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The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous- sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10-4), increased frequency of nonsynonymous SSNVs in Pan- Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10-17); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers. [ABSTRACT FROM AUTHOR]

Background: The tall cell variant of papillary thyroid carcinoma is an aggressive subtype that generally presents as a large tumor in the advanced stage; however, little is known about the tall cell variant of microcarcinoma (tumors measuring <1 cm). In this study, we compare the tall cell variant of microcarcinoma (microTCV) with classic papillary microcarcinomas to examine the hypothesis that, despite the small size, the microTCV may be more aggressive than the classic papillary microcarcinoma. Methods: We identified 27 microTCV patients and compared their clinicopathologic features and BRAFV600E mutational status with classic papillary microcarcinomas matched by age and size. The patients with microTCV included 22 women and 5 men aged 33 to 74 years (median age, 56 years). All patients underwent total thyroidectomy; 20 patients had lymph node dissection. Results: Tumor size in microTCV patients ranged from 2 mm to 10 mm (median, 7 mm). Extrathyroidal extension and lymphovascular invasion were seen in 9 (33%) and 4 (15%) tumors, respectively. Thirteen patients (48%) harbored multifocal papillary carcinomas. Metastasis to central compartment lymph nodes was seen in 8 patients and to lateral cervical nodes in 3 patients. Nine of the 25 patients (36%) presented at an advanced stage (stage III/IVA). The BRAFV600E mutation was detected in 25 of 27 tumors (92.6%). In contrast, age- and size-matched classic papillary microcarcinomas ( n=26) showed no extrathyroidal extension ( p=0.002), lymphovascular invasion in 1, central compartment lymph node metastasis in 2, lateral cervical node metastasis in 1, multifocal tumors in 10 (38.5%), the BRAFV600E mutation in 20 (76.9%), and it infrequently presented in stage III/IVA (7.7%, p=0.02). Conclusions: The microTCV form is associated with aggressive features at presentation, and it should be differentiated from other papillary thyroid microcarcinomas. [ABSTRACT FROM AUTHOR]

Drugs or cellular products that bind to gp100 are being investigated for treatment of cutaneous melanoma. The relative specificity of gp100 expression in melanocytes makes it an attractive target to harness for therapeutic intent. For example, Tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, has generated significant enthusiasm in recent years due to its success in improving outcomes for uveal melanoma and is being studied in cutaneous melanoma. However, the extent and intensity of gp100 expression in advanced cutaneous melanoma has not been well studied. Here, we interrogated a large cohort of primary and metastatic melanomas for gp100 expression by immunohistochemistry. Expression in metastatic samples was globally higher and almost uniformly positive, however the degree of intensity was variable. Using a quantitative immunofluorescence method, we confirmed the variability in expression. As gp100-binding drugs are assessed in clinical trials, the association between activity of the drugs and the level of gp100 expression should be studied in order to potentially improve patient selection. [ABSTRACT FROM AUTHOR]

An abstract of the article "DNA Extraction And Whole Genome Amplification From Cytology Specimens," by Adebowale J. Adeniran, Adriana Heguy, and Oscar Lin is presented.

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). Thirtyfour 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 followup, this should be considered when selecting patients for TOETVA. [ABSTRACT FROM AUTHOR]

