Faculty Bibliography

Lichen sclerosus (LS) is a chronic inflammatory condition of the vulva. Although LS is thought to arise from autoimmune mechanisms, it is unclear whether disease drivers differ by menopausal status-an important distinction given its potential progression to differentiated vulvar intraepithelial neoplasia (dVIN) and vulvar squamous cell carcinoma (VSCC). We performed a retrospective review of 182 biopsy-proven LS cases (2020-2025), stratified by menopause status. In addition, we examined 27 VSCC cases for PD-L1 staining to assess immune modulation and potential therapeutic relevance. Premenopausal patients were diagnosed at a much younger age (37.8 vs. 67.5 yr, P<0.001) and experienced longer delays to diagnosis (3.9 vs. 1.5 yr, P<0.001). Their biopsies were less often reported with definitive LS terminology (40% vs. 75%, P<0.001), suggesting under-recognition in younger women. Comorbidities were more common in this group, especially autoimmune disease (46.7% vs. 10.9%, P<0.001), whereas postmenopausal patients more frequently had atrophic vaginitis (15.9%, P=0.02). Progression to dVIN or VSCC occurred more often in postmenopause (13.1% vs. 8.9%), though this was not statistically significant. PD-L1 expression was frequent in VSCC and precursor lesions (HSIL: 80%; dVIN: 81%) and less common in LS (50%), though these differences were not statistically significant. Expression patterns varied by lesion type, suggesting potential differences in the local immune microenvironment. Taken together, these findings support differences in clinical presentation and immune features of LS by menopausal status, warranting further investigation in larger cohorts.

Black women with estrogen receptor-positive, HER2-negative (ER + /HER2-) breast cancer experience higher rates of distant recurrence and worse survival outcomes compared to White women. This may be due not only to disparities in social determinants of health, but also differences in the tumor microenvironment (TME), including TMEM (Tumor Microenvironment of Metastasis) doorway score. TMEM doorways serve as portals for cancer cell hematogenous dissemination to distant sites. While higher TMEM doorway scores have been observed in Black (compared to White) patients with residual ER + /HER2- breast cancer after neoadjuvant chemotherapy, this has not been evaluated in treatment-naïve primary breast cancers. Here, we report on a multi-institutional study to evaluate TMEM doorway score in 418 treatment-naïve archived human breast cancer samples, including 265 patients with ER + /HER2-, 102 with triple negative (TNBC), and 51 with HER2-positive breast cancer. In addition to analyzing TMEM doorway scores by race across breast cancer subtypes, we examined their association with distant recurrence and assessed whether the effect of TMEM doorway scores on recurrence differed by race. Black patients had significantly higher TMEM doorway score than White patients in the overall study population (median 29.9 vs 17.9, p < 0.001), in the ER + /HER2- (median 25.0 vs 16.8, p < 0.001) and the HER2-positive subset (median 37.2 vs 12.9, p = 0.003), but not in TNBC (median 36.2 vs 36.3, p = 0.86). Racial differences in macrophage density mirrored racial differences in the TMEM doorway score. In multivariate models including age, body mass index, tumor size, grade, lymph node status, and chemotherapy treatment, neither Black race nor TMEM doorway density was associated with a higher distant recurrence risk alone. However, there was a statistically significant interaction between race and high TMEM doorway score with respect to distant recurrence risk in ER + /HER2- patients; Black patients with high TMEM doorway score were 4.6-fold (95% CI 1.28-22.82, p = 0.03) and 4.2-fold (95% CI 1.17 - 18.23, p = 0.04) more likely to have a distant recurrence at 5-years and 10-years, respectively, while White patients with high TMEM doorway scores did not (p = 0.21, p = 0.11). Our study reveals racial disparities in the TME of women with ER + /HER2- breast cancer, which may play a critical role in driving disparities in breast cancer outcomes.

BACKGROUND:Testosterone is one of the strategies that transmasculine persons can elect in order to align physical traits to their gender identity. Previous studies have shown morphologic changes in the genital tract associated with testosterone. Here, we aim to evaluate cervicovaginal cytology specimens (Pap tests) and high-risk HPV (HR-HPV) testing from transmasculine individuals receiving testosterone. METHODS:This is a retrospective cohort of 61 transmasculine individuals receiving testosterone from 2013 to 2021. Cytologic diagnoses from 65 Pap tests were correlated with HPV status and histologic follow-up and compared with the institutional data and a cohort of cisgender women with atrophic changes. RESULTS:The median age was 28 years and median time of testosterone use was 3 years. Transmasculine persons showed significantly higher rates of HSIL (2%) and unsatisfactory (16%) when compared with the institutional data and atrophic cohort of cisgender women. After reviewing slides of 46 cases, additional findings were noted: atrophy was present in 87%, glycogenated cells were seen in 30%, and Lactobacilli were substantially decreased in 89%. Among 32 available HPV tests, 19% were positive for HR-HPV and 81% were negative. On histologic follow-up, all HR-HPV-positive cases with abnormal cytology showed HSIL, while none of the HPV-negative cases revealed HSIL. CONCLUSION/CONCLUSIONS:Our study cohort demonstrated a high percentage of abnormal Pap tests in transmasculine persons receiving testosterone. Testosterone seems to induce changes in squamous cells and shifts in vaginal flora. HR-HPV testing can be a useful adjunct in the workup of abnormal Pap tests from transmasculine individuals.

