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Background Activating point mutations of the RAS gene (NRAS, HRAS, and KRAS) can be seen in benign and malignant thyroid tumors; among these, NRAS mutations are more commonly seen. This study was conducted to evaluate the thyroid risk of malignancy (ROM) associated with RAS mutations in thyroid fine-needle aspiration (FNA) at the authors' institution. Methods The authors searched their electronic database system between January 2015 and May 2021 for thyroid FNA cases with any type of RAS mutation. Molecular alterations were identified with the ThyroSeq Genomic Classifier, ThyGeNEXT (thyroid oncogene panel)/ThyraMIR (miRNA classifier), or ThyroSure gene panel. Results A total of 127 cases (age, 51 ± 14 years; 100 females and 27 males) were identified, and 72 had histologic follow-up. The overall ROM associated with RAS mutations (with or without any other molecular alterations) was 29%, whereas the ROM was lower (18%) with RAS mutations only. Isolated NRAS, HRAS, and KRAS mutation-associated ROMs were 15%, 27%, and 14%, respectively. Among these RAS-mutated cases, the cases with a Bethesda category IV cytologic diagnosis had a higher ROM than the cases with a category III diagnosis (38% vs 17%). Twenty-one histologically confirmed malignant cases were mostly classified on cytology as category IV lesions (14 of 34; 41%), and the remainder were either category III (6 of 35; 17%) or V lesions (1 of 1; 100%). Conclusions This study demonstrated that the overall RAS mutation-associated ROM in thyroid FNA was intermediate (29%), and isolated HRAS mutations appeared to have a higher ROM (27%) than NRAS and KRAS mutations (15% and 14%, respectively).

Context.—Salivary gland-type tumors (SGTs) of the lung represent a distinct group of lung neoplasms. Pulmonary SGTs often pose diagnostic challenges, especially in small biopsy and cytology samples because of limited sample volume and overlapping morphology among pulmonary SGTs, metastatic SGTs of head and neck origin, and other lung tumors.Objective.—To identify the clinical characteristics, histomorphology, immunophenotypic features, and molecular alterations that are crucial for the diagnosis and differential diagnosis of pulmonary SGTs, especially in small biopsy and cytology specimens.Data Sources.—Literature review and authors' personal practice experience.Conclusions.—An accurate diagnosis of pulmonary SGTs can be achieved by careful evaluation of clinical findings and histomorphology in conjunction with immunohistochemical studies and molecular analysis.

Context.— Since 2016, transoral endoscopic thyroid resection with vestibular approach (TOETVA) has been increasingly performed in the United States. Although guidelines for the procedure are evolving, indeterminate and malignant preoperative cytopathologic diagnoses are not a contraindication. There are limited data related to the pathologic examination of these specimens. Objective.— To examine the clinicopathologic features of TOETVA specimens with particular attention to limitations of interpretation of pathologic parameters and final diagnosis. Design.— We reviewed age, sex, preoperative imaging and cytologic diagnoses, surgical pathology, and clinical follow-up data in TOETVA resections from our institution for procedures performed between March 2016 and December 2019. Results.— Fifty cases of TOETVA were identified, comprising 48 women and 2 men with a mean age of 47 years. Preoperative cytologic diagnoses were available in 47 cases and included 19 nondiagnostic/benign (Bethesda I/II), 24 follicular lesion of undetermined significance/suspicious for follicular neoplasm (Bethesda III/IV), and 4 suspicious/malignant diagnoses (Bethesda V/VI). Thirty-four cases (68%) among the surgical resection specimens showed disruption and/or fragmentation. Thirty-nine cases were negative for carcinoma, including hyperplasias and benign/indolent neoplasms. Eleven cases exhibited papillary thyroid carcinoma. Final diagnoses were reached in all disrupted/fragmented cases. In 2 cases of papillary thyroid carcinoma, tumor size, microscopic extrathyroidal extension, and margin status could not be determined. Conclusions.— A significant proportion of TOETVA specimens are disrupted/fragmented, which can compromise information about tumors, including size, number, margin status, and microscopic extrathyroidal extension. Given that these parameters inform treatment and follow-up, this should be considered when selecting patients for TOETVA.

Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid malignancy with high mortality rate. This malignancy arises in thyroid follicular cells either denovo or with an associated differentiated thyroid carcinoma component. Clinically, it usually presents as a rapidly enlarging mass, pain and locally compressive symptoms. Histopathologic variability and heterogeneity often pose diagnostic challenges, especially in scant and paucicellular specimens. This article describes the clinical, histopathologic and molecular features of ATC and also addresses the associated diagnostic limitations and challenges.

