Dermatopathology

Case Report

A 56-year-old woman with well-controlled hypertension, hyperlipidemia, and gastroesophageal reflux disease initially presented with itching and a rash in the perianal region of 1 year’s duration. She had been treated intermittently by her primary care physician over the past year for presumed hemorrhoids and a perianal fungal infection without improvement. Physical examination at the time of intitial presentation revealed a single, well-demarcated, scaly, pink plaque on the perianal area on the right buttock extending toward the anal canal (Figure 1). Histologic sections of a punch biopsy of the lesion showed a proliferation of cells with atypical nuclei and clear cytoplasm located throughout the epidermis (Figure 2A). Immunohistochemistry was positive for cytokeratin 7 (Figure 2B) and cytokeratin 20 (Figure 2C) and negative for melanoma antigen and human melanoma black 45. Following a negative workup for internal malignancy, which included basic laboratory testing (including serum carcinoembryonic antigen and cancer antigen 125 levels), computed tomography of the abdomen and pelvis, positron-emission tomography, Papanicolaou test, mammography, and colonoscopy, a diagnosis of primary extramammary Paget disease (EMPD) was made. The patient underwent wide local excision (Figure 3A) of the lesion with Mohs micrographic surgery tissue processing of marginal tissue (Figure 3B) with clear margins and reconstruction of the perianal region.

Four years later, the patient returned with new symptoms of bleeding when wiping the perianal region, pruritus, and fecal urgency of 3 to 4 months’ duration. Physical examination revealed scaly patches on the anus that were suspicious for recurrence of EMPD. Biopsies from the anal margin and anal canal confirmed recurrent EMPD involving the anal canal. Repeat evaluation for internal malignancy was negative.

Given the involvement of the anal canal, repeat wide local excision would have required anal resection and would therefore have been functionally impairing. The patient refused further surgical intervention as well as radiotherapy. Rather, a novel 16-week immunomodulatory regimen involving imiquimod cream 5% cream and low-dose oral cimetidine was started. To address the anal involvement, the patient was instructed to lubricate glycerin suppositories with the imiquimod cream and insert intra-anally once weekly. Dosing was adjusted based on the patient’s inflammatory response and tolerability, as she did initially report some flulike symptoms with the first few weeks of treatment. For most of the 16-week course, she applied 250 mg of imiquimod cream 5% to the perianal area 3 times weekly and 250 mg into the anal canal once weekly. Oral cimetidine initially was dosed at 800 mg twice daily as tolerated, but due to stomach irritation, the patient self-reduced her intake to 800 mg 3 times weekly.

To determine treatment response, scouting biopsies of the anal margin and anal canal were obtained 4 weeks after treatment cessation and demonstrated no evidence of residual disease. The patient resumed topical imiquimod applied once weekly into the anal canal and around the anus for a planned prolonged course of at least 1 year. To reduce the risk of recurrence, the patient continued taking oral cimetidine 800 mg 3 times weekly. Recommended follow-up included annual anoscopy or colonoscopy, serum carcinoembryonic antigen evaluation, and regular clinical monitoring by the dermatology and colorectal surgery teams.

Six months after completing the combination therapy, she was seen by the dermatology department and remained clinically free of disease (Figure 4). Anoscopy examination by the colorectal surgery department 4 months later showed no clinical evidence of malignancy.

Comment

Extramammary Paget disease is a rare intraepithelial adenocarcinoma with a predilection for white females and an average age of onset of 50 to 80 years.^1-3 The vulva, perianal region, scrotum, penis, and perineum are the most commonly affected sites.^1-3 Clinically, EMPD presents as a chronic, well-demarcated, scaly, and often expanding plaque. The incidence of EMPD is unknown, as there are only a few hundred cases reported in the literature.²

Extramammary Paget disease can occur primarily, arising in the epidermis at the sweat-gland level or from primitive epidermal basal cells, or secondarily due to pagetoid spread of malignant cells from an adjacent or contiguous underlying adnexal adenocarcinoma or visceral malignancy.² While primary EMPD is not associated with an underlying adenocarcinoma, it may become invasive, infiltrate the dermis, or metastasize via the lymphatics.² Secondary EMPD is associated with underlying malignancy most often originating in the gastrointestinal or genitourinary tracts.^1,2

Currently, treatment of primary EMPD typically is surgical with wide local excision or Mohs micrographic surgery.^1,2 However, margins often are positive, and the local recurrence rate is high (ie, 33%–66%).^2,3 There are a variety of other therapies that have been reported in the literature, including radiation, topical chemotherapeutics (eg, imiquimod, 5-fluorouracil, bleomycin), photodynamic therapy, and CO₂ laser ablation.^1,3 To our knowledge, there are no randomized controlled trials that compare surgery with other treatment options for EMPD.

Despite recurrence of EMPD with involvement of the anal canal, our patient refused further surgical intervention, as it would have required anal resection and radiotherapy due to the potentially negative impact on sphincter function. While investigating minimally invasive treatment options, we found several citations in the literature highlighting positive response with imiquimod cream 5% in patients with vulvar and periscrotal EMPD.^4,5 A large, systematic review that analyzed 63 cases of vulvar EMPD—nearly half of which were recurrences of a prior malignancy—reported a response rate of 52% to 80% following treatment with imiquimod.⁵ Almost 70% of patients achieved complete clearance while applying imiquimod 3 to 4 times weekly for a median of 4 months; however, little has been written about the effectiveness of topical imiquimod in EMPD. Knight et al⁶ reported the case of a 40-year-old woman with perianal EMPD who was treated with imiquimod 3 times weekly for 16 weeks. At the end of treatment, the patient was completely clear of disease both clinically and histologically on random biopsies of the perianal skin; however, the EMPD later recurred with lymph node metastasis 18 months after stopping treatment.⁶

Given the growing evidence demonstrating disease control of EMPD with topical imiquimod, we elected to utilize this agent in combination with oral cimetidine in our patient. Cimetidine, an H₂ receptor antagonist, has been shown to have antineoplastic properties in a broad range of preclinical and clinical studies for a number of different malignancies.⁷ Four distinct mechanisms of action have been shown. Cimetidine, which blocks the histamine pathway, has been shown to have a direct antiproliferative action on cancer cells.⁷ Histamine has been associated with increased regulatory T-cell activity, decreased antigen-presenting activity of dendritic cells, reduced natural killer cell activity, and increased myeloid-derived suppressor cell activity, which create an immunosuppressive tumor microenvironment in the setting of cancer. By blocking histamine and thus reversing this immunosuppressive environment, cimetidine demonstrates immunomodulatory effects.⁷ Cimetidine also has demonstrated an inhibitory effect on cancer cell adhesion to endothelial cells, which is noted to be independent of histamine-blocking activity.⁷ Finally, an antiangiogenic action is attributed to blocking of the upregulation of vascular endothelial growth factor that is normally induced by histamine.⁷

Cimetidine’s antineoplastic properties, specifically in the setting of colorectal cancer,⁸ were particularly compelling given our patient’s EMPD involvement of the anal canal. The most impressive clinical trial data showed a dramatically increased survival rate for colorectal cancer patients treated with oral cimetidine (800 mg once daily) and oral 5-fluorouracil (200 mg once daily) for 1 year following curative resection. The cimetidine-treated group had a 10-year survival rate of 84.6% versus 49.8% for the 5-fluorouracil–only group.⁸

Conclusion

We present this case of recurrent perianal and anal EMPD treated successfully with imiquimod cream 5% and oral cimetidine to highlight a potential alternative treatment regimen for poor surgical candidates with EMPD.

Case Report

A 56-year-old woman with well-controlled hypertension, hyperlipidemia, and gastroesophageal reflux disease initially presented with itching and a rash in the perianal region of 1 year’s duration. She had been treated intermittently by her primary care physician over the past year for presumed hemorrhoids and a perianal fungal infection without improvement. Physical examination at the time of intitial presentation revealed a single, well-demarcated, scaly, pink plaque on the perianal area on the right buttock extending toward the anal canal (Figure 1). Histologic sections of a punch biopsy of the lesion showed a proliferation of cells with atypical nuclei and clear cytoplasm located throughout the epidermis (Figure 2A). Immunohistochemistry was positive for cytokeratin 7 (Figure 2B) and cytokeratin 20 (Figure 2C) and negative for melanoma antigen and human melanoma black 45. Following a negative workup for internal malignancy, which included basic laboratory testing (including serum carcinoembryonic antigen and cancer antigen 125 levels), computed tomography of the abdomen and pelvis, positron-emission tomography, Papanicolaou test, mammography, and colonoscopy, a diagnosis of primary extramammary Paget disease (EMPD) was made. The patient underwent wide local excision (Figure 3A) of the lesion with Mohs micrographic surgery tissue processing of marginal tissue (Figure 3B) with clear margins and reconstruction of the perianal region.

Four years later, the patient returned with new symptoms of bleeding when wiping the perianal region, pruritus, and fecal urgency of 3 to 4 months’ duration. Physical examination revealed scaly patches on the anus that were suspicious for recurrence of EMPD. Biopsies from the anal margin and anal canal confirmed recurrent EMPD involving the anal canal. Repeat evaluation for internal malignancy was negative.

Given the involvement of the anal canal, repeat wide local excision would have required anal resection and would therefore have been functionally impairing. The patient refused further surgical intervention as well as radiotherapy. Rather, a novel 16-week immunomodulatory regimen involving imiquimod cream 5% cream and low-dose oral cimetidine was started. To address the anal involvement, the patient was instructed to lubricate glycerin suppositories with the imiquimod cream and insert intra-anally once weekly. Dosing was adjusted based on the patient’s inflammatory response and tolerability, as she did initially report some flulike symptoms with the first few weeks of treatment. For most of the 16-week course, she applied 250 mg of imiquimod cream 5% to the perianal area 3 times weekly and 250 mg into the anal canal once weekly. Oral cimetidine initially was dosed at 800 mg twice daily as tolerated, but due to stomach irritation, the patient self-reduced her intake to 800 mg 3 times weekly.

To determine treatment response, scouting biopsies of the anal margin and anal canal were obtained 4 weeks after treatment cessation and demonstrated no evidence of residual disease. The patient resumed topical imiquimod applied once weekly into the anal canal and around the anus for a planned prolonged course of at least 1 year. To reduce the risk of recurrence, the patient continued taking oral cimetidine 800 mg 3 times weekly. Recommended follow-up included annual anoscopy or colonoscopy, serum carcinoembryonic antigen evaluation, and regular clinical monitoring by the dermatology and colorectal surgery teams.

Six months after completing the combination therapy, she was seen by the dermatology department and remained clinically free of disease (Figure 4). Anoscopy examination by the colorectal surgery department 4 months later showed no clinical evidence of malignancy.

Comment

Extramammary Paget disease is a rare intraepithelial adenocarcinoma with a predilection for white females and an average age of onset of 50 to 80 years.^1-3 The vulva, perianal region, scrotum, penis, and perineum are the most commonly affected sites.^1-3 Clinically, EMPD presents as a chronic, well-demarcated, scaly, and often expanding plaque. The incidence of EMPD is unknown, as there are only a few hundred cases reported in the literature.²

Extramammary Paget disease can occur primarily, arising in the epidermis at the sweat-gland level or from primitive epidermal basal cells, or secondarily due to pagetoid spread of malignant cells from an adjacent or contiguous underlying adnexal adenocarcinoma or visceral malignancy.² While primary EMPD is not associated with an underlying adenocarcinoma, it may become invasive, infiltrate the dermis, or metastasize via the lymphatics.² Secondary EMPD is associated with underlying malignancy most often originating in the gastrointestinal or genitourinary tracts.^1,2

Currently, treatment of primary EMPD typically is surgical with wide local excision or Mohs micrographic surgery.^1,2 However, margins often are positive, and the local recurrence rate is high (ie, 33%–66%).^2,3 There are a variety of other therapies that have been reported in the literature, including radiation, topical chemotherapeutics (eg, imiquimod, 5-fluorouracil, bleomycin), photodynamic therapy, and CO₂ laser ablation.^1,3 To our knowledge, there are no randomized controlled trials that compare surgery with other treatment options for EMPD.

Despite recurrence of EMPD with involvement of the anal canal, our patient refused further surgical intervention, as it would have required anal resection and radiotherapy due to the potentially negative impact on sphincter function. While investigating minimally invasive treatment options, we found several citations in the literature highlighting positive response with imiquimod cream 5% in patients with vulvar and periscrotal EMPD.^4,5 A large, systematic review that analyzed 63 cases of vulvar EMPD—nearly half of which were recurrences of a prior malignancy—reported a response rate of 52% to 80% following treatment with imiquimod.⁵ Almost 70% of patients achieved complete clearance while applying imiquimod 3 to 4 times weekly for a median of 4 months; however, little has been written about the effectiveness of topical imiquimod in EMPD. Knight et al⁶ reported the case of a 40-year-old woman with perianal EMPD who was treated with imiquimod 3 times weekly for 16 weeks. At the end of treatment, the patient was completely clear of disease both clinically and histologically on random biopsies of the perianal skin; however, the EMPD later recurred with lymph node metastasis 18 months after stopping treatment.⁶

Given the growing evidence demonstrating disease control of EMPD with topical imiquimod, we elected to utilize this agent in combination with oral cimetidine in our patient. Cimetidine, an H₂ receptor antagonist, has been shown to have antineoplastic properties in a broad range of preclinical and clinical studies for a number of different malignancies.⁷ Four distinct mechanisms of action have been shown. Cimetidine, which blocks the histamine pathway, has been shown to have a direct antiproliferative action on cancer cells.⁷ Histamine has been associated with increased regulatory T-cell activity, decreased antigen-presenting activity of dendritic cells, reduced natural killer cell activity, and increased myeloid-derived suppressor cell activity, which create an immunosuppressive tumor microenvironment in the setting of cancer. By blocking histamine and thus reversing this immunosuppressive environment, cimetidine demonstrates immunomodulatory effects.⁷ Cimetidine also has demonstrated an inhibitory effect on cancer cell adhesion to endothelial cells, which is noted to be independent of histamine-blocking activity.⁷ Finally, an antiangiogenic action is attributed to blocking of the upregulation of vascular endothelial growth factor that is normally induced by histamine.⁷

Cimetidine’s antineoplastic properties, specifically in the setting of colorectal cancer,⁸ were particularly compelling given our patient’s EMPD involvement of the anal canal. The most impressive clinical trial data showed a dramatically increased survival rate for colorectal cancer patients treated with oral cimetidine (800 mg once daily) and oral 5-fluorouracil (200 mg once daily) for 1 year following curative resection. The cimetidine-treated group had a 10-year survival rate of 84.6% versus 49.8% for the 5-fluorouracil–only group.⁸

Conclusion

We present this case of recurrent perianal and anal EMPD treated successfully with imiquimod cream 5% and oral cimetidine to highlight a potential alternative treatment regimen for poor surgical candidates with EMPD.

Case Report

A 56-year-old woman with well-controlled hypertension, hyperlipidemia, and gastroesophageal reflux disease initially presented with itching and a rash in the perianal region of 1 year’s duration. She had been treated intermittently by her primary care physician over the past year for presumed hemorrhoids and a perianal fungal infection without improvement. Physical examination at the time of intitial presentation revealed a single, well-demarcated, scaly, pink plaque on the perianal area on the right buttock extending toward the anal canal (Figure 1). Histologic sections of a punch biopsy of the lesion showed a proliferation of cells with atypical nuclei and clear cytoplasm located throughout the epidermis (Figure 2A). Immunohistochemistry was positive for cytokeratin 7 (Figure 2B) and cytokeratin 20 (Figure 2C) and negative for melanoma antigen and human melanoma black 45. Following a negative workup for internal malignancy, which included basic laboratory testing (including serum carcinoembryonic antigen and cancer antigen 125 levels), computed tomography of the abdomen and pelvis, positron-emission tomography, Papanicolaou test, mammography, and colonoscopy, a diagnosis of primary extramammary Paget disease (EMPD) was made. The patient underwent wide local excision (Figure 3A) of the lesion with Mohs micrographic surgery tissue processing of marginal tissue (Figure 3B) with clear margins and reconstruction of the perianal region.

