The Development of High-grade Serous Carcinoma From Atypical Proliferative (Borderline) Serous Tumors and Low-grade Micropapillary Serous Carcinoma: A Morphologic and Molecular Genetic Analysis

Recently, we have proposed a model for the development of ovarian surface epithelial tumors. In this model, all histologic types of surface epithelial tumors are divided into 2 categories designated type I and type II which correspond to 2 pathways of tumorigenesis. Type I tumors include low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, malignant Brenner tumor, and clear cell carcinoma which develop slowly in a stepwise fashion from well-recognized precursors, namely atypical proliferative (borderline) tumors. Type II tumors are high-grade, rapidly growing tumors that typically have spread beyond the ovaries at presentation. They include high-grade serous carcinoma (“moderately” and “poorly” differentiated), malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma. These tumors are rarely associated with morphologically recognizable precursor lesions and it has been proposed that they develop “de novo” from ovarian inclusion cysts. This model implies that the pathogenesis of type I and type II tumors are separate and independent but it is not clear whether some type II tumors develop from type I tumors. In this study, we attempted to address this issue by determining the clonality of 6 cases of high-grade serous carcinomas that were closely associated with atypical proliferative serous (borderline) tumors and invasive low-grade micropapillary serous carcinomas. We reviewed 210 ovarian serous tumors from the surgical pathology files of the Johns Hopkins Hospital and identified 3 high-grade serous carcinoma that were directly associated with atypical proliferative serous (borderline) tumors and 3 that were associated with invasive low-grade micropapillary serous carcinomas. A morphologic continuum between the high-grade carcinoma and the low-grade tumors was observed in 4 cases whereas in the remaining 2 cases the high-grade and low-grade components were separate. Mutational analyses for KRAS, BRAF, and p53 genes were performed on microdissected samples from the high-grade and low-grade tumor areas for each case. All 6 tumors demonstrated wild-type BRAF and p53 genes. Only 2 of the 6 cases were informative from a molecular genetic standpoint. In those 2 cases we found the same mutations of KRAS in both the atypical proliferative serous (borderline) tumor and the high-grade serous carcinoma component of the tumor, indicating a clonal relationship. The above results suggest that the majority of high-grade and low-grade carcinomas develop independently but in rare cases, a high-grade serous carcinoma may arise from an atypical proliferative serous (borderline) tumor.

[1]  A. Dansonka-Mieszkowska,et al.  Geographical Variations in TP53 Mutational Spectrum in Ovarian Carcinomas , 2006, Annals of human genetics.

[2]  L. Cope,et al.  Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms , 2006, Cancer biology & therapy.

[3]  Wing H Wong,et al.  Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. , 2005, Cancer research.

[4]  I. Shih,et al.  Molecular Pathogenesis of Ovarian Borderline Tumors: New Insights and Old Challenges , 2005, Clinical Cancer Research.

[5]  I. Shih,et al.  Nuclear size distinguishes low- from high-grade ovarian serous carcinoma and predicts outcome. , 2005, Human pathology.

[6]  M. van de Rijn,et al.  Distinction between serous tumors of low malignant potential and serous carcinomas based on global mRNA expression profiling. , 2005, Gynecologic oncology.

[7]  Jalid Sehouli,et al.  Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential , 2005, Oncogene.

[8]  L. Cope,et al.  Patterns of p53 Mutations Separate Ovarian Serous Borderline Tumors and Low- and High-grade Carcinomas and Provide Support for a New Model of Ovarian Carcinogenesis: A Mutational Analysis With Immunohistochemical Correlation , 2005, The American journal of surgical pathology.

[9]  Chung-Liang Ho,et al.  Mutations of BRAF and KRAS Precede the Development of Ovarian Serous Borderline Tumors , 2004, Cancer Research.

[10]  P. Clement,et al.  Early recurrence of ovarian serous borderline tumor as high-grade carcinoma: a report of two cases. , 2004, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[11]  I. Shih,et al.  Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. , 2004, The American journal of pathology.

[12]  I. Shih,et al.  Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. , 2003, Journal of the National Cancer Institute.

[13]  E. Berns,et al.  TP53 and ovarian cancer , 2003, Human mutation.

[14]  I. Shih,et al.  Diverse tumorigenic pathways in ovarian serous carcinoma. , 2002, The American journal of pathology.

[15]  R. Scully,et al.  Early de novo ovarian carcinoma. A study of fourteen cases , 1994, Cancer.

[16]  H. Kitchener,et al.  p53 mutation is a common genetic event in ovarian carcinoma. , 1993, Cancer research.

[17]  A. Gadducci,et al.  P53 gene status in patients with advanced serous epithelial ovarian cancer in relation to response to paclitaxel- plus platinum-based chemotherapy and long-term clinical outcome. , 2006, Anticancer research.