Albert Su

SOX10 expression distinguishes desmoplastic melanoma from its histologic mimics.

Abstract:Desmoplastic melanoma (DM) presents diagnostic challenges due to histologic mimics and limited immunohistochemical staining. Although S100 usually stains DM, other melanoma markers (HMB-45 and Melan-A) are often negative. Dermal/subcutaneous mimics of DM [spindle cell/poorly differentiated squamous cell carcinoma, atypical fibroxanthoma (AFX), and sarcoma] show negative or unreliable immunohistochemical staining. Recently, SOX10 expression has been shown to be a sensitive and specific marker of DM. However, there are no published studies comparing the sensitivity and specificity of SOX10 for DM compared with its most common histologic mimics of the dermis/subcutis. We examined 76 cases, including DM (n = 15), spindle cell/poorly differentiated carcinoma (n = 18), AFX (n = 13), sarcoma with spindled morphology (n = 20), and malignant peripheral nerve sheath tumor (MPNST) (n = 10). Most (75%, 15/20) of sarcomas were centered in the dermis/subcutis and included sarcoma not otherwise specified, DFSP with sarcomatous transformation and myxofibrosarcoma. SOX10 was diffusely positive in 100% (15/15) of DMs and showed focal staining in 30% (3/10) of MPNSTs. All other tumors were negative for SOX10 [0% (0/18) of carcinomas, 0% (0/13) of AFXs, 0% (0/20) of sarcomas]. In conclusion, SOX10 is a highly useful marker to confirm the diagnosis of DM. In our study, SOX10 showed 100% sensitivity for DM and SOX10 was negative in all histologic mimics of the dermis/subcutis, including spindle cell carcinoma, AFX and sarcomas. Similar to S-100 protein, some MPNSTs show scattered positivity but did not show diffuse positivity seen in DM.

Secretory Carcinoma of the Skin Harboring ETV6 Gene Fusions: A Cutaneous Analogue to Secretory Carcinomas of the Breast and Salivary Glands.

Mammary analogue secretory carcinoma is a low-grade salivary gland carcinoma that exhibits analogous features to secretory carcinoma of the breast including the presence of a t(12;15) translocation resulting in the ETV6-NTRK3 gene fusion. Rare cases of purported secretory carcinoma of the skin adnexa have been reported, but their relationship to true secretory carcinoma of the breast and salivary glands is unclear, as they generally do not harbor ETV6 rearrangements. Cases of cutaneous neoplasms with histologic features identical to secretory carcinoma of the breast and salivary glands were identified from the consultation files of 3 academic medical institutions. Immunohistochemistry was performed for S100 protein, mammaglobin and STAT5a. Break-apart fluorescence in situ hybridization was used evaluate for disruption of the ETV6 gene. Six cases of cutaneous secretory carcinoma were identified. The tumors arose in 4 women and 2 men, ranging from 24 to 71 years in age (mean, 47 y). The carcinomas presented in the skin of the axilla (n=4), ventral neck (n=1), and cheek (n=1). The tumors arose in the superficial dermis in association with adnexal structures. None of the patients had a prior or concurrent breast or salivary gland tumor. They were histologically characterized by well-circumscribed but unencapsulated proliferations of bland, eosinophilic cells arranged in microcysts and follicles with intraluminal secretions. Ectopic breast or salivary gland tissue was not identified. The cases were diffusely positive for S100 protein (6 of 6), mammaglobin (6 of 6), and STAT5a (5 of 5). All 6 cases harbored rearrangements of ETV6. All tumors were treated by simple excision alone. No recurrences or metastases developed in the 2 cases with follow-up. Secretory carcinoma of the skin represents a phenotypic, immunohistochemical, and genetic counterpart to secretory carcinoma of the breast and salivary glands. This tumor entity is less anatomically restricted than previously supposed.

Intralymphatic cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis: expanding the spectrum of CD30-positive lymphoproliferative disorders.

Intravascular large B-cell lymphomas and EBV+ NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30+ T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK− ALCL. One ALK+ ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30+ TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK− ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK+ ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK− ALCL and related CD30+ ALK− TLPDs involving the lymphatics are part of an expanding spectrum of CD30+ TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.

