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Background DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates. POLE-driven tumors are relatively common in endometrial and colorectal cancer, and their presence is increasingly recognized in ovarian cancer (OC) of endometrioid type. POLE-driven cases possess an abundance of TCT > TAT and TCG > TTG somatic mutations characterized by mutational signature 10 from the Catalog of Somatic Mutations in Cancer (COSMIC). By quantifying the contribution of COSMIC mutational signature 10 in RNA sequencing (RNA-seq) we set out to identify POLE-driven tumors in a set of unselected Mayo Clinic OC. Methods Mutational profiles were calculated using expressed single-nucleotide variants (eSNV) in the Mayo Clinic OC tumors (n = 195), The Cancer Genome Atlas (TCGA) OC tumors (n = 419), and the Genotype-Tissue Expression (GTEx) normal ovarian tissues (n = 84). Non-negative Matrix Factorization (NMF) of the mutational profiles inferred the contribution per sample of four distinct mutational signatures, one of which corresponds to COSMIC mutational signature 10. Results In the Mayo Clinic OC cohort we identified six tumors with a predicted contribution from COSMIC mutational signature 10 of over five mutations per megabase. These six cases harbored known POLE hotspot mutations (P286R, S297F, V411L, and A456P) and were of endometrioid histotype (P = 5e−04). These six tumors had an early onset (average age of patients at onset, 48.33 years) when compared to non-POLE endometrioid OC cohort (average age at onset, 60.13 years; P = .008). Samples from TCGA and GTEx had a low COSMIC signature 10 contribution (median 0.16 mutations per megabase; maximum 1.78 mutations per megabase) and carried no POLE hotspot mutations. Conclusions From the largest cohort of RNA-seq from endometrioid OC to date (n = 53), we identified six hypermutated samples likely driven by POLE (frequency, 11%). Our result suggests the clinical need to screen for POLE driver mutations in endometrioid OC, which can guide enrollment in immunotherapy clinical trials.

Eicosanoids play important roles in the cardiovascular system. The metabolic disorders involving some eicosanoids in the pathophysiologic process include myocardial infarction and myocardial ischaemia-reperfusion injury. Percutaneous coronary intervention (PCI) is often the first-choice strategy for acute ST-segment elevation myocardial infarction (STEMI) according to current guidelines. This study aimed to investigate the dynamic eicosanoid metabolic profile in STEMI patients after PCI. The eicosanoid profiles in plasma of 20 patients at seven times (30 minutes before surgery; 6, 12, 24, and 72 hours after surgery; 1 day before discharge; and 28 days after surgery) were studied by using metabolomics. Levels of PGE2, PGD2, and TXA2 were decreased significantly and EETs contents were increased significantly at 6 hours after PCI. EETs were hydrolysed to DHETs within a short time after surgery (12-72 hours). 20-HETE content was significantly increased. In samples taken at the time of discharge and at follow-up after discharge, LTB4 level continued to increase. This work suggests that change in content of some functional eicosanoids may be involved in cardiac injury and repair after PCI in a synergistic manner.

