Ovarian borderline tumors in the 2014 WHO classification: evolving concepts and diagnostic criteria

Abstract

Borderline ovarian tumors (BOT) are uncommon but not rare epithelial ovarian neoplasms, intermediate between benign and malignant categories. Since BOT were first identified >40 years ago, they have inspired controversies disproportionate to their incidence. This review discusses diagnostic criteria for the histologic subtypes of BOT, highlighting areas of diagnostic challenges, ongoing controversies, and changes in terminology implemented by the recent 2014 WHO Classification of Tumours of the Female Genital Organs. Emerging knowledge supports the notion that subtypes of borderline ovarian tumors comprise distinct biologic, pathogenetic, and molecular entities, precluding a single unifying concept for BOT. Serous borderline tumors (SBT) share molecular and genetic alterations with low-grade serous carcinomas and can present at higher stages with peritoneal implants and/or lymph node involvement, which validates their borderline malignant potential. All other (non-serous) subtypes of BOT commonly present at stage I confined to the ovary(ies) and are associated with overall survival approaching that of the general population. An important change in the WHO 2014 classification is the new terminology of non-invasive implants associated with SBT, as any invasive foci (previously called "invasive implants") are now in line with their biological behavior considered peritoneal low-grade serous carcinoma (LGSC). The controversy regarding the terminology of non-serous borderline tumors, called by some pathologists "atypical proliferative tumor" in view of their largely benign behavior, has not been resolved. The concepts of intraepithelial carcinoma and microinvasion may evolve in further studies, as their presence appears to have no prognostic impact and is subject to considerable inter-observer variability.

Keywords: Borderline tumor; Diagnostic criteria; Ovary; WHO classification 2014.

Fig. 1

SBT with hierarchically branched papillae (a) covered by a single-layered or multilayered epithelium with pseudopapillary proliferations and secretory or ciliated serous differentiation (b). Micropapillary SBT demonstrates non-hierarchical “Medusa-like” branching and a more cellular stroma (c). Its epithelium is more cuboidal with “nuclear atypia greater than that allowed for conventional SBT” and often containing small nucleoli (d). Some micropapillary SBTs have a predominant cribriform epithelial proliferation (e). Microinvasion is characterized by small epithelial cell groups surrounded by retraction artifacts within a cell-rich fibroblastic stroma (f)

Fig. 2

MBT showing cystic glandular structures with papillary infoldings, columnar cells with abundant cytoplasmic mucin, admixed with goblet cells of variable degrees of maturation (a) and with basally located nuclei with no considerable nuclear atypia (b). MBT with microinvasion is characterized by small cell groups and glands with cytoplasmic eosinophilia within a normal ovarian stroma without desmoplastic change (c). MBT with intraepithelial carcinoma is characterized by focal high-grade nuclear atypia, commonly associated with more complex epithelial proliferations, next to conventional MBT structures with sharp transition (d). Mucinous carcinoma with expansile (“pushing border”) invasion shows confluent glandular and papillary epithelial proliferations without stromal desmoplasia (e). Mucinous carcinoma with destructive invasion demonstrates haphazardly infiltrating glands and is characterized by desmoplastic tumor stroma (f)

Fig. 3

Ovarian metastases mimicking MBT originating from various extra-ovarian primary tumors: metastatic low-grade appendiceal mucinous neoplasm (a), gastric intestinal type (b), colorectal (c), and pancreatic ductal adenocarcinoma (d)

Fig. 4

Brenner tumor (a) showing epithelial cell nests of variable size, with transitional cell-like morphology, embedded in a fibrous stroma. The epithelium-to-stroma ratio is even. Central cysts are lined by a single layer of columnar mucinous cells. Metaplastic Brenner tumor (b) demonstrates a cystic structure with predominance of mucinous epithelium. GATA3 (c) is diffusely expressed in Brenner tumors, and sometimes many luteinized stromal cells are present highlighted by calretinin stain (d). Brenner BOT are characterized by a significantly increased epithelium-to-stroma ratio (e) but share the same cytological details as benign Brenner tumor (f)

Fig. 5

SMBT demonstrating a papillary architecture with hierarchical branching (a). The epithelium is columnar with focal multilayering with papillary and pseudopapillary infoldings and variable cytoplasmic mucin content. Stroma and epithelium show infiltration by neutrophils (b). Immunohistochemical expression of ER (and/or PR) (c) and absence of WT1 (d) is typical

Fig. 6

EBT of adenofibromatous type with endometrioid glandular proliferations embedded in a fibroblastic stroma (a) with some epithelial cell nests consisting of a central squamous area (b). Glandular proliferations express CK7 (c) and ER (e). CK 8/18 is diffusely expressed (d) whereas the squamous areas are CK5/6-positive (f) and do also express CDX2 (not shown). Endometrioid cystadenofibroma (g) is characterized by round and cystic glands, evenly distributed in a fibroblastic stroma. Cystic/villoglandular EBTs (h) share the same architecture as SBTs but differ in their endometrioid cytology

Fig. 7

CCBT demonstrating variably sized glands lined by clear cells, evenly spaced with focal glandular crowding, and embedded in a fibromatous stroma (a), with mild to moderate nuclear atypia (b). In contrast, intracystic clear cell carcinoma demonstrates intracystic papillary proliferations lined by clear and hobnail cells (c) with high-grade nuclear atypia and prominent nucleoli (d)