Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta-analysis.

BACKGROUND: Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE-mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment. METHODS: A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one-stage meta-analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC). RESULTS: Three hundred fifty-nine women with POLE-mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47-7.58; log-rank P < .01). Except for stage (P < .01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease-specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5-14.2 years). Adjuvant treatment was not associated with outcome. CONCLUSIONS: Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de-escalating treatment for these patients. LAY SUMMARY: Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE). Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics. Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE-mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity. Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment.

Correction: TERT promoter mutation in adult granulosa cell tumor of the ovary.

The original version of this Article omitted the author Hannah van Meurs from the Department of Gynecology, Center for Gynecologic Oncology Amsterdam, Academic Medical Center, 1100 DD Amsterdam, The Netherlands. This has been corrected in both the PDF and HTML versions of the article.

ZC3H7B-BCOR-Rearranged Endometrial Stromal Sarcomas: A Distinct Subset Merits its Own Classification?

A 41-yr-old lady with abnormal uterine bleeding underwent total abdominal hysterectomy. Histologic assessment revealed an endometrial stromal sarcoma (ESS) with minimal cytologic atypia and low mitotic count (up to 7/10 high-power fields) with only focal myxoid areas, morphologically corresponding to a low-grade ESS. Immunohistochemical stains showed cyclin D1 and CD10 positivity, and negative staining for CD117 and progesterone receptor. This tumor was clinically aggressive and recurred 6 mo later. The patient died 19 mo following initial diagnosis. Molecular analysis revealed a ZC3H7B (exon 10)-BCOR (exon 7) gene fusion. Subsequent BCOR immunohistochemistry was weakly positive. ESS with ZC3H7B-BCOR gene fusion is classified as a low-grade ESS in some classification schemes, and is also characterized as being typically myxoid. This report supports emerging evidence that ESS with ZC3H7B-BCOR gene fusion may have an aggressive clinical course in spite of its low-grade histology. This report further expands the morphologic spectrum of ZC3H7B-BCOR fusion ESS to include nonmyxoid histology. Finally, this report underlines the value of molecular analysis in the proper classification of this aggressive tumor with deceptive low-grade histology.

TERT promoter mutation in adult granulosa cell tumor of the ovary.

The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERT to maintain telomere length and telomerase activity, which is a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified as gain-of-function mutations that promote transcriptional activation of TERT in multiple cancers, such as melanoma and glioblastoma. A recent study investigating TERT promoter mutations in ovarian carcinomas found C228T and C250T mutations in 15.9% of clear cell carcinomas. However, it is unknown whether these mutations are frequent in other ovarian cancer subtypes, in particular, sex cord-stromal tumors including adult granulosa cell tumors. We performed whole-genome sequencing on ten adult granulosa cell tumors with matched normal blood and identified a TERT C228T promoter mutation in 50% of tumors. We found that adult granulosa cell tumors with mutated TERT promoter have increased expression of TERT mRNA and exhibited significantly longer telomeres compared to those with wild-type TERT promoter. Extension cohort analysis using allelic discrimination revealed the TERT C228T mutation in 51 of 229 primary adult granulosa cell tumors (22%), 24 of 58 recurrent adult granulosa cell tumors (41%), and 1 of 22 other sex cord-stromal tumors (5%). There was a significant difference in overall survival between patients with TERT C228T promoter mutation in the primary tumors and those without it (p = 0.00253, log-rank test). In seven adult granulosa cell tumors, we found the TERT C228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggest that TERT C228T promoter mutations may have an important role in progression of adult granulosa cell tumors.

Mutation spectrum of POLE and POLD1 mutations in South East Asian women presenting with grade 3 endometrioid endometrial carcinomas.

