Asma Faruqi

Chemotherapy Response Score: Development and Validation of a System to Quantify Histopathologic Response to Neoadjuvant Chemotherapy in Tubo-Ovarian High-Grade Serous Carcinoma

PURPOSE To develop and validate a histopathologic scoring system for measuring response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIC to IV tubo-ovarian high-grade serous carcinoma. PATIENTS AND METHODS A six-tier histopathologic scoring system was proposed and applied to a test cohort (TC) of 62 patients treated with neoadjuvant chemotherapy and interval debulking surgery. Adnexal and omental sections were independently scored by three pathologists. On the basis of TC results, a three-tier chemotherapy response score (CRS) system was developed and applied to an independent validation cohort of 71 patients. RESULTS The initial system showed moderate interobserver reproducibility and prognostic stratification of TC patients when applied to the omentum but not to the adnexa. Condensed to a three-tier score, the system was highly reproducible (kappa, 0.75). When adjusted for age, stage, and debulking status, the score predicted progression-free survival (PFS; score 2 v 3; median PFS, 11.3 v 32.1 months; adjusted hazard ratio, 6.13; 95% CI, 2.13 to 17.68; P < .001). The three-tier CRS system applied to omental samples from the validation cohort showed high reproducibility (kappa, 0.67) and predicted PFS (CRS 1 and 2 v 3: median, 12 v 18 months; adjusted hazard ratio, 3.60; 95% CI, 1.69 to 7.66; P < .001). CRS 3 also predicted sensitivity to first-line platinum therapy (94.3% negative predictive value for progression < 6 months). A Web site was established to train pathologists to use the CRS system. CONCLUSION The CRS system is reproducible and shows prognostic significance for high-grade serous carcinoma. Implementation in international pathology reporting has been proposed by the International Collaboration on Cancer Reporting, and the system could potentially have an impact on patient care and research.

Is differentiated vulval intraepithelial neoplasia the precursor lesion of human papillomavirus-negative vulval squamous cell carcinoma?

Vulval squamous cell carcinoma appears to arise via 2 distinct pathways. A significant minority are associated with oncogenic human papillomavirus (HPV) infection and undifferentiated vulval intraepithelial neoplasia (VIN). However, the majority arises in the absence of HPV, on a background of chronic inflammation. Until recently, it was assumed that lichen sclerosus was the underlying inflammatory condition in the majority of HPV-negative cancers. This pathway of carcinogenesis has been less well studied than the HPV pathway. Emerging evidence implicates differentiated VIN (DVIN), rather than lichen sclerosus, as the most likely precursor lesion in HPV-negative vulval squamous cell carcinoma. Here we discuss the clinical and molecular evidence that implicates DVIN as a lesion with a high malignant potential. This lesion is probably underdiagnosed and may be undertreated. Better recognition of DVIN by gynecologists and pathologists may therefore offer an opportunity to prevent some vulval cancers.

Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma

Purpose: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response. Experimental Design: We obtained pre- and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response. Results: There was evidence of T-cell activation in omental biopsies after NACT: CD4+ T cells showed enhanced IFNγ production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8+ T-cell and CD45RO+ memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3+ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- versus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT. Conclusions: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025–36. ©2016 AACR.

Uterine Serous Carcinomas Frequently Metastasize to the Fallopian Tube and Can Mimic Serous Tubal Intraepithelial Carcinoma.