Objectives To evaluate the role of endoscopic ultrasound-guided fine needle aspiration cytology in identifying mucinous cystic lesions (MCLs) in histologically proven cases of intraductal papillary mucinous neoplasm (IPMN) or mucinous cystic neoplasm (MCN) and risk of malignancy associated with each cytologic category based on the Papanicolaou Society of Cytopathology (PSC) guidelines. Methods All resected cases with histologic diagnosis of IPMN or MCN at our institution from January 1, 2004, to August 31, 2019, with associated cytology were included. Available cytology slides of nondiagnostic (ND), negative/benign (BN), and atypical cytology (AC) cases were reviewed and reclassified based on the PSC guidelines. Results A total of 120 cases were identified, including 57 IPMNs with low-grade or moderate dysplasia (LGD/MD) and high-grade dysplasia (HGD), 34 MCNs with LGD/MD or HGD, and 29 IPMNs with invasive malignancy. After cytology slide review and reclassification, we observed that ND and BN cases were paucicellular and lacked ancillary testing (carcinoembryonic antigen levels or KRAS mutation analysis). The risk-of-malignancy rates were 33% for ND, 11% for BN, 28.5% for AC, 17% for MCL, and 100% for suspicious/positive cytologic diagnosis. Conclusions A multidisciplinary approach including combined use of cytology and ancillary testing is helpful in establishing a diagnosis of MCL and identifying associated malignancy.

Background Accessory spleen/or splenule (AS) can involve pancreas/or peripancreatic tissue and present as a mass-forming lesion, and on imaging studies, it stimulates concern for a neoplastic process. The current study reported the largest cohort of AS cases evaluated by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Methods We retrospectively reviewed our data base system for cases underwent EUS-FNA for pancreatic/or peripancreatic lesions, with "AS" in diagnosis or in note/or with a clinical concern in the history, from January 2010 to August 2019. Corresponding cytology slides were re-reviewed to identify the key cytomorphologic features. Results We identified 25 AS cases from 15 female and 10 male patients with a mean age of 55 years. Most patients presented with non-specific clinical symptoms or were identified as an incidental mass lesion. Majority of the lesions were located in or around the pancreatic tail region (68%) while the remainder in perisplenic region (32%). Rapid on-site evaluation (ROSE) was performed in nearly half of the cases (48%). Cytologically, AS shows a mixed population of medium to small-sized lymphocytes, clusters of lymphoid cells (LC), prominent vascularity (PV), scattered mixed inflammatory cells including eosinophils, and large platelet aggregates (LPAs). Among them, LC (P = .0079), PV and LPAs were the most helpful features for cytological diagnosis. Conclusion AS is a benign entity and may pose a diagnostic challenge due to its resemblance to a neoplastic process on imaging studies. EUS-FNA is an important tool to recognize AS by identifying its key cytologic features, thus may help to avoid unnecessary surgical management.

SMARCA4/BRG1-deficient tumors and those that have loss of SMARCA/BRG1 have been described as various aggressive carcinomas and sarcomas, including a subset of non-small cell lung carcinoma (NSCLC). Cytomorphologic features of NSCLCs are yet to be described. The objective of this study was to evaluate the cytomorphologic features, immunohistochemical profile, and molecular profile of SMARCA4/BRG1-deficient NSCLC (SMARCA4-dNSCLC).The authors retrospectively searched for cases with SMARCA4/BRG1 functional loss alterations, which were identified in molecular studies and further confirmed by immunocytochemistry, and they reviewed the cytomorphologic features. Tumors with BRG1 loss were also stained with an extensive antibody panel. Molecular profiling and clinical information of the identified cases were scrutinized.In total, 12 cytopathology cases from different anatomic sites were included. All cases showed variable expression of cytokeratin irrespective of type. One-half of cases had glandular features, followed by squamoid features, and poorly differentiated features. The most common cytologic features included sheets or papillary architecture, round or oval cell shapes, nuclear enlargement, moderate-to-marked pleomorphism, and coarse chromatin. Two cases with poorly differentiated cytomorphology had a predominance of single cells, scant cytoplasm, and macronucleoli. Variable expression of epithelial markers was noted in all cases. TP53 was the most frequently co-mutated gene in SMARCA4-dNSLCs.This study demonstrates that SMARCA4-dNSCLCs can have a wide spectrum of cytomorphologic features, ranging from a relatively well differentiated adenocarcinoma to a poorly differentiated/undifferentiated carcinoma, with the majority of cases exhibiting some high-grade features, such as mitosis, apoptosis, necrosis, and marked pleomorphism.

