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Background: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) recommends an upper limit of 10% for atypia of undetermined significance (AUS). Recent data suggest that this category might be overused when the rate of cases with molecular positive results is low. As a quality metric, the AUS and positive call rates for this facility's cytology laboratory and each cytopathologist (CP) were calculated. Methods: A retrospective analysis of all thyroid cytology cases in a 4.5‐year period was performed. Cases were stratified by TBSRTC, and molecular testing results were collected for indeterminate categories. The AUS rate was calculated for each CP and the laboratory. The molecular positive call rate (PCR) was calculated with and without the addition of currently negative to the positive results obtained from the ThyroSeq report. Results: A total of 7535 cases were classified as nondiagnostic, 7.6%; benign, 69%; AUS, 17.5%; follicular neoplasm/suspicious for follicular neoplasm, 1.4%; suspicious for malignancy, 0.7%; and malignant, 3.8%. The AUS rate for each CP ranged from 9.9% to 36.8%. The overall PCR was 24% (range, 13%–35.6% per CP). When including cases with currently negative results, the PCR increased to 35.5% for the cytology laboratory (range, 13%–42.6% per CP). Comparison analysis indicates a combination of overcalling benign cases and, less frequently, undercalling of higher TBSRTC category cases. Conclusions: The AUS rate in the context of PCR is a useful metric to assess cytology laboratory and cytopathologists' performance. Continuous feedback on this metric could help improve the overall quality of reporting thyroid cytology. Assessing the atypia of undetermined significance rate in the context of positive call rate and time serves as a valuable metric for evaluating cytopathologists proficiency and overall laboratory performance and helps identify trends to provide valuable feedback. [ABSTRACT FROM AUTHOR]

Background: Basaloid salivary gland neoplasm of uncertain malignant potential (B‐SUMP) is an indeterminate diagnostic subcategory, with pleomorphic adenoma (PA) representing the most common benign neoplasm. Pleomorphic adenoma gene 1 (PLAG1) staining is frequently seen in PAs and could aid in distinguishing them from other basaloid neoplasms. The authors evaluated the utility of PLAG1 immunocytochemistry (ICC) in differentiating PAs from other basaloid neoplasms in smears and liquid‐based cytology (LBC) specimens. Methods: In total, 45 B‐SUMP cytology aspirates and corresponding surgical excision specimens were identified. PLAG1 immunostaining was performed in all aspirates and surgical excision specimens and was scored as positive (strong/diffuse), equivocal (focal/weak), or negative. Results: PLAG1 ICC was performed directly on 38 smears and seven LBC specimens. PLAG1 was positive in 29 of 45 cases (64%), whereas six of 45 (13%) were equivocal, and 10 of 45 (22%) were negative. PLAG1‐positive aspirates included 26 (90%) PAs, two (7%) basal cell adenomas (BCAs), and one (3%) carcinoma ex‐PA. PLAG1‐equivocal aspirates included four (67%) PAs and two (33%) BCAs, whereas negative aspirates included five (50%) BCAs, four (40%) adenoid cystic carcinomas, and one (10%) metastatic adenosquamous carcinoma. The sensitivity, specificity, positive, and negative predictive values were 87%, 86%, 93%, and 75%, respectively. Diagnostic accuracy was 87%. Conclusions: PLAG1 ICC is useful when positive (strong/diffuse) and can be reliably performed on smears and LBC specimens. PLAG1 was positive in most PAs and in a small subset of BCAs. Therefore, in the absence of atypical cytologic features, PLAG1‐positive tumors could be diagnosed as benign, with a note favoring PA versus BCA. In contrast, PLAG1‐negative/equivocal tumors should remain in the B‐SUMP category. PLAG1 immunocytochemistry is useful for the diagnosis of pleomorphic adenoma when strong/diffusely positive and can be reliably performed directly on alcohol‐fixed conventional smears and liquid‐based cytology specimens. It may help enhance diagnostic accuracy in challenging cases and reduce indeterminate diagnoses. [ABSTRACT FROM AUTHOR]