Four years later, the patient returned with new symptoms of bleeding when wiping the perianal region, pruritus, and fecal urgency of 3 to 4 months’ duration. Physical examination revealed scaly patches on the anus that were suspicious for recurrence of EMPD. Biopsies from the anal margin and anal canal confirmed recurrent EMPD involving the anal canal. Repeat evaluation for internal malignancy was negative.

Given the involvement of the anal canal, repeat wide local excision would have required anal resection and would therefore have been functionally impairing. The patient refused further surgical intervention as well as radiotherapy. Rather, a novel 16-week immunomodulatory regimen involving imiquimod cream 5% cream and low-dose oral cimetidine was started. To address the anal involvement, the patient was instructed to lubricate glycerin suppositories with the imiquimod cream and insert intra-anally once weekly. Dosing was adjusted based on the patient’s inflammatory response and tolerability, as she did initially report some flulike symptoms with the first few weeks of treatment. For most of the 16-week course, she applied 250 mg of imiquimod cream 5% to the perianal area 3 times weekly and 250 mg into the anal canal once weekly. Oral cimetidine initially was dosed at 800 mg twice daily as tolerated, but due to stomach irritation, the patient self-reduced her intake to 800 mg 3 times weekly.

To determine treatment response, scouting biopsies of the anal margin and anal canal were obtained 4 weeks after treatment cessation and demonstrated no evidence of residual disease. The patient resumed topical imiquimod applied once weekly into the anal canal and around the anus for a planned prolonged course of at least 1 year. To reduce the risk of recurrence, the patient continued taking oral cimetidine 800 mg 3 times weekly. Recommended follow-up included annual anoscopy or colonoscopy, serum carcinoembryonic antigen evaluation, and regular clinical monitoring by the dermatology and colorectal surgery teams.

Six months after completing the combination therapy, she was seen by the dermatology department and remained clinically free of disease (Figure 4). Anoscopy examination by the colorectal surgery department 4 months later showed no clinical evidence of malignancy.

Comment

Extramammary Paget disease is a rare intraepithelial adenocarcinoma with a predilection for white females and an average age of onset of 50 to 80 years.^1-3 The vulva, perianal region, scrotum, penis, and perineum are the most commonly affected sites.^1-3 Clinically, EMPD presents as a chronic, well-demarcated, scaly, and often expanding plaque. The incidence of EMPD is unknown, as there are only a few hundred cases reported in the literature.²

Extramammary Paget disease can occur primarily, arising in the epidermis at the sweat-gland level or from primitive epidermal basal cells, or secondarily due to pagetoid spread of malignant cells from an adjacent or contiguous underlying adnexal adenocarcinoma or visceral malignancy.² While primary EMPD is not associated with an underlying adenocarcinoma, it may become invasive, infiltrate the dermis, or metastasize via the lymphatics.² Secondary EMPD is associated with underlying malignancy most often originating in the gastrointestinal or genitourinary tracts.^1,2

Currently, treatment of primary EMPD typically is surgical with wide local excision or Mohs micrographic surgery.^1,2 However, margins often are positive, and the local recurrence rate is high (ie, 33%–66%).^2,3 There are a variety of other therapies that have been reported in the literature, including radiation, topical chemotherapeutics (eg, imiquimod, 5-fluorouracil, bleomycin), photodynamic therapy, and CO₂ laser ablation.^1,3 To our knowledge, there are no randomized controlled trials that compare surgery with other treatment options for EMPD.

Despite recurrence of EMPD with involvement of the anal canal, our patient refused further surgical intervention, as it would have required anal resection and radiotherapy due to the potentially negative impact on sphincter function. While investigating minimally invasive treatment options, we found several citations in the literature highlighting positive response with imiquimod cream 5% in patients with vulvar and periscrotal EMPD.^4,5 A large, systematic review that analyzed 63 cases of vulvar EMPD—nearly half of which were recurrences of a prior malignancy—reported a response rate of 52% to 80% following treatment with imiquimod.⁵ Almost 70% of patients achieved complete clearance while applying imiquimod 3 to 4 times weekly for a median of 4 months; however, little has been written about the effectiveness of topical imiquimod in EMPD. Knight et al⁶ reported the case of a 40-year-old woman with perianal EMPD who was treated with imiquimod 3 times weekly for 16 weeks. At the end of treatment, the patient was completely clear of disease both clinically and histologically on random biopsies of the perianal skin; however, the EMPD later recurred with lymph node metastasis 18 months after stopping treatment.⁶

Given the growing evidence demonstrating disease control of EMPD with topical imiquimod, we elected to utilize this agent in combination with oral cimetidine in our patient. Cimetidine, an H₂ receptor antagonist, has been shown to have antineoplastic properties in a broad range of preclinical and clinical studies for a number of different malignancies.⁷ Four distinct mechanisms of action have been shown. Cimetidine, which blocks the histamine pathway, has been shown to have a direct antiproliferative action on cancer cells.⁷ Histamine has been associated with increased regulatory T-cell activity, decreased antigen-presenting activity of dendritic cells, reduced natural killer cell activity, and increased myeloid-derived suppressor cell activity, which create an immunosuppressive tumor microenvironment in the setting of cancer. By blocking histamine and thus reversing this immunosuppressive environment, cimetidine demonstrates immunomodulatory effects.⁷ Cimetidine also has demonstrated an inhibitory effect on cancer cell adhesion to endothelial cells, which is noted to be independent of histamine-blocking activity.⁷ Finally, an antiangiogenic action is attributed to blocking of the upregulation of vascular endothelial growth factor that is normally induced by histamine.⁷

Cimetidine’s antineoplastic properties, specifically in the setting of colorectal cancer,⁸ were particularly compelling given our patient’s EMPD involvement of the anal canal. The most impressive clinical trial data showed a dramatically increased survival rate for colorectal cancer patients treated with oral cimetidine (800 mg once daily) and oral 5-fluorouracil (200 mg once daily) for 1 year following curative resection. The cimetidine-treated group had a 10-year survival rate of 84.6% versus 49.8% for the 5-fluorouracil–only group.⁸

Conclusion

We present this case of recurrent perianal and anal EMPD treated successfully with imiquimod cream 5% and oral cimetidine to highlight a potential alternative treatment regimen for poor surgical candidates with EMPD.

The Diagnosis: Paraneoplastic Pemphigus

A workup for infectious organisms and vasculitis was negative. The patient reported unintentional weight loss despite taking oral steroids prescribed by her pulmonologist for severe obstructive lung disease that appeared to develop around the same time as the mouth ulcers.

Computed tomography of the abdomen revealed an 8.1-cm pelvic mass that a subsequent biopsy revealed to be a follicular dendritic cell sarcoma. Biopsies of the mouth ulcers showed a mildly hyperplastic mucosa with acantholysis and interface change with dyskeratosis. Direct immunofluorescence of the perilesional mucosa showed IgG and complement C3 in an intercellular distribution (Figure 1). The pathologic findings were consistent with a diagnosis of paraneoplastic pemphigus (PNP). Serologic testing via enzyme-linked immunosorbent assay, immunoblotting, and indirect immunofluorescence were not performed. The patient died within a few months after the initial presentation from bronchiolitis obliterans, a potentially fatal complication of PNP.

Paraneoplastic pemphigus is an autoimmune blistering disease associated with neoplasia, particularly lymphoproliferative disorders and thymoma.¹ Oral mucosal erosions and crusting along the lips commonly is seen along with cutaneous involvement. The main histologic features are interface changes with dyskeratosis and a lichenoid infiltrate and variable acantholysis.²

Direct immunofluorescence of perilesional skin classically shows IgG and complement C3 in an intercellular distribution, usually in a granular or linear distribution along the basement membrane. This same pattern of direct immunofluorescence is seen in pemphigus erythematosus; however, pemphigus erythematosus is clinically distinct from PNP, lacking mucosal involvement and affecting the face and/or seborrheic areas with an appearance more similar to seborrheic dermatitis or lupus erythematosus, depending on the patient.³ Indirect immunofluorescence with rat bladder epithelium typically is positive in PNP and can be a helpful feature in distinguishing PNP from other autoimmune blistering diseases (eg, pemphigus erythematosus, pemphigus vulgaris, pemphigus foliaceus).²

Immunoblotting assays via serology often detect numerous antigens in patients with PNP, including but not limited to plectin, desmoplakin, bullous pemphigoid antigens, envoplakin, desmoplakin II, and desmogleins 1 and 3.⁴ Some of these autoantibodies have been identified in tumors associated with paraneoplastic pemphigus, particularly Castleman disease and follicular dendritic cell sarcoma.

Acute graft-versus-host disease (GVHD) can have a similar histologic appearance to PNP with prominent dyskeratosis and characteristically shows satellite cell necrosis consisting of dyskeratosis with surrounding lymphocytes (Figure 2). Unlike PNP, acantholysis is not a feature of GVHD. Direct immunofluorescence typically is negative; however, nonspecific IgM and complement C3 deposition at the dermoepidermal junction and around the superficial vasculature has been reported in 39% of cases.⁵ Early chronic GVHD often shows retained lichenoid interface change, but late chronic GVHD has a sclerodermoid morphology that is easily distinguished histologically from PNP. Patients also have a history of either a bone marrow or solid organ transplant.⁶

Lichen planus also shows interface change with dyskeratosis and a lichenoid infiltrate; however, acantholysis typically is not seen and, there often is prominent hypergranulosis (Figure 3). Mucosal lesions often show more subtle features with decreased hyperkeratosis, more subtle hypergranulosis, and decreased interface change with plasma cells in the inflammatory infiltrate.⁶ Additionally, direct immunofluorescence is either negative or shows IgM-positive colloid bodies and/or an irregular band of fibrinogen at the dermoepidermal junction. The characteristic intercellular and granular/linear IgG positivity at the dermoepidermal junction of PNP is not seen.

Lupus erythematosus is an interface dermatitis with histologic features that can overlap with PNP, in addition to positive direct immunofluorescence, which has been seen in 50% to 94% of cases and can vary depending on previous steroid treatment and timing of the biopsy in the disease process.⁷ Unlike PNP, lupus erythematosus has a full-house pattern on direct immunofluorescence with IgG, IgM, IgA, and complement C3 deposition in a granular pattern at the dermoepidermal junction. While PNP also typically shows granular deposition of IgG and complement C3 at the dermoepidermal junction, there also is intercellular positivity without a full-house pattern. While both conditions show interface change, histologic features that distinguish lupus erythematosus from PNP are a superficial and deep perivascular lymphocytic infiltrate, basement membrane thickening, follicular plugging, and increased dermal mucin (Figure 4). Subacute lupus erythematosus and discoid lupus erythematosus can have similar histologic features, and definitive distinction on biopsy is not always possible; however, subacute lupus erythematosus shows milder follicular plugging and milder to absent basement membrane thickening, and the inflammatory infiltrate typically is sparser than in discoid lupus erythematosus.⁷ Subacute lupus erythematosus also can show anti-Ro/Sjögren syndrome antigen A antibodies, which typically are not seen in discoid lupus eythematosus.⁸

Stevens-Johnson syndrome (SJS) is on a spectrum with toxic epidermal necrolysis, with SJS involving less than 10% and toxic epidermal necrolysis involving 30% or more of the body surface area.⁵ Erythema multiforme also is on the histologic spectrum of SJS and toxic epidermal necrolysis; however, erythema multiforme typically is more inflammatory than SJS and toxic epidermal necrolysis. Stevens-Johnson syndrome typically affects older adults and shows both cutaneous and mucosal involvement; however, isolated mucosal involvement can be seen in children.⁵ Drugs, particularly sulfonamide antibiotics, usually are implicated as causative agents, but infections from Mycoplasma and other pathogens also may be the cause. There is notable clinical (with a combination of mucosal and cutaneous lesions) as well as histologic overlap between SJS and PNP. The density of the lichenoid infiltrate is variable, with dyskeratosis, basal cell hydropic degeneration, and occasional formation of subepidermal clefts (Figure 5). Unlike PNP, acantholysis is not a characteristic feature of SJS, and direct immunofluorescence generally is negative.

The Diagnosis: Paraneoplastic Pemphigus

A workup for infectious organisms and vasculitis was negative. The patient reported unintentional weight loss despite taking oral steroids prescribed by her pulmonologist for severe obstructive lung disease that appeared to develop around the same time as the mouth ulcers.

Computed tomography of the abdomen revealed an 8.1-cm pelvic mass that a subsequent biopsy revealed to be a follicular dendritic cell sarcoma. Biopsies of the mouth ulcers showed a mildly hyperplastic mucosa with acantholysis and interface change with dyskeratosis. Direct immunofluorescence of the perilesional mucosa showed IgG and complement C3 in an intercellular distribution (Figure 1). The pathologic findings were consistent with a diagnosis of paraneoplastic pemphigus (PNP). Serologic testing via enzyme-linked immunosorbent assay, immunoblotting, and indirect immunofluorescence were not performed. The patient died within a few months after the initial presentation from bronchiolitis obliterans, a potentially fatal complication of PNP.

Paraneoplastic pemphigus is an autoimmune blistering disease associated with neoplasia, particularly lymphoproliferative disorders and thymoma.¹ Oral mucosal erosions and crusting along the lips commonly is seen along with cutaneous involvement. The main histologic features are interface changes with dyskeratosis and a lichenoid infiltrate and variable acantholysis.²

Direct immunofluorescence of perilesional skin classically shows IgG and complement C3 in an intercellular distribution, usually in a granular or linear distribution along the basement membrane. This same pattern of direct immunofluorescence is seen in pemphigus erythematosus; however, pemphigus erythematosus is clinically distinct from PNP, lacking mucosal involvement and affecting the face and/or seborrheic areas with an appearance more similar to seborrheic dermatitis or lupus erythematosus, depending on the patient.³ Indirect immunofluorescence with rat bladder epithelium typically is positive in PNP and can be a helpful feature in distinguishing PNP from other autoimmune blistering diseases (eg, pemphigus erythematosus, pemphigus vulgaris, pemphigus foliaceus).²

Immunoblotting assays via serology often detect numerous antigens in patients with PNP, including but not limited to plectin, desmoplakin, bullous pemphigoid antigens, envoplakin, desmoplakin II, and desmogleins 1 and 3.⁴ Some of these autoantibodies have been identified in tumors associated with paraneoplastic pemphigus, particularly Castleman disease and follicular dendritic cell sarcoma.

Acute graft-versus-host disease (GVHD) can have a similar histologic appearance to PNP with prominent dyskeratosis and characteristically shows satellite cell necrosis consisting of dyskeratosis with surrounding lymphocytes (Figure 2). Unlike PNP, acantholysis is not a feature of GVHD. Direct immunofluorescence typically is negative; however, nonspecific IgM and complement C3 deposition at the dermoepidermal junction and around the superficial vasculature has been reported in 39% of cases.⁵ Early chronic GVHD often shows retained lichenoid interface change, but late chronic GVHD has a sclerodermoid morphology that is easily distinguished histologically from PNP. Patients also have a history of either a bone marrow or solid organ transplant.⁶

Lichen planus also shows interface change with dyskeratosis and a lichenoid infiltrate; however, acantholysis typically is not seen and, there often is prominent hypergranulosis (Figure 3). Mucosal lesions often show more subtle features with decreased hyperkeratosis, more subtle hypergranulosis, and decreased interface change with plasma cells in the inflammatory infiltrate.⁶ Additionally, direct immunofluorescence is either negative or shows IgM-positive colloid bodies and/or an irregular band of fibrinogen at the dermoepidermal junction. The characteristic intercellular and granular/linear IgG positivity at the dermoepidermal junction of PNP is not seen.

