Cardiovascular disease associated with methamphetamine use: a review.

Methamphetamine abuse is a global epidemic associated with a wide-ranging array of adverse effects on the cardiovascular system including dilated cardiomyopathy, malignant and benign arrhythmias, coronary vasospasm, and atherosclerotic coronary artery disease. While the acute behavioral manifestations of amphetamine abuse are the most easily clinically identified, cardiovascular toxicity is common in this patient population and should be considered in this setting due to its high morbidity and mortality. The specific mechanisms for amphetamine cardiotoxicity have not been fully established, but new research implicates activation of several cellular targets including Sigma-1 receptors and trace amine-associated receptor 1 (TAAR1) leading to a myriad of negative downstream effects including increased reactive oxygenating species (ROS), mitochondrial dysfunction, and modulations of intracellular calcium. Additional pathologic effects are mediated by increased circulating catecholamines, which when chronically activated have well-established adverse effects on the cardiovascular system. In this article, we present a case report followed by a current review of the epidemiology, pathophysiology, diagnosis, and treatment modalities of amphetamine-induced cardiovascular disease.

Interobserver reproducibility of the diagnosis of differentiated exophytic vulvar intraepithelial lesion (DEVIL) and the distinction from its mimics.

AIMS: Most vulvar squamous cell carcinomas are human papillomavirus (HPV)-associated or TP53-mutant. A third category of HPV-independent TP53-wild-type lesions is uncommon and not fully understood. Differentiated exophytic vulvar intraepithelial lesion (DEVIL) has been characterised as a precursor of this latter category. The reproducibility of the diagnosis of DEVIL and its distinction from lesions with overlapping morphology has not been studied. Our aim was to establish the interobserver agreement in the diagnosis of DEVIL and its distinction from neoplastic and reactive conditions of the vulva on haematoxylin and eosin evaluation. METHODS AND RESULTS: A set of 35 slides was evaluated by eight reviewers (two trainees and six practising gynaecological pathologists). The set included DEVIL, condyloma, established vulvar precursors [high-grade squamous intraepithelial lesion (HSIL) and differentiated vulvar intraepithelial neoplasia (dVIN)] with superimposed acanthosis or verruciform growth, lichen simplex chronicus (LSC), and psoriasis. Kappa (κ) values were calculated. Overall, interobserver agreement was moderate (κ = 0.56), improving to substantial (κ = 0.7) when evaluation was performed by practising pathologists. Agreement was strong for the diagnosis of HSIL (κ = 0.88), and substantial for the diagnosis of DEVIL (κ = 0.61), condyloma (κ = 0.79), and LSC (κ = 0.72). Agreement was moderate for the diagnosis of dVIN (κ = 0.59) and psoriasis (κ = 0.53). Perfect agreement (6/6) among practising pathologists was observed in 43% of cases, and majority agreement (5/6 or 4/6) was observed in 48% of cases. CONCLUSIONS: Reproducibility in the diagnosis of verruciform vulvar lesions, including the novel DEVIL, is acceptable overall. Reproducibility is higher for well-known lesions such as HSIL and condyloma than for more challenging diagnoses such as DEVIL, dVIN, and psoriasis. Agreement is higher among practising gynaecological pathologists, suggesting that training and experience improve reproducibility. Our findings support the inclusion of DEVIL as a diagnostic entity in the classification of vulvar squamous lesions.

Correlation of p16 immunostaining in cell-blocks with corresponding tissue specimens for squamous cell carcinomas of the oropharynx.

OBJECTIVE: The goal of this study was to evaluate the performance of p16 staining in cell-blocks vs tissue specimens as a surrogate marker for human papillomavirus (HPV) status in oropharyngeal squamous cell carcinomas. METHODS: Head and neck squamous cell carcinoma cases presenting as a neck mass with a p16 result on cytology and corresponding tissue specimens (1 January 2014 to 30 June 1920) were included in the study. The following were assessed from cell-block material: number of tumour clusters, percentage of tumour cells with p16 staining, and presence of staining in clusters vs single cells. Results were compared to tissue p16 status. Results of any other ancillary HPV testing were also noted. RESULTS: Forty-two head and neck squamous cell carcinoma neck metastases (35 oropharyngeal, five non-oropharyngeal, and 2 unknown primaries) were identified. The p16 staining pattern in cell-blocks was seen in single cells (27.6%), clusters (44.8%), or both (27.6%). The percentage of tumour cells staining for p16 in cell-blocks was much lower than in corresponding tissue specimens. There were four false negatives and one false positive (concurrent HPV DNA polymerase chain reaction testing was positive in cytology and surgical material). CONCLUSIONS: Compared to tissue, the cut-off for p16 interpretation in cell-blocks is substantially lower and staining may be present in single cells or clusters. In 96.9% of cases, any p16 staining in cell-blocks correlated with positive p16 staining in surgical specimens. However, a negative or discrepant p16 result on cell-block should prompt confirmatory HPV studies, as false negative p16 staining in cell-blocks is high.

