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.

Identification of Glandular (Acinar)/Tubule Formation in Invasive Carcinoma of the Breast: A Study to Determine Concordance Using the World Health Organization Definition.

CONTEXT.­: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. OBJECTIVE.­: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. DESIGN.­: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. RESULTS.­: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. CONCLUSIONS.­: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

Teratoma-associated and so-called pure Wilms tumour of the ovary represent two separate tumour types with distinct molecular features.

AIMS: Ovarian Wilms tumour (WT)/nephroblastoma is an extremely rare neoplasm that has been reported to occur in pure form or as a component of a teratomatous neoplasm. We hypothesized that teratoma-associated and pure ovarian WT may represent different tumour types with diverging molecular backgrounds. To test this hypothesis, we comprehensively characterized a series of five tumours originally diagnosed as ovarian WT. METHODS AND RESULTS: The five cases comprised three teratoma-associated (two mature and one immature) and two pure WTs. Two of the teratoma-associated WTs consisted of small nodular arrangements of "glandular"/epithelial structures, while the third consisted of both an epithelial and a diffuse spindle cell/blastemal component. The pure WTs consisted of "glandular" structures, which were positive for sex cord markers (including inhibin and SF1) together with a rhabdomyosarcomatous component. The two pure WTs harboured DICER1 pathogenic variants (PVs), while the three associated with teratomas were DICER1 wildtype. Panel-based DNA sequencing of four of the cases did not identify PVs in the other genes investigated. Analysis of the HA19/IGF2 imprinting region showed retention of imprinting in the pure WTs but loss of heterozygosity with hypomethylation of the ICR1 region in two of three teratoma-associated WTs. Furthermore, copy number variation and clustering-based whole-genome DNA methylation analyses identified divergent molecular profiles for pure and teratoma-associated WTs. CONCLUSION: Based on the morphological features, immunophenotype, and molecular findings (DICER1 PVs, copy number, and DNA methylation profiles), we suggest that the two cases diagnosed as pure primary ovarian WT represent moderately to poorly differentiated Sertoli Leydig cell tumours (SLCTs), while the tumours arising in teratomas represent true WTs. It is possible that at least some prior cases reported as pure primary ovarian WT represent SLCTs.

Practical Updates and Diagnostic Challenges in Endometrial Carcinoma.

CONTEXT.­: Clinical management of endometrial carcinoma largely depends on the morphologic parameters ascertained based on the pathologic evaluation of surgical resection specimens. However, there are numerous controversial and nonstandardized aspects of both the macroscopic and microscopic assessment of surgical specimens, including grossing, adequate sampling, diagnosis, staging, reporting, and ancillary testing. OBJECTIVE.­: To provide a comprehensive practical review of standardized grossing, key morphologic findings for reporting and staging, and diagnostic and prognostic use of ancillary testing in endometrial carcinomas. DATA SOURCES.­: The existing literature, recommendations of the International Society of Gynecological Pathologists, and specialty consensus guidelines. CONCLUSIONS.­: This review article summarizes important aspects of the grossing and sampling of surgical resection specimens for microscopic examination, key morphologic parameters that are required for reporting and staging, and morphologic features and immunoprofiles helpful in the differential diagnosis of low-grade and high-grade endometrial carcinomas, as well as the current status of the molecular classification of endometrial carcinoma and human epidermal growth factor receptor 2 testing in serous carcinoma. The information presented herein can be helpful in overcoming diagnostic challenges and issues related to the pathology reporting of endometrial carcinoma to practicing anatomic pathologists.

Targeted RNA Sequencing Highlights a Diverse Genomic and Morphologic Landscape in Low-grade Endometrial Stromal Sarcoma, Including Novel Fusion Genes.