Background: Fine‐needle aspiration cytology (FNAC) is generally the initial sampling method for salivary gland neoplasms. The cytomorphologic features of acinic cell carcinoma (AciCC) of salivary gland can overlap with other neoplastic and nonneoplastic entities. AciCCs harbor a recurrent t(4;9) rearrangement with upregulation of nuclear receptor subfamily 4 group A member 3 (NR4A3). NR4A3 protein overexpression has been shown to be highly sensitive and specific for the diagnosis of AciCC in histologic specimens and cell block preparations. However, data on NR4A3 immunocytochemistry (ICC) on conventional smears or liquid‐based cytology are limited. Methods: The authors identified 18 FNAC of histologically proven AciCC cases between 2013 and 2019. FNAC samples of diagnostic mimickers were likewise retrieved and included in the study cohort for comparison. The NOR1/NR4A3 mouse monoclonal antibody was applied directly to FNAC slides using a standard ICC technique. Results: The cohort included ethanol‐fixed Papanicolaou‐stained cytologic smears and liquid‐based preparations from 18 AciCC, one secretory carcinoma, four mucoepidermoid carcinomas, four salivary duct carcinomas, five pleomorphic adenomas (PA), five Warthin tumors, five oncocytomas, one oncocytic hyperplasia, and five nonneoplastic salivary gland cases. Strong nuclear staining for NR4A3 was present in all AciCC, weak nuclear staining was present in one PA, and all other non‐AciCC were negative (sensitivity, 100%; specificity, 97%). Conclusions: NR4A3 ICC can be used directly on FNAC conventional smears and liquid‐based cytology to reliably distinguish AciCC from its mimickers. This marker may be useful in cases where a cell block preparation is unavailable or inadequate. NR4A3 immunocytochemistry can be used directly on fine‐needle aspiration cytology conventional smears and liquid‐based cytology to reliably distinguish acinic cell carcinoma from its mimickers. This may be useful in cases where a cell block preparation is unavailable or inadequate. [ABSTRACT FROM AUTHOR]

Background: ThyroSeq assesses the probability of malignancy (POM) in thyroid fine‐needle aspiration cytology specimens diagnosed as atypia of undetermined significance (AUS). The authors investigated whether defined AUS subcategories are associated with specific molecular alterations, the molecular‐derived risk of malignancy (MDROM), and the risk of malignancy (ROM). Methods: Fine‐needle aspiration cytology reports of AUS and corresponding results from the ThyroSeq version 3 genomic classifier results were retrieved and subcategorized as follicular cells with either cytologic atypia (FC‐C), architectural atypia (FC‐A), both cytologic and architectural atypia (FC‐CA), or a predominance of Hurthle cells (PHC). The MDROM, ROM, and frequency of molecular alterations by subcategory were computed and analyzed, and p <.05 was considered significant. Results: The final analysis included 541 cases subdivided into 233 with FC‐A, 104 with FC‐C, 116 with FC‐CA, and 88 with PHC. The benign call rate and positive call rate for the AUS category were 72% and 28%, respectively, which varied between AUS subcategories. The MDROM by subcategory was 15.9% FC‐A, 20.5% FC‐C, 33.8% FC‐CA, and 14.4% PHC. Histologic follow‐up was available for 155 (28%) AUS cases with a follow‐up period ≥12 months. The 95% confidence intervals of the MDROMs overlapped with the ROMs. The highest MDROM and ROM were in the FC‐CA subcategory. RAS mutations were present in all subcategories. BRAF V600E mutations and papillary thyroid carcinoma were most frequent in the FC‐CA subcategory. Noninvasive follicular thyroid neoplasm with papillary‐like nuclear features was significantly more frequent in the FC‐C subcategory. Conclusions: The current results demonstrated that AUS subcategories are associated with specific genetic alterations, the MDROM, and the ROM. Molecular results and an awareness of various cancer probabilities within AUS subcategories can allow for a more tailored management. Fine‐needle aspiration cytology subcategories of atypia of undetermined significance have been associated with different probabilities of malignancy and risks of malignancy and are characterized by different molecular alterations. Molecular results and an awareness of various cancer probabilities within atypia of undetermined significance subcategories can allow more tailored management. [ABSTRACT FROM AUTHOR]

