in the context of new cutaneous nodules or granulomas, not only to detect concomitant infections but also to identify resistance patterns that might explain recurrent or recalcitrant disease. Immune reconstitution inflammatory syndrome also must be considered with new or worsening lesions, especially in the first months of therapy, as this is a common occurrence when immunosuppressive regimens are tapered to help manage infections.

In conclusion, M haemophilum is an underrecognized infection that presents as cutaneous nodules or lymphadenitis in immunocompromised or healthy individuals. Diagnosis requires a high index of suspicion because its unique growth requirements necessitate special laboratory techniques. Our case represents a classic presentation of this NTM infection in a patient with AML following allogenic stem cell transplantation. Repeat cultures, workup of potentially disseminated infections, and close follow-up are requisite to minimizing morbidity and mortality. A multidisciplinary approach involving infectious disease, medical oncology, radiology, and dermatology best manages this type of infection.

To the Editor:

The increase in nontuberculous mycobacteria (NTM) infections over the last 3 decades likely is multifaceted, including increased clinical awareness, improved laboratory diagnostics, growing numbers of immunocompromised patients, and an aging population.^1,2 Historically, the majority of mycobacteria-related diseases are due to Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium leprae.³

Mycobacterium haemophilum is a slow-growing acid-fast bacillus (AFB) that differs from other Mycobacterium species in that it requires iron-supplemented media and incubation temperatures of 30°C to 32°C for culture. As these requirements for growth are not standard for AFB cultures, M haemophilum infection may be underrecognized and underreported.³Mycobacterium haemophilum infections largely are cutaneous and generally are seen in AIDS patients and bone marrow transplant recipients who are iatrogenically immunosuppressed.^4,5 No species-specific treatment guidelines exist²; however, triple-drug therapy combining a macrolide, rifamycin, and a quinolone for a minimum of 12 months often is recommended.

A 64-year-old man with a history of coronary artery disease, hypertension, hyperlipidemia, and acute myelogenous leukemia (AML) underwent allogenic stem cell transplantation. His posttransplant course was complicated by multiple deep vein thromboses, hypogammaglobulinemia, and graft-vs-host disease (GVHD) of the skin and gastrointestinal tract that manifested as chronic diarrhea, which was managed with chronic prednisone. Thirteen months after the transplant, the patient presented to his outpatient oncologist (M.K.) for evaluation of painless, nonpruritic, erythematous papules and nodules that had emerged on the right side of the chest, right arm, and left leg of approximately 2 weeks’ duration.

On review of systems by oncology, the patient denied any fevers, chills, or night sweats but noted chronic loose nonbloody stools without abdominal pain, likely related to the GVHD. The patient’s medications included prednisone 20 mg once daily, fluconazole, amitriptyline, atovaquone, budesonide, dabigatran, metoprolol, pantoprazole, rosuvastatin, senna glycoside, spironolactone, tramadol, and valacyclovir.

Physical examination revealed multiple singular erythematous nodules on the right side of the chest (Figure 1A), right arm (Figure 1B), and left leg. There was no regional lymphadenopathy. The patient was afebrile and hemodynamically stable. A biopsy of the arm performed to rule out leukemia cutis revealed a granulomatous dermatitis with numerous AFB (Figures 2A and 2B), which were confirmed on Ziehl-Neelsen staining (Figures 2C and 2D). The presence of AFB raised concern for a disseminated mycobacterial infection. The patient was admitted to our institution approximately 1 week after the outpatient biopsy was performed. He was evaluated by infectious diseases (B.H.) and was recommended for repeat biopsy with AFB culture and for initiation of intravenous antibiotics.

The patient was evaluated by the dermatology consultation service on hospital day 1. At the time of consultation, the lesions were still painless but had enlarged. Two new satellite lesions were noted on his other extremities. Due to the widespread distribution of the lesions, there was concern for disseminated disease. The relatively rapid onset of new lesions increased concern for infection with rapid-growing mycobacteria, including Mycobacterium abscessus, Mycobacterium fortuitum, and Mycobacterium chelonae. A detailed history revealed that the patient’s wife had a fish tank, which supported the inclusion of Mycobacterium marinum in the differential; however, further questioning revealed that the patient never came in contact with the aquarium water. The initial outpatient biopsy had not been sent for culture. Following inpatient biopsy, the patient was initiated on empiric antimycobacterials, including imipenem, amikacin, clarithromycin, and levofloxacin. Computed tomography of the head was negative for cerebral involvement.

