Interobserver Agreement Across Subspecialties for Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia and Predictive Values of 20 Histologic Features.

CONTEXT.­: Differentiated vulvar intraepithelial neoplasia (dVIN) is a human papillomavirus-independent lesion with the potential for rapid progression to invasive squamous cell carcinoma (SCC). The histopathologic features of dVIN are diverse, have overlapping characteristics with lichen sclerosus (LS) and lichen simplex chronicus (LSC), and may be diagnosed by dermatopathologists or gynecologic pathologists because of the vulva's anatomic location. OBJECTIVES.­: To identify the salient histopathologic features of dVIN, particularly those that predict progression to SCC, and to evaluate interobserver agreement in diagnosing dVIN within the same subspecialty and across subspecialties. DESIGN.­: One general surgical pathologist, 2 pathology-trained dermatopathologists, and 1 gynecologic pathologist blinded to the final diagnoses were asked to record 20 histopathologic features and to provide their final interpretations on cases of dVIN (n = 65), LS (n = 126), LSC (n = 112), and LS with LSC (n = 6). RESULTS.­: Interobserver agreement for the 4 diagnoses and 10 histopathologic features was moderate. Logistic regression analysis indicated that keratin pearls, basal pleomorphism, and basal layer disarray were independent variables for diagnosing dVIN (coefficients 1.95, 1.97, and 0.91, respectively; P < .001) and progression to SCC (coefficients 1.96, 1.20, and 1.08, respectively; P < .001). CONCLUSIONS.­: There is no single histopathologic feature pathognomonic for dVIN; however, the presence of keratin pearls, basal pleomorphism, and basal layer disarray should raise high suspicion for dVIN and concurrent SCC. Expertise in both dermatologic and gynecologic pathology is beneficial for diagnosing dVIN.

p53/CK17 Dual Stain Improves Accuracy of Distinction Between Differentiated Vulvar Intraepithelial Neoplasia and Its Mimics.

Accurate diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN) is challenging, in part due to the sometimes subtle nature of its atypia. Many dVIN lesions demonstrate aberrant p53 staining; however, staining patterns overlap between dVIN and benign/reactive entities. We evaluate a p53/CK17 dual stain in an initial cohort of dVIN (n=30), benign vulvar skin (n=5), lichen sclerosus (LS, n=10), lichen simplex chronicus (LSC, n=10), and pseudoepitheliomatous hyperplasia (PEH, n=10). In the initial cohort, aberrant p53 staining was seen only in dVIN (50%, 15/30). Equivocal p53 staining patterns were seen in dVIN (37%, 11/30), LS (50%, 5/10), LSC (40%, 4/10), and PEH (40%, 4/10). All 30 dVIN cases were positive for CK17 (strong partial-thickness or full-thickness staining), but positive CK17 staining was also seen in LS (70%, 7/10), LSC (50%, 5/10), and PEH (100%, 10/10). In the initial cohort, the combination of aberrant p53 and positive CK17 was seen only for dVIN (50%, 15/30). Forty cases of LS with known follow-up (20 with progression to dVIN, 20 without) were stained to assess prognostic value. Three LS cases showed aberrant p53 staining with CK17 positivity; all progressed to dVIN. Equivocal p53 staining and CK17 positivity were seen in cases with and without progression. The p53/CK17 dual stain is more diagnostically useful than either stain alone. Negative/focal staining for CK17 argues against a diagnosis of dVIN, while aberrant p53 staining with CK17 positivity strongly supports the diagnosis.

KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Noncanonical Activin Pathway.

BACKGROUND & AIMS: Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A (lysine demethylase 6A) in PDAC development. METHODS: We performed a pancreatic tissue microarray analysis of KDM6A protein levels. We used human PDAC cell lines for KDM6A knockout and knockdown experiments. We performed bromouridine sequencing analysis to elucidate the effects of KDM6A loss on global transcription. We performed studies with Ptf1aCre; LSL-KrasG12D; Trp53R172H/+; Kdm6afl/fl or fl/Y, Ptf1aCre; Kdm6afl/fl or fl/Y, and orthotopic xenograft mice to investigate the impacts of Kdm6a deficiency on pancreatic tumorigenesis and pancreatitis. RESULTS: Loss of KDM6A was associated with metastasis in PDAC patients. Bromouridine sequencing analysis showed up-regulation of the epithelial-mesenchymal transition pathway in PDAC cells deficient in KDM6A. Loss of KDM6A promoted mesenchymal morphology, migration, and invasion in PDAC cells in vitro. Mechanistically, activin A and subsequent p38 activation likely mediated the role of KDM6A loss. Inhibiting either activin A or p38 reversed the effect. Pancreas-specific Kdm6a-knockout mice pancreata showed accelerated PDAC progression, developed a more aggressive undifferentiated type of PDAC, and increased metastases in the background of Kras and p53 mutations. Kdm6a-deficient pancreata in a pancreatitis model had a delayed recovery with increased PDAC precursor lesions compared with wild-type pancreata. CONCLUSIONS: Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a noncanonical p38-dependent activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be used as a therapeutic target for KDM6A-deficient PDACs.