OBJECTIVE: Somatic POLE mutations have been found in a subset of endometrioid ECs particularly in FIGO grade 3 tumors while POLD1 mutations are reportedly rare in ECs. While it has been suggested that POLE mutation confers good prognosis, the data remains conflicting. Our study aims to determine the mutation spectrum of somatic and germline POLE and POLD1 gene mutations in South East Asian (SEA) women with FIGO grade 3 endometrioid ECs. METHODS: Forty-seven patients diagnosed with FIGO grade 3 endometrioid EC, diagnosed between 2009 and 2013 were included. Next generation sequencing (NGS) using formalin fixed embedded (FFPE) tissue was utilized to sequence tumor and matched normal tissue. Tumors were also assessed for other clinicopathologic and microsatellite status phenotype. Survival curves for pathogenic somatic POLE mutated and wild-type tumors were estimated by Kaplan-Meier method. RESULTS: Pathogenic POLE (somatic or germline) and POLD1 (germline) mutations were detected in 29.7% (14/47) and 4.3% (2/47) patients, respectively. Three pathogenic germline mutations; one POLE and two POLD1 mutations were novel. Pathogenic germline and somatic POLE and POLD1 mutations were associated with 100% recurrence free survival. In contrast, among the wild-type POLE and POLD1 patients, 25% (8/32) had recurrence with 15.6% (5/32) subsequently dying of the disease. Somatic POLE-mutated tumors were more commonly associated with microsatellite stable (MSS) ECs (83% vs 49%; p=0.04) and peritumoral lymphocytic infiltration (75% vs 42%; p=0.05). All tumors with tumoral infiltrating lymphocytes exhibited peritumoral lymphocytic infiltrate but not vice versa. CONCLUSION: Mutations in POLE and POLD1 in SEA women with grade 3 endometrioid ECs are associated with improved recurrence free survival. Notably, germline mutations in either POLE/POLD1 were seen in 8.5% of patients who will require appropriate genetic counseling regarding risk of developing colorectal carcinoma and on the need for additional surveillance for colonic changes. MSS and peritumoral lymphocytic infiltration may be useful histological features for distinguishing POLE mutated grade 3 endometrioid ECs.

Virtual Remote Pathology Education in Support of Virtual Remote Gynecologic-Oncology Training: The Open Pathology Education Network Pilot Proof of Concept Experience.

CONTEXT.­: The subspecialty workforce in pathology globally is inadequate for the demands of many modern therapies. The Open Pathology Education Network (OPEN) was formed to augment the global pathology workforce. The International Gynecologic Cancer Society (IGCS) virtual gynecologic-oncology (gyn-onc) fellowship training identified needs for higher-level pathology support. OBJECTIVE.­: To report on an OPEN-IGCS pilot project to support gyn-onc and pathology education efforts in a developing country. DESIGN.­: Curriculum with learning objectives and content from open sources was assembled. Mentoring sessions included bidirectional case sharing. Trainees received sequential curricula assignments and had options for communication outside mentoring sessions. Pretest and posttest digital slide assessments were included. Mentors attended the gynecology tumor board, allowing for the assessment of quality and accuracy of pathology diagnosis for cases discussed. RESULTS.­: Learners completing the pretest and posttest showed substantial improvement, with 2 practicing pathologists improving their diagnostic scores from 60% to an average of 95%. A third trainee-level participant also improved, but to a lesser degree. Qualitative assessments included increased confidence in presentation and an increased ability to anticipate questions, raise issues of expanded differential diagnoses, and articulate appropriate workup. Observations of clinicians who participated also noted increased confidence in participating pathologists. Secondary value included establishing an expanded network of support in other subspecialties for participants. Pathologic issues at the tumor board decreased, from more than 50% in the first 3 months of study to 0% in the last 3 months of study. The curriculum was embedded into a self-paced learning portal at courses.open-pathology.org. CONCLUSIONS.­: The OPEN-IGCS collaboration model shows the potential to provide subspecialty pathology training remotely.

Yolk Sac Tumor of the Ovary: A Report of 150 Cases and Review of the Literature.

