Clinical and genomic landscape of RAS mutations in gynecologic cancers.

BACKGROUND: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications. METHODS: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by Kaplan-Meier method, and multivariable analysis was performed using Cox proportional-hazards model. RESULTS: Of 3328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs 60 years non-mutated), had higher prevalence of endometriosis (27.3% vs 16.9%), and lower grades (grade 1/2, 43.2% vs 8.1%, all p<0.0001). Highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n=9/9), mesonephric-like ovarian (83.3%, n=5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival (HR=1.3, p=0.001). Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN(28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS+MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy (8.4 years [95%CI 5.5-12.0] vs 5.5 years [95%CI 4.6-6.6], HR=0.67, p=0.031), this effect did not persist in multivariable analysis. CONCLUSION: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.

Extrauterine Mesonephric-like Carcinoma: A Comprehensive Single Institution Study of 33 Cases.

Extrauterine mesonephric-like carcinoma (ExUMLC) shares histologic, immunohistochemical (IHC), and molecular (MOL) features with endometrial mesonephric-like carcinoma (EnMLC). Its rarity and histologic overlap with Mullerian carcinomas contribute to underrecognition of ExUMLC. Aggressive behavior of EnMLC is well-documented; behavior of ExUMLC is yet to be characterized. This study presents the clinicopathologic, IHC, and MOL features of 33 ExUMLC identified over a 20-year time period (2002-2022) and compares the behavior of this cohort to more common upper gynecologic Mullerian carcinomas (low-grade endometrioid, LGEC; clear cell, CCC; high-grade serous, HGSC) and EnMLC diagnosed over the same time period. ExUMLC patients ranged from 37 to 74 years old (median=59 y); 13 presented with advanced stage (FIGO III/IV) disease. Most ExUMLC had the characteristic mixture of architectural patterns and cytologic features, as previously described. Two ExUMLC had sarcomatous differentiation, 1 with heterologous rhabdomyosarcoma. Twenty-one ExUMLC (63%) had associated endometriosis, and 7 (21%) arose in a borderline tumor. In 14 (42%) cases, ExUMLC was part of a mixed carcinoma representing >50% of the tumor in 12. Twenty-six cases (79%) were incorrectly classified as follows: LGEC or HGEC (12); adenocarcinoma, not otherwise specified (3); HGSC (3); LGSC (2); mixed carcinoma (1); carcinosarcoma, Mullerian type (2); seromucinous carcinoma (1); transitional pattern of HGSC (1); and female adnexal tumor of probable Wolffian origin (1). Three patients had occult synchronous endometrial LGEC. IHC facilitated diagnosis in all cases with an expression of GATA-3 and/or TTF-1 in conjunction with decreased hormone receptor expression in most tumors. MOL testing (n=20) identified a variety of mutations, most frequently: KRAS (15); TP53 (4); SPOP (4); and PIK3CA (4). ExUMLC and CCC were more likely to be associated with endometriosis ( P <0.0001). ExUMLC and HGSC had more recurrences compared with CCC and LGEC ( P <0.0001). Histologic subtype was associated with longer disease-free survival for LGEC and CCC versus HGSC and ExUMLC ( P <0.001). ExUMLC trended towards a similar poor overall survival as HGSC compared with LGEC and CCC, and EnMLC trended to shorter survival compared with ExUMLC. Neither finding reached significance. No differences were seen between EnMLC and ExUMLC with respect to presenting stage or recurrence. Staging, histotype, and endometriosis were associated with disease-free survival, but on multivariate analysis, only stage remained as an independent predictor of outcome. The tendency of ExUMLC to present at an advanced stage and have distant recurrence points to more aggressive behavior compared with LGEC with which it is most frequently confused, underscoring the importance of an accurate diagnosis.

SOX17: A Highly Sensitive and Specific Immunomarker for Ovarian and Endometrial Carcinomas.

