New insights into merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare aggressive cutaneous malignancy of the elderly and immunocompromised populations. The clinical presentation of MCC is nonspecific, with the majority of cases presenting as localized skin involvement. Histologically and immunophenotypically, MCC is defined by both neuroendocrine and epithelial differentiation. Recently, the Merkel cell polyomavirus has been implicated in the pathogenesis of MCC. In addition, there have been numerous studies evaluating the histologic and immunohistochemical characteristics of MCC as they relate to diagnosis and prognosis. The purpose of this paper is to review the most salient and clinically relevant updates in the pathogenesis and histologic features of MCC. Specific attention is given to the clinical and histologic predictors of prognosis, staging, and the controversies concerning sentinel lymph node biopsy and therapy.

Expression of alpha-methylacyl-CoA racemase (P504S) in sebaceous neoplasms.

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR), also known as P504S, is a protein that plays an important role in mitochondrial and peroxisomal beta-oxidation of branched-chain fatty acid and bile acid intermediates. AMACR has been established as a valuable diagnostic marker for prostate cancer and has recently been shown to be useful in the diagnosis of colorectal carcinoma. Despite the importance of lipid metabolism in sebum production by sebaceous glands of the skin, there are no studies evaluating the expression of AMACR in sebaceous neoplasms. METHODS: Five samples of normal sebaceous glands as well as five cases each of sebaceous hyperplasia (SH), sebaceous adenoma (SA), basal cell carcinoma (BCC) with sebaceous differentiation and extraocular sebaceous carcinoma (SC) were evaluated for immunohistochemical (IHC) expression of AMACR. Each case was reviewed by a single dermatopathologist and graded using a semi-objective grading schema. RESULTS: Normal sebaceous glands showed strong (4+) expression of AMACR. Among sebaceous neoplasms, SH showed the highest expression (4+), SA and BCC with sebaceous differentiation showed varied expression (2+ and 1+, respectively), and extraocular SC showed no expression of AMACR. CONCLUSIONS: The expression of AMACR is increased in benign sebaceous glands and SH; with decreasing AMACR expression in tumors with less sebaceous differentiation (i.e. SA and SC). These findings provide insight into the potential pathogenesis of sebaceous neoplasms while assisting in the microscopic distinction of SA from SC.

Bif-1 and Bax expression in cutaneous Merkel cell carcinoma.

BACKGROUND: Bax-interacting factor-1 (Bif-1) binds to Bax, which in turn activates this proapoptotic protein. In the absence of Bif-1, the ability to induce apoptosis through the intrinsic pathway is greatly reduced. Merkel cell carcinoma (MCC) classically shows an aggressive behavior and lack of response to chemotherapy, which remains unexplained. Previous studies have documented the presence of Bax in MCC, but Bif-1 expression has not been evaluated. Herein, the expression of Bif-1 and Bax in cutaneous MCC is examined. MATERIALS AND METHODS: The immunohistochemical expression of Bif-1 and Bax protein was examined in nine cases of MCC. Both positive and negative controls were conducted. All the cases were reviewed by a single dermatopathologist. RESULTS: Bif-1 was detected in nine cases (100%), and Bax was expressed in six cases (66%). The percent positive cells for Bif-1 in MCC ranged from 85% to 98% positive (mean 93.9%). At the same time, decreased Bax expression was shown with 0-8% positive cells (mean 3.45%). CONCLUSION: The increased expression of Bif-1 in MCC is associated with low levels of Bax staining. These findings suggest that the upregulation of Bif-1 could in part be responsible for tumorigenesis in cutaneous MCC. As shown, Bax and Bif-1 expression are not exclusively antithetical; therefore, future studies evaluating the expression of both proteins should be conducted.

Utility of p63 in the differential diagnosis of atypical fibroxanthoma and spindle cell squamous cell carcinoma.

