Triple collision tumor comprising Merkel cell carcinoma with an unusual immunophenotype, squamous cell carcinoma in situ, and basal cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine cancer which almost always exhibits the cytokeratin (CK)20+/thyroid transcription factor (TTF)-1- immunophenotype. MCC may occur concurrently with squamous cell carcinoma, Bowen disease, and/or basal cell carcinoma (BCC), with some evidence that MCCs which occur in conjunction with other neoplasms exhibit different immunophenotypes compared to pure MCC cases. We present a case of CK20-/TTF-1+ MCC concurrent with Bowen disease and BCC, and discuss possible differences in the pathogenesis of pure vs combined MCC. We also review the literature for this unusual immunophenotype, noting that most cases occur in combined MCC.

Onset of disseminated cutaneous nodules following toe amputation in heart transplant patient.

Alternaria spp. infections are rare, but organ transplant recipients and immunosuppressed patients are particularly at risk of developing cutaneous alternariosis. Although cutaneous alternariosis is well-defined, instances of disseminated infection are exceedingly rare. We report a case of disseminated Alternaria infection in an immunocompromised patient from a primary focus of ungual phaeohyphomycosis.

Langerhans Cell Histiocytosis Associated With Underlying Hematolymphoid Disorders in Adults: Report of 2 Cases and Review of the Literature.

Langerhans cell histiocytosis (LCH) is an uncommon disorder characterized by proliferation of abnormal LCs usually affecting children and adolescents. LCH in adults first presenting in the skin is rare. Although LCH and even LCH with a second malignancy may be more common in children, cutaneous LCH with a second hematologic malignancy has been more commonly identified in adults. The authors report 2 new cases of LCH in adult patients with underlying myelodysplasia and follicular lymphoma. The specimens were examined by routine microscopy and immunohistochemical stains for S100 protein and CD1a. Patients were elderly men with established diagnoses of follicular lymphoma and myelodysplasia, presented with follicular lesions and erythematous plaques involving intertriginous areas. Histologic examination revealed collections of mononuclear cells in upper dermis, which demonstrated strong positivity for S100 and CD1a, confirming their identity as LCs. BRAF analysis returned negative for detection of BRAF V600E mutation in both patients. The authors have recently encountered 2 cases of adult patients with skin-limited LCH predated by other lymphoproliferative disorders. The association between LCH and hematopoietic disorders may be explained by a common bone marrow precursor that is differentiating along different cell lines. Cutaneous LCH may be associated with underlying lymphoproliferative disorders and should be considered in the differential diagnosis of cutaneous eruptions in patients with hematopoietic disorders. Clinical follow-up evaluation of patients diagnosed with LCH for peripheral blood abnormalities and lymphadenopathy or "B symptoms" may be prudent in patients not already carrying a diagnosis of an underlying hematologic disorder.

New variant lymphomatoid papulosis type E preceding and coexisting with mycosis fungoides - a case report and review of the literature.

Angioinvasive (type E) lymphomatoid papulosis (LyP) is a recently described subtype of LyP presenting with eschar-like lesions that can be mistaken for aggressive forms of angiocentric cutaneous T-cell lymphoma. None of the cases of angioinvasive LyP described thus far have been associated with mycosis fungoides (MF). Herein, we describe a case of angioinvasive LyP type E coexisting with MF. The patient presented with an eschar on his chest and over time developed new nodules and large plaques with eschar formation, all of which resolved spontaneously over a period of a few weeks without intentional therapy. Biopsy revealed a CD30+ atypical inflammatory cell infiltrate with marked angiocentricity. Later, he developed erythematous annular scaly patches histologically consistent with MF. Our patient's clinical course confirms the indolent behavior characteristic of LyP despite the aggressive clinical and histologic appearance of lesions. The co-occurrence of angioinvasive LyP and MF in our patient highlights the propensity for LyP type E to coexist with MF, as is characteristic of other LyP subtypes, and supports the theory that LyP and MF are related T-cell lymphoproliferative disorders. Patients with LyP can present with large lesions exhibiting eschar formation and an atypical angiocentric/angiodestructive lymphoid infiltrate and should be spared overtreatment.

Generalized linear IgA dermatosis with palmar involvement.

