Interpretation of p53 Immunostains. P53 Mutations are Ubiquitous in High Grade Serous Carcinoma. Diffuse strong positive nuclear staining

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1 Stains for Tumor Classification p53 p16 WT1 HMGA2 P53 Mutations are Ubiquitous in High Grade Serous Carcinoma Source Ahmed et al Australian Ovarian Cancer Study Cancer Genome Atlas Research Network Cases TP53 mutation % mutated % Interpretation of p53 Immunostains Diffuse strong positive nuclear staining Missense mutation Complete absence of nuclear staining Null mutation (due to frameshift, splicing junction and nonsense mutations) Weak and patchy nuclear staining Wild type; no mutation 11

2 Positive total staining Negative focal weak staining Positive total lack of stain The Journal of Pathology 2010; 222: Positive p16 Negative p16 BRCA Mutations are the Most Common Cause of Hereditary Ovarian Cancer Lifetime risk of breast cancer 56-84% in women with BRCA1 or BRCA2 mutations BRCA1-7% of ovarian cancer cases 39-63% risk of ovarian cancer by age 70 Risk greatest after 40 years of age Accounts for 70% of hereditary ovarian cancer BRCA2-2% of ovarian cancer cases 11-27% risk of ovarian cancer by age 70 Risk greatest after 50 years of age 76% diagnosed after age 60 12

3 BRCA Proteins Play critical roles in maintenance of genomic stability, especially via homologous recombination. BRCA1 gene on chromosome 17 (17q 12-21) Smaller, 1683 amino acids Ubiquitin ligase, impact on DNA repair, transcriptional regulation, cell-cycle progression, and meiotic sex chromosome inactivation. BRCA2 gene on chromosome 13 (13q 12-13) Larger, 3,418 amino acids Integral component of homologous recombination machinery Altered pathways in High Grade Serous Carcinoma D Bell et al. Nature 474, (2011) Cancer Genome Atlas Research Network 13

4 Figure. Kaplan-Meier Estimates of Cumulative Survival According to BRCA1/2 Status Bolton, K. L. et al. JAMA 2012;307: Copyright restrictions may apply. Can pathologists recognize BRCA associated cancers by their histologic appearance? Histologic Features of BRCA1 Associated Carcinomas Fujiwara Serous or undifferentiated Marked atypia Giant bizarre nuclei Prominent TIL (>40/hpf) Numerous mitotic figures All 5 compatible with BRCA1 3 or 4 possibly compatible with BRCA1 0-2 not compatible with BRCA1 Soslow Serous SET features (solid, pseudoendometrioid, transitional) Geographic necrosis Prominent TIL (>37/ hpf) High mitotic rate (>51/10 hpf) BRCA related if 2 features BRCA indeterminate if 1 feature Not BRCA if no features Mod Pathol 2012; 25(4):

5 Pages Pages Mean age of ovarian cancer diagnosis 51, 54% diagnosed before age 50 -Prophylactic bilateral salpingo-oophorectomy (risk reducing salpingooophorectomy) reduces risk of ovarian cancer by 95% and risk of breast cancer by 50% Cross sections of the rest of the tube like a sausage Longitudinally block the fimbriated end of the tube 15

6 Sectioning of RRSO Specimens Case 4 Tubal Intraepithelial Carcinoma in an RRSO 1. Nuclei are enlarged, hyperchromatic, pleomorphic. 2. Nuclei are stratified, tufted. 3. Loss of polarity. 4. Mitotic figures, apoptotic bodies present. 5. Usually p53+, high percentage stain for MIB No invasion. 16

7 Pathology Review of 150 RRSO Cases Performed at UCSF Case Ovary FT Side Size Met Stage FU 1 Serous Neg Uni 0.9 mm None IA PP, 7y 2 Neg Serous, TIC, I Uni 8.2 mm None IA-0 NED, 7y 3 Neg Serous, TIC, F Uni 2.0 mm + Cyto IC NED, 4y 4 CIS, surface TIC, F Uni 1.0 mm None 0 NED, 3y 5 Serous Neg Bi 11, 3 mm LN IIIC AWT, 2y 6 Neg TIC, F Uni 1 mm None 0 NED, 1.5y 7 Neg TIC, F Uni 2 mm + Cyto IC NED, 1y 8 Neg TIC, I Uni 2 mm None 0 R 9 Serous Serous, TIC, F Ovary Bi FT Uni Ovary 13, 5.5 mm FT 6 mm LN + Cyto Positive findings in about 6% of patients IIIC R STIC Could be a Precursor of Pelvic High Grade Serous Carcinoma Kindleberger et al, 2007 Przybycin et al, 2010 Kuhn et al, % of high grade pelvic serous carcinomas associated with a STIC 60% of high grade pelvic serous carcinomas associated with a STIC 29 cases with a STIC and high grade pelvic serous carcinoma Same p53 mutation in STIC and ovarian carcinoma in 5/5 tested (100%) Same p53 mutation in 27/29 (93%) 17

8 Kindelberger DW et al. Am J Surg Pathol 2007;31: Findings in the Left Fallopian Tube of CTTR case 1 Serous Carcinoma Serous Tubal Intraepithelial Carcinoma 18

9 p53 p16 CASE 1 Diagnosis Pelvic High Grade Serous Carcinoma, Possibly Originating in the Fallopian Tube Case 2 The patient was a 53 year old woman. No clinical history was provided. She was treated by hysterectomy and BSO, with staging Tumor involved both ovaries, and there was seeding of the omentum, cul-desac peritoneum, and uterine serosa, and involvement of an omental lymph node 19