Atypical fibroxanthoma (AFX), spindle cell squamous cell carcinoma (SCSCC) and spindle cell melanoma are the primary entities in the differential diagnosis of a cytologically atypical spindle cell tumor arising on sun-damaged skin. AFX is generally regarded as a diagnosis of exclusion in this context: in the absence of S100 or keratin reactivity, a diagnosis of AFX is favored. However, keratin reactivity may be focal or even absent in SCSCC, and although numerous positive markers of AFX have been proposed, none has shown sufficient sensitivity and specificity for routine diagnostic use. We evaluated 20 AFX and 10 SCSCC with a panel of cytokeratins and p63 to assess the utility of the latter antibody in this differential diagnosis. All 10 SCSCC showed strong expression of p63, whereas all 20 AFX were p63 negative. Two additional cases (excluded from the study) were negative for keratins and S100 on initial shave biopsies, resulting in a favored diagnosis of AFX, but p63 stains performed retrospectively were positive. However, review of the excision specimens in both cases revealed deep subcutaneous extension, excluding AFX. p63 reactivity argues against the diagnosis of AFX and is therefore a useful addition to the standard immunohistochemical panel for cutaneous spindle cell neoplasms.

Malignant perivascular epithelioid cell tumor ('PEComa'): a case report and literature review of cutaneous/subcutaneous presentations.

Perivascular epithelioid cell (PEC) tumors, also called 'PEComas,' are distinct tumors showing PEC differentiation with characteristic histologic and immunophenotypic features. PEComas are rare tumors documented in the literature presenting in numerous anatomic sites including the thorax, abdomen, pelvis, soft tissue and skin. Criteria for malignancy does not exist for the subset of PEComas that pursue an aggressive clinical course. Herein, we present an unusual case of a malignant PEC tumor presenting as a scalp nodule in a patient with a prior diagnosis of 'melanoma' based upon the immunophenotypic profile of an excised enlarged cervical lymph node. The purpose of this case presentation is to further describe the rare clinical manifestations of a subcutaneous PEC tumor, emphasize the malignant potential of this entity, and review the literature focusing upon clinicopathologic features of cutaneous/subcutaneous PEComas.

CD117 immunoreactivity in atypical fibroxanthoma.

Atypical fibroxanthoma (AFX) is a spindle cell neoplasm of the skin seen typically on sun-damaged skin of the elderly. Though described as a benign entity, local recurrence and distant metastasis have been reported. This study aims to investigate the potential pathogenic role of CD117, the c-kit receptor in AFX. CD117 was detected in 15 of the 16 cases (94%). The percentage of positive cells for CD117 expression among all tumors was approximately 30%. CD117 proved to be a very sensitive marker of AFX. This antibody may be a useful diagnostic adjunct in AFX.

Acetylcholine receptor expression in Merkel cell carcinoma.

Neurocrest-derived tissues express muscarinic and nicotinic acetylcholine receptors (mAChR and nAChR respectively). These receptors are critical for migration of neurocrest-derived cells to their corresponding tissues during development. Recent reports demonstrate neurocrest-derived melanoma and numerous non-Merkel cell neuroendocrine tumors express both muscarinic and nicotinic receptors. In light of the controversy surrounding the origin and pathogenesis of Merkel cell carcinoma (MCC), we investigated the immunohistochemical expression of both mAChR and nAChR in MCC. Fifteen cases of primary non-metastatic cutaneous MCC archived at a large veterans' hospital and tertiary referral dermatopathology service were retrieved by computer-assisted search. Immunohistochemistry was utilized to evaluate the presence of M3, M5 and beta 2 nAChR expression. All the cases were confirmed prior to study by a single board certified dermatopathologist (MBM). Fifteen cases of primary cutaneous MCC were diffusely positive for M3 and M5 mAChR staining. All cases lacked immunohistochemical staining for the beta 2 nAChR. Despite the limited number of cases, MCC appears to uniformly express M3 and M5 receptors. These receptors have been linked to cell proliferation and migration which may confer a potential therapeutic target.

Immunohistochemical expression of survivin in cutaneous sebaceous lesions.

BACKGROUND: Survivin is a member of the inhibitor of apoptosis family of proteins implicated in the inhibition of apoptosis and cell cycle control, both crucial in the progression to malignancy. Survivin overexpression has been demonstrated in numerous malignancies including cutaneous squamous cell carcinoma and melanoma. To date, there are no studies evaluating the expression of survivin in sebaceous neoplasms. METHODS: Immunohistochemical expression of survivin was evaluated in a total of 20 extraocular sebaceous neoplasms: sebaceous hyperplasia (SH, 8), sebaceous adenoma (SA, 8), and sebaceous carcinoma (SC, 4). All the results were independently evaluated by a single dermatopathologist. RESULTS: Nuclear expression of survivin was present in 1.4% of lesional SH cells, 8.2% of SA cells, and 12.5% of SC cells. A significant difference in survivin expression with the Student t test was noted between SH and SA (P=0.01), SA and SC (P=0.05), and SH and SC (P=0.001). CONCLUSIONS: There is a statistically significant difference in survivin expression among SH, SA, and SC. These findings demonstrate the potential diagnostic utility of survivin, further assisting in the microscopic differentiation of benign and malignant sebaceous neoplasms. However, larger studies are needed to determine the significance of survivin expression as it relates to recurrence, metastatic potential, and outcome.

