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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]

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.

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.

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 AT-rich 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.