Low-Grade Ovarian Serous Neoplasms (Low-Grade Serous Carcinoma and Serous Borderline Tumor) Associated With High-Grade Serous Carcinoma or Undifferentiated Carcinoma

Abstract

Recent literature has suggested a dual pathway of ovarian serous carcinogenesis, with most serous carcinomas falling into 1 of 2 categories, low grade and high grade. These are considered to represent 2 distinct tumor types with a different underlying pathogenesis and associated with different molecular events, clinical behavior, and prognosis. Low-grade serous carcinoma is thought to evolve in many instances from a preexisting serous borderline tumor and cystadenoma. Given the distinct pathogenesis and different molecular events, it is expected that the coexistence of low-grade and high-grade serous carcinoma would be rare or may even be mutually exclusive; moreover, there are very few reported examples in the literature. We report a series of 7 cases in patients aged 34 to 78 years in whom ovarian low-grade serous carcinoma (4 cases, including 3 with associated serous borderline tumor), serous borderline tumor (2 cases), or seromucinous borderline tumor (1 case) was associated with a high-grade carcinoma, either high-grade serous (5 cases) or undifferentiated carcinoma (2 cases). The low-grade and high-grade components coexisted in the original neoplasm in 4 cases, and the high-grade component was present only in recurrence in 3 cases. In both instances, the undifferentiated carcinoma had a focal rhabdoid morphology, and alternative primary sites of tumor were excluded by a combination of clinical, radiologic, and pathologic parameters. We illustrate that low-grade serous carcinoma or serous borderline tumor ("low-grade" serous neoplasms) may rarely be associated with, and probably give rise to, a high-grade carcinoma, either high-grade serous or undifferentiated carcinoma. The coexistence of a low-grade serous neoplasm and undifferentiated carcinoma can be regarded as a form of dedifferentiation. p53 was diffusely positive in 4 of 6 high-grade carcinomas, which raises the possibility that secondary Tp53 mutation is important in high-grade transformation in some of these cases. WT1 was negative in the 2 undifferentiated carcinomas, and PAX8 was positive in 1, suggesting that the latter marker is more useful in helping to confirm a Mullerian origin in dedifferentiated low-grade serous neoplasms.

Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver

“…Specifically, a borderline tumor that is associated with a BRAF V600E mutation may be more likely to remain a borderline tumor and in only rare cases progress to carcinoma, whereas a borderline tumor that is associated with a TP53 or NRAS mutation, is on an obligate path to carcinoma; those with NRAS mutations resulting in grade 1 or grade 2 features, while those with TP53 mutations result in high-grade tumors with genomic instability and widespread copy number alterations. An alternative hypothesis for the development of high-grade serous invasive cancer with adjacent SBT is that the SBT component is not a precursor lesion, but is part of the invasive tumor that morphologically resembles SBT, representing a better differentiated component (15). If so, we would expect to see no genome-level difference (point mutation, copy number change) between the SBT and invasive components of SBT-EOC tumors, but may see differences in gene expression consistent with differentiation.…”

“…A review of 100 tumors reported areas of SBT in 2% of high-grade cases (2). Boyd and McCluggage described two cases (15). Dehari and colleagues (16) identified three cases of high-grade carcinoma associated with SBT (from 210 serous ovarian tumors) and in two cases mutation analysis showed the same KRAS mutations in both components, indicating a clonal relationship.…”

Ovarian Cancer: A Heterogeneous Disease

“…On a molecular level, LGSC are genomically stable and harbor somatic mutations in KRAS and BRAF in approximately half of cases; these mutations are mutually exclusive [22,23]. Although patients with LGSC may present with low-grade tumor recurrence, some cases of recurrence like HSGC or concomitant HGSC and LGSC have also been reported [24]. A thorough examination of the tumor is recommended in order to screen areas for HGSC.…”

Fallopian Tube as Main Source for Ovarian and Pelvic (Non-Endometrial)Serous Carcinomas

“…The acquisition of KRAS or BRAF and possibly other mutations in tubal derived inclusions and serous cystadenomas result in their transformation to serous borderline tumors and ultimately, low-grade serous carcinomas. Third, a small proportion of high-grade serous carcinomas may develop from low-grade serous carcinomas or serous borderline tumors after the acquisition of additional mutations such as TP53 [41,42]. The latter pathway may explain why in some high-grade serous carcinomas, there is neither evidence of tubal involvement nor TIC lesions.…”