Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied ...carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP.
GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m
and cisplatin 50 mg/m
(day 1), followed by paclitaxel 160 mg/m
(day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m
and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints.
From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37
41 months, respectively; hazard ratio HR, 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13
14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC (
= .40). More grade ≥ 3 thrombocytopenia (23%
12%), vomiting (7%
4%), diarrhea (6%
2%), and metabolic (14%
8%) toxicities were reported with TAP. Neutropenia (52%
80%) was more common with TC. Small HRQoL differences favored TC.
With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.
The optimal staging of tumors would reflect their biology and patterns of spread, permit accurate prognostication, and facilitate therapeutic decision-making. The last revision of the International ...Federation of Obstetricians and Gynecologists (FIGO) staging of uterine corpus tumors was in 1988, and it represented the transition from a clinical to a surgico-pathologic system. With 20 years of experience, we can now review the accuracy, reproducibility, and utility of this system. Pathologists are in a unique position to study each of these characteristics, comment on their ability to apply the criteria in daily practice, and offer suggestions to further improve the FIGO system. This paper selectively reviews some of the more problematic aspects of the current FIGO system, including the following: the distinction of tumors confined to the endometrium from those which are superficially myoinvasive; the method and utility of histologic grading of endometrial adenocarcinoma; the utility and reproducibility of the diagnosis of cervical epithelial and stromal invasion; the striking heterogeneity within and among stage III A, B, and C tumors and their differing prognostic significance. It concludes with recommendations for changes in a future revision of the FIGO staging of endometrial carcinoma.
The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with ...immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS.
ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women.
Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years.
Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.
Although most of Dr Scully's research addressed diseases of the ovary, about 10% of his published manuscripts focused on endometrial lesions, most often consisting of observations about unusual types ...or deceptive patterns of endometrial carcinoma that had not previously been described, or lesions for which the behavior had been unknown. He characterized and clarified the entity of clear cell carcinoma of the endometrium, and wrote about endometrial carcinomas with argyrophil, oxyphil, and giant cells, and those simulating microglandular hyperplasia of the cervix, as well as uterine papillary serous, squamous cell, and small cell carcinoma,. He provided a useful classification of precancers of the endometrium and also emphasized the relationship between estrogens and the development of some forms of uterine carcinoma. This article addresses the importance of his careful observations, focusing primarily on the potential relationship of 1 pattern of endometrial carcinoma that he described which has areas of microcystic, elongated, fragmented glands (MELF), frequently accompanied by a fibromyxoid or inflammatory stroma, to the recently described concept of epithelial mesenchymal transition. Endometrioid carcinomas with MELF frequently display a variety of immunohistochemical changes including reduced expression of E-cadherin, B-catenin, estrogen and progesterone receptors, Ki67, and overexpression of fascin, galactin-3, cyclin D1, and p16, as might be expected with epithelial mesenchymal transition. Additional studies will be needed to explain the significance of epithelial mesenchymal transition that occurs in carcinomas with regions of MELF.
The International Federation of Gynecology and Obstetrics (FIGO) staging of tumours of the uterine corpus, cervix and vulva was revised in 2009. The greatest impact of the revised staging was on ...carcinomas of the uterine corpus. Uterine sarcomas are now staged separately. Changes to the staging system for vulvar carcinomas largely reflect the significance of lymph node status. Only minor amendments have been introduced for cervical carcinomas, which remain the only gynaecological tumours to be staged clinically. These revisions, based on recent evidence, require careful, more detailed assessment of several histological parameters at each anatomical site. The present review deals with the evidence and rationale underpinning the revisions, and includes practical guidance on tumour staging. This covers the assessment and measurement of myoinvasion and evaluation of cervical, parametrial, serosal and vaginal involvement in carcinomas of the uterine corpus; the identification and accurate measurement of stromal invasion in cervical and vulvar carcinomas; the assessment of unusual variants of carcinoma at each of these sites; and the assessment of lymph node involvement.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects ...to determine if MMR status is prognostic or predictive.
Primary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, probable mutation (MMR defect not attributable to MLH1 methylation), or MSI-low. The relationships between MMR classes and clinicopathologic variables were assessed using contingency table tests and Cox proportional hazard models.
A total of 1,024 tumors were assigned to MMR classes. Epigenetic and probable mutations in MMR were significantly associated with higher grade and more frequent lymphovascular space invasion. Epigenetic defects were more common in patients with higher International Federation of Gynecology and Obstetrics stage. Overall, there were no differences in outcomes. Progression-free survival was, however, worse for women whose tumors had epigenetic MMR defects compared with the MMR normal group (hazard ratio, 1.37; P < .05; 95% CI, 1.00 to 1.86). An exploratory analysis of interaction between MMR status and adjuvant therapy showed a trend toward improved progression-free survival for probable MMR mutation cases.
