Progress in pathologyMolecular pathogenesis and extraovarian origin of epithelial ovarian cancer—Shifting the paradigm
Section snippets
Molecular pathogenesis of epithelial ovarian carcinoma
The introduction of the “borderline (low malignant potential)” category was an important step in refining the morphologic classification of EOC by identifying a group of tumors, defined as lacking destructive invasive growth that had a significantly better outcome than the invasive carcinomas. Because it was rare to find a borderline tumor coexisting with an invasive carcinoma, it was generally believed that they were unrelated. In 1996, a relationship between serous borderline tumor (SBT) and
Serous tumors
The conventional view of the origin of serous tumor has been that they were derived from the ovarian surface epithelium or cortical inclusion cysts. Therefore, there was surprise and skepticism when a group of Dutch investigators in 2001 first described tubal intraepithelial carcinomas, later designated “serous tubal intraepithelial carcinomas (STICs)” and occult invasive HGSCs in the fallopian tube that closely resembled ovarian HGSC, in women with a genetic predisposition to ovarian cancer
The new paradigm and its clinical implications
The aforementioned molecular genetic and morphologic studies have provided new insight into the pathogenesis and origin of EOC and, in so doing, have ushered in a new paradigm. These studies provide compelling evidence that contrary to what was previously believed, EOC is not primarily ovarian in origin but rather secondary leading to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors. This is not merely of
Conclusions
Recent morphologic, immunohistochemical, and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of EOC. The paradigm is based on a dualistic model of carcinogenesis that divides EOC into 2 broad categories designated types I and II. Type I tumors are generally indolent, present in stage I (tumor confined to the ovary), and develop from borderline tumors and endometriosis. They are characterized by specific mutations, including KRAS, BRAF,
References (96)
Origins and molecular pathology of ovarian cancer
Mod Pathol
(2005)- et al.
Acquisition of a second mutation of the Tp53 alleles immediately precedes epithelial morphological transformation in ovarian tumorigenicity
Gynecol Oncol
(2009) - et al.
Altered surface and cyst epithelium of ovaries removed prophylactically from women with a family history of ovarian cancer
Hum Pathol
(1999) - et al.
Evaluation of normal-sized ovaries associated with primary peritoneal serous carcinoma for possible precursors of ovarian serous carcinoma
Gynecol Oncol
(2007) - et al.
Ovarian tumorigenesis- a proposed model based on morphological and molecular genetic analysis
Am J Pathol
(2004) - et al.
A critical re-appraisal of BRCA1 methylation studies in ovarian cancer
Gynecol Oncol
(2010) - et al.
Low malignant potential tumors with micropapillary features are molecularly similar to low grade serous carcinoma of the ovary
Gynecol Oncol
(2010) - et al.
Distinction between serous tumors of low malignant potential and serous carcinomas based on global mRNA expression profiling
Gynecol Oncol
(2005) - et al.
KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants
Gynecol Oncol
(2006) - et al.
HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors
Cancer Cell
(2006)
Micropapillary serous carcinoma of the ovary has distinct patterns of chromosomal imbalances by comparative genomic hybridization compared with atypical proliferative serous tumors and serous carcinomas
Hum Pathol
Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas
Hum Pathol
Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/B-catenin and PI3K/Pten signaling pathways
Cancer Cell
Alternate molecular genetic pathways in ovarian carcinomas of common histological types
Hum Pathol
Beta-catenin expression pattern in stage I and II ovarian carcinomas: relationship with beta-catenin gene: mutations, clinicopathological features, and clinical outcome
Am J Pathol
Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma
Gynecol Oncol
Tubal ligation and risk of ovarian cancer
Lancet
BRCA1/2-related ovarian cancers are of tubal origin: a hypothesis
Gynecol Oncol
Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis
Gynecol Oncol
Clinical and pathologic findings of prophylactic salpingo-oophorectomies in 159 BRCA1 and BRCA2 carriers
Gynecol Oncol
Candidate serous cancer precursors in fallopian tube epithelium of BRCA1/2 mutation carriers
Mod Pathol
Ovarian cancer and hormone replacement therapy in the Million Women Study
Lancet
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial
Lancet
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial
Lancet
The structure of scientific revolutions, 3rd ed., enlarged
University of Chicago Press
Ovarian tumors
Gynecological and obstetrical pathology
Atlas of ovarian tumors
Atlas of tumor pathology. Section ix–fascicle 3: tumors of the female sex organs. Part 3: tumors of the ovary and fallopian tube
International Histological Classification of Tumours no. 9. Histological typing of ovarian tunours
Early de novo ovarian carcinoma. A study of fourteen cases
Cancer
Ovarian dysplasia: a review
Int J Gynecol Cancer
Ovarian dysplasia in prophylactic oophorectomy specimens: cytogenetic and morphometric correlations
Cancer
Microscopic benign and invasive malignant neoplasms and a cancer-prone phenotype in prophylactic oophorectomies
J Natl Cancer Inst
Histopathologic features of ovaries at increased risk for carcinoma. A case-control analysis
Int J Gynecol Pathol
Comparison of prophylactic oophorectomy specimens from carriers and noncarriers of a BRCA1 or BRCA2 gene mutation. United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group
J Natl Cancer Inst
Molecular events associated with dysplastic morphologic transformation and initiation of ovarian tumorigenicity
Cancer
Absence of premalignant histologic, molecular, or cell biologic alterations in prophylactic oophorectomy specimens from BRCA1 heterozygotes
Cancer
Ovarian epithelial dysplasia and prophylactic oophorectomy for genetic risk
Int J Gynecol Cancer
Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors
Am J Surg Pathol
Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma
Science
N Engl J Med
Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary
J Pathol
Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential
Oncogene
Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary
Cancer Res
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
Am J Surg Pathol
Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma
J Natl Cancer Inst
Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy
Cancer Res
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This study is supported by a CDMRP grant (no. OC100517) from the US Department of Defense.