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.

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.

Cystic fibrosis transmembrane conductance regulator is helpful in the distinction of extra-mammary Paget's disease from squamous cell carcinoma in situ (Bowen's disease).

Cystic fibrosis transmembrane conductance regulator (CFTR) represents a cAMP-dependent channel found in normal apocrine glands. The classification and histogenesis of extra-mammary Paget's disease (EMPD) remains controversial, but it is generally accepted that primary EMPD exhibits apocrine differentiation. Therefore, we examined the utility of CFTR in the differential diagnosis of EMPD and squamous cell carcinoma in situ (SCCIS). Twenty-five cases of SCCIS and 14 cases of EMPD were evaluated for immunohistochemical expression of CFTR. Expression was scored as 0 (<5% of cells positive), 1+ (5-75% of cells positive) or 2+ (>75% cells positive). Twenty-three of 25 cases of SCCIS showed no reactivity for CFTR, and the remaining 2 cases showed 1+ staining. Thirteen of 14 cases of EMPD showed 2+ staining, while 1 case showed 1+ staining. We recognize that the pathological appearance along with clinical history and site of occurrence are sufficient to distinguish EMPD and SCCIS in most instances. However, distinction between the two can become more challenging when the location and histopathology are not characteristic. We conclude that when an immunohistochemical panel is diagnostically necessary, the expression of CFTR favors a diagnosis of EMPD over SCCIS.

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.

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. METHODS: Skin biopsy specimens from four patients with EH on the extremities were studied. Architecture, extent of vascular proliferation and the presence of epithelioid endothelial cells were evaluated. The features of the inflammatory infiltrate were also assessed, including the distribution, depth, predominant cell type, presence of germinal centers, and distribution and number of CD30+ cells. RESULTS: All cases showed the typical lobular pattern of small vessels centered about a 'feeder' vessel. Larger vessels were lined by epithelioid endothelial cells. The mixed inflammatory infiltrate was nodular, perivascular and periadnexal. Germinal centers were seen in two cases. Large activated CD30+ lymphocytes were seen in all cases. CONCLUSIONS: EH can lead to diagnostic confusion with cutaneous lymphoma and other entities, especially when its mixed inflammatory infiltrate predominates over its vascular component and contains large activated CD30+ lymphocytes. Awareness that the presence of CD30+ activated lymphocytes is not specific for lymphoma and recognition of the vascular component is critical for proper diagnosis of EH.

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. METHODS: Skin biopsy specimens from three patients were evaluated for cytomorphology and degree of associated sclerosis, which was classified as either focal or diffuse. Immunohistochemical expression of epithelial membrane antigen (EMA), CD34 and S-100 was also assessed to facilitate further classification. RESULTS: Histopathologically, the tumors showed both focal and diffuse sclerosis, and lesional cells were generally spindled in shape. Immunohistochemical staining showed diffuse positivity for CD34 and focal or diffuse positivity for EMA. The cells uniformly lacked expression of S-100 protein. CONCLUSIONS: Sclerosing perineuriomas can occur in extra-acral locations and should be considered in the differential of EMA-positive cutaneous spindle-cell proliferations. It is also important to recognize that perineuriomas can express CD34 and should be considered in the differential diagnosis of CD34-positive cutaneous neoplasms.

Development of Pityriasis Amiantacea after Valproic Acid Therapy.

Here, we present the case of a 16-year-old male who developed pityriasis amiantacea (PA) after the use of valproic acid. We propose that the keratinocyte proliferative activity of valproic acid mediated through the inhibition of glycogen synthase kinase-3ß, and subsequent activation of the Wnt/ß-catenin pathway could play a role in the development of PA. We additionally review the most relevant characteristics of this disease.

Ataxia and cranial neuropathies from subcutaneously injected elemental mercury.

CONTEXT. Although neurological toxicity from elemental mercury vapor and organic mercury exposure has been commonly reported in the literature, it is rarely reported from soft tissue injection of elemental mercury. We present a case of neurological dysfunction from subcutaneous injection of elemental mercury. CASE DETAILS. A 35-year-old Latin American man subacutely developed gait ataxia, diplopia, and vomiting 1 year after subcutaneous injection of elemental mercury, a practice common in Afro-Caribbean and Latin-American cultures. Physical examination showed an indurated plaque on his right shoulder at the injection site, left third nerve and bilateral sixth nerve palsies, nystagmus, dysarthria, and gait and limb ataxia. The patient's serum and 24-h urine mercury levels were significantly elevated; he underwent excision of the mercury reservoir and chelation with dimercaptosuccinic acid but experienced only mild improvement after 1 year. DISCUSSION. Neurological sequelae from elemental mercury, specifically cognitive dysfunction, tremor, cortical myoclonus, and peripheral neuropathy, have been reported but cranial neuropathies, ataxia, cerebrospinal fluid pleocytosis, and the presence of anti-Purkinje cell type-Tr antibody have not. Treatment involves removal of any existing mercury reservoir and chelation; however, improvement in neurological dysfunction after treatment has rarely been reported in the literature.

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.

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.

Histopathologic changes of porcine dermis xenografts for transvaginal suburethral slings.

OBJECTIVE: The purpose of this study was to examine the histopathologic changes of HMDI (Hexamethylene di-isocyanate) cross-linked porcine dermis grafts used for suburethral sling surgery. STUDY DESIGN: Twelve patients underwent reoperation with graft removal for urinary retention or recurrent stress urinary incontinence after transvaginal sling surgery. Tissue specimens were available for pathologic evaluation in 7 patients. Graft specimens underwent histologic preparation including hematoxylin and eosin staining. A single pathologist reviewed the slides blinded to clinical outcomes. RESULTS: Histopathologic analyses revealed only limited collagen remodeling, and evidence of a foreign body type reaction was present in some specimens. In cases of recurrent stress incontinence, implants appeared to be completely replaced by dense fibroconnective tissue and moderate neovascularization without evidence of inflammation or graft remnants. CONCLUSION: HMDI cross-linked porcine dermal collagen implants result in variable tissue reactions that may have unpredictable clinical outcomes in different patients, raising questions about the overall tolerability and efficacy of these grafts in pelvic reconstructive surgery.