The Origin of Ovarian Carcinoma: Why the Debate Matters

March 1, 2012

By Sanjay Logani, M.D.

Ovarian cancer is the fifth deadliest cancer among American women. Unfortunately, despite all of the advances in early detection and improved cancer screening, ovarian cancer still has a disproportionately high mortality rate, which can be directly attributed to the difficulty diagnosing the disease in its early stages. As a result, most ovarian cancer patients are diagnosed too late with advanced-stage disease. Early detection of serous ovarian cancer would save the lives of many women, but there is no reliable screening test that has the sensitivity or the specificity to be useful in clinical practice.

Serous ovarian cancer is the most common subtype of epithelial ovarian cancer accounting for approximately 60% to 80% of ovarian cancer cases. The other major subtypes of epithelial ovarian cancer include endometrioid, clear cell, and mucinous carcinoma. While endometrioid and mucinous tumors often present at an early stage, serous and clear cell subtypes often show extraovarian spread at the time of clinical diagnosis. Less than 25% of the cases of serous or clear cell subtypes are detected at an early stage (stages I and II), a statistic which reflects grimly on the survival figures with these tumor subtypes.

New Developments in Approach:

• Thorough analysis of all fallopian tubes, especially in women who have risk-reducing surgeries because they are at high-risk for serous cancer.
• Discussion about the merits of removing the fallopian tubes or the just the fimbria in women at high risk of developing serous cancer (BRCA gene mutation carriers).
• Careful study of the fallopian tube epithelial cells as the starting point. 
• After a lengthy search, a precursor to this cancer has never been found in the ovary

The exact origin of ovarian epithelial cancer is still being debated with ovarian surface epithelium and fallopian tube epithelium being the leading contenders. While there is still much to learn about the origin of ovarian carcinoma, recent studies have uncovered some interesting findings.

Data collected from women with breast cancer and BRCA1 and BRCA2 gene mutation, who have had their ovaries and fallopian tubes removed to reduce the risk of ovarian cancer, has shed new light on the origin of ovarian cancer. Studies have found abnormal populations of cells in the fallopian tube samples taken from women with BRCA 1 or BRCA 2 gene mutations. Results of these studies have shown that up to 15 percent of women with the BRCA gene mutation have small, predominately non-invasive tumors within the fallopian tube fimbria, while about 33 percent had pre-malignant precursor lesions, called the p53 signature.

The p53 signature is a benign-appearing population of secretory cells that are characterized by DNA damage, p53 gene mutations, and accumulation of the p53 protein, the latter of which can be detected by tissue staining.

One of the functions of the p53 gene is to halt cell division when a cell has sustained DNA damage. However, if the p53 gene itself becomes disabled, damaged cells will proliferate and possibly lead to cancer. Repeated cellular injury and repair of the fallopian tube fimbria, secondary to repeated ovulatory cycles, might be the cause of the DNA damage that leads to the appearance of the p53 signature.

While it is interesting to debate the exact origin of ovarian epithelial carcinoma, the debate merits the question of why it matters. The answer is rather simplistic. Every year many women in the U.S. undergo hysterectomy for a benign condition such as uterine fibroids, dysmenorrhea or menorrhagia. It is a common surgical practice to leave the ovaries and fallopian tubes in the patient since many of these women are premenopausal. If the fallopian tube is indeed the site of origin of a significant proportion of pelvic serous carcinoma, then it begs the question that removal of the adnexa at the time of hysterectomy may be the best preventative tool we currently have to decrease the risk of pelvic serous carcinoma in our patients.

The focus of this update is to be aware of the latest research focusing on the fallopian tube as an important contender for the site of origin of the most common subtype of epithelial ovarian cancer and to be aware of the changing trend in the surgical practice of removal of bilateral adnexa for benign conditions in the hope of mitigating the risk for pelvic serous carcinoma.