We investigated the frequency, histopathologic, and immunohistochemical characteristics of tubal involvement in uterine serous carcinoma (USC) and aimed to clarify the relationship between “serous tubal intraepithelial carcinoma (STIC)” and USC in these cases. Cases of USC with complete tubal examination were prospectively collected and reviewed for the presence of tubal involvement. Immunohistochemical analysis for p53 and WT1 was performed on the endometrial and tubal tumor in cases with tubal involvement. Of 161 USC cases (pure USC or a component of a mixed carcinoma or a carcinosarcoma), 32 (20%) showed tubal involvement (unilateral: n=19; bilateral: n=13). The uterine tumors in cases with tubal involvement showed a trend toward increased likelihood of deep myometrial and lymphovascular invasion (LVI) compared with those without tubal involvement. The tubal fimbriae were involved in 15/32 cases. Tubal involvement was mucosal in 30/32 cases, mural in 14/32, serosal in 5/32, invasive in 22/32, and there was LVI in the tube in 13/32. STIC-like features were seen in 17/32 cases (7 as the only pattern of involvement, 9 with associated invasive carcinoma, and 5 with LVI). Immunostaining showed complete concordance of p53 and WT1 between the endometrial and tubal tumors in 26/32 cases, the majority being WT1 negative or only focally positive (19/26), and all exhibiting mutation-type p53 staining. On the basis of the histologic and immunohistochemical features, the tubal tumor was considered to represent metastatic USC in 26/32 cases, most likely metastatic USC in 2/32 cases, an independent tubal primary tumor in 3/32 cases, and to be of uncertain origin in the 1 remaining case. STIC-like lesions were considered to represent metastatic USC in 12/17 cases, most likely metastatic USC in 2/17 cases, an independent tubal primary in 2/17 cases, and of uncertain origin in the 1 remaining case. Tubal involvement, including STIC-like lesions, is seen in one fifth of USC when the tubes are examined in their entirety. The tubal involvement is metastatic in the vast majority of cases. Immunohistochemical studies assist, in most cases, in confirming the metastatic nature of the tubal disease. Consideration should be given to completely examining the fallopian tubes in apparent stage I or II USCs, as this will result in upstaging in a significant minority of cases.

The accuracy of frozen section diagnosis in apparent early ovarian cancer – results from a UK centre

Sir: There is marked variation in the use of intraoperative frozen section (FS) evaluation of adnexal malignancies in the UK. At our Centre FS is done regularly for several indications in gynaecological oncology, with significant workload implications for pathologists. We present the results of an audit of FS for suspected early ovarian cancer. The aim was to assess its accuracy and impact on patient management. We were advised by the Ethics Committee that because this study was an audit, formal National Research Ethics Service approval was not required. Accurate surgical staging is mandatory for optimal treatment of early ovarian cancer. The management options in apparent early ovarian cancer are either to stage all cases surgically, possibly unnecessarily, or to restage proven malignant cases at a second procedure. Reliable intraoperative diagnosis at the first operation enables the informed decision to proceed to full staging when indicated. Between October 2006 and May 2008 FS was considered in 71 patients with suspected early ovarian cancer. Ten cases were excluded: three because of extensive ovarian disease at laparotomy that had not been detected on preoperative imaging and seven because of non-ovarian neoplasms diagnosed through operative findings (three cases) or FS (four cases). Of the 61 cases of primary ovarian tumours, the mean age was 54 years and the majority had intermediate or high risk of malignancy index (RMI) (Table 1). Of these there were 20 (33%) malignant, 10 (16%) borderline and 31 (51%) benign tumours (Table 2). FS performed in 50 ⁄ 61 cases (82%) was found concordant with final pathology in 46 patients (92%). The overall sensitivity, specificity, positive predictive value and negative predictive value of FS for malignant and borderline ovarian tumours were 93%, 90%, 93% and 90%, respectively (Table 3). The four discrepancies were two mucinous neoplasms, one fibrothecoma with a focus of fibrosarcoma and one serous cystadenofibroma (Table 4). None of the patients in whom FS was carried out required second surgery for the ovarian tumour. It is significant that 40% of cases with borderline tumours in this study were young women keen to preserve fertility. As none was diagnosed as malignant on FS, conservative surgery was performed. The reported FS rate for ovarian lesions ranges from 4% to 47%. In our study this rate was 82%, a significant increase from 11% in comparable cases prior to the introduction in 2006 of current departmental guidelines. Decision not to perform FS shortens Table 2. Histological types of ovarian tumours

Papillary squamotransitional cell carcinoma of the uterine cervix: report of three cases and review of the literature

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The Chemotherapy Response Score (CRS): Interobserver Reproducibility in a Simple and Prognostically Relevant System for Reporting the Histologic Response to Neoadjuvant Chemotherapy in Tuboovarian High-grade Serous Carcinoma.