Acid-fast bacilli blood cultures were drawn per the recommendation from infectious diseases in an attempt to confirm disseminated disease; however, blood cultures remained negative. Tissue biopsy from the right arm was sent for AFB staining and culture. Many AFB were identified on microscopy, and growth was observed in the mycobacterial growth indicator tube after 6 days of incubation. The DNA probe was negative for M tuberculosis complex or Mycobacterium avium complex.

The patient was discharged on hospital day 6 on empiric therapy for rapid-growing mycobacteria while cultures were pending. The empiric regimen included intravenous imipenem 1 g every 6 hours, intravenous amikacin 1 g once daily, clarithromycin 500 mg every 12 hours, and levofloxacin 750 mg once daily. All solid media cultures were negative at the time of discharge.

The biopsy specimen proved difficult to culture on solid media using traditional methods. Three weeks after the inpatient biopsy, the microbiology laboratory reported that growth was observed on solid media that was incubated at 30°C and supplemented with iron. These findings were not characteristic of a rapidly growing mycobacteria (eg, M fortuitum, M chelonae, M abscessus) or M marinum but raised concern for infectionwith M haemophilum. Antimycobacterial treatment was adjusted to amikacin, clarithromycin, levofloxacin, and rifabutin.

Six weeks after the inpatient skin biopsy, final speciation confirmed infection with M haemophilum. The isolate proved susceptible to amikacin (minimal inhibitory concentration [MIC], 16), clarithromycin (MIC, 0.12), linezolid (MIC, <1), moxifloxacin (MIC, 0.5), rifabutin (MIC, <0.25), and trimethoprim-sulfamethoxazole (MIC, 0.5/9.5). The isolate was resistant to ciprofloxacin (MIC, 4), ethambutol (MIC, >16), and rifampin (MIC, 2). Based on these findings, an infectious disease specialist modified the treatment regimen to azithromycin 600 mg once daily, moxifloxacin 400 mg once daily, and rifabutin 300 mg once daily. Azithromycin was substituted for clarithromycin in an attempt to minimize the gastrointestinal side effects of the antibiotics. The infectious disease specialist was concerned that the clarithromycin could exacerbate the patient’s chronic GVHD-associated diarrhea, which posed a challenge to the oncologist, who was attempting to manage the patient’s GVHD and minimize the use of additional prednisone. At the time of this change, the patient was doing well clinically and denied any active skin lesions.

Four months later, he developed new left-sided neck swelling. Computed tomography revealed nonspecific enhancement involving the skin and superficial subcutaneous tissues in the left anterior neck. He was referred to otolaryngology given concern for recurrent infection vs leukemia cutis. He underwent excisional biopsy. Pathology was negative for malignancy but demonstrated subcutaneous necrotizing granulomatous inflammation with a positive AFB stain. Tissue AFB cultures revealed moderate AFB on direct stain, but there was no AFB growth at 12 weeks. Clarithromycin was restarted in place of azithromycin to increase the potency of the antimycobacterial regimen. Cultures from this neck biopsy were negative after 12 weeks of incubation.

In addition to this change in antibiotic coverage, the patient’s medical oncologist tapered the patient’s immunosuppression considerably. The patient subsequently completed 12 months of therapy with clarithromycin, moxifloxacin, and rifabutin starting from the time of the neck biopsy. He remained free of recurrence of mycobacterial infection for nearly 2 years until he died from an unrelated illness.

Nontuberculous mycobacteria are an ubiquitous environmental group.² Sources include soil and natural water (M avium), fish tanks and swimming pools (M marinum), and tap water and occasionally domestic animals (Mycobacterium kansasii). Additionally, rapidly growing NTM such as M abscessus, M chelonae, and M fortuitum have been isolated from soil and natural water supplies.³

Mycobacterium haemophilum is a fastidious organism with a predilection for skin of the chest and extremities. Iatrogenically or inherently immunocompromised patients are most commonly affected^6-11; however, there also have been reports in healthy patients.^12,13 Infections typically present as painless erythematous papules or nodules that eventually suppurate, ulcerate, and become painful. Presentations involving Fitz-Hugh–Curtis syndrome,¹³ new B-cell lymphoma,¹⁰ and lymphadenitis¹² also have been described. Beyond cutaneous involvement, M haemophilum has been cultured from bone, the synovium, the lungs, and the central nervous system.^4,9 The majority of morbidities occur in patients with lung involvement.⁴ Therefore, even patients presenting with isolated cutaneous disease require close follow-up.

