Somatic and Germline Mutations in Atypical Parathyroid Tumors.

This case series examines somatic and germline mutations in atypical parathyroid adenomas using broad next-generation sequencing of tumor samples obtained from patients who underwent surgical resection from 2020 to 2022.

Molecular Profiling of 50 734 Bethesda III-VI Thyroid Nodules by ThyroSeq v3: Implications for Personalized Management.

CONTEXT: Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine needle aspiration (FNA) samples has not been reported. OBJECTIVE: To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. METHODS: This retrospective analysis of FNA samples, tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier at UPMC Molecular and Genomic Pathology laboratory, analyzed the prevalence of diagnostic, prognostic, and targetable genetic alterations in a total of 50 734 BCIII-VI nodules from 48 225 patients. RESULTS: Among 50 734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alterations. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.9% of cases. CONCLUSION: In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutations and targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.

B1 Vitamin Deficiency After Bariatric Surgery, Prevalence, and Symptoms: a Systematic Review and Meta-analysis.

B1 deficiency is a very prevalent complication of bariatric surgery. This study reviews prevalence and symptoms of B1 vitamin deficiency after bariatric surgery. PubMed, Scopus, and Web of Science published were searched up to 10 Feb 2022, with the following keywords: Roux-en-Y gastric bypass, one anastomosis gastric bypass, Omega bypass, Mini bypass, Bariatric surgery OR Bariatric surgery, metabolic surgery, Weight loss surgery, Classic gastric bypass, Loop gastric bypass, Gastric Bypass, thiamine OR thiamin, beriberi, B1. A total of 11 studies examining 1494 patients were included in this meta-analysis. Twenty-seven percent of patients who underwent bariatric surgeries experience vitamin B1 deficiency. Thiamine supplements should be prescribed for the patients for the rest of their lives, and also standard post-surgery follow-ups are necessary in terms of monitoring dietary factors.

Retroperitoneal duodenal perforation due to COVID-19: An extremely rare case report.

Introduction and importance: Gastrointestinal (GI) symptoms are the most common extrapulmonary presentation of coronavirus disease 2019 (COVID-19) infection. GI perforation may be an unusual manifestation of COVID-19 infection. Case presentation: We report a 45-year-old man who presented with acute abdominal pain without any respiratory symptoms to our emergency department. Investigations revealed retroperitoneal duodenal perforation and fibrotic changes in lung bases. Laboratory findings demonstrated a positive polymerase chain reaction (PCR) test for COVID-19 and mild leukocytosis. Clinical discussion: COVID-19 related perforation of the retroperitoneal part of the duodenum is extremely rare, and to the best of our knowledge, this is the first reported case. With increasing COVID-19 infection, we might see more cases of GI perforation. In the era of COVID-19 pandemic, any abdominal signs and symptoms should alert the clinicians to consider COVID-19 diagnosis in the differential. Conclusion: Conservative management with close monitoring, antibiotic therapy and serial examinations were completely successful. The patient's general condition improved, and he was discharged on day 7 of hospitalization.

Non-Iodine-Avid Disease Is Highly Prevalent in Distant Metastatic Differentiated Thyroid Cancer With Papillary Histology.

CONTEXT: Patients with radioactive iodine (RAI) refractory metastatic differentiated thyroid cancer (DTC) have poor prognosis. Early identification of RAI refractoriness may improve care. OBJECTIVE: This work aimed to characterize DTC patients with distant metastases (DM) at diagnosis who presented with non-iodine-avid disease. METHODS: Retrospective analyses of DTC patients with DM at diagnosis who presented between 2012 and 2020 were performed. Iodine uptake in DM was correlated with tumor histology and mutational profile. The difference in uptake between BRAFV600E-like (BVL) and RAS-like (RL) cancers based on insights from The Cancer Genome Atlas was evaluated. RESULTS: Among 78 patients, 48.7% had negative uptake in DM on the first posttherapy scan. Negative scans were highly prevalent in papillary thyroid carcinoma (PTC) with papillary architecture, PTC with BRAFV600E mutation, and PTC with both BRAFV600E and TERT promoter mutations (71.1%, 80.9%, and 100%, respectively). BVL and RL tumors exhibited distinct uptake patterns with negative scan prevalence of 76.9% and 14.3% (P = .005). Multivariate logistical regression confirmed high odds of negative uptake in BVL tumors with either BVL mutations or papillary architecture, 19.8 (95% CI, 2.72-144), and low odds of negative uptake in RL tumors with either RL mutations or follicular architecture, 0.048 (95% CI, 0.006-0.344), after adjusting for age, sex, race, RAI preparation method, bone metastases, and RAI dose. Patients with negative scans were significantly older (62.4 vs 47.0 years, P = .03). CONCLUSION: Among DTC patients with DM at diagnosis, non-iodine-avid disease is highly prevalent in patients with BVL cancers, particularly with BRAFV600E and TERT promoter mutations, and is associated with an older age. Better strategies are needed to improve RAI treatment response for these patients.