PAX8 is the most commonly used immunomarker to link a carcinoma to the gynecologic tract; however, it lacks specificity. Through mining The Cancer Genome Atlas mRNA expression profile data, we identified SOX17 as a potential specific marker at the mRNA level for gynecologic tumors. To evaluate the utility of this marker in the identification of the gynecologic origin of a given carcinoma, we performed immunochemical staining in a large cohort of ovarian and endometrial cancer cases (n = 416), together with a large cohort of solid tumors from other organs (n = 1544) in tissue microarrays. Similar to PAX8, SOX17 was highly expressed in different subtypes of ovarian carcinoma (97.5% for SOX17 vs 97% for PAX8 in serous carcinoma, 90% vs 90% in endometrioid carcinoma, and 100% vs 100% in clear cell carcinoma), except for mucinous carcinoma (0% vs 27%), and was also highly expressed in different subtypes of endometrial carcinoma (88% vs 84% in endometrioid carcinoma, 100% vs 100% in serous and clear cell carcinoma). SOX17 was not expressed in thyroid and renal cell carcinomas, whereas PAX8 expression was high (86% and 85%, respectively). In addition, SOX17 was expressed at low levels in cervical adenocarcinoma (20%) and had no expression in cervical squamous carcinoma, mesothelioma, and carcinomas from the breast, lung, pancreas, colon, stomach, liver, bladder, and salivary gland. Our data indicate that SOX17 is not only a sensitive but also a specific marker for the origin of ovarian and endometrial carcinomas.

Localized Malignant Peritoneal Mesothelioma (LMPeM) in Women: A Clinicopathologic Study of 18 Cases.

Localized malignant peritoneal mesothelioma is a rare tumor with limited information in the literature. In this study, we present our experience with 18 cases seen in our hospital over a period of 43 years (1978 to 2021). Patients' median age was 55 years (y) (range: 33 to 79 y) and most of them were Caucasians. Patients presented with abdominal pain (11), ascites and right leg swelling (1), abdominal mass (1), and as incidental finding (1). Thirty percent of patients reported asbestos exposure, and all patients with available information had family history of tumors; a third had personal history of tumors. Seventy-seven percent had some form of abdominopelvic surgery and/or inflammatory process. Most cases had microscopic features typically seen in malignant mesothelioma; however, some cases had confounding features such as signet-ring cells, spindle cells, clear cell changes, and adenomatoid tumor-like appearance. BAP-1 by immunohistochemistry was lost in 1/3 cases. Only 1 patient underwent genetic testing and had an MSH2 germline mutation. Homozygous deletion of CDKN2A by FISH was not found in 1 tested case, although next-generation sequencing identified a CDKN2A pathogenic mutation. 16/18 (88%) had surgical treatment, and some also received adjuvant chemotherapy. The mean overall survival (OS) of our patients was 80.4 months (95% confidence interval: 54.3-106.52); the 3-year OS was 79%, while the 5-year OS was 52.6%. Fifty-three percent of patients had recurrences and 20% had tumor progression. Although the limited sample precludes definitive conclusions, small tumor size, low-grade cytology, and low mitotic index appeared to be associated with an indolent behavior.

Malignant Peritoneal Mesothelioma Associated With Endometriosis: A Clinicopathologic Study of 15 Cases.

Only a few cases of malignant peritoneal mesothelioma (MPeM) associated with endometriosis have been published; with chronic inflammation of the peritoneum associated with the latter being postulated as an inducing factor in the pathogenesis of this tumor. We assessed the clinicopathologic characteristics of MPeM associated with endometriosis to determine if there were other factors besides inflammation that may contribute to the pathogenesis in this patient population. Fifteen MPeM associated with endometriosis were retrieved from our files. Most presented with abdominal/pelvic pain, mass or distention; median age was 45 yr. Only 16% of patients had a history of asbestos exposure. In contrast, a third of the patients had a personal history of other neoplasms, and >80% had a family history of malignancies. Although most tumors had gross and microscopic features typical of MPeM, some had confounding features including "adhesion-like" appearance or gelatinous cysts/nodules, and signet ring cells. Tumors were epithelioid (9) and biphasic (6). MPeM was misdiagnosed as Müllerian carcinoma in 40% of cases. All patients (n=15) had cytoreductive surgery in addition to other therapies. Only 2/12 patients died of disease (17%). The 3- and 5-yr overall survival was 90%. MPeM associated with endometriosis tends to occur in patients with personal/familial history of malignancies, which may be a predisposing factor. In light of this finding, the role of endometriosis in the pathogenesis of MPeM is likely less relevant. The favorable outcome seen in these patients may be related to germline mutations or the hormonal milieu and needs further investigation.

Uterine Inflammatory Myofibroblastic Neoplasms With Aggressive Behavior, Including an Epithelioid Inflammatory Myofibroblastic Sarcoma: A Clinicopathologic Study of 9 Cases.