Keratoacanthoma and squamous cell carcinoma are distinct from a molecular perspective

Keratoacanthoma is a controversial entity. Some consider keratoacanthoma as a variant of squamous cell carcinoma, whereas others see it as a distinct self-resolving squamoproliferative lesion. Our objective is to examine the relationship of keratoacanthoma with squamous cell carcinoma and normal skin by using DNA microarrays. DNA microarray studies were performed on formalin-fixed and paraffin-embedded blocks from ten cases of actinic keratoacanthoma utilizing the U133plus2.0 array. These results were compared with our previously developed microarray database of ten squamous cell carcinoma and ten normal skin samples. Keratoacanthoma demonstrated 1449 differentially expressed genes in comparison with squamous cell carcinoma (>5-fold change: P<0.01) with 908 genes upregulated and 541 genes downregulated. Keratoacanthoma showed 2435 differentially expressed genes in comparison with normal skin (>5-fold change: P<0.01) with 1085 genes upregulated and 1350 genes downregulated. The most upregulated genes, comparing keratoacanthoma with normal skin included MALAT1, S100A8, CDR1, TPM4, and CALM1. The most downregulated genes included SCGB2A2, DCD, THRSP, ADIPOQ, adiponectin, and ADH1B. The molecular biological pathway analysis comparing keratoacanthoma with normal skin showed that cellular development, cellular growth and proliferation, cell death/apoptosis, and cell cycle pathways are prominently involved in the pathogenesis of keratoacanthoma. The most enriched canonical pathways were clathrin-mediated endocytosis signaling, molecular mechanisms of cancer and integrin signaling. The distinctive gene expression profile of keratoacanthoma reveals that it is molecularly distinct from squamous cell carcinoma. The molecular pathways and genes differentially expressed in comparing keratoacanthoma with normal skin suggest that keratoacanthoma is a neoplasm that can regress due to upregulation of the cell death/apoptosis pathway.

Is sentinel node susceptibility to metastases related to nodal immune modulation

Sentinel lymph nodes (SLNs), the initial site of regional metastases, directly receive lymph containing immune-modulatory cytokines and tumor cells from primary melanomas. Immune-suppressed SLNs are ideal for studies of tissue susceptibility to metastases. They show reduced antigen-presenting dendritic cells, activated T cells, high endothelial venules, and transvenular immigration of T cells. Tumor-induced immune suppression contributes to establishment of nodal metastases. SLNs may serve as an effective model to study reversal of tumor-induced immune suppression. We reviewed this topic in Nature Reviews of Immunology in 2006. We here summarize the Nature paper and provide additional results from ongoing studies and the recent literature.

De novo congenital melanoma: analysis of 2 cases with array comparative genomic hybridization.

Congenital melanoma is extraordinarily rare, and 3 types have been described: transplacental metastases from the mother, de novo congenital melanoma, and melanoma occurring in association with a congenital melanocytic nevus. We describe 2 reports of array comparative genomic hybridization analysis of de novo congenital melanoma. The first patient was male, and the second was female; both had a scalp lesion present at birth, which grew quickly. The scalp mass from patient 1 showed a heterogeneous, anaplastic melanocytic neoplasm with large size and depth, high mitotic rate, ulceration, and necrosis. The scalp mass from patient 2 showed a broad melanocytic neoplasm with single cell and junctional nested proliferation at the dermal-epidermal junction and cellular, confluent aggregates of highly atypical melanocytes in the dermis with high mitotic rate. Patient 1 had lung and liver metastases detected by radiologic imaging and was treated with cisplatin, vinblastine, and dacarbazine but expired at the age of 5 months. Patient 2 developed a metastasis to the right neck with similar histologic features, and pulmonary metastases were also detected by imaging. Patient 2 is currently alive at the age of 4 years. Array comparative genomic hybridization analysis of the first case revealed loss of chromosomes 3p26.3-p21.31, 5p15.33-q23.1, 11q15.5-q13.2, 14 (complete deletion), and 15q11.1-q22.31. The second case displayed gains in chromosomes 1q21.1-q44, 2p25.3-p11.1, 2q11.1-q37.3, 6p25.3-p11.1, 7p22.3-p11.2, 7q11.1-q36.3, 8p23.3-p11.1, 8q11.1-q24.3, 9p24.3-p11.2, 9q12-q34.3, 11q13.2-q13.4, 13q11-q34, 18p11.32-p11.21, 19p13.3-p11, 19q11-q13.43, 20p13-p11.1, and 20q11.21-q13.33. In both cases, the presence of multiple chromosomal aberrations corroborated the diagnosis of melanoma.

