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. 2012 Aug;36(8):1170-7.
doi: 10.1097/PAS.0b013e31825d9b8d.

Prediction of BRCA1 germline mutation status in women with ovarian cancer using morphology-based criteria: identification of a BRCA1 ovarian cancer phenotype

Mika Fujiwara  1 , Valerie A McGuire, Anna Felberg, Weiva Sieh, Alice S Whittemore, Teri A Longacre
Affiliations

Prediction of BRCA1 germline mutation status in women with ovarian cancer using morphology-based criteria: identification of a BRCA1 ovarian cancer phenotype

Mika Fujiwara et al. Am J Surg Pathol. 2012 Aug.

Abstract

Specific morphologic features that may predict BRCA1 germline mutation in ovarian cancer have neither been well described nor independently tested. We identified 5 morphologic features associated with BRCA1 mutation status in a series of 20 ovarian cancers from BRCA1 mutation carriers: (1) modified Nottingham grade 3; (2) serous/undifferentiated histology; (3) prominent intraepithelial lymphocytes; (4) marked nuclear atypia with giant/bizarre forms; and (5) abundant mitotic figures. These morphologic features were then tested on 325 ovarian tumors drawn from a population-based Greater Bay Area Cancer Registry and classified into 3 categories independent of the BRCA1 status: "Compatible with BRCA1," "Possibly compatible with BRCA1," and "Not compatible with BRCA1." All "Compatible with BRCA1" tumors were additionally investigated for presence of dominant adnexal mass, fallopian tube mucosal involvement, and uterine cornu involvement. The positive and negative predictive values for "Compatible with BRCA1" were 11/42 (26.2%) and 267/283 (94.3%), respectively, whereas combining the "Compatible with BRCA1" and "Possibly compatible with BRCA1" had positive and negative predictive values of 18/85 (21.2%) and 231/240 (96.3%), respectively. Although dominant adnexal mass and uterine cornu involvement did not add further predictive value, the likelihood of BRCA1 positivity increased to 42.9% when a tumor with "Compatible with BRCA1" histology was also associated with fallopian tube mucosal involvement. The combination of modified Nottingham grade 3 serous or undifferentiated histology, prominent intraepithelial lymphocytes, marked nuclear atypia with giant/bizarre nuclei, and high mitotic index should help to identify women for BRCA1 mutational analysis in the appropriate clinical setting. Ovarian tumors lacking this specific phenotype are unlikely to be associated with BRCA1 and should not undergo mutational analysis in the absence of other indications.

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Figures

Figure 1
Figure 1
Histologic subtypes of the 325 total cases. Undiff: Undifferentiated; Misc: Miscellaneous
Figure 2
Figure 2
Histologic categorization of cases. “Compatible with BRCA1” showing high grade serous histology (A), abundant mitotic figures, severe atypia with giant bizarre nuclei (B), and prominent intraepithelial lymphocytes (C).
Figure 3
Figure 3
Histologic categorization of cases. “Possibly compatible with BRCA1” showing high grade serous histology (A) without prominent intraepithelial lymphocytes (B), but with severe atypia with bizarre nuclei and only scattered mitotic figures (C).
Figure 4
Figure 4
“Not compatible with BRCA1” showing high grade histology with transitional features (A), few to no intraepithelial lymphocytes (B), monomorphous nuclei with minimal atypia, no giant/bizarre nuclei and no mitotic figures (C).
Figure 5
Figure 5
Histologic subtypes of the 27 BRCA1 positive cases. HG: High grade; C: Compatible with BRCA1; PC: Possibly compatible with BRCA1; NC: Not compatible with BRCA1. Undiff: Undifferentiated; LMP: low malignant potential
Figure 6
Figure 6
Relationship between cases with “Compatible with BRCA1” histology, presence of dominant mass, fallopian tube mucosal involvement and uterine cornu involvement and BRCA1 positive status; C: Compatible with BRCA1; DM: Dominant mass; FTM: Fallopian tube mucosal involvement; UC: Uterine cornu involvement
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