The experience with uterine inflammatory myofibroblastic neoplasms with an unfavorable outcome is limited. We present the clinicopathologic features of 9 such cases, including 8 inflammatory myofibroblastic tumors (IMTs) and 1 epithelioid inflammatory myofibroblastic sarcoma (EIMS). Median patient age for the IMT group was 50.5 years; the patient with EIMS was 43 years old. Patients presented with abnormal uterine bleeding, presumed fibroids, pelvic pain, arthralgia and low-grade fever, as well as an incidental finding. Median tumor size for the IMTs was 8.5 cm. The borders were either infiltrative or well-circumscribed. Histologically, IMTs were purely fascicular or myxoid or showed predominance of one or the other pattern. Seven tumors were spindled, and 1 was both spindled and epithelioid. Tumors had variable nuclear atypia, ranging from grade 1 to 3. All tumors had an inflammatory infiltrate-predominantly lymphocytic, majority had necrosis (62.5%) and none had lymphovascular invasion. 7/8 (87.5%) tumors were positive for ALK-1 by immunohistochemistry (IHC). One tumor was negative for ALK-1 by IHC but was positive for ALK fusion by fluorescence in situ hybridization and had TNS1-ALK fusion by next-generation sequencing (NGS). Three other tumors with NGS testing showed one of the following ALK-fusion partners: FN1, DCTN1, and IGFBP5. The EIMS had infiltrative borders, myxoid and hyalinized patterns, epithelioid cells, and no lymphovascular invasion. This tumor was ALK-1 positive by IHC, had ALK rearrangement by fluorescence in situ hybridization and RANBP2-ALK fusion by NGS. Extrauterine disease at time of diagnosis was noted in 2/8 (25%) of IMTs, and in the single case of EIMS. Seven patients had surgery as primary treatment, 1 patient had neoadjuvant chemotherapy and 1 patient declined treatment. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, radiotherapy or hormonal therapy. Most patients (71.4%) recurred within 24 months (mos). Two thirds of patients were alive with disease at last follow up (mean 43.6 mos). The patient with EIMS was alive with disease at 22 mos. IMT referral cases were initially diagnosed as smooth muscle tumors in 87.5% of cases; while the EIMS was diagnosed as high-grade endometrial stromal sarcoma. Lack of consideration of IMT in the differential diagnosis of smooth muscle tumors with myxoid features can result in misdiagnosis and under-utilization of targeted therapy in these patients.

TP53 variant allele frequency correlates with the chemotherapy response score in ovarian/fallopian tube/peritoneal high-grade serous carcinoma.

Molecular findings in ovarian, fallopian tube, and peritoneal high-grade serous carcinoma (HGSCa) are emerging as potential prognostic indicators. The chemotherapy response score (CRS) has been proposed as a histologic-based prognostic factor in patients with HGSCa treated with neoadjuvant chemotherapy (NACT). No study details the relationship between the mutational landscape of HGSCa and the CRS. This study addresses this issue using next-generation sequencing (NGS). We retrospectively identified 25 HGSCas treated with NACT and pathology material available to calculate the CRS. All cases had NGS on the primary debulking specimen post-NACT. The three-tier Böhm CRS was applied to the omentum or adnexa and calculated as a combined score. Tumor mutation burden (TMB) and TP53 variant allele frequency (VAF) were calculated and used in correlative analysis. All cases had at least one mutation, most commonly TP53 (25 cases, 100%). Other mutations were BRCA2 (one case, 4%), ARID1A (two cases, 8%), and 1 (4%) of each of the following: ERBB2, NTRK3, STK11, NTRK2, TSC1, PIK3CA, NF1, NOTCH3, CDK2, SMAD4, and PMS2. TMB ranged from 2.58 to 7.75 (median 3.84). There was no statistically significant relationship between the TMB and omental CRS, R-squared = 0.011 (P = 0.62); adnexal CRS, R-squared = 0.005 (P = 0.74); or with the combined CRS, R-squared = 0.009 (P = 0.65). Statistically significant correlation was found between the TP53 VAF and the omental CRS (R-squared = 0.28, P = 0.007), adnexal CRS (R-squared = 0.26, P = 0.01), and the combined CRS (R-squared = 0.33, P = 0.0026). The TP53 VAF was adjusted for percent of tumor present on the slide resulting in an average per cell TP53 mutational load, resulting in similar results with a statistically significant correlation between the average per cell TP53 mutational load and the omental CRS (R-squared = 0.27, P = 0.02), adnexal CRS (R-squared = 0.16, P = 0.05), and the combined CRS (R-squared = 0.23, P = 0.02). In summary, NGS confirmed TP53 mutations in all cases of HGSCa. TMB showed no correlation with the CRS. TP53 VAF and average per cell TP53 mutational load showed significant correlation with the CRS, whether graded on the adnexa or omentum or as a combined score, indicating concordance between molecular and histological findings following NACT.

