Clinical Outcome and Morphology-Based Analysis of p53 Aberrant and Mismatch Repair Protein-Deficient Ovarian Clear Cell Carcinoma and Their Association With p16, HER2, and PD-L1 Expression.

OBJECTIVES: We studied the prevalence and prognostic significance of mismatch repair deficient (MMRD) and p53 aberrant ovarian clear cell carcinoma (CCO) and their association with other prognostic and theranostic biomarkers (p16, HER2, PD-L1). We also aimed to identify morphologic features to serve as screening tools for immunohistochemical testing for these biomarkers. METHODS: Tissue microarrays with 3-mm cores from 71 pure CCOs were immunostained with PMS2, MSH6, p53, p16, HER2, and PD-L1. Expression status was correlated with tumor recurrence/disease progression and survival. It was also correlated with morphologic features (tumor size, nuclear grade, tumor architecture, mitotic activity, presence of endometriosis, tumor budding, and tumor inflammation). RESULTS: p53 aberrant tumors were associated with shorter overall and recurrence-free survivals (P = .002 and P = .01, respectively). In multivariate analysis, p53 aberrant status and tumor stage were independently associated with recurrence/disease progression (hazard ratio [HR] = 3.31, P = .037 and HR = 1.465, P = .004, respectively). p53 aberrant status was associated with tumor budding (P = .037). MMRD, p16, HER2, and PD-L1 expression had no prognostic significance. HER2 and PD-L1 were expressed in 56% and 35% of tumors, respectively. MMRD was associated with tumor expression of PD-L1 (P > .05) but not with tumor inflammation. CONCLUSIONS: Aberrant p53 in CCO is infrequent but associated with poor prognosis independent of stage. Presence of tumor budding could be a screening tool for p53 testing. High prevalence of HER2 and PD-L1 expression indicates the eligibility of patients with CCO for ongoing clinical trials using these therapeutic targets.

Intratumoral budding is associated with poor clinical outcome in early-stage clear cell carcinoma of ovary.

AIMS: Clear cell carcinoma of ovary (CCC) is considered a high-grade malignancy by default and the role of histological grading for assessing clinical outcome is not established. We aimed to evaluate histopathological features associated with clinical outcome in CCC patients. METHODS AND RESULTS: Seventy-six cases of CCC with available clinical follow-up information were studied. Histopathological features, including tumour size, architectural patterns, nuclear atypia, mitotic activity, intratumoral and peritumoral inflammation, presence of endometriosis, peritumoral and intratumoral budding, were evaluated. Multivariate analysis was performed with logistic regression and Kaplan-Meier survival curves with the log-rank test were used for survival analysis. Forty cases (53%) presented at stage I. Complete response to treatment was achieved in 65%, while 35% of patients had tumour recurrence or progression of disease despite treatment. At last follow-up, 13% had died of disease, 20% were alive with disease and 67% had no evidence of disease. Higher stage (P = 0.0016) and presence of intratumoral budding (P = 0.0454) were independently associated with recurrence/disease progression. Advanced stage (P = 0.0011), presence of lymph node involvement (P = 0.0003), intratumoral budding (P = 0.0023) and peritumoral budding (P = 0.0334) were significantly associated with shorter survival. Intratumoral budding was significantly associated with recurrent/progressive disease (P = 0.0195) and also shorter survival (P = 0.0277) within the cohort of low-stage (I/II) patients as well. CONCLUSION: We have shown that besides the classic prognostic factors of stage and lymph node status, the presence of tumour budding is associated with poorer outcome in patients with CCC. Specifically, evaluation of intratumoral budding may help to more clearly predict prognosis in patients with early-stage disease.

Gynaecological perivascular epithelioid cell tumour (PEComa): comparative analysis of proposed algorithms for prediction of clinical outcome.

AIMS: Perivascular epithelioid cell tumours (PEComas) are rare mesenchymal tumours that coexpress smooth muscle and melanocytic markers. They have a predilection for gynaecological organs, where they present a unique diagnostic challenge, because of morphological and immunohistochemical overlap with more common smooth muscle and stromal tumours. Limited information regarding the natural history, owing to the rarity of this tumour, makes accurate risk stratification difficult. We aimed to review clinicopathological features of gynaecological PEComa and compare accuracy of five different classification systems for prediction of prognosis. METHODS AND RESULTS: We have described the clinicopathological features of 13 new cases and tested five prognostic algorithms in a total of 67 cases of gynaecological PEComa. Receiver operating characteristic curves were constructed and areas under the curve (AUCs) were calculated to evaluate predictive accuracy. The modified gynaecological-specific algorithm showed high sensitivity and specificity and yielded the highest AUC (0.864). It's earlier version, the gynaecological-specific algorithm, suffered from lower specificity (AUC = 0.843). The post-hoc McNemar test confirmed significant differences between the performances of the modified gynaecological-specific algorithm and the gynaecological-specific algorithm (P = 0.008). The original Folpe algorithm for PEComas of all sites showed low specificity, had a lower AUC (0.591), and was inapplicable in 18% of cases. Its two later versions (the revised Folpe algorithm and the modified Folpe algorithm) also yielded lower AUCs (0.690 and 0.591, respectively). CONCLUSION: We have shown that the modified gynaecological-specific algorithm predicts the clinical outcome of gynaecological PEComa with high accuracy, and have validated its use for prognostic stratification of gynaecological PEComa.

