Expression of L1 Cell Adhesion Molecule, a Nephronal Principal Cell Marker, in Nephrogenic Adenoma.

Nephrogenic adenoma (NA) is a benign, reactive lesion seen predominantly in the urinary bladder and often associated with antecedent inflammation, instrumentation, or an operative history. Its histopathologic diversity can create diagnostic dilemmas and pathologists use morphologic evaluation along with available immunohistochemical (IHC) markers to navigate these challenges. IHC assays currently do not designate or specify NA's potential putative cell of origin. Leveraging single-cell RNA-sequencing technology, we nominated a principal (P) cell-collecting duct marker, L1 cell adhesion molecule (L1CAM), as a potential biomarker for NA. IHC characterization revealed L1CAM to be positive in all 35 (100%) patient samples of NA; negative expression was seen in the benign urothelium, benign prostatic glands, urothelial carcinoma (UCA) in situ, prostatic adenocarcinoma, majority of high-grade UCA, and metastatic UCA. In the study, we also used single-cell RNA sequencing to nominate a novel compendium of biomarkers specific for the proximal tubule, loop of Henle, and distal tubule (DT) (including P and intercalated cells), which can be used to perform nephronal mapping using RNA in situ hybridization and IHC technology. Employing this technique on NA we found enrichment of both the P-cell marker L1CAM and, the proximal tubule type-A and -B cell markers, PDZKI1P1 and PIGR, respectively. The cell-type markers for the intercalated cell of DTs (LINC01187 and FOXI1), and the loop of Henle (UMOD and IRX5), were found to be uniformly absent in NA. Overall, our findings show that based on cell type-specific implications of L1CAM expression, the shared expression pattern of L1CAM between DT P cells and NA. L1CAM expression will be of potential value in assisting surgical pathologists toward a diagnosis of NA in challenging patient samples.

Extragonadal germ cell tumors: A clinicopathologic study with emphasis on molecular features, clinical outcomes and associated secondary malignancies.

Extragonadal germ cell tumors (EGCTs) are rare, representing <5% of all germ cell tumors (GCTs). Whilst EGCTs share morphological and immunohistochemical features with their gonadal counterparts, they tend to be more aggressive and are frequently associated with secondary somatic malignancies. The aim of our study was to evaluate the clinical, morphological and immunohistochemical features, and to analyze tumors for chromosomal abnormalities of 12p, in addition to any novel genetic alterations, in a series of EGCTs. Seventy-seven EGCTs were included. Anterior mediastinum was the most common anatomic site, followed by central nervous system, retroperitoneum, sacroccygeal area, and neck. Whole genome SNP array identified isochromosome 12p in 26% of tumors. Additional cytogenetic abnormalities included the presence of gain of chr 21 in 37% of tumors. Somatic-type malignancies were identified in 8% of patients. Disease progression (metastasis and/or recurrence) was documented in 8 patients, most of whom died from their relapse. Three patients who died of disease had somatic-type malignancies. Mediastinal seminomas had a significantly better overall survival when compared to mediastinal non-seminomatous GCTs. Our study demonstrates that EGCTs share similar histologic features, but diverse clinical outcomes compared to their gonadal counterparts. Outcomes vary according to anatomic location and histologic subtypes. Our data corroborate that somatic-type malignancies are frequently encountered in mediastinal EGCTs and that their presence portends a poorer prognosis.

The Malignant Potential of Ovarian Steroid Cell Tumors Revisited: A Multi-institutional Clinicopathologic Analysis of 115 Cases.