Objectives Recent studies have shown that trichorhinophalangeal syndrome type 1 (TRPS1) is a sensitive and specific marker that shows positive staining in breast carcinoma. We conducted this study to evaluate the role of TRPS1 immunohistochemistry (IHC) in differentiating breast primary vs tumors from other primary sites in malignant pleural effusion cytology specimens (MPECSs). Methods We selected 61 MPECS cases with cell block material available to analyze TRPS1 IHC staining. Of these 61 cases, 38 cases were metastatic carcinoma (MC) from a breast primary. We primarily selected MC cases confirmed as breast origin based on GATA binding protein 3 IHC positivity, except in two of the cases. The remaining 23 MPECS cases were from various primary sites, including urothelial (n = 6), Müllerian (n = 6), lung adenocarcinoma (n = 6), malignant melanoma (MM; n = 3), and squamous cell carcinoma (SqCC; n = 2). Results TRPS1 expression was observed in 35 (92%) of 38 MCs of breast origin. The staining intensity was variable, with 18 (47%) cases showing strong nuclear expression. In comparison, no TRPS1 expression was seen in any cases of urothelial carcinoma, MM, and SqCC. However, four of six Müllerian MC cases demonstrated TRPS1 expression. Conclusions TRPS1 is a new marker that can be used in an IHC panel to investigate breast origin in MPECS.

Objectives Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy, and early diagnosis, often aided by fine-needle aspiration (FNA), is key to improving patient prognosis. While the current literature describes some of the cytologic features (CFs) of this entity, a comprehensive examination of the CFs has not yet been performed. Methods We retrospectively searched our electronic database for ATC cases with available slides between January 2008 and December 2019. Cases were examined for 22 CFs and compared with a control group of differentiated thyroid carcinoma. Results A total of 18 ATC cases meeting our inclusion criteria were identified. Most cases showed moderate to high cellularity (83%) and epithelioid cytomorphology (83%). Architecture included either predominantly groups/clusters of tumor cells (56%) or single tumor cells (44%). The other CFs were as follows: nuclear enlargement (100%), nuclear crowding (89%), nuclear membrane irregularities (100%), multinucleated tumor cells (33%), and background acute inflammatory cells (50%). Of the CFs examined, statistically significant differences between ATC and the control groups were found in the following: nuclear pleomorphism, coarse/clumped chromatin, macronucleoli, apoptosis, and necrosis. Conclusions Identification of key CFs in FNA coupled with the clinical history aids in the diagnosis of ATC and helps distinguish it from other mimickers.

Hyalinizing trabecular tumors are a follicular origin neoplasm of the thyroid that usually present as an asymptomatic, well circumscribed, solitary mass. However, diagnosis of a hyalinizing trabecular tumor may be challenging especially on fine needle aspiration cytology and requires careful examination of the specimen to rule out potential mimickers such as papillary thyroid carcinoma, medullary thyroid carcinoma, paraganglioma, other follicular patterned neoplasms, intrathyroidal parathyroid tissue, and metastatic disease. We will review the cytologic, histologic and molecular features of hyalinizing trabecular tumors that aid in distinction from these mimickers with overlapping morphologic features and help ensure proper diagnosis for appropriate management.

Background This study investigated p16 by immunohistochemistry (IHC) on cellblocks (CBs) and human papillomavirus (HPV) by polymerase chain reaction (PCR) in fine-needle aspiration (FNA) of head and neck squamous cell carcinoma (HNSCC). Methods Receiver operating characteristic (ROC) curve analysis was used to assess test performance in CBs compared with p16 IHC in 42 surgical specimens from patients with HNSCC and in correlation with HPV by PCR in cytology specimens. The study assessed HPV by PCR in FNA specimens as a substitute for p16 IHC in surgical specimens. Results Of 42 cases, 38 CBs showed malignant cells as cohesive clusters of viable cells with or without single tumor cells, whereas 4 specimens were composed exclusively of single tumor cells and degenerated cells. All p16-negative surgical specimens showed an absence of p16 staining in the corresponding CBs (n = 16). In the p16-positive surgical cases (n = 26), corresponding CBs with tumor clusters (n = 23) showed heterogeneous p16 expression ranging from 40% to 100%; however, scoring single cells was challenging and unreliable because of cellular degradation. ROC curve inspection showed the optimal threshold to be at least 40% p16 staining in tumor clusters with 100% sensitivity and specificity. In cases with inadequate CBs, HPV by PCR on needle rinse showed 88% sensitivity and 100% specificity for p16 expression in surgical specimens. Conclusions A cutoff of at least 40% p16 expression in tumor clusters may be appropriate for p16 positivity in cytology CB specimens. A positive HPV finding by PCR on needle rinse can be used as a substitute for p16 expression in surgical specimens.