Background: Current strategies in circulating tumor cell (CTC) isolation in pancreatic cancer heavily rely on the EpCAM and cytokeratin cell status. EpCAM is generally not considered a good marker given its transitory change during Epithelial to Mesenchymal Transition (EMT) or reverse EMT. There is a need to identify other surface markers to capture the complete repertoire of PDAC CTCs. The primary objective of the study is to characterize alternate surface biomarkers to EpCAM on CTCs that express low or negligible levels of surface EpCAM in pancreatic cancer patients. Methods: Flow cytometry and surface mass spectrometry were used to identify proteins expressed on the surface of PDAC CTCs in culture. CTCs were grown under conditions of attachment and in co-culture with naïve neutrophils. Putative biomarkers were then validated in GEMMs and patient samples. Results: Surface proteomic profiling of CTCs identified several novel protein biomarkers. ALCAM was identified as a novel robust marker in GEMM models and in patient samples. Conclusions: We identified several novel surface biomarkers on CTCs expressed under differing conditions of culture. ALCAM was validated and identified as a novel alternate surface marker on EpCAMlow CTCs. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) is a common gastric pathogen that infects approximately half of the world's population. Infection with H. pylori can lead to diverse pathological conditions, including chronic gastritis, peptic ulcer disease, and cancer. The latter is the most severe consequence of H. pylori infection. According to epidemiological studies, gastric infection with H. pylori is the strongest known risk factor for non-cardia gastric cancer (GC), which remains one of the leading causes of cancer-related deaths worldwide. However, it still remains to be poorly understood how host-microbe interactions result in cancer development in the human stomach. Here we focus on the H. pylori bacterial factors that affect the host ubiquitin proteasome system. We investigated E3 ubiquitin ligases SIVA1 and ULF that regulate p14ARF (p19ARF in mice) tumor suppressor. ARF plays a key role in regulation of the oncogenic stress response and is frequently inhibited during GC progression. Expression of ARF, SIVA1 and ULF proteins were investigated in gastroids, H. pylori-infected mice and human gastric tissues. The role of the H. pylori type IV secretion system was assessed using various H. pylori isogenic mutants. Our studies demonstrated that H. pylori infection results in induction of ULF, decrease in SIVA1 protein levels, and subsequent ubiquitination and degradation of p14ARF tumor suppressor. Bacterial CagA protein was found to sequentially bind to SIVA1 and ULF proteins. This process is regulated by CagA protein phosphorylation at the EPIYA motifs. Downregulation of ARF protein leads to inhibition of cellular apoptosis and oncogenic stress response that may promote gastric carcinogenesis. Author summary: Stomach infection with Helicobacter pylori bacteria is considered to be one of the strongest known risk factors for gastric cancer. Understanding mechanisms regulating carcinogenic interactions between bacteria and human cells is important for development of new effective therapies against gastric cancer. In this work, we report how bacterial protein CagA alters intracellular regulation inside human cells, causing inhibition of tumor suppression mechanism termed the Oncogenic Stress Response controlled by human protein p14ARF. Our studies revealed that bacterial protein CagA interacts with two human proteins SIVA1 and ULF, resulting in activation of ULF and rapid degradation of SIVA1 and p14ARF, which regulate cell death of tumorous cells. [ABSTRACT FROM AUTHOR]

Abstract Introduction Type 4 renal tubular acidosis is an uncommon clinical manifestation of systemic lupus erythematosus and has been reported to portend a poor prognosis. To the best of our knowledge, this is the first case report which highlights the successful management of a patient with systemic lupus erythematosus complicated by type 4 renal tubular acidosis who did not do poorly. Case presentation A 44-year-old Hispanic woman developed a non-anion gap hyperkalemic metabolic acidosis consistent with type 4 renal tubular acidosis while being treated in the hospital for recently diagnosed systemic lupus erythematosus with multi-organ involvement. She responded well to treatment with corticosteroids, hydroxychloroquine and mycophenolate mofetil. Normal renal function was achieved prior to discharge and remained normal at the patient's one-month follow-up examination. Conclusion This case increases awareness of an uncommon association between systemic lupus erythematosus and type 4 renal tubular acidosis and suggests a positive impact of early diagnosis and appropriate immunosuppressive treatment on the patient's outcome.