The utility of the Milan System as a risk stratification tool for salivary gland fine needle aspiration cytology specimens.

OBJECTIVE: To perform a retrospective investigation of our institutional experience with salivary gland fine needle aspirations (FNA) through the framework of The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) and assess the risks of neoplasm and malignancy for each diagnostic category. METHODS: All salivary gland FNAs performed from January 2009 to December 2016 were retrospectively categorised according to the MSRSGC. When available, pre-operative cytological results were correlated with subsequent histological follow-up. RESULTS: In total, 893 FNAs were reviewed. The specimens were retrospectively classified as nondiagnostic (ND: 13.5%), non-neoplastic (NN: 16.1%), atypia of undetermined significance (AUS: 10.8%), benign neoplasm (BN: 34.9%), salivary gland neoplasm of uncertain malignant potential (SUMP: 8.2%), suspicious for malignancy (SM: 2.7%) and malignant (M: 13.8%). Histological follow-up was available for 429 cases (48%); the majority (68.1%) were benign. The risks of neoplasm and malignancy for each category were as follows: ND: 64.5%, 16.1%; NN: 42.9%, 17.9%; AUS: 79.6%, 30.6%; BN: 100%, 2.2%; SUMP: 100%, 46.6%; SM: 94.7%, 78.9%; and M: 100%, 98.5%. CONCLUSIONS: The MSRSGC is a useful classification scheme for stratifying salivary gland lesions according to their associated risk of malignancy and guiding clinicians toward appropriate management. Diagnostic pitfalls are seen in a small proportion of cases and a multidisciplinary approach for assessing salivary gland pathology is essential in their evaluation.

Transitioning From Trainee to Practicing Pathologist: A Prospective Multi-institutional Survey of the Challenges Early Career Anatomic Pathologists Encounter When Entering Independent Practice.

CONTEXT.­: Pathology training programs generally prepare graduates well for the workforce, but there may be other aspects to navigating a job that make the transition from being a trainee to a practicing pathologist challenging. OBJECTIVE.­: To identify perceived challenges of independent practice for early career pathologists and assess how these impressions evolve throughout their first year. DESIGN.­: A survey was distributed to 12 anatomic pathology fellows from 4 institutions near the end of their final training year, and 6 months and 1 year after starting their first job. The surveys queried participants' comfort level with signing out cases independently and interacting with colleagues/trainees via Likert attitude scale questions, with free-text segments to elaborate on challenges experienced. RESULTS.­: The response rate to all 3 surveys was 100%. Confidence and comfort level with different aspects of independent sign-out increased incrementally over time. Main challenges encountered at 6 months included a high case load, signing out cases in areas outside of their subspecialty, time management, balancing teaching while signing out, laboratory issues, and developing relationships with clinicians. At 12 months, main challenges included time management, high case load, understaffing, laboratory issues, and signing out cases in areas outside of their subspecialty. CONCLUSIONS.­: This study identified real-time challenges faced by those adjusting to their first year of independent practice. By gaining a better understanding of the factors that make this transition challenging, we can find tailored ways to support our early career pathologists.

Targeted RNA Sequencing Highlights a Diverse Genomic and Morphologic Landscape in Low-grade Endometrial Stromal Sarcoma, Including Novel Fusion Genes.

Low-grade endometrial stromal sarcoma (LGESS) represents a morphologically and genetically heterogenous mesenchymal neoplasm. Previous work has shown that approximately half of LGESS are characterized by JAZF1::SUZ12 gene fusions, while a smaller proportion involves rearrangement of other genes. However, a subset of cases has no known genetic abnormalities. To better characterize the genomic landscape of LGESS, we interrogated a cohort with targeted RNA sequencing (RNA-Seq). Cases previously diagnosed as low-grade endometrial stromal neoplasia (n=51) were identified and re-reviewed for morphology and subjected to RNA-Seq, of which 47 were successfully sequenced. The median patient age was 49 years (range: 19 to 85). The most commonly detected fusions were JAZF1::SUZ12 (n=26, 55%) and BRD8::PHF1 (n=3, 6%). In addition to the usual/typical LGESS morphology, some JAZF1::SUZ12 fusion tumors showed other morphologies, including fibrous, smooth muscle, sex-cord differentiation, and myxoid change. Novel translocations were identified in 2 cases: MEAF6::PTGR2 and HCFC1::PHF1 . Ten tumors (21%) had no identifiable fusion, despite a similar morphology and immunophenotype to fusion-positive cases. This suggests that a subset of cases may be attributable to fusion products among genes that are not covered by the assay, or perhaps altogether different molecular mechanisms. In all, these findings confirm that RNA-Seq is a potentially useful ancillary test in the diagnosis of endometrial stromal neoplasms and highlight their diverse morphology.

