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Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Dusseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings The study included 7792 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p

Supplementary Data from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements

Supplementary Figure from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements

Purpose:Adult granulosa cell tumor (AGCT) is characterized by the somatic FOXL2 p.C134W mutation, and recurrences have been associated with TERT promoter and KMT2D-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers.Experimental Design:Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS) panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites.Results:We identified frequent KMT2C-truncating mutations along with other mutated genes implicated in the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, in addition to previously reported hotspot AKT1 and DICER1 mutations. Targeted transcriptome sequencing revealed recurrent TERT rearrangements (13%) involving partners CLPTM1L or DROSHA, and differential gene expression analysis showed FGFR1 upregulation in the TERT non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level, further supporting its diagnostic utility in distinguishing among these tumors.Conclusions:This is the largest comprehensive molecular study of JGCTs, where we further expand our current understanding of JGCT pathogenesis and demonstrate putative oncogenic drivers and TERT rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.

Supplementary Figure 2 from A Role for BRCA1 in Uterine Leiomyosarcoma

The Hippo pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo pathway is of prognostic significance to cancer patients. Here we show that the key targets of Hippo signaling, transcriptional coactivators Yki and Yap, play a conserved role in promoting ovarian cancer in flies and humans, respectively. Whereas studies linking Yap to cancer in other tissues have focused on overall Yap levels, we show for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap (nYap), or low levels of cytoplasmic phosphorylated Yap (cpYap), associated with poor survival from ovarian cancer. Patients with both high nYap and low cpYap had ∼50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. We find that Yap2 is the predominantly expressed Yap isoform in both the ovarian surface epithelium (OSE) and epithelial ovarian cancers. Overexpression of Yap2 and phosphorylation-defective Yap2-5SA in immortalized OSE cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage-independent growth, whereas Yap knockdown resulted in increased sensitivity to cisplatin-induced apoptosis. Findings argue that the Hippo signaling pathway defines an important pathway in progression of ovarian cancer. Cancer Res; 70(21); 8517–25. ©2010 AACR.

Supplementary Figure Legends 1-2, Methods and Materials from A Role for BRCA1 in Uterine Leiomyosarcoma

Supplementary Figure 1 from A Role for BRCA1 in Uterine Leiomyosarcoma

Supplementary Figure 1 from Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene

Supplementary Tables 1-2 from A Role for BRCA1 in Uterine Leiomyosarcoma

Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy with a low survival rate. Currently, there is no effective treatment for ULMS. Infrequent occurrences of human ULMS hamper the understanding of the initiation and progression of the disease, thereby limiting the ability to develop efficient therapies. To elucidate the roles of the p53 and BRCA1 tumor suppressor genes in gynecologic malignancies, we generated mice in which p53 and/or BRCA1 can be conditionally deleted using anti-Müllerian hormone type II receptor (Amhr2)–driven Cre recombinase. We showed that conditional deletion of p53 in mice results in the development of uterine tumors that resemble human ULMS and that concurrent deletion of p53 and BRCA1 significantly accelerates the progression of these tumors. This finding led to our hypothesis that BRCA1 may play a role in human ULMS development. Consistent with this hypothesis, we showed that the BRCA1 protein is absent in 29% of human ULMS and that BRCA1 promoter methylation is the likely mechanism of BRCA1 downregulation. These data indicate that the loss of BRCA1 function may be an important step in the progression of ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS. [Cancer Res 2009;69(21):8231–5]