Renal oncocytoma (RO) accounts for 5% of renal cancers and generally behaves as a benign tumor with favorable long-term prognosis. It is difficult to confidently distinguish between benign RO and other renal malignancies, particularly chromophobe renal cell carcinoma (chRCC). Therefore, RO is often managed aggressively with surgery. We sought to identify molecular biomarkers to distinguish RO from chRCC and other malignant renal cancer mimics. In a 44-patient discovery cohort, we identified a significant differential abundance of nine genes in RO relative to chRCC. These genes were used to train a classifier to distinguish RO from chRCC in an independent 57-patient cohort. The trained classifier was then validated in five independent cohorts comprising 89 total patients. This nine-gene classifier trained on the basis of differential gene expression showed 93% sensitivity and 98% specificity for distinguishing RO from chRCC across the pooled validation cohorts, with a c-statistic of 0.978. This tool may be a useful adjunct to other diagnostic modalities to decrease the diagnostic and management uncertainty associated with small renal masses and to enable clinicians to recommend more confidently less aggressive management for some tumors. Renal oncocytoma is generally a benign form of kidney cancer that does not necessarily require surgical removal. However, it is difficult to distinguish renal oncocytoma from other more aggressive forms of kidney cancer, so it is treated most commonly with surgery. We built a classification tool based on the RNA levels of nine genes that may help avoid these surgeries by reliably distinguishing renal oncocytoma from other forms of kidney cancer. We trained and validated a classifier to distinguish renal oncocytoma from chromophobe renal cell carcinoma based on differential RNA expression. This classifier may be used to decrease diagnostic and management uncertainty associated with small renal masses. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) with sarcomatoid and rhabdoid morphologies has an aggressive biological behavior and a typically poor prognosis. The current 2022 WHO classification of renal tumors does not include them as distinct histologic entities but rather as transformational changes that may arise in a background of various distinct histologic types of RCC. The sarcomatoid component shows malignant spindle cells that may grow as intersecting fascicles, which is reminiscent of pleomorphic undifferentiated sarcoma. The rhabdoid cells are epithelioid cells with eccentrically located vesicular nuclei with prominent nucleoli and large intracytoplasmic eosinophilic inclusions. Studies have shown that RCCs with sarcomatoid and rhabdoid differentiation have distinctive molecular features. Sarcomatoid RCC harbors shared genomic alterations in carcinomatous and rhabdoid components, but also enrichment of specific genomic alterations in the sarcomatoid element, suggesting molecular pathways for development of sarcomatoid growth from a common clonal ancestor. Rhabdoid differentiation also arises through clonal evolution although less is known of specific genomic alterations in rhabdoid cells. Historically, treatment has lacked efficacy, although recently immunotherapy with PD-1/PD-L1/CTLA-4 inhibitors has produced significant clinical responses. Reporting of sarcomatoid and rhabdoid features in renal cell carcinoma is required by the College of American Pathologists and the International Collaboration on Cancer Reporting. This manuscript reviews the clinical, pathologic, and molecular features of sarcomatoid RCC and rhabdoid RCC with emphasis on the morphologic features of these tumors, significance of diagnostic recognition, the molecular mechanisms of tumorigenesis and differentiation along sarcomatoid and rhabdoid lines, and advances in treatment, particularly immunotherapy., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Fine-needle aspiration (FNA) of ovarian cyst fluid remains useful for certain clinical circumstances despite low sensitivity and potential safety concerns. The current study aimed to reevaluate the performance of ovarian cystic fluid cytology following American College of Obstetricians and Gynecologists guidelines using a single-institution cohort., Methods: A total of 507 ovarian cyst FNA cases from 2013 to 2023 were reviewed. Patients' demographics and clinical and radiologic information were collected through the electronic database. The performance was calculated using corresponding surgical pathology diagnosis as the gold standard., Results: Overall, cytologic diagnoses were nondiagnostic (ND), negative for malignancy (NFM), atypical (ATY), suspicious for malignancy (SFM), and malignant (M) in 5 (1.0%), 478 (94.3%), 14 (2.7%), 2 (0.4%), and 8 (1.6%) cases, respectively. Among 349 specimens (68.8%) that had a corresponding surgical pathology, the rate of malignancy (including borderline tumors) was 1.2% (4 of 325) in NFM, 72.7% in ATY (8 of 11), and 100% in both SFM (2 of 2) and M (8 of 8) specimens. Considering NFM and ATY as negative results and SFM and M as positive results, overall, the sensitivity of ovarian cystic fluid cytology was 45.4% and the specificity was 100%., Conclusions: As an uncommon test, ovarian cystic fluid cytology has moderate sensitivity and high specificity. Despite limitations, ovarian cystic FNA cytology remains a valuable diagnostic tool in certain aspects., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: NKX3.1 is an emerging marker for tumors of prostatic origin; however, the utility and diagnostic values of NKX3.1 have not been broadly studied in cytology specimens. The purpose of this study is to determine the performance of NKX3.1, compared to prostatic specific antigen (PSA) and prostatic specific alkaline phosphatase (PSAP), as an organ-specific marker of metastatic prostatic adenocarcinoma (MPAC) in cytology specimens., Methods: The cytology specimens, which had been evaluated to include or exclude MPAC, were collected from our pathology database. Immunostains for PSA, PSAP, and NKX3.1 were performed on cell block sections., Results: A total of 118 cases were collected. In 37 MPACs, NKX3.1 was diffusely positive in 34 cases (92%) and focally positive in 3 cases (8%). PSA indicated diffuse positivity in 16 cases (43%), focal positivity in 13 (35%) cases, and was negative in 8 (22%) cases. PSAP immunostain was performed in only 12 MPACs, showing diffuse positivity in 5 (42%), focal positivity in 3 (25%), and negativity in 4 (33%) cases. Among the 81 non-metastatic prostatic adenocarcinoma cases, NKX3.1 was negative in 80 (99%) cases and focally positive in only 1 (1%) case; all cases with available PSA and PSAP staining were negative. The calculated sensitivities for NKX3.1, PSA, and PSAP were 100%, 78%, and 67%, respectively, while the specificities were 99%, 100%, and 100%, respectively., Conclusions: Compared to PSA and PSAP, NKX3.1 is more reliable as an individual marker for MPAC in cytology specimens. Combining NKX3.1 and PSA can be useful in some cases to enhance diagnostic utility., Competing Interests: Conflict of interest Dr. Adeniran has been an editorial board member (since May 2021) and Dr. Cai has been an editor-in-chief (since March 2021) of Journal of Clinical and Translational Pathology. The authors have no conflict of interest related to this publication.

Introduction: Evidence has demonstrated that tumor size is related to adverse oncologic outcomes in small renal tumors (≤ 4 cm). We evaluated the association of adverse pathologic features (APF) with tumor size and survival in patients with a small renal mass (SRM)., Materials and Methods: We retrospectively reviewed the pathologic characteristics of 380 surgically resected SRMs from a single institution. APFs included lymphovascular invasion, coagulative necrosis, sarcomatoid/rhabdoid features, papillary type II histology, and perinephric fat/renal sinus invasion. The number and type of APFs were compared with tumor size. Survival analysis was performed using the Kaplan-Meier method., Results: There were 244 (64.2%) males and 136 (35.8%) females. The median age was 61 years, and median tumor size was 2.7 cm. The median follow up time was 65 months. A significant association was found between tumor size and presence of APFs (p = 0.018). At least 1 APF could be found in 22%, 32%, 36%, and 49% of tumors ≤ 1 cm, 1 cm-2 cm, 2 cm-3 cm, and 3 cm-4 cm, respectively. There were no differences in overall survival or recurrence free survival when compared by tumor size at diagnosis (p = 0.22 and 0.15 respectively). Compared to patients with ≤ 1 APFs, disease specific survival was worse for patients with ≥ 2 APFs (p < 0.002)., Conclusion: Our data support that aggressive tumor biology in a SRM is associated with greater size. In patients with a SRM, the decision to pursue active surveillance and the trigger for intervention should take tumor size and APFs into consideration as this may have future oncologic implications.