Thomas A. Victor

The transcriptional repressor SNAIL is overexpressed in human colon cancer.

Overexpression of the transcriptional repressor, SNAIL, has been implicated in the pathogenesis of a number of malignancies; however, there are no previous reports on the role of SNAIL in colorectal cancers (CRCs). We, therefore, evaluated human CRC specimens for the presence of the SNAIL protein. Immunohistochemical studies were performed using samples obtained from archived CRC paraffin blocks and a tissue array. Tissue sections were probed with a polyclonal antibody to human SNAIL and scored by a gastrointestinal pathologist. SNAIL was not detectable in uninvolved mucosa, but immunoreactivity was evident in 78% of tumors. SNAIL protein expression did not correlate with subsite location or gender, however, SNAIL-positive tumors had an older mean age (58.9 ± 12.7 versus 49.8 ± 127; P = 0.028). Furthermore, there was a trend that CRCs with metastatic ability more frequently overexpressed SNAIL (100 versus 65%; P = 0.11). In conclusion, we demonstrate, for the first time, that SNAIL is upregulated in human colon cancer, which potentially may have significance in control of metastasis and possibly serve as a target for chemopreventive agents.

Cyclooxygenase-2 Expression during Immortalization and Breast Cancer Progression

Identification of molecular aberrations in premalignant human mammary epithelial cells (hMEC), the precursors for breast cancers, is a central goal in breast cancer biology. Recent studies implicated expression of cyclooxygenase 2 (COX-2) as a marker to identify precursor cells for breast cancer. In this study, we analyzed COX-2 expression in preselection and postselection hMEC cells and observed similar COX-2 levels in both cells. Interestingly, immortalization of postselection cells using various methods leads to a dramatic decrease in COX-2 expression. Similar to immortal cells, the majority of breast cancer cell lines expressed low levels of COX-2 protein. Finally, analyses of COX-2 expression in a series of specimens from reduction mammoplasty, adenosis, ductal carcinoma in situ, and infiltrating ductal carcinoma showed down-regulation of COX-2 expression during tumor progression. Importantly, down-regulation of COX-2 using small interfering RNA in cells showed no effect on cell proliferation, anchorage-independent growth, migration, or invasion. These results show that (a) COX-2 overexpression does not seem to predict a breast cancer precursor cell and does not provide advantage for the cell to be transformed; (b) inhibition of COX-2 does not affect hMEC growth and oncogenic behavior in the conditions analyzed; and (c) COX-2 expression is decreased in breast cancer cell lines and cancer specimens as compared with normal mammary epithelial cells.

Expression of MiTF may be helpful in differentiating cellular neurothekeoma from plexiform fibrohistiocytic tumor (histiocytoid predominant) in a partial biopsy specimen.

Background Overlapping histopathologic features of cellular neurothekeoma (CNT) and plexiform fibrohistiocytic tumor (PFHT), when both are predominantly composed of histiocytoid cells, make distinction between these entities challenging. Some have suggested that CNT and PFHT are related entities. No prior study has demonstrated a reliable immunohistochemical panel to differentiate these entities. Methods Skin biopsies diagnosed as CNT and PFHT, from 2004 to 2010 were retrieved with accompanying pathology reports. Each case was reviewed by at least 2 dermatopathologists and 2 soft tissue pathologists for confirmation of diagnosis. All cases were then evaluated for immunohistochemical expression of PAX2, NKIC3, CD10, and microphthalmia transcription factor (MiTF). Results Histopathologically, the histiocytoid areas of each tumor shared similar architecture, demonstrating nests and fascicles of histiocytoid to spindled cells, with some separation of nests by collagen bands. Both CNT and PFHT were uniformly positive for NKIC3 and CD10, and both were frequently PAX2 positive. MiTF was strongly and diffusely positive in CNT and was consistently negative in the PFHT. Conclusions CNT and PFHT share many histopathologic features and immunohistochemical staining patterns. Of the stains we evaluated, we found that expression of MiTF may be a reliable marker for distinguishing CNT from histiocytoid-predominant PFHT, especially in instances where only a small part of the tumor is sampled for evaluation.

Diffuse dermal angiomatosis associated with calciphylaxis.

Diffuse dermal angiomatosis (DDA) is a reactive proliferation of vascular channels within the dermis often associated with atherosclerosis. Based on our observation of a case of calciphylaxis (CP) with extensive DDA, we investigated a new possible association and incidence of DDA in patients with CP. These 2 rare conditions had not been reported previously in the same patient. In a retrospective review of skin biopsies taken between 1988 and 2006, 11 patients with histologically proven CP were identified and the medical records were reviewed. Two cases were excluded due to inadequate specimens for a thorough histologic evaluation. Nine patients with large necrotic plaques/ulcers were included in the study. Associated diseases were end-stage renal insufficiency (n = 7), parathyroidectomy for hyperparathyroidism (n = 3), thromboembolic events (n = 3), hypertension (n = 3), and diabetes mellitus (n = 2). Histologically, all cases had some degree of diffuse dermal proliferation of vascular channels with interstitial expression of CD31, as well as subcutaneous fat necrosis and calcification with medial vascular calcification. The extent of DDA did not correlate with the gravity or severity of disease. Based on our observation, DDA is a common histological finding encountered in the dermis adjacent to necrotizing ulcers in patients with CP.

Extra-acral cutaneous/soft tissue sclerosing perineurioma: an under-recognized entity in the differential of CD34-positive cutaneous neoplasms.