Uterine PEComas often present a diagnostic challenge as they share morphological and immunohistochemical features with smooth muscle tumors. Herein we evaluated a series of 19 uterine PEComas to compare the degree of melanocytic marker expression with their molecular profile. Patients ranged from 32–77 (median 48) years, with six tumors classified as malignant based on the modified gynecologic-specific prognostic algorithm. All patients with malignant PEComas were alive with disease or dead of disease at last follow-up, while all those of uncertain malignant potential were alive and well (median follow-up, 47 months). Seventeen of 19 (89%) PEComas harbored either a TSC1 or TSC2 alteration. One of the two remaining tumors showed a TFE3 rearrangement, but the other lacked alterations in all genes evaluated. All showed at least focal (usually strong) positivity for HMB-45, with 15/19 (79%) having >50% expression, while the tumor lacking TSC or TFE3 alterations was strongly positive in 10% of cells. Melan-A and MiTF were each positive in 15/19 (79%) tumors, but staining extent and intensity were much more variable than HMB-45. Five of six (83%) malignant PEComas also harbored alterations in TP53, ATRX, or RB1, findings not identified in any tumors of uncertain malignant potential. One malignant PEComa was microsatellite-unstable/mismatch repair protein-deficient. In summary, TSC alterations/TFE3 fusions and diffuse (>50%) HMB-45 expression are characteristic of uterine PEComas. In morphologically ambiguous mesenchymal neoplasms with myomelanocytic differentiation, especially those with metastatic or recurrent disease, next-generation sequencing is recommended to evaluate for TSC alterations; as such, patients can be eligible for targeted therapy.

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.

Uterine perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm that occasionally shares morphologic and immunohistochemical overlap with low- and high-grade endometrial stromal sarcoma (LGESS and HGESS). In this study, we sought to characterize the clinical, morphologic, genetic, and epigenetic features of five uterine sarcomas that display histologic features of LGESS, HGESS, and PEComa. All tumors demonstrated epithelioid cells often associated with a low-grade spindled component resembling LGESS, with both regions expressing CD10, ER, PR, variable HMB45, and Melan-A immunoreactivity, and strong cathepsin K and pS6 expression. Targeted massively parallel sequencing analysis revealed the presence of somatic TSC2 mutations in all five cases, of which four harbored concurrent or consecutive JAZF1-SUZ12 gene fusions. Unsupervised hierarchical clustering analysis of methylation profiles of TSC2-mutant uterine sarcomas (n = 4), LGESS (n = 10), and HGESS (n = 12) demonstrated two clusters consisting of (1) all LGESS and TSC2-mutant uterine sarcomas and (2) all HGESS. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, calcium, and Rap1 signaling. TSC2-mutant uterine sarcomas were responsive to hormone suppression, and mTOR inhibition demonstrated clinical benefit in four patients with these neoplasms. Our results suggest that these tumors represent histologically distinctive LGESS with TSC2 mutations. TSC2 mutations and JAZF1-SUZ12 fusion may help diagnose these tumors and possibly direct effective treatment.

We report four neoplasms of the kidney (2 cases) and uterus (2 cases) harboring rearrangements or amplifications of the GLI1 gene, which due to their unusual clinical presentation, morphology and immunoprofile mimicked other neoplasms, causing significant diagnostic challenge. The neoplasms occurred in four female patients ages 33–88 years. Histologically they all demonstrated nodular growth, solid architecture, bland epithelioid to ovoid spindle cells with pale cytoplasm set in a variably myxoid or hyalinized stroma. One uterine tumor also demonstrated a focal round cell pattern, while another demonstrated focal pleomorphism. Unlike most previously reported neoplasms with these genetic abnormalities, the neoplasms in the current series were negative for S100 protein and minimally reactive for actin. All labeled for CD10 and cyclin D1, while two labeled for estrogen receptor and BCOR and one labeled for desmin, raising consideration of endometrial stromal sarcoma, myxoid leiomyosarcoma, metastatic breast carcinoma, and glomus tumor. One renal neoplasm demonstrated a GLI1-FOXO4 gene fusion and the other harbored a GLI1 gene rearrangement (unknown partner). The two uterine neoplasms exhibited GLI1 gene amplifications. GLI1-altered neoplasms (particularly those with GLI1-amplification) show variable morphology and lack a consistent immunophenotype, and thus may trigger diagnostic challenges which can be resolved by molecular testing.