Uterine PEComatosis With TSC1 Mutation in a Patient With Tuberous Sclerosis: Case Report and Literature Review.

Uterine PEComatosis is a rare phenomenon characterized by the presence of multiple perivascular epithelioid cell tumors (PEComas) and/or microscopic proliferations of perivascular epithelioid cells. Herein, we report a case of PEComatosis arising in a 49-yr-old woman with a known history of tuberous sclerosis. Targeted next-generation sequencing revealed a TSC1 stopgain mutation (p.Q732X) in all tested nodules, with single-copy TSC1 loss or copy-neutral TSC1 loss of heterozygosity. To our knowledge, this is the second report of TSC1 inactivation in uterine PEComa and the first report of confirmed TSC1 abnormalities in PEComatosis.

Fat necrosis with an associated lymphocytic infiltrate represents a histopathologic clue that distinguishes cellular dermatofibroma from dermatofibrosarcoma protuberans.

BACKGROUND: Cellular dermatofibromas (CDFs) and dermatofibrosarcoma protuberans (DFSP) can be challenging to differentiate from one another. Morphologically, both entities commonly extend into the subcutis, exhibit high cellularity with limited cytologic atypia and have a mixed fascicular-to-storiform growth pattern. We sought to evaluate the significance of fat necrosis with an associated lymphocytic infiltrate as a histopathologic clue for distinguishing CDFs from DFSP. METHODS: We identified cases in our pathology database with a primary diagnosis of CDF or DFSP. Punch or excisional biopsy specimens with extension into the subcutis were selected. Previously biopsied lesions and specimens that did not interact with the subcutis were excluded. Histopathologic features were evaluated in hematoxylin and eosin stained sections. RESULTS: Fat necrosis with lymphocytic infiltrate was present in 20/20 cases of CDF. None of the 20 DFSP cases had fat necrosis with lymphocytic infiltrate although 4/20 had fat necrosis alone. CONCLUSIONS: Fat necrosis with associated lymphocytic response can aid in the distinction between CDF and DFSP.

The diagnosis of clinically significant oesophageal Candida infections: a reappraisal of clinicopathological findings.

AIMS: Distinguishing true oesophageal Candida infections from oral contaminants is a common diagnostic issue. Historically, histological features believed to indicate true infection included epithelial invasion by pseudohyphae and intraepithelial neutrophils. Whether or not these features correlate with endoscopic lesions, symptoms and response to therapy has never been tested in a large cohort. The aim of this study was to determine whether specific histological features correlate with clinical and endoscopic findings when Candida is found in oesophageal biopsies. METHODS AND RESULTS: We reviewed 271 biopsies in which Candida was detected. Cases were evaluated for the presence of desquamated epithelial cells, location/type of fungal forms, neutrophils, and ulceration. Medical records were reviewed for clinical history, endoscopic lesions, and response to antifungal therapy. Statistical analysis was used to determine whether any histological features significantly correlated with clinical variables. There were 120 males and 151 females with a mean age of 42 years. Fifty-nine per cent had symptoms referable to the oesophagus, particularly dysphagia (36%). Most (73%) patients had abnormal endoscopic findings, with plaques, ulcers, or macroscopic evidence of oesophagitis. Seventy-one per cent of patients with documented antifungal therapy showed symptomatic improvement. Overall, there was no statistically significant correlation between any histological feature and presenting symptoms, endoscopic findings, or response to therapy. Importantly, the lack of pseudohyphae, demonstrable invasion of intact epithelium or neutrophilic infiltrates did not exclude clinically significant infection. CONCLUSIONS: We conclude that detection of Candida in oesophageal biopsies is always potentially clinically significant. Treatment decisions should be made on the basis of an integration of clinical, endoscopic and histological findings.

Expression and prognostic value of NSD1 and SETD2 in pancreatic ductal adenocarcinoma and its precursor lesions.