Steroid cell tumors (SCTs) of the ovary are rare and understudied, and as such, uncertainties remain about their malignant potential, as well as clinicopathologic predictors of patient outcome. Based on a multi-institutional cohort of cases, we present findings from the largest study of SCT reported to date. Clinicopathologic data were documented on 115 cases of SCT that were assembled from 17 institutions. The median patient age was 55 years (range: 9 to 84). When measured, preoperative androgen levels were elevated in 84.2% (48/57) of patients. A total of 111 (96.5%) cases were classified as stage I (103 stage IA; 2 stage IB; 6 stage IC). The stage distribution for the remaining 4 patients was as follows: stage II (n = 1), III (n = 3; 1 IIIA, 1 IIIB, 1 IIIC). The median tumor size was 3 cm (range: 0.2 to 22). Cytologic atypia, microscopic tumor necrosis, microscopic tumor hemorrhage, and a mitotic index of >1 mitotic figure/10 high-power fields were present in 52% (60/115), 9.6% (11/115), 37% (43/115), and 19% (22/115) of cases, respectively. Of 115 patients, 7 (6.1%) recurred postexcision, 4 (3.5%) ultimately died of disease, and 10 (8.7%) either recurred, died of disease, or were advanced stage at presentation. The median duration to recurrence postresection was 33 months (range: 23 to 180). Four of the 7 recurrences were stage IA at baseline. Tumor size >4 cm, International Federation of Gynecology and Obstetrics (FIGO) stage ≥IB, tumor necrosis, and tumor hemorrhage were each significantly associated with reduced recurrence-free survival in log-rank tests and univariable Cox models, with age older than 65 years being of marginal significance (hazard ratio [HR]: 5.4, 95% CI: 1.0-30.0, P = 0.05). Multivariable analyses suggested that FIGO stage ≥IB (HR: 27.5, 95% CI: 2.6-290.5), and age older than >65 years (HR: 21.8, 95% CI: 1.6-303.9) were the only parameters that were independently associated with recurrence. Cross-section analyses showed that tumor necrosis, tumor hemorrhage, and larger tumor size were significantly associated with a FIGO stage ≥IB status, which bolstered the conclusion that they are not independent predictors of recurrence. In summary, <10% of SCTs are clinically malignant, a substantially lower frequency than has previously been reported in the literature. Clinicopathologic predictors of patient outcomes that are prospectively applicable in practice could not be definitively established. Recurrences may occur many years (up to 15 y in this study) after primary resection, even in stage IA cases.

Special Considerations in Classification and Workup of Endometrial Carcinomas.

CONTEXT.­: A variety of uncommon malignant endometrial tumors can be challenging to diagnose because of overlapping morphology with more common entities. In some cases, immunohistochemical stains and/or molecular testing allow for more definitive diagnosis or prognostication. OBJECTIVE.­: To review classic morphologic features of uncommon endometrial tumors, pathologic features of these tumors and their mimics, and the evidence for use of immunohistochemistry and molecular testing in the diagnosis of these tumors. DATA SOURCES.­: University of Michigan (Ann Arbor) cases and review of pertinent literature about each entity. CONCLUSIONS.­: Although each of these uncommon endometrial tumors has morphologic mimics, key histologic features, immunohistochemical stains, and molecular testing allow for accurate classification.

Hybrid Oncocytic Tumors (HOTs) in Birt-Hogg-Dubé Syndrome Patients-A Tale of Two Cities: Sequencing Analysis Reveals Dual Lineage Markers Capturing the 2 Cellular Populations of HOT.

Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of multifocal renal tumors, including hybrid oncocytic tumor (HOT) and chromophobe renal cell carcinoma (chRCC). HOT exhibits heterogenous histologic features overlapping with chRCC and benign renal oncocytoma, posing challenges in diagnosis of HOT and renal tumor entities resembling HOT. In this study, we performed integrative analysis of bulk and single-cell RNA sequencing data from renal tumors and normal kidney tissues, and nominated candidate biomarkers of HOT, L1CAM, and LINC01187 , which are also lineage-specific markers labeling the principal cell and intercalated cell lineages of the distal nephron, respectively. Our findings indicate the principal cell lineage marker L1CAM and intercalated cell lineage marker LINC01187 to be expressed mutually exclusively in a unique checkered pattern in BHD-associated HOTs, and these 2 lineage markers collectively capture the 2 distinct tumor epithelial populations seen to co-exist morphologically in HOTs. We further confirmed that the unique checkered expression pattern of L1CAM and LINC01187 distinguished HOT from chRCC, renal oncocytoma, and other major and rare renal cell carcinoma subtypes. We also characterized the histopathologic features and immunophenotypic features of oncocytosis in the background kidney of patients with BHD, as well as the intertumor and intratumor heterogeneity seen within HOT. We suggest that L1CAM and LINC01187 can serve as stand-alone diagnostic markers or as a panel for the diagnosis of HOT. These lineage markers will inform future studies on the evolution and interaction between the 2 transcriptionally distinct tumor epithelial populations in such tumors.

Lessons from 801 clinical TFE3/TFEB fluorescence in situ hybridization assays performed on renal cell carcinoma suspicious for MiTF family aberrations.

OBJECTIVES: Fluorescence in situ hybridization (FISH) assays for the detection of chromosomal rearrangements involving TFE3 and TFEB are considered the gold standard for the diagnosis of MiTF family altered renal cell carcinoma (MiTF-RCC). We reviewed 801 clinical TFE3/TFEB FISH assays performed at our tertiary-level institution between 2014 and 2023 on kidney tumors suspicious at the morphologic or biomarker level for MiTF aberrations. METHODS: We summarized and analyzed clinical information, TFE3/TFEB FISH results, and available biomarker staining results in a cohort of 453 consecutive kidney tumor cases suspicious for MiTF-RCC. RESULTS: In total, 61 of 434 (14%) kidney tumors were confirmed for TFE3 translocation; 10 of 367 cases (2.7%) were confirmed for TFEB translocation. Since TFEB amplification interpretation was implemented in our service line, 20 of 306 cases (6.5%) were diagnosed with TFEB amplification. Importantly, TFE3 and TFEB rearrangements were never co-detected within the same kidney tumor. Patients with TFEB amplification were significantly older (P < .001) than patients with TFE3 or TFEB translocation. Kidney tumors with TFEB amplification were seen to be at least 3 times as common as those with TFEB translocation. CONCLUSIONS: Clinical TFE3/TFEB FISH assays successfully identified and confirmed rare MiTF-RCC with TFE3 and TFEB rearrangements. Although morphologic and biomarker features associated with a kidney tumor may be suggestive of MiTF-RCC, clinical TFE3/TFEB FISH assays are crucial for a confirmation and definitive subclassification of patients with MiTF-RCC.

Herpes Pseudotumor Mimicking Cervical Cancer With Lymph Node Metastasis in an Immunocompetent Patient.

Anogenital herpes simplex virus (HSV) infection can rarely manifest as a pseudotumor, which some have termed "hypertrophic herpes." Almost all cases are in immunocompromised patients, typically with human immunodeficiency virus/acquired immune deficiency syndrome. This presentation often mimics malignancy clinically. We present a case of cervical HSV pseudotumor with associated lymphadenopathy in an immunocompetent woman, mimicking locally advanced cervical cancer. The lesion resolved with acyclovir therapy. We emphasize that (1) clinically suspected malignancy must be confirmed by pathologic examination; (2) infectious mimics must be considered when microscopic examination fails to confirm a clinically suspected anogenital malignancy, particularly in patients with compromised or unknown immune status; (3) morphologic hallmarks of infection may be focal; (4) co-infection with multiple sexually transmitted infections can occur, particularly in immunocompromised patients, and HSV or other infection does not per se exclude concurrent human papillomavirus-associated neoplasia; and (5) anogenital HSV pseudotumor should prompt clinical evaluation for human immunodeficiency virus or other immunosuppression.

Application of Current Pathologic Criteria for Atypical Placental Site Nodule Suggests That Refined Criteria Are Needed.