Background Hurthle cell features are frequently observed on the fine-needle aspiration (FNA) cytology of thyroid nodules and often pose a diagnostic challenge because of a significant overlap between cytomorphologic features seen in benign and malignant lesions. Molecular alterations (MAs) associated with these lesions are not well described. The objective of the current study was to evaluate the molecular profile of Hurthle cell lesions classified as Hurthle cell neoplasm (HCN) on cytologic evaluation. Methods The authors retrospectively reviewed their electronic database for cytologic diagnoses of HCN from January 1, 2017 to March 31, 2020. Results In total, 279 cases from 275 patients who had a diagnosis of HCN were included in the study. Molecular testing results were available in 85 cases (51 with MAs and 34 without MAs) and, of those, 42 had histologic follow-up available. Eight of 10 malignant cases had MAs, whereas the remaining 2 cases were negative for MAs. The most frequently encountered predominant genetic alterations or classifier findings were chromosome copy number alterations (n = 15), followed by NRAS (n = 8), KRAS (n = 7), suspicious (n = 6), EIF1AX (n = 4), TSHR (n = 3), gene overexpression (n = 3), positive microRNA classifier (n = 2), and 1 each of BRAF K601E, TERT, and HRAS mutations. One hundred thirty-seven cases had histologic follow-up available; of those, 28 were classified as malignant, and 109 were classified as benign (neoplastic and nonneoplastic). The overall risk of malignancy associated with HCN was 20%, and the risk of HCN with MAs was 25%. Conclusions The cytologic diagnosis of HCN includes various MAs without any obvious trend, and most malignant cases (80%) have some type of MA.

BACKGROUND Mesenchymal tumors (MTs) of upper gastrointestinal tract (UGIT) can show morphologic overlap thus posing a diagnostic challenge. This study evaluated the role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology in the diagnosis of UGIT-MTs and impact of rapid onsite evaluation (ROSE). METHODS We retrospectively search our electronic database between January 2001 and August 2019 for cases that underwent EUS-FNA for a submucosal/or intramural upper GI tract mass forming lesions. Data pertinent to immunostain expression in UGIT-MTs was also collected. RESULTS We identified 139 cases, of which 72 cases had subsequent surgical resection. The cytologic diagnoses included nondiagnostic, negative, atypical, suspicious for neoplasm and positive for neoplasm (PFN) in 11, 7, 11, 10, and 100 cases, respectively. Diagnosis of PFN was rendered in 51 of 69 cases with ROSE (74%) and in 49 of 70 cases without ROSE (70%). However, the cases with ROSE had a higher percentage of cases being precisely classified than without ROSE (86% vs 61%, P

Barrett's esophagus (BE) is a known precursor to esophageal adenocarcinoma. In the United States, a prevalence of up to 25% is reported in high risk populations and it is identified in about 5% of patients with gastroesophageal reflux disease (GERD). The diagnosis of BE requires endoscopically identifying columnar (“salmon colored”) mucosa, taking biopsies from targeted areas and then confirming histologically. The American College of Gastroenterologists updated its criteria in 2016, introducing a length requirement. This brief review addresses diagnosis of BE and its various associated challenges; identifying dysplasia, grading it, and management.

BACKGROUND This study was conducted to evaluate the diagnostic utility of cell block material in fine needle aspiration (FNA) of thyroid nodules. DESIGN A total of 242 thyroid fine need aspirations (FNAs) were performed between January 2015 and December 2015. Of those, all consecutive thyroid FNA cases with cell blocks (n = 140) from 129 patients (age: 58.9 ± 12.8 years) are included in this study. Cytology slides and cell blocks are reviewed for adequacy assessment based on the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) and then categorizing them into TBSRTC diagnostic categories. These cases are divided into two groups, combined cytology and cell block (C + CB) and cytology without cell block (C). RESULTS In the first group (C + CB), a total 140 cases are categorized in TBSRTC as follows: I: 13 (9.3%) cases, II: 78 (55.7%) cases, III: 7 (5%), IV: 16 (11.4%), V: 3(2.2%) and VI: 23 (16.4%). In the second group (C), the cases are classified in TBSRTC as follows: I: 23 (16.4%) cases, II: 70 (50%), III: 7 (5%), IV: 16 (11.4%), V: 3 (2.2%) and VI: 21 (15%). Nondiagnostic rate was 7.1% lower in the first group (C + CB) as compared with second group (C) (First group: 9.3% vs second group: 16.4%, P = .0764). CONCLUSIONS Combined use of cytology slides and cell block decreases the nondiagnostic rate up to 7.1% as compared with cytology without cell block.

The presence of thyroid tissue outside of the thyroid gland may occur in various clinical settings and anatomic locations and includes both benign and malignant differential diagnoses. Some of these entities include thyroglossal duct cyst, lingual thyroid, parasitic nodule, thyroid tissue within a lymph node and struma ovarii. In routine daily practice, these entities do pose diagnostic challenges for the pathologists. Differential diagnostic considerations depend largely on the location of lesion and the histologic features. A definitive diagnosis may remain unclear in some cases while knowledge is still evolving in others i.e., incidentally detected bland appearing thyroid follicles in a lateral neck lymph node. This article aims to elaborate on the various entities characterized by thyroid tissue outside of the thyroid gland, both benign and malignant, and the relevant differential diagnostic considerations.