Neoplastic cellularity is associated with clinical and molecular features of high-grade serous ovarian carcinoma

abstract

Highlights

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One-third of high-grade serous ovarian, peritoneal and fallopian tube carcinomas (HGSC) have low percentage of neoplastic nuclei (PNN < 70%).

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Higher PNN is associated with suboptimal cytoreduction and lower PNN is associated with inherited BRCA2 mutations.

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Molecular analyses of HGSC selected for high PNN exclude a significant fraction of patients.

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Objective

Most molecular analyses of high-grade serous ovarian, peritoneal and fallopian tube carcinomas (HGSC) require ≥ 70% tumor (neoplastic) cell nuclei. We characterized the distribution of the percentage of neoplastic nuclei (PNN) in a large cohort of HGSC and correlated PNN with clinical outcomes to determine the fraction of cases outside this range and whether this cut-off introduces selection bias.

Methods

Subjects were prospectively enrolled and normal and neoplastic tissues were snap-frozen. All subjects had grade 2 to 3 HGSC. Subjects that received neoadjuvant chemotherapy were excluded. PNN was determined by estimating the fraction of neoplastic nuclei relative to non-neoplastic nuclei on a representative hematoxylin and eosin stained frozen section from the primary neoplasm. Germline BRCA mutation status was determined with Sanger or BROCA sequencing.

Results

PNN was < 70% in 101 (33%) of 306 cases. PNN was significantly higher among subjects without optimal cytoreduction (P = 0.018). 55 subjects had germline BRCA1/BRCA2 mutations. HGSC associated with BRCA2 but not BRCA1 mutations had significantly lower PNN compared to HGSC in non-carriers (54% vs. 70%, P = 0.018). Overall survival was not significantly different between subjects with < 70% or ≥ 70% PNN (median survival 51.8 vs. 46.6 months, P = 0.858).

Conclusions

One-third of HGSC has PNN < 70%. Higher PNN is associated with suboptimal cytoreduction, while lower PNN is associated with inherited BRCA2 mutations. Our findings suggest a nonrandom distribution of PNN that may reflect cancer biology. Further studies exploring the stromal microenvironment are needed. Molecular analyses of HGSC selected for high PNN exclude a significant fraction of patients.