Atypical placental site nodules (APSNs) are histologically intermediate between placental site nodules (PSNs) and epithelioid trophoblastic tumors (ETTs). Little data exists to characterize these lesions and the risk of transformation from PSN to ETT. Recent World Health Organization (WHO) criteria for distinction of APSN are vague and not objectively defined. We identified cases signed out as PSN (n=33) and APSN (n=11) and aimed to characterize, statistically compare, and assess the risk of transformation in PSNs using data including size, location, mitotic rate, Ki-67 proliferation index, trophoblastic cells per high-power field, presence of severe cytologic atypia, beta-human chorionic gonadotropin levels, time since last pregnancy, presence of calcification, necrosis, or apoptosis, and follow-up results. All cases were confirmed to be positive for p63, and a Ki-67/AE1/AE3 dual stain was used to evaluate the Ki-67 proliferation index in the trophoblastic cells. In our cohort, slight changes in the interpretation of WHO criteria for PSN and APSN led to marked differences in the proportion of PSNs flagged as "atypical." There was no statistically significant difference in the persistence of APSN versus non-APSN. None of the PSNs transformed to ETT. Current criteria for distinction between PSN and APSN are largely subjective. More objective, clearly defined, and clinically meaningful criteria are needed to distinguish between PSN and APSN, thus aiding in assessing the rare risk of transformation to ETT.

Interobserver Agreement Across Subspecialties for Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia and Predictive Values of 20 Histologic Features.

CONTEXT.­: Differentiated vulvar intraepithelial neoplasia (dVIN) is a human papillomavirus-independent lesion with the potential for rapid progression to invasive squamous cell carcinoma (SCC). The histopathologic features of dVIN are diverse, have overlapping characteristics with lichen sclerosus (LS) and lichen simplex chronicus (LSC), and may be diagnosed by dermatopathologists or gynecologic pathologists because of the vulva's anatomic location. OBJECTIVES.­: To identify the salient histopathologic features of dVIN, particularly those that predict progression to SCC, and to evaluate interobserver agreement in diagnosing dVIN within the same subspecialty and across subspecialties. DESIGN.­: One general surgical pathologist, 2 pathology-trained dermatopathologists, and 1 gynecologic pathologist blinded to the final diagnoses were asked to record 20 histopathologic features and to provide their final interpretations on cases of dVIN (n = 65), LS (n = 126), LSC (n = 112), and LS with LSC (n = 6). RESULTS.­: Interobserver agreement for the 4 diagnoses and 10 histopathologic features was moderate. Logistic regression analysis indicated that keratin pearls, basal pleomorphism, and basal layer disarray were independent variables for diagnosing dVIN (coefficients 1.95, 1.97, and 0.91, respectively; P < .001) and progression to SCC (coefficients 1.96, 1.20, and 1.08, respectively; P < .001). CONCLUSIONS.­: There is no single histopathologic feature pathognomonic for dVIN; however, the presence of keratin pearls, basal pleomorphism, and basal layer disarray should raise high suspicion for dVIN and concurrent SCC. Expertise in both dermatologic and gynecologic pathology is beneficial for diagnosing dVIN.

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

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.

Unusual Ovarian Tumors With Endometrioid Proliferations Co-Expressing Estrogen Receptor and CDX-2 Arising in Cystadenofibromatous Background: Report of 3 Cases.

This report describes 3 cases of ovarian tumors with unusual glandular proliferations co-expressing estrogen receptor and CDX-2 by immunohistochemistry set in cystadenofibromatous background. Targeted next-generation sequencing was performed on the cyst lining epithelium and glandular proliferations for all cases; CTNNB1 mutations were detected in the glandular proliferations of all neoplasms. The cyst lining of case 1 demonstrated a different CTNNB1 mutation from the matched glandular proliferation. No mutations were detected in the cyst lining from case 2. The cyst lining and glandular proliferation for case 3 harbored identical ATM and PIK3CA mutations with an additional CTNNB1 mutation in the glandular proliferation. To our knowledge, this is the first reported series of endometrioid proliferations with co-expression of estrogen receptor and CDX-2 in cystadenofibromatous background.