HIK1083 and trefoil factor 2 (TFF2) are known to be expressed in gastric-type carcinoma (GAS), but they do not reliably mark all GASs, and focal expression can be missed in biopsy specimens. We aimed to investigate whether claudin-18 and alpha-methylacyl-CoA racemase (AMACR) could be surrogate markers to separate GAS from other types of endocervical adenocarcinoma (ECA) and to compare their usefulness with that of HIK1083 and TFF2. Claudin-18 and AMACR immunohistochemistry was performed, and the results were compared with that of TFF2 and HIK1083, using whole sections of 75 ECAs (22 GASs and 53 non-GASs) and 179 ECAs with tissue microarrays (TMAs). TMAs were built to simulate the assessment of immunohistochemical stains in small biopsies. Any membranous (claudin-18) or cytoplasmic/membranous (AMACR, TFF2, HIK1083) staining of5% of tumor cells was considered positive. Of 75 ECAs with whole sections, claudin-18 was significantly more frequently expressed in GASs (21/22) compared with non-GASs (8/53) (P0.01). In ECAs with TMAs, claudin-18 expression was significantly frequent in GASs (15/23, 65.2%) than in non-GASs (3/152, 2.0%; all usual-type) (P0.01). All claudin-18-positive GASs showed intense staining except 1 case. Claudin-18 shared the same degree of sensitivity and specificity with HIK1083 and TFF2. Three clear cell carcinomas were positive for claudin-18, but none showed intense staining. AMACR was expressed in a subset of ECAs and showed no impact in distinguishing between GAS and other ECAs. Our results suggest that claudin-18 is a promising surrogate marker to separate GAS from other types of ECA, including clear cell carcinoma.

PURPOSE: The 2018 International Federation of Gynecology and Obstetrics (FIGO) update on cervical cancer staging eliminated horizontal tumor extent (HZTE) as a staging parameter in stage IA (microscopic) disease. We aimed to determine whether HZTE correlates with outcomes in early stage ECAs and FIGO should reinstate HZTE as a staging parameter in futures updates. METHODS: We retrospectively analyzed 416 FIGO 2009 stage I ECAs from 17 institutions and re-assigned stage using FIGO 2018. Correlation between HZTE, overall (OS) and recurrence free survival (RFS) was performed using univariable and multivariable analyses. RESULTS: Re-staging 416 cases resulted in 126 (30.3%) IA and 290 (69.7%) IB cases; 85 (67.5%) IA tumors had HZTE ≤7mm, while 41 (32.5%) were >7mm; 32 (11%) IB tumors had HZTE ≤7mm, while 258 (89%) were >7mm (p=0.0001). Four (3.2%) IA (1 IA1, 3 IA2) patients developed recurrence (3 ≤7mm, 1 >7mm) compared to 41 (14.1%) IB patients (p=0.002). Fourteen IB and no IA patients died of disease (8 IB1, 1 ≤7mm). Cox univariate analysis demonstrated that only RFS is significantly influenced by HZTE (p=0.01), while OS and RFS were not influenced by HZTE on multivariate analysis. CONCLUSION: HZTE has limited prognostic value in early stage ECAs and is only associated with RFS on univariate but not multivariate analysis. HZTE does not improve prognostication of patients with stage I ECAs as per 2018 FIGO staging. Consequently, the rationale to remove this variable from FIGO staging is justified for ECAs.

Herein we evaluated a series of 21 embryonal rhabdomyosarcomas of the uterine corpus (ucERMS), a rare neoplasm, to characterize their morphology, genomics, and behavior. Patients ranged from 27 to 73 (median 52) years and tumors from 4 to 15 (median 9) cm, with extrauterine disease noted in two. Follow-up (median 16 months) was available for 14/21 patients; nine were alive and well, four died of disease, and one died from other causes. Most tumors (16/21) showed predominantly classic morphology, comprised of alternating hyper- and hypocellular areas of primitive small cells and differentiating rhabdomyoblasts in a loose myxoid/edematous stroma. A cambium layer was noted in all; seven had heterologous elements (six with fetal-type cartilage) and eight displayed focal anaplasia. The remaining five neoplasms showed only a minor component (

We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 (median 39) years and the tumors from 4.5 to 25.5 (median 11) cm. Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median 9 per 10 high-power fields). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2–40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphological, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome.

Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n = 68) were subjected to massively parallel sequencing targeting 410-468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n = 21), PAs (n = 178), and IGAs (n = 148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle-related genes including TP53 (41% vs 5%, p

Although 2014 World Health Organization criteria require unequivocal glandular and squamous differentiation for a diagnosis of cervical adenosquamous carcinoma, in practice, adenosquamous carcinoma diagnoses are often made in tumors that lack unequivocal squamous and/or glandular differentiation. Considering the ambiguous etiologic, morphological, and clinical features and outcomes associated with adenosquamous carcinomas, we sought to redefine these tumors. We reviewed slides from 59 initially diagnosed adenosquamous carcinomas (including glassy cell carcinoma and related lesions) to confirm an adenosquamous carcinoma diagnosis only in the presence of unequivocal malignant glandular and squamous differentiation. Select cases underwent immunohistochemical profiling as well as human papillomavirus (HPV) testing by in situ hybridization. Of the 59 cases originally classified as adenosquamous carcinomas, 34 retained their adenosquamous carcinoma diagnosis, 9 were reclassified as pure invasive stratified mucin-producing carcinomas, 10 as invasive stratified mucin-producing carcinomas with other components (such as HPV-associated mucinous, usual-type, or adenosquamous carcinomas), and 4 as HPV-associated usual or mucinous adenocarcinomas with benign-appearing squamous metaplasia. Two glassy cell carcinomas were reclassified as poorly differentiated usual-type carcinomas based on morphology and immunophenotype. There were significant immunophenotypic differences between adenosquamous carcinomas and pure invasive stratified mucin-producing carcinomas with regard to HPV (p 0.0001), PAX8 (p = 0.038; more in adenosquamous carcinoma), p40 (p 0.0001; more in adenosquamous carcinoma), p63 (p = 0.0018; more in adenosquamous carcinoma) and MUC6 (p 0.0001; less in adenosquamous carcinoma), HNF-1beta (p = 0.0023), vimentin (p = 0.0003), p53 (p = 0.0004), and CK7 (p = 0.0002) expression. Survival outcomes were similar between all groups. Adenosquamous carcinomas should be diagnosed only in the presence of unequivocal malignant glandular and squamous differentiation. The two putative glassy cell carcinomas studied did not meet our criteria for adenosquamous carcinoma, and categorizing them as such should be reconsidered.

The incidence of endocervical adenocarcinoma, the second most common cervical cancer in the world, has been on the rise. While most cervical cancers are squamous cell carcinomas and associated with high-risk oncogenic human papillomavirus (HPV), approximately 15% of endocervical adenocarcinomas, which now represent about one quarter of all cervical cancers, are HPV-independent. In this review, we will focus on the shortcomings of historical histologic classification systems of female genital tract tumors as they pertain to endocervical adenocarcinomas, and we will highlight the advantages of the new International Endocervical Adenocarcinoma Criteria and Classification system, which forms the basis for the WHO 2020 classification. We will cover the various histologic types, subtypes, and variants of endocervical adenocarcinoma with regard to morphology, immunophenotype, molecular genetics, HPV status and differential diagnosis, and we will provide International Society of Gynecological Pathologists recommendations for diagnosing these tumors.

The International Federation of Gynecology and Obstetrics (FIGO) updated its staging system for cervical cancer in 2018 with changes that affect size criteria for early stage disease, as well as including pathology and radiology in addition to clinical assessment to be used in staging. Lymph node involvement was also included in the staging system. In early stage disease, pathologic findings are crucial in determining stage, which in turn determine treatment and prognosis for the patient. Therefore, it is imperative that there are unified and consistent methods and recommendations for assessing and reporting pathologic parameters for accurate staging. We describe the changes in the revised FIGO staging scheme and discuss controversial issues in cervical cancer staging from a pathologic perspective. We also provide practical recommendations regarding these parameters based on literature review and/or expert opinion/consensus.