Lupus erythematosus is an interface dermatitis with histologic features that can overlap with PNP, in addition to positive direct immunofluorescence, which has been seen in 50% to 94% of cases and can vary depending on previous steroid treatment and timing of the biopsy in the disease process.⁷ Unlike PNP, lupus erythematosus has a full-house pattern on direct immunofluorescence with IgG, IgM, IgA, and complement C3 deposition in a granular pattern at the dermoepidermal junction. While PNP also typically shows granular deposition of IgG and complement C3 at the dermoepidermal junction, there also is intercellular positivity without a full-house pattern. While both conditions show interface change, histologic features that distinguish lupus erythematosus from PNP are a superficial and deep perivascular lymphocytic infiltrate, basement membrane thickening, follicular plugging, and increased dermal mucin (Figure 4). Subacute lupus erythematosus and discoid lupus erythematosus can have similar histologic features, and definitive distinction on biopsy is not always possible; however, subacute lupus erythematosus shows milder follicular plugging and milder to absent basement membrane thickening, and the inflammatory infiltrate typically is sparser than in discoid lupus erythematosus.⁷ Subacute lupus erythematosus also can show anti-Ro/Sjögren syndrome antigen A antibodies, which typically are not seen in discoid lupus eythematosus.⁸

Stevens-Johnson syndrome (SJS) is on a spectrum with toxic epidermal necrolysis, with SJS involving less than 10% and toxic epidermal necrolysis involving 30% or more of the body surface area.⁵ Erythema multiforme also is on the histologic spectrum of SJS and toxic epidermal necrolysis; however, erythema multiforme typically is more inflammatory than SJS and toxic epidermal necrolysis. Stevens-Johnson syndrome typically affects older adults and shows both cutaneous and mucosal involvement; however, isolated mucosal involvement can be seen in children.⁵ Drugs, particularly sulfonamide antibiotics, usually are implicated as causative agents, but infections from Mycoplasma and other pathogens also may be the cause. There is notable clinical (with a combination of mucosal and cutaneous lesions) as well as histologic overlap between SJS and PNP. The density of the lichenoid infiltrate is variable, with dyskeratosis, basal cell hydropic degeneration, and occasional formation of subepidermal clefts (Figure 5). Unlike PNP, acantholysis is not a characteristic feature of SJS, and direct immunofluorescence generally is negative.

The Diagnosis: Paraneoplastic Pemphigus

A workup for infectious organisms and vasculitis was negative. The patient reported unintentional weight loss despite taking oral steroids prescribed by her pulmonologist for severe obstructive lung disease that appeared to develop around the same time as the mouth ulcers.

Computed tomography of the abdomen revealed an 8.1-cm pelvic mass that a subsequent biopsy revealed to be a follicular dendritic cell sarcoma. Biopsies of the mouth ulcers showed a mildly hyperplastic mucosa with acantholysis and interface change with dyskeratosis. Direct immunofluorescence of the perilesional mucosa showed IgG and complement C3 in an intercellular distribution (Figure 1). The pathologic findings were consistent with a diagnosis of paraneoplastic pemphigus (PNP). Serologic testing via enzyme-linked immunosorbent assay, immunoblotting, and indirect immunofluorescence were not performed. The patient died within a few months after the initial presentation from bronchiolitis obliterans, a potentially fatal complication of PNP.

Paraneoplastic pemphigus is an autoimmune blistering disease associated with neoplasia, particularly lymphoproliferative disorders and thymoma.¹ Oral mucosal erosions and crusting along the lips commonly is seen along with cutaneous involvement. The main histologic features are interface changes with dyskeratosis and a lichenoid infiltrate and variable acantholysis.²

Direct immunofluorescence of perilesional skin classically shows IgG and complement C3 in an intercellular distribution, usually in a granular or linear distribution along the basement membrane. This same pattern of direct immunofluorescence is seen in pemphigus erythematosus; however, pemphigus erythematosus is clinically distinct from PNP, lacking mucosal involvement and affecting the face and/or seborrheic areas with an appearance more similar to seborrheic dermatitis or lupus erythematosus, depending on the patient.³ Indirect immunofluorescence with rat bladder epithelium typically is positive in PNP and can be a helpful feature in distinguishing PNP from other autoimmune blistering diseases (eg, pemphigus erythematosus, pemphigus vulgaris, pemphigus foliaceus).²

Immunoblotting assays via serology often detect numerous antigens in patients with PNP, including but not limited to plectin, desmoplakin, bullous pemphigoid antigens, envoplakin, desmoplakin II, and desmogleins 1 and 3.⁴ Some of these autoantibodies have been identified in tumors associated with paraneoplastic pemphigus, particularly Castleman disease and follicular dendritic cell sarcoma.

Acute graft-versus-host disease (GVHD) can have a similar histologic appearance to PNP with prominent dyskeratosis and characteristically shows satellite cell necrosis consisting of dyskeratosis with surrounding lymphocytes (Figure 2). Unlike PNP, acantholysis is not a feature of GVHD. Direct immunofluorescence typically is negative; however, nonspecific IgM and complement C3 deposition at the dermoepidermal junction and around the superficial vasculature has been reported in 39% of cases.⁵ Early chronic GVHD often shows retained lichenoid interface change, but late chronic GVHD has a sclerodermoid morphology that is easily distinguished histologically from PNP. Patients also have a history of either a bone marrow or solid organ transplant.⁶

Lichen planus also shows interface change with dyskeratosis and a lichenoid infiltrate; however, acantholysis typically is not seen and, there often is prominent hypergranulosis (Figure 3). Mucosal lesions often show more subtle features with decreased hyperkeratosis, more subtle hypergranulosis, and decreased interface change with plasma cells in the inflammatory infiltrate.⁶ Additionally, direct immunofluorescence is either negative or shows IgM-positive colloid bodies and/or an irregular band of fibrinogen at the dermoepidermal junction. The characteristic intercellular and granular/linear IgG positivity at the dermoepidermal junction of PNP is not seen.

Lupus erythematosus is an interface dermatitis with histologic features that can overlap with PNP, in addition to positive direct immunofluorescence, which has been seen in 50% to 94% of cases and can vary depending on previous steroid treatment and timing of the biopsy in the disease process.⁷ Unlike PNP, lupus erythematosus has a full-house pattern on direct immunofluorescence with IgG, IgM, IgA, and complement C3 deposition in a granular pattern at the dermoepidermal junction. While PNP also typically shows granular deposition of IgG and complement C3 at the dermoepidermal junction, there also is intercellular positivity without a full-house pattern. While both conditions show interface change, histologic features that distinguish lupus erythematosus from PNP are a superficial and deep perivascular lymphocytic infiltrate, basement membrane thickening, follicular plugging, and increased dermal mucin (Figure 4). Subacute lupus erythematosus and discoid lupus erythematosus can have similar histologic features, and definitive distinction on biopsy is not always possible; however, subacute lupus erythematosus shows milder follicular plugging and milder to absent basement membrane thickening, and the inflammatory infiltrate typically is sparser than in discoid lupus erythematosus.⁷ Subacute lupus erythematosus also can show anti-Ro/Sjögren syndrome antigen A antibodies, which typically are not seen in discoid lupus eythematosus.⁸

Stevens-Johnson syndrome (SJS) is on a spectrum with toxic epidermal necrolysis, with SJS involving less than 10% and toxic epidermal necrolysis involving 30% or more of the body surface area.⁵ Erythema multiforme also is on the histologic spectrum of SJS and toxic epidermal necrolysis; however, erythema multiforme typically is more inflammatory than SJS and toxic epidermal necrolysis. Stevens-Johnson syndrome typically affects older adults and shows both cutaneous and mucosal involvement; however, isolated mucosal involvement can be seen in children.⁵ Drugs, particularly sulfonamide antibiotics, usually are implicated as causative agents, but infections from Mycoplasma and other pathogens also may be the cause. There is notable clinical (with a combination of mucosal and cutaneous lesions) as well as histologic overlap between SJS and PNP. The density of the lichenoid infiltrate is variable, with dyskeratosis, basal cell hydropic degeneration, and occasional formation of subepidermal clefts (Figure 5). Unlike PNP, acantholysis is not a characteristic feature of SJS, and direct immunofluorescence generally is negative.

Intralymphatic histiocytosis was first described in 1994.¹ To date, at least 70 cases have been reported in the English-language literature, the majority being associated with systemic or local inflammatory conditions such as rheumatoid arthritis (RA), malignancy, and metal prostheses. The remaining cases arose independent of any detectable disease process.² The clinical lesion localizes to areas around surgical scars or inflamed joints and generally presents with erythematous livedoid papules and plaques. Because of its rarity, pathologists and clinicians may be unfamiliar with this entity, leading to delayed or missed diagnoses.

Although the pathogenesis of intralymphatic histiocytosis remains unclear, it may be related to dysregulated immune signaling. The condition follows a chronic, relapsing-remitting course that has shown variable response to topical and systemic treatments. We present a rare case of intralymphatic histiocytosis associated with joint replacement/metal prosthesis^3-14 that was responsive to a novel treatment with intralesional steroid injection and pressure bandage.

Case Report

An 89-year-old woman presented with a relapsing and remitting rash on the right calf and popliteal fossa of 11 months’ duration. It was becoming more painful over time and recently began to hurt when walking. Her medical history was remarkable for deep vein thromboses of the bilateral legs, Factor V Leiden deficiency, osteoarthritis, and a popliteal (Baker) cyst on the right leg that ruptured 22 months prior to presentation. Her surgical history included bilateral knee replacements (10 years and 2 years prior to the current presentation for the right and left knees, respectively). Her international normalized ratio (2.0) was therapeutic on warfarin.

Initially, swelling, pain, and redness developed in the right calf, and recurrent right-leg deep venous thrombosis was ruled out by Doppler ultrasound. The findings were considered to be secondary to inflammation from a popliteal cyst. Symptoms persisted despite application of warm compresses, leg elevation, and compression stockings. Treatment with doxycycline prescribed by the patient’s primary care physician 9 months prior for presumed cellulitis produced little improvement. Physical examination revealed a well-healed vertical scar on the right calf from an incisional biopsy within an 8-cm, tender, erythematous, indurated, sclerotic plaque with erythematous streaks radiating from the center of the plaque (Figure 1). There also was red-brown, indurated discoloration on the right shin.

Fine-needle aspiration of the lesion revealed red blood cells and histiocytes. Laboratory studies showed an elevated erythrocyte sedimentation rate of 74 mm/h (reference range, 0–30 mm/h) and a C-reactive protein level of 39 mg/L (reference range, 0–10 mg/L). An incisional biopsy including the muscular fascia showed dense dermal fibrosis with chronic inflammation and scarring. A dermatopathologist (G. A. S.) reviewed the case and confirmed variable fibrosis and chronic inflammation associated with edema in the dermis and epidermal acanthosis. Inspection of vessels in the mid to upper dermis in one area revealed stellate, thin-walled, vascular structures that contained bland epithelioid cells lining the lumen as well as packed within the vessels. The epithelioid cells did not show atypia or mitotic figures, and they did not show intracytoplasmic vacuoles (Figure 2). Immunocytochemical staining for D2-40 was strongly positive in cells lining the vessels, consistent with lymphatics (Figure 3). CD68 immunohistochemistry for histiocytes stained the cells within the lymphatics (Figure 4). A diagnosis of intralymphatic histiocytosis was made.

Intralesional triamcinolone acetonide 10 mg/cc×1.6 cc was injected into the plaque once monthly for 2 consecutive months, and daily compression with a pressure bandage of the right lower leg was initiated. Four months after the first treatment with this regimen, the plaque was smaller and no longer sclerotic or painful, and the erythema was markedly reduced (Figure 5). Clinical and symptomatic improvement continued at 1-year follow-up.

Comment

Intralymphatic histiocytosis is a rare cutaneous disorder defined histologically by histiocytes within the lumina of lymphatics. In addition to the current case, our review of PubMed articles indexed for MEDLINE using the search term intralymphatic histiocytosis yielded more than 70 total cases. The condition has a slight female predominance and typically is seen in individuals over the age of 60 years (age range, 16–89 years).¹² Many cases are associated with RA/elevated rheumatoid factor.^2,4,8,15-30 At least 9 cases of intralymphatic histiocytosis were associated with premalignant or malignant conditions (ie, adenocarcinoma of the breasts, lungs, and colon; Merkel cell carcinoma; melanoma; melanoma in situ; Mullerian carcinoma, gammopathy).^4,15,31-34 Primary disease, defined as occurring in patients who are otherwise healthy, was noted in at least 10 cases.^{1,2,4,12,35,36} Finally, intralymphatic histiocytosis was identified in areas adjacent to metal implants and joint replacements or exploration in approximately 15 cases (including the current case).^3-14,29,37

The condition presents with papules, plaques, and nodules in the setting of characteristic livedoid discoloration; however, some patients present with nonspecific nodules or plaques. Lesions may be symptomatic (eg, pruritic, tender) or asymptomatic. The histologic features of intralymphatic histiocytosis are distinctive but may be focal, as in our case, and the diagnosis is easily missed. The histologic differential diagnosis includes diseases in which intravascular accumulations of cells may be seen, including intravascular B-cell lymphoma, which can be excluded with stains that detect B cells (CD20/CD79a), and reactive angioendotheliomatosis, a benign proliferation of endothelial cells, which may be excluded with stains against endothelial markers (CD31/CD34). The course typically is chronic, and treatment with topical steroids,^3,9,15,22,26 cyclophosphamide,¹⁵ local radiation,¹ thalidomide,³⁵ pentoxifylline,⁷ and RA medications (eg, prednisolone, methotrexate, nonsteroidal anti-inflammatory drugs, hydroxychloroquine) generally are ineffective.^2,16,20,25 Symptoms may improve with joint replacement,⁴ excision of the involved lesion, treatment of an associated malignancy/infection,^33,36,38,39 nonsteroidal anti-inflammatory drugs, intra-articular steroid injection,¹⁸ amoxicillin and aspirin,¹⁹ infliximab,²⁵ pressure bandage application,²⁶ steroid-containing adhesive application,¹⁸ arthrocentesis,^3,27 oral pentoxifylline,²¹ tacrolimus,²⁹ CO₂ laser,⁴⁰ prednisolone,⁴¹ and tocilizumab.²⁸ Treatment of associated RA is beneficial in rare cases.^{2,15,20,25,26}

The pathogenesis of intralymphatic histiocytosis has not been elucidated with certainty but may represent an abnormal proliferative response of histiocytes and vessels in response to chronic systemic or local inflammation. Lymphangiectasis caused by lymphatic obstruction secondary to trauma, surgical manipulation, or chronic inflammation can promote lymphostasis and slowed clearance of antigens producing an accumulation of histiocytes and subsequent local immunologic reactions, thus an “immunocompromised district” is formed.⁴² It also is thought that rheumatic or prosthetic joints produce inflammatory mediator–rich (namely tumor necrosis factor α) synovial fluid that drains and collects within the dilated lymphatics, creating a nidus for histiocytes.^1,5 In one case, treatment with an anti–tumor necrosis factor antibody (infliximab) improved the skin presentation and rheumatoid joint pain.²⁵ Bakr et al² noted an association with increased intralymphatic macrophage HLA-DR expression. This T-cell surface receptor typically is upregulated in cases of chronic antigen stimulation and autoimmune conditions.