Cervical Lymph Node Features Predictive of Suboptimal Adequacy During Ultrasound-Guided Fine-Needle Aspiration in Thyroid Cancer Patients.

PURPOSE: To determine the rate of cytologic and diagnostic adequacy and identify features associated with suboptimal tissue sampling in ultrasound-guided fine-needle aspiration (US-FNA) of suspected nodal disease in thyroid cancer patients. METHODS: A single-institution pathology database was queried for lymph node FNA reports in thyroid cancer patients from 2014 to 2019. Charts were reviewed for demographics, body mass index (BMI), prior thyroidectomy, cancer type, and subsequent surgery. Ultrasound images were retrospectively reviewed for location, size, depth from skin, cystic components, macrocalcification, echogenic foci, and internal vascularity score. Pathology reports were categorized as cellular and diagnostic, hypocellular/acellular but diagnostic with abnormal cells or thyroglobulin levels, or hypocellular and nondiagnostic. Correlation and multivariate regression analyses were performed. RESULTS: Initial query yielded 552 lesions in 343 subjects. Following exclusion, 377 lesions in 255 subjects were included. Mean patient age was 48.5 years (14-90), BMI 28.5, and 66.7% female and 33.3% male. The majority (95.3%) had papillary thyroid carcinoma (PTC); and 65.5% had prior thyroidectomy. 17.7% of lesions were hypocellular/acellular (suboptimal), and 5.6% nondiagnostic. Patient factors had no association (P >.05). Right-sidedness and hypovascularity were associated with hypocellularity (P <.05). Higher long/short-axis ratio and cystic foci were weakly associated. On multivariate analysis, right-sidedness (odds ratio [OR] 1.99; confidence interval [CI] 1.10-3.57) and lower vascularity score (OR 0.54; CI 0.39-0.73) were predictive of suboptimal sampling. CONCLUSION: US-FNA has high diagnostic yield and cellular sample rate. Lesion size had no effect. Right-sidedness and lower vascularity scores were predictive of suboptimal tissue. Identifying these features and expected sample adequacy rates can inform management decisions for thyroid cancer patients with cervical lymphadenopathy.

Fine-needle aspiration performance during cytopathology fellowship: what do the ACGME case logs show us?

INTRODUCTION: Cytopathology fellows are required to enter their fine-needle aspiration (FNA) case numbers in an online data collection system, the Accreditation Council for Graduate Medical Education (ACGME) Case Log system. This study reviewed this data to examine trends in FNA case numbers during fellowship training. METHODS: A retrospective review of the ACGME Accreditation Data System (ADS) FNA Case Log data was performed for academic years 2006-2019. For 2006-2016, total and average numbers of FNAs performed per academic year were available. After 2016, data also included the number of programs and trainees, national averages, standard deviation, minimum, median, maximum, and percentiles for the number of FNAs performed. RESULTS: The number of FNAs documented by cytopathology fellows has gradually increased from 2006 (average 10.9) to 2013 (average 18.6) and dramatically increased in 2014 (average 38.0). Averages have remained greater than 30 FNAs documented per academic year since 2014, with some variation. However, a decline was observed in 2019, likely due to the COVID-19 pandemic. CONCLUSIONS: FNA procedures reported in the ACGME Case Log System indicate vast differences in cytopathology fellowship educational experiences and settings. After logging FNAs becoming an ACGME requirement in 2013, the average number of FNAs has been greater than 30 per year and provides some guidance for programs with respect to the number of FNAs being reported by cytopathology fellows nationally.

Excellence Available Everywhere: The Virtual Pathology Grand Rounds Experience.

OBJECTIVES: The goal is to describe the use of a virtual platform in the delivery of Virtual Pathology Grand Rounds (VPGR) and discuss the overall experience from the perspective of hosts, speakers, and participants. METHODS: Zoom was a natural choice for an online format because virtual platforms had been increasingly used to conduct meetings and medical education. VPGR hosted 14 speakers on a variety of topics, including subspecialty anatomic pathology material, digital pathology, molecular pathology, and medical education. RESULTS: There were 221 registrants and 114 participants for the first lecture, reaching a maximum of 1,268 registrants for the 12th lecture and the maximum limit of 300 participants during 3 lectures. Speakers stated that VPGR conveniently provided career-building opportunities through partnerships with host universities and remote attendance. Participants identified a lack of interpersonal communication and technical challenges as downsides. CONCLUSIONS: VPGR serves as strong proof of concept for the feasibility and demand for high-quality, remote academic pathology talks.

