Despite advances in medicine, ovarian cancer remains the deadliest of the gynecological malignancies. Herein we present the latest information on the pathophysiology of ovarian cancer and its significance for ovarian cancer screening and prevention. A new paradigm for ovarian cancer pathogenesis presupposes 2 distinct types of ovarian epithelial carcinoma with distinct molecular profiles: type I and type II carcinomas. Type I tumors include endometrioid, clear-cell carcinoma, and low-grade serous carcinoma and mostly arise via defined sequence either from endometriosis or from borderline serous tumors, mostly presenting in an early stage. More frequent type II carcinomas are usually high-grade serous tumors, and recent evidence suggests that the majority arise from the fimbriated end of the fallopian tube. Subsequently, high-grade serous carcinomas usually present at advanced stages, likely as a consequence of the rapid peritoneal seeding from the open ends of the fallopian tubes. On the other hand, careful clinical evaluation should be performed along with risk stratification and targeted treatment of women with premalignant conditions leading to type I cancers, most notably endometriosis and endometriomas. Although the chance of malignant transformation is low, an understanding of this link offers a possibility of prevention and early intervention. This new evidence explains difficulties in ovarian cancer screening and helps in forming new recommendations for ovarian cancer risk evaluation and prophylactic treatments.
Ovarian cancer is the second most common gynecological malignancy in developed countries and the most lethal. In the United States, there are approximately 22,000 new cases of ovarian cancer diagnosed each year and 14,000 cancer-related deaths.
The majority of ovarian cancers are of epithelial origin, whereas fewer ovarian cancers develop from the remaining cell types, such as sex-cord stromal, germ cell, or mixed cell–type tumors. The most common histological subtypes of epithelial ovarian carcinomas are serous (68-71%), endometrioid (9-11%), clear cell (12-13%), mucinous (3%), transitional (1%), and mixed histologies (6%). At the time of diagnosis, the majority of epithelial ovarian cancers are advanced-stage, high-grade serous carcinomas and have a poor prognosis compared with early-stage carcinomas.
In the last 50 years, despite advances in cytoreductive radical surgery and cytotoxic chemotherapy, marginal improvement has been seen in the overall survival of patients with ovarian cancer. Attempts at early detection strategies in the last 2 decades have failed to provide survival benefit. Although the potential benefit of an effective screening strategy for ovarian cancer is great, to date studies have not shown any decrease in morbidity and mortality.
The best example is the Prostate, Lung, Colorectal, and Ovarian cancer screening trial, which evaluated the effect of combined modality screening (ie, transvaginal ultrasound and CA-125 serum level) for ovarian cancer. The Prostate, Lung, Colorectal, and Ovarian trial did not find any reduction in ovarian cancer mortality using screening with cancer antigen 125 and transvaginal ultrasound.
Another large multicenter, randomized controlled trial currently looking at not only mortality but also cost, acceptance by patients, and physical and psychosocial morbidities associated with transvaginal ultrasound and CA-125 screening is the United Kingdom Collaborative Trial of Ovarian Cancer Screening.
New evidence suggests that high-grade serous carcinoma, frequently presenting as an advanced stage, often originates from the fimbriated end of the fallopian tube. This is in contrast to low-grade serous endometrioid and clear cell histology, which mostly presents in the early stage and mostly originates from borderline serous carcinoma or endometriosis. Herein we will discuss new perspectives in the pathophysiology of different histologies of epithelial ovarian cancer and present some possible preventative steps in decreasing the risks of this malignancy and possible future screening methodologies.
Etiology
The etiology of ovarian cancer remains poorly understood, and the source population of epithelial ovarian cancer progenitors has become a matter of controversy. Traditionally, the ovarian surface epithelium was thought to be the primary source of ovarian malignancies. Indeed, the theory of incessant ovulation presupposes that repetitive involvement of the ovarian surface in the process of ovulation is a risk factor for ovarian cancer.
Factors associated with ovulation include injury and repair of the ovarian surface epithelium in response to follicle rupture, inflammatory effects of the ovarian environment surrounding ruptured follicle, entrapment of ovarian surface epithelium cells within the ovary with resulting inclusion cyst formation, and steroid hormone effects of the uniquely high concentrations of progesterone, androgens, and estrogen in the local ovarian environment during each menstrual cycle. Evidence has accumulated, however, to suggest that many cases of epithelial ovarian cancer originate in the distal portion of the fallopian tube, more precisely the fimbrial epithelium.
The initial evidence implicating the fimbrial epithelium came from risk-reducing salpingo-oophorectomies in women who had either BRCA gene mutations or a strong family history of ovarian cancer. When the entire tube was serially examined, foci of small in situ tubal intraepithelial carcinoma (TIC) were found. These are regions of dysplasia within tubal epithelium that demonstrate high levels of TP53 mutations.