Conclusion

Our patient had a history of a joint prosthesis and a popliteal cyst, which could have altered lymphatic drainage promoting abnormal immune cell trafficking contributing to the development of intralymphatic histiocytosis. The response to intralesional steroids supports this pathogenic hypothesis. Specifically, direct injection of the area suppressed the immune dysregulation, while compression lessened the degree of lymphostasis. In light of previously reported cases of intralymphatic histiocytosis in association with metal implants,^3-9 we suggest that the condition should be considered in patients with chronic painful livedoid nodules or plaques around an affected joint, even in the absence of RA. The dermatopathologist should be warned to search carefully for the subtle but distinctive histologic features of the disease that confirm the diagnosis. Treatment with intralesional triamcinolone acetonide with an overlying pressure wrap has minimal side effects and can work quickly with sustained benefits.

Intralymphatic histiocytosis was first described in 1994.¹ To date, at least 70 cases have been reported in the English-language literature, the majority being associated with systemic or local inflammatory conditions such as rheumatoid arthritis (RA), malignancy, and metal prostheses. The remaining cases arose independent of any detectable disease process.² The clinical lesion localizes to areas around surgical scars or inflamed joints and generally presents with erythematous livedoid papules and plaques. Because of its rarity, pathologists and clinicians may be unfamiliar with this entity, leading to delayed or missed diagnoses.

Although the pathogenesis of intralymphatic histiocytosis remains unclear, it may be related to dysregulated immune signaling. The condition follows a chronic, relapsing-remitting course that has shown variable response to topical and systemic treatments. We present a rare case of intralymphatic histiocytosis associated with joint replacement/metal prosthesis^3-14 that was responsive to a novel treatment with intralesional steroid injection and pressure bandage.

Case Report

An 89-year-old woman presented with a relapsing and remitting rash on the right calf and popliteal fossa of 11 months’ duration. It was becoming more painful over time and recently began to hurt when walking. Her medical history was remarkable for deep vein thromboses of the bilateral legs, Factor V Leiden deficiency, osteoarthritis, and a popliteal (Baker) cyst on the right leg that ruptured 22 months prior to presentation. Her surgical history included bilateral knee replacements (10 years and 2 years prior to the current presentation for the right and left knees, respectively). Her international normalized ratio (2.0) was therapeutic on warfarin.

Initially, swelling, pain, and redness developed in the right calf, and recurrent right-leg deep venous thrombosis was ruled out by Doppler ultrasound. The findings were considered to be secondary to inflammation from a popliteal cyst. Symptoms persisted despite application of warm compresses, leg elevation, and compression stockings. Treatment with doxycycline prescribed by the patient’s primary care physician 9 months prior for presumed cellulitis produced little improvement. Physical examination revealed a well-healed vertical scar on the right calf from an incisional biopsy within an 8-cm, tender, erythematous, indurated, sclerotic plaque with erythematous streaks radiating from the center of the plaque (Figure 1). There also was red-brown, indurated discoloration on the right shin.

Fine-needle aspiration of the lesion revealed red blood cells and histiocytes. Laboratory studies showed an elevated erythrocyte sedimentation rate of 74 mm/h (reference range, 0–30 mm/h) and a C-reactive protein level of 39 mg/L (reference range, 0–10 mg/L). An incisional biopsy including the muscular fascia showed dense dermal fibrosis with chronic inflammation and scarring. A dermatopathologist (G. A. S.) reviewed the case and confirmed variable fibrosis and chronic inflammation associated with edema in the dermis and epidermal acanthosis. Inspection of vessels in the mid to upper dermis in one area revealed stellate, thin-walled, vascular structures that contained bland epithelioid cells lining the lumen as well as packed within the vessels. The epithelioid cells did not show atypia or mitotic figures, and they did not show intracytoplasmic vacuoles (Figure 2). Immunocytochemical staining for D2-40 was strongly positive in cells lining the vessels, consistent with lymphatics (Figure 3). CD68 immunohistochemistry for histiocytes stained the cells within the lymphatics (Figure 4). A diagnosis of intralymphatic histiocytosis was made.

Intralesional triamcinolone acetonide 10 mg/cc×1.6 cc was injected into the plaque once monthly for 2 consecutive months, and daily compression with a pressure bandage of the right lower leg was initiated. Four months after the first treatment with this regimen, the plaque was smaller and no longer sclerotic or painful, and the erythema was markedly reduced (Figure 5). Clinical and symptomatic improvement continued at 1-year follow-up.

Comment

Intralymphatic histiocytosis is a rare cutaneous disorder defined histologically by histiocytes within the lumina of lymphatics. In addition to the current case, our review of PubMed articles indexed for MEDLINE using the search term intralymphatic histiocytosis yielded more than 70 total cases. The condition has a slight female predominance and typically is seen in individuals over the age of 60 years (age range, 16–89 years).¹² Many cases are associated with RA/elevated rheumatoid factor.^2,4,8,15-30 At least 9 cases of intralymphatic histiocytosis were associated with premalignant or malignant conditions (ie, adenocarcinoma of the breasts, lungs, and colon; Merkel cell carcinoma; melanoma; melanoma in situ; Mullerian carcinoma, gammopathy).^4,15,31-34 Primary disease, defined as occurring in patients who are otherwise healthy, was noted in at least 10 cases.^{1,2,4,12,35,36} Finally, intralymphatic histiocytosis was identified in areas adjacent to metal implants and joint replacements or exploration in approximately 15 cases (including the current case).^3-14,29,37

The condition presents with papules, plaques, and nodules in the setting of characteristic livedoid discoloration; however, some patients present with nonspecific nodules or plaques. Lesions may be symptomatic (eg, pruritic, tender) or asymptomatic. The histologic features of intralymphatic histiocytosis are distinctive but may be focal, as in our case, and the diagnosis is easily missed. The histologic differential diagnosis includes diseases in which intravascular accumulations of cells may be seen, including intravascular B-cell lymphoma, which can be excluded with stains that detect B cells (CD20/CD79a), and reactive angioendotheliomatosis, a benign proliferation of endothelial cells, which may be excluded with stains against endothelial markers (CD31/CD34). The course typically is chronic, and treatment with topical steroids,^3,9,15,22,26 cyclophosphamide,¹⁵ local radiation,¹ thalidomide,³⁵ pentoxifylline,⁷ and RA medications (eg, prednisolone, methotrexate, nonsteroidal anti-inflammatory drugs, hydroxychloroquine) generally are ineffective.^2,16,20,25 Symptoms may improve with joint replacement,⁴ excision of the involved lesion, treatment of an associated malignancy/infection,^33,36,38,39 nonsteroidal anti-inflammatory drugs, intra-articular steroid injection,¹⁸ amoxicillin and aspirin,¹⁹ infliximab,²⁵ pressure bandage application,²⁶ steroid-containing adhesive application,¹⁸ arthrocentesis,^3,27 oral pentoxifylline,²¹ tacrolimus,²⁹ CO₂ laser,⁴⁰ prednisolone,⁴¹ and tocilizumab.²⁸ Treatment of associated RA is beneficial in rare cases.^{2,15,20,25,26}

The pathogenesis of intralymphatic histiocytosis has not been elucidated with certainty but may represent an abnormal proliferative response of histiocytes and vessels in response to chronic systemic or local inflammation. Lymphangiectasis caused by lymphatic obstruction secondary to trauma, surgical manipulation, or chronic inflammation can promote lymphostasis and slowed clearance of antigens producing an accumulation of histiocytes and subsequent local immunologic reactions, thus an “immunocompromised district” is formed.⁴² It also is thought that rheumatic or prosthetic joints produce inflammatory mediator–rich (namely tumor necrosis factor α) synovial fluid that drains and collects within the dilated lymphatics, creating a nidus for histiocytes.^1,5 In one case, treatment with an anti–tumor necrosis factor antibody (infliximab) improved the skin presentation and rheumatoid joint pain.²⁵ Bakr et al² noted an association with increased intralymphatic macrophage HLA-DR expression. This T-cell surface receptor typically is upregulated in cases of chronic antigen stimulation and autoimmune conditions.

Conclusion

Our patient had a history of a joint prosthesis and a popliteal cyst, which could have altered lymphatic drainage promoting abnormal immune cell trafficking contributing to the development of intralymphatic histiocytosis. The response to intralesional steroids supports this pathogenic hypothesis. Specifically, direct injection of the area suppressed the immune dysregulation, while compression lessened the degree of lymphostasis. In light of previously reported cases of intralymphatic histiocytosis in association with metal implants,^3-9 we suggest that the condition should be considered in patients with chronic painful livedoid nodules or plaques around an affected joint, even in the absence of RA. The dermatopathologist should be warned to search carefully for the subtle but distinctive histologic features of the disease that confirm the diagnosis. Treatment with intralesional triamcinolone acetonide with an overlying pressure wrap has minimal side effects and can work quickly with sustained benefits.

Intralymphatic histiocytosis was first described in 1994.¹ To date, at least 70 cases have been reported in the English-language literature, the majority being associated with systemic or local inflammatory conditions such as rheumatoid arthritis (RA), malignancy, and metal prostheses. The remaining cases arose independent of any detectable disease process.² The clinical lesion localizes to areas around surgical scars or inflamed joints and generally presents with erythematous livedoid papules and plaques. Because of its rarity, pathologists and clinicians may be unfamiliar with this entity, leading to delayed or missed diagnoses.

Although the pathogenesis of intralymphatic histiocytosis remains unclear, it may be related to dysregulated immune signaling. The condition follows a chronic, relapsing-remitting course that has shown variable response to topical and systemic treatments. We present a rare case of intralymphatic histiocytosis associated with joint replacement/metal prosthesis^3-14 that was responsive to a novel treatment with intralesional steroid injection and pressure bandage.

Case Report

An 89-year-old woman presented with a relapsing and remitting rash on the right calf and popliteal fossa of 11 months’ duration. It was becoming more painful over time and recently began to hurt when walking. Her medical history was remarkable for deep vein thromboses of the bilateral legs, Factor V Leiden deficiency, osteoarthritis, and a popliteal (Baker) cyst on the right leg that ruptured 22 months prior to presentation. Her surgical history included bilateral knee replacements (10 years and 2 years prior to the current presentation for the right and left knees, respectively). Her international normalized ratio (2.0) was therapeutic on warfarin.

Initially, swelling, pain, and redness developed in the right calf, and recurrent right-leg deep venous thrombosis was ruled out by Doppler ultrasound. The findings were considered to be secondary to inflammation from a popliteal cyst. Symptoms persisted despite application of warm compresses, leg elevation, and compression stockings. Treatment with doxycycline prescribed by the patient’s primary care physician 9 months prior for presumed cellulitis produced little improvement. Physical examination revealed a well-healed vertical scar on the right calf from an incisional biopsy within an 8-cm, tender, erythematous, indurated, sclerotic plaque with erythematous streaks radiating from the center of the plaque (Figure 1). There also was red-brown, indurated discoloration on the right shin.

Fine-needle aspiration of the lesion revealed red blood cells and histiocytes. Laboratory studies showed an elevated erythrocyte sedimentation rate of 74 mm/h (reference range, 0–30 mm/h) and a C-reactive protein level of 39 mg/L (reference range, 0–10 mg/L). An incisional biopsy including the muscular fascia showed dense dermal fibrosis with chronic inflammation and scarring. A dermatopathologist (G. A. S.) reviewed the case and confirmed variable fibrosis and chronic inflammation associated with edema in the dermis and epidermal acanthosis. Inspection of vessels in the mid to upper dermis in one area revealed stellate, thin-walled, vascular structures that contained bland epithelioid cells lining the lumen as well as packed within the vessels. The epithelioid cells did not show atypia or mitotic figures, and they did not show intracytoplasmic vacuoles (Figure 2). Immunocytochemical staining for D2-40 was strongly positive in cells lining the vessels, consistent with lymphatics (Figure 3). CD68 immunohistochemistry for histiocytes stained the cells within the lymphatics (Figure 4). A diagnosis of intralymphatic histiocytosis was made.

Intralesional triamcinolone acetonide 10 mg/cc×1.6 cc was injected into the plaque once monthly for 2 consecutive months, and daily compression with a pressure bandage of the right lower leg was initiated. Four months after the first treatment with this regimen, the plaque was smaller and no longer sclerotic or painful, and the erythema was markedly reduced (Figure 5). Clinical and symptomatic improvement continued at 1-year follow-up.

Comment

Intralymphatic histiocytosis is a rare cutaneous disorder defined histologically by histiocytes within the lumina of lymphatics. In addition to the current case, our review of PubMed articles indexed for MEDLINE using the search term intralymphatic histiocytosis yielded more than 70 total cases. The condition has a slight female predominance and typically is seen in individuals over the age of 60 years (age range, 16–89 years).¹² Many cases are associated with RA/elevated rheumatoid factor.^2,4,8,15-30 At least 9 cases of intralymphatic histiocytosis were associated with premalignant or malignant conditions (ie, adenocarcinoma of the breasts, lungs, and colon; Merkel cell carcinoma; melanoma; melanoma in situ; Mullerian carcinoma, gammopathy).^4,15,31-34 Primary disease, defined as occurring in patients who are otherwise healthy, was noted in at least 10 cases.^{1,2,4,12,35,36} Finally, intralymphatic histiocytosis was identified in areas adjacent to metal implants and joint replacements or exploration in approximately 15 cases (including the current case).^3-14,29,37

The condition presents with papules, plaques, and nodules in the setting of characteristic livedoid discoloration; however, some patients present with nonspecific nodules or plaques. Lesions may be symptomatic (eg, pruritic, tender) or asymptomatic. The histologic features of intralymphatic histiocytosis are distinctive but may be focal, as in our case, and the diagnosis is easily missed. The histologic differential diagnosis includes diseases in which intravascular accumulations of cells may be seen, including intravascular B-cell lymphoma, which can be excluded with stains that detect B cells (CD20/CD79a), and reactive angioendotheliomatosis, a benign proliferation of endothelial cells, which may be excluded with stains against endothelial markers (CD31/CD34). The course typically is chronic, and treatment with topical steroids,^3,9,15,22,26 cyclophosphamide,¹⁵ local radiation,¹ thalidomide,³⁵ pentoxifylline,⁷ and RA medications (eg, prednisolone, methotrexate, nonsteroidal anti-inflammatory drugs, hydroxychloroquine) generally are ineffective.^2,16,20,25 Symptoms may improve with joint replacement,⁴ excision of the involved lesion, treatment of an associated malignancy/infection,^33,36,38,39 nonsteroidal anti-inflammatory drugs, intra-articular steroid injection,¹⁸ amoxicillin and aspirin,¹⁹ infliximab,²⁵ pressure bandage application,²⁶ steroid-containing adhesive application,¹⁸ arthrocentesis,^3,27 oral pentoxifylline,²¹ tacrolimus,²⁹ CO₂ laser,⁴⁰ prednisolone,⁴¹ and tocilizumab.²⁸ Treatment of associated RA is beneficial in rare cases.^{2,15,20,25,26}

The pathogenesis of intralymphatic histiocytosis has not been elucidated with certainty but may represent an abnormal proliferative response of histiocytes and vessels in response to chronic systemic or local inflammation. Lymphangiectasis caused by lymphatic obstruction secondary to trauma, surgical manipulation, or chronic inflammation can promote lymphostasis and slowed clearance of antigens producing an accumulation of histiocytes and subsequent local immunologic reactions, thus an “immunocompromised district” is formed.⁴² It also is thought that rheumatic or prosthetic joints produce inflammatory mediator–rich (namely tumor necrosis factor α) synovial fluid that drains and collects within the dilated lymphatics, creating a nidus for histiocytes.^1,5 In one case, treatment with an anti–tumor necrosis factor antibody (infliximab) improved the skin presentation and rheumatoid joint pain.²⁵ Bakr et al² noted an association with increased intralymphatic macrophage HLA-DR expression. This T-cell surface receptor typically is upregulated in cases of chronic antigen stimulation and autoimmune conditions.