Reproducibility of scoring criteria for HER2 immunohistochemistry in endometrial serous carcinoma: a multi-institutional interobserver agreement study.

Targeted anti-human epidermal growth factor receptor 2 (HER2) therapy has recently been proven to improve progression-free and overall survival of patients with advanced stage or recurrent endometrial serous carcinoma. To date, no specific pathology HER2 testing or scoring guidelines exist for endometrial cancer. However, based on evidence from the recent successful clinical trial and comprehensive pre-trial pathologic studies, a new set of HER2 scoring criteria have been proposed for endometrial serous carcinoma-distinct from the existing breast and gastric cancer-specific criteria. We present the first study assessing interobserver agreement of HER2 scores using the proposed serous endometrial cancer-specific scoring system. A digitally scanned set of 40 HER2-immunostained slides of endometrial serous carcinoma were sent to seven gynecologic pathologists, who independently assigned HER2 scores for each slide following a brief tutorial. Follow-up fluorescent in situ hybridization (FISH) for HER2 gene amplification was performed on cases with interobserver disagreement when a 2+ HER2 score was assigned by at least one observer. Complete agreement of HER2 scores among all 7 observers was achieved on 15 cases, and all but one case had an agreement by at least 4 observers. The overall agreement was 72.3% (kappa 0.60), 77.5% (kappa 0.65), and 83.3% (kappa 0.65), using four (0 to 3+ ), three (0/1+ , 2+ , 3+ ), or two (0/1+ , 2/3+ ) HER2 scoring categories, respectively. Based on the combination of HER2 immunostaining scores and FISH, the interobserver disagreement may have potentially resulted in a clinically significant difference in HER2 status only in three tumors. We conclude, that the proposed serous endometrial cancer-specific HER2 scoring criteria are reproducible among gynecologic pathologists with moderate to substantial interobserver agreement rates comparable to those of previously reported in breast and gastric carcinomas. Our findings significantly strengthen the foundation for establishing endometrial cancer-specific HER2 scoring guidelines in the future.

Immunohistochemical Loss of DPC4 in Tumors With Mucinous Differentiation Arising in or Involving the Gynecologic Tract.

DPC4 immunohistochemistry (IHC) is usually part of the work-up of mucinous neoplasms in the ovary where the distinction between an ovarian primary and metastatic pancreaticobiliary adenocarcinoma (PanACa) must be made. Although DPC4 IHC is lost in about 55% (46%-61%) of PanACas and typically retained in most primary ovarian mucinous neoplasms, no study has evaluated the expression of this marker in a large cohort of neoplasms arising in or involving gynecologic (GYN) organs. In this study, we retrospectively analyzed the expression of DPC4 IHC in a total of 251 tumors and lesions related to the GYN tract in which DPC4 IHC stain was performed during the initial pathology evaluation. Of these, 138 were primary GYN tumors and lesions, 31 were metastatic GYN tumors involving non-GYN sites, and 83 were metastatic non-GYN tumors involving the GYN tract. We identified 27 cases with loss of DPC4 IHC expression of which 20 cases met the inclusion criteria (i.e. clinical information was available to determine the site of tumor origin). We observed that loss of DPC4 nuclear expression was most commonly seen in tumors of endocervical origin (n=7), of which 5 were gastric-type cervical adenocarcinomas (GCxACa) and 2 were usual-type cervical adenocarcinomas, either primary or metastatic. This was followed by tumors of the pancreaticobiliary tract (n=5), ovary (n=2), and appendix (n=1). In addition, 1 gastric-type vaginal adenocarcinoma (GVaACa) also showed loss of DPC4. Our findings indicate that in female patients with mucinous neoplasms involving the ovary or other sites, with loss of DPC4 by IHC, and negative pancreaticobiliary imaging, the possibility of an occult GCx/GVaACa, and rarely an ovarian primary must be considered.

