Linglei Ma

Expression of polycomb group protein EZH2 in nevi and melanoma.

Background:  Enhancer of zeste homolog 2 (EZH2), a polycomb group protein that regulates the cell cycle, has recently been implicated in the progression of several human cancers. We sought to determine the pattern of EZH2 expression in benign and malignant melanocytic tumors to see if EZH2 might play a role in melanoma pathogenesis and progression.

From Melanocyte to Metastatic Malignant Melanoma

Malignant melanoma is one of the most aggressive malignancies in human and is responsible for almost 60% of lethal skin tumors. Its incidence has been increasing in white population in the past two decades. There is a complex interaction of environmental (exogenous) and endogenous, including genetic, risk factors in developing malignant melanoma. 8–12% of familial melanomas occur in a familial setting related to mutation of the CDKN2A gene that encodes p16. The aim of this is to briefly review the microanatomy and physiology of the melanocytes, epidemiology, risk factors, clinical presentation, historical classification and histopathology and, more in details, the most recent discoveries in biology and genetics of malignant melanoma. At the end, the final version of 2009 AJCC malignant melanoma staging and classification is presented.

D2-40, a novel immunohistochemical marker in differentiating dermatofibroma from dermatofibrosarcoma protuberans

The distinction between dermatofibroma, particularly cellular variant, and dermatofibrosarcoma protuberans in excisional biopsies is usually straightforward. However, a separation between the two may be sometimes challenging, especially in superficial biopsies. Although factor XIIIa and CD34 immunostains are useful in differentiating dermatofibroma and dermatofibrosarcoma protuberans in most instances, focal CD34 positivity may be seen in cellular fibrous histiocytoma. Some cases reveal overlapping immunostain results. D2-40 identifies a 40-kDa O-linked sialoglycoprotein present on a variety of tissues including testicular germ cell tumors as well as lymphatic endothelium. In this study, we investigated the utility of D2-40 in separating dermatofibroma from dermatofibrosarcoma protuberans and compared the results with other commonly used immunostains. Fifty-six cases of dermatofibroma (including six cellular variant) and 29 cases of dermatofibrosarcoma protuberans were retrieved from the archives of Department of Anatomic Pathology at Sunnybrook Health Sciences Center in University of Toronto. We applied factor XIIIa, CD34, and monoclonal mouse anti-D2-40 immunostains to formalin-fixed, paraffin-embedded tissue sections. All 56 (100%) cases of dermatofibroma demonstrated strong and diffuse immunoreactivity to D2-40 in the spindle cells and stroma. Similarly, factor XIIIa showed strong and diffuse positivity in the spindle cells. Nearly all dermatofibromas were negative for CD34 except one case revealing focal positivity. None of dermatofibrosarcoma protuberans cases were labeled by D2-40, although four cases showed weak and patchy background staining in contrary to diffuse, strong, and crisp staining seen in dermatofibromas. Our results indicate that D2-40 seems to be a sensitive immunohistochemical marker for dermatofibromas, including cellular variant. Focal and faint D2-40 staining may be seen in the stroma of dermatofibrosarcoma protuberans. Our findings suggest that D2-40 can be used as a complementary immunostain to factor XIIIa and CD34 in problematic and challenging cases on superficial biopsies.

Fatal subcutaneous panniculitis‐like T‐cell lymphoma with interface change and dermal mucin, a dead ringer for lupus erythematosus

We report a 48‐year‐old man who presented with ulcerated plaques and nodules of the lower extremities. Skin biopsies revealed a dense lymphocytic infiltrate involving the dermis and the subcutis in a lobular and septal pattern. No overt cytological atypia was present. Notably, several features resembling lupus erythematosus were present, including vacuolar interface change and abundant dermal mucin deposition. The patient developed pulmonary nodules, and a lung biopsy showed a perivascular and interstitial lymphoid infiltrate without overt atypia. The cutaneous and pulmonary lymphoid infiltrates showed similar immunohistochemical profiles: CD3+ CD4– CD8+/– CD56+. Monoclonal rearrangements of the T‐cell receptor γ gene with similar migration patterns were identified from both locations. The patient developed fatal hemophagocytic syndrome, involving liver, spleen, lymph nodes, and bone marrow. This case is one amongst the rare reports of subcutaneous panniculitis‐like T‐cell lymphoma with systemic involvement.