Conclusion

Our patient had a history of a joint prosthesis and a popliteal cyst, which could have altered lymphatic drainage promoting abnormal immune cell trafficking contributing to the development of intralymphatic histiocytosis. The response to intralesional steroids supports this pathogenic hypothesis. Specifically, direct injection of the area suppressed the immune dysregulation, while compression lessened the degree of lymphostasis. In light of previously reported cases of intralymphatic histiocytosis in association with metal implants,^3-9 we suggest that the condition should be considered in patients with chronic painful livedoid nodules or plaques around an affected joint, even in the absence of RA. The dermatopathologist should be warned to search carefully for the subtle but distinctive histologic features of the disease that confirm the diagnosis. Treatment with intralesional triamcinolone acetonide with an overlying pressure wrap has minimal side effects and can work quickly with sustained benefits.

The Diagnosis: Polypoid Dermatofibroma

Histologic examination revealed a poorly demarcated lesion localized in the dermis that was composed of an admixture of fibroblastlike cells, histiocytes, siderophages, multinucleated giant cells, and hemorrhage (Figure). Based on these findings, a diagnosis of polypoid dermatofibroma (DF) was made. No further treatment was necessary because the lesion was completely excised.

Dermatofibromas, also known as benign fibrous histiocytomas, are common, benign, mesenchymal, fibrosing tumors of the skin that appear predominantly on the legs in in women, but any part of the body in either sex can be affected. Clinically, DFs show the dimple sign when laterally squeezed and can be painful spontaneously or when rubbed. Histologically, DFs are poorly demarcated lesions composed of a variable admixture of fibroblastlike cells, histiocytes (some of which may be xanthomatous or multinucleated), and blood vessels. The etiology still remains unclear. Most investigators consider DF to be a reactive process, but some think that it is a benign mesenchymal tumor.^1,2

Many subtypes of DF have been described based on their unique architectural, cellular, stromal, and clinical features.^2,3 Polypoid DF is a rare variant that comprises only 3% of reported cases4 and tends to be larger than other DF subtypes. Requena et al⁵ reported 12 cases of giant DF, another clinical subtype, that were larger than 5 cm in diameter, most of which had a polypoid appearance.

Moreover, 3 distinct variants of DF with unique histologic features tend to show polypoid morphology.^3,4 In epithelioid fibrous histiocytoma, also known as epithelioid cell histiocytoma, at least 50% of the lesion is composed of rounded or polygonal epithelioid cells with abundant eosinophilic cytoplasm and round to oval nuclei containing small eosinophilic nucleoli.⁴ A grenz zone generally is lacking and numerous small blood vessels are a constant feature of epithelioid fibrous histiocytoma. The other variant of DF that also tends to have a polypoid appearance is lipidized fibrous histiocytoma, or ankle-type fibrous histiocytoma, which usually arises below the knee, especially around the ankle, and often becomes larger than common DF.⁴ Lastly, atypical polypoid DF is a benign, polyp-shaped lesion that shows hypercellularity with striking nuclear atypism and scattered mitotic figures in addition to the ordinary histologic features of DF.³

Acquired fibrokeratomas manifest as solitary dome-shaped, flesh-colored protrusions usually located on the feet and hands. Sclerotic fibroma is a rare cutaneous neoplasm that presents as a solitary, translucent or waxy nodule or as multiple nodules when it is part of Cowden disease. Fibromas, also known as skin tags, are common cutaneous tumors that appear in intertriginous areas and frequently adopt a pedunculated morphology. Although clinically some of these lesions may resemble polypoid DF, the differential diagnosis is made by histologic examination.

Dermatofibroma is a common cutaneous tumor that follows a benign course. It can adopt multiple morphologies. Awareness of this rare variant may aid in its appropriate diagnosis and management. Dermatofibromas are benign neoplasms, and therefore they usually do not require treatment. If they become symptomatic or are bothersome to the patient, the treatment of choice is surgical removal.
 

The Diagnosis: Polypoid Dermatofibroma

Histologic examination revealed a poorly demarcated lesion localized in the dermis that was composed of an admixture of fibroblastlike cells, histiocytes, siderophages, multinucleated giant cells, and hemorrhage (Figure). Based on these findings, a diagnosis of polypoid dermatofibroma (DF) was made. No further treatment was necessary because the lesion was completely excised.

Dermatofibromas, also known as benign fibrous histiocytomas, are common, benign, mesenchymal, fibrosing tumors of the skin that appear predominantly on the legs in in women, but any part of the body in either sex can be affected. Clinically, DFs show the dimple sign when laterally squeezed and can be painful spontaneously or when rubbed. Histologically, DFs are poorly demarcated lesions composed of a variable admixture of fibroblastlike cells, histiocytes (some of which may be xanthomatous or multinucleated), and blood vessels. The etiology still remains unclear. Most investigators consider DF to be a reactive process, but some think that it is a benign mesenchymal tumor.^1,2

Many subtypes of DF have been described based on their unique architectural, cellular, stromal, and clinical features.^2,3 Polypoid DF is a rare variant that comprises only 3% of reported cases4 and tends to be larger than other DF subtypes. Requena et al⁵ reported 12 cases of giant DF, another clinical subtype, that were larger than 5 cm in diameter, most of which had a polypoid appearance.

Moreover, 3 distinct variants of DF with unique histologic features tend to show polypoid morphology.^3,4 In epithelioid fibrous histiocytoma, also known as epithelioid cell histiocytoma, at least 50% of the lesion is composed of rounded or polygonal epithelioid cells with abundant eosinophilic cytoplasm and round to oval nuclei containing small eosinophilic nucleoli.⁴ A grenz zone generally is lacking and numerous small blood vessels are a constant feature of epithelioid fibrous histiocytoma. The other variant of DF that also tends to have a polypoid appearance is lipidized fibrous histiocytoma, or ankle-type fibrous histiocytoma, which usually arises below the knee, especially around the ankle, and often becomes larger than common DF.⁴ Lastly, atypical polypoid DF is a benign, polyp-shaped lesion that shows hypercellularity with striking nuclear atypism and scattered mitotic figures in addition to the ordinary histologic features of DF.³

Acquired fibrokeratomas manifest as solitary dome-shaped, flesh-colored protrusions usually located on the feet and hands. Sclerotic fibroma is a rare cutaneous neoplasm that presents as a solitary, translucent or waxy nodule or as multiple nodules when it is part of Cowden disease. Fibromas, also known as skin tags, are common cutaneous tumors that appear in intertriginous areas and frequently adopt a pedunculated morphology. Although clinically some of these lesions may resemble polypoid DF, the differential diagnosis is made by histologic examination.

Dermatofibroma is a common cutaneous tumor that follows a benign course. It can adopt multiple morphologies. Awareness of this rare variant may aid in its appropriate diagnosis and management. Dermatofibromas are benign neoplasms, and therefore they usually do not require treatment. If they become symptomatic or are bothersome to the patient, the treatment of choice is surgical removal.
 

The Diagnosis: Polypoid Dermatofibroma

Histologic examination revealed a poorly demarcated lesion localized in the dermis that was composed of an admixture of fibroblastlike cells, histiocytes, siderophages, multinucleated giant cells, and hemorrhage (Figure). Based on these findings, a diagnosis of polypoid dermatofibroma (DF) was made. No further treatment was necessary because the lesion was completely excised.

Dermatofibromas, also known as benign fibrous histiocytomas, are common, benign, mesenchymal, fibrosing tumors of the skin that appear predominantly on the legs in in women, but any part of the body in either sex can be affected. Clinically, DFs show the dimple sign when laterally squeezed and can be painful spontaneously or when rubbed. Histologically, DFs are poorly demarcated lesions composed of a variable admixture of fibroblastlike cells, histiocytes (some of which may be xanthomatous or multinucleated), and blood vessels. The etiology still remains unclear. Most investigators consider DF to be a reactive process, but some think that it is a benign mesenchymal tumor.^1,2

Many subtypes of DF have been described based on their unique architectural, cellular, stromal, and clinical features.^2,3 Polypoid DF is a rare variant that comprises only 3% of reported cases4 and tends to be larger than other DF subtypes. Requena et al⁵ reported 12 cases of giant DF, another clinical subtype, that were larger than 5 cm in diameter, most of which had a polypoid appearance.

Moreover, 3 distinct variants of DF with unique histologic features tend to show polypoid morphology.^3,4 In epithelioid fibrous histiocytoma, also known as epithelioid cell histiocytoma, at least 50% of the lesion is composed of rounded or polygonal epithelioid cells with abundant eosinophilic cytoplasm and round to oval nuclei containing small eosinophilic nucleoli.⁴ A grenz zone generally is lacking and numerous small blood vessels are a constant feature of epithelioid fibrous histiocytoma. The other variant of DF that also tends to have a polypoid appearance is lipidized fibrous histiocytoma, or ankle-type fibrous histiocytoma, which usually arises below the knee, especially around the ankle, and often becomes larger than common DF.⁴ Lastly, atypical polypoid DF is a benign, polyp-shaped lesion that shows hypercellularity with striking nuclear atypism and scattered mitotic figures in addition to the ordinary histologic features of DF.³

Acquired fibrokeratomas manifest as solitary dome-shaped, flesh-colored protrusions usually located on the feet and hands. Sclerotic fibroma is a rare cutaneous neoplasm that presents as a solitary, translucent or waxy nodule or as multiple nodules when it is part of Cowden disease. Fibromas, also known as skin tags, are common cutaneous tumors that appear in intertriginous areas and frequently adopt a pedunculated morphology. Although clinically some of these lesions may resemble polypoid DF, the differential diagnosis is made by histologic examination.

Dermatofibroma is a common cutaneous tumor that follows a benign course. It can adopt multiple morphologies. Awareness of this rare variant may aid in its appropriate diagnosis and management. Dermatofibromas are benign neoplasms, and therefore they usually do not require treatment. If they become symptomatic or are bothersome to the patient, the treatment of choice is surgical removal.
 

A study using an ex vivo model to evaluate a seborrheic keratosis (SK) treatment shows that a topical application of 40% hydrogen peroxide is gentler on skin than a 5- or 10-second treatment with liquid nitrogen, particularly with respect to melanocytes, suggesting that the former may be less likely to produce disfiguring damage.

The 40% hydrogen peroxide solution (Eskata), also known as A-101, received Food and Drug Administration approval for the treatment of “seborrheic keratoses that are raised” in December, 2017. The study was published online in the Journal of the American Academy of Dermatology.

Melanocyte damage can lead to significant dyschromia, a poor cosmetic outcome that can have a tremendous impact on quality of life for dark-skinned patients, in whom it produces white spots. “A lot of these destructive approaches, especially liquid nitrogen, can leave more disfigurement upon treatment than the lesion itself,” the study’s lead author Adam Friedman, MD, said in an interview.

Melanocytes are particularly vulnerable to the effects of cold, so the destructive potential of liquid nitrogen is no surprise. But Dr. Friedman of the department of dermatology, George Washington University, Washington, wanted to get a better understanding of the impact of the new treatment on different skin cell types and the toxicity profile, so he approached the manufacturer, Aclaris Therapeutics, to do a study.

His team tested 40% hydrogen peroxide treatment and liquid nitrogen cryosurgery on a validated ex vivo human reconstituted full-thickness model derived from Fitzpatrick V skin, with 5 or 10 seconds of cryosurgery or 1 or 2 mcL of 40% hydrogen peroxide.

Using standard a hematoxylin and eosin stain as well as immunohistochemical staining to examine the architecture and cells types of the skin model following both treatments, the researchers found that 5- and 10-second cryosurgery resulted in significant thinning of the epidermis and increased cell death. There was also separation at the dermal-epidermal junction, which was more prominent in the 10-second cryosurgery group, although present even with a 5-second freeze cycle.

The hydrogen peroxide–treated groups showed acanthosis of the epidermis and mild pallor, but this was less noticeable than in the cryosurgery specimens. There was no epidermal clefting in the hydrogen peroxide–treated samples.

Tunel staining revealed 16.4 (plus or minus 0.6424) apoptotic cells per high-powered field in the 5-second cryosurgery experiment and 20.6 (plus or minus 0.6424) in the 10-second procedure. For the hydrogen peroxide treatment, those numbers were 8.65 (plus or minus 0.4122) in the 1 mcL experiment and 12.4 (plus or minus 0.3728) in the 2 mcL experiment.

As expected, melanocytes fared better with the hydrogen peroxide treatment. In the untreated samples, there were 2.5 melanocytes (plus or minus 0.1987) in the untreated sample and 2.0 (plus or minus 0.5000) melanocytes in the vehicle-treated sample. In the 5-second cryosurgery sample, there were 0.45 melanocytes (plus or minus 0.1535), and in the 10 second cryosurgery sample there were 0.2 (plus or minus 0.0918) melanocytes. In contrast, with the 1-mcL hydrogen peroxide-treated sample, there were 1.95 melanocytes in both the 1-mcL and 2-mcL samples (plus or minus 0.1535 for both groups).

“From a cytotoxicity perspective, [40% hydrogen peroxide] was much less toxic to the epidermis than the liquid nitrogen,” Dr. Friedman said. These results, he added, “offer us a lot of insight in terms of how damaging liquid nitrogen is, and it’s good to be reminded of that so that we don’t cause too much harm.”

The authors noted that a clinical trial evaluating the risk of hypopigmentation and hyperpigmentation with 40% hydrogen peroxide in people with darker skin types is underway. In the study, hydrogen peroxide is used to treat dermatosis papulosa nigra.

The study was funded by Aclaris Therapeutics. Senior author Adam Friedman, MD, is a consultant for Aclaris. Dr. Friedman is on the editorial board of Dermatology News.

SOURCE: Kao S et al. J Am Acad Dermatol. 2018 Mar 27. doi: 10.1016/j.jaad.2018.03.034.

A study using an ex vivo model to evaluate a seborrheic keratosis (SK) treatment shows that a topical application of 40% hydrogen peroxide is gentler on skin than a 5- or 10-second treatment with liquid nitrogen, particularly with respect to melanocytes, suggesting that the former may be less likely to produce disfiguring damage.

The 40% hydrogen peroxide solution (Eskata), also known as A-101, received Food and Drug Administration approval for the treatment of “seborrheic keratoses that are raised” in December, 2017. The study was published online in the Journal of the American Academy of Dermatology.

Melanocyte damage can lead to significant dyschromia, a poor cosmetic outcome that can have a tremendous impact on quality of life for dark-skinned patients, in whom it produces white spots. “A lot of these destructive approaches, especially liquid nitrogen, can leave more disfigurement upon treatment than the lesion itself,” the study’s lead author Adam Friedman, MD, said in an interview.

Melanocytes are particularly vulnerable to the effects of cold, so the destructive potential of liquid nitrogen is no surprise. But Dr. Friedman of the department of dermatology, George Washington University, Washington, wanted to get a better understanding of the impact of the new treatment on different skin cell types and the toxicity profile, so he approached the manufacturer, Aclaris Therapeutics, to do a study.

His team tested 40% hydrogen peroxide treatment and liquid nitrogen cryosurgery on a validated ex vivo human reconstituted full-thickness model derived from Fitzpatrick V skin, with 5 or 10 seconds of cryosurgery or 1 or 2 mcL of 40% hydrogen peroxide.

Using standard a hematoxylin and eosin stain as well as immunohistochemical staining to examine the architecture and cells types of the skin model following both treatments, the researchers found that 5- and 10-second cryosurgery resulted in significant thinning of the epidermis and increased cell death. There was also separation at the dermal-epidermal junction, which was more prominent in the 10-second cryosurgery group, although present even with a 5-second freeze cycle.

