Immunophenotypic analysis of angiomyolipoma with epithelial cysts, comparison to mixed epithelial and stromal tumors and epithelial and stromal elements of normal kidney and ovaries.

Angiomyolipoma with epithelial cysts (AMLEC) is a rare variant of renal angiomyolipoma (AML). It is characterized by a conventional AML component admixed with epithelial cysts within an "ovarian-like" stroma. Mixed epithelial and stromal tumor (MEST) is another renal neoplasm featuring epithelial cysts and "ovarian-like" stroma. While there is consensus that in MEST the epithelial and stromal components are neoplastic, in AMLEC it has been hypothesized that the epithelial component may represent renal tubular entrapment or ovarian-like transdifferentiation of tumor cells. The aim of this study was to compare the immunophenotypes of the epithelial-stromal components of AMLEC and MEST, with normal kidney and ovary to provide additional insights into the pathogenesis and relationships of these entities. In this study, we analyzed eight cases of AMLEC and 14 cases of MEST from 2003 to 2023. We used tissue microarrays, full sections, or unstained slides with an immunohistochemical panel including renal and ovarian markers: SF1, ER, PR, AR, PAX8, WT1, GATA3, CA-IX, p16, inhibin A, and BCL2. We compared these cases with ten non-neoplastic ovary and kidney samples. Our findings indicate that the epithelial component of AMLEC and MEST resembles hormone receptor positive renal tubular epithelium (AR + /ER - /PR -). AMLEC's stromal component resembled hormone receptor positive renal stroma, while MEST's resembled ovarian stroma, supporting mullerian transdifferentiation. Our study showed that the epithelial and stromal components of AMLEC and MEST are immunophenotypically different and also differ from normal tissues. Our findings suggest that in AMLEC, the epithelial-stromal component represents a hormonally driven proliferation of non-neoplastic renal elements within a dysregulated tumor microenvironment.

Metastatic germ cell tumors in serous cavities and cerebrospinal fluid: A single-center experience.

BACKGROUND: Metastatic germ cell tumors (GCTs) involving body cavity effusions and cerebrospinal fluid (CSF) are rare. Diagnosis is challenging because of limited morphological and clinicopathological information in the literature. METHODS: A database search of our institution from 1990 to 2024 identified 27 cases of metastatic GCTs, comprising five pediatric and 22 adolescent and adult patients, in serous cavities or the CSF, including peritoneal (15), pleural (nine), CSF (two), and pericardial (one) fluid. RESULTS: The most common primary site was the testis (n = 10), followed by the ovaries (n = 7), mediastinum (n = 4), retroperitoneum (n = 3), pineal gland (n = 2), and sacrum/coccyx (n = 1). The primary tumors in 14 patients were mixed GCTs (six with a seminoma component), followed by immature teratomas (six), yolk sac tumors (three), embryonal carcinomas (two), pure seminomas (one), and postpubertal teratomas (one). The median interval between primary tumor diagnosis and diagnosis of fluid positivity was 7 months (range: 0-134 months). In nine cases, the malignant fluid was diagnosed simultaneously with or within 1 month of the primary tumor. GCT subtyping was performed on 23 of the 27 cytological specimens. Twenty-four patients (89%) also had metastases to other sites. Thirteen patients died of the disease (48%), with a median survival time of 4 months. CONCLUSIONS: Metastatic GCTs in serous effusions and CSF are often associated with disseminated disease and poor prognosis. Subtyping can be performed by cytomorphology combined with immunohistochemistry.

Incidental findings during donor liver assessment: Single center experience.

Intraoperative consultation of donor liver is an important part of transplant evaluation and determination of liver eligibility. In this study, we describe incidental pathologic findings discovered during the pretransplant evaluation of liver donors in our Institution from 1/2010 to 12/2022. During this 13-year period 369 intraoperative consultations from 262 liver donors were performed. Of those cases, incidental findings were identified in 22 cases (5.9 %) from 19 donors (7.3 %); two donors had more than one lesion. The median age of this subset of patients was 53 years (range: 18-70) and females predominated (63 %). Sixteen of the donors had abnormal findings in the liver: 6 bile duct hamartoma (BDH), 5 hyalinized nodule with Histoplasma capsulatum, 5 focal nodular hyperplasia (FNH), 2 bile duct adenomas (BDA), 1 biliary cyst and 1 hemangioma. One donor had both FNH and a BDH. One BDH and 1 BDA case was misdiagnosed as malignancy during the frozen section evaluation. Three donors had extrahepatic pathologies: a pancreatic tail schwannoma, a low-grade appendiceal mucinous neoplasm, and a lymph node with metastatic endometrial endometrioid adenocarcinoma. Of the 19 livers, the final organ disposition was available for 9: 6 were transplanted (67 %) and 3 were discarded (33 %). Two of the 3 discarded organs were misdiagnosed BDH and BDA cases, and one was incorrectly reported as having 90 % microvesicular steatosis during the frozen assessment. We present the clinicopathologic characteristics of liver donors with incidental findings during the pre-transplant evaluation which could lead to unwarranted graft dismissal if misdiagnosed. Additionally, incidental fungal infections can have implications for immunosuppressive therapy and the decision to use or reject the graft.

Myxoid epithelioid smooth muscle tumor of the vulva: A distinct entity with MEF2D::NCOA2 gene fusion.

Smooth muscle tumors are the most common mesenchymal tumors of the female genital tract, including the vulva. Since vulvar smooth muscle tumors are rare, our understanding of them compared to their uterine counterparts continues to evolve. Herein, we present two cases of morphologically distinct myxoid epithelioid smooth muscle tumors of the vulva with novel MEF2D::NCOA2 gene fusion. The tumors involved 24 and 37-year-old women. Both tumors presented as palpable vulvar masses that were circumscribed, measuring 2.8 and 5.1 cm in greatest dimension. Histologically, they were composed of epithelioid to spindle-shaped cells with minimal cytologic atypia and prominent myxoid matrix. Rare mitotic figures were present (1-3 mitotic figures per 10 high-power field (HPF)), and no areas of tumor necrosis were identified. By immunohistochemistry, the neoplastic cells strongly expressed smooth muscle actin, calponin, and desmin, confirming smooth muscle origin. Next-generation sequencing identified identical MEF2D::NCOA2 gene fusions. These two cases demonstrate that at least a subset of myxoid epithelioid smooth muscle tumors of the vulva represent a distinct entity characterized by a novel MEF2D::NCOA2 gene fusion. Importantly, recognition of the distinct morphologic and genetic features of these tumors is key to understanding the biological potential of these rare tumors.

A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283.

OBJECTIVE: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. METHODS: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. RESULTS: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. CONCLUSIONS: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.

Metaplastic Breast Carcinoma in U.S. Population: Racial Disparities, Survival Benefit of Adjuvant Chemoradiation and Future Personalized Treatment with Genomic Landscape.

PURPOSE: In this population-based study, we aim to identify factors that are influential on the survival outcome in MBC and investigate novel molecular approaches in personalized disease management. METHODS: The data of this study were collected from the SEER database from 2000-2018. A total of 5315 cases were extracted from the database. The data were evaluated for demographics, tumor characteristics, metastasis, and treatment. Survival analysis was completed by using SAS software for multivariate analysis, univariate analysis, and non-parametric survival analysis. The molecular data with the most common mutations in MBC were extracted from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. RESULTS: The mean age at the time of presentation was 63.1 with a standard deviation (SD) of 14.2 years. Most patients were White (77.3%) with 15.7% Black patients, 6.1% Asian or Pacific Islander, and 0.5% American Indian. Histologically, most of the reported tumors were grade III (74.4%); 37% of the cases were triple negative (ER-, PR- and HER2-), whereas the hormone status was unknown in 46% of the cases. Spread was localized in 67.3% of patients while 26.3% had regional spread and 6.3% had distant metastases. Most tumors were unilateral (99.9%) and between 20-50 mm in size (50.6%). The lungs were the most common site for distant metastasis at diagnosis (3.42%) followed by bone (1.94%), liver (0.98%), and brain (0.56%). A combination of surgery, chemotherapy, and radiation therapy was the most common treatment with a cause-specific survival rate of 78.1% (95% CI = 75.4-80.4). The overall survival rate at 5 years was 63.6% (95% confidence interval (CI) = 62.0-65.1) with a cause-specific survival of 71.1% (95% CI = 69.5-72.6). Cause-specific survival was found to be 63.2% (95% CI = 58.9-67.1) in Black patients as compared to 72.4% (95% CI = 70.1-74.1) in White patients. Black patients also presented with higher rates of grade III disease, distant metastasis, and larger tumor size. On multivariate analysis, age > 60, grade III+, metastasis, and tumor size > 50 mm were associated with worse survival. The most common mutations in MBC identified in COSMIC data were TP53, PIK3CA, LRP1B, PTEN, and KMT2C. CONCLUSION: Though rare, MBC is aggressive, with poor prognosis associated with high-grade tumors, metastasis, tumor size over 50 mm, and advanced age at the time of presentation. Overall, Black women had worse clinical outcomes. MBC is difficult to treat and carries a poor prognosis that affects various races disproportionately. Continued enhancement of treatment strategies to foster more individualized care as well as continued enrollment in clinical trials are needed to improve outcomes among patients with MBC.

Endocrine cell micronests in an ovarian mucinous borderline tumor: a potential diagnostic pitfall for microinvasion.

The occurrence of endocrine cell micronests in ovarian tumors is rarely reported. To our knowledge, there are only three prior cases reported to date: one occurring in an ovarian mucinous cystadenoma, one in an ovarian mucinous cystadenofibroma, and another in an ovarian mucinous carcinoma with a predominant borderline component. This is a 27-year-old woman that presented with a one-month history of abdominal pain and fullness. Imaging studies revealed a large multiloculated cystic and solid mass measuring 23 cm occupying the majority of the pelvis and abdomen concerning for a primary ovarian malignancy. The patient underwent a right salpingo-oophorectomy with appendectomy. Histologic sections from the ovary showed a multiloculated, cystic and focally solid mass lined by gastrointestinal-type mucinous epithelium with variable degrees of proliferation accounting for greater than 10% of the tumor. In addition to the mucinous epithelial component, there were several foci of bland, monotonous epithelioid cells arranged in solid nests with focal tubular/acinar formation within the fibrous septa and mucinous epithelium. Immunohistochemical studies showed that these cells were positive for cytokeratin, EMA, and synaptophysin, while negative for inhibin. The Ki-67 proliferation index was low (<1%). The presence of endocrine cell nests associated with an ovarian mucinous neoplasm is a rare phenomenon. Whether this represents preservation of endocrine cells in the context of epithelial degeneration or an independent neoplastic component is unclear. Progression related to this endocrine cell proliferation is unlikely and the recognition of this phenomenon holds more diagnostic value than prognostic significance, as it could be confused with microinvasion or sex cord stromal elements.

Malignant Gonadal Germ Cell Tumors (Other Than Pure Germinoma) in Patients With Disorders of Sex Development: A Report of 21 Cases Based Largely on the Collection of Dr Robert E. Scully, Illustrating a High Frequency of Yolk Sac Tumor With Prominent Hepatoid and Glandular Features.

We describe 21 nonpure germinomatous gonadal germ cell tumors (9 with a germinoma component), all but 1 associated with gonadoblastoma, in patients with disorders of sex development who ranged from 7 to 36 years old (average, 20 y). Twenty patients were clinically described as phenotypic females with ambiguous genitalia/virilization and primary amenorrhea. The most common documented peripheral karyotype was 46,XY (10/12; 83%). Fifteen of 16 tumors with available clinicopathologic data were unilateral. They ranged from 7 to 30 cm (mean, 15.5 cm) and were solid and cystic with frequent necrosis and hemorrhage. Gonadoblastoma, in its classic (70%), dissecting (5%), or combined (25%) forms, was identified in all but 1. The malignant germ cell tumors were typically mixed except for 5 pure yolk sac tumors and 1 expansile gonadoblastoma with syncytiotrophoblast cells. When admixed, the most common component was yolk sac tumor (n=10), followed by germinoma (n=9), embryonal carcinoma (n=5), choriocarcinoma (n=4), immature teratoma (n=3), and teratoma (n=2). Typical morphologic patterns of yolk sac neoplasia, including reticular/microcystic, solid (including blastema-like), and endodermal sinus (Schiller-Duval bodies), were seen, as well as glandular (n=10) and hepatoid (n=6) differentiation, with cystically dilated glands and diffuse hepatoid morphology in 3 and 2 tumors, respectively. Two yolk sac tumors showed a sarcomatoid pattern. Somatic-type malignancies (alveolar rhabdomyosarcoma and low-grade spindle cell sarcoma, not otherwise specified) were identified in 1 case each. This is the first large series of germ cell tumors other than typical pure germinoma associated with gonadoblastoma. The high frequency of yolk sac tumor with glandular (especially cystic glandular) and hepatoid morphologies is noteworthy, and their presence should prompt further evaluation for an associated gonadoblastoma and possible disorder of sex development.

mTOR Pathway Activation Assessed by Immunohistochemistry in Cervical Biopsies of HPV-associated Endocervical Adenocarcinomas (HPVA): Correlation With Silva Invasion Patterns.

The Silva pattern of invasion, recently introduced to stratify patients at risk for lymph node metastases in human papillomavirus-associated endocervical adenocarcinomas (HPVAs), can only be assessed in cone and loop electrosurgical excision procedure excisions with negative margins or in a hysterectomy specimen. Previous studies found associations between destructive stromal invasion patterns (Silva patterns B and C) and mutations in genes involved in the MEK/PI3K pathways that activate the mammalian target of rapamycin (mTOR) pathway. The primary aim of this study was to use cervical biopsies to determine whether markers of mTOR pathway activation associate with aggressive invasion patterns in matched excision specimens. The status of the markers in small biopsy specimens should allow us to predict the final and biologically relevant pattern of invasion in a resection specimen. Being able to predict the final pattern of invasion is important, since prediction as Silva A, for example, might encourage conservative clinical management. If the pattern in the resection specimen is B with lymphovascular invasion or C, further surgery can be performed 34 HPVA biopsies were evaluated for expression of pS6, pERK, and HIF1α. Immunohistochemical stains were scored semiquantitatively, ranging from 0 to 4+ with scores 2 to 4+ considered positive, and Silva pattern was determined in follow-up excisional specimens. Silva patterns recognized in excisional specimens were distributed as follows: pattern A (n=8), pattern B (n=4), and pattern C (n=22). Statistically significant associations were found comparing pS6 and pERK immunohistochemistry with Silva pattern (P=0.034 and 0.05, respectively). Of the 3 markers tested, pERK was the most powerful for distinguishing between pattern A and patterns B and C (P=0.026; odds ratio: 6.75, 95% confidence interval: 1.111-41.001). Although the negative predictive values were disappointing, the positive predictive values were encouraging: 90% for pERK, 88% for pS6 and 100% for HIF1α. mTOR pathway activation assessed by immunohistochemistry in cervical biopsies of HPVA correlate with Silva invasion patterns.

The cytology of salivary gland neoplasms with globules of extracellular matrix: Case-based review of adenoid cystic carcinoma and its potential mimics.

Fine needle aspiration (FNA) cytology is an important tool for diagnosing salivary gland neoplasms and for guiding clinical management. The classic adenoid cystic carcinoma (AdCC) is a basaloid neoplasm with abundant extracellular matrix. The presence globules of extracellular matrix are quite characteristic of AdCC but not diagnostic. We selected from our files six FNA cases that contained at least some globules of amorphous matrix that are similar to the ones seen in AdCC. The aim of this case-based review is to discuss the pitfalls and some of the common differential diagnoses of AdCC in FNA cytology. By the end of this review, we hope to have shared with the readers the lessons we learned from these cases and to highlight the key criteria needed to make a correct diagnosis of AdCC based on cytomorphology. The importance of considering other entities, in addition to AdCC, whenever a salivary gland FNA presents with globules is emphasized.

Clinicopathologic Characteristics of Mesonephric Adenocarcinomas and Mesonephric-like Adenocarcinomas in the Gynecologic Tract: A Multi-institutional Study.

Mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA) are uncommon neoplasms of the gynecologic tract that have until recently been poorly understood. Although their morphologic, immunohistochemical, and molecular profiles have been recently defined, little is known about their clinical behavior. Small studies have demonstrated inconsistent findings and no large studies have examined the clinical behavior of these adenocarcinomas. In this multi-institutional study, representing the largest and most stringently defined cohort of cases to date, we examined the clinicopathologic features of 99 MAs and MLAs (30 MAs of the uterine cervix, 44 MLAs of the endometrium, and 25 MLAs of the ovary). Only tumors with characteristic mesonephric morphology and either immunohistochemical or molecular support were included. Our results demonstrate that the majority of mesonephric neoplasms presented at an advanced stage (II to IV) (15/25 [60%] MA of the cervix, 25/43 [58%] MLA of the endometrium, and 7/18 [39%] MLA of the ovary). The majority (46/89 [52%] overall, 12/24 [50%] MA of the cervix, 24/41 [59%] MLA of the endometrium, and 10/24 [42%] MLA of the ovary) developed recurrences, most commonly distant (9/12 [75%] MA of the cervix, 22/24 [92%] MLA of the endometrium, and 5/9 [56%] MLA of the ovary). The 5-year disease-specific survival was 74% (n=26) for MA of cervix, 72% (n=43) for MLA of endometrium, and 71% (n=23) for MLA of ovary. Our results confirm that mesonephric neoplasms are a clinically aggressive group of gynecologic carcinomas that typically present at an advanced stage, with a predilection for pulmonary recurrence.

DNA Mismatch Repair-deficient Endometrial Carcinosarcomas Portend Distinct Clinical, Morphologic, and Molecular Features Compared With Traditional Carcinosarcomas.

Uterine carcinosarcomas (UCSs) are aggressive neoplasms composed of high-grade malignant epithelial and mesenchymal elements with most (∼90%) showing TP53 abnormalities. A subset, however, shows mismatch repair deficiency (MMR-D). We sought to describe their clinical, morphologic, and molecular features. Clinicopathologic data of MMR-D UCSs were recorded including age, stage, follow-up, mismatch repair and p53 immunohistochemistry (IHC), MLH1 promoter methylation status, and germline alterations, TP53 mutation status, microsatellite instability and mutational burden by massively parallel sequencing. Seventeen (6.2%) MMR-D were identified among 276 UCSs. Of MMR-D UCSs, the median age was 60 years. mismatch repair IHC loss is as follows: MLH1/PMS2 65%, MSH2/MSH6 18%, MSH6 12%, and PMS2 6%. MLH1 promoter methylation and Lynch syndrome was identified in 47% and 12% of cases, respectively. Cases with p53 IHC showed the following patterns: wild-type 70%, aberrant 20%, and equivocal 10%. Of cases with sequencing, 88% were hypermutated and microsatellite instability high. High-grade endometrioid, undifferentiated, and clear cell carcinoma was present in 53%, 41%, and 6% of cases, respectively and 47% also showed a low-grade endometrioid component. Most patients presented at an early stage (67%) and upon follow-up, 18% died of disease, 65% showed no evidence of disease, while 18% are alive with disease. Patients with MMR-D UCS are younger than the reported median age (70 y) for traditional UCS and most do not show p53 abnormalities. Low-grade endometrioid and undifferentiated carcinoma were seen in approximately half of all cases. Although UCSs have a high tendency for early extrauterine spread, most patients in our cohort presented at an early stage and at follow-up were no evidence of disease. MMR-D UCSs display distinct clinical, morphologic, and molecular features compared with traditional UCSs.

The predictive value of positive and suspicious urine cytology: Are they different?

BACKGROUND: Urine cytology evaluation is an effective test in the detection of high-grade urothelial carcinoma (HGUC). While the guideline distinguishes the 2 categories: "positive for HGUC" (PHGUC) and "suspicious for HGUC" (SHGUC), the association between these categories with their subsequent follow-up biopsies remains unclear. This study aims to determine and compare the positive predictive value (PPV) of the specimens in PHGUC and SHGUC categories with their respective histologic diagnoses. METHODS: During the period of 03/01/2008 to 07/31/2018, urine cytology cases diagnosed as PHGUC and SHGUC with subsequent bladder biopsy within 12 months were retrieved. All cases were correlated with first biopsy obtained during 12 months of cytology specimen. Biopsy result with HGUC, carcinoma in situ, or non-urothelial carcinoma diagnoses were considered as concordance. RESULTS: 378 cases (229 SHGUC and 149 PHGUC) were identified from 263 patients. For the 229 SHGUC cases, the PPV was 72% (n = 166) and for the 149 PHGUC cases, the PPV was 85% (n = 127). While both categories have high PPV, they are statistically significant (p < 0.0001). Additionally, 33 cases were found to have low-grade urothelial carcinoma (LGUC), constituting a portion of discordant results. CONCLUSION: PHGUC and SHGUC categories are both associated with a high risk of malignancy, however, there is a statistically significant difference between them in our study, supporting the PSRUC guidelines of two separate categories. In instances when urine cytology is discordant with biopsy results, further investigation and clinical follow up is warranted. LGUC appears to remain a common pitfall especially in the suspicious category.

Invasive Stratified Mucinous Carcinoma (iSMC) of the Cervix Often Presents With High-risk Features That Are Determinants of Poor Outcome: An International Multicenter Study.

Invasive stratified mucinous carcinoma (iSMC) has been suggested to represent an aggressive subtype of endocervical adenocarcinoma. We sought to investigate the outcomes of iSMC and determine which clinical and pathologic parameters may influence the prognosis. Slides from 52 cases of iSMC were collected and classified as follows: pure iSMC (>90% of the entire tumor) and iSMC mixed with other human papillomavirus-associated adenocarcinoma components (miSMC) (>10%, but <90% of the entire tumor). Clinical and pathologic parameters were evaluated and compared with overall survival (OS) and recurrence-free survival (RFS). One third of patients with iSMC presented with lymph node metastases (LNM) and 25% developed local recurrences, whereas 4 (7.7%) developed distant recurrences. 29 cases (55.8%) were pure iSMC, whereas 23 cases (44.23%) were miSMC. OS was 74.7% in pure iSMC versus 85.2% in miSMC (P=0.287). RFS was 56.5% in pure iSMC and 72.9% in miSMC (P=0.185). At 5 years, OS in stage I was 88.9% versus stage II to IV 30% (P=0.004), whereas RFS in stage I was 73.9% versus stage II to IV 38.1% (P=0.02). OS was influenced by International Federation of Gynecology and Obstetrics (FIGO) stage (P=0.013), tumor size (P=0.02), LNM (P=0.015), and local recurrence (P=0.022), whereas RFS was influenced by FIGO stage (P=0.031), tumor size (P=0.001), local recurrence (P=0.009), LNM (P=0.008), and type of surgical treatment (P=0.044). iSMC is an aggressive cervical tumor biologically different from other human papillomavirus-associated adenocarcinomas due to the propensity for LNM, local/distant recurrence. FIGO stage, tumor size, LNM, and presence of local/pelvic recurrences are determinants of outcome in iSMCs.

Invasive Stratified Mucin-producing Carcinoma (ISMC) of the Cervix: A Study on Morphologic Diversity.

Invasive stratified mucin-producing carcinoma (ISMC) is a recently described tumor with similar morphology to the stratified mucin-producing intraepithelial lesion. Stratified mucin-producing intraepithelial lesion and ISMC likely arise from human papillomavirus (HPV)-infected reserve cells in the cervical transformation zone that retain their pluripotential ability to differentiate into various architectural and cytologic patterns. This is important, as small studies have suggested that ISMC may be a morphologic pattern associated with more aggressive behavior than usual HPV-associated adenocarcinoma. We sought to study the morphologic spectrum of this entity and its associations with other, more conventional patterns of HPV-associated carcinomas. Full slide sets from 52 cases of ISMC were reviewed by an international panel of gynecologic pathologists and classified according to the new International Endocervical Criteria and Classification system. Tumors were categorized as ISMC if they demonstrated stromal invasion by solid nests of neoplastic cells with at least focal areas of mucin stratified throughout the entire thickness, as opposed to conventional tall columnar cells with luminal gland formation. Tumors comprising pure ISMC, and those mixed with other morphologic patterns, were included in the analysis. Twenty-nine pure ISMCs (56%) and 23 ISMCs mixed with other components (44%) were identified. Other components included 13 cases of usual-type adenocarcinoma, 6 adenosquamous carcinoma, 3 mucinous-type adenocarcinoma, 1 high-grade neuroendocrine carcinoma. ISMC displayed architectural diversity (insular, lumen-forming, solid, papillary, trabecular, micropapillary, single cells) and variable cytologic appearance (eosinophilic cytoplasm, cytoplasmic clearing, histiocytoid features, glassy cell-like features, signet ring-like features, bizarre nuclei, squamoid differentiation). Awareness of the spectrum of morphologies in ISMC is important for accurate and reproducible diagnosis so that future studies to determine the clinical significance of ISMC can be conducted.

Endometrial Carcinomas with a "Serous" Component in Young Women Are Enriched for DNA Mismatch Repair Deficiency, Lynch Syndrome, and POLE Exonuclease Domain Mutations.

Endometrial carcinoma (EC), as described by Bokhman, has historically been classified as Type I (low-grade, hormone-dependant, young patients, good prognosis) or Type II (high-grade, hormone-independent, older patients, poor prognosis). This classification is no longer pragmatic, however, as EC is a much more heterogeneous disease. Four molecular subtypes of EC were identified by The Cancer Genome Atlas (TCGA), and subsequent studies have demonstrated its utility in predicting prognosis. While endometrial serous carcinoma (ESC), the prototypical Type II EC, largely occurs in older women, younger women with ESC were not accounted for in the Bokhman model and were underrepresented in the TCGA study. We hypothesized that a subset of ESCs in young patients do not represent bona fide serous carcinomas but rather high-grade endometrioid carcinomas mimicking a serous phenotype. We identified ESCs and mixed endometrioid/serous carcinomas in women <60 years (n=37), and analyzed their clinical, morphologic, immunohistochemical, and molecular characteristics. Sixteen percent showed mismatch repair deficiency (MMR-D) and 11% were diagnosed with Lynch syndrome. Additionally, 16% of cases tested harbored a hotspot POLE exonuclease domain mutation (POLE-EDM). Morphologically, 47% of tumors showed confirmatory endometrioid features, including atypical hyperplasia, a low-grade endometrioid carcinoma component, or squamous differentiation. Clinically, the overall survival in patients with MMR-D and POLE-EDM was significantly better than that of patients without these features (P=0.0329). In conclusion, ESCs in young patients comprise a heterogeneous group of tumors, demonstrating diverse clinical, immunohistochemical, morphologic, and molecular features which have implications for prognosis and adjuvant therapy.

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary.

Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n = 7), primary aGCTs that subsequently recurred (n = 9) and their matched recurrences (n = 9), and aGCT recurrences without matched primary tumors (n = 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p = 0.017). In addition, mutations affecting TP53, MED12, and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

Napsin-A and AMACR are Superior to HNF-1ß in Distinguishing Between Mesonephric Carcinomas and Clear Cell Carcinomas of the Gynecologic Tract.

Mesonephric carcinoma is a rare gynecologic neoplasm commonly mistaken for clear cell carcinoma, because of their overlapping morphologic features. Both tumors are negative for estrogen receptor and p16, magnifying this diagnostic dilemma. Recently, hepatocyte nuclear factor-1 beta (HNF-1ß), a marker for clear cell carcinoma, has also been shown to be positive in mesonephric carcinomas. Other more recent markers for clear cell carcinoma, however, such as Napsin-A and alpha-methylacyl-CoA racemase (AMACR), have not yet been studied in mesonephric carcinomas. Here we examine HNF-1ß, AMACR, and Napsin-A immunohistochemistry in 18 mesonephric and 55 endometrial/cervical clear cell carcinomas. HNF-1ß was considered positive if nuclear staining was present in ≥70% of cells and at least moderate intensity; for Napsin-A and AMACR, any cytoplasmic staining was considered positive (≥1%). H-scores were determined by multiplying the intensity score by proportion score. HNF-1ß was positive in a substantial portion of mesonephric carcinomas (9/18, 50%; H-score 98) and clear cell carcinomas (34/55, 62%; H-score 163) and did not distinguish between the 2 entities (specificity, 50%; P-value of H-score=0.08). Napsin-A and AMACR expression was significantly higher in clear cell [43/55 (78%) and 41/55 (75%), respectively] than mesonephric carcinomas [4/18 (22%) and 4/18 (22%) respectively], and helpful in this differential (specificity: 78% and 78%; P<0.05 for both). When Napsin-A and AMACR staining were seen in mesonephric carcinomas, staining was focal (≤5%), whereas staining in clear cell carcinomas was patchy/diffuse. In summary, Napsin-A and AMACR are helpful in distinguishing mesonephric carcinomas from clear cell carcinomas of the female genital tract, but HNF-1ß is not.

Clinicopathologic Association and Prognostic Value of MELF Pattern in Invasive Endocervical Adenocarcinoma (ECA) as Classified by IECC.

Microcystic, elongated, and fragmented (MELF) pattern of myometrial invasion is correlated with lymphovascular invasion (LVI) and lymph node metastases in uterine endometrioid carcinoma but has not been described in endocervical adenocarcinoma (ECA). A total of 457 ECAs were collected, and clinical/morphologic parameters correlated with follow-up data. Potential associations between MELF pattern and age, human papillomavirus status, tumor size/grade, LVI, lymph node metastases, Silva pattern were analyzed. Statistical analyses of overall survival (OS), disease-free survival, progression-free survival (PFS) were conducted using Kaplan-Meier analysis, and compared using the Log-rank test. Of 292 ECAs analyzed, 94 (32.19%) showed MELF invasion pattern (MELF-positive). Significant statistical correlation was found between MELF-positive and tumor size (P=0.0017), LVI (P=0.007), Silva pattern (P=0.0005); age, human papillomavirus status, tumor grade, lymph node metastases did not correlate. Fifty-five of 292 patients recurred (18.83%): 18/94 (19.14%) MELF-positive, 37/198 (18.68%) MELF-negative. PFS in MELF-positive: 77.2% and 64.5% at 5 and 10 yr, respectively; PFS in MELF-negative: 82% and 68.5% at 5 and 10 yr, respectively. On multivariate analysis for PFS and other prognostic parameters, only LVI was statistically significant (P=0.001). OS in MELF-positive was 86% and 74.1% at 5 and 10 yr, respectively; OS in MELF-negative, was 89.7% and 86% at 5 and 10 yr, respectively. Median survival was worse in MELF-positive (199.8 mo) versus MELF-negative (226.1 mo); this was not statistically significant. On multivariate analysis for OS and other prognostic parameters, only tumor stage was statistically significant (P=0.002). In ECAs, MELF is not independently associated with survival. Pathologic characteristics of MELF-positive (size, LVI, Silva pattern) versus MELF-negative tumors differ significantly.

Low-grade squamous intraepithelial lesion, cannot rule out high-grade lesion: Diagnosis, histological outcomes and human papillomavirus results.

BACKGROUND: The 2014 Bethesda System for Reporting Cervical Cytology classifies squamous intraepithelial lesions (SILs) of cervix into two main categories: low-grade SIL (LSIL) and high-grade SIL (HSIL). In some clinical practices, the LSIL cannot rule out high-grade lesion (LROH) interpretive category is used in cases with LSIL and findings that may raise the possibility of HSIL. Our purpose is to assess follow-up histopathology and high-risk human papillomavirus (hrHPV) results in patients with LROH, in comparison with LSIL, atypical squamous cells, cannot rule out HSIL (ASC-H), and HSIL in our institution. DESIGN: Cervical Papanicolaou tests with LROH, LSIL, ASC-H and HSIL interpretation, surgical follow-up, and hrHPV status were retrieved from the computer database from May 2014 to December 2016. RESULTS: Of 109 963 total Papanicolaou tests, LROH comprised 0.3%, LSIL 3.1%, ASC-H 0.2% and HSIL 0.4%. Only 3272 cases with surgical diagnoses were included in the study. The most common histological outcome for ASC-H was cervical intraepithelial neoplasia (CIN)2/3 (32.6%); LSIL was CIN 1 (45.7%); LROH was CIN 1 (46.7%) and HSIL was CIN 2/3 (64.4%). For LROH and LSIL, 31.1% and 7.5% respectively, had CIN 2/3. Approximately 79% of cases were hrHPV positive. Of LROH cases with surgical follow-up, 86.9% tested hrHPV positive, accounting for the second most common positive group after HSIL (92.6%). CONCLUSION: In our study cohort, LROH interpretation is associated with a higher number of CIN 2 or higher lesions on follow-up compared to patients with LSIL (P < 0.0001), and is associated with a significant percentage of positive other hrHPV, supporting LROH as a useful diagnostic category that triggers appropriate follow-up in affected women.