Linear IgA bullous dermatosis (LABD) is a sub-epidermal blistering disorder characterized by deposition of IgA along the basement membrane zone (BMZ) as detected by immunofluorescence microscopy. The diagnosis is made by clinicopathologic correlation with immunofluorescence confirmation. Differentiation from other bullous dermatoses is important because therapeutic measures differ. Prompt initiation of the appropriate therapies can have a major impact on outcomes. We present three cases with prominent palmar involvement to alert the clinician of this potential physical exam finding and to consider LABD in the right context.

Cutaneous malignant peripheral nerve sheath tumors.

Cutaneous malignant peripheral nerve sheath tumors (MPNSTs) are rare entities compared with their deep soft tissue counterparts. We describe two cases of cutaneous MPNSTs. The first case, occurring in a 27-year-old woman with neurofibromatosis I, presented with recent growth of a pre-existing nodule on her back. A biopsy showed a densely cellular area within a conventional neurofibroma composed of atypical, hyperchromatic epithelioid and spindled cells with frequent mitotic figures (MFs). The second case presented in an 88-year-old man with no stigmata of neurofibromatosis as a rapidly growing subcutaneous tumor of the right calf. A biopsy showed a diffuse neurofibroma that abruptly transitioned to a densely cellular proliferation of hyperchromatic atypical spindled cells arranged in short fascicles with frequent MFs. The diagnosis of MPNST was rendered in both cases. MPNSTs of the dermis and subcutis are rare sarcomas. They can occur as sporadic tumors or in the setting of neurofibromatosis. They are often associated with pre-existing neurofibromas. Increase in size of pre-existing neurofibromas is an indication for biopsy. Recognition of the cellular atypia, increased cellularity and mitotic activity is key to the diagnosis.

IL-4 production by CD8+ lymphomatoid papulosis, type C, attracts background eosinophils.

There are two subsets of CD8+ T cells: Tc1 and Tc2. INF-gamma production by Tc1 cells causes granulomatous inflammation. IL-4 production by Tc2 cells attracts eosinophils. A 76-year-Caucasian female presented with CD8+ lymphomatoid papulosis (LyP), type C. We hypothesized that the LyP cells belonged to the Tc2 subset because of abundant background eosinophils. Hematoxylin and eosin and immunohistochemical stains were carried out on tissue sections from a skin punch biopsy. Antibodies for immunohistochemical stains included CD3, CD4, CD5, CD7, CD8, CD30, CD56, ALK-1, clusterin and IL-4. There was involvement of the dermis by a dense lymphoid infiltrate composed of large atypical cells and numerous eosinophils. The LyP cells expressed CD5, CD8, CD30 and IL-4. Keratinocytes showed a membranous pattern of immunoreactivity for IL-4. IL-4 production by CD8+ LyP, type C indicates that it belongs to the Tc2 subset. The cytokine milieu produced by the LyP cells attracted eosinophils. The IL-13R complex on keratinocytes bound IL-4 and produced a membranous staining pattern. Although CD8+ LyP is rare, we believe that this CD30+ lymphoproliferative disorder should be included in the World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous T-cell lymphomas.

miRNA expression profiles of premalignant and malignant arsenic-induced skin lesions.

Arsenic, a naturally occurring element, contaminates the drinking water of over 200 million people globally. Chronic arsenic exposure causes multiple cancers including those originating from skin, lung and bladder, and is associated with liver, kidney, and prostate cancers. Skin is the primary target organ for arsenic toxicity; chronic toxicity initially manifests as non-malignant hyperkeratoses (HK) and subsequently advances to malignant lesions, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In this study, we evaluate the miRNA expression profiles of premalignant (3 HK) and malignant (3 BCC and 3 SCC) skin lesions from individuals chronically exposed to high levels of arsenic (59-172 ppb) in their drinking water in West Bengal, India. The lesions were histologically complex requiring histopathologic identification of keratinocytes to be isolated for RNA analyses. Keratinocytes were harvested using Laser Capture Microdissection and miRNA expression profiles were determined using TaqMan® Array Human MiRNA A Card v2.0. Thirty-five miRNAs were differentially expressed among the three lesion types analyzed. Two miRNAs (miR-425-5p and miR-433) were induced in both BCC and SCC relative to HK indicating their association with malignancy. Two other miRNAs (miR-184 and miR-576-3p) were induced in SCC relative to both BCC and HK suggesting selective induction in tumors capable of metastasis. Six miRNAs (miR-29c, miR-381, miR-452, miR-487b, miR-494 and miR-590-5p) were selectively suppressed in BCC relative to both SCC and HK. In conclusion, the differential miRNA expression was both phenotype- and stage-related. These miRNAs are potential biomarkers and may serve as therapy targets for arsenic-induced internal tumors.