The hydrogen peroxide–treated groups showed acanthosis of the epidermis and mild pallor, but this was less noticeable than in the cryosurgery specimens. There was no epidermal clefting in the hydrogen peroxide–treated samples.

Tunel staining revealed 16.4 (plus or minus 0.6424) apoptotic cells per high-powered field in the 5-second cryosurgery experiment and 20.6 (plus or minus 0.6424) in the 10-second procedure. For the hydrogen peroxide treatment, those numbers were 8.65 (plus or minus 0.4122) in the 1 mcL experiment and 12.4 (plus or minus 0.3728) in the 2 mcL experiment.

As expected, melanocytes fared better with the hydrogen peroxide treatment. In the untreated samples, there were 2.5 melanocytes (plus or minus 0.1987) in the untreated sample and 2.0 (plus or minus 0.5000) melanocytes in the vehicle-treated sample. In the 5-second cryosurgery sample, there were 0.45 melanocytes (plus or minus 0.1535), and in the 10 second cryosurgery sample there were 0.2 (plus or minus 0.0918) melanocytes. In contrast, with the 1-mcL hydrogen peroxide-treated sample, there were 1.95 melanocytes in both the 1-mcL and 2-mcL samples (plus or minus 0.1535 for both groups).

“From a cytotoxicity perspective, [40% hydrogen peroxide] was much less toxic to the epidermis than the liquid nitrogen,” Dr. Friedman said. These results, he added, “offer us a lot of insight in terms of how damaging liquid nitrogen is, and it’s good to be reminded of that so that we don’t cause too much harm.”

The authors noted that a clinical trial evaluating the risk of hypopigmentation and hyperpigmentation with 40% hydrogen peroxide in people with darker skin types is underway. In the study, hydrogen peroxide is used to treat dermatosis papulosa nigra.

The study was funded by Aclaris Therapeutics. Senior author Adam Friedman, MD, is a consultant for Aclaris. Dr. Friedman is on the editorial board of Dermatology News.

SOURCE: Kao S et al. J Am Acad Dermatol. 2018 Mar 27. doi: 10.1016/j.jaad.2018.03.034.

A study using an ex vivo model to evaluate a seborrheic keratosis (SK) treatment shows that a topical application of 40% hydrogen peroxide is gentler on skin than a 5- or 10-second treatment with liquid nitrogen, particularly with respect to melanocytes, suggesting that the former may be less likely to produce disfiguring damage.

The 40% hydrogen peroxide solution (Eskata), also known as A-101, received Food and Drug Administration approval for the treatment of “seborrheic keratoses that are raised” in December, 2017. The study was published online in the Journal of the American Academy of Dermatology.

Melanocyte damage can lead to significant dyschromia, a poor cosmetic outcome that can have a tremendous impact on quality of life for dark-skinned patients, in whom it produces white spots. “A lot of these destructive approaches, especially liquid nitrogen, can leave more disfigurement upon treatment than the lesion itself,” the study’s lead author Adam Friedman, MD, said in an interview.

Melanocytes are particularly vulnerable to the effects of cold, so the destructive potential of liquid nitrogen is no surprise. But Dr. Friedman of the department of dermatology, George Washington University, Washington, wanted to get a better understanding of the impact of the new treatment on different skin cell types and the toxicity profile, so he approached the manufacturer, Aclaris Therapeutics, to do a study.

His team tested 40% hydrogen peroxide treatment and liquid nitrogen cryosurgery on a validated ex vivo human reconstituted full-thickness model derived from Fitzpatrick V skin, with 5 or 10 seconds of cryosurgery or 1 or 2 mcL of 40% hydrogen peroxide.

Using standard a hematoxylin and eosin stain as well as immunohistochemical staining to examine the architecture and cells types of the skin model following both treatments, the researchers found that 5- and 10-second cryosurgery resulted in significant thinning of the epidermis and increased cell death. There was also separation at the dermal-epidermal junction, which was more prominent in the 10-second cryosurgery group, although present even with a 5-second freeze cycle.

The hydrogen peroxide–treated groups showed acanthosis of the epidermis and mild pallor, but this was less noticeable than in the cryosurgery specimens. There was no epidermal clefting in the hydrogen peroxide–treated samples.

Tunel staining revealed 16.4 (plus or minus 0.6424) apoptotic cells per high-powered field in the 5-second cryosurgery experiment and 20.6 (plus or minus 0.6424) in the 10-second procedure. For the hydrogen peroxide treatment, those numbers were 8.65 (plus or minus 0.4122) in the 1 mcL experiment and 12.4 (plus or minus 0.3728) in the 2 mcL experiment.

As expected, melanocytes fared better with the hydrogen peroxide treatment. In the untreated samples, there were 2.5 melanocytes (plus or minus 0.1987) in the untreated sample and 2.0 (plus or minus 0.5000) melanocytes in the vehicle-treated sample. In the 5-second cryosurgery sample, there were 0.45 melanocytes (plus or minus 0.1535), and in the 10 second cryosurgery sample there were 0.2 (plus or minus 0.0918) melanocytes. In contrast, with the 1-mcL hydrogen peroxide-treated sample, there were 1.95 melanocytes in both the 1-mcL and 2-mcL samples (plus or minus 0.1535 for both groups).

“From a cytotoxicity perspective, [40% hydrogen peroxide] was much less toxic to the epidermis than the liquid nitrogen,” Dr. Friedman said. These results, he added, “offer us a lot of insight in terms of how damaging liquid nitrogen is, and it’s good to be reminded of that so that we don’t cause too much harm.”

The authors noted that a clinical trial evaluating the risk of hypopigmentation and hyperpigmentation with 40% hydrogen peroxide in people with darker skin types is underway. In the study, hydrogen peroxide is used to treat dermatosis papulosa nigra.

The study was funded by Aclaris Therapeutics. Senior author Adam Friedman, MD, is a consultant for Aclaris. Dr. Friedman is on the editorial board of Dermatology News.

SOURCE: Kao S et al. J Am Acad Dermatol. 2018 Mar 27. doi: 10.1016/j.jaad.2018.03.034.

KAUAI, HAWAII – Melanoma staging in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual implements better stratification of stage III melanoma patients, resulting in an evidence-based improved prognosis for many of them, Laura Korb Ferris, MD, PhD, said at the Hawaii Dermatology Seminar provided by Skin Disease Education Foundation/Global Academy for Medical Education.

Dr. Ferris, of the department of dermatology, University of Pittsburgh, highlighted some of the key changes in the eighth edition of the AJCC staging manual, which is now in effect. She also described the clinical implications of important updates introduced in the 2018 National Comprehensive Cancer Network (NCCN) guidelines for the diagnosis and management of melanoma.

The AJCC eighth edition

The eighth edition is built upon an AJCC database of more than 46,000 patients with stage I-III melanoma diagnosed since 1998 at 10 academic medical centers. The AJCC panel made no changes in stage IV melanoma guidance because the newer targeted therapies have rapidly changed treatment outcomes in that setting and longer follow-up is needed to assess the full impact.

Courtesy RegionalDerm.com

The current edition of the AJCC melanoma staging manual creates a new subcategory within pathologic stage III. In the melanoma staging world, that’s exciting news, especially because this change has important implications for prognosis.

This fourth subcategory, stage IIID, is for melanomas, which in the Tumor, Nodes, Metastasis (TNM) classification scheme, are primary tumor stage T4b, meaning greater than 4.0 mm in thickness and with ulceration; regional lymph node N3a, b, or c, based upon the number of metastatic nodes involved and whether they were clinically occult nodal metastases detected by sentinel lymph node biopsy (SLNB) or clinically detected; and M0, meaning no distant metastatic disease. In the 8th edition, the AJCC staging system can be applied in patients with T2 through T4 primary melanoma only if they have undergone SLNB.

Courtesy RegionalDerm.com

Among the other key points to remember about the eighth edition of AJCC:

• Tumor thickness is now measured to the nearest 0.1 mm rather than to the nearest 0.01 mm, as previously. Thus, a 0.75-mm-thick melanoma is now rounded up to 0.8 mm, while a 0.74-mm melanoma becomes a 0.7-mm tumor.
• Based upon recent evidence, tumors that are 0.8-1.0 mm thick, with or without ulceration, are now classified at T1b. So are ulcerated lesions that are less than 0.8 mm.
• Dermal mitotic rate is no longer used in staging T1 tumors, although it’s still supposed to be included in pathology reports.
• The T category definitions of primary tumors have been clarified in the eighth edition. A tumor is now classified as T0 only if there is no evidence of a primary tumor. Tx is employed when the primary tumor thickness can’t be determined, as for example when the biopsy specimen was obtained by curettage. Tis is utilized for melanoma in situ.
• The N subcategory definitions of regional nodal status have been revised. Microsatellites, clinical satellites, and in-transit metastases are now categorized as N1c, N2c, or N3c based upon the number of tumor-involved regional lymph nodes. These features are no longer defined by their size or distance from the primary tumor.

2018 NCCN melanoma guidelines

The guidelines have been revised to recommend against SLNB if a patient’s pretest probability of finding a positive SLN is less than 5%. This includes patients who have a clinical stage IA/T1a melanoma with a Breslow thickness of less than 0.8 mm without ulceration.

Courtesy RegionalDerm.com

Bruce Jancin/MDedge News

What about completion lymphadenectomy in the SLN-positive melanoma patient?

Completion lymph node dissection looks increasingly like a procedure in search of an indication. Results of the National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial–II (MSLT-II) demonstrated not even a hint of a difference in 3-year melanoma-specific survival in 1,934 melanoma patients with sentinel lymph node metastases regardless of whether they were randomized to immediate completion lymph node dissection or ultrasound-based nodal monitoring. Moreover, completion lymphadenectomy was associated with significant morbidity: a 24.1% incidence of lymphedema, compared with a 6.3% rate in the observation group (N Engl J Med. 2017 Jun 8;376[23]:2211-22).

On the other hand, Dr. Ferris noted that many newer drugs are being approved for the treatment of stage III melanoma, and in all the pivotal clinical trials, patients had to have undergone completion lymph node dissection as a condition of participation. So the surgery becomes a consideration if physicians want to use the newer agents the way they were used successfully in the trials.

The full eighth edition of the AJCC cancer staging manual is available for purchase. For physicians with a specific interest in melanoma, Dr. Ferris recommended as an extremely useful alternative the AJCC expert writing panel’s free downloadable summary of the evidence-based changes made in melanoma staging (CA Cancer J Clin. 2017 Nov;67[6]:472-92). The 2018 NCCN guidelines (Melanoma. Version 1.2018 Oct. 11, 2017) are available for free (www.NCCN.org).

Dr. Ferris reported serving as a consultant to DermTech.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

KAUAI, HAWAII – Melanoma staging in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual implements better stratification of stage III melanoma patients, resulting in an evidence-based improved prognosis for many of them, Laura Korb Ferris, MD, PhD, said at the Hawaii Dermatology Seminar provided by Skin Disease Education Foundation/Global Academy for Medical Education.

Dr. Ferris, of the department of dermatology, University of Pittsburgh, highlighted some of the key changes in the eighth edition of the AJCC staging manual, which is now in effect. She also described the clinical implications of important updates introduced in the 2018 National Comprehensive Cancer Network (NCCN) guidelines for the diagnosis and management of melanoma.

The AJCC eighth edition

The eighth edition is built upon an AJCC database of more than 46,000 patients with stage I-III melanoma diagnosed since 1998 at 10 academic medical centers. The AJCC panel made no changes in stage IV melanoma guidance because the newer targeted therapies have rapidly changed treatment outcomes in that setting and longer follow-up is needed to assess the full impact.

Courtesy RegionalDerm.com

The current edition of the AJCC melanoma staging manual creates a new subcategory within pathologic stage III. In the melanoma staging world, that’s exciting news, especially because this change has important implications for prognosis.

This fourth subcategory, stage IIID, is for melanomas, which in the Tumor, Nodes, Metastasis (TNM) classification scheme, are primary tumor stage T4b, meaning greater than 4.0 mm in thickness and with ulceration; regional lymph node N3a, b, or c, based upon the number of metastatic nodes involved and whether they were clinically occult nodal metastases detected by sentinel lymph node biopsy (SLNB) or clinically detected; and M0, meaning no distant metastatic disease. In the 8th edition, the AJCC staging system can be applied in patients with T2 through T4 primary melanoma only if they have undergone SLNB.

Courtesy RegionalDerm.com

Among the other key points to remember about the eighth edition of AJCC:

• Tumor thickness is now measured to the nearest 0.1 mm rather than to the nearest 0.01 mm, as previously. Thus, a 0.75-mm-thick melanoma is now rounded up to 0.8 mm, while a 0.74-mm melanoma becomes a 0.7-mm tumor.
• Based upon recent evidence, tumors that are 0.8-1.0 mm thick, with or without ulceration, are now classified at T1b. So are ulcerated lesions that are less than 0.8 mm.
• Dermal mitotic rate is no longer used in staging T1 tumors, although it’s still supposed to be included in pathology reports.
• The T category definitions of primary tumors have been clarified in the eighth edition. A tumor is now classified as T0 only if there is no evidence of a primary tumor. Tx is employed when the primary tumor thickness can’t be determined, as for example when the biopsy specimen was obtained by curettage. Tis is utilized for melanoma in situ.
• The N subcategory definitions of regional nodal status have been revised. Microsatellites, clinical satellites, and in-transit metastases are now categorized as N1c, N2c, or N3c based upon the number of tumor-involved regional lymph nodes. These features are no longer defined by their size or distance from the primary tumor.

2018 NCCN melanoma guidelines

The guidelines have been revised to recommend against SLNB if a patient’s pretest probability of finding a positive SLN is less than 5%. This includes patients who have a clinical stage IA/T1a melanoma with a Breslow thickness of less than 0.8 mm without ulceration.

Courtesy RegionalDerm.com

Bruce Jancin/MDedge News

What about completion lymphadenectomy in the SLN-positive melanoma patient?

Completion lymph node dissection looks increasingly like a procedure in search of an indication. Results of the National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial–II (MSLT-II) demonstrated not even a hint of a difference in 3-year melanoma-specific survival in 1,934 melanoma patients with sentinel lymph node metastases regardless of whether they were randomized to immediate completion lymph node dissection or ultrasound-based nodal monitoring. Moreover, completion lymphadenectomy was associated with significant morbidity: a 24.1% incidence of lymphedema, compared with a 6.3% rate in the observation group (N Engl J Med. 2017 Jun 8;376[23]:2211-22).

On the other hand, Dr. Ferris noted that many newer drugs are being approved for the treatment of stage III melanoma, and in all the pivotal clinical trials, patients had to have undergone completion lymph node dissection as a condition of participation. So the surgery becomes a consideration if physicians want to use the newer agents the way they were used successfully in the trials.

The full eighth edition of the AJCC cancer staging manual is available for purchase. For physicians with a specific interest in melanoma, Dr. Ferris recommended as an extremely useful alternative the AJCC expert writing panel’s free downloadable summary of the evidence-based changes made in melanoma staging (CA Cancer J Clin. 2017 Nov;67[6]:472-92). The 2018 NCCN guidelines (Melanoma. Version 1.2018 Oct. 11, 2017) are available for free (www.NCCN.org).

Dr. Ferris reported serving as a consultant to DermTech.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

KAUAI, HAWAII – Melanoma staging in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual implements better stratification of stage III melanoma patients, resulting in an evidence-based improved prognosis for many of them, Laura Korb Ferris, MD, PhD, said at the Hawaii Dermatology Seminar provided by Skin Disease Education Foundation/Global Academy for Medical Education.