MMR defects in EECs are associated with a number of well-established poor prognostic indicators. Women with tumors that had MMR defects were likely to have higher-grade cancers and more frequent lymphovascular space invasion. Surprisingly, outcomes in these patients were similar to patients with MMR normal tumors, suggesting that MMR defects may counteract the effects of negative prognostic factors. Altered immune surveillance of MMR-deficient tumors, and other host/tumor interactions, is likely to determine outcomes for patients with MMR-deficient tumors.
Abstract Objective To report clinical and pathologic relationships with disease spread in endometrial cancer patients. Methods Surgical candidates with uterine cancer (adenocarcinoma or ...carcinosarcoma) who were eligible to participate in a surgical pathological study to create a clinically annotated tissue biorepository to support translational and clinical research studies. All patients were to undergo a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. From 2003–2007, open eligibility enrollment was conducted, and from 2007–2011, eligibility was restricted to enrich underrepresented patients or those at high risk. Results This report details clinical pathological relationships associated with extra uterine disease spread of 5866 evaluable patients including those with endometrioid histology as well as papillary serous, clear cell and carcinosarcoma histologies. Review of unrestricted enrollment was constructed in an effort to capture a cross-section population representative of endometrial cancers seen by the GOG participating members. Evaluation of this group of patients suggested the more natural incidence of different surgical pathological findings as well as demographic information. The addition of 2151 patients enrolled during the restricted time interval allowed a total of 1630 poor histotype patients available for further analysis. As expected, endometrioid (E) cancers represented the largest enrollment and particularly E grade 1 and 2 (G1 and 2) were more frequently confined to the uterus. Grade 3 (G3) endometrioid cancers as well as the poor histotype (papillary serous, clear cell and carcinosarcoma) had a much greater propensity for extant disease. Conclusions This study confirms the previously reported surgical pathological findings for endometrioid cancers but in addition, using a large database of papillary serous, clear cell and carcinosarcoma, surgical pathological findings substantiate the categorization of poor histotypes for these cancers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To investigate, in a phase III randomized trial, whether postoperative external-beam irradiation to the standard pelvic field improves the recurrence-free interval and overall survival (OS) in women ...with Stage IB cervical cancers with negative lymph nodes and certain poor prognostic features treated by radical hysterectomy and pelvic lymphadenectomy.
Eligible patients had Stage IB cervical cancer with negative lymph nodes but with 2 or more of the following features: more than one third (deep) stromal invasion, capillary lymphatic space involvement, and tumor diameter of 4 cm or more. The study group included 277 patients: 137 randomized to pelvic irradiation (RT) and 140 randomized to observation (OBS). The planned pelvic dose was from 46 Gy in 23 fractions to 50.4 Gy in 28 fractions.
Of the 67 recurrences, 24 were in the RT arm and 43 were in the OBS arm. The RT arm showed a statistically significant (46%) reduction in risk of recurrence (hazard ratio HR = 0.54, 90% confidence interval CI = 0.35 to 0.81, p = 0.007) and a statistically significant reduction in risk of progression or death (HR = 0.58, 90% CI = 0.40 to 0.85, p = 0.009). With RT, 8.8% of patients (3 of 34) with adenosquamous or adenocarcinoma tumors recurred vs. 44.0% (11 of 25) in OBS. Fewer recurrences were seen with RT in patients with adenocarcinoma or adenosquamous histologies relative to others (HR for RT by histology interaction = 0.23, 90% CI = 0.07 to 0.74, p = 0.019). After an extensive follow-up period, 67 deaths have occurred: 27 RT patients and 40 OBS patients. The improvement in overall survival (HR = 0.70, 90% CI = 0.45 to 1.05, p = 0.074) with RT did not reach statistical significance.
Pelvic radiotherapy after radical surgery significantly reduces the risk of recurrence and prolongs progression-free survival in women with Stage IB cervical cancer. RT appears to be particularly beneficial for patients with adenocarcinoma or adenosquamous histologies. Circumstances that may have influenced the overall survival differences are considered.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome ...screening and molecular risk stratification.
Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods.
Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53–3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10–7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04–4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status.
A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system.
•Molecular classification of endometrioid endometrial cancers identifies cases at increased risk for recurrence.•Women whose tumors have copy number alterations have reduced progression-free and cancer-specific survival.•~8% of endometrioid endometrial cancers are copy number altered, the majority of which are low grade, low stage cases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The terminology for human papillomavirus (HPV)-associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It ...often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) project was co-sponsored by the College of American Pathologists (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) and included 5 working groups; three work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted upon at the consensus meeting. The final approved recommendations standardize biologically-relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.
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