Dermatopathology

Case Report

An 85-year-old woman presented with a painless red plaque on the right bicep of 5 years’ duration. The patient had not seen a physician in the last 63 years and had unsuccessfully attempted to treat the plaque by occlusion with an adhesive bandage. A review of systems was negative for pain, pruritus, bleeding, fever, unexplained weight loss, and night sweats. Physical examination revealed a raised, 2×4×1-cm, red, nontender, ulcerated plaque with slight exudate and gelatinous texture on the right bicep (Figure 1). Full-body skin examination revealed erythema and swelling of the right wrist and forearm consistent with cellulitis as well as tinea pedis and onychomycosis of the toenails of both feet.

Figure 1. A raised, red, nontender, ulcerated plaque with slight exudate and gelatinous texture on the right bicep. Figure 2. The tumor was comprised of gland-forming cells and exhibited crowding, pleomorphism, enlarged hyperchromatic nuclei, and mitotic division figures (H&E, original magnification ×100). Figure 3. Mucicarmine staining highlighted sialomucin within the glandular component (original magnification ×400).

Hematoxylin and eosin as well as mucicarmine staining of a shave biopsy from the lesion demonstrated an invasive epithelial neoplasm comprised of squamoid and gland-forming cells broadly attached to the epidermis, which suggested a primary cutaneous origin (Figures 2 and 3). The tumor cells were arranged in infiltrating cords and nests; they exhibited crowding, pleomorphism, enlarged hyperchromatic nuclei, and mitotic division figures. Epithelial mucin (sialomucin) within the glandular component was highlighted on mucicarmine staining. The gland-forming segment of the tumor was strongly positive for cytokeratin (CK) 7. Gastrointestinal tumors were excluded on negative CDX2 and CK20 staining, pulmonary and thyroid tumors were excluded on negative thyroid transcription factor 1 staining, and endometrial and ovarian tumors were excluded with negative estrogen receptor staining. On physical examination the breasts were soft, nontender, and without deformity. A chest radiograph demonstrated normal heart size and pulmonary vasculature with mild bibasilar atelectasis and no areas of consolidation. Given these clinical findings along with a negative history of cancer and negative estrogen receptor staining, breast cancer was excluded from the differential diagnosis, and the diagnosis of cASC was made. The tumor was excised using Mohs micrographic surgery and was free of recurrence at 6- and 12-month follow-up.

Comment

Primary cutaneous adenosquamous carcinoma (cASC) is an aggressive subtype of squamous cell carcinoma that was first described in 1985.¹ It typically presents as an erythematous, indurated, keratotic papule or plaque with a predilection for the face, scalp, and upper extremities of immunocompromised individuals and elderly men.^2,3 Biopsies generally demonstrate a malignant epithelial neoplasm arising from the epidermis and exhibiting squamous and glandular differentiation. The glandular segment usually is indistinguishable from adenocarcinoma and can be highlighted on CK7, carcinoembryonic antigen, mucicarmine, and periodic acid–Schiff staining. The squamous segment typically is indistinguishable from squamous cell carcinoma and shows aberrant keratinization and intercellular bridges. Tumors often are deeply invasive, poorly differentiated, and associated with a desmoplastic stromal reaction. Local recurrence rates are between 22% and 26%,⁴ but metastasis is rare. Surgical excision is the mainstay of therapy. When clear margins cannot be obtained using Mohs micrographic surgery, adjuvant external beam radiation therapy and epidermal growth factor receptor inhibitors can be used to treat locally recurrent cASCs.²

The differential diagnosis for cASC includes cutaneous mucoepidermoid carcinoma, cutaneous acantholytic squamous cell carcinoma, and cutaneous manifestations of metastatic visceral adenosquamous carcinoma. Mucoepidermoid carcinoma sometimes is used interchangeably with cASC in the literature, but it is a different cutaneous neoplasm that forms goblet cells, intermediate cells, and squamous cells. It is considered the cutaneous analogue of salivary gland mucoepidermoid carcinoma and does not exhibit the anaplasia, stromal desmoplasia, and aggressive course of cASC.⁵ The acantholytic subtype of squamous cell carcinoma forms glandlike spaces due to poor adhesion between keratinocytes, but the glandlike spaces do not form mucin or stain positive for CK7 or carcinoembryonic antigen. Adenosquamous carcinomas are well recognized in the lungs, breasts, genitourinary tract, pancreas, and gastroenteric system. Visceral tumor metastasis to the skin should be excluded by appropriate screening.

Conclusion

Although cASCs are not commonly encountered in clinical practice, accurate diagnosis of these lesions is important due to their potentially aggressive behavior. Misdiagnosis and improper treatment could be attributed to lack of awareness of this type of lesion.

Case Report

An 85-year-old woman presented with a painless red plaque on the right bicep of 5 years’ duration. The patient had not seen a physician in the last 63 years and had unsuccessfully attempted to treat the plaque by occlusion with an adhesive bandage. A review of systems was negative for pain, pruritus, bleeding, fever, unexplained weight loss, and night sweats. Physical examination revealed a raised, 2×4×1-cm, red, nontender, ulcerated plaque with slight exudate and gelatinous texture on the right bicep (Figure 1). Full-body skin examination revealed erythema and swelling of the right wrist and forearm consistent with cellulitis as well as tinea pedis and onychomycosis of the toenails of both feet.

Figure 1. A raised, red, nontender, ulcerated plaque with slight exudate and gelatinous texture on the right bicep. Figure 2. The tumor was comprised of gland-forming cells and exhibited crowding, pleomorphism, enlarged hyperchromatic nuclei, and mitotic division figures (H&E, original magnification ×100). Figure 3. Mucicarmine staining highlighted sialomucin within the glandular component (original magnification ×400).

Hematoxylin and eosin as well as mucicarmine staining of a shave biopsy from the lesion demonstrated an invasive epithelial neoplasm comprised of squamoid and gland-forming cells broadly attached to the epidermis, which suggested a primary cutaneous origin (Figures 2 and 3). The tumor cells were arranged in infiltrating cords and nests; they exhibited crowding, pleomorphism, enlarged hyperchromatic nuclei, and mitotic division figures. Epithelial mucin (sialomucin) within the glandular component was highlighted on mucicarmine staining. The gland-forming segment of the tumor was strongly positive for cytokeratin (CK) 7. Gastrointestinal tumors were excluded on negative CDX2 and CK20 staining, pulmonary and thyroid tumors were excluded on negative thyroid transcription factor 1 staining, and endometrial and ovarian tumors were excluded with negative estrogen receptor staining. On physical examination the breasts were soft, nontender, and without deformity. A chest radiograph demonstrated normal heart size and pulmonary vasculature with mild bibasilar atelectasis and no areas of consolidation. Given these clinical findings along with a negative history of cancer and negative estrogen receptor staining, breast cancer was excluded from the differential diagnosis, and the diagnosis of cASC was made. The tumor was excised using Mohs micrographic surgery and was free of recurrence at 6- and 12-month follow-up.

Comment

Primary cutaneous adenosquamous carcinoma (cASC) is an aggressive subtype of squamous cell carcinoma that was first described in 1985.¹ It typically presents as an erythematous, indurated, keratotic papule or plaque with a predilection for the face, scalp, and upper extremities of immunocompromised individuals and elderly men.^2,3 Biopsies generally demonstrate a malignant epithelial neoplasm arising from the epidermis and exhibiting squamous and glandular differentiation. The glandular segment usually is indistinguishable from adenocarcinoma and can be highlighted on CK7, carcinoembryonic antigen, mucicarmine, and periodic acid–Schiff staining. The squamous segment typically is indistinguishable from squamous cell carcinoma and shows aberrant keratinization and intercellular bridges. Tumors often are deeply invasive, poorly differentiated, and associated with a desmoplastic stromal reaction. Local recurrence rates are between 22% and 26%,⁴ but metastasis is rare. Surgical excision is the mainstay of therapy. When clear margins cannot be obtained using Mohs micrographic surgery, adjuvant external beam radiation therapy and epidermal growth factor receptor inhibitors can be used to treat locally recurrent cASCs.²

The differential diagnosis for cASC includes cutaneous mucoepidermoid carcinoma, cutaneous acantholytic squamous cell carcinoma, and cutaneous manifestations of metastatic visceral adenosquamous carcinoma. Mucoepidermoid carcinoma sometimes is used interchangeably with cASC in the literature, but it is a different cutaneous neoplasm that forms goblet cells, intermediate cells, and squamous cells. It is considered the cutaneous analogue of salivary gland mucoepidermoid carcinoma and does not exhibit the anaplasia, stromal desmoplasia, and aggressive course of cASC.⁵ The acantholytic subtype of squamous cell carcinoma forms glandlike spaces due to poor adhesion between keratinocytes, but the glandlike spaces do not form mucin or stain positive for CK7 or carcinoembryonic antigen. Adenosquamous carcinomas are well recognized in the lungs, breasts, genitourinary tract, pancreas, and gastroenteric system. Visceral tumor metastasis to the skin should be excluded by appropriate screening.

Conclusion

Although cASCs are not commonly encountered in clinical practice, accurate diagnosis of these lesions is important due to their potentially aggressive behavior. Misdiagnosis and improper treatment could be attributed to lack of awareness of this type of lesion.

Case Report

An 85-year-old woman presented with a painless red plaque on the right bicep of 5 years’ duration. The patient had not seen a physician in the last 63 years and had unsuccessfully attempted to treat the plaque by occlusion with an adhesive bandage. A review of systems was negative for pain, pruritus, bleeding, fever, unexplained weight loss, and night sweats. Physical examination revealed a raised, 2×4×1-cm, red, nontender, ulcerated plaque with slight exudate and gelatinous texture on the right bicep (Figure 1). Full-body skin examination revealed erythema and swelling of the right wrist and forearm consistent with cellulitis as well as tinea pedis and onychomycosis of the toenails of both feet.

Figure 1. A raised, red, nontender, ulcerated plaque with slight exudate and gelatinous texture on the right bicep. Figure 2. The tumor was comprised of gland-forming cells and exhibited crowding, pleomorphism, enlarged hyperchromatic nuclei, and mitotic division figures (H&E, original magnification ×100). Figure 3. Mucicarmine staining highlighted sialomucin within the glandular component (original magnification ×400).

Hematoxylin and eosin as well as mucicarmine staining of a shave biopsy from the lesion demonstrated an invasive epithelial neoplasm comprised of squamoid and gland-forming cells broadly attached to the epidermis, which suggested a primary cutaneous origin (Figures 2 and 3). The tumor cells were arranged in infiltrating cords and nests; they exhibited crowding, pleomorphism, enlarged hyperchromatic nuclei, and mitotic division figures. Epithelial mucin (sialomucin) within the glandular component was highlighted on mucicarmine staining. The gland-forming segment of the tumor was strongly positive for cytokeratin (CK) 7. Gastrointestinal tumors were excluded on negative CDX2 and CK20 staining, pulmonary and thyroid tumors were excluded on negative thyroid transcription factor 1 staining, and endometrial and ovarian tumors were excluded with negative estrogen receptor staining. On physical examination the breasts were soft, nontender, and without deformity. A chest radiograph demonstrated normal heart size and pulmonary vasculature with mild bibasilar atelectasis and no areas of consolidation. Given these clinical findings along with a negative history of cancer and negative estrogen receptor staining, breast cancer was excluded from the differential diagnosis, and the diagnosis of cASC was made. The tumor was excised using Mohs micrographic surgery and was free of recurrence at 6- and 12-month follow-up.