Dr. Ferris, of the department of dermatology, University of Pittsburgh, highlighted some of the key changes in the eighth edition of the AJCC staging manual, which is now in effect. She also described the clinical implications of important updates introduced in the 2018 National Comprehensive Cancer Network (NCCN) guidelines for the diagnosis and management of melanoma.

The AJCC eighth edition

The eighth edition is built upon an AJCC database of more than 46,000 patients with stage I-III melanoma diagnosed since 1998 at 10 academic medical centers. The AJCC panel made no changes in stage IV melanoma guidance because the newer targeted therapies have rapidly changed treatment outcomes in that setting and longer follow-up is needed to assess the full impact.

Courtesy RegionalDerm.com

The current edition of the AJCC melanoma staging manual creates a new subcategory within pathologic stage III. In the melanoma staging world, that’s exciting news, especially because this change has important implications for prognosis.

This fourth subcategory, stage IIID, is for melanomas, which in the Tumor, Nodes, Metastasis (TNM) classification scheme, are primary tumor stage T4b, meaning greater than 4.0 mm in thickness and with ulceration; regional lymph node N3a, b, or c, based upon the number of metastatic nodes involved and whether they were clinically occult nodal metastases detected by sentinel lymph node biopsy (SLNB) or clinically detected; and M0, meaning no distant metastatic disease. In the 8th edition, the AJCC staging system can be applied in patients with T2 through T4 primary melanoma only if they have undergone SLNB.

Courtesy RegionalDerm.com

Among the other key points to remember about the eighth edition of AJCC:

• Tumor thickness is now measured to the nearest 0.1 mm rather than to the nearest 0.01 mm, as previously. Thus, a 0.75-mm-thick melanoma is now rounded up to 0.8 mm, while a 0.74-mm melanoma becomes a 0.7-mm tumor.
• Based upon recent evidence, tumors that are 0.8-1.0 mm thick, with or without ulceration, are now classified at T1b. So are ulcerated lesions that are less than 0.8 mm.
• Dermal mitotic rate is no longer used in staging T1 tumors, although it’s still supposed to be included in pathology reports.
• The T category definitions of primary tumors have been clarified in the eighth edition. A tumor is now classified as T0 only if there is no evidence of a primary tumor. Tx is employed when the primary tumor thickness can’t be determined, as for example when the biopsy specimen was obtained by curettage. Tis is utilized for melanoma in situ.
• The N subcategory definitions of regional nodal status have been revised. Microsatellites, clinical satellites, and in-transit metastases are now categorized as N1c, N2c, or N3c based upon the number of tumor-involved regional lymph nodes. These features are no longer defined by their size or distance from the primary tumor.

2018 NCCN melanoma guidelines

The guidelines have been revised to recommend against SLNB if a patient’s pretest probability of finding a positive SLN is less than 5%. This includes patients who have a clinical stage IA/T1a melanoma with a Breslow thickness of less than 0.8 mm without ulceration.

Courtesy RegionalDerm.com

Bruce Jancin/MDedge News

What about completion lymphadenectomy in the SLN-positive melanoma patient?

Completion lymph node dissection looks increasingly like a procedure in search of an indication. Results of the National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial–II (MSLT-II) demonstrated not even a hint of a difference in 3-year melanoma-specific survival in 1,934 melanoma patients with sentinel lymph node metastases regardless of whether they were randomized to immediate completion lymph node dissection or ultrasound-based nodal monitoring. Moreover, completion lymphadenectomy was associated with significant morbidity: a 24.1% incidence of lymphedema, compared with a 6.3% rate in the observation group (N Engl J Med. 2017 Jun 8;376[23]:2211-22).

On the other hand, Dr. Ferris noted that many newer drugs are being approved for the treatment of stage III melanoma, and in all the pivotal clinical trials, patients had to have undergone completion lymph node dissection as a condition of participation. So the surgery becomes a consideration if physicians want to use the newer agents the way they were used successfully in the trials.

The full eighth edition of the AJCC cancer staging manual is available for purchase. For physicians with a specific interest in melanoma, Dr. Ferris recommended as an extremely useful alternative the AJCC expert writing panel’s free downloadable summary of the evidence-based changes made in melanoma staging (CA Cancer J Clin. 2017 Nov;67[6]:472-92). The 2018 NCCN guidelines (Melanoma. Version 1.2018 Oct. 11, 2017) are available for free (www.NCCN.org).

Dr. Ferris reported serving as a consultant to DermTech.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Lues Maligna

Laboratory evaluation demonstrated a total CD4 count of 26 cells/μL (reference range, 443-1471 cells/μL) with a viral load of 1,770,111 copies/mL (reference range, 0 copies/mL), as well as a positive rapid plasma reagin (RPR) test with a titer of 1:8 (reference range, nonreactive). A reactive treponemal antibody test confirmed a true positive RPR test result. Viral culture as well as direct fluorescence antibodies for varicella-zoster virus and an active vesicle of herpes simplex virus (HSV) were negative. Serum immunoglobulin titers for varicella-zoster virus demonstrated low IgM with a positive IgG demonstrating immunity without recent infection. Blood and lesional skin tissue cultures were negative for additional infectious etiologies including bacterial and fungal elements. A lumbar puncture was not performed.

Biopsy of a papulonodule on the left arm demonstrated a lichenoid lymphohistiocytic infiltrate with superficial and deep inflammation (Figure 1). Neutrophils also were noted within a follicle with ballooning and acantholysis within the follicular epithelium. Additional staining for Mycobacterium, HSV-1, HSV-2, and Treponema were negative. In the clinical setting, this histologic pattern was most consistent with secondary syphilis. Pityriasis lichenoides et varioliformis acuta also was included in the histopathologic differential diagnosis by a dermatopathologist (M.C.).

Based on the clinical, microbiologic, and histopathologic findings, a diagnosis of lues maligna (cutaneous secondary syphilis) with a vesiculonecrotic presentation was made. The patient's low RPR titer was attributed to profound immunosuppression, while a confirmation of syphilis infection was made with treponemal antibody testing. Histopathologic examination was consistent with lues maligna and did not demonstrate evidence of any other infectious etiologies.

Following 7 days of intravenous penicillin, the patient demonstrated dramatic improvement of all skin lesions and was discharged receiving once-weekly intramuscular penicillin for 4 weeks. In accordance with the diagnosis, the patient demonstrated rapid improvement of the lesions following appropriate antibiotic therapy.

After the diagnosis of lues maligna was made, the patient disclosed a sexual encounter with a male partner 6 weeks prior to the current presentation, after which he developed a self-resolving genital ulcer suspicious for a primary chancre.

Increasing rates of syphilis transmission have been attributed to males aged 15 to 44 years who have sexual encounters with other males.¹ Although syphilis commonly is known as the great mimicker, syphilology texts state that lesions are not associated with syphilis if vesicles are part of the cutaneous eruption in an adult.² However, rare reports of secondary syphilis presenting as vesicles, pustules, bullae, and pityriasis lichenoides et varioliformis acuta-like eruptions also have been documented.^2-4

Initial screening for suspected syphilis involves sensitive, but not specific, nontreponemal RPR testing reported in the form of a titer. Nontreponemal titers in human immunodeficiency virus-positive individuals can be unusually high or low, fluctuate rapidly, and/or be unresponsive to antibiotic therapy.¹

Lues maligna is a rare form of malignant secondary syphilis that most commonly presents in human immunodeficiency virus-positive hosts.⁵ Although lues maligna often presents with ulceronodular lesions, 2 cases presenting with vesiculonecrotic lesions also have been reported.⁶ Patients often experience systemic symptoms including fever, fatigue, and joint pain. Rapid plasma reagin titers can range from 1:8 to 1:128 in affected individuals.⁶ Diagnosis is dependent on serologic and histologic confirmation while ruling out viral, fungal, and bacterial etiologies. Characteristic red-brown lesions of secondary syphilis involving the palms and soles (Figure 2) alsoaid in diagnosis.¹ Additionally, identification of the Jarisch-Herxheimer reaction following treatment and rapid response to antibiotic therapy are helpful diagnostic findings.^6,7 While histopathologic examination of lues maligna typically does not reveal evidence of spirochetes, it also is important to rule out other infectious etiologies.⁷

Our case emphasizes the importance of early recognition and treatment of the variable clinical, laboratory, and histologic presentations of lues maligna.

The Diagnosis: Lues Maligna

Laboratory evaluation demonstrated a total CD4 count of 26 cells/μL (reference range, 443-1471 cells/μL) with a viral load of 1,770,111 copies/mL (reference range, 0 copies/mL), as well as a positive rapid plasma reagin (RPR) test with a titer of 1:8 (reference range, nonreactive). A reactive treponemal antibody test confirmed a true positive RPR test result. Viral culture as well as direct fluorescence antibodies for varicella-zoster virus and an active vesicle of herpes simplex virus (HSV) were negative. Serum immunoglobulin titers for varicella-zoster virus demonstrated low IgM with a positive IgG demonstrating immunity without recent infection. Blood and lesional skin tissue cultures were negative for additional infectious etiologies including bacterial and fungal elements. A lumbar puncture was not performed.

Biopsy of a papulonodule on the left arm demonstrated a lichenoid lymphohistiocytic infiltrate with superficial and deep inflammation (Figure 1). Neutrophils also were noted within a follicle with ballooning and acantholysis within the follicular epithelium. Additional staining for Mycobacterium, HSV-1, HSV-2, and Treponema were negative. In the clinical setting, this histologic pattern was most consistent with secondary syphilis. Pityriasis lichenoides et varioliformis acuta also was included in the histopathologic differential diagnosis by a dermatopathologist (M.C.).

Based on the clinical, microbiologic, and histopathologic findings, a diagnosis of lues maligna (cutaneous secondary syphilis) with a vesiculonecrotic presentation was made. The patient's low RPR titer was attributed to profound immunosuppression, while a confirmation of syphilis infection was made with treponemal antibody testing. Histopathologic examination was consistent with lues maligna and did not demonstrate evidence of any other infectious etiologies.

Following 7 days of intravenous penicillin, the patient demonstrated dramatic improvement of all skin lesions and was discharged receiving once-weekly intramuscular penicillin for 4 weeks. In accordance with the diagnosis, the patient demonstrated rapid improvement of the lesions following appropriate antibiotic therapy.

After the diagnosis of lues maligna was made, the patient disclosed a sexual encounter with a male partner 6 weeks prior to the current presentation, after which he developed a self-resolving genital ulcer suspicious for a primary chancre.

Increasing rates of syphilis transmission have been attributed to males aged 15 to 44 years who have sexual encounters with other males.¹ Although syphilis commonly is known as the great mimicker, syphilology texts state that lesions are not associated with syphilis if vesicles are part of the cutaneous eruption in an adult.² However, rare reports of secondary syphilis presenting as vesicles, pustules, bullae, and pityriasis lichenoides et varioliformis acuta-like eruptions also have been documented.^2-4

Initial screening for suspected syphilis involves sensitive, but not specific, nontreponemal RPR testing reported in the form of a titer. Nontreponemal titers in human immunodeficiency virus-positive individuals can be unusually high or low, fluctuate rapidly, and/or be unresponsive to antibiotic therapy.¹

Lues maligna is a rare form of malignant secondary syphilis that most commonly presents in human immunodeficiency virus-positive hosts.⁵ Although lues maligna often presents with ulceronodular lesions, 2 cases presenting with vesiculonecrotic lesions also have been reported.⁶ Patients often experience systemic symptoms including fever, fatigue, and joint pain. Rapid plasma reagin titers can range from 1:8 to 1:128 in affected individuals.⁶ Diagnosis is dependent on serologic and histologic confirmation while ruling out viral, fungal, and bacterial etiologies. Characteristic red-brown lesions of secondary syphilis involving the palms and soles (Figure 2) alsoaid in diagnosis.¹ Additionally, identification of the Jarisch-Herxheimer reaction following treatment and rapid response to antibiotic therapy are helpful diagnostic findings.^6,7 While histopathologic examination of lues maligna typically does not reveal evidence of spirochetes, it also is important to rule out other infectious etiologies.⁷

Our case emphasizes the importance of early recognition and treatment of the variable clinical, laboratory, and histologic presentations of lues maligna.

The Diagnosis: Lues Maligna

Laboratory evaluation demonstrated a total CD4 count of 26 cells/μL (reference range, 443-1471 cells/μL) with a viral load of 1,770,111 copies/mL (reference range, 0 copies/mL), as well as a positive rapid plasma reagin (RPR) test with a titer of 1:8 (reference range, nonreactive). A reactive treponemal antibody test confirmed a true positive RPR test result. Viral culture as well as direct fluorescence antibodies for varicella-zoster virus and an active vesicle of herpes simplex virus (HSV) were negative. Serum immunoglobulin titers for varicella-zoster virus demonstrated low IgM with a positive IgG demonstrating immunity without recent infection. Blood and lesional skin tissue cultures were negative for additional infectious etiologies including bacterial and fungal elements. A lumbar puncture was not performed.

Biopsy of a papulonodule on the left arm demonstrated a lichenoid lymphohistiocytic infiltrate with superficial and deep inflammation (Figure 1). Neutrophils also were noted within a follicle with ballooning and acantholysis within the follicular epithelium. Additional staining for Mycobacterium, HSV-1, HSV-2, and Treponema were negative. In the clinical setting, this histologic pattern was most consistent with secondary syphilis. Pityriasis lichenoides et varioliformis acuta also was included in the histopathologic differential diagnosis by a dermatopathologist (M.C.).

Based on the clinical, microbiologic, and histopathologic findings, a diagnosis of lues maligna (cutaneous secondary syphilis) with a vesiculonecrotic presentation was made. The patient's low RPR titer was attributed to profound immunosuppression, while a confirmation of syphilis infection was made with treponemal antibody testing. Histopathologic examination was consistent with lues maligna and did not demonstrate evidence of any other infectious etiologies.

Following 7 days of intravenous penicillin, the patient demonstrated dramatic improvement of all skin lesions and was discharged receiving once-weekly intramuscular penicillin for 4 weeks. In accordance with the diagnosis, the patient demonstrated rapid improvement of the lesions following appropriate antibiotic therapy.

After the diagnosis of lues maligna was made, the patient disclosed a sexual encounter with a male partner 6 weeks prior to the current presentation, after which he developed a self-resolving genital ulcer suspicious for a primary chancre.

Increasing rates of syphilis transmission have been attributed to males aged 15 to 44 years who have sexual encounters with other males.¹ Although syphilis commonly is known as the great mimicker, syphilology texts state that lesions are not associated with syphilis if vesicles are part of the cutaneous eruption in an adult.² However, rare reports of secondary syphilis presenting as vesicles, pustules, bullae, and pityriasis lichenoides et varioliformis acuta-like eruptions also have been documented.^2-4

Initial screening for suspected syphilis involves sensitive, but not specific, nontreponemal RPR testing reported in the form of a titer. Nontreponemal titers in human immunodeficiency virus-positive individuals can be unusually high or low, fluctuate rapidly, and/or be unresponsive to antibiotic therapy.¹

Lues maligna is a rare form of malignant secondary syphilis that most commonly presents in human immunodeficiency virus-positive hosts.⁵ Although lues maligna often presents with ulceronodular lesions, 2 cases presenting with vesiculonecrotic lesions also have been reported.⁶ Patients often experience systemic symptoms including fever, fatigue, and joint pain. Rapid plasma reagin titers can range from 1:8 to 1:128 in affected individuals.⁶ Diagnosis is dependent on serologic and histologic confirmation while ruling out viral, fungal, and bacterial etiologies. Characteristic red-brown lesions of secondary syphilis involving the palms and soles (Figure 2) alsoaid in diagnosis.¹ Additionally, identification of the Jarisch-Herxheimer reaction following treatment and rapid response to antibiotic therapy are helpful diagnostic findings.^6,7 While histopathologic examination of lues maligna typically does not reveal evidence of spirochetes, it also is important to rule out other infectious etiologies.⁷

Our case emphasizes the importance of early recognition and treatment of the variable clinical, laboratory, and histologic presentations of lues maligna.