A 3-tier histopathologic scoring system, the chemotherapy response score (CRS), was previously devised for reporting the histologic response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIc/IV tuboovarian high-grade serous carcinoma. This has been shown to predict the outcome and offer additional information to other methods of assessing the treatment response. In the present study, the reproducibility of this scoring system was assessed by determining the interobserver agreement among reporting pathologists. A total of 5 groups each comprising 3 pathologists with different levels of expertise were selected. The participants underwent an online tutorial on how to apply the CRS system. 40 cases (38 cases in 2 appraiser groups) were scored individually by each of the 15 pathologists. The interobserver reproducibility was calculated using Fleiss’ &kgr;, Kendall’s coefficient of concordance, and the absolute agreement between (a) individual pathologists within 1 group, (b) with the majority score agreement between all groups, and (c) with all individual scores. The CRS system was found to be highly reproducible among all the pathologists’ groups (&kgr;=0.761). The agreement in identifying the group of patients with the best response to chemotherapy was exceptionally high (&kgr;=0.926). We conclude that CRS has a high interobserver reproducibility, especially in identifying the subgroup of patients with the best chemotherapy response, justifying its inclusion in clinical trials and reporting practice.

Tubal handling significantly affects site assignment in non-uterine high-grade serous carcinoma

Manish M Subramaniam Alvin Lim Soon Tiong Lim Tse Hui Victor Lee Kwan Min Shantha Amrith Thomas Paulraj Thamboo Department of Pathology, National University Health System, Singapore, Singapore, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore, Cytogenetics Laboratory, Department of Pathology, Singapore General Hospital, Singapore, Singapore, and Department of Ophthalmology, National University Health System, Singapore, Singapore

Extrauterine high-grade serous carcinomas with bilateral adnexal involvement as the only two disease sites are clonal based on tp53 sequencing results: implications for biology, classification, and staging

A previous multicenter study of 67 cases of Stage I/II tubo-ovarian high-grade serous carcinoma with complete tubal sampling identified 7 cases in which there were only two disease sites, comprising tumor involving opposite adnexa with no extra-adnexal involvement. This study aimed to determine whether such low-stage extrauterine high-grade serous carcinomas with only two sites of involvement, located on opposite adnexa, have identical or different TP53 mutations in order to investigate their clonal relationship. DNA extracted from both sites of involvement was subjected to TP53 sequencing (n=6) or sequencing of one site and mutation confirmation by droplet digital PCR for the other site (n=1). Of the 7 cases analyzed, 1 case had unilateral serous tubal intraepithelial carcinoma with contralateral ovarian high-grade serous carcinoma, 3 had tubal high-grade serous carcinomas (±serous tubal intraepithelial carcinoma) with contralateral ovarian high-grade serous carcinoma, 2 had bilateral ovarian high-grade serous carcinomas with normal tubes, and 1 had bilateral fallopian tube high-grade serous carcinoma with normal ovaries. All 7 cases showed identical TP53 mutations in tumor from both disease sites. Therefore, these rare cases of high-grade serous carcinoma confined to opposite adnexa all show clonal identity between the two sites of involvement, suggesting unifocal origin and metastasis rather than multifocal origin. Our results suggest that serous tubal intraepithelial carcinoma or adnexal high-grade serous carcinoma can metastasize to the contralateral adnexa without peritoneal involvement. Given the clonal relationship between the two sites, such cases should be considered stage II, with stage I reserved for cases with unilateral and unifocal adnexal involvement. Furthermore, serous tubal intraepithelial carcinoma without invasion should be taken to constitute a disease site for staging purposes.

A comparison of p53 and WT1 immunohistochemical expression patterns in tubo‐ovarian high‐grade serous carcinoma before and after neoadjuvant chemotherapy

The treatment of patients with tubo‐ovarian high‐grade serous carcinoma (HGSC) is increasingly based on diagnosis on small biopsy samples, and the first surgical sample is often taken post‐chemotherapy. p53 and WT1 are important diagnostic markers for HGSC. The effect of neoadjuvant chemotherapy on p53 and WT1 expression has not been widely studied. We aimed to compare p53 and WT1 expression in paired pre‐chemotherapy and post‐chemotherapy samples of HGSC.