Comment

Primary cutaneous adenosquamous carcinoma (cASC) is an aggressive subtype of squamous cell carcinoma that was first described in 1985.¹ It typically presents as an erythematous, indurated, keratotic papule or plaque with a predilection for the face, scalp, and upper extremities of immunocompromised individuals and elderly men.^2,3 Biopsies generally demonstrate a malignant epithelial neoplasm arising from the epidermis and exhibiting squamous and glandular differentiation. The glandular segment usually is indistinguishable from adenocarcinoma and can be highlighted on CK7, carcinoembryonic antigen, mucicarmine, and periodic acid–Schiff staining. The squamous segment typically is indistinguishable from squamous cell carcinoma and shows aberrant keratinization and intercellular bridges. Tumors often are deeply invasive, poorly differentiated, and associated with a desmoplastic stromal reaction. Local recurrence rates are between 22% and 26%,⁴ but metastasis is rare. Surgical excision is the mainstay of therapy. When clear margins cannot be obtained using Mohs micrographic surgery, adjuvant external beam radiation therapy and epidermal growth factor receptor inhibitors can be used to treat locally recurrent cASCs.²

The differential diagnosis for cASC includes cutaneous mucoepidermoid carcinoma, cutaneous acantholytic squamous cell carcinoma, and cutaneous manifestations of metastatic visceral adenosquamous carcinoma. Mucoepidermoid carcinoma sometimes is used interchangeably with cASC in the literature, but it is a different cutaneous neoplasm that forms goblet cells, intermediate cells, and squamous cells. It is considered the cutaneous analogue of salivary gland mucoepidermoid carcinoma and does not exhibit the anaplasia, stromal desmoplasia, and aggressive course of cASC.⁵ The acantholytic subtype of squamous cell carcinoma forms glandlike spaces due to poor adhesion between keratinocytes, but the glandlike spaces do not form mucin or stain positive for CK7 or carcinoembryonic antigen. Adenosquamous carcinomas are well recognized in the lungs, breasts, genitourinary tract, pancreas, and gastroenteric system. Visceral tumor metastasis to the skin should be excluded by appropriate screening.

Conclusion

Although cASCs are not commonly encountered in clinical practice, accurate diagnosis of these lesions is important due to their potentially aggressive behavior. Misdiagnosis and improper treatment could be attributed to lack of awareness of this type of lesion.

Pemphigus vulgaris (PV) is a rare autoimmune bullous dermatosis that has not shown a predilection toward a particular race or sex.¹ Autoantibodies for desmoglein 1 and desmoglein 3, members of the cadherin family that are involved in cellular adhesion, have been linked to the pathogenesis of PV.² These autoantibodies play a role in the loss of cell-to-cell adhesion in the basal and suprabasal layers of the deep epidermis while cellular adhesion in the superficial epidermis remains intact, leading to the clinical presentation of epidermal blistering and ulcerations most commonly found on the scalp, face, groin, and axillae. Diagnosis typically is made based on skin biopsy and confirmed by direct immunofluorescence. Histologically, PV displays acantholysis and suprabasal cleft formation. Immunofluorescence may show IgG antibodies against the PV antigen in the epidermis.³ Once a diagnosis has been made, treatment typically consists of systemic steroids, as the use of steroids has had great effect in preventing infections, sepsis, and fatality that were once associated with PV.⁴ Mortality rates associated with PV have decreased to 10% to 15% with systemic steroids from a mortality rate as high as 70% in the presteroid era.^1,5 Treatment of PV during pregnancy, as in our patient, requires obstetric and pediatric consultations before therapy is initiated. Use of corticosteroids during pregnancy can be potentially dangerous to the fetus, particularly if high doses are necessary to control maternal disease.^6,7

Case Report

A 34-year-old pregnant woman at 6 weeks’ gestation presented with widespread blistering dermatitis and associated burning and pruritus. Her obstetrical history was gravida 3, para 2. The patient reported a “rash” on the scalp that had developed 9 months prior. She had been treated as an outpatient at an outside institution with topical antibiotics and antifungal medications, yet the dermatitis progressed. Three weeks prior to hospitalization, the rash was present on the skin and mucosal surfaces, including the groin, chest, face, hard palate, buccal mucosa, lips (Figure 1), and back (Figure 2). Nontender bullae ruptured after 3 days, releasing clear, yellow, serous fluid with associated burning and pruritus. The bullae were hemorrhagic and erythematous at the base.

Figure 1. Facial involvement with bullae, crusted hemorrhagic lesions, and eschar in a 34-year-old pregnant woman.

Figure 2. Involvement of the back with bullae in various stages. Some bullae were intact while others newly erupted.

Figure 3. Superinfected and flaking scalp.

Figure 4. Biopsy revealed suprabasal acantholysis with a tombstone effect of residual basal cells (H&E, original magnification ×200).

At the current presentation, the patient had several excoriated 1- to 2-cm oval denudations; some were crusted with eschar. Nikolsky sign was negative. Multiple confluent bullous lesions had erupted on the entire scalp with a thick, impetiginous, yellow crust. She had a wet, boggy, foul-smelling, superinfected scalp that was mildly tender to touch with flaking tissue debris (Figure 3). A white blood cell count was 13.2×109/L (reference range, 4.5–11.0×109/L) with 5% eosinophils (reference range, 2.7%). The differential diagnosis included bullous impetigo, pemphigoid, Stevens-Johnson syndrome, dermatitis herpetiformis, and pemphigus vulgaris.

Biopsies of the scalp and back were taken and showed suprabasal acantholysis with a tombstone effect of residual basal cells standing up on the basement membrane without the characteristic acantholysis into skin appendages (Figure 4). The acantholytic cells in the bullous chamber did not round up as in Hailey-Hailey disease nor was there the dyskeratosis of Grover disease. Direct immunofluorescence on an elbow punch biopsy found diffuse 1+ intercellular IgG in the epidermis and diffuse 1+ basal intercellular C3, and was negative for IgA, IgM, and C1q, thus confirming a diagnosis of PV.

The patient was started on prednisone 20 mg once daily. An increase to prednisone 60 mg led to initial improvement of symptoms, but there was a relapse after several days, which is typical of PV in pregnancy,⁷ prompting the dose to be increased to 120 mg. Following alleviation of symptoms, the dose was later tapered back to 60 mg. No lesions were present at discharge or for 2.5 months thereafter, as the prednisone was tapered from 60 to 45 mg daily after discharge.

On follow-up, the patient’s PV was well controlled, but the prednisone dose was back up to 60 mg daily because of 2 new skin lesions that had developed since her last visit 2.5 months prior. Ultrasonography showed no fetal abnormalities as the pregnancy progressed to 28 weeks’ gestation. The patient developed hypertension and went into premature labor due to placenta previa. The neonate showed no skin lesions or anomalies while in the neonatal intensive care unit. The mother’s prednisone dose was tapered from 60 to 20 mg daily while the white blood cell count was 7.1×10⁹/L with 2% eosinophils and a new scalp lesion appeared. Seven months after her initial discharge from the hospital for the dermatologic condition, she was no longer nursing and azathioprine was added to prednisone 60 mg daily.

Comment

Pemphigus vulgaris is associated with infertility in its active phase; therefore, PV during pregnancy is rare.⁸ Pregnancy may exacerbate PV, which has been a similar finding in other well-documented autoimmune diseases.⁷ One review of PV in pregnancy reported that 11 of 49 patients (22%) experienced an exacerbation of the disease.⁸ This finding pre-sents 2 problems: (1) severe active disease during pregnancy with high antibody titers has been shown to heighten risk for morbidity and mortality for the fetus, and (2) a patient with active PV during pregnancy may require systemic therapy with doses high enough to subdue the disease. The presence of PV was a challenge throughout our patient’s pregnancy. Transient skin lesions may occasionally appear in the neonate and seem to have an increased association with severe active PV in the mother; however, neonatal PV also has been present in mild cases in the mother.⁷ These lesions are secondary to passive transplacental transfer of PV antibodies but do not have long-lasting clinical implications because of an antibody’s brief half-life.⁹ The lesions either spontaneously resolve or can be treated with a topical corticosteroid.

Treatment with high-dose systemic corticosteroids or immunosuppressants can be problematic because of the risks posed to the fetus, especially if the mother must be treated when the embryo is particularly susceptible (eg, during organogenesis).¹⁰ If a woman with known PV is planning to become pregnant, it is recommended to first control and suppress the disease so that therapy can be minimal during the pregnancy. It also is recommended to use aggressive topical therapy if possible to control PV in a pregnant woman.⁸ This option would not have been efficacious in our patient because of her severe widespread disease.

Prednisone is considered one of the first-line treatments of PV and has been historically successful as a treatment for pregnant patients with PV if maintained at a low dosage. Prednisone, similar to other corticosteroids, can cross the placental barrier and can increase the chance of premature birth, infection, and mortality in high doses.⁷ Similar to prednisone, azathioprine is not recommended during pregnancy, but if use is necessary, it is suggested to keep the dose low to prevent fetal harm.¹¹ Inadequate treatment and control of PV can be life threatening to the patient because of the severe infection that may ensue; thus it is necessary for the health of the patient and fetus to suppress the PV. One alternative to treatment with steroids and immunosuppressants is plasma exchange, which has been successful in the clinical context of pregnancy.¹² The cons of plasma exchange are repeat procedures, the need to give the patient more immunosuppressants to prevent a rejection, and the return of the autoantibody.⁷

Several studies have evaluated the safety and efficacy of rituximab in the treatment of refractory PV. Multiple case reports state that both 1 and 2 courses of intravenous rituximab therapy at a dosage of 375 mg per square meter of body surface area affected once weekly for 4 weeks proved to be useful in clinical improvement for patients with refractory disease.^13,14 Studies are currently underway to look at the effects of rituximab on pregnancy and the fetus. Preliminary findings show neonates may have B-cell abnormalities initially yet recover fully without infectious complications or sequelae.¹⁵ Rituximab currently is a pregnancy category C drug, and women are counseled to avoid pregnancy for at least 12 months after rituximab exposure and use contraception while actively taking the drug.¹⁶

Conclusion

Contrary to traditional thinking, PV itself may be associated with poor neonatal outcome, including prematurity and fetal death. These complications seem to be restricted to pregnancies with clinically severe PV.⁷ Our patient decided to progress with her pregnancy despite the potential risk to the fetus from the disease and treatment. Ultimately, the infant was delivered prematurely but was free of disease.