Low-grade endometrial stromal sarcoma (LGESS) represents a morphologically and genetically heterogenous mesenchymal neoplasm. Previous work has shown that approximately half of LGESS are characterized by JAZF1::SUZ12 gene fusions, while a smaller proportion involves rearrangement of other genes. However, a subset of cases has no known genetic abnormalities. To better characterize the genomic landscape of LGESS, we interrogated a cohort with targeted RNA sequencing (RNA-Seq). Cases previously diagnosed as low-grade endometrial stromal neoplasia (n=51) were identified and re-reviewed for morphology and subjected to RNA-Seq, of which 47 were successfully sequenced. The median patient age was 49 years (range: 19 to 85). The most commonly detected fusions were JAZF1::SUZ12 (n=26, 55%) and BRD8::PHF1 (n=3, 6%). In addition to the usual/typical LGESS morphology, some JAZF1::SUZ12 fusion tumors showed other morphologies, including fibrous, smooth muscle, sex-cord differentiation, and myxoid change. Novel translocations were identified in 2 cases: MEAF6::PTGR2 and HCFC1::PHF1 . Ten tumors (21%) had no identifiable fusion, despite a similar morphology and immunophenotype to fusion-positive cases. This suggests that a subset of cases may be attributable to fusion products among genes that are not covered by the assay, or perhaps altogether different molecular mechanisms. In all, these findings confirm that RNA-Seq is a potentially useful ancillary test in the diagnosis of endometrial stromal neoplasms and highlight their diverse morphology.

Subspecialized breast pathologists have suboptimal interobserver agreement in Ki-67 evaluation using 20% as the cutoff.

PURPOSE: Ki-67 expression levels in breast cancer have prognostic and predictive significance. Therefore, accurate Ki-67 evaluation is important for optimal patient care. Although an algorithm developed by the International Ki-67 in Breast Cancer Working Group (IKWG) improves interobserver variability, it is tedious and time-consuming. In this study, we simplify IKWG algorithm and evaluate its interobserver agreement among breast pathologists in Ki-67 evaluation. METHODS: Six subspecialized breast pathologists (4 juniors, 2 seniors) assessed the percentage of positive cells in 5% increments in 57 immunostained Ki-67 slides. The time spent on each slide was recorded. Two rounds of ring study (R1, R2) were performed before and after training with the modified IKWG algorithm (eyeballing method at 400× instead of counting 100 tumor nuclei per area). Concordance was assessed using Kendall's and Kappa coefficients. RESULTS: Analysis of ordinal scale ratings for all categories with 5% increments showed almost perfect agreement in R1 (0.821) and substantial in R2 (0.793); Seniors and juniors had substantial agreement in R1 (0.718 vs. 0.649) and R2 (0.756 vs. 0.658). In dichotomous scale analysis using 20% as the cutoff, the overall agreement was moderate in R1 (0.437) and R2 (0.479), among seniors (R1: 0.436; R2: 0.437) and juniors (R1: 0.445; R2: 0.505). Average scoring time per case was higher in R2 (71 vs. 37 s). CONCLUSION: The modified IKWG algorithm does not significantly improve interobserver agreement. A better algorithm or assistance from digital image analysis is needed to improve interobserver variability in Ki-67 evaluation.

Sarcomas With RAD51B Fusions Are Associated With a Heterogeneous Phenotype.

RAD51B-rearranged sarcomas are rare neoplasms that exhibit a heterogeneous morphology. To date, 6 cases have been reported, all involving the uterus, including 4 perivascular epithelioid cell tumors (PEComas) and 2 leiomyosarcomas (LMS). In this study, we describe the morphologic, immunohistochemical, and molecular features of 8 additional sarcomas with RAD51B rearrangement, including the first extrauterine example. All patients were women with a median age of 57 years at presentation. Seven tumors originated in the uterus, and one in the lower extremity soft tissue, with a median tumor size of 12 cm. Histologically, 4 tumors showed predominantly spindle cell morphology with eosinophilic fibrillary cytoplasm, with or without nuclear pleomorphism, whereas 2 tumors exhibited pleomorphic epithelioid cells, featuring clear to eosinophilic, granular cytoplasm. Two neoplasms exhibited undifferentiated cytomorphology, including one with uniform small blue round cells. All tumors showed high-grade cytologic atypia and high mitotic activity (median: 30/10 high-power fields), whereas coagulative necrosis was noted in 6 cases and lymphovascular invasion in 2. By immunohistochemistry, 2 showed myoid and melanocytic markers in keeping with PEComa, whereas 4 cases were only positive for smooth muscle markers consistent with LMS (including 3 myxoid). The remaining 2 cases had a nonspecific immunoprofile. Five cases tested by targeted RNA sequencing (Archer FusionPlex, Illumina TruSight) showed different fusion partners (HMGA2, PDDC1, and CEP170). RAD51B rearrangements were identified by FISH in the remaining 3 cases. Targeted DNA sequencing in 2 cases was negative for TSC gene alterations. Clinical outcome, available in 5 patients (median follow-up, 19 months), revealed 3 local recurrences, 2 lung metastases, and 4 deaths due to disease. Our results expand the spectrum of sarcomas with RAD51B fusions, demonstrating variable clinical presentations, morphologic spectrum, and fusion partners. These tumors have a predilection for a uterine location, with either LMS, PEComa, or undifferentiated phenotypes, and are associated with an aggressive clinical course.

Comprehensive Clinical-Pathologic Assessment of Malignant Phyllodes Tumors: Proposing Refined Diagnostic Criteria.

The latest World Health Organization classification of breast tumors recommends diagnosing malignant phyllodes tumors (MPTs) when all 5 morphologic features are present: permeative borders, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses per 10 high-power fields (HPF), and stromal overgrowth. We assessed the performance of this recommendation to capture MPTs and features predictive of distant metastasis in a multi-institutional retrospective study. Of 65 MPTs, most cases had at least focally permeative borders (58, 89%), with marked stromal cellularity in 40 (61.5%), marked atypia in 38 (58.5%), ≥10 mitoses per 10 HPF in 50 (77%), and stromal overgrowth in 56 (86%). Distant metastases were observed in 20 (31%) patients (median follow-up 24.5 mo, 1 to 204). Only 13 of 65 (20%) cases had all 5 morphologic features, while only 7 of 20 (35%) cases with distant metastases had all 5 features. In univariate analysis, only marked stromal atypia ( P =0.004) and cellularity ( P =0.017) were associated with decreased distant metastasis-free survival. In multivariate Cox regression, the combination of stromal overgrowth, marked stromal cellularity, and atypia (C-index 0.721, 95% CI: 0.578, 0.863) was associated with decreased distant metastasis-free survival. The current World Health Organization recommendation will miss a significant number of MPTs with distant metastases. We propose refined diagnostic criteria for MPTs: (1) stromal overgrowth combined with ≥1 feature(s) (marked cellularity, marked atypia, or ≥10 mitoses per 10 HPF), or (2) in the absence of stromal overgrowth, marked cellularity combined with ≥1 feature(s) (permeative borders, marked atypia, or ≥10 mitoses per 10 HPF).

Low interobserver agreement among subspecialised breast pathologists in evaluating HER2-low breast cancer.

AIMS: Metastatic HER2-low breast cancer (HLBC) can be treated by trastuzumab deruxtecan. Assessment of low levels of HER2 protein expression suffers from poor interobserver reproducibility. The aim of the study was to evaluate the interobserver agreement among subspecialised breast pathologists and develop a practical algorithm for assessing HLBC. METHODS: Six breast pathologists (4 juniors, 2 seniors) evaluated 106 HER2 immunostained slides with 0/1+expression. Two rounds (R1, R2) of ring study were performed before and after training with a modified Ki-67 algorithm, and concordance was assessed. RESULTS: Agreement with 5% increments increased from substantial to almost perfect (R1: 0.796, R2: 0.804), and remained substantial for three categories (<1% vs 1%-10% vs >10%) (R1: 0.768, R2: 0.764). Seniors and juniors had almost perfect agreement with 5% increments (R1: 0.859 and 0.821, R2: 0.872 and 0.813). For the three categories, agreement remained almost perfect among seniors (R1: 0.837, R2: 0.860) and substantial among juniors (R1: 0.792, R2: 0.768). Binary analysis showed suboptimal agreement, decreasing for both juniors and seniors from substantial (R1: 0.650 and 0.620) to moderate (R2: 0.560 and 0.554) using the 1% cut-off, and increasing from moderate to substantial (R1: 0.478, R2: 0.712) among seniors but remaining moderate (R1: 0.576, R2: 0.465) among juniors using the 10% cut-off. The average scoring time per case was higher (72 vs 92 s). CONCLUSIONS: Subspecialised breast pathologists have suboptimal agreement for immunohistochemical evaluation of HLBC using the modified Ki-67 methodology. An urgent need remains for a new assay/algorithm to reliably evaluate HLBC.

Intraoperative assessment of axillary sentinel lymph nodes by telepathology.

PURPOSE: Although axillary dissection is no longer indicated for many breast cancer patients with 1-2 positive axillary sentinel lymph nodes (ASLN), intraoperative ASLN assessment is still performed in many institutions for patients undergoing mastectomy or neoadjuvant therapy. With recent advancements in digital pathology, pathologists increasingly evaluate ASLN via remote telepathology. We aimed to compare the performance characteristics of remote telepathology and conventional on-site intraoperative ASLN assessment. METHODS: Data from ASLN evaluation for breast cancer patients performed at two sites between April 2021 and October 2022 was collated. Remote telepathology consultation was conducted via the Aperio eSlideManager system. RESULTS: A total of 385 patients were identified during the study period (83 telepathology, 302 on-site evaluations). Although not statistically significant (P = 0.20), the overall discrepancy rate between intraoperative and final diagnoses was slightly higher at 9.6% (8/83) for telepathology compared with 5.3% (16/302) for on-site assessment. Further comparison of performance characteristics of ASLN assessment between telepathology and conventional on-site evaluation revealed no statistically significant differences between deferral rates, discrepancy rates, interpretive or sampling errors, major or minor disagreements, false negative or false positive results as well as clinical impact and turn-around time (P ≥ 0.12). CONCLUSION: ASLN assessment via telepathology is not significantly different from conventional on-site evaluation, although it shows a slightly higher overall discrepancy rate between intraoperative and final diagnoses (9.6% vs. 5.3%). Further studies are warranted to ensure accuracy of ASLN assessment via telepathology.

DNA Methylation Signature of Synchronous Endometrioid Endometrial and Ovarian Carcinomas.

Next-generation sequencing (NGS) studies have demonstrated that co-occurring sporadic endometrioid endometrial carcinoma (EEC) and endometrioid ovarian carcinoma (EOC) are clonally related, suggesting that they originate from a single primary tumor. Despite clonality, synchronous EEC and EOC when diagnosed at early stage behave indolently, similar to isolated primary EEC or isolated primary EOC. In the present study, we compared the DNA methylation signatures of co-occurring EEC and EOC with those of isolated primary EEC and isolated primary EOC. We also performed targeted NGS to assess the clonal relatedness of 7 co-occurring EEC and EOC (4 synchronous EEC and EOC and 3 metastatic EEC based on pathologic criteria). NGS confirmed a clonal relationship in all co-occurring EEC and EOC. DNA methylation profiling showed distinct epigenetic signatures of isolated primary EEC and isolated primary EOC. Endometrial tumors from co-occurring EEC and EOC clustered with isolated primary EEC while their ovarian counterparts clustered with isolated primary EOC. Three co-occurring EEC and EOC cases with peritoneal lesions showed a closer epigenetic signature and copy number variation profile between the peritoneal lesion and EOC than EEC. In conclusion, synchronous sporadic EEC and EOC are clonally related but demonstrate a shift in DNA methylation signatures between ovarian and endometrial tumors as well as epigenetic overlap between ovarian and peritoneal tumors. Our results suggest that tumor microenvironment in the ovary may play a role in epigenetic modulation of metastatic EEC.

Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP.

PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS: The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION: End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.

Mammary Spindle Cell Proliferations on Core Needle Biopsy: Is Excision Always Necessary?

Mammary spindle cell proliferations (SCPs) encompass a wide range of lesions and can be challenging to accurately diagnose on core needle biopsies (CNBs). Most SCPs are excised for definitive diagnosis. In the era of minimally invasive therapy, some SCP may be followed conservatively. We aim to examine the spectrum of SCP diagnosed on CNB and evaluate if excision of benign/indeterminate SCP is always required. We identified patients with SCP across 3 institutions. The CNB were classified into benign, indeterminate, or malignant. Available excisional specimens were used to classify the lesion as benign or malignant. Clinical variables were reviewed. A total of 197 SCP met the inclusion criteria, including 100 (53%) CNB classified as benign, 52 (26%) indeterminate, and 36 (19%) malignant. Nine patients had excisions without a preceding CNB. Excision was performed in 47% of benign, 87% of indeterminate, and 86% malignant CNB. Of 123 excised SCP, 77 (63%) were benign, while 44 (36%) were malignant. Most benign lesions were not suspicious radiologically (67%), while indeterminate and malignant lesions were more likely to be suspicious (44% and 75%, respectively; P <0.001). Malignant lesions tended to present as larger, rapidly growing, masses. Most mammary SCP are benign (63% of excisions). Appropriate ancillary tests can safely exclude some malignant entities. We encourage narrowing down the differential diagnosis to pertinent entities based on clinical presentation, imaging, histology, immunohistochemistry, and molecular studies, if applicable. Patients with mammary SCP may be spared surgery provided accurate pathologic diagnosis and appropriate correlation with imaging and clinical data.

Inflammatory Lesions of the Breast.

CONTEXT.­: Inflammatory lesions of the breast are rare but not infrequently pose problems both clinically and morphologically, particularly on needle core biopsies. These lesions range from acute inflammatory conditions to chronic lymphoplasmacytic and lymphohistiocytic to granulomatous inflammatory diseases. OBJECTIVE.­: To provide a comprehensive overview of inflammatory lesions of the breast, with etiopathogenesis and clinical, radiologic, and pathologic features as well as differential diagnostic considerations, clinical management, and prognosis. DATA SOURCES.­: The existing literature in the English language, including original research articles and review articles describing inflammatory lesions of the breast. CONCLUSIONS.­: Inflammatory lesions of the breast are characterized by a wide variety of clinical, radiologic, and morphologic features. The histopathologic differential diagnosis often includes a neoplastic process requiring ancillary studies and correlation with clinical and radiologic findings. Although most specimens display nonspecific findings precluding a definitive pathologic diagnosis, pathologists have a unique opportunity to play a crucial role in identifying key histologic features suggestive of certain entities, such as cystic neutrophilic granulomatous mastitis, immunoglobulin (Ig) G4 mastitis, or squamous metaplasia of lactiferous ducts, in the right clinical and radiologic context, and thereby guiding optimal and timely clinical management. The information presented herein will be helpful to practicing anatomic pathologists and pathology trainees in becoming more familiar with specific morphologic features and overcoming differential diagnostic challenges related to pathology reporting of inflammatory lesions of the breast.

Gestational trophoblastic disease: an update.

Gestational trophoblastic diseases (GTD) encompass a spectrum of rare pre-malignant and malignant entities originating from trophoblastic tissue. This updated review will highlight important radiological features, pathology and classification, and provide insight into the clinical management of these uncommon disorders. There is a wide geographic variation with the incidence of hydatidiform mole varying between 0.57 and 2 per 1000 pregnancies. The use of ultrasound (US) in the management of early pregnancy symptoms and complications has positively impacted the earlier detection of these diseases and resulted in diminished morbidity. Additional imaging modalities are reserved for problem solving or assessment of pulmonary manifestations of molar pregnancy. Having an awareness of their pleomorphic sonographic presentation and additional pathology that can mimic GTD is critical to avoiding pitfalls. Histologic and molecular analysis further aids in differential diagnosis. Gestational trophoblastic neoplasia (GTN) is inclusive of all malignant GTDs, and arises after 20% of molar pregnancies but can also be seen with non-molar gestations. Biochemical monitoring with human chorionic gonadotrophin is imperative for ongoing monitoring and surveillance and allows early detection of this entity. Doppler US is used for confirmation of diagnosis with magnetic resonance imaging (MRI) reserved for problem solving or assessment of myometrial invasion. This is of heightened relevance in patients undergoing surgical management. Cross sectional imaging is reserved for patients in the setting of GTN for the purposes of staging, prognostication and in the setting of recurrent disease. This may require a combination of computed tomography, MRI and positron emission tomography. Doppler US can provide insight into chemotherapeutic response/predict resistance in patients with GTN. As our understanding of these disorders evolves, there has been maturation in management options with a shift from traditional chemotherapy to innovative immunotherapy, particularly in the setting of resistant or high-risk disease.

Expanding the molecular spectrum of gene fusions in endometrial stromal sarcoma: Novel subunits of the chromatin remodeling complexes PRC2 and NuA4/TIP60 as alternative fusion partners.

Endometrial stromal sarcomas (ESS) are morphologically and molecularly heterogeneous. We report novel gene fusions (EPC1::EED, EPC1::EZH2, ING3::PHF1) identified by targeted RNA sequencing in five cases. The ING3::PHF1-fusion positive ESS presented in a 58-year-old female as extrauterine mesocolonic, ovarian masses, and displayed large, monomorphic ovoid-to-epithelioid cells arranged in solid sheets. The patient remained alive with disease 13 months after surgery. The three ESS with EPC1::EED occurred in the uterine corpus in patients with a median age of 58 years (range 27-62 years). One tumor showed a uniform epithelioid nested morphology, while the other two were composed of monomorphic spindle cells in fascicles with elevated mitotic figures, focal tumor cell necrosis, and lymphovascular invasion. At a median follow-up of 20 months, two patients developed local recurrence, including one with concomitant distant metastasis, while one patient remained free of disease. All three patients were alive at the last follow-up. The EPC1::EZH2-fusion positive ESS presented in a 52-year-old female in the uterus, and displayed uniform spindled cells arranged in short fascicles, with focally elevated mitotic activity but without necrosis. The patient remained free of disease 3 months after surgery. All cases were diffusely positive for CD10; four diffusely express estrogen and progesterone receptors. Our study expands the molecular spectrum of EPC1 and PHF1-related gene fusions in ESS to include additional novel subunits of the PRC2 and/or NuA4/TIP60 complexes. These cases displayed a monomorphic epithelioid or spindled phenotype, spanning low-grade and high-grade cytomorphology, all expressing CD10 and commonly ER and PR, and are prone to local and/or distant spread.