Malignant Mesothelioma of the Peritoneum in Women: A Clinicopathologic Study of 164 Cases.

Malignant mesothelioma of the peritoneum in women is an uncommon tumor. In this study, we present the clinicopathologic features of 164 such cases seen in our institution over a period of 42 years (1974-2016). Clinical information, pathologic findings, immunohistochemical results, and follow-up were recorded. Hematoxylin and eosin-stained slides were reviewed in all cases. Patients ranged in age from 3 to 85 years, median: 49 years. Most patients presented with abdominal/pelvic pain, although some were asymptomatic, presented with paraneoplastic syndromes or cervical lymphadenopathy. Overall, 9% of patients had a history of direct or indirect exposure to asbestos. In total, 31% and 69% of patients had either a personal or family history of other tumors; most of these tumors are currently recognized as part of a syndrome. Genetic testing information was available in 5 patients: BAP-1 germline mutation (1), type 2 neurofibromatosis (1), Lynch syndrome (1), McCune-Albright syndrome (1), no BAP-1 or TP53 mutation (1). Most cases had gross and microscopic features typical of malignant mesothelioma of the peritoneum in women; however, some had confounding features such as gelatinous appearance, signet ring or clear cells, and well-differentiated papillary mesothelioma-like areas. Calretinin and WT-1 were the markers more frequently expressed, and up to 23% of the cases showed PAX-8 expression. Patients' treatments predominantly included: chemotherapy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. On multivariate analysis, the predominance of deciduoid cells, nuclear grade 3, and the absence of surgical treatment were associated with worse overall survival (OS). For all patients, the 3- and 5-year OS were 74.3% and 57.4%, respectively. The 3- and 5-year OS for patients treated with cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy were 88.9% and 77.8%, respectively.

High-grade Neuroendocrine Carcinomas of the Vulva: A Clinicopathologic Study of 16 Cases.

Vulvar high-grade neuroendocrine carcinomas (HGNECs) are rare and primarily thought to represent Merkel cell carcinoma (MCC). We present the clinicopathologic features of 16 such cases, the largest series to date. Patients were most often White, postmenopausal, and symptomatic from a palpable vulvar mass/nodule. Tumors ranged from 0.7 to 6 cm and most commonly involved the labium majus. Majority of the cases were pure HGNECs (15/16) with small cell (SC) morphology (14/16); 2 were large cell neuroendocrine carcinomas, of which 1 was combined with moderately differentiated adenocarcinoma. All tumors expressed synaptophysin. Of the 14 HGNECs with SC morphology, 6 were CK20-positive MCCs with characteristic CAM5.2 and neurofilament (NF) expression. Five of these MCCs were positive for Merkel cell polyoma virus large T-antigen (MCPyVLTAg). In contrast, 6 HGNECs with SC morphology were negative for CK20, NF, and MCPyVLTAg and classified as SCNECs. High-risk human papilloma virus was positive in all SCNECs and negative in all MCCs. One case of HGNEC with SC morphology could not be entirely characterized due to lack of tissue for ancillary testing. Five of 12 (42%) cases had a discrepant diagnosis initially rendered. Most patients (10/15) presented with International Federation of Gynecology and Obstetrics stage III or IV disease. Usual sites of metastasis included inguinal lymph node, liver, bone, and lung. Twelve patients underwent surgery with adjuvant chemotherapy and/or radiation therapy, 1 received adjuvant immunotherapy, and 1 patient received neoadjuvant chemotherapy followed by surgery and adjuvant radiation therapy. Median overall survival was 24 months (range: 7 to 103 mo), and overall 5-year survival was 12% (95% confidence interval: 1% to 39%). In summary, vulvar HGNECs are rare, aggressive neoplasms that can be further subclassified into MCC, SCNEC, and large cell neuroendocrine carcinoma. CK20, CAM5.2, NF, TTF-1, MCPyVLTAg, and high-risk human papilloma virus facilitate the distinction of MCC from SCNEC. Proper identification of vulvar HGNECs is critical for patient management.

Prophylactic Risk-reducing Hysterectomies and Bilateral Salpingo-oophorectomies in Patients With Lynch Syndrome: A Clinicopathologic Study of 29 Cases and Review of the Literature.