Diagnostic value of CD163 in cutaneous spindle cell lesions

Background:  The histologic diagnosis of atypical fibroxanthoma (AFX) can sometimes be challenging. No specific marker exists to confirm the diagnosis other than excluding other entities. CD163 has been shown to have great specificity for tumors of monocyte/histiocyte lineage. In this study, we evaluated the diagnostic utility of CD163 in diagnosing AFX and in identifying skin lesions with histiocytic/dendritic derivation.

Primary localized laryngeal amyloidosis: report of 3 cases with long-term follow-up and review of the literature.

CONTEXT Localized laryngeal amyloidosis is an uncommon condition with limited long-term follow-up studies. The precise etiology and pathogenesis are not entirely clear. OBJECTIVE To further characterize the histopathologic features and possible pathogenesis of localized laryngeal amyloidosis. DESIGN Three cases of primary localized laryngeal amyloidosis were identified at our institutions from 1980 to 2003. The clinical features and histologic and immunohistochemical patterns were evaluated. Systemic workups were pursued during the long-term follow-up. RESULTS The common presentation of the patients was hoarseness. The lesions involved vocal cords, anterior commissure, and ventricle. Microscopically, the amyloid was present within the submucosa with an adjacent lymphoplasmacytic infiltrate. The plasma cells and amyloid demonstrated monoclonal light chain restriction in all 3 cases (2 lambda, 1 kappa). No evidence of systemic amyloidosis or an overt B-cell lymphoma was found in these patients. Two patients with long-term follow-up underwent subsequent surgical removals for multiple recurrences, which occurred within 1 year of the initial diagnosis. CONCLUSIONS The demonstration of monoclonal light chain expression in the plasmacytic infiltrate and amyloid component in the absence of systemic lymphomas indicates that localized laryngeal amyloidosis may represent a form of benign monoclonal plasma cell dyscrasia. A close follow-up of the patients may be indicated for early detection of recurrences.

The expression of MUM1 in cutaneous T-cell lymphoproliferative disorders

MUM1 is a member of the interferon regulatory factor family of transcription factors. It is normally expressed in plasma cells, late B cells, and activated T cells, and has been described in several B-cell malignancies. Although its expression has been reported in some T-cell neoplasms, the full range and character of expression have not been explored. We studied 58 cases of T-cell lymphoproliferative lesions, including systemic and cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis (LyP), mycosis fungoides (MF), MF with large cell transformation, and Sézary syndrome (SS). Nearly all cutaneous (5/5) and systemic anaplastic large cell lymphomas (4/5) were positive for MUM1, mainly in the large cell population. Similarly, 12 of 16 types A and C LyP showed MUM1 reactivity in greater than 50% of the large cells. Focal MUM1 staining was seen in 3 type B LyP, mostly in reactive lymphoid cells. All 9 MF with large cell transformation expressed MUM1 in large cells, where it paralleled CD30 expression. In comparison, most MF (11/12) were MUM1 negative. Interestingly, all SS cases (8/8) were MUM1 positive, 3 of which demonstrated diffuse staining. There was a significant difference in MUM1 expression between MF and SS groups as well as between MF and large cell transformation of MF groups (P < .001 for both). In summary, MUM1 is not helpful in separating different types of CD30-positive lymphoproliferative disorders. Potentially, MUM1 could serve as an adjunct marker for SS and/or large cell transformation of MF.

