Pei Hui

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.

STR genotyping diagnosis of hydatidiform moles: an assessment of 2871 consecutive products of conceptions

This study evaluated the incidence of hydatidiform moles in a tertiary care setting and examined the efficacy of short tandem repeat genotyping (STR) as a primary ancillary diagnostic tool for molar gestations. Consecutive products of conceptions undergoing genotyping were analyzed. A total of 2871 cases were analyzed, comprising 1693 in-house and 1178 consultation specimens. Patient ages ranged from 10 to 57 years (mean 32, median 33). Laser microdissection was performed in 138 specimens. STR genotyping yielded a definitive diagnosis in 99.5% of cases (2857/2871), classifying them as 282 complete moles (241 monospermic, 41 dispermic), 564 partial moles (546 dispermic, 12 monospermic, 6 triandric tetraploid), and 2006 non-molar gestations (including 125 trisomies, 24 digynic triploids, 4 egg donor conceptions, 1 trigynic tetraploid, 3 androgenetic/biparental mosaics, 2 chimeric twin gestations with a molar component of either monospermic complete mole or heterozygous partial mole, and 1 trigynic tetraploid). Among molar gestations, complete and partial moles accounted for 38.6% and 61.4% of in-house cases and 28.2% and 72.0% of consultation cases, respectively. Notably, complete moles occurred exclusively in patients younger than 15 or older than 50. The mean turnaround time for STR genotyping was 5.3 days overall (5.7 days for in-house and 4.8 days for consultation cases). Hydatidiform moles accounted for 29.4% of the study cohort in our tertiary care setting, with partial hydatidiform moles comprising two-thirds of these cases. With an average turnaround time of 5.3 days and a 99.5% success rate, STR genotyping demonstrated high efficiency in the accurate diagnosis and classification of hydatidiform moles.

Diandric triploid partial mole versus digynic nonmolar triploidy: is morphological assessment sufficient for the diagnostic distinction?

AimsDiagnostic separation of diandric triploid gestation, i.e. partial mole from digynic triploid gestation, is clinically relevant, as the former may progress to postmolar gestational trophoblastic neoplasia. The aim of the study was to investigate if the combination of abnormal histology combined with ploidy analysis‐based triploidy is sufficient to accurately diagnose partial mole.Methods and ResultsA genotype–phenotype correlation study was undertaken to reappraise histological parameters among 20 diandric triploid gestations and 22 digynic triploid gestations of comparable patient age, gestational weeks, and clinical presentations. Two villous populations, irregular villous contours, pseudoinclusions, and syncytiotrophoblast knuckles, were common in both groups. Villous size ≥2.5 mm, cistern formation, trophoblastic hyperplasia, and syncytiotrophoblast lacunae were significantly more common in the partial hydatidiform mole. Cistern formation had the highest positive predictive value (PPV) (93%) and highest specificity (96%) for diandric triploid gestation, although the sensitivity was 70%. Cistern formation combined with villous size ≥2.5 mm or trophoblast hyperplasia or syncytiotrophoblast lacunae had 100% specificity and PPV, but a marginal sensitivity of 60%–65%. A moderate interobserver agreement (Kappa = 0.57, Gwet's AC1 = 0.59) was achieved among four observers who assigned diagnosis of diandric triploid gestation or digynic triploidy solely based on histology.ConclusionsNone of histological parameters are unique to either diandric triploid gestation or digynic triploid gestation. Cistern formation is the most powerful discriminator, with 93% PPV and 70% sensitivity for diandric triploid gestation. While cistern formation combined with either trophoblastic hyperplasia or villous size ≥2.5 mm or syncytiotrophoblast lacunae has 100% PPV and specificity for diandric triploid gestation, the sensitivity is only 60% to 65%. Therefore, in the presence of triploidy, histological assessment is unable to precisely classify 35% to 40% of diandric triploid gestations or partial moles.

Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147)

Abstract Purpose: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. Patients and Methods: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. Results: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. Conclusions: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

KRAS mutation in primary ovarian serous borderline tumors correlates with tumor recurrence

Oncogenic activation of the mitogen-activated protein kinase (MAPK) pathway due to KRAS or BRAF gain-of-function mutation is frequently found in ovarian serous borderline tumor (SBT) and their extraovarian implants. We investigated mutational status of KRAS and BRAF of the primary ovarian SBTs that had a high stage presentation in correlation with clinical outcome. Among 39 consecutive primary SBTs with either invasive implants (20 cases) or non-invasive implants (19 cases), KRAS and BRAF mutational analysis was informative in 34 cases. Sixteen cases (47%) harbored a KRAS mutation, while 5 cases (15%) had a BRAF V600E mutation. High-stage disease (IIIC) was seen in 31% (5/16) of patients with a KRAS mutation and 39% (7/18) of patients without a KRAS mutation (p = 0.64). KRAS mutations were present in 9/16 (56%) tumors with invasive implants/LGSC versus 7/18 (39%) tumors with non-invasive implants (p = 0.31). BRAF mutation was seen in 5 cases with non-invasive implants. Tumor recurrence was seen in 31% (5/16) of patients with a KRAS mutation, compared to 6% (1/18) of patients without a KRAS mutation (p = 0.04). A KRAS mutation predicted an adverse disease-free survival (31% survival at 160 months) compared to those with wild-type KRAS (94% at 160 months; log-rank test, p = 0.037; HR 4.47). In conclusion, KRAS mutation in primary ovarian SBTs is significantly associated with a worse disease-free survival, independent of the high tumor stage or histological subtypes of extraovarian implant. KRAS mutation testing of primary ovarian SBT may servce as a useful biomarker for tumor recurrence.