One hundred fifty yolk sac tumors (YSTs) of the ovary in patients from 1 to 61 (mean: 21.5) years of age are described; 75% of the patients were in the second and third decades and only 1 was above 50 years of age. The clinical manifestations were typically related to a fast-growing adnexal mass; endocrine manifestations (hirsutism) were present in only 2 cases. The tumors were all unilateral and 70% were ≥15 cm; an associated dermoid cyst was present in 20 cases. The tumors were solid and cystic in 57% of the cases, 25% were multicystic, and 18% uniformly solid. The solid tissue was typically tan to pink or yellow and often friable with hemorrhage and necrosis; smaller solid neoplasms were sometime uniformly yellow. The most common histologic pattern was reticular composed of an irregular meshwork of spaces that was conspicuous in 68% of the neoplasms but present to at least a minor degree in all of them. That appearance almost always merged with small to large cysts that were prominent in about 40% of tumors. In 25% of the tumors, cysts sometimes associated with a cellular stroma (the polyvesicular pattern), were present but conspicuous in only half these cases. One third of the tumors had a labyrinthine pattern, 22% glands, and 6% a festoon pattern. Papillae with a central blood vessel (Schiller-Duval bodies) were seen in one-third of the tumors but were numerous in only 5% of them. Nonspecific appearing papillae were seen in 10% of the tumors. A solid growth of cells with pale cytoplasm was seen in one-third of the tumors but was conspicuous in only half of that subset. The solid appearance was typically reminiscent of that of dysgerminoma, but lacked the septa and lymphocytic infiltrate of that neoplasm. Nine tumors had a component of cells with scant cytoplasm resulting in a blastema-like appearance and 3 had cells with abundant clear cytoplasm. Cords and clusters of cells were common but did not dominate the microscopic appearance. The stroma typically had a nonspecific collagenous to edematous appearance. Stromal luteinization was seen in 12 tumors; in 5 this was likely due to the patient being pregnant. Two tumors had minor foci of cells that resembled hepatocytes. Hyaline bodies were seen in most of the tumors and were often conspicuous. The neoplastic cells typically had modest amounts of lightly staining cytoplasm and only mild nuclear pleomorphism. Cells lining cysts were often flattened sometimes resulting in a deceptively innocuous appearance. Many of the tumors (mostly consultation cases), caused diagnostic difficulty; tumors in the differential diagnosis included clear cell carcinoma, embryonal carcinoma, Sertoli-Leydig cell tumor, and juvenile granulosa cell tumor. The patient age and marked elevation of the serum alpha-fetoprotein level (if measured) is helpful in many of these considerations. The overtly malignant gross appearance of most YSTs contrasts with certain other tumors in the differential and the association of some YSTs with dermoid cyst and many clear cell carcinomas with endometriosis may be helpful. The vast majority of ovarian YSTs are dominated microscopically by merging of reticular and cystic patterns which, although focally mimicked by other neoplasms, are in general characteristic, and distinctive features of other neoplasms are absent. Immunohistochemistry, particularly for alpha-fetoprotein and glypican 3, and lack of staining for various markers of other neoplasms is helpful but overlap exists and these results must be considered in the context of the overall clinical, gross, and microscopic features. YSTs dominated by hepatoid and glandular features are rare and their categorization as YSTs should be done cautiously if thoroughly sampled tumors show no evidence of classic features of YST emphasized herein and first elaborated by the Danish investigator Gunnar Teilum whose seminal observations have stood the test of time.

Determining the benefit of neoadjuvant chemotherapy in reduction of axillary dissection rates in Z0011 trial cohort with high nodal burden.

Background: In breast cancer patients fulfilling the Z0011 trial criteria, axillary lymph node dissection (ALND) is reserved for patients with a high nodal burden of ≥3 metastatic nodes. In this group of patients, to avoid an ALND, neoadjuvant chemotherapy (NACT) could be given instead to achieve nodal pathological complete response (pCR). However, the benefit of NACT in achieving nodal pCR and avoiding ALND in this group of patients is unknown. We aimed to determine the nodal pCR rate in this group of patients who otherwise would have needed an ALND. Methods: cT1-2N0 breast cancer patients, with histologically proven nodal metastasis, who underwent NACT were identified from a prospectively maintained database. The sonographic criteria of ≥3 abnormal nodes, which has been reported as highly predictive of high nodal burden, was then used to identify the high nodal burden group. Nodal pCR was determined based on the ALND following NACT. Results: Twenty-four patients with high nodal burden were identified. Mean age was 55.2 years. 91.7% had invasive ductal carcinoma and 29.2% had grade III cancer. 54.2% achieved nodal pCR which was associated with ypT (P=0.006). Nodal pCR was 75%, 70% and 30% in the triple negative, human epidermal growth factor receptor2 (HER2) positive and ER/PR+HER2- tumors, respectively. Conclusions: In the postulated T1-2 breast cancer patients with high nodal burden, needing an upfront ALND, NACT could result in nodal pCR of 54.2%, with higher pCR in certain subtypes. Hence, to minimize ALND risk, NACT should be offered in this high nodal burden group.

Morphologic and Molecular Heterogeneity of Cervical Neuroendocrine Neoplasia: A Report of 14 Cases.