Phenylephrine-induced microvascular occlusion syndrome in a patient with a heterozygous factor V Leiden mutation.

BACKGROUND: Cutaneous microvascular occlusion syndromes (MOS) present with noninflammatory retiform purpura with variable outcomes that are dependent on the severity, duration, and specific underlying cause. Transient cases are often associated with few sequelae, while severe forms such as symmetrical peripheral gangrene may be associated with amputation and death. OBSERVATIONS: A middle-aged man developed MOS after exposure to phenylephrine hydrochloride and experienced complete resolution when treatment with the vasopressor was discontinued. Further evaluation detected a previously subclinical heterozygous factor V Leiden mutation. CONCLUSIONS: We propose that phenylephrine-mediated vasoconstriction superimposed on an underlying thrombotic predisposition precipitated the transient MOS. The role of vasopressors in the development of cutaneous MOS is well documented in the critical care literature; however, it is underrepresented in the dermatologic literature, and, to our knowledge, there are no reports of phenylephrine use inducing MOS. We hope to raise awareness of the potential role of vasopressor medications in causing MOS.

Tissue eosinophilia as an indicator of drug-induced cutaneous small-vessel vasculitis.

OBJECTIVE: To determine whether tissue eosinophilia is a reliable indicator of a drug-induced etiology in biopsy samples demonstrating leukocytoclastic vasculitis. DESIGN: Retrospective medical record review with concurrent histopathologic analysis. SETTING: University-affiliated dermatology practice. PATIENTS: Sixty-three patients with cutaneous small-vessel vasculitis meeting specific inclusion criteria were divided into drug-induced (n = 16) and non-drug-induced (n = 47) groups. MAIN OUTCOME MEASURES: Corresponding histopathologic material was reviewed by a dermatopathologist masked to the etiologic associations. An eosinophil ratio was calculated for each patient, derived from the mean eosinophil score (averaging eosinophil counts from 10 high-power histologic fields), and expressed in relation to the intensity of inflammation in the histopathologic slides examined. Eosinophilia ratios were compared for both groups using the Mann-Whitney test. RESULTS: A significant difference was found in mean eosinophil ratios in the drug-induced vs non-drug-induced groups (5.20 vs 1.05; P = .01). Vascular fibrin deposition was present in both groups and was not found to be significantly different (P = .78). Clinical evidence of systemic vasculitis was present in 2 patients (13%) in the drug-induced group vs 15 (32%) in the non-drug-induced group. Fourteen patients (88%) in the drug-induced group had a short-term disease course vs 27 (57%) in the non-drug-induced group. CONCLUSIONS: Tissue eosinophilia is established as a reliable indicator of drug induction in cutaneous small vessel vasculitis. Drug-induced small-vessel vasculitis generally follows a short-term disease course without development of systemic involvement. This information may be useful for guiding management decisions, especially when the etiology is unclear.

African tick bite fever: a not-so-uncommon illness in international travelers.

BACKGROUND: African tick bite fever is a rickettsial illness that has recently emerged as a significant disease among international travelers. The vector is the Amblyomma tick, which is endemic to sub-Saharan Africa and parts of the eastern Caribbean. OBSERVATIONS: We describe a middle-aged woman who returned from a mission trip to Zimbabwe with an influenzalike illness and inoculation eschar; she also had a history of travel to a game farm. Biopsy revealed a histopathologic pattern consistent with an infectious pathogenesis. Immunohistochemical staining confirmed the presence of rickettsial organisms. In light of the patient's history, the clinical constellation of signs and symptoms, and the results of ancillary laboratory testing, a diagnosis of African tick bite fever was made. The patient was treated with doxycycline hydrochloride and had an uncomplicated course. CONCLUSIONS: This report further highlights the epidemiological and clinical features of African tick bite fever. With the increase in international travel, it is important to recognize the illness in those who have been to endemic countries and to counsel patients regarding preventive measures for planned travel.

Thalidomide in the treatment of recalcitrant Sweet's syndrome associated with myelodysplasia.

Sweet's syndrome is a neutrophilic dermatosis characterized by tender, erythematous, pseudovesicular plaques that can be associated with hematologic malignancy. We report a patient with recalcitrant Sweet's syndrome that preceded the development of myelodysplastic syndrome by 30 months. The delay between the onset of Sweet's syndrome and the subsequent diagnosis of myelodysplasia highlights the need for thorough and repeated evaluation for underlying malignancy in patients with such a course. Although corticosteroids are the initial treatment of choice, this patient's eruption was only partially responsive to high-dose prednisone and was refractory to metronidazole, dapsone, and methotrexate. Treatment with thalidomide resulted in complete resolution of the cutaneous lesions within one month of therapy.