Background Tumoral melanosis clinically resembles metastatic melanoma, occurs in the context of regressed disease, and requires evaluation to rule out underlying melanoma and metastatic disease. Histopathology demonstrates a nodular infiltrate of melanophages in the dermis, subcutaneous tissue, deep soft tissue, or lymph nodes in the absence of viable melanocytes. Recent limited reports of tumoral melanosis in the context of immunotherapy with ipilimumab (monoclonal antibody targeting CTLA-4) as well as nivolumab and pembrolizumab (humanized monoclonal antibodies against programmed death 1 receptor) highlight a unique presentation representative of treatment-related tumor regression and an association with a favorable clinical response. Objective To describe our experience with tumoral melanosis in the setting of immunotherapy for metastatic melanoma and elucidate the clinical and histopathological features. Methods Retrospective case series from a single tertiary care institution. Results We describe 10 cases of patients with metastatic melanoma who received treatment with immunotherapy before the development of tumoral melanosis. Length of time between the initiation of therapy and the onset of tumoral melanosis ranged from 2 to 20 months with a mean time of 10 months. At the end of the follow-up period, 8 patients were classified as having a complete or partial response to treatment with immunotherapy. One patient had progression of visceral and cutaneous disease on ipilimumab despite developing tumoral melanosis, and 1 patient had yet to undergo repeat imaging. Furthermore, at the end of follow-up, 3 patients were alive with no evidence of active disease, 5 patients were alive with disease, and 1 patient was deceased, although this patient died of a cardiovascular event unrelated to his underlying melanoma. Of the patients who were classified as alive with disease, 2 patients had minimal remaining disease, and 2 patients had an almost complete response on immunotherapy with recurrence of visceral metastases after immunotherapy was discontinued. One patient developed new peritoneal and cutaneous metastases on pembrolizumab despite development of tumoral melanosis. Conclusions The underlying biologic mechanisms and prognostic implications of tumoral melanosis in the setting of immunotherapy remain to be elucidated. Further prospective studies with a larger cohort and prolonged follow-up are necessary to better understand the incidence, prevalence, and oncologic outcomes in patients with tumoral melanosis who receive immunotherapy.

Hidradenoma papilliferum (HP) is a benign adnexal neoplasm of the vulva that typically presents as a unilateral, flesh-colored papule in the labium majus in middle-aged Caucasian women. It is considered to be a close counterpart of the intraductal papilloma of the breast. Malignant transformation is rare with few reports in the literature. We present a case of vulvar mammary-type apocrine hidradenocarcinoma arising in an HP.

Pigment-synthesizing melanoma (PSM) describes a morphologically and genetically diverse group of melanomas. In contrast, pigmented epithelioid melanocytoma (PEM) encompasses a spectrum of indolent tumors now classified as borderline/intermediate melanocytic tumors. Herein, we report a case of widely metastatic heavily pigmented epithelioid melanoma with fatal outcome in a 36-year-old woman. Next-generation sequencing identified somatic (tumoral) mutations in BRAF V600E, PTEN, NOTCH1, and ERBB3. By contrast, GNAQ and GNA11 were wild type. Prkar1α and p16 expression were maintained. Identification of mutations in NOTCH1 and ERBB3 may support the diagnosis of heavily pigmented epithelioid melanoma. In contrast, PRKCA fusion genes and PRKAR1A mutations support the diagnosis of PEM. Given the heterogeneity, potential overlap (loss of Prkar1α expression), and evolving genetic profiles of these two distinct groups of tumors, careful appraisal of molecular profiles in the light of histomorphology and clinical history is necessary for distinction between PEM and PSMs including heavily pigmented epithelioid melanomas, with significant potential impact on prognosis and therapy.

Enteric duplication cysts (EDCs) are rare congenital malformations consisting of double-walled cystic or tubular structures lined by gastrointestinal type epithelium. EDCs share a common muscular wall and blood supply with the adjacent duplicated bowel with very rare exceptions. The majority of EDCs are intraabdominal with cases less commonly intrathoracic or thoracoabdominal. To the best of our knowledge, we present the first reported case of primary cutaneous EDC to occur outside the abdominal and thoracic cavities. A 17-year-old male without a significant medical or surgical history underwent excision of a cystic nodule on the left hip. On histopathology, a dermal to subcuticular cyst exhibited an epithelial lining with 2 distinct components including cuboidal to columnar mucinous cells (CK7+, CK20-, and CDX2-) and complex glandular colonic-type mucosa (CK7-, CK20+, and CDX2+). A thick muscular wall resembling muscularis mucosa and muscularis propria surrounded the cyst. Findings supported a primary cutaneous enteric duplication cyst of uncertain developmental etiology. The novel nature of this entity could represent a diagnostic challenge.