The International Society of Gynecological Pathologists (ISGyP) Endocervical Adenocarcinoma Project aims to provide evidence-based guidance for the pathologic evaluation, classification, and reporting of endocervical adenocarcinoma. This review presents the recommendations pertaining to gross evaluation and intraoperative consultation of specimens obtained from patients in the setting of cervical cancer. The recommendations are the product of review of published peer-reviewed evidence, international guidelines and institutional grossing manuals, as well as deliberation within this working group. The discussion presented herein details the approach to the different specimen types encountered in practice: loop electrosurgical excision procedure, cone, trachelectomy, radical hysterectomy, pelvic exenteration, and lymphadenectomy specimens. Guidelines for intraoperative evaluation of trachelectomy and sentinel lymph node specimens are also addressed. Correlation with ISGyP recommendations on cancer staging, which appear as a separate review in this issue, is also included when appropriate. While conceived in the framework of endocervical adenocarcinoma, most of the discussion and recommendations can also be applied to other cervical malignancies.

Histopathologic classification of endocervical adenocarcinomas (EAC) has recently changed, with the new system based on human papillomavirus (HPV)-related morphologic features being incorporated into the 5th edition of the WHO Blue Book (Classification of Tumours of the Female Genital Tract). There has also been the introduction of a pattern-based classification system to assess invasion in HPV-associated (HPVA) endocervical adenocarcinomas that stratifies tumors into 3 groups with different prognoses. To facilitate the introduction of these changes into routine clinical practice, websites with training sets and test sets of scanned whole slide images were designed to improve diagnostic performance in histotype classification of endocervical adenocarcinoma based on the International Endocervical Adenocarcinoma Criteria and Classification (IECC) and assessment of Silva pattern of invasion in HPVA endocervical adenocarcinomas. We report on the diagnostic results of those who have participated thus far in these educational websites. Our goal was to identify areas where diagnostic performance was suboptimal and future educational efforts could be directed. There was very good ability to distinguish HPVA from HPV-independent adenocarcinomas within the WHO/IECC classification, with some challenges in the diagnosis of HPV-independent subtypes, especially mesonephric carcinoma. Diagnosis of HPVA subtypes was not consistent. For the Silva classification, the main challenge was related to distinction between pattern A and pattern B, with a tendency for participants to overdiagnose pattern B invasion. These observations can serve as the basis for more targeted efforts to improve diagnostic performance.

There is a lack of consensus regarding the prognostic value of grading endocervical adenocarcinomas and currently, no universally applied, validated system for grading exists. Several grading schemes have been proposed, most incorporating an evaluation of tumor architecture and nuclear morphology and these are often based on the International Federation of Gynecology and Obstetrics (FIGO) system for endometrial endometrioid carcinoma, although some schemes modify the proportion of solid tumor required to separate grades 1 and 2 from 5% to 10%. In the absence of a validated system, we endorse this approach for most human papillomavirus-associated endocervical adenocarcinomas and, based on the available evidence, recommend that tumors with ≤10% solid growth be designated grade 1, 11% to 50% solid growth grade 2 and >50% solid growth grade 3. Tumors should be upgraded in the presence of marked nuclear atypia involving the majority (>50%) of the tumor. Grading is not recommended for human papillomavirus-independent adenocarcinomas, since no validated system has been suggested and most of these neoplasms exhibit intrinsically aggressive behavior regardless of their morphologic appearance. Importantly, grading should not be performed for gastric-type adenocarcinomas, particularly as these tumors may appear deceptively "low-grade" yet still exhibit aggressive behavior. Recently devised, validated and reproducible etiology and pattern-based tumor classification systems for endocervical adenocarcinomas appear to offer more effective risk stratification than tumor grading and, in the future, these systems may render the provision of a tumor grade redundant.

Background Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. Methods Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. Results Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of “abnormal” results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. Conclusion Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.