A unique case of sclerosing polycystic adenosis of the sinonasal tract

Sclerosing polycystic adenosis is an extremely uncommon, recently described, sclerosing lesion of the salivary glands that appears histologically similar to fibrocystic changes of the breast. The key histopathologic features of sclerosing polycystic adenosis include lobular proliferation of ductal and acinar elements, cystically dilated ducts exhibiting frequent apocrine and sebaceous metaplasia, eosinophilic intracytoplasmic granules within some acinar-type cells, intraductal epithelial hyperplasia, and dense fibrosis. Most described cases have occurred in the major salivary glands, particularly the parotid gland. Although most authorities consider sclerosing polycystic adenosis to be a pseudoneoplastic process, the occurrence of dysplasia and carcinoma in situ of ductal epithelium reported recurrence rates of up to 30%, and recent evidence of clonality suggests a possible neoplastic etiology. However, there have been no cases of metastasis. Herein, we report the first case of sclerosing polycystic adenosis of the sinonasal tract in a 79-year-old woman presenting with a sinonasal mass.

Differentiating cutaneous squamous cell carcinoma and pseudoepitheliomatous hyperplasia by multiplex qRT-PCR

Squamous cell carcinoma is the second most common cutaneous malignancy. The diagnosis can occasionally be difficult as there are many lesions that are mimics, clinically and on pathologic examination. One of the most challenging lesions to differentiate from squamous cell carcinoma is pseudoepitheliomatous hyperplasia, a reactive proliferation of the epidermis that can be encountered secondary to a variety of inflammatory and neoplastic conditions. Utilizing the data set from our previously performed DNA microarray studies on formalin-fixed and paraffin-embedded tissue, we found that the genes C15orf48 and KRT9 had a distinct and robust gene expression pattern in distinguishing squamous cell carcinoma from pseudoepitheliomatous hyperplasia. C15orf48 had higher expression than KRT9 in squamous cell carcinoma, but lower expression than KRT9 in pseudoepitheliomatous hyperplasia. We developed and blindly validated a multiplex TaqMan PCR assay that utilizes these two highly discriminatory genes, which can be performed on material extracted from formalin-fixed and paraffin-embedded tissue. The TaqMan assay was able to differentiate squamous cell carcinoma from pseudoepitheliomatous hyperplasia in 54 of 58 cases (93%). Squamous cell carcinoma was accurately identified in 27 of 28 cases (96%); pseudoepitheliomatous hyperplasia in 27 of 30 cases (90%). This multiplex TaqMan PCR assay may be used as a helpful ancillary molecular diagnostic test to accurately distinguish squamous cell carcinoma from pseudoepitheliomatous hyperplasia in challenging cases.

Pleomorphic adenoma of the vulva, clinical reminder of a rare occurrence

Pleomorphic adenoma, also known as mixed tumor, is a benign tumor which typically presents as a painless and persistent mass. The majority of pleomorphic adenomas involve the salivary glands, most commonly the parotid gland. Other sites include breast and skin. It is a rare tumor in the vulva. In this article we are reporting a case of pleomorphic adenoma of labia with characteristic pathologic and clinical findings, as reminder of a common benign neoplasm occurring with rare locality.

Squamous Cell Carcinoma Arising From Keratoacanthoma: An Evaluation by RT-PCR.

and squamous eddies. The pathophysiology behind FI in the various previously reported associations is unclear. In general, the prevailing theory is that there is a release of cytokines from mesenchymal tissue that induce epidermal differentiation of adnexal structures. Induction of other adnexal structures, particularly sebaceous differentiation, is very common in association with dermatofibromas. Park et al recently summarized the spectrum of etiologies that have been proposed to date for induction of follicular differentiation in the assorted observed cutaneous pathologies. Interestingly, a recent study suggests that, although the normal embryologic development of hair follicles is dependent on molecular crosstalk between the dermis and epidermis, FI is triggered by an initial epidermal signal. It is unclear how epidermal signaling and regeneration change in the setting of abnormal, dermal cellular proliferations such as dermatofibromas and other intradermal tumors. In the case of an intradermal melanocytic nevus, it is possible that there are some unidentified characteristics that melanocytes, as normal epidermal cells, possess that may result in an ability to induce the molecular crosstalk to enable follicular differentiation. The association of an intradermal nevus with overlying FI has not previously been reported in the literature. The present case calls into question the mechanism of FI and the role of melanocytes in the molecular crosstalk between the epidermis and dermis in the differentiation of adnexal structures. Many authors have also called into question whether tumor of FI might represent a spectrum of reactive changes associated with other tumors (as nearly 25% of cases occur in association with other neoplasms). Additionally, dermatopathologists should consider follicular differentiation overlying intradermal nevi in the differential diagnosis of collision lesion of nevus with basal cell carcinoma or follicular tumors.