Background. Obstructive sleep apnea (OSA) is closely related to the incidence and progression of coronary artery disease (CAD), and the mechanisms linking OSA and CAD are multifactorial. C1q/TNF-related protein-9 (CTRP9) is a novel adipokine that protects the heart against ischemic injury and ameliorates cardiac remodeling. We aimed to ascertain the clinical relevance of CTRP9 with OSA prevalence in patients with CAD. Methods. From August 2016 to March 2019, consecutive eligible patients with CAD (n=154; angina pectoris, n=88; acute myocardial infarction [AMI], n=66) underwent cardiorespiratory polygraphy. OSA was defined as an apnea-hypopnea index (AHI) ≥15 events·h−1. Plasma CTRP9 concentrations were measured by ELISA method. Results. Moderate/severe OSA was present in 89 patients (57.8%). CTRP9 levels were significantly decreased in the moderate/severe OSA group than in the no/mild OSA group (4.7 [4.1-5.2] ng/mL vs. 4.9 [4.4-6.0] ng/mL, P=0.003). The difference between groups was only observed in patients with AMI (3.0 [2.3-4.9] vs. 4.5 [3.2-7.9], P=0.009). Correlation analysis showed that CTRP9 levels were negatively correlated with AHI (r=−0.238, P=0.003) and oxygen desaturation index (r=−0.234, P=0.004) and positively correlated with left ventricular ejection fraction (r=0.251, P=0.004) in all subjects. Multivariate analysis showed that male gender (OR 3.099, 95% CI 1.029-9.330, P=0.044), BMI (OR 1.148, 95% CI 1.040-1.268, P=0.006), and CTRP9 levels (OR 0.726, 95% CI 0.592-0.890, P=0.002) were independently associated with the prevalence of moderate/severe OSA. Conclusions. Plasma CTRP9 levels were independently related to the prevalence of moderate/severe OSA in patients with CAD, suggesting that CTRP9 might play a role in the pathogenesis of CAD exacerbated by OSA.

Calciphylaxis is a rare syndrome of vascular calcification with thrombosis that occurs most often in patients with end-stage renal disease, and it frequently portends a guarded prognosis. Rarely, nonuremic calciphylaxis (NUC) may occur; in this context, a strongly supportive histology is crucial in establishing the diagnosis. Herein, we describe 2 cases of NUC associated with pseudoxanthoma elasticum-like changes, identified in both initial nondiagnostic and subsequent diagnostic biopsy specimens. This unusual but helpful histologic finding may support the early diagnosis and treatment of a potentially life-threatening disease in the context of subtle histopathologic vascular changes or in the absence of classic clinical or laboratory findings.

Amicrobial pustulosis of the folds (APF) is a rare disease characterized by aseptic pustular lesions involving cutaneous folds, typically occurring in the context of an autoimmune disorder. We present 4 patients with APF, focusing on clinical and histopathologic characteristics to improve the recognition of this entity. All 4 patients had intertriginous and extra-intertriginous involvement. Common histopathologic features of skin biopsies in these patients were intracorneal, subcorneal, intraepidermal, perivascular, perifollicular and interstitial neutrophilic inflammation. Pustules overlying adnexal ostium and papillary dermal edema were consistently observed. The pustules were negative for microorganisms on stain testing. In these cases, associated conditions were undifferentiated connective tissue disease, systemic lupus erythematosus, antiphospholipid syndrome, Crohn disease and Hashimoto thyroiditis. The aforementioned clinical and histopathologic characteristics of patients with suspected or diagnosed connective tissue disorders should lead to suspicion for APF.

Serous borderline ovarian tumor (SBOT) and high-grade serous ovarian cancer (HGSOC) are two distinct subtypes of epithelial ovarian tumors, with markedly different biologic background, behavior, prognosis, and treatment. However, the histologic diagnosis of serous ovarian tumors can be subjectively variable and labor-intensive as multiple tumor slides/blocks need to be thoroughly examined to search for these features. In this study, we aimed to evaluate technical feasibility of using digital pathological approaches to facilitate objective and scalable diagnosis screening for SBOT and HGSOC. Based on Groovy scripts and QuPath, a novel informatics system was developed to facilitate interactive annotation and imaging data exchange for machine learning purposes. Through this developed system, cellular boundaries were detected and expanded set of cellular features were extracted to represent cell- and tissue-level characteristics. According to our evaluation, cell-level classification was accurately achieved for both tumor and stroma cells with greater than 90% accuracy. Upon further re-examinations, 44.2% of the misclassified cells were due to over-/under-segmentations or low-quality of imaging areas. For a total number of 6,485 imaging patches with sufficient tumor and stroma cells (ten of each at least), we achieved 91-95% accuracy to differentiate HGSOC v. SBOT. When all the patches were considered for a WSI to make consensus prediction, 97% accuracy was achieved for accurately classifying all patients, indicating that cellular features digitally extracted from pathological images can be used for cell classification and SBOT v. HGSOC differentiation. Introducing digital pathology into ovarian cancer research could be beneficial to discover potential clinical implications., Comment: 17 pages, 8 figures