HER2 and EGFR expression in cutaneous spindle squamous cell carcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) and HER2, members of the Erb family of transmembrane receptor tyrosine kinases (RTK), are responsible for communicating extracellular signals to the nucleus. Moreover, EGFR and HER2 are implicated in tumorgenesis. Immunohistochemical studies have demonstrated that approximately 80% of cutaneous squamous cell carcinomas (SCC) express EGFR. To date, the expression of EGFR and HER2 has not been evaluated in primary cutaneous spindle squamous cell carcinoma (SSC). In extracutaneous spindle squamous cell carcinoma, there is evidence implicating the expression of RTK as a strong, independent prognostic indicator of potentially poor outcome. The purpose of this study is to investigate the expression of EGFR and HER2 in SSC, using immunohistochemical methods. MATERIALS AND METHODS: Thirteen cases of primary nonmetastatic cutaneous SSC archived at a large veterans' hospital and tertiary referral dermatopathology service were retrieved via a computer-assisted search. Immunohistochemistry was used to evaluate the presence of EGFR and/or HER2 expression. All cases were confirmed before study by a single, board-certified dermatopathologist. RESULTS: All 13 cases (100%) evaluated for the presence of HER2 were nonimmunoreactive for the receptor. Only one of the 13 cases (<8%) stained positive for EGFR. CONCLUSIONS: In several malignancies, the overexpression EGFR and HER2 is associated with clinically aggressive behavior. Despite a limited sample size, EGFR and HER2 are not overexpressed in SSC; this is cognate with the current opinion that SSC possesses limited metastatic potential. With prior reports demonstrating that approximately 80% of cutaneous SCC express EGFR, the negative expression of EGFR and HER2 in SSC presents the potential variable nature of the histologic subtypes of SCC, which can have prognostic and therapeutic implications.

Cryptic "chromo-fibroma".

Chromoblastomycosis is an uncommon chronic fungal infection capable of presenting in a variety of clinical guises. Herein, we present the histopathological features of an unusual dermal response engendered by this organism, consisting of dermal effacement by a spindle cell proliferation arranged in sweeping fascicles.

Purple penile papules.

Molluscum contagiosum may present in a variety of clinical and pathologic guises. We present the clinicopathologic features of an unusual case that initially was misinterpreted as bowenoid papulosis. The relevant histologic attributes of this case include the presence of a violaceous hyperplastic squamous epithelium adjacent to the infected keratinocytes. The presence of this violaceous cytoplasmic staining should prompt a search for molluscum in the appropriate clinical context.

A case series and immunophenotypic analysis of CK20-/CK7+ primary neuroendocrine carcinoma of the skin.

BACKGROUND: The diagnosis of Merkel cell carcinoma (MCC) can be rather challenging; therefore, the immunohistochemical profile is important in confirming the microscopic diagnosis. Characteristic of the neuroendocrine and epithelial differentiation of MCC, antibodies to cytokeratin (CK) 20, CK7, epithelial membrane antigen, and neuron-specific enolase among others, are used in confirming the diagnosis. As reported in the literature, the majority of MCC express CK20 and are CK7 negative. Herein, we present a case series of seven patients with CK20-/CK7+ primary cutaneous neuroendocrine carcinoma. METHODS: All cases of MCC with specific CK20-/CK7+ staining on file at a large Veterans' hospital and tertiary referral dermatopathology service were reviewed. All seven cases were analyzed for clinical, pathologic and immunophenotypic attributes. All specimens were submitted for immunohistochemical staining and interpreted by a single dermatopathologist. RESULTS: All the cases showed diffuse cytoplasmic staining for CK7 and positive staining for synaptophysin. CK20 and thyroid transcription factor-1 staining was negative. CONCLUSIONS: Herein we have presented a hitherto unreported group of patients with CK20-/CK7+ primary neuroendocrine carcinoma of the skin. The purpose of this case series is to describe a new immunophenotypic variant of MCC, while further expanding the differential diagnosis of tumors included in the subset of neoplasms showing CK20-/CK7+ staining.