Endometrial, Ovarian, and Peritoneal Involvement by Endometrioid Carcinoma, Yolk Sac Tumor, and Endometriosis: Molecular Evidence for a Shared Precursor.

Recent studies have provided molecular confirmation that a subset of yolk sac tumors is somatically derived. Somatically derived yolk sac tumors are typically diagnosed in older women and are often seen adjacent to epithelial proliferations (such as endometriosis or endometrioid carcinoma) with which they share mutations. Here, we present a case of a postmenopausal woman with a yolk sac tumor and endometriosis in the right ovary, endometriosis with glandular crowding and reactive changes in the left ovary, endometrial endometrioid carcinoma, and yolk sac tumor involving the serosa of the colon. Targeted next-generation sequencing of these five tumor components demonstrated identical mutations in PTEN (p.R130G), PIK3CA (p.G1049S), FGFR2 (p.S252W), and FBXW7 (p.R689Q), suggesting that all components arose from a common precursor. The endometrial endometrioid carcinoma harbored additional exclusive mutations involving PIK3CA (p.H1048R) and CTNNB1 (p.S37F).

Characterization of Intercalated Cell Markers KIT and LINC01187 in Chromophobe Renal Cell Carcinoma and Other Renal Neoplasms.

Introduction. Chromophobe renal cell carcinoma (chromophobe RCC) is the third major subcategory of renal tumors after clear cell RCC and papillary RCC, accounting for approximately 5% of all RCC subtypes. Other oncocytic neoplasms seen commonly in surgical pathology practice include the eosinophilic variant of chromophobe RCC, renal oncocytoma, and low-grade oncocytic unclassified RCC. Methods. In our recent next-generation sequencing based study, we nominated a lineage-specific novel biomarker LINC01187 (long intergenic non-protein coding RNA 1187) which was found to be enriched in chromophobe RCC. Like KIT (cluster of differentiation 117; CD117), a clinically utilized chromophobe RCC related biomarker, LINC01187 is expressed in intercalated cells of the nephron. In this follow-up study, we performed KIT immunohistochemistry and LINC01187 RNA in situ hybridization (RNA-ISH) on a cohort of chromophobe RCC and other renal neoplasms, characterized the expression patterns, and quantified the expression signals of the two biomarkers in both primary and metastatic settings. Results. LINC01187, in comparison to KIT, exhibits stronger and more uniform expression within tumors while maintaining temporal and spatial consistency. LINC01187 also is devoid of intra-tumoral heterogeneous expression pattern, a phenomenon commonly noted with KIT. Conclusions. LINC01187 expression can augment the currently utilized KIT assay and help facilitate easy microscopic analyses in routine surgical pathology practice.

Comorbid Vulvar Lichen Sclerosus and High-Grade Squamous Intraepithelial Lesions: A Management Conundrum.

OBJECTIVE: This study aimed to determine if treating lichen sclerosus (LS) with high-potency topical corticosteroids (TCS) increases the risk of high-grade squamous intraepithelial lesion (HSIL) recurrence in patients with comorbid vulvar LS and HSIL. METHODS: This is a retrospective study of patients with comorbid vulvar LS and HSIL treated with TCS between 2015 and 2020. Patients with clinically diagnosed or biopsy-proven LS and biopsy-proven HSIL of the vulva were included. Clinical data included demographics, tobacco use, immune-modifying conditions, specimen pathology, treatment types, and HSIL recurrence. Bivariate analysis was performed to compare demographic and clinical characteristics between patients with and without HSIL recurrence. RESULTS: Twenty-six patients with comorbid LS and HSIL were identified. The median age was 66.0 years and median time in treatment for LS was 5.5 years. Thirteen (50%) had recurrence of HSIL and 13 (50%) did not have recurrence. Exposure to high-potency TCS was present in 20 (77%) patients, with 17 (65%) having use of more than 1-year duration and 9 (35%) having use at the time of HSIL diagnosis. When comparing the groups with and without HSIL recurrence, there was no significant difference in high-potency TCS exposure, duration of use, or use at time of HSIL diagnosis. CONCLUSIONS: High-potency TCS use for the treatment of LS did not seem to increase the risk of HSIL recurrence in patients with comorbid vulvar LS and HSIL. This suggests that high-potency TCS can be appropriately used for the treatment of LS even when HPV-associated disease is present.

