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Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the preferred method for diagnosing pancreatic masses. While the diagnostic success of EUS-FNA is widely accepted, the actual performance of EUS-FNA is not known. This study sought to define the EUS-FNA accuracy compared with the gold standard, surgically resected specimens. The study was a single institution, retrospective, and chart review of patients with surgically resected pancreatic specimens from 2005 to 2015 with a preoperative EUS-FNA or biliary brushing. Cytological reports were organized from least concerning (i.e., low chance of malignancy) to most concerning (high chance of malignancy) into eight cytologic categories. We identified 741 cytologic cases: 530 EUS-FNA and 211 endoscopic brushings. For EUS-FNA samples, 62.5% of "benign" samples proved to be "benign" on surgical pathology. A cytologic diagnosis of "suspicious for malignancy" or "positive for malignancy" were concordant with a cancer diagnosis on surgical pathology 93.3% and 98.0% of cases, respectively. EUS-FNA proved to be highly reliable at diagnosing malignancy for cytologic samples that were "suspicious" or "positive" for malignancy. Paired with supportive clinical data, these interpretations may be used to justify cancer treatment.

Background Basaloid salivary gland neoplasms (BSNs), which include benign primary tumors and primary or metastatic malignancies, show overlapping morphology in fine-needle aspiration (FNA). The Milan system recommends assigning a grade (low or high) to malignant salivary neoplasms because of the impact on surgical planning. This study investigated cytomorphologic features of BSNs on FNA that would help to favor a high-grade malignancy over a low-grade malignancy or a benign tumor. Methods Two pathologists performed a double-blinded cytologic evaluation of FNA cases diagnosed as BSNs that had corresponding surgical resections. The diagnosis made with the Milan system was correlated with the final surgical diagnosis and grade. Cytologic sensitivity, specificity, and predictive values were calculated. Results There were 132 BSN FNA cases; cytology slides were available for 77 of 87 patients who had undergone resection. The risk of malignancy for the benign neoplasm (BN), salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SFM), and malignant categories were 13.6%, 22%, 100%, and 100%, respectively. The sensitivity of the malignant/SFM category was 51.7%; another 37.9% of confirmed malignancies were diagnosed as SUMP. The specificity of the BN category was 86%. Favoring a high-grade malignancy on FNA had 100% accuracy (5 of 5). Favoring a low-grade malignancy on FNA had 75% accuracy (6 of 8). The most specific cytomorphologic clues for a high-grade malignancy were necrotic/apoptotic debris, mitoses, discohesion, and anisonucleosis. Conclusions BSNs encompass a broad spectrum of primary and metastatic tumors. Necrotic/apoptotic debris, mitotic activity, discohesion, and significant anisonucleosis, alone or especially in combination, should make a cytopathologist suspect a high-grade malignancy.

Background Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs). Methods The pathology archives of 5 institutions were searched for BDBs with HCC involvement. Results A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5 years (range, 22-80 years). The median hepatic tumor size was 6.2 cm (range, 2.2-13.0 cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α-fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5 months. Conclusions HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports.

Introduction Fine-needle aspiration (FNA) of nodal metastases plays a key role in the diagnosis of oropharyngeal squamous cell carcinoma (OPSCC). Because of significant clinical implications of human papillomavirus (HPV)-related OPSCC, immunohistochemistry for p16 as a surrogate marker for high-risk HPV is an important ancillary test. After our laboratory switched from CytoLyt to formalin fixative for FNA needle rinses generating cell block (CB) material, we investigated the impact of this protocol change on the accuracy of p16 results. Materials and methods FNA specimens of head and neck lesions with p16 staining performed on CB, from 1 year before and after the implementation of formalin-fixed CB (FCB) were identified. Nuclear and cytoplasmic p16 expression was scored and compared to p16 status on corresponding surgical specimens. Results There were no false-positive results with either fixative. CytoLyt-fixed CB (CCB) had 47% (7 of 15) false-negative cases, whereas FCB had none, with 100% diagnostic accuracy for p16-negative (n = 6) and p16-positive (n = 15) results. False-negative CCB showed 0% to 10% nuclear and 0% to 65% weak cytoplasmic staining, whereas true-positive CCB showed 10% to 85% nuclear and 35% to 90% cytoplasmic staining. p16-negative FCB showed 0% nuclear and cytoplasmic staining, and p16-positive FCB showed 30% to 100% moderate-strong nuclear and cytoplasmic staining. Interobserver variability was greater with CCB. Conclusions In our laboratory, formalin fixation of CB material improved the accuracy of p16 interpretation. Staining in FCB was also more robust than CCB, which showed weaker cytoplasmic and more focal nuclear staining. Therefore, we advocate formalin fixation for head and neck cytology specimens that may require p16 testing.

