Enhanced cutaneous Rock2 expression as a marker of Rho Kinase pathway activation in autoimmune disease and Kohlemeier-Degos disease.

The small guanosine triphosphatase Rho and its target Rho kinase are involved in a heterogeneous spectrum of cellular activities, many of which are integral to cytoskeletal organization. Furthermore, the Rho kinases result in NF kappa beta activation and hence the induction of various pro-inflammatory cytokines including TNF-alpha, IL-1B and IL-6. ROCK2 is a downstream protein, whose expression is indicative of Rho Kinase activation. Given the diverse effects of Rho-kinase, including a potentially critical role in augmenting inflammation, ROCK2 expression was examined in biopsies of select autoimmune connective tissue diseases as compared to control diagnoses. Select cases of lupus erythematosus, dermatomyositis, autoimmune sclerodermoid disorders and Kohlmeier-Degos disease (a distinctive vasculopathy that occurs in the other aforesaid conditions but also as a forme fruste microvascular and arteriopathic syndrome) were studied. Control biopsies included normal skin and cutaneous inflammatory conditions unrelated to collagen vascular disease/autoimmune disease. We found ROCK2 expression significantly increased in biopsies of lupus erythematosus, dermatomyositis, scleroderma and Kohlmeier-Degos disease. A pattern emerged of consistent marked ROCK2 upregulation in endothelium and variable expression in inflammatory cells and epithelium. While expression was undetectable in normal skin, it was found in inflamed skin unrelated to specific autoimmune disease. The staining pattern could approach that seen in study group cases but was less pronounced and preferentially upregulated in the endothelium, with a lesser extent of staining in the epidermis and inflammatory cells. Rho kinase is a driving factor in diverse cutaneous diseases especially autoimmune disease and Kohlmeier-Degos disease. This significantly upregulated pathway defines a potential target for biologic therapy.

Monoclonal plasma cell infiltrates in the setting of cutaneous follicular helper T cell lymphoproliferative disorders.

There is a growing recognition that some primary cutaneous T cell lymphomas of the skin exhibit a follicular helper T cell phenotype best exemplified by primary cutaneous CD4+ small/medium sized pleomorphic T cell lymphoma. The follicular helper T cells is an evolutionary function in a common TH1 cell under the influence of other cell types most notably monocyte derived dendritic cells but also plasma cells. In addition, the skin defines a characteristic organ site of involvement for angioimmunoblastic T-cell lymphoma (AITL); the first recognized form of follicular helper T cell lymphoma. One of the hallmarks of the follicular helper T cell lymphomas a significant degree of post germinal center B cell hyperplasia. We encountered 7 cases of primary cutaneous follicular helper T cell and four cases of AITL, in which the biopsies contained a light chain restricted plasma cell infiltrate in the skin. There were no features that suggested an atypical or more aggressive clinical course in association with the identification of this light chain restricted plasmacytic infiltrates except one case of AITL in whom a diffuse large cell B cell lymphoma subsequently developed. There was no association with Epstein-Barr virus (EBV) infection light chain restricted plasma cell infiltrate in any of the eleven cases. The basis of these infiltrates is likely a reciprocal functional one reflecting the role of follicular helper T cells in the induction of B cell hyperplasia and the role of plasma cells as a countercheck balance controlling the extent of follicular helper T cell hyperplasia. B cell clonality, plasma cell atypia and blastic B cell transformation can occur without implying a malignant transformation.

BAP1-deficient tumor/nevus with germline aberration: A potential pitfall in assessing melanocytic neoplasms with single nucleotide polymorphism array.

BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene, located on chromosome 3p21, encoding BAP1 nuclear protein, which is associated with a subset of melanocytic tumors with distinct cytologic features. Single nucleotide polymorphism array (SNP-array) is a molecular karyotyping technique that can detect copy number variations and loss of heterozygosity in various fresh and formalin-fixed paraffin-embedded tissues. Herein we present a 56-year-old female, who presented with a lesion on her left nose/cheek that was growing in size and changing in color. Histopathology was characteristic of a BAP1-deficient melanocytic neoplasm, with a biphasic population of cytologically bland conventional nevomelanocytes and a proliferation of large epithelioid melanocytes with abundant eosinophilic cytoplasm. Immunohistochemistry for BAP1 showed loss of nuclear labeling in the epithelioid melanocytes. SNP-array revealed a chromosome 21q22.1 monoaberration with no chromosome 3 abnormalities. The detection of this aberration prompted a discussion as to whether the lesion was best designated as a nevus or tumor. SNP-array on the patient's blood showed the same monoaberration of chromosome 21q22.1. This case emphasizes the importance of interpreting microarray results in the context of morphology, as germline aberrations can be a pitfall when assessing the genomic stability of a melanocytic proliferation by SNP array.

Epidermotropic presentation by splenic B-cell lymphoma: The importance of clinical-pathologic correlation.