Pemphigus vulgaris (PV) is a rare autoimmune bullous dermatosis that has not shown a predilection toward a particular race or sex.¹ Autoantibodies for desmoglein 1 and desmoglein 3, members of the cadherin family that are involved in cellular adhesion, have been linked to the pathogenesis of PV.² These autoantibodies play a role in the loss of cell-to-cell adhesion in the basal and suprabasal layers of the deep epidermis while cellular adhesion in the superficial epidermis remains intact, leading to the clinical presentation of epidermal blistering and ulcerations most commonly found on the scalp, face, groin, and axillae. Diagnosis typically is made based on skin biopsy and confirmed by direct immunofluorescence. Histologically, PV displays acantholysis and suprabasal cleft formation. Immunofluorescence may show IgG antibodies against the PV antigen in the epidermis.³ Once a diagnosis has been made, treatment typically consists of systemic steroids, as the use of steroids has had great effect in preventing infections, sepsis, and fatality that were once associated with PV.⁴ Mortality rates associated with PV have decreased to 10% to 15% with systemic steroids from a mortality rate as high as 70% in the presteroid era.^1,5 Treatment of PV during pregnancy, as in our patient, requires obstetric and pediatric consultations before therapy is initiated. Use of corticosteroids during pregnancy can be potentially dangerous to the fetus, particularly if high doses are necessary to control maternal disease.^6,7

Case Report

A 34-year-old pregnant woman at 6 weeks’ gestation presented with widespread blistering dermatitis and associated burning and pruritus. Her obstetrical history was gravida 3, para 2. The patient reported a “rash” on the scalp that had developed 9 months prior. She had been treated as an outpatient at an outside institution with topical antibiotics and antifungal medications, yet the dermatitis progressed. Three weeks prior to hospitalization, the rash was present on the skin and mucosal surfaces, including the groin, chest, face, hard palate, buccal mucosa, lips (Figure 1), and back (Figure 2). Nontender bullae ruptured after 3 days, releasing clear, yellow, serous fluid with associated burning and pruritus. The bullae were hemorrhagic and erythematous at the base.

Figure 1. Facial involvement with bullae, crusted hemorrhagic lesions, and eschar in a 34-year-old pregnant woman.

Figure 2. Involvement of the back with bullae in various stages. Some bullae were intact while others newly erupted.

Figure 3. Superinfected and flaking scalp.

Figure 4. Biopsy revealed suprabasal acantholysis with a tombstone effect of residual basal cells (H&E, original magnification ×200).

At the current presentation, the patient had several excoriated 1- to 2-cm oval denudations; some were crusted with eschar. Nikolsky sign was negative. Multiple confluent bullous lesions had erupted on the entire scalp with a thick, impetiginous, yellow crust. She had a wet, boggy, foul-smelling, superinfected scalp that was mildly tender to touch with flaking tissue debris (Figure 3). A white blood cell count was 13.2×109/L (reference range, 4.5–11.0×109/L) with 5% eosinophils (reference range, 2.7%). The differential diagnosis included bullous impetigo, pemphigoid, Stevens-Johnson syndrome, dermatitis herpetiformis, and pemphigus vulgaris.

Biopsies of the scalp and back were taken and showed suprabasal acantholysis with a tombstone effect of residual basal cells standing up on the basement membrane without the characteristic acantholysis into skin appendages (Figure 4). The acantholytic cells in the bullous chamber did not round up as in Hailey-Hailey disease nor was there the dyskeratosis of Grover disease. Direct immunofluorescence on an elbow punch biopsy found diffuse 1+ intercellular IgG in the epidermis and diffuse 1+ basal intercellular C3, and was negative for IgA, IgM, and C1q, thus confirming a diagnosis of PV.

The patient was started on prednisone 20 mg once daily. An increase to prednisone 60 mg led to initial improvement of symptoms, but there was a relapse after several days, which is typical of PV in pregnancy,⁷ prompting the dose to be increased to 120 mg. Following alleviation of symptoms, the dose was later tapered back to 60 mg. No lesions were present at discharge or for 2.5 months thereafter, as the prednisone was tapered from 60 to 45 mg daily after discharge.

On follow-up, the patient’s PV was well controlled, but the prednisone dose was back up to 60 mg daily because of 2 new skin lesions that had developed since her last visit 2.5 months prior. Ultrasonography showed no fetal abnormalities as the pregnancy progressed to 28 weeks’ gestation. The patient developed hypertension and went into premature labor due to placenta previa. The neonate showed no skin lesions or anomalies while in the neonatal intensive care unit. The mother’s prednisone dose was tapered from 60 to 20 mg daily while the white blood cell count was 7.1×10⁹/L with 2% eosinophils and a new scalp lesion appeared. Seven months after her initial discharge from the hospital for the dermatologic condition, she was no longer nursing and azathioprine was added to prednisone 60 mg daily.

Comment

Pemphigus vulgaris is associated with infertility in its active phase; therefore, PV during pregnancy is rare.⁸ Pregnancy may exacerbate PV, which has been a similar finding in other well-documented autoimmune diseases.⁷ One review of PV in pregnancy reported that 11 of 49 patients (22%) experienced an exacerbation of the disease.⁸ This finding pre-sents 2 problems: (1) severe active disease during pregnancy with high antibody titers has been shown to heighten risk for morbidity and mortality for the fetus, and (2) a patient with active PV during pregnancy may require systemic therapy with doses high enough to subdue the disease. The presence of PV was a challenge throughout our patient’s pregnancy. Transient skin lesions may occasionally appear in the neonate and seem to have an increased association with severe active PV in the mother; however, neonatal PV also has been present in mild cases in the mother.⁷ These lesions are secondary to passive transplacental transfer of PV antibodies but do not have long-lasting clinical implications because of an antibody’s brief half-life.⁹ The lesions either spontaneously resolve or can be treated with a topical corticosteroid.

Treatment with high-dose systemic corticosteroids or immunosuppressants can be problematic because of the risks posed to the fetus, especially if the mother must be treated when the embryo is particularly susceptible (eg, during organogenesis).¹⁰ If a woman with known PV is planning to become pregnant, it is recommended to first control and suppress the disease so that therapy can be minimal during the pregnancy. It also is recommended to use aggressive topical therapy if possible to control PV in a pregnant woman.⁸ This option would not have been efficacious in our patient because of her severe widespread disease.

Prednisone is considered one of the first-line treatments of PV and has been historically successful as a treatment for pregnant patients with PV if maintained at a low dosage. Prednisone, similar to other corticosteroids, can cross the placental barrier and can increase the chance of premature birth, infection, and mortality in high doses.⁷ Similar to prednisone, azathioprine is not recommended during pregnancy, but if use is necessary, it is suggested to keep the dose low to prevent fetal harm.¹¹ Inadequate treatment and control of PV can be life threatening to the patient because of the severe infection that may ensue; thus it is necessary for the health of the patient and fetus to suppress the PV. One alternative to treatment with steroids and immunosuppressants is plasma exchange, which has been successful in the clinical context of pregnancy.¹² The cons of plasma exchange are repeat procedures, the need to give the patient more immunosuppressants to prevent a rejection, and the return of the autoantibody.⁷

Several studies have evaluated the safety and efficacy of rituximab in the treatment of refractory PV. Multiple case reports state that both 1 and 2 courses of intravenous rituximab therapy at a dosage of 375 mg per square meter of body surface area affected once weekly for 4 weeks proved to be useful in clinical improvement for patients with refractory disease.^13,14 Studies are currently underway to look at the effects of rituximab on pregnancy and the fetus. Preliminary findings show neonates may have B-cell abnormalities initially yet recover fully without infectious complications or sequelae.¹⁵ Rituximab currently is a pregnancy category C drug, and women are counseled to avoid pregnancy for at least 12 months after rituximab exposure and use contraception while actively taking the drug.¹⁶

Conclusion

Contrary to traditional thinking, PV itself may be associated with poor neonatal outcome, including prematurity and fetal death. These complications seem to be restricted to pregnancies with clinically severe PV.⁷ Our patient decided to progress with her pregnancy despite the potential risk to the fetus from the disease and treatment. Ultimately, the infant was delivered prematurely but was free of disease.

Pemphigus vulgaris (PV) is a rare autoimmune bullous dermatosis that has not shown a predilection toward a particular race or sex.¹ Autoantibodies for desmoglein 1 and desmoglein 3, members of the cadherin family that are involved in cellular adhesion, have been linked to the pathogenesis of PV.² These autoantibodies play a role in the loss of cell-to-cell adhesion in the basal and suprabasal layers of the deep epidermis while cellular adhesion in the superficial epidermis remains intact, leading to the clinical presentation of epidermal blistering and ulcerations most commonly found on the scalp, face, groin, and axillae. Diagnosis typically is made based on skin biopsy and confirmed by direct immunofluorescence. Histologically, PV displays acantholysis and suprabasal cleft formation. Immunofluorescence may show IgG antibodies against the PV antigen in the epidermis.³ Once a diagnosis has been made, treatment typically consists of systemic steroids, as the use of steroids has had great effect in preventing infections, sepsis, and fatality that were once associated with PV.⁴ Mortality rates associated with PV have decreased to 10% to 15% with systemic steroids from a mortality rate as high as 70% in the presteroid era.^1,5 Treatment of PV during pregnancy, as in our patient, requires obstetric and pediatric consultations before therapy is initiated. Use of corticosteroids during pregnancy can be potentially dangerous to the fetus, particularly if high doses are necessary to control maternal disease.^6,7

Case Report

A 34-year-old pregnant woman at 6 weeks’ gestation presented with widespread blistering dermatitis and associated burning and pruritus. Her obstetrical history was gravida 3, para 2. The patient reported a “rash” on the scalp that had developed 9 months prior. She had been treated as an outpatient at an outside institution with topical antibiotics and antifungal medications, yet the dermatitis progressed. Three weeks prior to hospitalization, the rash was present on the skin and mucosal surfaces, including the groin, chest, face, hard palate, buccal mucosa, lips (Figure 1), and back (Figure 2). Nontender bullae ruptured after 3 days, releasing clear, yellow, serous fluid with associated burning and pruritus. The bullae were hemorrhagic and erythematous at the base.

Figure 1. Facial involvement with bullae, crusted hemorrhagic lesions, and eschar in a 34-year-old pregnant woman.

Figure 2. Involvement of the back with bullae in various stages. Some bullae were intact while others newly erupted.

Figure 3. Superinfected and flaking scalp.

Figure 4. Biopsy revealed suprabasal acantholysis with a tombstone effect of residual basal cells (H&E, original magnification ×200).

At the current presentation, the patient had several excoriated 1- to 2-cm oval denudations; some were crusted with eschar. Nikolsky sign was negative. Multiple confluent bullous lesions had erupted on the entire scalp with a thick, impetiginous, yellow crust. She had a wet, boggy, foul-smelling, superinfected scalp that was mildly tender to touch with flaking tissue debris (Figure 3). A white blood cell count was 13.2×109/L (reference range, 4.5–11.0×109/L) with 5% eosinophils (reference range, 2.7%). The differential diagnosis included bullous impetigo, pemphigoid, Stevens-Johnson syndrome, dermatitis herpetiformis, and pemphigus vulgaris.