Background: Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response.Methods: Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features.Results: A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-β levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10.Conclusions: Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-β could be a predictive biomarker for response to pembrolizumab. [ABSTRACT FROM AUTHOR]

Yttrium-90 (Y-90) trans-arterial radioembolization (TARE) is used in the management of unresectable hepatocellular carcinoma (HCC). During the last 5 years, dosimetry software has been developed to allow for a more rigorous approach of dose prescription in Y-90 TARE. We present here a case study of a 77-year-old woman diagnosed with HCC, who underwent a Y-90 TARE as a bridge procedure to liver resection. This clinical scenario represents a unique opportunity to illustrate the predictive value of dosimetric findings correlating dosimetry with pathological findings. In this case, Y-90 TARE dosimetry was predictive of treatment response in which the tumor received a mean dose of 156 Gy and demonstrated a complete pathologic response. [ABSTRACT FROM AUTHOR]

Background. Epithelioid hemangioendothelioma (EHE) is an uncommon malignant endothelial neoplasm that most commonly arises in soft tissue, bone, lung, and liver. Crohn's disease (CD) is an inflammatory bowel disease of unknown etiology that is frequently associated with complications including strictures, fistulas/fissures, and neoplasms. Case description. A 43-year-old woman with a 6-year history of severe CD presented with anal pain and bleeding. She had prior partial colectomy for a stricture and a diverting ileostomy for perianal fissures and stricture. Colonoscopy showed severe chronic active colitis, stricture at 30 cm of anal verge, and a perianal fistula. The patient underwent total proctocolectomy. The colonic mucosa exhibited segmental ulceration and irregular thickening of the colon wall. Beneath an ulcer of the anal canal within the muscularis propria was a 1.2-cm poorly circumscribed, firm, white-tan mass. The mass was composed of cords and groups of large epithelioid endothelial cells with intracytoplasmic vacuoles enmeshed in a myxohyaline stroma. Immunohistochemically, the tumor cells were positive for ERG, CD31, and CAMTA1 and focally positive for keratin and SMA. Next-generation sequencing revealed a WWTR1-CMATA1 fusion. The morphology, immunoprofile, and molecular genetics were diagnostic of EHE. Discussion. Long-standing inflammatory bowel disease is associated with significant risk for developing neoplasms, usually carcinomas, which can be indistinguishable radiologically and clinically from nonneoplastic complications. These tumors are often identified as an incidental finding in specimens resected for clinically severe disease. This is the first report of EHE arising in the bowel affected by CD, and it mimicked mural fibrosis and fissures. [ABSTRACT FROM AUTHOR]

Highlights • Gastric lipomas may become symptomatic when ≥10 cm, at which point they are classified as giant gastric lipomas. • Giant gastric lipomas are extremely rare, with only 6 prior cases reported in the English worldwide literature since 1980. • Gastric lipoma density is similar to peripheral fat on CT, −80 to −120 Hounsfield units, which is nearly pathognomonic. • Circumferential excision of gastric lipomas with a clear margin of normal tissue is adequate for symptomatic resection. • Preservation of gastric continuity via gastrotomy and primary closure avoids complications of gastrojejunostomy. Abstract Introduction Lipomas are uncommon tumors of the gastrointestinal tract; gastric lipomas account for <1% of all gastric tumors encountered (Nickloes and Sutphin [1]). Giant gastric lipomas, defined as ≥10 cm, are exceedingly rare with only 6 cases reported since 1980 (Cappell et al., Termos et al., Singh et al., Ramaraj et al., Rao et al., Priyadarshi et al., Neto et al. [3–9]). We hereby present a case of a giant gastric lipoma that became symptomatic seven years after its initial identification and was excised preserving gastric continuity. Case presentation Our patient is a 58-year-old African American male with a 3 cm gastric mass incidentally found on CT in 2010. In September of 2017, the patient presented with severe epigastric pain, nausea, and vomiting. Abdominal CT scan revealed an increase in size of the patient's gastric lesion to 7.2 × 10.3 × 7.3 cm. He underwent an exploratory laparotomy with transverse anterior gastrotomy and primary closure. Pathologic examination revealed a 12 cm submucosal, well-circumscribed, non-encapsulated mass comprised of mature adipose tissue without atypia or mitotic figures, consistent with lipoma. Discussion The majority of gastric lipomas are asymptomatic, identified on CT scan as round/ovoid masses with low attenuation and homogenous appearance, measuring −80 to −120 Hounsfield units. These findings are nearly pathognomonic. Due to the benign nature of gastric lipomas, circumferential excision with a clear margin of normal tissue is adequate for symptomatic resection. This is the second report of giant gastric lipoma excised with continuity preserving partial gastrectomy, avoiding gastrojejunostomy complications. Conclusion Fatty tumors are rare in the gastrointestinal tract, yet lipomas must be on the differential when masses are found with Hounsfield units similar to peripheral fat. [ABSTRACT FROM AUTHOR]