CONTEXT.—/UNASSIGNED:Gender-affirming surgery is part of a multidisciplinary approach in gender transitioning. Deeper histologic examination may strengthen care for transmasculine individuals and increase the understanding of the influence of hormonal therapy in specific organs. OBJECTIVE.—/UNASSIGNED:To evaluate and catalogue histologic findings of tissue obtained from gender-affirming gynecologic surgery and cervical cytology specimens. DESIGN.—/UNASSIGNED:This is an institutional review board-approved retrospective study that included transmasculine individuals who underwent gender-affirming gynecologic surgery from January 2015 to June 2020. All surgical gynecologic pathology and cervical cytology slides were reviewed by 2 pathologists. RESULTS.—/UNASSIGNED:Fifty-five patients were included, which represented 40 uteri, 35 bilateral ovaries, 15 vaginectomy specimens, and 24 cervical cytology results. The median age was 27 years (range, 18-56) and 94% (50 of 53) of patients were receiving testosterone for at least 1 year. Seventy-five percent (30 of 40) of endometria were inactive, while 25% (10 of 40) showed evidence of cycling. Transitional cell metaplasia was the most common finding in the cervix (17 of 40) and vagina (15 of 15), reflecting a high percentage (4 of 24) of unsatisfactory or ASC-US (atypical squamous cells of undetermined significance) cervical cytologies. Prostatic-type glands were identified in 20% (8 of 40) of cervices and 67% (10 of 15) of vaginectomy specimens. Multiple bilateral cystic follicles and evidence of follicular maturation were present in 57% (20 of 35) of cases. Four cases showed paratubal epididymis-like mesonephric remnant hypertrophy. CONCLUSIONS.—/UNASSIGNED:A comprehensive evaluation of tissue from gender-affirming surgery increases knowledge of the changes following androgen therapy in transmasculine individuals and may contribute to optimal patient care by raising awareness of normal histologic variations in this population.

Introduction: Testosterone therapy is one of the strategies that transmasculine persons can elect in order to align physical traits to their gender identity. Previous studies demonstrated that testosterone can induce morphologic changes in the genital tract. Here, we aim to evaluate cervicovaginal cytology specimens from transmasculine individuals receiving testosterone.
Material(s) and Method(s): This is a retrospective study that included 33 transmasculine individuals receiving testosterone with available cervicovaginal cytology reports or slides for review from 2013 to 2021.
Result(s): The median age was 28 years (range: 19-56) and median time of testosterone use was 2.6 years (range: 0.3-25). Thirty-five cervicovaginal cytology reports were included with the following results: 25 negative for intraepithelial lesion or malignancy (71%), 3 atypical squamous cells of undetermined significance (ASCUS) (9%), 2 high-grade squamous intraepithelial lesion (HSIL) (6%), and 5 unsatisfactory (14%). Endocervical component was present in 74% of cases (36/35). Among 19 available HPV tests, 5 were positive for high-risk HPV (2 negative, 1 ASCUS and 2 HSIL), and 14 were negative (11 negative, 1 ASCUS and 2 unsatisfactory). No evidence of other cervicovaginal infection was detected. After reviewing slides of 18 cases, additional findings not included in pathology reports were noted. Atrophy (Figure 1A), a known mimicker of HSIL, was present in 94% (17/18), including those with ASCUS (Figure 2A) and HSIL (Figure 2B). Glycogenated cells (Figure 1B), which can be mistaken for koilocytes, were seen in 22% (4/18). Lactobacilli were substantially decreased in 94% (17/18) (Figure 3A, 3B).
Conclusion(s): Our study cohort demonstrated a high percentage of abnormal cervicovaginal smears in transmasculine persons receiving testosterone. Changes following testosterone administration can represent diagnostic pitfalls of squamous lesions. Testosterone seems to induce changes in the vaginal flora. [Formula presented] [Formula presented] [Formula presented]
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Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. Here, we employ high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. Substantial enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent >60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch-Jagged signaling. In breast cancers from patients, the density of TMEM doorways correlates with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites.