Ovarian cancer – where are we today?

The keynote lecture given by Robert Kurman was one of several highlights of the first joint IAP/ESP Congress in Cologne. With the development of a dualistic model of ovarian cancer a paradigm shift has occurred. What does this mean for the pathologist, the clinician and – most important – the patient?

Paradigm shift in ovarian carcinomas origins research

The keynote lecture given by Robert Kurman was one of several highlights of the first joint IAP/ESP Congress in Cologne. With the development of a dualistic model of ovarian cancer a paradigm shift has occurred. What does this mean for the pathologist, the clinician and – most important – the patient?

Does the vast majority of ovarian carcinomas originate from the ovarian epithelium as understandably has been believed for a long time? No, says Professor Robert Kurman (Johns Hopkins Medicine, USA), one of the world’s leading pathologists. In a very comprehensive and lively presentation he made clear why he thinks the time has come for a true paradigm shift. Recently evidence has amounted suggesting that fallopian tube epithelium – be it benign or malignant – that implants on the ovary acts as the source of low-grade and high-grade serous carcinoma (LGSC and HGSC, respectively).

Also endometrioid and clear cell carcinomas can be regarded as involving the ovary secondarily. It is widely accepted that endometriosis develops from retrograde menstruation and serves as precursor for these malignancies. Maybe even the mucinous and transitional cell (Brenner) tumors might possibly be not derived from the ovary initially, but from transitional epithelial nests located in paraovarian locations at the tubo-peritoneal junction.

Major characteristics of type I and type II tumors

Clinicopathologic and molecular features of type I and type II ovarian carcinomas are:

Type I:

• About 25 % of ovarian cancer
• Usually present at stage I (confined to ovary)
• Prognosis excellent – 90 % survival
• Slow growth
• TP53 mutations absent
• Early detection possible
• Risk factor – endometriosis for endometrioid and clear cell

Type II:

• About 75 % of ovarian cancer
• 75 % present at advanced stage
• Prognosis poor – 30 % survival
• Fast growth
• TP53 mutations present
• Early detection very difficult
• Risk factor – BRCA mutation (usually germ line)

"It now appears that type I and type II ovarian tumors develop independently along different molecular pathways and outside the ovary", Kurman stated. In conclusion the only true primary ovarian neoplasms would be gonadal stromal and germ cell tumors similar to testicular tumors. According to Kurman a large number of molecular and histopathologic studies back the adapted dualistic model that initially has been proposed more than a decade ago. Looking at it in more detail it describes entirely different groups of diseases.

What are the clinical implications of the new paradigm?

Shifting the early events of ovarian carcinogenesis to the fallopian tube and endometrium instead of the ovary has important clinical implications. For example, preventive salpingectomy with ovarian conservation may improve patient care by reducing the burden of ovarian cancer while preserving hormonal function and fertility. Kurman presented several further examples, some of which we briefly summarize here:

• The vast majority of of type I tumors are stage IA. Therefore unilateral salpingo-oophorectomy seems to be therapeutically sufficient and adjuvant chemotherapy is of no added benefit. As long as the cancer is confined to the ovary, staging rarely detects occult disease, with the exception of
• For type II tumors the world looks different: Radical surgery and chemotherapy lengthen the interval to relapse but overall survival has not changed in over 50 years. Why? A possible answer might be that these treatments are directed at established cancers but not at the mechanisms by which cells become neoplastic. Like for other diseases a more rational approach to cancer treatment should focus on prevention and screening rather than on curing advances cases.
• In about 50 % of HGSC the homologous recombination repair (HRR) is defective, opening a therapeutic window by inhibition of the enzyme poly (ADP-ribose) polymerase (PARP).
• Germline BRCA mutations are a risk factor for type II ovarian cancer. Therefore bilateral removal of the fallopian tube and ovary serves as a so-called "risk reducing salpingo-oophorectomy" (RRSO) for the affected women. Women with previous serous tubal intraepithelial carcinomas (STIC) and positive peritoneal cytology should probably just be oberserved. An adjuvant therapy might be considered. Invasive cancer should be treated with chemotherapy. Using CA 125 and transvaginal ultrasound in the follow-up lacks sufficient sensitivity to detect early recurrence. The evidence for these recommendations is based on relatively small numbers.
• The screening for type II tumors with CA 125 and transvaginal ultrasound has not provided a survival benefit.
• Oral contraceptives (OCPs) are effective in the prevention of ovarian cancer. An epidemiologic analysis of 100,000 women showed that the risk reduction increased with time of usage and persisted for more than 30 years after the use had ceased.

Robert Kurman ended up his philosophically underlaid presentation with an inspiring picture of the particular value pathology has to contribute to health care: "Pathologists are biology watchers: We are in a unique position to take advantage of the data generated by the most powerful techniques in the laboratory, combine it with our knowledge of clinical behaviour, integrate it with what we see under the microscope and elucidate mechanisms of disease."

Source:
1. Kurman RJ, Shih I-M. The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded.Am J Pathol. 2016;186(4):733-47.
2. Kurman R. Keynote lecture: The dualistic model of ovarian cancer. Implications for early detection, prevention and treatment (ESP Symeonidis Lecture). IAP/ESP Congress. Cologne, 28 September 2016.