Expression of the embryonic morphogen Nodal in cutaneous melanocytic lesions

Nodal, a potent embryonic morphogen in the transforming growth factor-β family, is a proposed key regulator of melanoma tumorigenicity. However, there has been no systematic study of Nodal expression in melanocytic lesions. We investigated Nodal expression by immunohistochemistry in 269 melanocytic lesions, including compound nevi, dysplastic nevi, congenital nevi, Spitz nevi, melanoma in situ, malignant melanoma including the variant desmoplastic melanoma, and metastatic melanoma. We found that the Nodal expression was significantly increased in malignant lesions (including melanoma in situ, malignant melanoma, and metastatic melanoma) compared with compound nevi, Spitz nevi, and dysplastic nevi. Surprisingly, congenital nevi expressed a level of Nodal comparable with malignant lesions, whereas desmoplastic melanoma showed lower expression than nondesmoplastic malignant melanoma (P<0.05). Deep melanoma (Breslow depth >1 mm) displayed a higher percentage of Nodal-positive tumor cells than did superficial melanoma (Breslow depth ≤1 mm), although there was no statistical difference in the overall staining intensity (P=0.18). Melanomas in situ showed a lower level of Nodal expression than did deep melanomas and metastatic melanomas (P<0.05). The low expression of Nodal in normal and dysplastic nevi, and its increasing expression with the progression of malignant lesions, are suggestive of a role for Nodal in melanoma progression.

Expression of γ-H2AX in melanocytic lesions

gamma-H2AX is a marker of activated DNA damage and is overexpressed in many malignancies and their precursor lesions. Previous studies have demonstrated the expression of gamma-H2AX in melanoma and dysplastic nevus, but its diagnostic and prognostic utility in a full range of melanocytic lesions has not been fully studied. In the current study, we investigated gamma-H2AX expression in a total of 162 melanocytic lesions. We found that gamma-H2AX was observed at higher levels (percentage and intensity of staining) in melanoma in situ (12/13), primary cutaneous melanoma (32/33; with the exception of desmoplastic melanoma), and metastatic melanoma (58/62), which was statistically different from that in benign nevus (7/9), dysplastic nevus (6/10), and Spitz nevus (5/9) considered together (P < .0001). Of note, desmoplastic melanoma (20/26) demonstrated weak or negative gamma-H2AX staining. The expression of gamma-H2AX did not show significant correlation with many melanoma prognostic factors, including Breslow depth, mitotic rate, and sentinel lymph node status. Except for desmoplastic melanoma, no difference in gamma-H2AX levels was observed among various melanoma subtypes. The overexpression of gamma-H2AX in melanoma as opposed to nevus indicates its possible role in melanomagenesis. Based on the overlap in subsets of nevi and melanomas, the potential clinical utility of this antibody remains uncertain until further studies have been carried out in a larger cohort of melanocytic lesions, including borderline cases.

DEK expression in melanocytic Lesions

The diagnosis of malignant melanoma presents a clinical challenge and relies principally on histopathological evaluation. Previous studies have indicated that increased expression of the DEK oncogene, a chromatin-bound factor, could contribute to the development of melanoma and may be a frequent event in melanoma progression. Here, we investigated DEK expression by immunohistochemistry in a total of 147 melanocytic lesions, including ordinary nevi, dysplastic nevi, Spitz nevi, melanoma in situ, primary invasive melanomas, and metastatic melanomas. Most benign nevi (ordinary, dysplastic, and Spitz nevi) were negative or exhibited weak staining for DEK, with only 4 of 49 cases showing strong staining. Similar to benign nevi, melanoma in situ also demonstrated low levels of DEK expression. In contrast, the expression of DEK in primary invasive melanomas was significantly higher than benign nevi (P < .0001). Moreover, DEK expression was significantly increased in deep melanomas (Breslow depth >1 mm) and metastatic melanomas as compared with superficial melanomas (Breslow depth ≤1 mm) (P < .05). Our findings indicate that DEK overexpression may be a frequent event in invasive melanomas, and further augmentation of DEK expression may be associated with the acquisition of ominous features such as deep dermal invasion and metastasis. These data suggest a role of DEK in melanoma progression.