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CASE 17

CASE 17. Michael H. Roh, MD, PhD Assistant Professor of Pathology University of Michigan Health System. History. 37 y.o. G1P1 patient with a strong family history of ovarian cancer including an aunt who was diagnosed with ovarian cancer at the age of 40.  

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CASE 17

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  1. CASE 17 Michael H. Roh, MD, PhD Assistant Professor of Pathology University of Michigan Health System

  2. History • 37 y.o. G1P1 patient with a strong family history of ovarian cancer including an aunt who was diagnosed with ovarian cancer at the age of 40.   • Based on this early onset of ovarian cancer in the family, genetic testing was performed and the patient was found to be a BRCA2 gene mutation carrier.

  3. History • The patient elected to undergo a prophylactic bilateral salpingo-oophorectomy. • The slide represents serial sections from the right distal fallopian tube which was entirely submitted for histologic evaluation.

  4. Microscopic Findings

  5. p53

  6. Ki-67/Mib-1

  7. Diagnosis • Right ovary and fallopian tube: Serous tubal intraepithelial carcinoma (STIC) in the distal fallopian tube. Ovary is negative for tumor. • Left ovary and fallopian tube: Negative for tumor. • Pelvic washing: Positive for adenocarcinoma.

  8. Ovarian Carcinoma • 21,880 estimated new cases in 2010, accounting for 3% of all cancers in women. • Leading cause of death from gynecologic cancers with 13,850 estimated deaths in 2010. • Lifetime risk of approximately 1.7% in the general population. • Up to 46% in those with BRCA1 & BRCA2 mutations Jemal et al., 2010 Lancaster et al., 2007

  9. Ovarian carcinogenesis Type 1 Type 2 - most lethal Endometrioid, mucinous, clear cell and low grade serous carcinomas K-Ras, B-Raf, b-catenin, PTEN Often develop in a step-wise manner from cortical inclusion cysts and endometriosis to borderline tumors to invasive malignancies. High grade serous carcinoma, carcinosarcoma p53 Often present in later stages and appear to arise from ovary, tube and peritoneum without morphologic intermediates Fallopian tube Ovary Ovary ? Singer et al. 2005; Shih and Kurman, 2004

  10. High-grade serous carcinomas • Often involve the surface of the ovaries and frequently show omental / peritoneal involvement at the time of detection • Due to extensive disease spread, identification of the precursor lesion(s) has been elusive.

  11. Assigning a Site of Origin of Pelvic Serous Carcinomas Adapted from FIGO and WHO classifications

  12. Origin of high-grade serous carcinomas Conflicting reports regarding the existence of ovarian serous dysplasia and accumulations of p53 protein in cortical inclusion cysts and on the ovarian surface epithelium.

  13. Prophylactic oophorectomies

  14. Patients with BRCA Mutations Provide a Model for Early Ovarian Cancer Opportunity to evaluate the tubes and ovaries in women who undergo prophylactic salpingo-oophorectomy and detect tumors early in their course. Colgan et al., Am J Surg Path, 2001; Leeper et al., Gynecol Oncol, 2002; Powell et al., J Clin Oncol, 2005; Finch et al., Gynecol Oncol, 2005; Cass et al., Obstet Gynecol, 2005; Medeiros et al., Am J Surg Path, 2006

  15. SEE-FIM Protocol Sectioning and extensively examining the fimbriated end of the fallopian tube. Based on the hypothesis that the fimbriated end is susceptible to the development of tubal neoplasia. Medeiros et al., Am J Surg Path, 2006

  16. Early serous carcinoma in BRCA+ prophylactic specimens

  17. Early Serous Carcinoma in BRCA+ Women is found in the Distal Tube • Seven early cancers detected in BRCA+ patients over a two year period. • All were in the fallopian tube (in association with tubal intraepithelial carcinoma). • Six of seven were in the fimbria. • Ovarian involvement in two cases (surface implants). Callahan et al., J Clin Oncol, 2007

  18. Features of Serous Tubal IntraepithelialCarcinomas (STICs) • Composed of a stretch of neoplastic secretory cells in continuity with normal salpingeal epithelium (secretory + ciliated cells). • Significant atypia with hyperchromatic nuclei with prominent nucleoli; increased N/C ratio. • Loss of cell polarity & increased nuclear pseudostratification. • Mutations in the p53 tumor suppressor gene.

  19. Immunohistochemistry H&E PAX8 p73 p53 Normal FT TIC Roh et al. Am J Surg Pathol, 2009.

  20. The “p53 Signature” H & E p53 Ki-67/Mib-1

  21. Evidence that STICs arise from p53 signatures Both entities share the same p53 mutation Lee et al, J Pathol, 2007

  22. p53Mib-1p53Mib-1Mib-1 Serous Carcinogenic Sequence in the Fimbria DNA damage p53 mutation + expansion DNA damage p53 mutation + expansion + proliferation DNA damage p53 mutation + expansion + proliferation + malignancy Step I Step II Step III Latent precursor (p53 signature) Tubal intrepithelial lesions in transition (TILT) TIC Jarboe et al. Int J Gynecol Pathol, 2008

  23. p53 Immunohistochemistry • Missense mutations are the most commonly encountered p53 mutations and are associated with p53 overexpression. Roh et al. Mod Pathol, 2010.

  24. p53(-) / PAX-2(-) STIC p53 PAX-2 Roh et al. Mod Pathol, 2010.

  25. Case 17: Mib-1 & PAX-2 Immunohistochemistry

  26. Question Is the distal fallopian tube an origin for serous carcinoma in patients without BRCA mutations?

  27. Serous carcinoma cases where the fallopian tubes were entirely submitted (SEE-FIM): Kindelberger et al, Am J Surg Pathol,2007: 55 cases of high grade pelvic serous carcinoma: 29 (48%) STICs Carlson et al, J Clin Oncol, 2008: 19 cases of primary peritoneal serous carcinoma: 9 (47%) cases with STICs

  28. Coexisting STIC & Ovarian Surface Carcinoma Kindelberger et al., Am J Surg Pathol, 2007

  29. p53 Mutations in STIC and Concurrent Ovarian Serous Carcinoma Kindelberger et al., Am J Surg Pathol, 2007

  30. Coexisting STIC and Primary Peritoneal Carcinoma Distal Tube Omentum P53 MIB-1 Carlson et al. J Clin Oncol, 2008

  31. p53 Mutations in STIC and Concurrent Primary Peritoneal Serous Carcinoma Carlson et al. J Clin Oncol, 2008

  32. Parameters Corresponding to Sites of Origin Dominant Ovarian Mass (DOM) Tubal Intraepithelial Carcinoma (TIC) STIC+ DOM+

  33. * p = 0.003 ** p = 0.001 Roh et al. Am J Surg Pathol, 2009.

  34. Two Pathways for Ovarian Cancer Pathogenesis Kindelberger et al. 2007

  35. What is the prognosis for patients in which early serous in-situ carcinomas are detected? Should these patients be given chemotherapy?

  36. Outcomes in Stage 0 Disease Carlson et al, 2008 p53

  37. www.pointproject.org

  38. Acknowledgements • BWH Division of Women’s and Perinatal Pathology • Christopher P. Crum, MD • David Kindelberger, MD • Yonghee Lee, MD • Elke Jarboe, MD • Joe Carlson, MD, PhD • Dana Semmel, MD • Ann Folkins, MD • Martin C. Chang, MD, PhD • Dana Farber Cancer Institute • Yosuf Yassin • Alexander Miron, PhD

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