Mycobacterium haemophilum is a slowly proliferating organism that is unable to grow in standard egg-potato (Lowenstein-Jensen) medium or agar base (Middlebrook 7H10 or 7H11 agar) without iron supplementation (ferric ammonium citrate, hemin, or hemoglobin). It also requires temperatures of 30°C to 32°C for growth. Its iron requisite is unique, but species such as M marinum and Mycobacterium ulcerans also share reduced temperature requirements. Without a high index of suspicion, growth often is absent because standard Mycobacterium culture techniques will not foster organism growth. Our case demonstrated that special culture instructions must be relayed to the laboratory, even in the face of positive AFB smears. Failure to request hemin and modified incubation temperatures may have contributed to the negative AFB blood culture in our patient.

Due to the relatively rare incidence of M haemophilum infection, there are no known randomized controlled trials guiding antibiotic regimens. Infectious disease specialists often treat empirically with triple-drug therapy derived from locally reported species susceptibilities. The largest case series to date did not identify resistance to amikacin, ciprofloxacin, or clarithromycin.⁴ Our case identified a novel finding of ciprofloxacin and rifampin resistance, which may highlight the emergence of a newly resistant strain of M haemophilum. Of note, one case of rifampin resistance has been reported, but the culture was drawn from a postmortem specimen in the setting of previously rifampin-sensitive isolates.⁴ Empiric therapies should be guided by hospital susceptibility reports and expert consultation.

Coinfection with 2 or more NTM—including M tuberculosis, M leprae, and M fortuitum—has been reported.^8,14 Temporally distinct coinfections with M leprae and M haemophilum also have been described.¹⁵ Thus, practitioners should have a low threshold for repeat cultures in the context of new cutaneous nodules or granulomas, not only to detect concomitant infections but also to identify resistance patterns that might explain recurrent or recalcitrant disease. Immune reconstitution inflammatory syndrome also must be considered with new or worsening lesions, especially in the first months of therapy, as this is a common occurrence when immunosuppressive regimens are tapered to help manage infections.

In conclusion, M haemophilum is an underrecognized infection that presents as cutaneous nodules or lymphadenitis in immunocompromised or healthy individuals. Diagnosis requires a high index of suspicion because its unique growth requirements necessitate special laboratory techniques. Our case represents a classic presentation of this NTM infection in a patient with AML following allogenic stem cell transplantation. Repeat cultures, workup of potentially disseminated infections, and close follow-up are requisite to minimizing morbidity and mortality. A multidisciplinary approach involving infectious disease, medical oncology, radiology, and dermatology best manages this type of infection.

To the Editor:

The increase in nontuberculous mycobacteria (NTM) infections over the last 3 decades likely is multifaceted, including increased clinical awareness, improved laboratory diagnostics, growing numbers of immunocompromised patients, and an aging population.^1,2 Historically, the majority of mycobacteria-related diseases are due to Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium leprae.³

Mycobacterium haemophilum is a slow-growing acid-fast bacillus (AFB) that differs from other Mycobacterium species in that it requires iron-supplemented media and incubation temperatures of 30°C to 32°C for culture. As these requirements for growth are not standard for AFB cultures, M haemophilum infection may be underrecognized and underreported.³Mycobacterium haemophilum infections largely are cutaneous and generally are seen in AIDS patients and bone marrow transplant recipients who are iatrogenically immunosuppressed.^4,5 No species-specific treatment guidelines exist²; however, triple-drug therapy combining a macrolide, rifamycin, and a quinolone for a minimum of 12 months often is recommended.

A 64-year-old man with a history of coronary artery disease, hypertension, hyperlipidemia, and acute myelogenous leukemia (AML) underwent allogenic stem cell transplantation. His posttransplant course was complicated by multiple deep vein thromboses, hypogammaglobulinemia, and graft-vs-host disease (GVHD) of the skin and gastrointestinal tract that manifested as chronic diarrhea, which was managed with chronic prednisone. Thirteen months after the transplant, the patient presented to his outpatient oncologist (M.K.) for evaluation of painless, nonpruritic, erythematous papules and nodules that had emerged on the right side of the chest, right arm, and left leg of approximately 2 weeks’ duration.