Biopsies of the scalp and back were taken and showed suprabasal acantholysis with a tombstone effect of residual basal cells standing up on the basement membrane without the characteristic acantholysis into skin appendages (Figure 4). The acantholytic cells in the bullous chamber did not round up as in Hailey-Hailey disease nor was there the dyskeratosis of Grover disease. Direct immunofluorescence on an elbow punch biopsy found diffuse 1+ intercellular IgG in the epidermis and diffuse 1+ basal intercellular C3, and was negative for IgA, IgM, and C1q, thus confirming a diagnosis of PV.

The patient was started on prednisone 20 mg once daily. An increase to prednisone 60 mg led to initial improvement of symptoms, but there was a relapse after several days, which is typical of PV in pregnancy,⁷ prompting the dose to be increased to 120 mg. Following alleviation of symptoms, the dose was later tapered back to 60 mg. No lesions were present at discharge or for 2.5 months thereafter, as the prednisone was tapered from 60 to 45 mg daily after discharge.

On follow-up, the patient’s PV was well controlled, but the prednisone dose was back up to 60 mg daily because of 2 new skin lesions that had developed since her last visit 2.5 months prior. Ultrasonography showed no fetal abnormalities as the pregnancy progressed to 28 weeks’ gestation. The patient developed hypertension and went into premature labor due to placenta previa. The neonate showed no skin lesions or anomalies while in the neonatal intensive care unit. The mother’s prednisone dose was tapered from 60 to 20 mg daily while the white blood cell count was 7.1×10⁹/L with 2% eosinophils and a new scalp lesion appeared. Seven months after her initial discharge from the hospital for the dermatologic condition, she was no longer nursing and azathioprine was added to prednisone 60 mg daily.

Comment

Pemphigus vulgaris is associated with infertility in its active phase; therefore, PV during pregnancy is rare.⁸ Pregnancy may exacerbate PV, which has been a similar finding in other well-documented autoimmune diseases.⁷ One review of PV in pregnancy reported that 11 of 49 patients (22%) experienced an exacerbation of the disease.⁸ This finding pre-sents 2 problems: (1) severe active disease during pregnancy with high antibody titers has been shown to heighten risk for morbidity and mortality for the fetus, and (2) a patient with active PV during pregnancy may require systemic therapy with doses high enough to subdue the disease. The presence of PV was a challenge throughout our patient’s pregnancy. Transient skin lesions may occasionally appear in the neonate and seem to have an increased association with severe active PV in the mother; however, neonatal PV also has been present in mild cases in the mother.⁷ These lesions are secondary to passive transplacental transfer of PV antibodies but do not have long-lasting clinical implications because of an antibody’s brief half-life.⁹ The lesions either spontaneously resolve or can be treated with a topical corticosteroid.

Treatment with high-dose systemic corticosteroids or immunosuppressants can be problematic because of the risks posed to the fetus, especially if the mother must be treated when the embryo is particularly susceptible (eg, during organogenesis).¹⁰ If a woman with known PV is planning to become pregnant, it is recommended to first control and suppress the disease so that therapy can be minimal during the pregnancy. It also is recommended to use aggressive topical therapy if possible to control PV in a pregnant woman.⁸ This option would not have been efficacious in our patient because of her severe widespread disease.

Prednisone is considered one of the first-line treatments of PV and has been historically successful as a treatment for pregnant patients with PV if maintained at a low dosage. Prednisone, similar to other corticosteroids, can cross the placental barrier and can increase the chance of premature birth, infection, and mortality in high doses.⁷ Similar to prednisone, azathioprine is not recommended during pregnancy, but if use is necessary, it is suggested to keep the dose low to prevent fetal harm.¹¹ Inadequate treatment and control of PV can be life threatening to the patient because of the severe infection that may ensue; thus it is necessary for the health of the patient and fetus to suppress the PV. One alternative to treatment with steroids and immunosuppressants is plasma exchange, which has been successful in the clinical context of pregnancy.¹² The cons of plasma exchange are repeat procedures, the need to give the patient more immunosuppressants to prevent a rejection, and the return of the autoantibody.⁷

Several studies have evaluated the safety and efficacy of rituximab in the treatment of refractory PV. Multiple case reports state that both 1 and 2 courses of intravenous rituximab therapy at a dosage of 375 mg per square meter of body surface area affected once weekly for 4 weeks proved to be useful in clinical improvement for patients with refractory disease.^13,14 Studies are currently underway to look at the effects of rituximab on pregnancy and the fetus. Preliminary findings show neonates may have B-cell abnormalities initially yet recover fully without infectious complications or sequelae.¹⁵ Rituximab currently is a pregnancy category C drug, and women are counseled to avoid pregnancy for at least 12 months after rituximab exposure and use contraception while actively taking the drug.¹⁶

Conclusion

Contrary to traditional thinking, PV itself may be associated with poor neonatal outcome, including prematurity and fetal death. These complications seem to be restricted to pregnancies with clinically severe PV.⁷ Our patient decided to progress with her pregnancy despite the potential risk to the fetus from the disease and treatment. Ultimately, the infant was delivered prematurely but was free of disease.

The Diagnosis: Adult-Onset Xanthogranuloma

Biopsies of the lesions on the neck (Figure 1) and back were performed. Histologic analyses revealed a diffuse dermatitis consisting of foamy histiocytes admixed with a few Touton-type giant cells in the dermis (Figure 2), which was associated with an inflammatory infiltrate of eosinophils and lymphocytes. Laboratory investigations revealed mild thrombocytopenia with a platelet count of 134×10⁹/L (reference range, 140–440×10⁹/L). Other investigations including biochemistry, lipid, serum electrophoresis, and chest radiogram were normal. A bone marrow trephine biopsy and flow cytometry were performed and were normal. Magnetic resonance imaging revealed periorbital soft-tissue masses that did not extend into the orbits.

Figure 1. Firm plaques with a yellowish tinge over the side of the neck

Figure 2. A dense infiltrate of foamy histiocytes in the dermis (A) associated with a Touton-type giant cell (arrow) and an inflammatory infiltrate consisting of eosinophils and lymphocytes (B)(both H&E, original magnifications ×200 and ×400).

Adult-onset xanthogranuloma (AXG) is a rare disease entity, usually presenting in the third to fourth decades of life. The condition typically presents as a red to yellow-brown nodular cutaneous lesion located on the scalp, face, neck, trunk, or limbs. The presentation typically consists of a solitary lesion, occurring in 70% to 89% of cases,¹ but more rarely, as in this case, lesions can be multiple or even disseminated.

Histologically, AXG presents as a dense, well-circumscribed, histiocytic infiltrate consisting of lipophages possessing foamy cytoplasm and giant cells. The presence of histiocytic giant cells differentiates AXG from xanthelasma, a clinical differential diagnosis in this case, and xanthoma. In AXG, there are 4 main types of histiocytes: xanthomatized, spindle shaped, vacuolated, and oncocytic.² They can be seen in variable proportions, together with different types of giant cells (eg, Touton, foreign body, ground glass, nonspecific). A mixed infiltrate of eosinophils, lymphocytes, plasma cells, and neutrophils also may be seen scattered throughout the lesion.²

Correlating with the clinical and histological features of xanthogranuloma, the firm plaques and nodules represent the dense dermal infiltration of histiocytes that may extend into the subcutis. The lesions demonstrate a time-dependent progression both clinically and histologically. Early lesions are comprised of a dense monomorphous nonlipid histiocytic inflammatory infiltrate, and they clinically appear more erythematous. In mature lesions, as in our patient, the infiltrate is predominantly composed of lipid-laden histiocytes with associated Touton giant cells. They appear more yellowish on clinical presentation.

Adult-onset xanthogranuloma is part of a rare heterogenous group of disorders termed adult orbital xanthogranulomatous disease, which includes 3 other syndromes: necrobiotic xanthogranuloma, adult-onset asthma and periocular xanthogranuloma, and Erdheim-Chester disease.

Necrobiotic xanthogranuloma is clinically characterized by the presence of subcutaneous lesions that ulcerate in approximately 40% to 50% of cases and is histologically characterized by necrobiosis with palisading epithelioid histiocytes. It also is systemically associated with paraproteinemia and multiple myeloma.³

Adult-onset asthma and periocular xanthogranuloma is characterized by yellowish papules and nodules predominantly over the lower eyelids that are histologically comprised of lymphoid follicles with reactive germinal centers. It is associated with asthma, which normally is severe and often occurs almost simultaneously with the periorbital lesions.⁴

There are no definite diagnostic criteria for Erdheim-Chester disease and the diagnosis is usually based on radiologic findings of osteosclerosis and histopathologic evidence of foamy histiocytic infiltration. Systemic manifestations are common with lymphohistiocytic infiltration of the heart, lungs, pericardium, bones, and intestines. Prognosis is uniformly dismal.

Based on the clinical presentation of a nonulcerative papulonodular eruption and the absence of systemic involvement including asthma, we made the diagnosis of AXG. In view of the heterogeneity among these clinical entities as well as the time-based evolution of the lesions involved, we continued to monitor the patient for 2 years and there was no development of other systemic manifestations and hematologic abnormalities.

In contrast to the more common form of juvenile-onset xanthogranuloma, the adult type is not associated with widespread visceral lesions. Hence extensive screening investigations for systemic disease generally are not necessary. Another difference is that AXG has been associated with hematologic abnormalities, including essential thrombocytosis, chronic lymphocytic leukemia, large B-cell lymphoma, and monoclonal gammopathy.^5,6 In our patient, the presence of thrombocytopenia and older age caused us to be concerned about an associated hematologic malignancy; therefore, a bone marrow biopsy and flow cytometry were performed.

Adult-onset xanthogranuloma typically is an asymptomatic and self-healing disease and therefore treatment usually is not required. Spontaneous regression of xanthogranuloma was observed to occur in 54% of cases with a median duration of 22 months,⁷ though lesions were noted to last as long as 15 years.⁸ When treatment is necessary, a combination of local and systemic corticosteroids, cytotoxic agents, and radiotherapy have been routinely used. In particular, intralesional corticosteroid therapy has been found to be efficacious in controlling symptoms and signs of AXG affecting the eyelids and orbits while avoiding the systemic side effects of other agents.⁹

Because our patient’s lesions were longstanding and disfiguring, we opted for active intervention with intralesional triamcinolone, which resulted in only a slight reduction in size of the lesions. The lesions remain largely unchanged in 2 years of follow-up.

The Diagnosis: Adult-Onset Xanthogranuloma

Biopsies of the lesions on the neck (Figure 1) and back were performed. Histologic analyses revealed a diffuse dermatitis consisting of foamy histiocytes admixed with a few Touton-type giant cells in the dermis (Figure 2), which was associated with an inflammatory infiltrate of eosinophils and lymphocytes. Laboratory investigations revealed mild thrombocytopenia with a platelet count of 134×10⁹/L (reference range, 140–440×10⁹/L). Other investigations including biochemistry, lipid, serum electrophoresis, and chest radiogram were normal. A bone marrow trephine biopsy and flow cytometry were performed and were normal. Magnetic resonance imaging revealed periorbital soft-tissue masses that did not extend into the orbits.

Figure 1. Firm plaques with a yellowish tinge over the side of the neck

Figure 2. A dense infiltrate of foamy histiocytes in the dermis (A) associated with a Touton-type giant cell (arrow) and an inflammatory infiltrate consisting of eosinophils and lymphocytes (B)(both H&E, original magnifications ×200 and ×400).