Background Periodic Acid Schiff-Diastase (PAS-D) staining is used routinely in dermatopathology. Conventionally, parakeratosis or intracorneal neutrophils justify use of PAS-D stain to identify dermatophytosis. We aimed to investigate the histopathological features of superficial dermatophytosis. Methods Skin biopsies with PAS-D stain were retrospectively reviewed by a blinded dermatopathologist. Histopathologic findings in cases with dermatophytosis were compared to those without. Results We studied 110 cases, of which 63 were PAS-D positive for dermatophytes. Dermatophytes were identified on H&E staining in 49 (77.8%) of the PAS-D-positive cases. Diffuse compact orthokeratosis (79.37%, p

Nodular fasciitis (NF) is a clonal self-limited neoplastic proliferation characterized by rearrangements of the USP6 locus in most examples. To our knowledge well-documented malignant behavior has never been previously observed in NF. In this report we present an unusual case of NF with classical histologic features that showed a protracted clinical course characterized by multiple recurrences and eventual metastatic behavior over a period of 10 years. Molecular analyses revealed the presence and amplification of the novel PPPR6-USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of NF. © 2016 Wiley Periodicals, Inc.

Cardiac rupture (CR) is a complication of acute myocardial infarction (AMI) that is associated with a high mortality rate. This study aimed to identify the risk factors for CR in patients with AMI. Medline, Cochrane, EMBASE, and Google Scholar databases were searched for relevant literature published through September 16, 2018. Eligible studies included patients with AMI and compared factors between patients with and without CR. Sixteen studies were identified and included in the meta-analysis. Results revealed that female gender (pooled OR=2.72, 95% CI 2.04 to 3.63, p

We report herein two cases of reactive capillary hemangiomas during the clinical trials of SHR-1210, a humanized anti-PD-1 IgG4 antibody.A female in her 20s with a history of stage IVa Hodgkin's ly...

Capillary hemangiomas, the most common vascular tumors of the sinonasal region, are benign endothelial neoplasms, typically growing in an easily recognized lobular pattern. Some sinonasal capillary hemangiomas may show atypical features, such as high cellularity or mitotic activity, and represent more challenging diagnoses. Over the past several years we have seen in consultation a number of examples of sinonasal capillary hemangiomas displaying very striking stromal myxoid change and hyalinization, features that have received scant attention in the past. Available slides from 16 sinonasal capillary hemangiomas previously coded as showing such changes were retrieved from our archives. Submitting diagnoses included "query angiofibroma, rule out malignancy" (N=4), "vascular polyp, rule out malignancy" (N=3), "query malignant vascular tumor" (N=4), "sinonasal hemangiopericytoma" (N=1), and "benign vascular tumor" (N=1). Available radiographic studies often showed worrisome features. Grossly, the tumors ranged from 1.1 to 6.0 cm and appeared as ulcerated, vascular-appearing polyps. Microscopically, the tumors showed striking stromal myxoid change and/or hyalinization, which largely obscured the underlying lobular capillary arrangement. Within this myxohyaline matrix, a florid capillary proliferation was present, frequently with nonatypical mitotic activity. In some instances a branching, "hemangiopericytoma-like" vascular pattern was present in areas. The overall cellularity was low to moderate, and endothelial atypia or hyperchromatism was absent. Ulceration and thrombosis were frequently present. Immunostains to CD31, CD34, and SMA highlighted areas of lobular growth pattern inapparent on the routinely stained slides. Four tested cases were negative for androgen receptors and β-catenin. Follow-up from 12 patients revealed no local recurrences or metastases. Awareness of that sinonasal capillary hemangioma may show these unusual stromal changes, and the use of ancillary immunohistochemistry to highlight its lobular growth pattern should allow its confident distinction from more aggressive endothelial tumors (eg, angiosarcoma) and from nonendothelial tumors, including nasopharyngeal angiofibroma, solitary fibrous tumor, and sinonasal hemangiopericytoma-like tumor.