Reproductive Organ Pathology of Individuals Undergoing Gender-Affirming Surgery.

As gender-affirming surgeries become more routine, it is increasingly important for pathologists to recognize the expected histologic changes seen in various tissues secondary to gender-affirming hormone therapy. For example, exogenous testosterone-related squamous atrophy or transitional cell metaplasia of the cervix may be confused for high-grade squamous intraepithelial lesion. In addition to distinguishing between benign and dysplastic/malignant features, pathologists should be mindful of the phrasing of their reports and aim to use objective, nongendered language.

p53/CK17 Dual Stain Improves Accuracy of Distinction Between Differentiated Vulvar Intraepithelial Neoplasia and Its Mimics.

Accurate diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN) is challenging, in part due to the sometimes subtle nature of its atypia. Many dVIN lesions demonstrate aberrant p53 staining; however, staining patterns overlap between dVIN and benign/reactive entities. We evaluate a p53/CK17 dual stain in an initial cohort of dVIN (n=30), benign vulvar skin (n=5), lichen sclerosus (LS, n=10), lichen simplex chronicus (LSC, n=10), and pseudoepitheliomatous hyperplasia (PEH, n=10). In the initial cohort, aberrant p53 staining was seen only in dVIN (50%, 15/30). Equivocal p53 staining patterns were seen in dVIN (37%, 11/30), LS (50%, 5/10), LSC (40%, 4/10), and PEH (40%, 4/10). All 30 dVIN cases were positive for CK17 (strong partial-thickness or full-thickness staining), but positive CK17 staining was also seen in LS (70%, 7/10), LSC (50%, 5/10), and PEH (100%, 10/10). In the initial cohort, the combination of aberrant p53 and positive CK17 was seen only for dVIN (50%, 15/30). Forty cases of LS with known follow-up (20 with progression to dVIN, 20 without) were stained to assess prognostic value. Three LS cases showed aberrant p53 staining with CK17 positivity; all progressed to dVIN. Equivocal p53 staining and CK17 positivity were seen in cases with and without progression. The p53/CK17 dual stain is more diagnostically useful than either stain alone. Negative/focal staining for CK17 argues against a diagnosis of dVIN, while aberrant p53 staining with CK17 positivity strongly supports the diagnosis.

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

AIMS: Distinction 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 RESULTS: Cases 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. CONCLUSIONS: While 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.

Uterine PEComatosis With TSC1 Mutation in a Patient With Tuberous Sclerosis: Case Report and Literature Review.

Uterine PEComatosis is a rare phenomenon characterized by the presence of multiple perivascular epithelioid cell tumors (PEComas) and/or microscopic proliferations of perivascular epithelioid cells. Herein, we report a case of PEComatosis arising in a 49-yr-old woman with a known history of tuberous sclerosis. Targeted next-generation sequencing revealed a TSC1 stopgain mutation (p.Q732X) in all tested nodules, with single-copy TSC1 loss or copy-neutral TSC1 loss of heterozygosity. To our knowledge, this is the second report of TSC1 inactivation in uterine PEComa and the first report of confirmed TSC1 abnormalities in PEComatosis.

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.

AIMS: As 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 RESULTS: We 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%). CONCLUSION: NKX3.1-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.