title: Neoplastic cellularity is associated with clinical and molecular features of high-grade serous ovarian carcinoma.
abstract: 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. 46.6months, 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.
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, United States. Electronic address: cbmorse@uw.edu.
authors: Christopher B
authors: CB
authors: Morse
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, United States.
authors: Barbara M
authors: BM
authors: Norquist
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, United States.
authors: Maria I
authors: MI
authors: Harrell
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, United States.
authors: Kathy J
authors: KJ
authors: Agnew
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, United States.
authors: Heidi J
authors: HJ
authors: Gray
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, United States.
authors: Renata R
authors: RR
authors: Urban
authors: Division of Pathology, University of Washington, Seattle, WA 98195, United States.
authors: Rochelle L
authors: RL
authors: Garcia
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, United States.
authors: Barbara A
authors: BA
authors: Goff
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, United States.
authors: Elizabeth M
authors: EM
authors: Swisher
mesh_terms: D000328:Adult; D000368:Aged; D002467:Cell Nucleus / Q000473:pathology; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000473:pathology*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D011446:Prospective Studies
keywords: BRCA1; BRCA2; Cancer histology; Ovarian cancer