Lynch syndrome (LS) is associated with an increased risk for colorectal, endometrial, and ovarian carcinomas in women. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy (RRHSO) has been shown to be a cost-effective form of management and prevention of gynecological malignancies in patients with LS. Studies of incidental gynecologic malignancies identified in RRHSO are limited. In addition, recommendations on optimal handling of this type of specimen have ranged from submitting for microscopic examination the entire endometrium, fallopian tubes and ovaries to submitting only routine representative sections of these organs. In this study, we present the clinicopathologic findings of 29 cases of LS patients that underwent risk-reducing gynecologic surgery at our institution over a period of 13 yr. Clinical-pathologic information was obtained from the patients' charts and pathology reports. Significant pathologic abnormalities were identified in 17% (5/29) of cases, all showing endometrial hyperplasia. Four of them with atypical and 1 without atypical. All of our cases with endometrial pathology had significant findings on preoperative endometrial sampling. To further study the recommendation of in toto submission of the endometrium, ovaries and fallopian tubes and the utility of preoperative endometrial sampling, we undertook a literature review of all the reported cases of incidental pathologic findings identified in RRHSO. The findings of our cohort and the literature reviewed support in toto submission of endometrium, and adnexal structures in the absence of gross lesions. In addition, our findings show a definite benefit for preoperative endometrial sampling as part of the workup for LS patients undergoing RRHSO.

Gynaecological malignancies and sentinel lymph node mapping: an update.

Assessment of pelvic, para-aortic or inguinal lymph nodes (LNs) provides not only important prognostic information, but also determines the need for adjuvant treatment. Sentinel lymph node (SLN) biopsy has the potential to provide this prognostic information, while reducing morbidity compared with extended LN dissection. This review discusses the clinical and pathological aspects of SLN biopsy in gynaecological cancer.

A 3-Tier Chemotherapy Response Score for Ovarian/Fallopian Tube/Peritoneal High-grade Serous Carcinoma: Is it Clinically Relevant?

The chemotherapy response score (CRS) is used to score histopathologic response to neoadjuvant chemotherapy (NACT) of patients with extrauterine high-grade serous carcinoma. This study was undertaken to determine if the CRS in the omentum, adnexa or when combined correlates with (1) progression-free survival (PFS) or overall survival (OS), (2) laparoscopic score of abdominal disease, (3) Cancer antigen 125 levels, (4) BRCA status, and (5) platinum-resistant disease. A total of 158 cases were retrospectively collected that received NACT between April 2013 and February 2018 at a single institution. The 3-tier Böhm CRS system was applied to the omentum and adnexa. Survival outcomes between scored subgroups were analyzed using Cox proportional hazards regression. Spearman rank correlation analyses were used to assess CRS and clinical data. A total of 119 cases were treated only with carboplatin/paclitaxel. Omental CRS was: 1 (23 cases, 19.3%), 2 (65 cases, 54.6%), and 3 (31 cases, 26.1%), whereas adnexal CRS was: 1 (50 cases, 42%), 2 (48 cases, 40.3%) and 3 (21 cases, 17.6%). The omental CRS was significantly associated with PFS as a 2-tier score (hazard ratio [HR]=0.612, 95% confidence interval [CI]: 0.378-0.989, P=0.045) but not associated with the PFS using the 3-tier score or with OS using either system. Adnexal CRS was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.49, 95% CI: 0.263-0.914, P=0.025) and 2-tier scores (HR=0.535, 95% CI: 0.297-0.963, P=0.037). The combined score was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.348, 95% CI: 0.137-0.88, P=0.026) and 2-tier scores (HR=0.364, 95% CI: 0.148-0.896, P=0.028). No CRS system used associated with laparoscopic assessment of disease. CRS in the omentum had no significant association with platinum resistance; however, the adnexal CRS 1/2 were 3 times as likely to develop platinum resistance compared with CRS 3 (relative risk=3.94, 95% CI: 1.03-15.09, P=0.046). The CRS, when used on the omentum, adnexa, and as a combined score, was significantly associated with PFS but not with OS. Adnexal CRS 1/2 are more likely to develop platinum-resistant disease. Therefore, the use of this pathology parameter may be useful for clinical management.

Mesonephric-like Carcinoma of the Endometrium: A Subset of Endometrial Carcinoma With an Aggressive Behavior.