Epigenetic regulation is emerging as a critical mechanism for pancreatic ductal adenocarcinoma (PDA) development. Histone methylation is an important regulatory mechanism, altering chromatin structure and promoter accessibility and causing aberrant gene expression. NSD1 and SETD2 genes encoding two histone H3K36 methyltransferases, are mutated or altered in 8-10% of PDA cases. However, whether there is altered protein expression of NSD1 or SETD2 in PDA and its precursors, and whether they have diagnostic or prognostic utility is unknown. Tissue microarrays composed of a total of 190 and 192 duplicated cases of PDA (n=74 and 75), metastatic PDA (n=17 and 18), pancreatic intraepithelial neoplasia (PanIN; n=19 and 24), intraductal papillary mucinous neoplasm (IPMN; n=36), mucinous cystic neoplasm (MCN; n=12) and benign pancreatic tissues (n=27 and 32) were analysed for expression of NSD1 and SETD2 by immunohistochemistry. We assessed intensity and percentage of positive cells. NSD1 expression was significantly increased in metastatic PDA compared to benign ducts, primary PDA, and all other lesions combined (p=0.03, 0.02, and 0.03 respectively). Additionally, significantly decreased SETD2 protein expression was found in metastatic PDA and PanIN lesions compared to benign ducts (p=0.04 and 0.007, respectively). High NSD1 expression was associated with clinical stage III/IV disease (p=0.026), tumour grade 2 (p=0.022), use of neoadjuvant therapy (p=0.037), and overall higher clinical stage (p=0.022). There is no significant difference in overall and progression-free survival between NSD1/SETD2 high and low PDA. Expression of NSD1 and SETD2 is specifically altered in metastatic PDA and some of the PDA precursor lesions, supporting their important role in PDA development and metastasis. In addition, increased NSD1 expression is significantly associated with higher clinical stage and neoadjuvant therapy, suggesting that NSD1 may be a useful prognostic marker.

Epstein-Barr Virus Hepatitis: A Review of Clinicopathologic Features and Differential Diagnosis.

CONTEXT.­: The liver is frequently affected by Epstein-Barr virus (EBV) infection, but involvement is commonly subclinical and self-limited. Severe and potentially fatal EBV hepatitis has also been occasionally reported in immunocompromised patients and, even more rarely, in immunocompetent individuals. OBJECTIVE.­: To provide a review of the clinicopathologic findings of EBV hepatitis, with a focus on microscopic features and ancillary testing with a brief discussion of the differential diagnosis. DATA SOURCES.­: Analysis of the pertinent literature (PubMed) and clinical practice experience based on institutional materials. CONCLUSIONS.­: Characteristic microscopic findings in EBV hepatitis include a diffuse lymphocytic sinusoidal infiltrate in a "string of beads" pattern, expansion of portal tracts by a predominantly lymphocytic infiltrate, and intact lobular architecture. In situ hybridization of EBV-encoded RNA is a helpful ancillary test. Correlation of clinical history, laboratory findings, and histopathologic features is essential to distinguish EBV hepatitis from autoimmune liver diseases, transplant rejection, lymphomas, and drug-induced liver injury.

Simple Mucinous Cyst of the Pancreas: Review and Update.

CONTEXT: - According to the 2014 Baltimore Consensus Meeting, simple mucinous cysts are defined as macroscopic cysts that are greater than 1 cm in size with gastric-type flat mucinous lining and minimal cytologic atypia without ovarian-type stroma. This lesion has not been widely recognized and has undergone a recent nomenclature change owing to unclear pathogenesis and biologic behavior. Mucinous pancreatic cystic lesions are generally considered precursor lesions of pancreatic adenocarcinoma. However, simple mucinous cysts generally have benign behavior with no recurrence or malignant transformation during short follow-up periods. OBJECTIVE: - To provide a brief update and summary of the evolving nomenclature and current knowledge of simple mucinous cysts with an overview of their clinical, histopathologic, immunohistochemical, and molecular characteristics, as well as discussion of their differential diagnoses and biological behavior. DATA SOURCES: - Analysis of the pertinent literature (PubMed) and authors' clinical practice experience based on institutional and consultation materials. CONCLUSIONS: - Simple mucinous cyst has undergone a nomenclature evolution from mucinous nonneoplastic cyst to the current recommended name of simple mucinous cyst to reflect its unclear pathogenesis and progression. The malignant potential of simple mucinous cyst is still debatable. Recent molecular studies support a neoplastic process, but these cysts generally exhibit benign behavior without recurrence or malignant transformation. Therefore, accurate diagnosis of simple mucinous cysts is critical to distinguish them from other more common and aggressive mucinous pancreatic cysts. Studies with larger cohorts and longer clinical follow-up data are needed to further determine the biologic behavior of this cyst and implications for prognosis.