International Journal of Gynecological Pathology最新文献

GLI1 -altered tumors of the gynecologic tract are extremely rare. We report 3 cases of ovarian PTCH1::GLI1 fusion tumor in patients ranging from 54 to 58 yrs of age, who presented with unilateral FIGO stage I tumors. The tumors ranged from 12 to 20 cm and consisted of uniform epithelioid cells with eosinophilic/clear cytoplasm, arranged in nests and trabeculae surrounded by delicate vessels. Variable features included short spindle cells within a myxoid stroma, follicles, small glands/Call-Exner body-like structures, dilated vessels/blood lakes, focal pleomorphism, nuclear grooves, and necrosis. Mitoses ranged from 1 to 10/10 HPFs. Immunohistochemical marker results/number of tumors tested (including primary tumors and recurrences) were as follows: positive for SF-1 (6/6), CD56 (4/4), EMA (3/5), keratins (3/5), SMA (2/5), CD10 (3/4), S100 (3/4), caldesmon (2/3), D2-40 (2/2), Ber-EP4 (2/2), and MOC-31 (1/1), and negative for WT-1 (5/5), calretinin (5/5), inhibin (4/5), ER (4/5), and PR (5/5). Diagnoses initially rendered included adult granulosa cell tumor, unclassified sex cord-stromal tumor, low-grade Müllerian adenocarcinoma, and low-grade endometrioid stromal sarcoma. Surgery was the primary treatment for all. One patient had multiple recurrences at 7, 9, and 13 yrs, had additional surgery, received chemotherapy and radiotherapy, and was alive with no evidence of disease at 13.6 yrs. Another patient had omental recurrence at 5 yrs, received chemotherapy, immunotherapy, and tyrosine kinase inhibitor-targeted therapy, and was alive with disease at 7.9 yrs. The third patient was alive with no evidence of disease at 2 mos. Ovarian PTCH1::GLI1 fusion tumors represent a diagnostic challenge and may recur after several years. Their proper recognition may prompt the use of targeted therapy.

Histotype and grade of endometrial carcinoma (EC) have been cornerstones of risk assessment, as both are known to be associated with differences in prognosis. The aim of this study was to analyze the prognostic significance of grade and histotype (comparing low-grade endometrioid, high-grade endometrioid, serous, and all others) within each EC molecular subtype, with further stratification by stage. A cohort of 2478 patients with EC were identified from our center. Disease-specific survival was compared for tumors of each molecular subtype after stratification of patients into 1 of 4 groups (low-grade endometrioid, high-grade endometrioid, serous, other). In addition, a systematic review of the literature was undertaken to identify all previous studies where the prognostic significance of grade and histotype within molecular subtypes was reported. Grade and histotype were not of prognostic significance in POLE mut or p53abn EC across all stages and when just considering stage I ECs. MMRd low-grade ECs were associated with a better prognosis; however, they were also associated with lower stage disease, and within stage I tumors, grade and histotype were not of prognostic significance. Grade and histotype were of prognostic significance in NSMP ECs, in all stages and in the subset of stage I tumors ( P <0.001 for both analyses). On a systematic review of the literature, we identified 7 studies; there was no prognostic significance of grade and histotype (comparing low-grade endometrioid, high-grade endometrioid and serous) in POLE mut, and p53abn EC, and no prognostic significance of grade and histotype independent of stage in MMRd. Histotype and grade are strongly associated with prognosis in NSMP EC, but not in other molecular subtypes.

Pure ductal-type mesonephric remnants in the uterine cervix are rare. We report an unusual case in a 31-yr-old of cervical mesonephric remnants of predominantly ductal type exhibiting seminal vesicle-like differentiation in a female-to-male transgender patient receiving long-term testosterone therapy. To the best of our knowledge, this phenomenon has not been previously reported. The impact of testosterone on the female genital tract is likely to be encountered more frequently due to increasing rates of gender-affirming surgery, including long-term androgen use. Awareness of the morphologic features is important as such changes may be misinterpreted as premalignant or malignant lesions. In reporting this unusual case, we briefly review lesions derived from cervical mesonephric remnants and testosterone-associated changes in the female genital tract.