Endometrial mesonephric-like carcinomas (MLCa) are uncommon with <50 reported cases thus far. Previous studies have characterized the histologic, immunohistochemical, and molecular features of MLCa; however, there is limited information with respect to outcome. This single-institution study of 23 uterine MLCas characterizes the behavior of such a neoplasm. Uterine MLCas (2004-present) had review of histologic features, immunohistochemical results, molecular profile, and clinical information (stage, treatment, follow-up). The behavior of MLCa was compared with low-grade endometrioid carcinomas (ECas) and uterine serous carcinomas (USCs) treated at our institution from 2004 to present. All MLCas had a mixture of previously described architectural and cytologic features most notably ductal and/or tubular architecture (21/23), nuclei resembling those of papillary thyroid carcinoma (18/23), and at least focal intraluminal eosinophilic secretions (20/23). Immunoperoxidase studies facilitated diagnosis in 22 cases: CD10, 10/10; calretinin, 5/15; estrogen receptor (≥10% nuclei), 6/21; progesterone receptor, 1/15; GATA-3, 15/16; TTF-1, 11/16. Fourteen of 17 tested cases had a KRAS mutation (7 as the only alteration; 7 with additional mutations including PIK [n=5]; PTEN [n=2], CTNNB1 [n=1]).One case had mutations in PTEN, PIK, and CTNNB1 without KRAS; 2 cases had no detectable somatic mutation. Overall, 48% of patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage 3 or 4 disease with the following uterine risk factors: >50% myometrial invasion, 20/23; lymphovascular space invasion, 16/23; cervical stromal invasion, 7/23. Twenty patients had adjuvant therapy (7 radiation only; 13 chemotherapy±radiation), whereas 3 patients had either unknown or declined therapy. Follow-up was known for 21 patients: 17 patients had recurrences or never achieved remission with the lung being the most common recurrence site (n=9); 7 patients died of disease. The median progression-free survival was 18.2 months for MLCa compared with 183 months for ECa and 67.1 months for USC. The median overall survival for MLCa was 70.6 months compared with 139.1 months for USC (median survival for ECa not reached). Uterine MLCa is uncommon with most tumors recognized by architectural heterogeneity, vesicular, overlapping nuclei with grooves, and eosinophilic luminal secretions. The typical immunoprofile includes low to absent expression of hormone receptors but at least focal expression of GATA-3 and/or TTF-1. Most tested cases had a KRAS mutation although genetic mutations typically associated with ECa are not uncommon. Compared with more commonly encountered types of ECa, MLCa is more aggressive with a tendency towards earlier and distant recurrence.

Germ Cell Tumors of the Female Genital Tract.

Ovarian germ cell tumors are a histologically diverse group of neoplasms with a common origin in the primitive germ cell. The vast majority are represented by mature cystic teratoma. In the minority are malignant germ cell tumors including immature teratoma, dysgerminoma, yolk sac tumor, embryonal cell carcinoma, and choriocarcinoma. This article reviews the histologic and immunohistochemical features of the most common ovarian germ cell tumors. The differential diagnoses for each are discussed.

Endometrial Carcinoma, Grossing and Processing Issues: Recommendations of the International Society of Gynecologic Pathologists.

Endometrial cancer is the most common gynecologic neoplasm in developed countries; however, updated universal guidelines are currently not available to handle specimens obtained during the surgical treatment of patients affected by this disease. This article presents recommendations on how to gross and submit sections for microscopic examination of hysterectomy specimens and other tissues removed during the surgical management of endometrial cancer such as salpingo-oophorectomy, omentectomy, and lymph node dissection-including sentinel lymph nodes. In addition, the intraoperative assessment of some of these specimens is addressed. These recommendations are based on a review of the literature, grossing manuals from various institutions, and a collaborative effort by a subgroup of the Endometrial Cancer Task Force of the International Society of Gynecological Pathologists. The aim of these recommendations is to standardize the processing of endometrial cancer specimens which is vital for adequate pathological reporting and will ultimately improve our understanding of this disease.

Role of Radiation Therapy in the Multidisciplinary Management of Uterine Carcinosarcoma.