Background: Perineuriomas are an uncommon group of tumors composed of perineurial cells of peripheral nerve sheath lineage. Variants include soft tissue (extraneural), intraneural, sclerosing, reticular and plexiform forms. Sclerosing perineuriomas have been reported to occur almost exclusively on the hands of young men. Herein, we report three extra‐acral cutaneous/soft tissue perineuriomas that show significant associated sclerosis.

Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) arising on the extremities

Background: Epithelioid hemangioma (EH) is a benign vascular proliferation usually accompanied by a mixed inflammatory infiltrate.

Cellular neurothekeoma with fascicular growth features mimicking cellular dermatofibroma.

Background:Cellular neurothekeoma (CNT) is a benign cutaneous mesenchymal neoplasm. Most demonstrate a lobulated to micronodular architecture. Rarely, CNT demonstrates a predominantly fascicular growth pattern, without prominent sclerosis and thus can mimic cellular dermatofibroma (DF). Methods:Three CNT with a predominantly fascicular pattern were obtained. The clinicopathologic features and accompanying immunohistochemical stains were evaluated. Results:All cases demonstrated a moderately cellular proliferation of epithelioid to spindle cells with pale to eosinophilic slightly granular cytoplasm, vesicular nuclei, and a single nucleolus arranged in a fascicular pattern with thick collagen bundles at the periphery (collagen trapping). One case had prominent epidermal hyperplasia. The neoplastic cells expressed NKI-C3, CD10, and micropthalmia transcription factor and lacked expression of factor XIIIa, S-100, epithelial membrane antigen, and CD34. Conclusions:Our cases showed an unusual pattern of CNT with a predominantly fascicular growth pattern, thickened collagen bundles at the periphery, and occasionally epidermal hyperplasia. The overlap with cellular DF is striking. The presence of plump to epithelioid cytomorphology with abundant cytoplasm, with focally prominent nucleoli; the presence of focal lobulated to micronodular growth pattern along with micropthalmia transcription factor positivity; and lack of factor XIIIa expression are helpful in distinguishing fascicular CNT from cellular DFs.

Bilateral areolar leiomyomas in a patient undergoing BRAF inhibition therapy for melanoma.

BRAF inhibition therapy, used to treat melanomas with BRAF mutations, is associated with both neoplastic and non‐neoplastic cutaneous side effects including squamous cell carcinomas, warty dyskeratomas, verrucous keratoses, photosensitivity and widespread eruptions that present histopathologically as acantholytic dyskeratosis. We report a case of a patient undergoing BRAF inhibition therapy for disseminated melanoma with a V600E mutation who developed bilateral areolar leiomyomas, one of which was biopsied and the other of which resolved after discontinuation of vemurafenib therapy. To our knowledge, this is the first reported case of a mesenchymal neoplasm developing in association with BRAF inhibition therapy.

Granulomatous and lichenoid dermatitis after IgG4 anti-PD-1 monoclonal antibody therapy for advanced cancer

Nivolumab is a fully human IgG4 monoclonal antibody directed against programmed cell death protein 1 (PD‐1). PD‐1 inhibition allows T‐cell activation and recruitment to destroy cancer cells. Checkpoint inhibitors have shown significant survival advantage and relatively low side‐effects in comparison with conventional chemotherapy in several types of advanced cancer. Granulomatous cutaneous reactions have been reported showing sarcoidal and panniculitic morphology. Here we present a case of drug‐induced lichenoid and granulomatous dermatitis after checkpoint inhibitor therapy observed in a 63‐year‐old male treated with nivolumab for advanced glioblastoma. This morphology has not been previously reported. We documented a high number of CD8+ T‐cells within the lesions. Additionally, we review the side‐effects observed with the use of checkpoint inhibitors, with special focus on cutaneous manifestations.

Spindle cell lipoma with collagen rosettes.

To the Editor, Spindle cell lipoma classically occurs as a solitary, subcutaneous mass on the back, neck or shoulder area of middle-aged men. In contrast, intradermal spindle cell lipomas are more common in women and show no site predilection. Histopathologically, spindle cell lipomas are composed of variable proportions of mature adipocytes and a fibrous or myxoid stroma with short-spindled cells and characteristic ropey collagen. The spindled cells have elongated nuclei, which are characteristically arranged in short parallel arrays described as ‘schools of fish’. Sometimes, a palisaded configuration reminiscent of a neural neoplasm is present. The spindle cells uniformly express CD34. Rarely, there may be a significant vascular component, conspicuous myxoid stroma or osseous/cartilaginous metaplasia, and these alterations can cause diagnostic difficulty. Previously described microscopical variants include pleomorphic, ‘low-fat’ or ‘fat-free’, myxoid, hemangiopericytoma-like, or pseudoangiomatous spindle cell lipomata.1,2 Herein, we present a previously unreported distinctive variant of spindle cell lipoma containing collagen rosettes. We briefly discuss the differential diagnosis for spindle cell proliferations that form rosettes and pseudorosettes. A 47-year-old female presented with a right shoulder mass. The submitted specimen consisted of a 1.0 × 0.6 cm2 ellipse of unremarkable skin with underlying subcutaneous tissue that had been excised to a depth of 2.6 cm. On gross examination, the subcutaneous tissue was noted to have a nodular appearance. Histopathological examination revealed a relatively well-circumscribed, moderately cellular spindle cell proliferation within the reticular dermis and subcutis. The spindled cells were embedded within a ropey collagenous matrix with a minor component of adipose tissue, thus resembling a ‘low-fat’ spindle cell lipoma. Additionally, there were multiple foci in which the spindle cells condensed around A