Author(s): Magro, Cynthia; Guo, Ruifeng; Nguyen, Giang Huong; Tsang, Hamilton; Momtahen, Shabnam | Abstract: Background: Lymphomatoid drug reactions can mimic endogenous T and B cell lymphoproliferative diseases.Objectives: We present a novel form of cutaneous drug reaction with features of pityriasis lichenoides (PL), a recognized form of T cell dyscrasia. Methods: Ten cases were studied where a cutaneous eruption exhibiting semblance to PL within a few weeks to months after starting a particular drug. Results: The patient cohort comprised 7 females and 3 males with the mean age of 60 years. Widely distributederythematous cutaneous lesions were present in 6 cases whereas a more localized distribution was seen in three cases. The most frequently implicated drugsassociated with the eruption were antidepressants and statins. Histologic examination showed a morphologic picture identical to PL including marked epitheliotropism of mildly atypical lymphocytes, psoriasiform epidermal hyperplasia, dyskeratosis, hemorrhage, and a thick parakeratotic scale. Therewas a significant reduction in the expression of CD7 and CD62L amid the T cells. Regression of the eruption occurred in all cases excluding one. Conclusion: Thefindings conform the categorization of this process as a form of T-cell dyscrasia albeit one that is reversible, dependent on the drug withdrawal. The limitationof our study includes the retrospective design of the study.

Deep penetrating nevi (DPN) are a relatively uncommon subtype of melanocytic nevi. A small subset of these lesions exhibit atypical features (cytologic and architectural atypia, mitotic activity) seen in melanoma. These lesions we term the deep penetrating nevuslike borderline tumor. Unequivocal melanomas can show overlapping morphologic features of DPN, which have been termed plexiform melanomas. 40 cases of DPN-like borderline tumor were identified along with 6 cases of plexiform melanoma. Clinical follow up was obtained, along with cytogenetic analysis in the form of fluorescent in situ hybridization (FISH) and/or comparative genomic hybridization (CGH). The DPN-like borderline tumor cases included 24 females and 16 males. Of sentinel lymph node biopsies performed, 1/3 of cases showed lymph node involvement. All patients where an aggressive clinical approach was adopted remain free of disease. All 6 DPN-like borderline tumor cases tested by CGH showed normal cytogenetics, as did 7 of 9 cases tested by FISH. Of the plexiform melanomas, 4/6 patients died of disease. In 3 cases there was morphologic progression from a DPN-like borderline tumor to overt melanoma. In one case of progression, cytogenetics was normal in the DPN-like borderline tumor and then abnormal in the progressed melanoma. DPN-like borderline tumors are melanocytic tumors associated with a high incidence of regional lymph node disease and exhibiting the potential for melanoma progression despite a normal cytogenetic profile. Patients with these lesions should be aggressively managed, with at least complete re-excision and consideration of sentinel node biopsy, regardless of cytogenetic data.

Sinonasal non-keratinizing squamous cell carcinoma (SCC), previously designated as transitional cell carcinoma or cylindrical cell carcinoma, is an uncommon malignant neoplasm with distinct histopathological features, considered to be a low-grade malignancy that usually occurs in elderly patients. Extensive local invasion is uncommon. Here we report a case of 90-year-old woman whose original presentation was as erythematous nasal skin nodules, biopsy of which showed a dermal tumor with features of sinonasal non-keratinizing SCC. No epidermal dysplasia was present. A subsequent computed tomography scan confirmed the presence of an endophytic tumor on the nasal sidewall. The initial presentation of sinonasal non-keratinizing SCC as a skin lesion is previously unreported to our knowledge. Diagnosis in this context requires accurate evaluation of the histopathology as well as a comprehensive knowledge of pathology specific to this anatomic location.