OBJECTIVES: This study aimed to evaluate the impact of radiation therapy on outcomes for patients with uterine carcinosarcoma (UC). METHODS/MATERIALS: We retrospectively reviewed the records of 155 women with stage I (98), II (11), or III (46) UC who underwent total abdominal hysterectomy/bilateral salpingo-oophorectomy at our institution between 1990 and 2011. Survival rates were assessed using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were performed. RESULTS: Seventy-six patients (49%) received radiation therapy: 38 (50%) had vaginal cuff brachytherapy (VBT) alone and 38 had external beam radiation therapy (EBRT) ± VBT. Seventy patients (45%) received chemotherapy (12 concurrent, 49 adjuvant, 9 both). The 5-year overall survival rate was 48.6% (stage I, 53.8%; II, 30.0%; and III, 42.5%). The disease-specific survival (DSS) rate was 57.2% (stage I, 60.9%; II, 44.4%; and III, 51.8%). Patients treated with EBRT had a higher 5-year pelvic disease control rate (88.3%) than did patients treated with VBT only (67.4%) or no radiation (71.2%; P = 0.04). In stage III patients, EBRT was associated with higher 5-year pelvic disease control (90.0% vs 55.5%, P = 0.046), DSS (64.6% vs 46.4%, P = 0.13), and overall survival (64.6% vs 34.0%, P = 0.04) rates. For all 155 patients, age at least 65 years, cervical involvement, and lymph vascular space invasion were correlated with lower DSS on univariate and multivariate analyses. In addition, treatment with concurrent chemoradiation therapy was independently associated with a higher DSS rate on multivariate analysis. CONCLUSIONS: Patients with UC have a high rate of relapse in the regional nodes and distant sites. External beam radiation therapy improves locoregional control in all stages and may improve survival in stage III patients who are at the highest risk of pelvic relapse.

Sensitivity and negative predictive value for sentinel lymph node biopsy in women with early-stage cervical cancer.

OBJECTIVE: The role of sentinel lymph node (SLN) biopsy alone for staging of early-stage cervical cancer remains controversial. We aimed to determine the validity of this technique in women with early-stage cervical cancer. METHODS: We retrospectively reviewed women with early-stage cervical cancer who underwent SLN mapping followed by complete pelvic lymphadenectomy as part of initial surgical management from August 1997 through October 2015. All modes of surgical approach were included. Lymphatic mapping was performed using blue dye, technetium-99m sulfur colloid (Tc-99), and/or indocyanine green (ICG). We determined SLN detection rates, sensitivity and negative predictive value. RESULTS: One hundred eighty-eight patients were included, and 35 (19%) had lymph node metastases. At least one SLN was identified in 170 patients (90%), and bilateral SLNs were identified in 117 patients (62%). The majority of SLNs (83%) were found in the pelvis. There was no difference in detection rates between mapping agents, surgical approach, patients with and without prior conization or between patients with tumors <2cm and ≥2cm. The detection rate for bilateral SLNs was significantly lower in women with body mass index (BMI)>30kg/m2 than in women with lower BMI (p=0.03). Metastatic disease in sentinel nodes was detected by H&E staining in 78% of cases and required ultrastaging/immunohistochemistry in 22% of cases. Only one patient had a false-negative result, yielding a sensitivity of 96.4% (95% CI 79.8%-99.8%) and negative predictive value of 99.3% (95% CI 95.6%-100%). The false-negative rate was 3.6%. CONCLUSIONS: In these women with early-stage cervical cancer, SLN biopsy had very high sensitivity and negative predictive value. We believe it is time to change the standard of care for women with early-stage cervical cancer to SLN biopsy only.

Unusual Presentations of Gynecologic Tumors: Extragonadal Yolk Sac Tumor of the Vulva.

Extragonadal germ cell tumors are uncommon, and although they morphologically resemble their gonadal counterparts, unexpected gonadal presentation increases the potential for erroneous diagnoses. Yolk sac tumor is a malignant germ cell tumor characterized by an extraembryonic yolk sac line of differentiation, and relative to other germ cell tumors, is characterized by varied and diverse histologic patterns. When occurring outside of typical age parameters or in extragonadal locations, the histologic variability of yolk sac tumor and its tendency to mimic somatic tumors pose diagnostic challenges. Because extragonadal yolk sac tumor of the vulva is very rare, with only isolated case reports and small series in the literature, it is often not considered in the differential diagnosis. As both prognosis and management of yolk sac tumor differ significantly from those of somatic tumors, accurate diagnosis is essential. This review discusses histologic features of extragonadal yolk sac tumor, addresses somatic tumors arising in the vulva for which yolk sac tumor may be confused, and provides guidance with respect to the use of immunohistochemistry in the diagnosis of yolk sac tumor.