On review of systems by oncology, the patient denied any fevers, chills, or night sweats but noted chronic loose nonbloody stools without abdominal pain, likely related to the GVHD. The patient’s medications included prednisone 20 mg once daily, fluconazole, amitriptyline, atovaquone, budesonide, dabigatran, metoprolol, pantoprazole, rosuvastatin, senna glycoside, spironolactone, tramadol, and valacyclovir.

Physical examination revealed multiple singular erythematous nodules on the right side of the chest (Figure 1A), right arm (Figure 1B), and left leg. There was no regional lymphadenopathy. The patient was afebrile and hemodynamically stable. A biopsy of the arm performed to rule out leukemia cutis revealed a granulomatous dermatitis with numerous AFB (Figures 2A and 2B), which were confirmed on Ziehl-Neelsen staining (Figures 2C and 2D). The presence of AFB raised concern for a disseminated mycobacterial infection. The patient was admitted to our institution approximately 1 week after the outpatient biopsy was performed. He was evaluated by infectious diseases (B.H.) and was recommended for repeat biopsy with AFB culture and for initiation of intravenous antibiotics.

The patient was evaluated by the dermatology consultation service on hospital day 1. At the time of consultation, the lesions were still painless but had enlarged. Two new satellite lesions were noted on his other extremities. Due to the widespread distribution of the lesions, there was concern for disseminated disease. The relatively rapid onset of new lesions increased concern for infection with rapid-growing mycobacteria, including Mycobacterium abscessus, Mycobacterium fortuitum, and Mycobacterium chelonae. A detailed history revealed that the patient’s wife had a fish tank, which supported the inclusion of Mycobacterium marinum in the differential; however, further questioning revealed that the patient never came in contact with the aquarium water. The initial outpatient biopsy had not been sent for culture. Following inpatient biopsy, the patient was initiated on empiric antimycobacterials, including imipenem, amikacin, clarithromycin, and levofloxacin. Computed tomography of the head was negative for cerebral involvement.

Acid-fast bacilli blood cultures were drawn per the recommendation from infectious diseases in an attempt to confirm disseminated disease; however, blood cultures remained negative. Tissue biopsy from the right arm was sent for AFB staining and culture. Many AFB were identified on microscopy, and growth was observed in the mycobacterial growth indicator tube after 6 days of incubation. The DNA probe was negative for M tuberculosis complex or Mycobacterium avium complex.

The patient was discharged on hospital day 6 on empiric therapy for rapid-growing mycobacteria while cultures were pending. The empiric regimen included intravenous imipenem 1 g every 6 hours, intravenous amikacin 1 g once daily, clarithromycin 500 mg every 12 hours, and levofloxacin 750 mg once daily. All solid media cultures were negative at the time of discharge.

The biopsy specimen proved difficult to culture on solid media using traditional methods. Three weeks after the inpatient biopsy, the microbiology laboratory reported that growth was observed on solid media that was incubated at 30°C and supplemented with iron. These findings were not characteristic of a rapidly growing mycobacteria (eg, M fortuitum, M chelonae, M abscessus) or M marinum but raised concern for infectionwith M haemophilum. Antimycobacterial treatment was adjusted to amikacin, clarithromycin, levofloxacin, and rifabutin.

Six weeks after the inpatient skin biopsy, final speciation confirmed infection with M haemophilum. The isolate proved susceptible to amikacin (minimal inhibitory concentration [MIC], 16), clarithromycin (MIC, 0.12), linezolid (MIC, <1), moxifloxacin (MIC, 0.5), rifabutin (MIC, <0.25), and trimethoprim-sulfamethoxazole (MIC, 0.5/9.5). The isolate was resistant to ciprofloxacin (MIC, 4), ethambutol (MIC, >16), and rifampin (MIC, 2). Based on these findings, an infectious disease specialist modified the treatment regimen to azithromycin 600 mg once daily, moxifloxacin 400 mg once daily, and rifabutin 300 mg once daily. Azithromycin was substituted for clarithromycin in an attempt to minimize the gastrointestinal side effects of the antibiotics. The infectious disease specialist was concerned that the clarithromycin could exacerbate the patient’s chronic GVHD-associated diarrhea, which posed a challenge to the oncologist, who was attempting to manage the patient’s GVHD and minimize the use of additional prednisone. At the time of this change, the patient was doing well clinically and denied any active skin lesions.