There are exceedingly rare reports of patients with epidermotropic B-cell lymphomas. A subset presented with intermittent, variably pruritic papular eruptions and involvement of their spleens, peripheral blood and bone marrow at the time of diagnosis. Furthermore, some experienced an indolent course despite dissemination of their lymphomas. We report a 66-year-old woman with a 12-year history of intermittent eruptions of non-pruritic, salmon-colored papules on her torso and proximal extremities that occurred in winter and resolved with outdoor activity in spring. Skin biopsy revealed an epidermotropic B-cell lymphoma with a non-specific B-cell phenotype and heavy chain class switching with IgG expression. On workup, our patient exhibited mild splenomegaly and low-level involvement of her peripheral blood and bone marrow by a kappa-restricted B-cell population. A splenic B-cell lymphoma was diagnosed. Considering her longstanding history and absences of cytopenias, our patient has been followed without splenectomy or systemic therapy. Furthermore, the papules have responded dramatically to narrowband UVB. Our case and a review of similar rare reports aim to raise awareness among dermatopathologists and dermatologists of a clinically distinct and indolent subset of epidermotropic splenic lymphomas with characteristic clinical and histologic findings.

Evaluating melanocytic lesions with single nucleotide polymorphism (SNP) chromosomal microarray.

Histopathology is the gold standard for diagnosing melanocytic lesions; however, distinguishing benign versus malignant is not always clear histologically. Single nucleotide polymorphism (SNP) microarray analysis may help in making a definitive diagnosis. Here, we share our experience with the Oncoscan FFPE Assay and demonstrate its diagnostic utility in the context of ambiguous melanocytic lesions. Eleven archival melanocytic lesions, including three benign nevi, four melanomas, three BAP1-deficient Spitzoid nevi and one nevoid melanoma were selected for validation. SNP-array was performed according to the manufacturer's protocol, using the recommended 80ng of DNA; however, as little as 15ng was used if the extraction yield was lower. Concordance was assessed with H&E and various combinations of BAP1 and p16 immunohistochemical stains (IHC) and external reference laboratory chromosomal microarray results. After validation, the SNP array was utilized to make definitive diagnoses in four challenging cases. Oncoscan SNP array findings were in concordance with H&E, IHC, and reference laboratory chromosomal microarray testing. The SNP-based microarray can accurately detect copy number changes and aid in making a more definitive diagnosis of challenging melanocytic lesions. This can be accomplished using significantly less DNA than is required by other microarray technologies.

Association of IgG4 response and autoimmune pancreatitis with intraductal papillary-mucinous neoplasms.

OBJECTIVES: Concurrent intraductal papillary-mucinous neoplasm (IPMN) and autoimmune pancreatitis (AIP) was observed in a patient (index case) at our institution. Cases of coincidental IPMN and type 1 AIP and concurrent ductal adenocarcinoma (PDAC) and AIP have been previously reported. In this study we evaluate the hypothesis that IPMN elicits an IgG4 response. METHODS: Twenty-one pancreases (including the index case) with IPMN resected at our institution were studied. H&E stained slides were reviewed and blocks of peritumoral pancreas were immunostained with IgG4 to look for IgG4-positive plasma cells. RESULTS: We found evidence of variable IgG4 overexpression in 4/21 (19%) of IPMN. These included the index case and three others without stigmata of AIP. CONCLUSION: A small subset of pancreatic neoplasms including intraductal papillary-mucinous neoplasms (IPMN) is associated with an IgG4 autoimmune response that sometimes progresses to peritumoral type 1 AIP and less often to diffuse AIP and IgG4-related systemic disease.

Fatal hemorrhage due to a spontaneous factor V inhibitor with lupus anticoagulant properties.

: Factor V inhibitors are rare and have varied clinical presentations. We report on a 76-year-old female admitted to the hospital for pneumonia and treated with multiple antibiotics. Her baseline prothrombin time was 15.6 s and the activated partial thromboplastin time was 35 s. On admission day 10, she developed arm weakness and brain imaging showed a subdural hematoma. The prothrombin time was now 59.1 s with an activated partial thromboplastin time of more than 160 s and a normal thrombin time. A mixing study did not correct the clotting times and coagulation factor assays showed a nonspecific inhibition pattern. Only factor V activity remained low with serial dilutions, however, and a 70 Bethesda Unit inhibitor was identified. Aggressive supportive care was initiated but the patient succumbed to the effects of the intracranial hemorrhage. Factor V inhibitors may display lupus anticoagulant properties and may cause catastrophic bleeding. Our case illustrates that these inhibitors can arise quickly and supports an association with antibiotics.

Proliferative lesion of anogenital mammary-like glands in the setting of Cowden syndrome: case report and review of the literature.

Mammary-like glands are normal appendages of anogenital skin and can give rise to epithelial and stromal tumors that closely resemble breast tumors. Cowden syndrome is an autosomal-dominant cancer-predisposition syndrome that is associated with increased risk of various benign and malignant tumors including breast cancers. Here, we report the first case of a proliferative lesion of mammary-like glands in the setting of Cowden syndrome. A 27-year-old female with Cowden syndrome (R130Q-PTEN mutation) presented with a 1-cm tender, polypoid perianal lesion. An excisional biopsy revealed a circumscribed, lobulated lesion with fibromyxoid stroma and epithelial hyperplasia with apocrine and columnar cell changes that was arranged in papillary, micropapillary and focal cribriform architecture. The features strikingly resembled proliferative changes commonly seen in the breast. Interestingly, the patient subsequently developed an atypical complex sclerosing lesion of the breast. Given the increased risk of breast neoplasia in Cowden syndrome, and the morphologic relationship between breast glands and mammary-like glands, this case raises the possibility of an increased risk of neoplasia arising in mammary-like glands in the setting of Cowden syndrome.