Molecular cytopathology diagnosis of a lung neoplasm: Case report of an unusual non-small cell carcinoma with MET exon 14 skipping mutation.

Here we report the combined cytological and molecular diagnosis of a lung mass. The cytology and extensive immunohistochemistry on an endobronchial ultrasound-guided fine needle aspiration biopsy were inconclusive. By genomic profiling of the cell block material, we identified a MET exon 14 skipping mutation that indicated a lung origin and made the patient eligible for the tyrosine kinase inhibitor, crizotinib. This case is a prime example of complementing adequate aspiration and cell block processing techniques with molecular testing. Such an approach would augment the usability of fine needle aspiration biopsy, both as a diagnostic modality and as the first line to find therapeutic targets in the era of precision medicine.

Disseminated Legionella micdadei infection in a liver transplant patient presenting as pulmonary nodules and a laryngeal lesion.

We report a liver transplant patient with disseminated Legionella micdadei infection with pulmonary, laryngeal, and suspected muscle involvement. This organism, which stains weakly acid-fast, primarily affects immunocompromised patients. The diagnosis is difficult to make; in this case, the organism was identified via molecular diagnostics on laryngeal and pulmonary biopsy tissue.

PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism.

Molecular mechanisms mediating tonic secretion of parathyroid hormone (PTH) in response to hypocalcaemia and hyperparathyroidism (HPT) are unclear. Here we demonstrate increased heterocomplex formation between the calcium-sensing receptor (CaSR) and metabotropic γ-aminobutyric acid (GABA) B1 receptor (GABAB1R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABAB1R or glutamic acid decarboxylase 1 and 2 in PTGs produces hypocalcaemia and hypoparathyroidism, and prevents PTH hypersecretion in PTGs cultured from mouse models of hereditary HPT and dietary calcium-deficiency. Cobinding of the CaSR/GABAB1R complex by baclofen and high extracellular calcium blocks the coupling of heterotrimeric G-proteins to homomeric CaSRs in cultured cells and promotes PTH secretion in cultured mouse PTGs. These results combined with the ability of PTG to synthesize GABA support a critical autocrine action of GABA/GABAB1R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABAB1R heteromer to HPT.

The diagnostic utility of next-generation sequencing on FNA biopsies of melanocytic uveal lesions.

BACKGROUND: Uveal melanoma is highly aggressive, and overall prognosis depends on mutation status. Fine-needle aspiration biopsies (FNABs) play an important role in obtaining fresh tissue for cytologic diagnosis and molecular studies. It has been suggested that, although FNAB usually provides high diagnostic accuracy, there may be limited cellularity, which may compromise diagnostic potential for molecular studies. FNABs of uveal melanocytic lesions were evaluated to assess sample adequacy for both cytologic evaluation and next-generation sequencing (NGS). METHODS: The authors retrospectively evaluated 36 cases of melanocytic uveal lesions from 2015 to 2018. Samples were obtained by ophthalmologist-performed FNAB and aliquoted for cytology and NGS. Various combinations of direct smears, liquid-based cytology slides, cell blocks, and immunohistochemical stains for melanocytic markers were performed. All samples were tested for molecular alterations using hybrid-capture-based NGS. RESULTS: There was sufficient material for cytologic diagnosis in 33 of 36 cases (92%), for NGS testing in 30 of 36 cases (83%), and for both cytologic diagnosis and NGS testing in 28 of 36 cases (78%). Of 7 cases that were cytologically categorized as indeterminate or diagnosed as "atypical" or "nondiagnostic," NGS testing was sufficient and diagnostic for melanoma in 5 cases. Of the cases diagnosed as melanoma on pathology, 20 cases (87%) had concordant NGS testing results, 2 lacked molecular alterations, and 1 was insufficient for testing. CONCLUSIONS: FNA sampling of melanocytic uveal lesions is adequate for both cytologic diagnosis and NGS testing. In a subset of cases in which pathologic findings were indeterminate, NGS testing results were clarifying for diagnosis. In addition, specific molecular alterations identified can aid in evaluating prognosis and guide further management.

Case report of a neuroendocrine tumor of the thyroid gland with limited calcitonin expression: a diagnostic challenge.

