Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management

Abstract

Hereditary ovarian cancer accounts for at least 5% of the estimated 22,000 new cases of this disease during 2009. During this same time, over 15,000 will die from malignancy ascribed to ovarian origin. The bulk of these hereditary cases fits the hereditary breast-ovarian cancer syndrome, while virtually all of the remainder will be consonant with the Lynch syndrome, disorders which are autosomal dominantly inherited. Advances in molecular genetics have led to the identification of BRCA1 and BRCA2 gene mutations which predispose to the hereditary breast-ovarian cancer syndrome, and mutations in mismatch repair genes, the most common of which are MSH2 and MLH1, which predispose to Lynch syndrome. These discoveries enable relatively certain diagnosis, limited only by their variable penetrance, so that identification of mutation carriers through a comprehensive cancer family history might be possible. This paper reviews the subject of hereditary ovarian cancer, with particular attention to its molecular genetic basis, its pathology, and its phenotypic/genotypic heterogeneity.

Figure 1

The pedigree of one of the families involved in the linkage studies that demonstrated that the 17q12–q23 locus for early‐onset breast cancer was also associated with hereditary ovarian cancer (Narod et al., 1991).

Figure 2

Pedigree of an HBOC family with multiple occurrences of ovarian cancer in concert with carcinoma of the breast wherein a BRCA1 mutation was found. Note also the strikingly early onset of ovarian cancer shown in III‐2 with onset at age 33, along with early onset in additional individuals shown in the pedigree.

Figure 3

Pedigree depicting an HBOC family with a known BRCA2 mutation. Notable are the two individuals with ovarian and breast cancer (II‐2, II‐3).

Figure 4

Pedigree of a family showing the Lynch syndrome as evidenced by early‐onset colorectal cancer as shown in individual III‐3, in whom the disease was diagnosed at 32 years of age with death at the same age. Note also occurrences of carcinoma of the ovary and endometrium in individuals IV‐9, IV‐15, and IV‐16. Individual III‐7 was diagnosed with ovarian cancer; her mother (II‐4) had “uterine cancer,” but we do not have the pathology so we cannot exclude endometrial cancer.

Figure 5

Pedigree of another example of a Lynch syndrome family with multiple occurrences of early‐onset ovarian cancer. Note individual II‐6 with carcinoma of the ovary and endometrium at age 46 years, carcinoma of the cecum at age 47 years, and of the sigmoid colon at age 56 years. That individual has a daughter with early‐onset ovarian cancer (III‐13) and another daughter (III‐16) with carcinoma of the ovary, endometrium, and colon.

Figure 6

Schematic representation of a dualistic model depicting the development of ovarian cancer. Low‐grade carcinomas are thought to develop in a stepwise manner from an atypical proliferative tumor through a noninvasive stage (LMP) before becoming invasive. These tumors are frequently associated with K‐RAS or BRAF mutations and loss of PTEN. Somatic high‐grade carcinomas (most commonly serous) develop from the ovarian surface epithelium and/or inclusion cysts without morphologically recognizable intermediate stages. K‐RAS and BRAF mutations are less common in these tumors, whereas TP53 is frequently mutated as well as members of the PI3K/AKT pathway. In hereditary forms of this disease (far left), the initial step in BRCA1 or BRCA2 mutation carriers is thought to consist of a TP53 mutation followed by genotoxic injury (p53 signature). In the fimbria, a tubal intraepithelial carcinoma (TIC) develops in some instances and may invade locally or spread to other peritoneal surfaces, such as the ovary and pelvis. Depending on the location and rate of tumor growth, the tumor might be diagnosed as a primary tubal, ovarian, or peritoneal carcinoma. Whether somatic ovarian cancers arise via the fimbria route remains to be demonstrated.

Figure 7

Serous papillary carcinoma, 200×, H&E. Arrow shows cross‐section of a papilla.

Figure 8

Mucinous carcinoma, 200×, H&E. Arrow shows tall columnar cells with intracytoplasmic mucin.

Figure 9

Endometrioid carcinoma, 200×, H&E. Arrow shows columnar cells with complex gland formation.

Figure 10

Clear cell carcinoma, 200×, H&E. Numerous vacuolated cells are seen.

Figure 11

Immunohistochemical analysis of a tubal intraepithelial carcinoma (TIC) and a concurrent ovarian serous carcinoma diagnosed in a 59 year old. The tumor and TIC both stained strongly for p53 and MIB1 (the proliferative marker Ki‐67). Images were taken under 40× and 400× magnification, respectively (Q. Cai and Godwin, unpublished data).

Figure 12

Immunohistochemical analysis showing examples of a p53 signature (brown staining cells) found in benign‐appearing distal fallopian tube mucosa from two individuals. Images were taken under 200× magnification.

Figure 13

This remarkable family contains an excess of ovarian carcinoma in association with carcinoma of the breast. It appears from the clinical standpoint to be a classical HBOC kindred. However, BRCA1, BRCA2, p53, and PTEN have all been evaluated only to find a complete absence of any cancer‐causing mutations. This pedigree clearly shows the diagnostic dilemma that may take place in assessing pedigrees with the advantage of a molecular genetic search for cancer‐causing germline mutations while turning up an absence of any diagnostic certainty.