One of the most severe complications of systemic medications is the development of a life-threatening rash, especially toxic epidermal necrolysis (TEN). Most patients can expect a full recovery if the complicating medication is discontinued early on in its course.¹ When suspected TEN does not improve despite discontinuation of the detrimental medication, other diseases must be considered, particularly immunobullous and infectious etiologies. Treatment of these diseases differs substantially; therefore, a quick diagnosis is crucial. We present a case of a patient with an acute blistering eruption that was initially diagnosed and managed as TEN but physical examination and histopathologic confirmed another diagnosis. We review key examination findings that can help differentiate the causes of an acute blistering eruption with mucosal involvement, allowing for earlier diagnosis and treatment of these patients.

Case Report

An 85-year-old immunocompetent man was admitted to an outside hospital with a pruritic blistering eruption associated with myalgia, weakness, and fatigue of 3 weeks’ duration. The eruption initiated on the scalp and face and then spread down to the trunk and proximal arms and legs, with oral erosions also reported. An outside dermatologist was consulted on admission and performed a skin biopsy; the initial pathology was read as TEN. The patient was admitted to our institution on the same day, and all potentially complicating medications were stopped. He was treated with intravenous (IV) methylprednisolone sodium succinate 125 mg twice daily for 4 days and prednisone 40 mg daily for 9 days. With the rash worsening, the patient was restarted on methylprednisolone sodium succinate 40 mg every 8 hours approximately 3 weeks after admission, along with IV immunoglobulin at 2 g/kg over 3 days. When the patient did not respond to treatment, he was transferred to the University of California Irvine Medical Center for a higher level of care.

At that time, physical examination revealed numerous confluent erosions with honey-colored crust involving the entire face (Figure 1A) and sharp demarcation at the cutaneous lip (Figure 1B). There was a large erosion on the dorsal aspect of the tongue, but the rest of the oral mucosa was spared. The trunk and proximal extremities showed numerous grouped, punched-out erosions with scalloped borders (Figure 1C). A repeat skin biopsy showed an ulcer with viral cytopathic changes. Immunoperoxidase studies demonstrated positive staining for herpes simplex virus (HSV) type 1 (Figure 2). The original slides were a frozen section from an outside facility and could not be obtained. A tissue culture and direct fluorescent antibody also confirmed HSV-1, and the patient was diagnosed with disseminated herpes. He was rapidly tapered off of the steroids and started on IV acyclovir 10 mg/kg every 8 hours for 21 days. All prior erosions reepithelialized within 7 days of treatment (Figure 3). The patient had an otherwise uncomplicated hospital course and was discharged on hospital day 21.

Comment

A patient with an acute generalized blistering eruption requires urgent workup and treatment given the potentially devastating sequelae. Toxic epidermal necrolysis and immunobullous diseases often are the first diagnoses to be ruled out. Certainly infections such as HSV can cause a vesicular and erosive eruption, especially in the setting of a poorly controlled dermatitis, but they typically are not in the same differential as the other diagnoses.

Clinical Presentation
This case highlights 2 key physical examination findings that can alert the clinician to a possible underlying herpetic infection. First, the distribution of this patient’s oral lesions was telling. In most cases of TEN or pemphigus vulgaris, there is notable involvement of the oral mucosa, particularly the buccal and labial mucosa. Although herpes can involve any mucocutaneous surface, it does have a predilection for keratinized tissue, with the tongue and cutaneous lip commonly involved.^2,3 Our patient had a solitary linear erosion on the dorsal aspect of the tongue, but the rest of the oral cavity was strikingly spared. In addition, the erosions around the mouth stopped right at the cutaneous lip, sparing the labial mucosa (Figure 1B).

Second, the configuration of the erosions on the trunk, arms, and legs was diagnostic. Herpes classically presents as a cluster of vesicles overlying an erythematous base. When these vesicles rupture, punched-out erosions are left behind. Because these vesicles often are grouped, they can develop a scalloped border, which is a helpful indicator of HSV (Figure 1C). When these erosions become more confluent and irregular, the distinction from other conditions may not be as clear. A careful skin examination often can show areas that have preserved this herpetiform configuration.

Immune Compromise
Additionally, this case is illustrative of how immunosuppression and immunocompromise can affect the clinical presentation of HSV infection. Herpetic infections in the immunocompromised host tend to have a more protracted course, with chronic enlarging ulcers involving multiple sites. Furthermore, the morphology often is atypical, with ulcerodestructive, pustular, exophytic, and verrucous features as illustrated in this case. It is important to be mindful of these characteristics of HSV to properly diagnose an immunocompromised host.

Conclusion

This case is a good reminder that not everything that blisters and involves the mucosa is due to a hypersensitivity state such as TEN and Stevens-Johnson syndrome or an immunobullous disorder such as pemphigus vulgaris and pemphigus vegetans. The fact that this patient was worsening despite drug cessation, high-dose steroids, and IV immunoglobulin should have indicated a misdiagnosis. This case also shows that the early histopathologic findings of disseminated HSV and TEN can be nonspecific, and viral cytopathic changes may not always be obvious early in the disease.

Disseminated HSV should be considered in the differential diagnosis of a patient with an acute blistering eruption with mucosal involvement, and careful history and physical examination should be taken to rule out a viral etiology.

One of the most severe complications of systemic medications is the development of a life-threatening rash, especially toxic epidermal necrolysis (TEN). Most patients can expect a full recovery if the complicating medication is discontinued early on in its course.¹ When suspected TEN does not improve despite discontinuation of the detrimental medication, other diseases must be considered, particularly immunobullous and infectious etiologies. Treatment of these diseases differs substantially; therefore, a quick diagnosis is crucial. We present a case of a patient with an acute blistering eruption that was initially diagnosed and managed as TEN but physical examination and histopathologic confirmed another diagnosis. We review key examination findings that can help differentiate the causes of an acute blistering eruption with mucosal involvement, allowing for earlier diagnosis and treatment of these patients.

Case Report

An 85-year-old immunocompetent man was admitted to an outside hospital with a pruritic blistering eruption associated with myalgia, weakness, and fatigue of 3 weeks’ duration. The eruption initiated on the scalp and face and then spread down to the trunk and proximal arms and legs, with oral erosions also reported. An outside dermatologist was consulted on admission and performed a skin biopsy; the initial pathology was read as TEN. The patient was admitted to our institution on the same day, and all potentially complicating medications were stopped. He was treated with intravenous (IV) methylprednisolone sodium succinate 125 mg twice daily for 4 days and prednisone 40 mg daily for 9 days. With the rash worsening, the patient was restarted on methylprednisolone sodium succinate 40 mg every 8 hours approximately 3 weeks after admission, along with IV immunoglobulin at 2 g/kg over 3 days. When the patient did not respond to treatment, he was transferred to the University of California Irvine Medical Center for a higher level of care.

At that time, physical examination revealed numerous confluent erosions with honey-colored crust involving the entire face (Figure 1A) and sharp demarcation at the cutaneous lip (Figure 1B). There was a large erosion on the dorsal aspect of the tongue, but the rest of the oral mucosa was spared. The trunk and proximal extremities showed numerous grouped, punched-out erosions with scalloped borders (Figure 1C). A repeat skin biopsy showed an ulcer with viral cytopathic changes. Immunoperoxidase studies demonstrated positive staining for herpes simplex virus (HSV) type 1 (Figure 2). The original slides were a frozen section from an outside facility and could not be obtained. A tissue culture and direct fluorescent antibody also confirmed HSV-1, and the patient was diagnosed with disseminated herpes. He was rapidly tapered off of the steroids and started on IV acyclovir 10 mg/kg every 8 hours for 21 days. All prior erosions reepithelialized within 7 days of treatment (Figure 3). The patient had an otherwise uncomplicated hospital course and was discharged on hospital day 21.

Comment

A patient with an acute generalized blistering eruption requires urgent workup and treatment given the potentially devastating sequelae. Toxic epidermal necrolysis and immunobullous diseases often are the first diagnoses to be ruled out. Certainly infections such as HSV can cause a vesicular and erosive eruption, especially in the setting of a poorly controlled dermatitis, but they typically are not in the same differential as the other diagnoses.

Clinical Presentation
This case highlights 2 key physical examination findings that can alert the clinician to a possible underlying herpetic infection. First, the distribution of this patient’s oral lesions was telling. In most cases of TEN or pemphigus vulgaris, there is notable involvement of the oral mucosa, particularly the buccal and labial mucosa. Although herpes can involve any mucocutaneous surface, it does have a predilection for keratinized tissue, with the tongue and cutaneous lip commonly involved.^2,3 Our patient had a solitary linear erosion on the dorsal aspect of the tongue, but the rest of the oral cavity was strikingly spared. In addition, the erosions around the mouth stopped right at the cutaneous lip, sparing the labial mucosa (Figure 1B).

Second, the configuration of the erosions on the trunk, arms, and legs was diagnostic. Herpes classically presents as a cluster of vesicles overlying an erythematous base. When these vesicles rupture, punched-out erosions are left behind. Because these vesicles often are grouped, they can develop a scalloped border, which is a helpful indicator of HSV (Figure 1C). When these erosions become more confluent and irregular, the distinction from other conditions may not be as clear. A careful skin examination often can show areas that have preserved this herpetiform configuration.

Immune Compromise
Additionally, this case is illustrative of how immunosuppression and immunocompromise can affect the clinical presentation of HSV infection. Herpetic infections in the immunocompromised host tend to have a more protracted course, with chronic enlarging ulcers involving multiple sites. Furthermore, the morphology often is atypical, with ulcerodestructive, pustular, exophytic, and verrucous features as illustrated in this case. It is important to be mindful of these characteristics of HSV to properly diagnose an immunocompromised host.

Conclusion

This case is a good reminder that not everything that blisters and involves the mucosa is due to a hypersensitivity state such as TEN and Stevens-Johnson syndrome or an immunobullous disorder such as pemphigus vulgaris and pemphigus vegetans. The fact that this patient was worsening despite drug cessation, high-dose steroids, and IV immunoglobulin should have indicated a misdiagnosis. This case also shows that the early histopathologic findings of disseminated HSV and TEN can be nonspecific, and viral cytopathic changes may not always be obvious early in the disease.

Disseminated HSV should be considered in the differential diagnosis of a patient with an acute blistering eruption with mucosal involvement, and careful history and physical examination should be taken to rule out a viral etiology.

One of the most severe complications of systemic medications is the development of a life-threatening rash, especially toxic epidermal necrolysis (TEN). Most patients can expect a full recovery if the complicating medication is discontinued early on in its course.¹ When suspected TEN does not improve despite discontinuation of the detrimental medication, other diseases must be considered, particularly immunobullous and infectious etiologies. Treatment of these diseases differs substantially; therefore, a quick diagnosis is crucial. We present a case of a patient with an acute blistering eruption that was initially diagnosed and managed as TEN but physical examination and histopathologic confirmed another diagnosis. We review key examination findings that can help differentiate the causes of an acute blistering eruption with mucosal involvement, allowing for earlier diagnosis and treatment of these patients.

Case Report

An 85-year-old immunocompetent man was admitted to an outside hospital with a pruritic blistering eruption associated with myalgia, weakness, and fatigue of 3 weeks’ duration. The eruption initiated on the scalp and face and then spread down to the trunk and proximal arms and legs, with oral erosions also reported. An outside dermatologist was consulted on admission and performed a skin biopsy; the initial pathology was read as TEN. The patient was admitted to our institution on the same day, and all potentially complicating medications were stopped. He was treated with intravenous (IV) methylprednisolone sodium succinate 125 mg twice daily for 4 days and prednisone 40 mg daily for 9 days. With the rash worsening, the patient was restarted on methylprednisolone sodium succinate 40 mg every 8 hours approximately 3 weeks after admission, along with IV immunoglobulin at 2 g/kg over 3 days. When the patient did not respond to treatment, he was transferred to the University of California Irvine Medical Center for a higher level of care.

At that time, physical examination revealed numerous confluent erosions with honey-colored crust involving the entire face (Figure 1A) and sharp demarcation at the cutaneous lip (Figure 1B). There was a large erosion on the dorsal aspect of the tongue, but the rest of the oral mucosa was spared. The trunk and proximal extremities showed numerous grouped, punched-out erosions with scalloped borders (Figure 1C). A repeat skin biopsy showed an ulcer with viral cytopathic changes. Immunoperoxidase studies demonstrated positive staining for herpes simplex virus (HSV) type 1 (Figure 2). The original slides were a frozen section from an outside facility and could not be obtained. A tissue culture and direct fluorescent antibody also confirmed HSV-1, and the patient was diagnosed with disseminated herpes. He was rapidly tapered off of the steroids and started on IV acyclovir 10 mg/kg every 8 hours for 21 days. All prior erosions reepithelialized within 7 days of treatment (Figure 3). The patient had an otherwise uncomplicated hospital course and was discharged on hospital day 21.

Comment

A patient with an acute generalized blistering eruption requires urgent workup and treatment given the potentially devastating sequelae. Toxic epidermal necrolysis and immunobullous diseases often are the first diagnoses to be ruled out. Certainly infections such as HSV can cause a vesicular and erosive eruption, especially in the setting of a poorly controlled dermatitis, but they typically are not in the same differential as the other diagnoses.

Clinical Presentation
This case highlights 2 key physical examination findings that can alert the clinician to a possible underlying herpetic infection. First, the distribution of this patient’s oral lesions was telling. In most cases of TEN or pemphigus vulgaris, there is notable involvement of the oral mucosa, particularly the buccal and labial mucosa. Although herpes can involve any mucocutaneous surface, it does have a predilection for keratinized tissue, with the tongue and cutaneous lip commonly involved.^2,3 Our patient had a solitary linear erosion on the dorsal aspect of the tongue, but the rest of the oral cavity was strikingly spared. In addition, the erosions around the mouth stopped right at the cutaneous lip, sparing the labial mucosa (Figure 1B).

Second, the configuration of the erosions on the trunk, arms, and legs was diagnostic. Herpes classically presents as a cluster of vesicles overlying an erythematous base. When these vesicles rupture, punched-out erosions are left behind. Because these vesicles often are grouped, they can develop a scalloped border, which is a helpful indicator of HSV (Figure 1C). When these erosions become more confluent and irregular, the distinction from other conditions may not be as clear. A careful skin examination often can show areas that have preserved this herpetiform configuration.

Immune Compromise
Additionally, this case is illustrative of how immunosuppression and immunocompromise can affect the clinical presentation of HSV infection. Herpetic infections in the immunocompromised host tend to have a more protracted course, with chronic enlarging ulcers involving multiple sites. Furthermore, the morphology often is atypical, with ulcerodestructive, pustular, exophytic, and verrucous features as illustrated in this case. It is important to be mindful of these characteristics of HSV to properly diagnose an immunocompromised host.

Conclusion

This case is a good reminder that not everything that blisters and involves the mucosa is due to a hypersensitivity state such as TEN and Stevens-Johnson syndrome or an immunobullous disorder such as pemphigus vulgaris and pemphigus vegetans. The fact that this patient was worsening despite drug cessation, high-dose steroids, and IV immunoglobulin should have indicated a misdiagnosis. This case also shows that the early histopathologic findings of disseminated HSV and TEN can be nonspecific, and viral cytopathic changes may not always be obvious early in the disease.

Disseminated HSV should be considered in the differential diagnosis of a patient with an acute blistering eruption with mucosal involvement, and careful history and physical examination should be taken to rule out a viral etiology.