In 2023, the College of American Pathologists (CAP) supported histotype-specific scoring for HER2 testing in endometrial serous carcinoma based on enrollment criteria for trastuzumab eligibility in the NCT01367002 clinical trial. However, in 2024, the DESTINY-PanTumor02 trial showed the benefit of trastuzumab-deruxtecan in patients with HER2-IHC 2+ and 3+ tumors using CAP gastric scoring, resulting in confusion about how these criteria relate. We compare the results of these scoring schemes by interobserver agreement and correlation with HER2/Chromosome 17 dual in situ hybridization (DISH). Six observers scored 44 HER2-IHC stained p53-abnormal endometrial carcinoma specimens in tissue microarray (TMA) format by endometrial serous (NCT01367002) and gastric systems. Interobserver agreement for HER2 scores (0, 1+, 2+, and 3+) was 81.5% (kappa=0.75) for endometrial serous and 84.6% (kappa=0.79) for gastric scoring. Eight specimens showed discordant HER2 endometrial serous and gastric scores: 4 endometrial serous 1+/gastric 0 and 4 endometrial serous 2+/gastric 3+. HER2-IHC-DISH discordance occurred in 4 specimens by gastric criteria (IHC 3+/DISH negative) and 1 specimen by endometrial serous criteria (IHC 3+/DISH negative). Endometrial serous and gastric HER2-IHC scoring schemes show similar interobserver agreement. In instances of minimal, faint HER2 staining, the endometrial serous score may be 1+ when the gastric score is 0. In instances of limited, strong HER2 staining, the endometrial serous score may be 2+ when the gastric score is 3+. The endometrial serous scheme appears more concordant with DISH results than the gastric scheme, which shows non-infrequent IHC 3+ cases without HER2-DISH amplification. We emphasize recognition of HER2-IHC therapy-specific scoring in endometrial carcinomas, as these scoring systems are similar but not identical.

The term verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN) was coined to describe HPV-independent p53-wildtype lesions with characteristic clinicopathologic characteristics and association with vulvar squamous cell carcinoma (vSCC). We aimed to expand on the molecular landscape of vaVIN using comprehensive sequencing and copy number variation profiling. vaVIN diagnosis in institutional cases was confirmed by a second review, plus negative p16 and wildtype p53 by immunohistochemistry. Multigene next-generation sequencing and shallow-whole genome sequencing were used to survey for single-nucleotide variants (SNV), copy number alterations, and structural variants. Targeted TERT promoter sequencing was also carried out. Nineteen patients with vaVIN were included; 4 had concurrent vSCC. The median patient age was 74 (range 56-90) years. Genomic aberrations were noted in 18 cases (95%) as follows: PIK3CA in 10 (53%), CDKN2A in 7 (37%), HRAS in 6 (32%), FAT1 and NOTCH1-2 in 5 each (26%), TSC2 in 2 (11%), and PTEN , ARID2 , and KRAS in 1 (5%) each. TERT promoter variants were detected in 11 of 13 cases successfully tested (85%). Five vaVINs harbored a TP53 variant but showed wild-type p53 immunohistochemical expression. In one of these, the concurrent carcinoma showed abnormal p53 and biallelic TP53 mutations. Out of 15 patients with follow-up (mean: 20, range: 2-50 mo), vaVIN persistence/recurrence was seen in 8 (53%), and subsequent vSCC in 2 (13%). At the last encounter, 3 (20%) patients had persistent disease and 1 (7%) died of vSCC. vaVIN is characterized by a wider molecular spectrum, beyond known alterations in PIK3CA , HRAS , and ARID2, to include TERT promoter, CDKN2A , FAT1 , and NOTCH1-2, which are characteristic of HPV-independent vSCC. vaVIN can occur with concurrent or subsequent carcinoma, sometimes with fatal outcomes. These findings support the concept of vaVIN as a neoplastic process within the family of HPV-independent vulvar neoplasia.