Adult-onset xanthogranuloma (AXG) is a rare disease entity, usually presenting in the third to fourth decades of life. The condition typically presents as a red to yellow-brown nodular cutaneous lesion located on the scalp, face, neck, trunk, or limbs. The presentation typically consists of a solitary lesion, occurring in 70% to 89% of cases,¹ but more rarely, as in this case, lesions can be multiple or even disseminated.

Histologically, AXG presents as a dense, well-circumscribed, histiocytic infiltrate consisting of lipophages possessing foamy cytoplasm and giant cells. The presence of histiocytic giant cells differentiates AXG from xanthelasma, a clinical differential diagnosis in this case, and xanthoma. In AXG, there are 4 main types of histiocytes: xanthomatized, spindle shaped, vacuolated, and oncocytic.² They can be seen in variable proportions, together with different types of giant cells (eg, Touton, foreign body, ground glass, nonspecific). A mixed infiltrate of eosinophils, lymphocytes, plasma cells, and neutrophils also may be seen scattered throughout the lesion.²

Correlating with the clinical and histological features of xanthogranuloma, the firm plaques and nodules represent the dense dermal infiltration of histiocytes that may extend into the subcutis. The lesions demonstrate a time-dependent progression both clinically and histologically. Early lesions are comprised of a dense monomorphous nonlipid histiocytic inflammatory infiltrate, and they clinically appear more erythematous. In mature lesions, as in our patient, the infiltrate is predominantly composed of lipid-laden histiocytes with associated Touton giant cells. They appear more yellowish on clinical presentation.

Adult-onset xanthogranuloma is part of a rare heterogenous group of disorders termed adult orbital xanthogranulomatous disease, which includes 3 other syndromes: necrobiotic xanthogranuloma, adult-onset asthma and periocular xanthogranuloma, and Erdheim-Chester disease.

Necrobiotic xanthogranuloma is clinically characterized by the presence of subcutaneous lesions that ulcerate in approximately 40% to 50% of cases and is histologically characterized by necrobiosis with palisading epithelioid histiocytes. It also is systemically associated with paraproteinemia and multiple myeloma.³

Adult-onset asthma and periocular xanthogranuloma is characterized by yellowish papules and nodules predominantly over the lower eyelids that are histologically comprised of lymphoid follicles with reactive germinal centers. It is associated with asthma, which normally is severe and often occurs almost simultaneously with the periorbital lesions.⁴

There are no definite diagnostic criteria for Erdheim-Chester disease and the diagnosis is usually based on radiologic findings of osteosclerosis and histopathologic evidence of foamy histiocytic infiltration. Systemic manifestations are common with lymphohistiocytic infiltration of the heart, lungs, pericardium, bones, and intestines. Prognosis is uniformly dismal.

Based on the clinical presentation of a nonulcerative papulonodular eruption and the absence of systemic involvement including asthma, we made the diagnosis of AXG. In view of the heterogeneity among these clinical entities as well as the time-based evolution of the lesions involved, we continued to monitor the patient for 2 years and there was no development of other systemic manifestations and hematologic abnormalities.

In contrast to the more common form of juvenile-onset xanthogranuloma, the adult type is not associated with widespread visceral lesions. Hence extensive screening investigations for systemic disease generally are not necessary. Another difference is that AXG has been associated with hematologic abnormalities, including essential thrombocytosis, chronic lymphocytic leukemia, large B-cell lymphoma, and monoclonal gammopathy.^5,6 In our patient, the presence of thrombocytopenia and older age caused us to be concerned about an associated hematologic malignancy; therefore, a bone marrow biopsy and flow cytometry were performed.

Adult-onset xanthogranuloma typically is an asymptomatic and self-healing disease and therefore treatment usually is not required. Spontaneous regression of xanthogranuloma was observed to occur in 54% of cases with a median duration of 22 months,⁷ though lesions were noted to last as long as 15 years.⁸ When treatment is necessary, a combination of local and systemic corticosteroids, cytotoxic agents, and radiotherapy have been routinely used. In particular, intralesional corticosteroid therapy has been found to be efficacious in controlling symptoms and signs of AXG affecting the eyelids and orbits while avoiding the systemic side effects of other agents.⁹

Because our patient’s lesions were longstanding and disfiguring, we opted for active intervention with intralesional triamcinolone, which resulted in only a slight reduction in size of the lesions. The lesions remain largely unchanged in 2 years of follow-up.

The Diagnosis: Adult-Onset Xanthogranuloma

Biopsies of the lesions on the neck (Figure 1) and back were performed. Histologic analyses revealed a diffuse dermatitis consisting of foamy histiocytes admixed with a few Touton-type giant cells in the dermis (Figure 2), which was associated with an inflammatory infiltrate of eosinophils and lymphocytes. Laboratory investigations revealed mild thrombocytopenia with a platelet count of 134×10⁹/L (reference range, 140–440×10⁹/L). Other investigations including biochemistry, lipid, serum electrophoresis, and chest radiogram were normal. A bone marrow trephine biopsy and flow cytometry were performed and were normal. Magnetic resonance imaging revealed periorbital soft-tissue masses that did not extend into the orbits.

Figure 1. Firm plaques with a yellowish tinge over the side of the neck

Figure 2. A dense infiltrate of foamy histiocytes in the dermis (A) associated with a Touton-type giant cell (arrow) and an inflammatory infiltrate consisting of eosinophils and lymphocytes (B)(both H&E, original magnifications ×200 and ×400).

Adult-onset xanthogranuloma (AXG) is a rare disease entity, usually presenting in the third to fourth decades of life. The condition typically presents as a red to yellow-brown nodular cutaneous lesion located on the scalp, face, neck, trunk, or limbs. The presentation typically consists of a solitary lesion, occurring in 70% to 89% of cases,¹ but more rarely, as in this case, lesions can be multiple or even disseminated.

Histologically, AXG presents as a dense, well-circumscribed, histiocytic infiltrate consisting of lipophages possessing foamy cytoplasm and giant cells. The presence of histiocytic giant cells differentiates AXG from xanthelasma, a clinical differential diagnosis in this case, and xanthoma. In AXG, there are 4 main types of histiocytes: xanthomatized, spindle shaped, vacuolated, and oncocytic.² They can be seen in variable proportions, together with different types of giant cells (eg, Touton, foreign body, ground glass, nonspecific). A mixed infiltrate of eosinophils, lymphocytes, plasma cells, and neutrophils also may be seen scattered throughout the lesion.²

Correlating with the clinical and histological features of xanthogranuloma, the firm plaques and nodules represent the dense dermal infiltration of histiocytes that may extend into the subcutis. The lesions demonstrate a time-dependent progression both clinically and histologically. Early lesions are comprised of a dense monomorphous nonlipid histiocytic inflammatory infiltrate, and they clinically appear more erythematous. In mature lesions, as in our patient, the infiltrate is predominantly composed of lipid-laden histiocytes with associated Touton giant cells. They appear more yellowish on clinical presentation.

Adult-onset xanthogranuloma is part of a rare heterogenous group of disorders termed adult orbital xanthogranulomatous disease, which includes 3 other syndromes: necrobiotic xanthogranuloma, adult-onset asthma and periocular xanthogranuloma, and Erdheim-Chester disease.

Necrobiotic xanthogranuloma is clinically characterized by the presence of subcutaneous lesions that ulcerate in approximately 40% to 50% of cases and is histologically characterized by necrobiosis with palisading epithelioid histiocytes. It also is systemically associated with paraproteinemia and multiple myeloma.³

Adult-onset asthma and periocular xanthogranuloma is characterized by yellowish papules and nodules predominantly over the lower eyelids that are histologically comprised of lymphoid follicles with reactive germinal centers. It is associated with asthma, which normally is severe and often occurs almost simultaneously with the periorbital lesions.⁴

There are no definite diagnostic criteria for Erdheim-Chester disease and the diagnosis is usually based on radiologic findings of osteosclerosis and histopathologic evidence of foamy histiocytic infiltration. Systemic manifestations are common with lymphohistiocytic infiltration of the heart, lungs, pericardium, bones, and intestines. Prognosis is uniformly dismal.

Based on the clinical presentation of a nonulcerative papulonodular eruption and the absence of systemic involvement including asthma, we made the diagnosis of AXG. In view of the heterogeneity among these clinical entities as well as the time-based evolution of the lesions involved, we continued to monitor the patient for 2 years and there was no development of other systemic manifestations and hematologic abnormalities.

In contrast to the more common form of juvenile-onset xanthogranuloma, the adult type is not associated with widespread visceral lesions. Hence extensive screening investigations for systemic disease generally are not necessary. Another difference is that AXG has been associated with hematologic abnormalities, including essential thrombocytosis, chronic lymphocytic leukemia, large B-cell lymphoma, and monoclonal gammopathy.^5,6 In our patient, the presence of thrombocytopenia and older age caused us to be concerned about an associated hematologic malignancy; therefore, a bone marrow biopsy and flow cytometry were performed.

Adult-onset xanthogranuloma typically is an asymptomatic and self-healing disease and therefore treatment usually is not required. Spontaneous regression of xanthogranuloma was observed to occur in 54% of cases with a median duration of 22 months,⁷ though lesions were noted to last as long as 15 years.⁸ When treatment is necessary, a combination of local and systemic corticosteroids, cytotoxic agents, and radiotherapy have been routinely used. In particular, intralesional corticosteroid therapy has been found to be efficacious in controlling symptoms and signs of AXG affecting the eyelids and orbits while avoiding the systemic side effects of other agents.⁹

Because our patient’s lesions were longstanding and disfiguring, we opted for active intervention with intralesional triamcinolone, which resulted in only a slight reduction in size of the lesions. The lesions remain largely unchanged in 2 years of follow-up.

Glomus tumors (GTs) are uncommon benign tumors originating in the neuromyoarterial elements of the glomus body, an arteriovenous shunt specialized in thermoregulation.¹ Glomus tumors usually occur in the distal extremities of young adults² and rarely are seen in the deep soft tissue or viscera. Malignant GTs are rare and highly aggressive tumors that have been associated with both local recurrence and distant metastasis.^1-11 Glomus tumors have been subdivided into 3 groups with different prognoses²: (1) malignant GT with metastatic potential (subfascial or visceral location, >2 cm in size, atypical mitotic figures, >5 mitoses per 50 high-power fields [HPFs], marked nuclear atypia); (2) symplastic GT (benign tumor with nuclear pleomorphism without mitotic activity); and (3) GT of uncertain malignant potential (GTUMP)(absence of metastatic disease, favorable prognosis, at least 1 feature of malignant GTs other than marked nuclear atypia [eg, high mitotic activity, >2 cm in size, deep location]).^1,2

We report a case of GTUMP with unusual clinicopathologic features in a 74-year-old man that was treated via wide surgical excision. No local recurrence or distant metastasis was noted at 3-year follow-up.