Four months later, he developed new left-sided neck swelling. Computed tomography revealed nonspecific enhancement involving the skin and superficial subcutaneous tissues in the left anterior neck. He was referred to otolaryngology given concern for recurrent infection vs leukemia cutis. He underwent excisional biopsy. Pathology was negative for malignancy but demonstrated subcutaneous necrotizing granulomatous inflammation with a positive AFB stain. Tissue AFB cultures revealed moderate AFB on direct stain, but there was no AFB growth at 12 weeks. Clarithromycin was restarted in place of azithromycin to increase the potency of the antimycobacterial regimen. Cultures from this neck biopsy were negative after 12 weeks of incubation.

In addition to this change in antibiotic coverage, the patient’s medical oncologist tapered the patient’s immunosuppression considerably. The patient subsequently completed 12 months of therapy with clarithromycin, moxifloxacin, and rifabutin starting from the time of the neck biopsy. He remained free of recurrence of mycobacterial infection for nearly 2 years until he died from an unrelated illness.

Nontuberculous mycobacteria are an ubiquitous environmental group.² Sources include soil and natural water (M avium), fish tanks and swimming pools (M marinum), and tap water and occasionally domestic animals (Mycobacterium kansasii). Additionally, rapidly growing NTM such as M abscessus, M chelonae, and M fortuitum have been isolated from soil and natural water supplies.³

Mycobacterium haemophilum is a fastidious organism with a predilection for skin of the chest and extremities. Iatrogenically or inherently immunocompromised patients are most commonly affected^6-11; however, there also have been reports in healthy patients.^12,13 Infections typically present as painless erythematous papules or nodules that eventually suppurate, ulcerate, and become painful. Presentations involving Fitz-Hugh–Curtis syndrome,¹³ new B-cell lymphoma,¹⁰ and lymphadenitis¹² also have been described. Beyond cutaneous involvement, M haemophilum has been cultured from bone, the synovium, the lungs, and the central nervous system.^4,9 The majority of morbidities occur in patients with lung involvement.⁴ Therefore, even patients presenting with isolated cutaneous disease require close follow-up.

Mycobacterium haemophilum is a slowly proliferating organism that is unable to grow in standard egg-potato (Lowenstein-Jensen) medium or agar base (Middlebrook 7H10 or 7H11 agar) without iron supplementation (ferric ammonium citrate, hemin, or hemoglobin). It also requires temperatures of 30°C to 32°C for growth. Its iron requisite is unique, but species such as M marinum and Mycobacterium ulcerans also share reduced temperature requirements. Without a high index of suspicion, growth often is absent because standard Mycobacterium culture techniques will not foster organism growth. Our case demonstrated that special culture instructions must be relayed to the laboratory, even in the face of positive AFB smears. Failure to request hemin and modified incubation temperatures may have contributed to the negative AFB blood culture in our patient.

Due to the relatively rare incidence of M haemophilum infection, there are no known randomized controlled trials guiding antibiotic regimens. Infectious disease specialists often treat empirically with triple-drug therapy derived from locally reported species susceptibilities. The largest case series to date did not identify resistance to amikacin, ciprofloxacin, or clarithromycin.⁴ Our case identified a novel finding of ciprofloxacin and rifampin resistance, which may highlight the emergence of a newly resistant strain of M haemophilum. Of note, one case of rifampin resistance has been reported, but the culture was drawn from a postmortem specimen in the setting of previously rifampin-sensitive isolates.⁴ Empiric therapies should be guided by hospital susceptibility reports and expert consultation.

Coinfection with 2 or more NTM—including M tuberculosis, M leprae, and M fortuitum—has been reported.^8,14 Temporally distinct coinfections with M leprae and M haemophilum also have been described.¹⁵ Thus, practitioners should have a low threshold for repeat cultures in the context of new cutaneous nodules or granulomas, not only to detect concomitant infections but also to identify resistance patterns that might explain recurrent or recalcitrant disease. Immune reconstitution inflammatory syndrome also must be considered with new or worsening lesions, especially in the first months of therapy, as this is a common occurrence when immunosuppressive regimens are tapered to help manage infections.

In conclusion, M haemophilum is an underrecognized infection that presents as cutaneous nodules or lymphadenitis in immunocompromised or healthy individuals. Diagnosis requires a high index of suspicion because its unique growth requirements necessitate special laboratory techniques. Our case represents a classic presentation of this NTM infection in a patient with AML following allogenic stem cell transplantation. Repeat cultures, workup of potentially disseminated infections, and close follow-up are requisite to minimizing morbidity and mortality. A multidisciplinary approach involving infectious disease, medical oncology, radiology, and dermatology best manages this type of infection.