ObjectivePrognostic factors for endocervical adernocarcinomas are well known, but little is known about prognostic biomarkers influencing outcome for the newly defined International Federation of Gynecology and Obstetrics (FIGO) 2018 IB sub-stages. The aim of this study was to identify prognostic biomarkers influencing recurrence-free and overall survival for FIGO 2018 stage IB cervical adenocarcinoma sub-types. We sought to identify these factors using a large international multi-institutional series of cases.MethodsStage IB endocervical adenocarcinomas were retrospectively collected from nine international institutions; full slide sets (n=464) were used to assign prognostic biomarkers. Inclusion criteria were the following: FIGO stage IB endocervical adenocarcinomas with follow-up in which all paraffin blocks/glass slides were available for review and/or additional studies and the patient was surgically treated from 1985 to 2019. The types of specimens included in the study were conizations, trachelectomies, and simple/radical hysterectomies with or without lymph node samples. We excluded in situ carcinomas, squamous cell carcinomas, adenosquamous carcinomas, tumors with a neuroendocrine component, carcinosarcomas, and any tumor showing clinical, macroscopic, or microscopic features suggesting a lower uterine segment, uterine corpus, or an adnexal primary origin. Tumors treated with neoadjuvant chemotherapy and/or radiation therapy were also excluded, as well as biopsies and loop electrosurgical excision procedures.ResultsOf 464 cases, 225 (48%) were stage IB1, 177 (38%) were stage IB2, and 62 (13%) were stage IB3. Five-year and 10-year recurrence-free survivals were statistically different among stage IB sub-types (p=0.005). Silva pattern of invasion was significant for recurrence-free survival at 5 and 10 years (p=0.04); overall survival and recurrence-free survival were higher in human papillomavirus (HPV)-associated cases (p=0.007 and p=0.001, respectively) and in cases without lymphovascular invasion (p=0.004 and p=0.00001, respectively). Factors that significantly influenced recurrence-free survival were HPV-independent status (p=0.05; HR 2.31; 95% CI 1.02 to 5.46), presence of lymphovascular invasion (p=0.011; HR 3.50; 95% CI 1.33 to 9.19), and presence of lymph node metastasis (p=0.016; HR 2.66; 95% CI 1.20 to 5.90).ConclusionHPV status and the presence of lymphovascular invasion are prognosticators in stage IB endocervical adenocarcinoma sub-types. These parameters should be included in future sub-staging modifications of FIGO stage IB endocervical adenocarcinomas and in treatment strategies.

Secondary involvement of the uterine cervix by non-gynecologic neoplasms is rare accounting for 50.5) (p=0.01). Mean time to identification of cervical metastases was

Female adnexal tumors of probable Wolffian origin are rare and present a diagnostic challenge due to their morphological and immunohistochemical overlap with more common ovarian and broad ligament entities. We evaluated the morphological, immunohistochemical, and molecular features of 15 tumors of probable Wolffian origin. Patients ranged from 32 to 69 (mean 47) years and tumors from 1.8 to 30 (mean 10) cm. All except one arose in para-adnexal soft tissues. Follow-up was available for six patients, five of whom were alive and well, while the sixth, who had extra-adnexal disease at diagnosis, died from unrelated causes. The following patterns were noted: tubular (all tumors), solid 11/15 (73%), sieve-like 7/15 (47%), and reticular 1/15 (7%). A myxoid background was present in 3/15 (20%) of tumors and eosinophilic luminal secretions in 11/15 (73%). Most tumors (12/15, 80%) had low-grade nuclear atypia, while three showed foci with scattered high-grade atypia. Mitotic index ranged from 0 to 17 (mean 4) per ten high-power fields. Tumors were positive for pankeratin and negative for TTF-1. EMA, GATA3, and PAX8 were positive in 2/10 (20%; focal), 3/15 (20%; focal), and 1/15 (7%; focal) of tumors, respectively. CD10, SF-1, calretinin, inhibin, ER, PR, cytokeratin 7, and WT1 were variably expressed. Pathogenic mutations were rare and included STK11 (n = 3), APC (n = 1), and MBD4 (n = 1). Copy number variations were detected in the three tumors with STK11 mutations and a myxoid background. These data demonstrate that female adnexal tumors of probable Wolffian origin are morphologically and immunohistochemically diverse, but infrequently harbor pathogenic mutations. However, their lack of mutations in contrast to their mimickers may be a valuable tool in diagnostically difficult cases.