Cytology of Benign Peritoneal Fluids and Pelvic Washing Specimens: Diagnostic Cytomorphologic Features and Pitfalls.

BACKGROUND: Pelvic washing and peritoneal fluid cytology specimens are used to detect peritoneal spread of malignancies. In most cases, identification of malignancy in these specimens is straightforward, but benign processes may occasionally mimic neoplasia and cause diagnostic difficulty. SUMMARY: In this article, we perform a focused review of common benign entities encountered in pelvic washing and peritoneal fluid specimens during routine practice which may cause difficulty and discuss helpful features for avoiding diagnostic pitfalls. KEY MESSAGES: Application of strict cytomorphologic criteria, along with judicious use of ancillary studies and correlation with clinical, intraoperative, radiologic, and other pathologic findings, can help resolve most problematic cases.

TERT gene rearrangement in chordomas and comparison to other TERT-rearranged solid tumors.

Chordomas are rare, slow-growing neoplasms thought to arise from the foetal notochord remnant. A limited number of studies that examined the mutational profiles in chordomas identified potential driver mutations, including duplication in the TBXT gene (encoding brachyury), mutations in the PI3K/AKT signaling pathway, and loss of the CDKN2A gene. Most chordomas remain without clear driver mutations, and no fusion genes have been identified thus far. We discovered a novel TERT in-frame fusion involving RPH3AL (exon 5) and TERT (exon 2) in the index chordoma case. We screened a discovery cohort of 18 additional chordoma cases for TERT gene rearrangement by FISH, in which TERT rearrangement was identified in one additional case. In our independent, validation cohort of 36 chordomas, no TERT rearrangement was observed by FISH. Immunohistochemistry optimized for nuclear TERT expression showed at least focal TERT expression in 40/55 (72.7%) chordomas. Selected cases underwent molecular genetic profiling, which showed low tumor mutational burdens (TMBs) without obvious driver oncogenic mutations. We next examined a cohort of 1,913 solid tumor patients for TERT rearrangements, and TERT fusions involving exon 2 were observed in 7/1,913 (0.4%) cases. The seven tumors comprised five glial tumors, and two poorly differentiated carcinomas. In contrast to chordomas, the other TERT-rearranged tumors were notable for higher TMBs, frequent TP53 mutations (6/7) and presence of other driver oncogenic mutations, including a concurrent fusion (TRIM24-MET). In conclusion, TERT gene rearrangements are seen in a small subset (2/55, 3.6%) of chordomas. In contrast to other TERT-rearranged tumors, where the TERT rearrangements are likely passenger events, the possibility that TERT protein overexpression representing a key event in chordoma tumorigenesis is left open.

Developing an interactive and illustrative laboratory management curriculum for cytopathology trainees.

Laboratory management is a critically important but often overlooked portion of cytopathology training. Indeed, recent surveys of new-in-practice pathologists have consistently shown this to be an area of deficiency. Fortunately, there are a multitude of resources available to fill this need.1-6 These resources, such as government websites and publications by professional organizations, are often freely accessible to everyone; however, the information they provide is scattered across the vast expanse of cyberspace. We offer this educational module to bridge those gaps and string together a web of resources. The curriculum content includes a pretest to assess the trainee's knowledge and a tree of clickable subject headings covering basic laboratory management topics that a graduating cytopathology fellow should be familiar with. Each subject heading is linked to a summary of the subject using tables and visual diagrams with hyperlinks to specific online resources and additional detailed information. A posttest is included to provide instant feedback. Although by no means comprehensive, we hope this will provide a stepping stone for our readers to build a sound laboratory management foundation that may guide their practice.

Role of Ancillary Techniques in Cervical Biopsy and Endocervical Curettage Specimens as Follow-Up to Papanicolaou Test Results Indicating a Diagnosis of Atypical Squamous Cells, Cannot Exclude High-Grade Squamous Intraepithelial Lesion, or High-Grade Squamous Intraepithelial Lesion.

The Papanicolaou (PAP) test is widely used to screen for cervical cancer. All high-grade lesions such as atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H), and high-grade squamous intraepithelial lesion, identified on a PAP test should be followed-up by a confirmatory cervical biopsy. In this review, we discuss the challenges in interpreting cervical tissue specimens and the various ancillary techniques used in the evaluation of cervical dysplasia. Ancillary studies include deeper levels, p16 immunohistochemistry (IHC), human papillomavirus (HPV) testing, and, importantly, cyto-histologic correlation. Of these, p16 IHC is consistently sensitive and specific for detecting HSIL. HPV RNA in situ hybridization (ISH) is a newer technique with excellent sensitivity and specificity for detecting virally infected cells and it may be more broadly applicable to both low- and high-grade squamous intraepithelial lesions.