Introduction Reported upgrade rate to malignancy of radial scars (RS) ranges widely (0%-40%) making management controversial. Methods A retrospective chart review was performed on patients with RS on core needle biopsy (CNB). Upgrade rates to malignancy and atypia on surgical excision were evaluated. Results Of 127 patients with RS on CNB, 53 were excluded due to malignancy or missing records. Of 74 patients reviewed, 52 (70.3%) had surgical excision with four (7.7%) upgraded to malignancy. Eight patients (10.8%) had atypia with RS on CNB with two (25%) upgraded to malignancy. When isolated RS was on CNB, 2 of 44 (4.5%) upgraded to malignancy while 15 of 44 (34%) had atypia on excision. Of 22 patients (29.7%) who did not have excision, zero developed cancer. Conclusion We found higher than expected upgrade rates of isolated RS to atypia which can alter management. Additionally, 25% of RS with atypia upgraded to malignancy suggesting these patients are at higher risk.

Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance. Significance: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens. Cancer Discov; 8(5); 568–81. ©2018 AACR. See related commentary by Sullivan, p. 532. See related article by Romano et al., p. 556. This article is highlighted in the In This Issue feature, p. 517

Therapy for non-small cell lung carcinoma (NSCLC) is currently determined by histologic subtype and the presence or absence of actionable mutations. Accurate subclassification is therefore essential for appropriate selection of cases for molecular studies and guiding treatment. The gold standard for subclassification of NSCLC is identification of differentiating morphologic features in correlation with diagnostic immunohistochemistry (IHC) in cases of poorly differentiated carcinoma. Whereas Napsin A, TTF1, and p40 antibodies have been used individually for the subtyping of NSCLC, few studies have examined the 3 in cocktail form. Using a novel triple IHC antibody cocktail (TNP) composed of TTF1 (brown nuclear), Napsin A (red granular cytoplasmic), and p40 (red nuclear), a randomized, double-blinded subclassification was performed on a representative histologic section of 32 previously resected primary NSCLCs. TNP results were then compared with the gold-standard diagnosis. TNP accurately identified all (100%, 10/10) squamous cell carcinomas (SCCs) (p40+/TTF1-/Napsin A-) and 89% (16/18) of adenocarcinomas (ADCs) (p40-/TTF1+/Napsin A+). TNP was negative in 7 (20%) tumors (p40-/TTF1-/Napsin A-), including 2 mucinous ADCs. TNP showed no overlapping or discordant immunostaining. Using traditional IHC with p63, CK5/6, and TTF1, all TNP (-) cases remained unclassifiable. With the exception of mucinous ADC, which was TNP negative, all TNP cases correlated with gold-standard diagnosis; 78% of tumors were also definitively classified as either ADC or SCC and required only a single slide for classification.

Background The cytologic features of undifferentiated pancreatic carcinoma with osteoclastic giant cells (UOC) are rarely described. Methods Cytologic and clinicopathologic characteristics in 15 UOC fine-needle aspiration (FNA) specimens were analyzed. Results FNA specimens were obtained from 6 men and 8 women with a mean age of 65 years who had UOCs (head, n = 7; body, n = 3; and tail, n = 4) with a mean radiologic size 7.3 cm, and some had a cystic component (n = 9). Three cell types (osteoclastic giant cells, pleomorphic tumor giant cells, and spindled/histiocytoid cells) were observed in 12 of 15 specimens (80%); and pancreatic ductal adenocarcinoma (PDAC) was present in 11 specimens. FNA diagnoses were UOC (n = 6), PDAC (n = 5), poorly differentiated carcinoma (n = 2), "suspicious for neoplasm" (n = 1), and "negative" (n = 1). Five of 5 specimens with osteoclastic giant cells were positive for cluster of differentiation 68 (CD68) (a glycoprotein that binds to low-density lipoprotein). Pleomorphic tumor giant cells and spindled/histiocytoid cells were positive for pancytokeratin (6 of 7 specimens), CAM5.2 (2 of 3 specimens), and epithelial membrane antigen (2 of 2 specimens). INI-1 protein expression was retained in 3 of 3 specimens. The Ki-67 labeling index was assessed in 3 specimens and was 12%, 18%, and 40%; 4 of 12 resected UOCs were pure, and 8 were mixed with PDAC. One resection specimen had intraductal papillary mucinous neoplasm, and 2 had mucinous cystic neoplasms. The median overall survival (OS) of patients who had UOCs identified on FNA was 8 months (6 died [OS, 8 months; range, 2-22 months], and 8 remained alive [OS, 3 months; range, 1-27 months]), which was similar to the survival of 74 patients who had PDACs identified on FNA (OS, 15 months; P = .279) but worse than that of the 27 patients with UOCs who did not undergo FNA (OS, 92 months; P = .0135). Conclusions The 3 classical UOC cell types are identifiable on FNA, making cytologic diagnosis possible if considered in the differential. A PDAC component is often also observed. The survival advantage of UOC over pure PDAC appears to be negated by FNA and requires further investigation. Cancer Cytopathol 2017;125:563-75. © 2017 American Cancer Society.