Intravenous leiomyomatosis (IVL) is an unusual uterine smooth muscle proliferation that can be associated with aggressive clinical behavior despite a histologically benign appearance. It has some overlapping molecular characteristics with both uterine leiomyoma and leiomyosarcoma based on limited genetic data. In this study, we assessed the clinical and morphological characteristics of 28 IVL and their correlation with molecular features and protein expression, using array comparative genomic hybridization (aCGH) and Cyclin D1, p16, phosphorylated-Rb, SMARCB1, SOX10, CAIX, SDHB and FH immunohistochemistry. The most common morphologies were cellular (n = 15), usual (n = 11), and vascular (n = 5; including 3 cellular IVL showing both vascular and cellular features). Among the immunohistochemical findings, the most striking was that all IVL showed differential expression of either p16 or Cyclin D1 in comparison to surrounding nonneoplastic tissue. Cytoplasmic phosphorylated-Rb was present in all but one IVL with hyalinization. SMARCB1, FH, and SDHB were retained; S0X10 and CAIX were not expressed. The most common genetic alterations involved 1p (39%), 22q (36%), 2q (29%), 1q (25%), 13q (21%), and 14q (21%). Hierarchical clustering analysis of recurrent aberrations revealed three molecular groups: Groups 1 (29%) and 2 (18%) with associated del(22q), and Group 3 (18%) with del(10q). The remaining IVL had nonspecific or no alterations by aCGH. Genomic index scores were calculated for all cases and showed no significant difference between the 14 IVL associated with aggressive clinical behavior (extrauterine extension or recurrence) and those without (median scores 5.15 vs 3.5). Among the 5 IVL associated with recurrence, 4 had a vascular morphology and 3 had alterations of 8q. Recurrent chromosome alterations detected herein overlap with those observed in the spectrum of uterine smooth muscle tumors and involve genes implicated in mesenchymal tumors at different sites with distinct morphological features.

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.

Low-stage, low-grade endometrioid endometrial carcinoma (EEC), the most common histologic type of endometrial cancer, typically has a favorable prognosis. A subset of these cancers, however, displays an aggressive clinical course with early recurrences, including distant relapses. All statistical tests were 2-sided. Using a combination of whole-exome and targeted capture sequencing of 65 FIGO stage IA and IB grade 1 EECs treated with surgery alone, we demonstrate that chromosome 1q gain (odds ratio [OR] = 8.09, 95% confidence interval [CI] = 1.59 to 54.6; P = .02), PIK3CA mutation (OR = 9.16, 95% CI = 1.95 to 61.8; P = .01), and DNA mismatch repair-deficient molecular subtype (OR = 7.92, 95% CI = 1.44 to 87.6; P = .02) are independent predictors of early recurrences within 3 years in this patient population. Chromosome 1q gain was validated in an independent dataset of stage I grade 1 EECs subjected to whole-exome sequencing. Our findings expand on the repertoire of genomic parameters that should be considered in the evaluation of patients with low-stage, low-grade EEC.

Background Erythropoiesis‐stimulating agents effectively improve the hemoglobin levels in a fraction of anemic patients with myelodysplastic syndromes (MDS). Higher doses (HD) of recombinant human erythropoietin (rhEPO) have been proposed to overcome suboptimal response rates observed in MDS patients treated with lower “standard doses” (SD) of rhEPO. However, a direct comparison between the different doses of rhEPO is lacking. Methods A cohort of 104 MDS patients treated with HD was retrospectively compared to 208 patients treated with SD in a propensity score‐matched analysis to evaluate hematological improvement‐erythroid (HI‐E) rate induced by the different doses of rhEPO. The impact of rhEPO doses on survival and progression to leukemia was also investigated. Results Overall HI‐E rate was 52.6%. No difference was observed between different rhEPO doses (P = .28) in matched cohorts; in a subgroup analysis, transfusion‐dependent patients and patients with higher IPSS‐R score obtained a higher HI‐E rate with HD, although without significant impact on overall survival (OS). Achievement of HI‐E resulted in superior OS. At univariate analysis, a higher HI‐E rate was observed in transfusion‐independent patients (P, When compared in a propensity‐score matched analysis, standard doses of rhEPO showed similar effects to those of higher doses in anemic MDS patients. Achievement of favorable response with hematologic improvement in this clinical scenario is possible by reducing drug doses and costs.