Case Report

A 74-year-old man presented to the Unit of Surgery with a slowly progressing, painful, ulcerated, 2.5-cm, red-blue nodule on the forehead (Figure 1). An excisional biopsy of the nodule was performed. Histologically, the dermis and superficial subcutis were filled with a proliferation of atypical epithelioid cells to slightly spindled cells. Both cells displayed a weakly eosinophilic cytoplasm with indistinct membranes and larger ovoid nuclei, some with prominent nucleoli. Neoplastic cells showed a disordered arrangement or were organized in short fascicles separated by slitlike spaces, vascular lumens of various sizes, or hemorrhagic stroma resembling angiosarcoma or Kaposi sarcoma (Figure 2). No areas of necrosis were noted. Pleomorphic nuclei and some mitotic figures also were identified, but they were not atypical and showed fewer than 5 mitoses per 50 HPFs. Immunohistochemically, the neoplastic cells stained positive for vimentin, caldesmon (Figure 3), and a–smooth muscle actin, and they stained negative for cytokeratins, desmin, CD34, factor VIII–related antigen, S-100 protein, and the latent nuclear antigen of Kaposi sarcoma–associated herpesvirus. The Ki-67 labeling index revealed less than 20% positive cells.

Figure 1. A painful, red-blue, ulcerated nodule on the forehead of a 74-year-old man.

Figure 2. The tumor was composed of atypical epithelioid cells to slightly spindled cells with indistinct membranes and larger ovoid nuclei, some with prominent nucleoli in a disordered arrangement or rather in short fascicles separated in a hemorrhagic background (H&E, original magnification ×40).

Figure 3. The neoplastic cells stained positive for caldesmon (original magnification ×20).

Figure 4. A focus of round to polygonal tumor cells reminiscent of a preexisting benign-appearing glomus tumor was found on biopsy following reexcision (H&E, original magnification ×20).

Because the tumor involved margins of excision, the patient successfully underwent wide reexcision with adequate margins. Histological examination of the reexcised specimen showed a focus of bland, round to polygonal tumor cells with the features of glomus cells (Figure 4). On the basis of the histologic features of both specimens, the lesion was classified as a GT. The biggest problem in our case was the classification of the lesion according to established pathologic criteria. We considered this case to be borderline because the lesion was greater than 2 cm but the location was superficial; marked atypia with sarcomatoid features also were present, but there was an absence of necrosis and fewer than 5 mitoses per 50 HPFs. For these reasons, we diagnosed this problematic lesion as a GTUMP. Following reexcision, the patient underwent strict follow-up. Wound healing was uncomplicated and the patient showed no local recurrence or distant metastasis at 3-year follow-up.

Comment

Clinically metastatic and histologically malignant GTs are exceptional.^3-11 The classification system for GTs based on histologic criteria subdivided these tumors into 3 groups with different prognoses.² Malignant GTs are highly aggressive tumors with metastatic potential, symplastic GTs are considered to be a degenerative phenomenon, and GTUMPs have a favorable clinical outcome and absence of metastatic disease.¹²

Diagnosis of malignant GTs and symplastic GTs is relatively easy in the presence of typical uniform, small, round epithelioid cells (glomus cells) located around blood vessels. Immunohistochemistry may be useful, as GTs express smooth muscle actin and caldesmon. Over the years the existence and diagnosis of malignant GT has been questioned because a residual component of benign GT in the surgical biopsy is useful in diagnosis but is not always present^1-3 and because an unusual pattern may be present in malignant tumors with prevalent spindle cells resembling fibrosarcoma, leiomyosarcoma, spindle cell angiosarcoma, and spindle cell melanoma.¹ In the absence of a preexisting GT, the differential diagnosis may be difficult; in such cases, a panel of immunohistochemical markers including smooth muscle actin, caldesmon, desmin, S-100, human melanoma black-45 (HMB-45), CD34, and CD31 is always necessary. The GTUMP category was introduced for GTs that demonstrate marked nuclear atypia but do not fulfill histologic criteria for malignancy. Along with other tumors of uncertain malignant potential, borderline cases should be considered GTUMPs to guarantee wide excision of the tumor with negative margins and an adequate follow-up due to the possibility of local recurrence or distant metastasis. In our patient, a diagnosis of GTUMP was made. Additionally, our case demonstrates some previously unreported features of GTUMPs, such as spindled cells in short fascicles separated by slitlike spaces, small vessels, and hemorrhagic stroma resembling Kaposi sarcoma. Along with these unusual sarcomatous features, the superficial location of the lesion, absence of necrosis, and a mitotic count of less than 5 per 50 HPFs were suggestive of an uncertain malignant potential for this tumor.

Distinction between malignant GTs and GTUMPs in the presence of unusual histologic features may be difficult.¹² Glomus tumors that do not fulfill criteria for malignancy but have at least 1 atypical feature other than nuclear pleomorphism should be named GTUMPs. According to classification criteria, a true malignant GT is a highly aggressive tumor with metastatic potential. In a case series reported by Folpe et al,² 38% (20/52) of malignant GTs showed metastases, while metastatic disease was not observed in the tumors classified as GTUMPs. Wide surgical excision or Mohs micrographic surgery¹³ are the treatments of choice for malignant GTs and GTUMPs. Complete excision of the lesion with negative margins is always necessary in cases of GTUMPs. After the diagnosis of GTUMP, adequate follow-up should berecommended due to the possibility of local recurrence or distant metastasis.

Conclusion

Malignant GTs and GTUMPs are rare, and the nomenclature and classification of these tumors is controversial. These findings and the difficulty of differential diagnosis in a continuum between benignity and malignancy prompted our report.

Glomus tumors (GTs) are uncommon benign tumors originating in the neuromyoarterial elements of the glomus body, an arteriovenous shunt specialized in thermoregulation.¹ Glomus tumors usually occur in the distal extremities of young adults² and rarely are seen in the deep soft tissue or viscera. Malignant GTs are rare and highly aggressive tumors that have been associated with both local recurrence and distant metastasis.^1-11 Glomus tumors have been subdivided into 3 groups with different prognoses²: (1) malignant GT with metastatic potential (subfascial or visceral location, >2 cm in size, atypical mitotic figures, >5 mitoses per 50 high-power fields [HPFs], marked nuclear atypia); (2) symplastic GT (benign tumor with nuclear pleomorphism without mitotic activity); and (3) GT of uncertain malignant potential (GTUMP)(absence of metastatic disease, favorable prognosis, at least 1 feature of malignant GTs other than marked nuclear atypia [eg, high mitotic activity, >2 cm in size, deep location]).^1,2

We report a case of GTUMP with unusual clinicopathologic features in a 74-year-old man that was treated via wide surgical excision. No local recurrence or distant metastasis was noted at 3-year follow-up.

Case Report

A 74-year-old man presented to the Unit of Surgery with a slowly progressing, painful, ulcerated, 2.5-cm, red-blue nodule on the forehead (Figure 1). An excisional biopsy of the nodule was performed. Histologically, the dermis and superficial subcutis were filled with a proliferation of atypical epithelioid cells to slightly spindled cells. Both cells displayed a weakly eosinophilic cytoplasm with indistinct membranes and larger ovoid nuclei, some with prominent nucleoli. Neoplastic cells showed a disordered arrangement or were organized in short fascicles separated by slitlike spaces, vascular lumens of various sizes, or hemorrhagic stroma resembling angiosarcoma or Kaposi sarcoma (Figure 2). No areas of necrosis were noted. Pleomorphic nuclei and some mitotic figures also were identified, but they were not atypical and showed fewer than 5 mitoses per 50 HPFs. Immunohistochemically, the neoplastic cells stained positive for vimentin, caldesmon (Figure 3), and a–smooth muscle actin, and they stained negative for cytokeratins, desmin, CD34, factor VIII–related antigen, S-100 protein, and the latent nuclear antigen of Kaposi sarcoma–associated herpesvirus. The Ki-67 labeling index revealed less than 20% positive cells.

Figure 1. A painful, red-blue, ulcerated nodule on the forehead of a 74-year-old man.

Figure 2. The tumor was composed of atypical epithelioid cells to slightly spindled cells with indistinct membranes and larger ovoid nuclei, some with prominent nucleoli in a disordered arrangement or rather in short fascicles separated in a hemorrhagic background (H&E, original magnification ×40).

Figure 3. The neoplastic cells stained positive for caldesmon (original magnification ×20).

Figure 4. A focus of round to polygonal tumor cells reminiscent of a preexisting benign-appearing glomus tumor was found on biopsy following reexcision (H&E, original magnification ×20).

Because the tumor involved margins of excision, the patient successfully underwent wide reexcision with adequate margins. Histological examination of the reexcised specimen showed a focus of bland, round to polygonal tumor cells with the features of glomus cells (Figure 4). On the basis of the histologic features of both specimens, the lesion was classified as a GT. The biggest problem in our case was the classification of the lesion according to established pathologic criteria. We considered this case to be borderline because the lesion was greater than 2 cm but the location was superficial; marked atypia with sarcomatoid features also were present, but there was an absence of necrosis and fewer than 5 mitoses per 50 HPFs. For these reasons, we diagnosed this problematic lesion as a GTUMP. Following reexcision, the patient underwent strict follow-up. Wound healing was uncomplicated and the patient showed no local recurrence or distant metastasis at 3-year follow-up.

Comment

Clinically metastatic and histologically malignant GTs are exceptional.^3-11 The classification system for GTs based on histologic criteria subdivided these tumors into 3 groups with different prognoses.² Malignant GTs are highly aggressive tumors with metastatic potential, symplastic GTs are considered to be a degenerative phenomenon, and GTUMPs have a favorable clinical outcome and absence of metastatic disease.¹²

Diagnosis of malignant GTs and symplastic GTs is relatively easy in the presence of typical uniform, small, round epithelioid cells (glomus cells) located around blood vessels. Immunohistochemistry may be useful, as GTs express smooth muscle actin and caldesmon. Over the years the existence and diagnosis of malignant GT has been questioned because a residual component of benign GT in the surgical biopsy is useful in diagnosis but is not always present^1-3 and because an unusual pattern may be present in malignant tumors with prevalent spindle cells resembling fibrosarcoma, leiomyosarcoma, spindle cell angiosarcoma, and spindle cell melanoma.¹ In the absence of a preexisting GT, the differential diagnosis may be difficult; in such cases, a panel of immunohistochemical markers including smooth muscle actin, caldesmon, desmin, S-100, human melanoma black-45 (HMB-45), CD34, and CD31 is always necessary. The GTUMP category was introduced for GTs that demonstrate marked nuclear atypia but do not fulfill histologic criteria for malignancy. Along with other tumors of uncertain malignant potential, borderline cases should be considered GTUMPs to guarantee wide excision of the tumor with negative margins and an adequate follow-up due to the possibility of local recurrence or distant metastasis. In our patient, a diagnosis of GTUMP was made. Additionally, our case demonstrates some previously unreported features of GTUMPs, such as spindled cells in short fascicles separated by slitlike spaces, small vessels, and hemorrhagic stroma resembling Kaposi sarcoma. Along with these unusual sarcomatous features, the superficial location of the lesion, absence of necrosis, and a mitotic count of less than 5 per 50 HPFs were suggestive of an uncertain malignant potential for this tumor.

