Stephanie L. Skala

Patterns of SATB2 and p16 reactivity aid in the distinction of atypical polypoid adenomyoma from myoinvasive endometrioid carcinoma and benign adenomyomatous polyp on endometrial sampling

AimsAtypical polypoid adenomyoma (APAM) is an uncommon uterine lesion composed of complex endometrioid glands with frequent squamous morular metaplasia and fibromuscular stroma. On endometrial curettage, biopsy or polypectomy specimens, the admixture of endometrioid glands and smooth muscle raises the differential diagnosis of myoinvasive endometrioid carcinoma. Reproductive‐age APAM patients may opt for fertility preservation, whereas myoinvasive carcinoma is treated surgically. One previous study reported an incidental finding that the stroma of APAM, in contrast to that of other polypoid lesions, was SATB2‐positive. APAM has also been reported to show increased stromal p16 staining. We aimed to assess whether SATB2 and p16 are useful stains for the distinction of APAM from myoinvasive carcinoma and benign adenomyomatous polyps.Methods and resultsCases of ‘atypical polypoid adenomyoma’ (n = 32), ‘adenomyomatous polyp’ (n = 39) and ‘myoinvasive endometrioid carcinoma’ (n = 30) were identified. Morphological features were assessed, along with the intensity and extent of SATB2 and p16 staining in the stromal component of each lesion. SATB2 expression was seen in the stromal components of 30 of 32 (94%) APAMs, versus none of 39 (0%) benign adenomyomatous polyps and five of 30 (17%) myoinvasive endometrioid carcinomas. Stromal p16 expression was seen in 31 of 31 (100%) APAMs, versus 20 of 39 (51%) benign adenomyomatous polyps and 12 of 30 (40%) myoinvasive endometrioid carcinomas.ConclusionsPatchy to diffuse SATB2 and block‐type p16 staining of fibromuscular stroma separating atypical endometrioid glands is more consistent with APAM than with myoinvasive endometrioid carcinoma. These stains are potentially useful adjuncts to careful morphological evaluation of endometrial biopsies/curettings.

Utility of p63 and PTEN staining in distinguishing cervical microglandular hyperplasia from endometrial endometrioid carcinoma with microglandular/mucinous features

AimsDistinction between well‐differentiated endometrial carcinoma (EMCA) with microglandular/mucinous features and benign endocervical microglandular hyperplasia (MGH) can be a diagnostic challenge, especially when tissue is limited. The immunostains used to distinguish endocervical and endometrial carcinoma are less useful when the differential diagnosis is MGH. Here, we investigate the utility of p63 and phosphatase and tensin homologue (PTEN) to aid accurate classification.Methods and resultsCases obtained from our pathology archives included 25 EMCA with mucinous/microglandular features, 26 MGH and nine atypical microglandular proliferations. Cases were assessed for glandular architecture, presence of mucinous and/or eosinophilic luminal secretions, subnuclear vacuoles, foamy histiocytes, inflammation, squamous metaplasia, cytological atypia and mitotic activity. The presence and pattern of immunohistochemical staining for p63 and PTEN was recorded. Microglandular proliferations with cytological atypia, mitotic activity, foamy histiocytes and complex glandular architecture were more commonly seen in EMCA, while small glands, bland nuclei and subnuclear vacuoles were enriched in MGH. All MGH cases displayed p63‐positive subcolumnar reserve cells and retained PTEN expression. Four EMCA cases showed non‐specific focal p63 staining either at the surface of the tumour or in areas of squamous differentiation. p63 and PTEN immunostains accurately predicted the final diagnosis for 3 atypical microglandular proliferation cases with follow‐up.ConclusionsWhile there are morphological characteristics that differentiate EMCA and MGH, there is frequent overlap between these entities. Nonetheless, the pattern and extent of p63 and PTEN can aid accurate classification. Consistent p63‐positive subcolumnar reserve cells were seen only in MGH.

Small-Molecule–Mediated Stabilization of PP2A Modulates the Homologous Recombination Pathway and Potentiates DNA Damage-Induced Cell Death

Abstract High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061–induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions. Watch the interview with Analisa DiFeo, PhD, recipient of the 2025 Molecular Cancer Therapeutics Award for Outstanding Journal Article: https://vimeo.com/1100470225

Surface prostatic metaplasia, transitional cell metaplasia and superficial clusters of small basophilic cells in the uterine cervix: prevalence in gender‐affirming hysterectomies and comparison with benign hysterectomies from cisgender women

AimsAs gender‐affirming surgery is becoming more common, it is important for pathologists to recognize potential benign findings to avoid misinterpretation. Cervical transitional cell metaplasia and superficial clusters of small basophilic cells have been described in the context of gender‐affirming testosterone therapy; these findings may be misdiagnosed as high‐grade squamous intraepithelial lesions or endometrial cells on Pap smears. Prostatic metaplasia has been reported in the surface squamous epithelium of the vagina and the uterine cervix in individuals undergoing gender‐affirming androgen therapy; this finding is often associated with NKX3.1‐positive basal keratinocytes. The aim of this study was to assess the morphological and immunohistochemical features of the uterine cervix in gender‐affirming hysterectomies in comparison with benign hysterectomies from cisgender women.Methods and resultsWe assessed the morphological and immunohistochemical features of the uterine cervix in 49 gender‐affirming hysterectomies as compared with 57 hysterectomies from cisgender patients to establish the relative prevalences of surface prostatic metaplasia, NKX3.1‐positive basal keratinocytes, transitional cell metaplasia, and small basophilic cells in the cervical squamous epithelium. The cervical tissue from the gender‐affirming therapy cohort showed significantly higher prevalences of NKX3.1‐positive basal keratinocytes (86% versus 1.8%), transitional cell metaplasia (80% versus 3.5%), superficial clusters of small basophilic cells (67% versus 7%), and surface prostatic metaplasia (43% versus 3.5%).ConclusionNKX3.1‐positive basal keratinocytes, transitional cell metaplasia, small basophilic cells and surface prostatic metaplasia are all more prevalent in the cervices of individuals receiving gender‐affirming testosterone therapy; awareness of this fact allows pathologists to avoid the overdiagnosis of dysplasia or the recommendation of unnecessary follow‐up procedures.