Application of the Milan System for Reporting Submandibular Gland Cytopathology: An international, multi-institutional study.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a 6-tier diagnostic category system with associated risks of malignancy (ROMs) and management recommendations. Submandibular gland fine-needle aspiration (FNA) is uncommon with a higher frequency of inflammatory lesions and a higher relative proportion of malignancy, and this may affect the ROM and subsequent management. This study evaluated the application of the MSRSGC and the ROM for each diagnostic category for 734 submandibular gland FNAs. METHODS: Submandibular gland FNA cytology specimens from 15 international institutions (2013-2017) were retrospectively assigned to an MSRSGC diagnostic category as follows: nondiagnostic, nonneoplastic, atypia of undetermined significance (AUS), benign neoplasm, salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SM), or malignant. A correlation with the available histopathologic follow-up was performed, and the ROM was calculated for each MSRSGC diagnostic category. RESULTS: The case cohort of 734 aspirates was reclassified according to the MSRSGC as follows: nondiagnostic, 21.4% (0%-50%); nonneoplastic, 24.2% (9.1%-53.6%); AUS, 6.7% (0%-14.3%); benign neoplasm, 18.3% (0%-52.5%); SUMP, 12% (0%-37.7%); SM, 3.5% (0%-12.5%); and malignant, 13.9% (2%-31.3%). The histopathologic follow-up was available for 333 cases (45.4%). The ROMs were as follows: nondiagnostic, 10.6%; nonneoplastic, 7.5%; AUS, 27.6%; benign neoplasm, 3.2%; SUMP, 41.9%; SM, 82.3%; and malignant, 93.6%. CONCLUSIONS: This multi-institutional study shows that the ROM of each MSRSGC category for submandibular gland FNA is similar to that reported for parotid gland FNA, although the reported rates for the different MSRSGC categories were variable across institutions. Thus, the MSRSGC can be reliably applied to submandibular gland FNA.

Idiopathic Myointimal Hyperplasia of Mesenteric Veins of the Ileum and Colon in a Patient with Crohn's Disease: A Case Report and Brief Review of the Literature.

Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is a rare disease characterized by intimal smooth muscle proliferation, leading to the thickening of small to medium-sized mesenteric veins. This vascular disease mimics inflammatory bowel disease (IBD) clinically and endoscopically, while showing ischemic mucosal changes without the classic features of IBD on biopsy. Given the mixed picture, this entity is frequently misdiagnosed. Surgical resection of the diseased bowel segment reveals the true etiology of the pathology and is curative. We describe a case of a 59-year-old man with a long-standing history of Crohn's disease refractory to medical therapy and status after multiple small bowel resections. The patient underwent a subtotal abdominal colectomy with pathology showing dense, indurated mesenteric adipose tissue, significant muscularis propria hypertrophy, and myointimal hyperplasia of the mesenteric veins in a peri-ileal and pericolic distribution, as confirmed by elastin stain. No evidence of mucosal ischemic changes or findings of chronicity or acuity were seen. IMHMV, a rare disease with a mixed presentation, poses a significant diagnostic challenge to clinicians and pathologists.

Fine-needle aspiration cytology of endometriosis.

Endometriosis commonly involves the pelvis, but may also present as a palpable mass in extrapelvic sites, such as the abdominal wall or inguinal region, where it can be evaluated by fine needle aspiration (FNA). In this report, we illustrate the findings seen in seven cases of endometriosis diagnosed by FNA in patients with a chief complaint of pain associated with an abdominal wall or pelvic mass, occurring in a setting of prior pelvic surgery. The most common previous surgery was Cesarean section (n = 6), followed by hysterectomy (n = 2), and hernia repair (n = 1). In all cases, cytologic examination revealed a glandular component composed largely of orderly fragments of cohesive epithelial cells, a spindle cell stromal component presenting either as loosely organized tissue fragments or single cells, and rare hemosiderin-laden macrophages. Four cases showed focal cytologic atypia in the glandular component with extreme nuclear atypia identified in two of these cases. Atypical features included nuclear crowding and disorganization, nuclear enlargement, hyperchromasia with irregular chromatin distribution and anisonucleosis, raising the possibility of a coexistent malignancy and recommendation for excision. Although malignancy was not identified in follow-up surgical excision specimens, the wide range of cytomorphologic changes that can be seen in FNA specimens of endometriosis should be recognized. Diagn. Cytopathol. 2017;45:359-363. © 2016 Wiley Periodicals, Inc.