Distinction between malignant GTs and GTUMPs in the presence of unusual histologic features may be difficult.¹² Glomus tumors that do not fulfill criteria for malignancy but have at least 1 atypical feature other than nuclear pleomorphism should be named GTUMPs. According to classification criteria, a true malignant GT is a highly aggressive tumor with metastatic potential. In a case series reported by Folpe et al,² 38% (20/52) of malignant GTs showed metastases, while metastatic disease was not observed in the tumors classified as GTUMPs. Wide surgical excision or Mohs micrographic surgery¹³ are the treatments of choice for malignant GTs and GTUMPs. Complete excision of the lesion with negative margins is always necessary in cases of GTUMPs. After the diagnosis of GTUMP, adequate follow-up should berecommended due to the possibility of local recurrence or distant metastasis.

Conclusion

Malignant GTs and GTUMPs are rare, and the nomenclature and classification of these tumors is controversial. These findings and the difficulty of differential diagnosis in a continuum between benignity and malignancy prompted our report.

Glomus tumors (GTs) are uncommon benign tumors originating in the neuromyoarterial elements of the glomus body, an arteriovenous shunt specialized in thermoregulation.¹ Glomus tumors usually occur in the distal extremities of young adults² and rarely are seen in the deep soft tissue or viscera. Malignant GTs are rare and highly aggressive tumors that have been associated with both local recurrence and distant metastasis.^1-11 Glomus tumors have been subdivided into 3 groups with different prognoses²: (1) malignant GT with metastatic potential (subfascial or visceral location, >2 cm in size, atypical mitotic figures, >5 mitoses per 50 high-power fields [HPFs], marked nuclear atypia); (2) symplastic GT (benign tumor with nuclear pleomorphism without mitotic activity); and (3) GT of uncertain malignant potential (GTUMP)(absence of metastatic disease, favorable prognosis, at least 1 feature of malignant GTs other than marked nuclear atypia [eg, high mitotic activity, >2 cm in size, deep location]).^1,2

We report a case of GTUMP with unusual clinicopathologic features in a 74-year-old man that was treated via wide surgical excision. No local recurrence or distant metastasis was noted at 3-year follow-up.

Case Report

A 74-year-old man presented to the Unit of Surgery with a slowly progressing, painful, ulcerated, 2.5-cm, red-blue nodule on the forehead (Figure 1). An excisional biopsy of the nodule was performed. Histologically, the dermis and superficial subcutis were filled with a proliferation of atypical epithelioid cells to slightly spindled cells. Both cells displayed a weakly eosinophilic cytoplasm with indistinct membranes and larger ovoid nuclei, some with prominent nucleoli. Neoplastic cells showed a disordered arrangement or were organized in short fascicles separated by slitlike spaces, vascular lumens of various sizes, or hemorrhagic stroma resembling angiosarcoma or Kaposi sarcoma (Figure 2). No areas of necrosis were noted. Pleomorphic nuclei and some mitotic figures also were identified, but they were not atypical and showed fewer than 5 mitoses per 50 HPFs. Immunohistochemically, the neoplastic cells stained positive for vimentin, caldesmon (Figure 3), and a–smooth muscle actin, and they stained negative for cytokeratins, desmin, CD34, factor VIII–related antigen, S-100 protein, and the latent nuclear antigen of Kaposi sarcoma–associated herpesvirus. The Ki-67 labeling index revealed less than 20% positive cells.

Figure 1. A painful, red-blue, ulcerated nodule on the forehead of a 74-year-old man.

Figure 2. The tumor was composed of atypical epithelioid cells to slightly spindled cells with indistinct membranes and larger ovoid nuclei, some with prominent nucleoli in a disordered arrangement or rather in short fascicles separated in a hemorrhagic background (H&E, original magnification ×40).

Figure 3. The neoplastic cells stained positive for caldesmon (original magnification ×20).

Figure 4. A focus of round to polygonal tumor cells reminiscent of a preexisting benign-appearing glomus tumor was found on biopsy following reexcision (H&E, original magnification ×20).

Because the tumor involved margins of excision, the patient successfully underwent wide reexcision with adequate margins. Histological examination of the reexcised specimen showed a focus of bland, round to polygonal tumor cells with the features of glomus cells (Figure 4). On the basis of the histologic features of both specimens, the lesion was classified as a GT. The biggest problem in our case was the classification of the lesion according to established pathologic criteria. We considered this case to be borderline because the lesion was greater than 2 cm but the location was superficial; marked atypia with sarcomatoid features also were present, but there was an absence of necrosis and fewer than 5 mitoses per 50 HPFs. For these reasons, we diagnosed this problematic lesion as a GTUMP. Following reexcision, the patient underwent strict follow-up. Wound healing was uncomplicated and the patient showed no local recurrence or distant metastasis at 3-year follow-up.

Comment

Clinically metastatic and histologically malignant GTs are exceptional.^3-11 The classification system for GTs based on histologic criteria subdivided these tumors into 3 groups with different prognoses.² Malignant GTs are highly aggressive tumors with metastatic potential, symplastic GTs are considered to be a degenerative phenomenon, and GTUMPs have a favorable clinical outcome and absence of metastatic disease.¹²

Diagnosis of malignant GTs and symplastic GTs is relatively easy in the presence of typical uniform, small, round epithelioid cells (glomus cells) located around blood vessels. Immunohistochemistry may be useful, as GTs express smooth muscle actin and caldesmon. Over the years the existence and diagnosis of malignant GT has been questioned because a residual component of benign GT in the surgical biopsy is useful in diagnosis but is not always present^1-3 and because an unusual pattern may be present in malignant tumors with prevalent spindle cells resembling fibrosarcoma, leiomyosarcoma, spindle cell angiosarcoma, and spindle cell melanoma.¹ In the absence of a preexisting GT, the differential diagnosis may be difficult; in such cases, a panel of immunohistochemical markers including smooth muscle actin, caldesmon, desmin, S-100, human melanoma black-45 (HMB-45), CD34, and CD31 is always necessary. The GTUMP category was introduced for GTs that demonstrate marked nuclear atypia but do not fulfill histologic criteria for malignancy. Along with other tumors of uncertain malignant potential, borderline cases should be considered GTUMPs to guarantee wide excision of the tumor with negative margins and an adequate follow-up due to the possibility of local recurrence or distant metastasis. In our patient, a diagnosis of GTUMP was made. Additionally, our case demonstrates some previously unreported features of GTUMPs, such as spindled cells in short fascicles separated by slitlike spaces, small vessels, and hemorrhagic stroma resembling Kaposi sarcoma. Along with these unusual sarcomatous features, the superficial location of the lesion, absence of necrosis, and a mitotic count of less than 5 per 50 HPFs were suggestive of an uncertain malignant potential for this tumor.

Distinction between malignant GTs and GTUMPs in the presence of unusual histologic features may be difficult.¹² Glomus tumors that do not fulfill criteria for malignancy but have at least 1 atypical feature other than nuclear pleomorphism should be named GTUMPs. According to classification criteria, a true malignant GT is a highly aggressive tumor with metastatic potential. In a case series reported by Folpe et al,² 38% (20/52) of malignant GTs showed metastases, while metastatic disease was not observed in the tumors classified as GTUMPs. Wide surgical excision or Mohs micrographic surgery¹³ are the treatments of choice for malignant GTs and GTUMPs. Complete excision of the lesion with negative margins is always necessary in cases of GTUMPs. After the diagnosis of GTUMP, adequate follow-up should berecommended due to the possibility of local recurrence or distant metastasis.

Conclusion

Malignant GTs and GTUMPs are rare, and the nomenclature and classification of these tumors is controversial. These findings and the difficulty of differential diagnosis in a continuum between benignity and malignancy prompted our report.

To the Editor:
A 78-year-old man presented with erythematous circular skin papules that were widely scattered over the trunk. He denied recent contact with ill individuals and denied any systemic symptoms indicating internal involvement or malignancy leading to possible paraneoplastic presentation. Physical examination showed erythematous, circular, slightly elevated plaques of varying sizes scattered over the trunk (Figure 1) and right axilla.

Figure 1. Nontender, erythematous, brown nodules scattered over the trunk.

Figure 2. Light microscopy revealed Langerhans cells filling the superficial dermis, abutting the epidermis, and extending into the deep dermis with surrounding inflammatory infiltrates (CD1a, original magnification ×100).

Figure 3. Langerhans cells appeared strongly positive for CD1a (original magnification ×400).

Biopsies of lesions were taken and stained with immunoperoxidase. On light microscopy there was a reticular and papillary dermal dense infiltrate of cells with indented nuclei (Figure 2). At higher magnification, cells appeared strongly positive for CD1a (Figure 3) and S-100 protein, which was histologically consistent with adult-type Langerhans cell histiocytosis (ALCH).

Computed tomography of the head, chest, abdomen, and pelvis were ordered to rule out spread of ALCH to other organ sites. Results were clear of evidence of systemic spread. Additionally, a complete blood cell count and comprehensive metabolic panel were within reference range.

He was started on topical tacrolimus; however, most of the lesions resolved on their own. As a result, tacrolimus was discontinued due to its propensity to cause skin irritation and lack of change in disease progression. At 3-month follow-up, he was prescribed triamcinolone acetonide cream 0.1% for minor outbreaks. After 2 years, he was completely clear of all skin signs of ALCH.

Adult-type Langerhans cell histiocytosis is characterized as a group of disorders associated with abnormal spread and proliferation of dendritic cells of the epidermis. The disease primarily affects children aged 1 to 4 years. It is estimated that only 1 to 2 cases of ALCH per million occur.¹ The pathophysiology of ALCH is unknown; it is speculated that it may be associated with a reactive inflammatory process triggered by proliferation of Langerhans-type dendritic cells. It is possible that the release of multiple cytokines by dendritic cells and T cells in ALCH lesions leads to erythematous eruptions and can contribute to spontaneous remission of the disorder.² Various cases of ALCH have reported high serum levels of IL-17 and IL-10 proinflammatory cytokines, supporting the theory of an inflammatory etiology of ALCH.³

Comparative genomic hybridization with loss of heterozygosity of pulmonary lesions has provided further evidence to suggest that chromosomal aberrations also may contribute to the pathophysiology of ALCH.⁴ One study evaluated 14 cases of pulmonary ALCH for loss of heterozygosity and found allelic loss of 1p, 1q, 3p, 5p, 17p, and 22q.⁵ In addition, allelic loss of 1 or more tumor suppressor genes was identified in 19 of 24 specimens, suggesting a neoplastic type of pathology through uncontrolled cellular proliferation.⁶

Lesions of ALCH can be broad but typically present as red-brown maculopapular lesions with petechiae that erupt over the trunk, axilla, and perivulvar or retroauricular regions.⁷ The papules may unify to form an erythematous, weeping, or crusted eruption that appears similar to seborrheic dermatitis. Typically the lesions remit on their own; however, lesions can recur with the same or decreased severity as the primary eruption. Complications have been noted with lesions, particularly secondary infection and ulceration.⁷

Systemic involvement has been noted in adults, particularly in the lungs. Patients typically present with chronic cough, dyspnea, and chest pain with evidence of a solitary nodular lesion on radiologic testing. In addition, bone involvement has been noted as eosinophilic granulomas that can produce osteolytic lesions that lead to spontaneous fractures. Use of corticosteroids and immunosuppressive agents, as opposed to just observation, is warranted in cases of systemic involvement, according to the National Cancer Institute.⁷

Exact treatment modalities have not yet been elucidated due to the ambiguity of pathogenesis. In addition, ALCH is known to remit and relapse in patients, which increases the difficulty in evaluating the efficacy of particular treatments. Trials conducted by the Histiocyte Society have shown that treatment regimens should be tailored to disease severity. Epidermal involvement of ALCH typically responds to corticosteroid creams, whereas patients with systemic involvement respond well to strong chemotherapeutic agents such as vincristine and prednisone with mercaptopurine.⁸ However, as demonstrated in our case, lesions may remit on their own and use of corticosteroids and immunosuppressive agents may lead to further detriment without treating disease progression.