Junctions between different types of epithelia are hotspots for carcinogenesis. The peritoneal mesothelium of the mesovarium transitions to the ovarian surface epithelium at the ovarian hilus (the ovarian surface epithelium-peritoneal junction). There are limited histologic data on this junction in humans. We examined 143 examples of this junctional region in 76 patients with normal ovaries and in 150 patients with extrauterine high-grade serous carcinoma (HGSC). In the absence of significant pathologic processes in the region, this is normally a clearly demarcated, quiescent junction that is usually present directly over the interface of the ovarian stroma with the fibrovascular tissue of the mesovarium. When the ovarian surface epithelium (OSE) and mesothelial linings are well-preserved, the epithelial change at this junction is clearly visible when the OSE is cuboidal or columnar (seen in 79%). When the OSE is flat, no junction is visible (21%). The junction is sharply demarcated in 69%, and in 10% the OSE displays a progressively shorter epithelial height in its transition to the flat mesothelium. Transitional cell metaplasia occurs in the immediate vicinity in 11% of cases. In women with HGSC, tumor was present within 2 mm of this region in 41%. Carcinoma was confined to the ovarian/peritoneal surface in 15% and invaded the stroma without surface involvement in 16%. Carcinoma involved both the surface and invaded the underlying stroma in 11%. In our previous report from this cohort, 40% had serous tubal intraepithelial carcinoma (STIC). In the junctional region, intraepithelial HGSC was seen at the ovarian or peritoneal surface or within ovarian surface epithelial inclusions in 7 cases. Among these 7, fallopian tube tissue was evaluable in 5, and STIC was present in 2 (40%). Our findings characterize the histologic features of the normal ovarian surface epithelium-peritoneal junction and the involvement of this region in extrauterine HGSC.

Recently, criteria for p53 immunohistochemistry (IHC) interpretation were described in squamous neoplasia of the vulva. This pattern-based approach detailed 2 wild-type patterns (scattered and basal-sparing) and 4 mutant patterns (parabasal/diffuse overexpression, basal overexpression, null, and cytoplasmic). However, the proficiency of pathologist read-out has not been studied. We created an online tool to evaluate p53 IHC interpretation proficiency. p53 IHC on 90 vulvar biopsies (n=31 squamous insitu /premalignant and n=59 benign lesions) were scanned (without corresponding H&E). Fifteen pathologists assessed 45 cases in Module A and assigned each case as wild-type or mutant via the 6 p53 IHC patterns. Following Module A, participants were given the suggested p53 IHC pattern and TP53 sequencing data for each case. After self-review, pathologists completed a second 45 case set (Module B). The average pathologist score per case increased from Module A to Module B (69.8%-87.7%, P =0.0005). Pathologist proficiency was excellent in the parabasal/diffuse (100%-100%), null (93.3%-90.0%), and basal-sparing (88.9%-100%) patterns. The greatest discrepancy was due to the interpretation of the basal overexpression pattern in cases that were TP53 wild-type by sequencing, but this improved with educational intervention. Scores for the scattered pattern improved from 64.9% to 82.8% and basal overexpression from 73.3% to 91.1% after completion of the training module. Pathologists should exhibit caution when interpreting p53 IHC as basal overexpression, as this pattern can be seen in the absence of TP53 alterations. There were 2 cases with convincing p53 IHC abnormal patterns (1 parabasal/diffuse and 1 null) without TP53 mutations by sequencing.

Mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA) are rare gynecological neoplasms that sometimes exhibit morphologic overlap with clear cell carcinoma (CCC), which may lead to diagnostic challenges. Napsin-A is regarded as the most specific immunohistochemical marker of CCC, but its expression in MLA and MA has not been widely investigated. This study investigated the expression of Napsin-A in a series of MAs and MLAs to determine its utility in distinguishing these neoplasms from CCC. The cohort included 32 MLAs arising in the ovary, endometrium, abdominal wall, and sigmoid mesocolon, 13 cervical MLAs, 2 ovarian mesonephric-like carcinosarcomas, and 1 cervical mesonephric carcinosarcoma, with Napsin-A immunohistochemistry performed on whole-slide tissue sections. Napsin-A staining was positive in 17 of 48 cases (35.4%), with focal granular cytoplasmic expression ranging from 1% to 40%. In all, 13/32 (40.6%) MLAs, 2/13 (15.4%) MAs, and 2/3 (66.7%) mesonephric or mesonephric-like carcinosarcomas were positive. Our results demonstrate that Napsin-A is expressed in a significant subset of MLAs and MAs. Given the morphologic and immunohistochemical overlap, this may contribute to misclassification as CCC, especially in cases with ambiguous morphology. Pathologists should be aware of this diagnostic pitfall and employ a panel of markers rather than relying on a single marker.