Neuroendocrine neoplasms (NENs) of the cervix are rare aggressive tumors associated with poor prognosis and only limited treatment options. Although there is some literature on molecular underpinnings of cervical small cell neuroendocrine carcinomas (SCNECs), detailed morphologic and associated molecular characteristics of cervical NENs remains to be elucidated. Herein, 14 NENs (SCNEC: 6, large cell neuroendocrine carcinoma [LCNEC]: 6, neuroendocrine tumor [NET]: 2), including 5 admixed with human papillomavirus (HPV)-associated adenocarcinoma (carcinoma admixed with neuroendocrine carcinoma) were analyzed. All except 3 SCNECs were HPV16/18 positive. TP53 (3) and/or RB1 (4) alterations (3 concurrent) were only seen in SCNECs (4/6) and were enriched in the HPV16/18-negative tumors. The other most common molecular changes in neuroendocrine carcinomas (NECs) overlapping with those reported in the literature for cervical carcinomas involved PI3K/MAPK pathway (4) and MYC (4) and were seen in both SCNECs and LCNECs. In contrast, the 2 NETs lacked any significant alterations. Two LCNECs admixed with adenocarcinoma had enough material to sequence separately each component. In both pathogenic alterations were shared between the 2 components, including ERBB2 amplification in one and an MSH6 mutation with MYC amplification in the other. Overall, these findings suggest that cervical HPV-associated NETs are genomically silent and high-grade NECs (regardless of small or large cell morphology) share molecular pathways with common cervical carcinomas as it has been reported in the endometrium and are different from NECs at other sites. Molecular analysis of these highly malignant neoplasms might inform the clinical management for potential therapeutic targets.

Adult-type granulosa cell tumor of the ovary: a FOXL2-centric disease.

Adult-type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord-stromal tumors and 2-5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one-third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole-genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon-based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle-related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation.

Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a multisystem disorder caused by germline heterozygous NF1 loss-of-function variants. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein, which functions by down-regulating RAS/RAF/MAPK-signalling pathways. Somatic NF1 aberrations frequently occur in sporadic ovarian cancer (OC), but the incidence of OC in NF1 patients is rare. Here we report the germline and somatic findings for two unrelated patients with NF1 and high-grade serous OC. Germline testing revealed a heterozygous NF1 pathogenic variant in each patient, c.7096_7101del (p.Asn2366_Phe2367del) and c.964delA (p.Ile322Leufs*54), respectively. No germline variants in well-established OC predisposition genes were detected, including BRCA1 and BRCA2. Tumor loss-of-heterozygosity analysis demonstrated loss of the wild type NF1 allele for both patients. Biallelic NF1 inactivation occurs as part of OC pathogenesis in NF1 patients. Although the penetrance of NF1-associated OC is insufficient to warrant risk-reducing interventions, our findings highlight the potential for therapies targeting the RAS/RAF/MAPK-signalling pathway for these cases.

Relative Validity of the Eat and Track (EaT) Smartphone App for Collection of Dietary Intake Data in 18-to-30-Year Olds.

(1) Background: Smartphone dietary assessment apps can be acceptable and valid data collection methods but have predominantly been validated in highly educated women, and none specifically measured eating-out habits in young adults. (2) Methods: Participants recorded their food and beverage consumption for three days using the Eat and Track (EaT) app, and intakes were compared with three dietitian-administered 24-h recall interviews matched to the same days as the reference method. Wilcoxon signed-rank or t-tests, correlation coefficients and Bland⁻Altman plots assessed agreement between the two methods for energy and percentage energy from nutrients (%E). (3) Results: One hundred and eighty nine of 216 participants (54% females, 60% resided in higher socioeconomic areas, 49% university-educated) completed the study. There were significant differences in median energy intake between methods (p < 0.001), but the EaT app had acceptable agreement for most nutrient densities at the group level. Correlation coefficients ranged from r = 0.56 (%E fat) to 0.82 (%E sugars), and between 85% and 94% of participants were cross-classified into the same or adjacent quartiles. Bland⁻Altman plots showed wide limits of agreement but no obvious biases for nutrient densities except carbohydrate in males. (4) Conclusions: The EaT app can be used to assess group nutrient densities in a general population of 18-to-30-year olds.

Hereditary Syndromes Manifesting as Endometrial Carcinoma: How Can Pathological Features Aid Risk Assessment?

Endometrial carcinoma is the most common gynecological tumor worldwide. It can be the presenting malignancy, acting as the harbinger, of an undiagnosed hereditary syndrome. Up to 50% of females with Lynch syndrome present in this manner. Differentiation between Lynch, Muir-Torre, and Cowden syndromes can at times be challenging due to the overlapping features. Our review emphasizes on the strengths, pitfalls, and limitations of microscopic features as well as immunohistochemical and polymerase chain reaction- (PCR-) based tests used by laboratories to screen for DNA mismatch repair (MMR) and PTEN gene mutations in patients to enable a more targeted and cost effective approach in the use of confirmatory gene mutational analysis tests. This is crucial towards initiating timely and appropriate surveillance measures for the patient and affected family members. We also review the evidence postulating on the possible inclusion of uterine serous carcinoma as part of the spectrum of malignancies seen in hereditary breast and ovarian carcinoma syndrome, driven by mutations in BRCA1/2.