Because of a low prevalence among adults, ALCH is difficult to recognize and diagnose, and the uncertainty of the pathogenesis of ALCH limits treatment alternatives. Further study into proper treatment modalities is warranted given that the remitting and relapsing course of the disease and cosmetic quandaries are detrimental to patient well-being. Our case illustrates that it is appropriate to simply monitor lesions for cases limited to cutaneous involvement. Systemic agents may be used when there are signs of organ involvement outside the skin, but providers must proceed to do so with caution.

To the Editor:
A 78-year-old man presented with erythematous circular skin papules that were widely scattered over the trunk. He denied recent contact with ill individuals and denied any systemic symptoms indicating internal involvement or malignancy leading to possible paraneoplastic presentation. Physical examination showed erythematous, circular, slightly elevated plaques of varying sizes scattered over the trunk (Figure 1) and right axilla.

Figure 1. Nontender, erythematous, brown nodules scattered over the trunk.

Figure 2. Light microscopy revealed Langerhans cells filling the superficial dermis, abutting the epidermis, and extending into the deep dermis with surrounding inflammatory infiltrates (CD1a, original magnification ×100).

Figure 3. Langerhans cells appeared strongly positive for CD1a (original magnification ×400).

Biopsies of lesions were taken and stained with immunoperoxidase. On light microscopy there was a reticular and papillary dermal dense infiltrate of cells with indented nuclei (Figure 2). At higher magnification, cells appeared strongly positive for CD1a (Figure 3) and S-100 protein, which was histologically consistent with adult-type Langerhans cell histiocytosis (ALCH).

Computed tomography of the head, chest, abdomen, and pelvis were ordered to rule out spread of ALCH to other organ sites. Results were clear of evidence of systemic spread. Additionally, a complete blood cell count and comprehensive metabolic panel were within reference range.

He was started on topical tacrolimus; however, most of the lesions resolved on their own. As a result, tacrolimus was discontinued due to its propensity to cause skin irritation and lack of change in disease progression. At 3-month follow-up, he was prescribed triamcinolone acetonide cream 0.1% for minor outbreaks. After 2 years, he was completely clear of all skin signs of ALCH.

Adult-type Langerhans cell histiocytosis is characterized as a group of disorders associated with abnormal spread and proliferation of dendritic cells of the epidermis. The disease primarily affects children aged 1 to 4 years. It is estimated that only 1 to 2 cases of ALCH per million occur.¹ The pathophysiology of ALCH is unknown; it is speculated that it may be associated with a reactive inflammatory process triggered by proliferation of Langerhans-type dendritic cells. It is possible that the release of multiple cytokines by dendritic cells and T cells in ALCH lesions leads to erythematous eruptions and can contribute to spontaneous remission of the disorder.² Various cases of ALCH have reported high serum levels of IL-17 and IL-10 proinflammatory cytokines, supporting the theory of an inflammatory etiology of ALCH.³

Comparative genomic hybridization with loss of heterozygosity of pulmonary lesions has provided further evidence to suggest that chromosomal aberrations also may contribute to the pathophysiology of ALCH.⁴ One study evaluated 14 cases of pulmonary ALCH for loss of heterozygosity and found allelic loss of 1p, 1q, 3p, 5p, 17p, and 22q.⁵ In addition, allelic loss of 1 or more tumor suppressor genes was identified in 19 of 24 specimens, suggesting a neoplastic type of pathology through uncontrolled cellular proliferation.⁶

Lesions of ALCH can be broad but typically present as red-brown maculopapular lesions with petechiae that erupt over the trunk, axilla, and perivulvar or retroauricular regions.⁷ The papules may unify to form an erythematous, weeping, or crusted eruption that appears similar to seborrheic dermatitis. Typically the lesions remit on their own; however, lesions can recur with the same or decreased severity as the primary eruption. Complications have been noted with lesions, particularly secondary infection and ulceration.⁷

Systemic involvement has been noted in adults, particularly in the lungs. Patients typically present with chronic cough, dyspnea, and chest pain with evidence of a solitary nodular lesion on radiologic testing. In addition, bone involvement has been noted as eosinophilic granulomas that can produce osteolytic lesions that lead to spontaneous fractures. Use of corticosteroids and immunosuppressive agents, as opposed to just observation, is warranted in cases of systemic involvement, according to the National Cancer Institute.⁷

Exact treatment modalities have not yet been elucidated due to the ambiguity of pathogenesis. In addition, ALCH is known to remit and relapse in patients, which increases the difficulty in evaluating the efficacy of particular treatments. Trials conducted by the Histiocyte Society have shown that treatment regimens should be tailored to disease severity. Epidermal involvement of ALCH typically responds to corticosteroid creams, whereas patients with systemic involvement respond well to strong chemotherapeutic agents such as vincristine and prednisone with mercaptopurine.⁸ However, as demonstrated in our case, lesions may remit on their own and use of corticosteroids and immunosuppressive agents may lead to further detriment without treating disease progression.

Because of a low prevalence among adults, ALCH is difficult to recognize and diagnose, and the uncertainty of the pathogenesis of ALCH limits treatment alternatives. Further study into proper treatment modalities is warranted given that the remitting and relapsing course of the disease and cosmetic quandaries are detrimental to patient well-being. Our case illustrates that it is appropriate to simply monitor lesions for cases limited to cutaneous involvement. Systemic agents may be used when there are signs of organ involvement outside the skin, but providers must proceed to do so with caution.

To the Editor:
A 78-year-old man presented with erythematous circular skin papules that were widely scattered over the trunk. He denied recent contact with ill individuals and denied any systemic symptoms indicating internal involvement or malignancy leading to possible paraneoplastic presentation. Physical examination showed erythematous, circular, slightly elevated plaques of varying sizes scattered over the trunk (Figure 1) and right axilla.

Figure 1. Nontender, erythematous, brown nodules scattered over the trunk.

Figure 2. Light microscopy revealed Langerhans cells filling the superficial dermis, abutting the epidermis, and extending into the deep dermis with surrounding inflammatory infiltrates (CD1a, original magnification ×100).

Figure 3. Langerhans cells appeared strongly positive for CD1a (original magnification ×400).

Biopsies of lesions were taken and stained with immunoperoxidase. On light microscopy there was a reticular and papillary dermal dense infiltrate of cells with indented nuclei (Figure 2). At higher magnification, cells appeared strongly positive for CD1a (Figure 3) and S-100 protein, which was histologically consistent with adult-type Langerhans cell histiocytosis (ALCH).

Computed tomography of the head, chest, abdomen, and pelvis were ordered to rule out spread of ALCH to other organ sites. Results were clear of evidence of systemic spread. Additionally, a complete blood cell count and comprehensive metabolic panel were within reference range.

He was started on topical tacrolimus; however, most of the lesions resolved on their own. As a result, tacrolimus was discontinued due to its propensity to cause skin irritation and lack of change in disease progression. At 3-month follow-up, he was prescribed triamcinolone acetonide cream 0.1% for minor outbreaks. After 2 years, he was completely clear of all skin signs of ALCH.

Adult-type Langerhans cell histiocytosis is characterized as a group of disorders associated with abnormal spread and proliferation of dendritic cells of the epidermis. The disease primarily affects children aged 1 to 4 years. It is estimated that only 1 to 2 cases of ALCH per million occur.¹ The pathophysiology of ALCH is unknown; it is speculated that it may be associated with a reactive inflammatory process triggered by proliferation of Langerhans-type dendritic cells. It is possible that the release of multiple cytokines by dendritic cells and T cells in ALCH lesions leads to erythematous eruptions and can contribute to spontaneous remission of the disorder.² Various cases of ALCH have reported high serum levels of IL-17 and IL-10 proinflammatory cytokines, supporting the theory of an inflammatory etiology of ALCH.³

Comparative genomic hybridization with loss of heterozygosity of pulmonary lesions has provided further evidence to suggest that chromosomal aberrations also may contribute to the pathophysiology of ALCH.⁴ One study evaluated 14 cases of pulmonary ALCH for loss of heterozygosity and found allelic loss of 1p, 1q, 3p, 5p, 17p, and 22q.⁵ In addition, allelic loss of 1 or more tumor suppressor genes was identified in 19 of 24 specimens, suggesting a neoplastic type of pathology through uncontrolled cellular proliferation.⁶

Lesions of ALCH can be broad but typically present as red-brown maculopapular lesions with petechiae that erupt over the trunk, axilla, and perivulvar or retroauricular regions.⁷ The papules may unify to form an erythematous, weeping, or crusted eruption that appears similar to seborrheic dermatitis. Typically the lesions remit on their own; however, lesions can recur with the same or decreased severity as the primary eruption. Complications have been noted with lesions, particularly secondary infection and ulceration.⁷

Systemic involvement has been noted in adults, particularly in the lungs. Patients typically present with chronic cough, dyspnea, and chest pain with evidence of a solitary nodular lesion on radiologic testing. In addition, bone involvement has been noted as eosinophilic granulomas that can produce osteolytic lesions that lead to spontaneous fractures. Use of corticosteroids and immunosuppressive agents, as opposed to just observation, is warranted in cases of systemic involvement, according to the National Cancer Institute.⁷

Exact treatment modalities have not yet been elucidated due to the ambiguity of pathogenesis. In addition, ALCH is known to remit and relapse in patients, which increases the difficulty in evaluating the efficacy of particular treatments. Trials conducted by the Histiocyte Society have shown that treatment regimens should be tailored to disease severity. Epidermal involvement of ALCH typically responds to corticosteroid creams, whereas patients with systemic involvement respond well to strong chemotherapeutic agents such as vincristine and prednisone with mercaptopurine.⁸ However, as demonstrated in our case, lesions may remit on their own and use of corticosteroids and immunosuppressive agents may lead to further detriment without treating disease progression.

Because of a low prevalence among adults, ALCH is difficult to recognize and diagnose, and the uncertainty of the pathogenesis of ALCH limits treatment alternatives. Further study into proper treatment modalities is warranted given that the remitting and relapsing course of the disease and cosmetic quandaries are detrimental to patient well-being. Our case illustrates that it is appropriate to simply monitor lesions for cases limited to cutaneous involvement. Systemic agents may be used when there are signs of organ involvement outside the skin, but providers must proceed to do so with caution.