Exceptional Response to Nivolumab in a 13-Year-Old Female with Metastatic HPV-Negative Cervical Carcinoma.

Cervical carcinoma is associated with high-risk human papillomavirus (HPV) DNA integration and usually occurs after age 21 (peak 45 years), as reflected in screening guidelines. Between 1999 and 2008, cervical carcinoma rate in adolescents aged 15-19 years was 0.15 per 100,000. HPV-negative cervical carcinoma is rare in adolescents. The youngest previously reported case was 15 years old. Treatment options for cervical carcinoma are limited after first-line therapy. Immune checkpoint inhibitors blocking programmed death receptor (PD-1) and its ligand, PD-L1, have shown objective clinical responses and are tolerable in adults with gynecologic cancers. This class of agents is well tolerated in pediatric patients. PD-1/PD-L1 is commonly expressed in gynecologic cancers but its expression may not predict clinical response. We describe an exceptional response to single agent nivolumab postradiation therapy in a 13-year-old adolescent with poorly differentiated cervical carcinoma and widespread metastatic disease.

Pattern-based classification of invasive endocervical adenocarcinoma, depth of invasion measurement and distinction from adenocarcinoma in situ: interobserver variation among gynecologic pathologists.

A pattern-based classification for invasive endocervical adenocarcinoma has been proposed as predictive of the risk of nodal metastases. We aimed to determine the reproducibility of such classification in the context of common diagnostic challenges: distinction between in situ and invasive adenocarcinoma and depth of invasion measurement. Nine gynecologic pathologists independently reviewed 96 cases of endocervical adenocarcinoma (two slides per case). They diagnosed each case as in situ or invasive carcinoma classifying the latter following the pattern-based classification as pattern A (non-destructive), B (focally destructive) or C (diffusely destructive). Depth of invasion, when applicable, was measured (mm). Overall, diagnostic reproducibility of pattern diagnosis was good (κ=0.65). Perfect agreement (9/9 reviewers) was seen in only 11 cases (11%), all destructively invasive (10 pattern C and 1 pattern B). In all, ≥5/9 reviewer concordance was achieved in 82/96 cases (85%). Distinction between in situ and invasive carcinoma, regardless of the pattern, showed only slight agreement (κ=0.37). Likewise, distinction restricted to in situ versus pattern A was poor (κ=0.23). Distinction between non-destructive (in situ+pattern A) and destructive (patterns B+C) carcinoma showed significantly higher agreement (κ=0.62). Estimation of depth of invasion showed excellent reproducibility (ICC=0.82). However, different measurements resulting in differing FIGO stages were common (from at least 1 reviewer in 79% cases). On the basis of interobserver agreement, the pattern-based classification is best at diagnosing destructive invasion, which carries a risk for nodal metastases. Agreement in diagnosing in situ versus invasive carcinoma, including pattern A, was poor. Given the nil risk of nodal spread in in situ and pattern A lesions, the term 'endocervical adenocarcinoma with non-destructive growth' can be considered when the distinction is difficult, after excluding destructive invasion. Depth of invasion measurement was highly reproducible among pathologists; thus, the pattern-based approach can complement, but should not replace, the depth of invasion metric.

Recently described entities in the gynaecological tract.

In recent years there have been significant advances in our understanding of female genital tract tumours due to the fact that new molecular abnormalities and translocations have been identified in certain neoplasms. Also, terminology of various lesions in the gynaecological tract has changed and a couple of new entities have been described.In this review we will highlight some mesenchymal neoplasms including gynaecological perivascular epithelioid cell tumour (PEComa), inflammatory myofibroblastic tumour (IMT) occurring in the uterus and discuss and review terminology of endometrial stromal neoplasms.A recently described entity, gastric type endocervical adenocarcinoma will be reviewed, summarising its most salient microscopic and clinical features. The newly proposed endocervical adenocarcinoma classification system by Silva and collegues will be reviewed as well.Finally, a particular high-grade endometrial carcinoma (undifferentiated endometrial carcinoma) will be discussed highlighting the importance of its recognition and differential diagnosis.

Invasion patterns of metastatic high-grade serous carcinoma of ovary or fallopian tube associated with BRCA deficiency.

High-grade serous carcinomas of the uterine adnexa with BRCA1 deficiency (high-grade serous carcinomas-BRCA) have recently been described to demonstrate characteristic histopathological features. We hypothesize that metastatic high-grade serous carcinomas-BRCA cases exhibit characteristic morphological features as well. We studied 102 high-grade serous carcinomas with known BRCA1 and BRCA2 genotype from the archives of the Department of Pathology at Memorial Sloan-Kettering Cancer Center. The primary site morphological characteristics of these cases were reported previously; we now focus solely on tumor morphology in sites other than the uterine adnexa (ie, metastatic sites). The study group consisted of the following case types: 13 BRCA1 germline mutations; 5 BRCA1 somatic mutations; 10 BRCA1 promoter methylation; 4 BRCA2 germline mutations; 1 BRCA2 somatic mutation; 11 lacking BRCA1 or BRCA2 abnormality; 58 cases lacking BRCA1 or BRCA2 germline mutation. Two observers independently scored invasion patterns and microscopic tumor architecture while blinded to genotype. Concordance between observers and correlations between metastatic patterns and the following indices were studied: genotype, primary site tumor characteristics, and BRCA1 immunohistochemistry. Concordance between observers was excellent (κ values >0.9). All cases with BRCA1 or 2 abnormalities showed either pushing pattern metastases (76%) or infiltrative metastases composed only of micropapillae (24%). In contrast, all cases lacking BRCA1 or 2 abnormalities showed infiltrative metastases that contained combinations of papillary, glandular, and, rarely, cribriform and micropapillary architecture (P<0.0001 for comparison with pushing metastasis and P<0.001 for comparison with purely micropapillary architecture). Morphological assessment of metastatic carcinomas, a highly reproducible exercise, accurately correlated with BRCA1 status in every case, unlike morphological assessment of primary site adnexal high-grade serous carcinomas or BRCA1 immunohistochemistry. Metastatic high-grade serous carcinomas-BRCAs exhibit characteristic morphological features that appear more sensitive and specific for BRCA mutations than two other morphologically based prediction systems and should be easier to apply in practice. These findings should be validated prospectively in an independent cohort.

An update on vulvar intraepithelial neoplasia: terminology and a practical approach to diagnosis.

There are two distinct types of vulvar intraepithelial neoplasia (VIN), which differ in their clinical presentation, aetiology, pathogenesis and histological/immunophenotypical features. One form driven by high-risk human papilloma virus infection usually occurs in young women and has been termed classic or usual VIN (uVIN). The other, not related to viral infection, occurs in postmenopausal women with chronic skin conditions such as lichen sclerosus and lichen simplex chronicus and is termed differentiated or simplex-type VIN. The latter is the precursor lesion of the most common type of squamous cell carcinoma (SCC) in the vulva, namely keratinizing SCC (representing 60% of cases). In contrast, uVIN usually gives rise to basaloid or warty SCC (40% of cases). The histological features of uVIN are similar to those of high grade lesions encountered in other lower anogenital tract sites (hyperchomatic nuclei with high nuclear to cytoplasmic ratios and increased mitotic activity). However, differentiated VIN has very subtle histopathological changes and often escapes diagnosis. Since uVIN is driven by high-risk human papilloma virus infections, p16 immunohistochemistry is diffusely positive in these lesions and is characterized with a high Ki-67 proliferation index. In contrast, differentiated or simplex-type VIN is consistently negative for p16 and the majority of the cases harbour TP53 mutations, correlating with p53 positivity by immunohistochemistry.