Objectives: The objective of this study was to determine if spatial distribution of multiparametric magnetic resonance imaging–transrectal ultrasound (mpMRI-TRUS) fusion biopsy cores to the index lesion reveals trends in the detection of intra-lesion Gleason heterogeneity and a more optimal prostate biopsy strategy. Methods: Index lesion was the lesion with longest diameter on T2-weighted (T2W)-MRI. In cohort 1, fusion biopsy cores biopsies were taken in areas in the center of the target as well as 1 cm laterally on each side. For cohort 2, targeted biopsies were taken from the center of the lesion only. Heterogeneity was defined as difference in maximum Gleason score obtained from fusion cores in the center of the index lesion versus cores obtained from the periphery (cohort 1), or any difference in maximum Gleason score obtained from fusion cores targeted to the index lesion (cohort 2) compared with systematic 12 cores TRUS biopsy. Results: Ninety-nine consecutive patients (35 and 64 in cohorts 1 and 2, respectively) with median age (SD) and prostate-specific antigen (PSA) of 66.9 (±5.9) and 9.7 (±8.2) respectively, were included. Age, PSA, Prostate Imaging Reporting and Data System (PI-RADS) score, and preoperative MRI lesion size were not significantly different between cohorts. Gleason heterogeneity was observed at a significantly higher rate in cohort 1 versus cohort 2 (58% versus 24%; p = 0.041). In cohort 1, cores obtained from the center of the lesion had higher Gleason score than cores obtained from the periphery of the targeted lesion in 57% of cases. Conclusions: We demonstrate that there is observable tumor heterogeneity in biopsy specimens, and that increased number of cores, as well as cores focused on the center and periphery of the largest lesion in the prostate, provide more comprehensive diagnostic information about the patient’s clinical risk category than taking nonspecific cores targeted within the tumor.

BACKGROUND This study describes the cytologic features of 26 angiosarcomas diagnosed on fine-needle aspiration. METHODS Twenty-six angiosarcomas from 20 patients were confirmed by cytomorphology and immunocytochemical (immunohistochemistry) positivity for at least 2 of 3 vascular markers. Specimens were examined for spindled/epithelioid/plasmacytoid single cells, 3-dimensional clusters, multiple prominent/bar-shaped nucleoli (5 times longer than their width), chromatin strands, abnormal mitoses, necrosis, and vasoformative features. RESULTS Eight males and 12 females with a mean age of 52 years (range, 2-94 years) underwent aspiration of tumors in the following: soft tissue or skin/subcutis (n = 10), bone (n = 4), nodes (n = 5), lung (n = 2), liver (n = 2), heart (n = 1), parotid gland (n = 1), and pleural fluid (n = 1). An angiosarcoma diagnosis was rendered for 24 of the 26 cases (92%); 1 was diagnosed as “atypical cells, cannot exclude angiosarcoma,” and another was diagnosed as a malignant vascular neoplasm. Abnormal mitoses were most frequent (85%), and they were followed by single malignant cells (81%: epithelioid [69%], spindled [62%], and plasmacytoid [19%]), 3-dimensional clusters (54%), multiple prominent (62%) or bar-shaped nucleoli (54%), and chromatin strands (31%). Vasoformative features, including hemophagocytosis (54%), cytoplasmic lumina/vacuoles (69%) containing red blood cells (54%)/neutrophils (31%), and endothelial wrapping (69%), were seen in 88%; 23% had all vasoformative features, 88% had at least 1, and 12% had none. CONCLUSIONS Angiosarcomas show a range of cytomorphologic features that make them potentially recognizable on cytology. Although vasoformative features are highly suggestive, they are not specific for angiosarcoma and may be seen in some nonvascular neoplasms. Immunohistochemistry and a high index of suspicion are required for an accurate diagnosis. Cancer Cytopathol 2016. © 2016 American Cancer Society.

Metastatic cancer remains a clinical challenge; however, patients diagnosed prior to metastatic dissemination have a good prognosis. The transcription factor, TWIST1 has been implicated in enhancing the migration and invasion steps within the metastatic cascade, but the range of TWIST1-regulated targets is poorly described. In this study, we performed expression profiling to identify the TWIST1-regulated transcriptome of melanoma cells. Gene ontology pathway analysis revealed that TWIST1 and epithelial to mesenchymal transition (EMT) were inversely correlated with levels of cell adhesion molecule 1 (CADM1). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrated that TWIST1 physically interacts with the CADM1 promoter, suggesting TWIST1 directly represses CADM1 levels. Increased expression of CADM1 resulted in significant inhibition of motility and invasiveness of melanoma cells. In addition, elevated CADM1 elicited caspase-independent cell death in non-adherent conditions. Expression array analysis suggests that CADM1 directed non-adherent cell death is associated with loss of mitochondrial membrane potential and subsequent failure of oxidative phosphorylation pathways. Importantly, tissue microarray analysis and clinical data from TCGA indicate that CADM1 expression is inversely associated with melanoma progression and positively correlated with better overall survival in patients. Together, these data suggest that CADM1 exerts tumor suppressive functions in melanoma by reducing invasive potential and may be considered a biomarker for favorable prognosis.

In the original version of [this article][1] ([1][2]), an error in Fig. 6C was introduced by the compositor during the production of the paper. Specifically, the Raptor Western blot was improperly shifted. The figure has been corrected in the latest online HTML and PDF versions of the article. The