Later similar lesions were found in the fimbrial epithelium of a significant number of cases of sporadic ovarian carcinomas. Przybycin et al identified TIC in 60% of consecutive ovarian cancer cases when tubes were systematically examined. Yet these precursor lesions were not found in the fimbrial epithelium of nonserous types of ovarian carcinoma.
Classification and new theories
Several groups have now convincingly established that there are 2 distinct types of epithelial ovarian carcinoma: type I and type II. Type I tumors arise via well-recognized sequence either from borderline serous tumors or from endometriosis and include low-grade serous carcinoma, endometrioid, and clear-cell carcinoma. These tumors are often early stage and low-grade tumors, with a relatively indolent disease course. Type II carcinomas are more frequent, usually of serous histology, are high grade, and seem to originate from the fimbrial epithelium in up to 60% of the cases. Subsequently, high-grade serous carcinomas present clinically as stage 3 or 4 disease, consistent with the hypothesis of peritoneal seeding by malignant cells from the fimbriated end of the tubes.
The molecular profile of the 2 types are different and correlate well with the distinct nature of type I and type II carcinomas. Type I carcinomas are characterized by KRAS , BRAF , ERBB2 , CTNNB1 , PTEN , PIK3CA , ARID1A , PPP2R1A , and BCL2 mutations. On the other hand, the majority of type II tumors are characterized by TP53 mutations. Indeed, the TP53 mutations are present in almost 96% of high-grade serous ovarian carcinomas of the Cancer Genome Atlas dataset.
Role of the fallopian tube and high-grade serous carcinoma
Today we understand that the rapid progression of high-grade serous carcinomas is consistent with seeding of the peritoneal cavity by malignant cells from the fimbriated ends of the fallopian tubes. What not so long ago was thought to be a precursor lesion in the fimbrial epithelium of BRCA carriers is now found in up to 60% of all cases of epithelial ovarian cancer. The precursor lesion, serous TIC, has now been defined and it typically consists of secretory cells, lacks the ciliated cells of a normal fallopian tube, has a TP53 signature, and is associated with a high degree of DNA repair pathway alterations including BRCA and BRCA -like mutation.
The Gynecologic Oncology Group is currently completing a nonrandomized prospective trial comparing longitudinal screening with CA-125 and ultrasound to risk-reducing bilateral salpingo-oophorectomy in a high genetic risk population. The results from the surgical intervention arm of Gynecologic Oncologic Group (GOG-0199) found that 2.6% of women undergoing risk reducing salpingo-oophorectomy were diagnosed with ovarian/tubal neoplasm’s (4.6% of BRCA1 mutation carriers, 3.5% of BRCA2 mutation carriers, and 0.5% of noncarriers). Overall, 56% of women with ovarian/tubal neoplasia had serous TIC or stage I or II invasive cancer.
Classification and new theories
Several groups have now convincingly established that there are 2 distinct types of epithelial ovarian carcinoma: type I and type II. Type I tumors arise via well-recognized sequence either from borderline serous tumors or from endometriosis and include low-grade serous carcinoma, endometrioid, and clear-cell carcinoma. These tumors are often early stage and low-grade tumors, with a relatively indolent disease course. Type II carcinomas are more frequent, usually of serous histology, are high grade, and seem to originate from the fimbrial epithelium in up to 60% of the cases. Subsequently, high-grade serous carcinomas present clinically as stage 3 or 4 disease, consistent with the hypothesis of peritoneal seeding by malignant cells from the fimbriated end of the tubes.
The molecular profile of the 2 types are different and correlate well with the distinct nature of type I and type II carcinomas. Type I carcinomas are characterized by KRAS , BRAF , ERBB2 , CTNNB1 , PTEN , PIK3CA , ARID1A , PPP2R1A , and BCL2 mutations. On the other hand, the majority of type II tumors are characterized by TP53 mutations. Indeed, the TP53 mutations are present in almost 96% of high-grade serous ovarian carcinomas of the Cancer Genome Atlas dataset.
Role of the fallopian tube and high-grade serous carcinoma
Today we understand that the rapid progression of high-grade serous carcinomas is consistent with seeding of the peritoneal cavity by malignant cells from the fimbriated ends of the fallopian tubes. What not so long ago was thought to be a precursor lesion in the fimbrial epithelium of BRCA carriers is now found in up to 60% of all cases of epithelial ovarian cancer. The precursor lesion, serous TIC, has now been defined and it typically consists of secretory cells, lacks the ciliated cells of a normal fallopian tube, has a TP53 signature, and is associated with a high degree of DNA repair pathway alterations including BRCA and BRCA -like mutation.
The Gynecologic Oncology Group is currently completing a nonrandomized prospective trial comparing longitudinal screening with CA-125 and ultrasound to risk-reducing bilateral salpingo-oophorectomy in a high genetic risk population. The results from the surgical intervention arm of Gynecologic Oncologic Group (GOG-0199) found that 2.6% of women undergoing risk reducing salpingo-oophorectomy were diagnosed with ovarian/tubal neoplasm’s (4.6% of BRCA1 mutation carriers, 3.5% of BRCA2 mutation carriers, and 0.5% of noncarriers). Overall, 56% of women with ovarian/tubal neoplasia had serous TIC or stage I or II invasive cancer.
Role of endometriosis and endometrioid and clear cell carcinoma
The association between endometriosis and ovarian cancer has perplexed clinicians and scientists for many years since it was first reported by Sampson. Several epidemiological studies have suggested the link between endometriosis and ovarian cancer. This was recently corroborated by the study assessing the association between self-reported endometriosis and risk of ovarian cancer.
Data collected from 13 original studies analyzed a total of 13,226 controls and 7911 women with invasive ovarian cancer, of which 818 (6.1%) and 738 (9.3%), respectively, reported a history of endometriosis. Self-reported endometriosis was associated with significantly increased risk for clear cell cancer (odds ratio [OR], 3.05), endometrioid cancer (OR, 2.21), and low-grade serous invasive ovarian cancers (OR, 2.21). There was no association between endometriosis and a risk for high-grade serous carcinoma.
In another metaanalysis, Kim et al investigated the impact of endometriosis on the risk and prognosis for ovarian cancer and evaluated the clinicopathological characteristics of endometriosis-associated ovarian cancer in comparison with nonendometriosis-associated ovarian cancer. Again, it was confirmed that endometriod and clear-cell carcinomas are more common in endometriosis-associated ovarian cancer (relative risks [RRs], 1.759 and 2.606, respectively), whereas serous carcinoma was less frequent in endometriosis-associated ovarian cancer than in the nonendometriosis-associated group (RR, 0.733).
The causes of malignant transformation of endometriosis are not clear, but several genetic, immunological, and hormonal factors have been implicated. Recent evidence links the role of microenvironment to the process of malignant transformation of endometriosis. Indeed, endometriosis is an inflammatory state, as a result of retrograde menstruation. Suryawanshi et al implicated a role of a complement system in malignant transformation. Specifically the group has reported for the first time the up-regulation of chronic activation of the complement pathway in women with endometriosis and its protumorigenic role.
Clinical implications
Keeping in mind these new findings, it is not surprising that early detection of high-grade serous carcinoma of the ovary is extremely challenging using current methods of mainly pelvic ultrasound and serum CA-125. The occult early lesion in the fallopian tube and the rapid seeding of the peritoneal cavity via the tubes are some of the theories proposed to describe the emergence of impressive ovarian masses as well as other peritoneal tumors. Thus, at the time of diagnosis, clinicians are faced with already advanced disease. In light of these findings, we need to focus on new strategies for the early detection of high-grade serous carcinomas, shifting our thinking toward the earliest precursor lesion within the fallopian tube.
Similarly, the methods for the early detection of type I ovarian carcinomas parallel our understanding of their precursor lesions and biology of their development. Endometriosis, defined as the presence of endometrial-like glands and stroma at extrauterine sites, is a chronic disease occurring in approximately 10% of women. Although endometriosis is considered a benign disease, it has several features that are characteristic of invasive cancers. Some of these features include invasion of the stroma of the organ in which it involves, development of local and distant foci, and high recurrence rate after treatment.
One of the most common sites of endometriosis is the ovary. Ovarian endometriosis is of particular interest because a proportion of ovarian cancers arise from ovarian endometriotic lesions, particularly clear-cell and endometrioid ovarian carcinomas. Although useful, both serum CA-125 and transvaginal ultrasound are poor screening modalities in differentiating malignant tumors from benign ones.
Clinical presentation of ovarian cancer associated with endometriosis includes symptoms that are typically attributed to endometriosis, including pelvic pain, exacerbation of dysmenorrhea, dyspareunia, and vaginal bleeding. In a series reported by Deligdisch et al, all stage I nonserous ovarian carcinomas were diagnosed based on associated symptomatology, such as pelvic pain with endometriosis/adnexal masses or vaginal bleeding associated with an underlying endometrial pathology. Pathology revealed an endometriotic ovarian cyst in 39 of 54 women with stage I nonserous ovarian carcinoma compared with 1 of 22 with stage I serous ovarian carcinoma. Furthermore, 33 of 54 women with stage I nonserous ovarian carcinoma proved to have endometrial carcinoma, hyperplasia, or polyp, compared with 4 of 22 women with stage I serous ovarian carcinoma. Therefore, we recommend the evaluation of the endometrium in symptomatic patients with endometriosis and an ovarian mass to rule out possible coexisting malignancies.
Endometrioid and clear-cell ovarian carcinomas associated with endometriosis usually present with an adnexal mass that may be associated with endometrioma. It appears therefore that a discreet set of symptoms associated with different ovarian carcinoma histologies exist and may be helpful in establishing programs for early detection of cancers associated with endometriosis.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