Medullary thyroid carcinoma (MTC) is a malignant tumor of the parafollicular cells, which produce calcitonin. As a result, calcitonin is an important tool for diagnosing MTC. When there is focal or no calcitonin staining, diagnosis of MTC can be challenging as this may suggest differences in cell origin and in prognosis and recurrence of the disease. The prognosis and guidelines for management and follow up for MTC remain inconclusive. Here, we present a case of primary neuroendocrine tumor of the thyroid gland with only focal calcitonin staining on immunohistochemistry and low serum calcitonin level despite a tumor size of almost 4 cm. The assumption of C-cell origin was made from positive staining for carcinoembryonic agent (CEA), thyroid transcription factor 1 (TTF-1) and paired box 8 (PAX8) without expression of thyroglobulin (Tg). The patient underwent thyroid lobectomy and follow-up monitoring with ultrasound and measurements of calcitonin and CEA levels, without any further surgical intervention. Few cases of neuroendocrine tumors with limited calcitonin expression have been published and the etiology and prognosis are still unknown. Our case suggests that limited calcitonin expression cannot completely exclude the diagnosis of MTC. This rare type of MTC should be differentiated from the typical presentation of MTC. Treatment and post-operative surveillance should be tailored based on the individual.

Squamous differentiation in papillary thyroid carcinoma: a rare feature of aggressive disease.

BACKGROUND: Papillary thyroid carcinoma with squamous differentiation (PTC-SD) is a poorly understood pathologic finding of unknown clinical significance. Selected case reports have suggested that PTC-SD is an aggressive tumor with a poor prognosis. Here we present the largest case series of PTC-SD reported in the United States. MATERIALS AND METHODS: The cancer registry at our tertiary care referral center was reviewed to identify all patients from 1995-2015 who had been diagnosed with PTC-SD on initial total thyroidectomy or lymph node dissection for recurrent disease. All cases were reviewed by an endocrine pathologist to confirm the diagnosis. Patient demographic, pathology, and outcomes data were collected and reviewed. RESULTS: During the study period, ten patients were diagnosed with PTC-SD, six in the primary tumor at the time of initial surgery, and four in lymph node metastases during surgery for recurrent disease. The median age at diagnosis was 56 y and half of the patients were male. Aggressive features such as multifocality (67%), extrathyroidal extension (67%), positive margin (89%), lymph node metastases (80%), and extranodal extension (60%) were far more prominent than is typically seen in classic PTC. Long-term follow-up (median 56.5 mo) demonstrated high rates of locoregional recurrence (60%), pulmonary metastases (30%), and mortality (10%). CONCLUSIONS: Squamous differentiation is a rare finding in PTC that is associated with aggressive pathologic features and poor long-term outcomes. This phenomenon may represent a step in progression toward dedifferentiation; thus, patients with PTC-SD should have close, life-long surveillance and should be treated according to evidence-based guidelines for high-risk thyroid cancers.

Cytology cases of the week: an educational tool that improves trainee exposure to cytology.

INTRODUCTION: The Accreditation Council for Graduate Medical Education requires residents to examine 1500 cytology specimens by the end of residency. Cytology cases of the week (COWs) were instituted in 2010-2011 in an effort to increase trainee exposure to cytology. MATERIALS AND METHODS: Images of 2 to 5 cases with basic clinical information are sent to residents weekly. Residents have 1 week to respond by e-mail; after which, correct answers are e-mailed. Cytology resident in-service examination (RISE) scores were used to assess the effectiveness of COWs. Additionally, a feedback survey was distributed to trainees to determine the perception of COWs as a teaching tool. RESULTS: An unpaired two-sided t test showed residents who participated in COWs scored 15.4% higher on the RISE than residents who participated minimally or not at all over the 5-year period (P < 0.05). In 2014-2015 and 2015-2016, when COWs were minimally and not at all offered, we saw a significant decrease in average cytology RISE scores compared with prior years when COWs were offered (P < 0.05). There was no correlation between percentage of correctly submitted answers for COWs and RISE scores. The vast majority (83%) of trainees reported participating in COWs for self-study, and the majority (86%) felt participation in COWs increased their cytology knowledge. Major reasons for not participating included technical challenges and time limitations. CONCLUSIONS: COWs are an effective educational tool that increase resident fund of knowledge in cytology. Residents who participate in COWs perform higher on the RISE, regardless of percentage of correctly submitted answers.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a review for pathologists.

The rising incidence of papillary thyroid carcinoma is linked in part to inclusion of noninvasive follicular variant of papillary thyroid carcinoma. Despite its designation as carcinoma, noninvasive follicular variant of papillary thyroid carcinoma appears to be exceptionally indolent, often over treated by current treatment practices. Additionally, criteria for diagnosis have historically been subjective and challenging. Recently, an international multidisciplinary collaborative group performed a clinicopathologic survey of such cases with extended follow-up and concluded based on the outcome data that a revision in nomenclature was warranted, proposing 'Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).' This monograph is a synopsis and guide for pathologists on NIFTP and focuses on histologic features, including inclusion and exclusion criteria used to define NIFTP, as well as grossing guidelines, reporting practices, and potential diagnostic limitations.