Uterine Sarcoma With FGFR1-TACC1 Gene Fusion: A Case Report and Review of the Literature.

With the growing availability of RNA sequencing technology in the pathology laboratory, new gene fusion-associated malignancies are increasingly being characterized. In this article, we describe the second ever reported case of a uterine sarcoma harboring a FGFR1-TACC1 gene fusion. The patient, a 53-yr-old perimenopausal woman, was found to have a 6 cm mass spanning the lower uterine segment and endocervix. Histologically, this was a spindle cell neoplasm with coagulative necrosis, moderate cytologic atypia, and increased mitotic activity. By immunohistochemistry, the neoplastic cells coexpressed CD34 and S100, and lacked smooth muscle marker expression. RNA sequencing revealed the presence of a FGFR1-TACC1 gene fusion. This report provides further evidence to suggest that FGFR1-TACC1 may be a recurrent fusion in a subset of uterine sarcomas. RNA sequencing using a panel that includes FGFR-TACC family fusions should be considered for uterine sarcomas that do not fit conventional diagnostic criteria, particularly as tumors with these fusions may be amenable to targeted therapy.

Are Columnar Cell Lesions the Earliest Non-Obligate Precursor in the Low-Grade Breast Neoplasia Pathway?

Columnar cell lesions (CCLs) of the breast comprise a spectrum of morphologic alterations of the terminal duct lobular unit involving variably dilated and enlarged acini lined by columnar epithelial cells. The World Health Organization currently classifies CCLs without atypia as columnar cell change (CCC) and columnar cell hyperplasia (CCH), whereas flat epithelial atypia (FEA) is a unifying term encompassing both CCC and CCH with cytologic atypia. CCLs have been increasingly recognized in stereotactic core needle biopsies (CNBs) performed for the assessment of calcifications. CCLs are believed to represent the earliest non-obligate precursor of low-grade invasive breast carcinomas as they share molecular alterations and often coexist with entities in the low-grade breast neoplasia pathway. Despite this association, however, the risk of progression of CCLs to invasive breast carcinoma appears low and may not exceed that of concurrent proliferative lesions. As the reported upgrade rates of pure CCL/FEA when identified as the most advanced high-risk lesion on CNB vary widely, the management of FEA diagnosed on CNB remains controversial. This review will include a historical overview of CCLs and will examine histologic diagnostic criteria, molecular alterations, prognosis and issues related to upgrade rates and clinical management.

Recurrent uterine inflammatory myofibroblastic tumor previously managed as leiomyosarcoma has sustained response to alectinib.

Soft tissue sarcomas encompass a wide range of histologic subtypes with varied clinical implications. The incorporation of comprehensive genetic profiling into clinical practice is refining our ability to make these distinctions in diagnosis to better reflect prognosis and clinical behavior of a tumor. In this report, we describe a case of recurrent inflammatory myofibroblastic tumor (IMT) of the uterus, initially diagnosed and managed as leiomyosarcoma. At the time of recurrence, the patient was found to have a TNS1-ALK rearrangement and was treated successfully with alectinib, a second-generation anaplastic lymphoma kinase (ALK)-inhibitor. She had a complete response by imaging six months after initiation of alectinib and remains without evidence of disease at 36 months follow-up. Pathology review in the setting of her known ALK fusion and the 2020 update to the World Health Organization Classification of Female Genital Tumors led to a change in diagnosis from leiomyosarcoma to IMT. Our case highlights the role of molecular testing in the diagnosis and management of uterine mesenchymal tumors and the efficacy of alectinib in this ALK-rearranged recurrent IMT of the uterus. Care must be taken to differentiate between IMT and other uterine mesenchymal tumors as this distinction can impact prognosis and management. Furthermore, this case adds to the growing body of evidence supporting the paradigm shift toward developing molecularly targeted therapies rather than disease site-specific treatments, especially in cases of recurrence as recommended by the National Comprehensive Cancer Network.