Rohit Bhargava

A comprehensive analysis of SOX17 expression by immunohistochemistry in human epithelial tumors, with an emphasis on gynecologic tumors

Abstract Objectives The objective of this study was to evaluate SOX17, a transcription factor from the Sry high-mobility group–related box superfamily, as a diagnostic marker to determine site of origin using both whole-tissue sections and tissue microarrays (TMAs). Methods SOX17 immunohistochemistry was performed on gynecologic and nongynecologic tissues (N = 1004) using whole-tissue sections and both internally constructed and commercially available TMAs. SOX17 nuclear reactivity was scored as positive or negative on the whole-tissue sections and using the semiquantitative H score method on TMAs. Results Using both whole-tissue sections and TMAs, SOX17 was positive in 94% (n = 155) of endometrial tumors and 96% (n = 242) of ovarian tumors. All breast cases (n = 241) and vulvar/cervical squamous cell carcinomas (n = 150) were negative. Among 1004 tumors from 20 sites, the only organs with positive tumors were ovary, uterus, and testis. Conclusions SOX17 is a sensitive and specific marker for gynecologic origin in the tissues tested and may be a valuable adjunct to PAX8 and other commonly used markers to confirm endometrial or ovarian origin. SOX17 expression is lower in mucinous tumors, endocervical adenocarcinoma, high-grade neuroendocrine tumors, and undifferentiated/dedifferentiated endometrial carcinoma.

ARID1A, BRG1, and INI1 deficiency in undifferentiated and dedifferentiated endometrial carcinoma: a clinicopathologic, immunohistochemical, and next-generation sequencing analysis of a case series from a single institution

Undifferentiated/dedifferentiated endometrial carcinomas (UDEC and DDEC) are rare, aggressive uterine neoplasms, with no specific line of differentiation. A significant proportion of these cases feature mutations of SWI/SNF chromatin remodeling complex members, including ARID1A, SMARCA4, and SMARCB1 genes. To study these entities more comprehensively, we identified 10 UDECs and 10 DDECs from our pathology archives, obtained clinicopathologic findings and follow-up data, and performed immunohistochemical studies for ARID1A, BRG1 (SMARCA4), and INI1 (SMARCB1) proteins. In addition, we successfully conducted targeted next-generation sequencing for 23 samples, including 7 UDECs, and 7 undifferentiated and 9 well/moderately-differentiated components of DDECs. Cases consisted of 18 hysterectomies and 2 curettage/biopsy specimens. Patient age ranged from 47 to 77 years (median, 59 years), with a median tumor size of 8.0 cm (range, 2.5-13.0 cm). All cases demonstrated lymphovascular invasion and the majority (13/20) were FIGO stage III-IV. By immunohistochemistry, ARID1A loss was observed in 15 cases, BRG1 loss in 4, and all cases had intact INI1 expression. A trend for enrichment of the undifferentiated component of DDECs for ARID1A loss was seen, although not statistically significant. Sequencing revealed frequent pathogenic mutations in PTEN, PIK3CA, ARID1A, CTNNB1, and RNF43, a recurrent MAX pathogenic mutation, and MYC and 12p copy number gains. In DDECs, the undifferentiated component featured a higher tumor mutational burden compared to the well/moderately-differentiated component; however, the mutational landscape largely overlapped. Overall, our study provides deep insights into the mutational landscape of UDEC/DDEC, SWI/SNF chromatin remodeling complex member status, and their potential relationships with tumor features.

The clinical significance of atypical glandular cells in Papanicolaou tests: changes in diagnostic patterns over 15 years at a single institution

Detection of atypical glandular cells (AGCs) by Papanicolaou (Pap) test remains a significant challenge in gynecological cytology. We compared follow-up diagnoses, age groups, and human papillomavirus (HPV) results for AGC at our institution to that of our previous study (study period 2008-2013). AGC Paps diagnosed and HPV results between January 2020 and June 2024 were obtained from the database at UPMC Magee-Womens Hospital. Of the total 188,320 Paps performed during the study period, 1025 had AGC diagnoses comprising 0.54% of the total. A total of 92.2% of cases had a companion HPV test, with positive HPV results seen in 32.9% of cases. Overall, 33.3% (286/859) of AGC cases had subsequent significant histologic findings (cervical intraepithelial neoplasia 2 and 3, adenocarcinoma in-situ, endocervical adenocarcinoma, endometrial lesions, metastatic carcinoma). Detection of cervical lesions was highest in women <30 years (50%) and significantly decreased with increasing age (P < 0.0001). Identification of endometrial lesions was highest in the ≥50-year group (P < 0.0001). Nearly half of AGC/HPV-positive cases had significant cervical findings, while these were detected in only 2.1% of AGC/HPV-negative cases (P < 0.0001). Endometrial lesions were identified in 25.7% of AGC/HPV-negative cases, but only in <1% of AGC/HPV-positive cases (P < 0.0001). Significant differences were identified comparing the 2 study periods: increased HPV testing (P < 0.0001), increased HPV-positivity (P = 0.0029), decreased AGC rate (P < 0.0001), and increased endometrial lesions on follow-up (P < 0.0001). Our findings continue to support HPV results and patient age as valuable data in triaging AGC. AGC/HPV-positive results frequently suggest a cervical/HPV-related lesion, often in younger patients. Conversely, AGC/HPV-negative results, especially in patients ≥50 years, support noncervical lesional origins.