Vascular inflammation (vasculitis) in sweet syndrome: a clinicopathologic study of 28 biopsy specimens from 21 patients.

BACKGROUND: Sweet syndrome is characterized by painful, erythematous plaques of rapid onset accompanied by fever. Absence of vasculitis is a histologic criterion for diagnosis. However, recent reports suggest that vasculitis should not exclude the diagnosis. We hypothesized that vasculitis can occur in Sweet syndrome and that it represents an epiphenomenon rather than a primary immune-mediated process. DESIGN: Skin biopsy specimens from patients with Sweet syndrome were reviewed to determine the prevalence of vasculitis. The clinicopathologic features of cases with vasculitis were evaluated for statistically significant associations. Specimens with vasculitis underwent immunofluorescence staining. SETTING: University department of dermatology, university hospital, and private practice. PATIENTS: Medical records and biopsy specimens of 21 patients meeting diagnostic criteria for Sweet syndrome were reviewed. INTERVENTIONS: None. RESULTS: The prevalence of vasculitis was 29% (6 of 21 patients). There was a significant association of vasculitis with lesions of longer duration (P =.02). Vascular immunoglobulin and complement could not be demonstrated in cases of Sweet syndrome with vasculitis. CONCLUSIONS: Vasculitis is not a primary, immune-mediated process in Sweet syndrome but occurs secondary to noxious products released from neutrophils. Blood vessels in lesions of longer duration are more likely to develop vasculitis than those of shorter duration because of prolonged exposure to noxious metabolites. Vasculitis does not exclude a diagnosis of Sweet syndrome.

Histopathologic recognition of involved margins of lentigo maligna excised by staged excision: an interobserver comparison study.

OBJECTIVES: To assess interobserver and intraobserver concordance for identifying positive and negative margins in staged excisions of lentigo maligna and lentigo maligna melanoma and to determine if control biopsy specimens are useful to improve concordance. DESIGN: Retrospective, randomized interobserver and intraobserver comparison study of archived pathologic specimens. The study was conducted in 3 phases, and slides were evaluated blindly and independently by 5 pathologists: in phase 1, all slides were randomized and diagnosed as positive or negative. In phase 2, every third slide was evaluated again and diagnosed as positive or negative. In phase 3, slides were organized into cases, allowing evaluation of each margin in the context of the positive control (tumor from the center of the lesion) and negative control (control biopsy specimen), if available. SETTING: University referral center. STUDY MATERIAL: A total of 301 glass microscopic slides from 27 patients who underwent staged excision for lentigo maligna or lentigo maligna melanoma from March 1997 to April 2001. MAIN OUTCOME MEASURES: Interobserver and intraobserver concordance between original diagnoses and study diagnoses rendered on all slides by 5 pathologists. RESULTS: Phase 1 and 3 agreement was moderate (kappa range, 0.4-0.5). Phase 2 (intraobserver) agreement was moderate to good for all pathologists (kappa range, 0.6-0.9). Subset analysis revealed a statistically significant increase in agreement with the use of a control strip biopsy specimen for difficult slides. CONCLUSIONS: Interobserver concordance for margin analysis in lentigo maligna and lentigo maligna melanoma is moderate, and intraobserver concordance is moderate to good. A control strip biopsy specimen may improve concordance in some cases.

Nonhealing ulcer secondary to factor V Leiden mutation and cryofibrinogenemia.

Factor V Leiden is the most common genetic thrombophilia in people of European descent, and is important to recognize as it can have significant implications in dermatology. We report a case of a 30-year-old man who presented for evaluation and treatment of a chronic ulceration on the site of his stump following a below the knee amputation which had been performed for non-healing ulcerations. Despite a variety of treatments, his ulcer persisted. He was referred to a dermatologist who performed a biopsy that was interpreted ass non-specific, and treatment was started for pyoderma gangrenosum. Further investigation revealed a homozygous factor V Leiden mutation and cryofibrinogenemia. He was tapered off of the methylprednisolone and was improving on stanozolol. He healed well after surgery and no new ulcerations have developed. This case highlights the importance of considering this mutation in a non-healing leg ulcer.