Amplification of MDM2 and Loss of p16 Expression: Do They Have a Role in Malignant Transformation of Ovarian Brenner Tumor?

OBJECTIVES: To review the significance of MDM2 and cyclin D1 expression and loss of p16 expression in malignant and borderline Brenner tumors (BTs) of the ovary. METHODS: We describe 2 new cases of ovarian BT, 1 malignant and 1 borderline. We studied MDM2, p16, and cyclin D1 expression by immunohistochemistry in the benign, borderline, and malignant components of these 2 cases and in 5 additional cases of benign BT. We also reviewed and summarized the literature on the clinical, immunohistochemical and molecular characteristics of borderline and malignant BTs (BdBTs and MBTs). RESULTS: Nuclear expression of MDM2 was seen only in the MBT. Loss of p16 expression was seen in both BdBT and MBT. Cyclin D1 expression was in proportion to the degree of malignancy. Amplification of MDM2, loss of CDKN2A (p16-encoding gene), and amplification of CCND1 (cyclin D1-encoding gene) were confirmed by commercial next-generation sequencing in the case of MBT. CONCLUSIONS: We are the first to report immunohistochemical expression of MDM2 in an MBT. Amplification of MDM2 and loss of p16 expression may have a role in malignant transformation of BT.

Inflammatory Myofibroblastic Tumor in Female Genital Tract.

CONTEXT.­: Inflammatory myofibroblastic tumor is a mesenchymal neoplasm of low malignant potential. It was first described in lung, but is known to occur in many extrapulmonary sites including female genital organs, most commonly the uterus. It has a high recurrence rate and a low risk for metastasis. A more recently described aggressive variant, epithelioid myofibroblastic sarcoma with a predilection for the abdominal cavity of males, has also been recently reported to occur in the ovary. This tumor is composed of spindled and epithelioid myofibroblasts in a variably myxoid stroma and commonly shows a fascicular growth pattern with positive staining for desmin, smooth muscle actin, and CD10, which may mimic a smooth muscle or endometrial stromal neoplasm. In the female genital tract it has the potential for being misdiagnosed as a leiomyoma, endometrial stromal tumor, or as a myxoid leiomyosarcoma, resulting in undertreatment or overtreatment. It harbors rearrangements in the ALK gene, resulting in abnormal expression of ALK protein. Immunostaining for ALK is a helpful diagnostic tool. OBJECTIVE.­: To provide a brief review of clinical, histologic, immunohistochemical, and molecular features of inflammatory myofibroblastic tumor with emphasis on possible diagnostic pitfalls in the female genital tract. DATA SOURCES.­: Review of pertinent literature on inflammatory myofibroblastic tumor occurring in the female genital tract and personal experience of the authors. CONCLUSIONS.­: Inflammatory myofibroblastic tumor in the female genital tract can mimic other more common benign and malignant tumors like leiomyoma, leiomyosarcoma, and endometrial stromal sarcoma. Familiarity with clinical and histologic features and use of ALK immunostaining can be critical for correct diagnosis.

Fascin expression in serous tumors of ovary correlates with aggressiveness of malignancy.

Ovarian serous tumors make up about one-fourth of all ovarian tumors. There is a spectrum of proliferation and cellular atypia in these tumors with benign serous cystadenoma, borderline tumors, and low grade or type I serous carcinoma at the lower end and type II or high-grade serous papillary cystadenocarcinoma at the higher end. Fascin is a globular actin cross-linking protein involved in cell motility that has been shown to be upregulated in many human neoplasms and associated with the aggressiveness of malignancy. The aim of this study was to investigate fascin expression in serous tumors of ovary and to evaluate its relationship with the aggressiveness of tumor. Sections from a total of 66 serous tumors of ovary were collected including 26 serous carcinomas, 20 borderline serous tumors, and 20 benign serous cystadenomas. Ten benign ovaries with inclusion cysts were used as controls. Sections were immunostained with fascin. Fascin expression was significantly increased in borderline (13/20, 65%) and malignant serous tumors (22/26, 84%) compared with benign serous cystadenoma (0/20) (P<0.001). There was increased quantitative expression of fascin in carcinoma compared with borderline tumors (diffuse versus patchy). Fascin expression also correlated well with the tumor grade in serous carcinoma cases with 8/12 (66%) of grade I/II tumors staining positive compared with all 14 (100%) of grade III tumors showing fascin expression (P<0.05). Our findings suggest that upregulation of fascin plays a role in increasing aggressiveness of serous ovarian tumors and could potentially be a molecular therapeutic target and a prognostic marker.