Introduction

Ovarian cancer is the seventh most common cancer diagnosis among women worldwide, and it is the fifth most common cancer diagnosis among women in higher-resource regions . The world rate is estimated to be 6.3 per 100,000 women, and it is highest in resource-rich countries (9.3 per 100,000 women) . Primary peritoneal cancer and primary fallopian tube cancer are rare malignancies but share many similarities with the most common type of ovarian cancer and the prototype tumor occurring in women with BRCA1 or BRCA2 germ-line mutations, that is, high-grade serous carcinoma (HGSC) (in the past, referred to as “papillary serous carcinoma”). Clinically, these three cancers are managed in a similar manner .

The main purpose of staging systems is twofold: to provide standard terminology that allows a comparison of patients between centers, and to assign patients and their tumors to prognostic groups requiring specific treatments. Ovarian cancer is staged surgically and pathologically, and the last revision of the International Federation of Gynecology and Obstetrics (FIGO) staging classification was made in 1988 (Rio de Janeiro). After 24 years of use, the FIGO Committee on Gynecologic Oncology felt that it was time to revise this classification to improve accuracy, utility, and reproducibility. Cancer staging evolves continuously as scientific developments occur, diagnostic methods improve, and more accurate prognostic information becomes available. Over the past quarter of a century, several scientific developments have challenged traditional concepts in ovarian cancer. First, it was recognized that ovarian cancer is not a homogeneous disease, but rather a group of diseases – each with different morphology and biological behavior. Approximately 90% of ovarian cancers are carcinomas (malignant epithelial tumors) and, based on histopathology, immunohistochemistry, and molecular genetic analysis, at least five main types are currently distinguished: HGSC (70%), endometrioid carcinoma (EC (10%)), clear-cell carcinoma (CCC (10%)), mucinous carcinoma (MC (3%)), and low-grade serous carcinoma (LGSC (<5%)) ( Fig. 1 ). These tumor types (which account for 98% of ovarian carcinomas) can be reproducibly diagnosed by light microscopy and are inherently different diseases, as indicated by differences in epidemiologic and genetic risk factors; precursor lesions; patterns of spread; and molecular events during oncogenesis, response to chemotherapy, and prognosis . Much less common are malignant germ cell tumors (dysgerminomas, yolk sac tumors, and immature teratomas (3% of ovarian cancers)) and potentially malignant sex cord–stromal tumors (1–2%, mainly granulosa cell tumors). The biomarker expression profile within a given histotype is consistent across stages. Ovarian cancers differ primarily based on histologic type.

Representative examples of the five main types of ovarian carcinoma, which together account for 98% of cases: A. High-grade serous carcinoma; B. Low-grade serous carcinoma; C. Endometrioid carcinoma; D. Mucinous carcinoma; and E. Clear cell carcinoma.

In the era of personalized cancer medicine, a reproducible histopathologic diagnosis of tumor cell type is a sine qua non for successful treatment. Different tumor histotypes respond differently to chemotherapy. Even if different patterns of dissemination justify the use of separate staging systems for each type of ovarian carcinoma, such a complex classification would not be practical. For the sake of simplicity, the FIGO Committee chose a flexible staging system that takes into account the most relevant prognostic parameters shared by all tumor types. It was unanimously agreed that histologic type should be designated at staging (i.e., HGSC, EC, CCC, MC, and LGSC; other or cannot be classified; and malignant germ cell tumors and potentially malignant sex cord–stromal tumors).

Another discovery that influenced the new FIGO staging occurred in 2001, when patients with BRCA mutation (breast–ovarian cancer syndrome) undergoing risk-reducing salpingo-oophorectomy (RRSO) were found to have high-grade serous tubal intraepithelial carcinoma (STIC) not in the ovary but in the fallopian tube and, particularly, in the fimbria . Although STIC is capable of metastasizing and, therefore, cannot be considered carcinoma in situ, compelling evidence for a tubal origin of BRCA -positive HGSC (approximately 6% of BRCA cases) has accumulated over the past decade . High-grade STIC has also been found in an undetermined number of advanced-stage sporadic HGSCs associated with ovarian tumor masses and in rare cases of primary tubal or peritoneal HGSCs without obvious ovarian involvement. The relative proportion of HGSCs of ovarian and tubal derivation is unknown, mainly because tumor growth in advanced-stage cancers conceals the primary site. Even in cases involving BRCA mutation, evidence of a tubal origin of HGSCs is incomplete and a multicentric origin of these tumors (i.e., arising from ovarian surface mesothelial invaginations or inclusion cysts with subsequent müllerian neometaplasia , from implantation of tubal-type epithelium into the ovary (endosalpingiosis), or from the pelvic peritoneum (the so-called secondary müllerian system )) cannot be excluded.

Whereas asymptomatic BRCA + women undergoing RRSO have been found to have STIC in 6% of cases, symptomatic rapidly progressive BRCA + tumors discovered at the advanced stage in younger patients are less likely to be associated with STIC. This paradox questions the effectiveness of salpingectomy alone in preventing HGSC in BRCA + women .

The above findings suggest that the fallopian tube is linked to only some HGSCs and that the remaining cases originate from the nearby peritoneum/ovarian surface epithelium. Recently, it has been hypothesized that cytokeratin7-positive embryonic/stem cells would be capable of Müllerian differentiation in cortical epithelial inclusion cysts resulting from ovarian surface epithelium (mesothelium) invaginations. Thus, embryonic progenitors would give rise to immunophenotypically distinct neoplastic progeny , which would support the old concept of “ Müllerian neometaplasia.”

As indicated above, HGSCs and LGSCs are fundamentally different tumor types and, consequently, different diseases. HGSCs are the most common ovarian carcinomas and most patients present with advanced-stage disease (approximately 80%); tumors confined to the ovary at diagnosis are distinctly uncommon (<10%). By contrast, LGSCs are much less common, usually contain a serous borderline component, and carry KRAS and BRAF mutations . HGSCs are not associated with serous borderline tumors and typically exhibit TP53 mutations and BRCA abnormalities resulting in chromosomal instability and widespread DNA copy number changes. This highly aberrant genome is the hallmark of HGSC and allows further evolution into different molecular subtypes associated with clinical outcome.

The putative tubal or peritoneal origin applies exclusively to HGSCs and not to the vast majority of ECs and CCCs, which are thought to arise in the ovary from endometriosis. However, because of the higher frequency of HGSCs and their apparent multicentric origin along Müllerian-derived tissues, the Committee felt that the FIGO staging of ovarian, peritoneal, and fallopian tube cancers should be considered collectively. The primary site (i.e., ovary, fallopian tube, or peritoneum) should be designated where possible. In some cases, it might not be possible to delineate the primary site clearly; such cases should be listed as “undesignated.”

Although a significant number of HGSCs might not arise from the ovary, and the term “ovarian cancer” would not be pathogenically precise in every case, ovarian involvement is the rule in almost all cases. In view of the rarity of HGSCs associated with tubal tumor masses, it is unlikely that all HGSCs originate in the fallopian tube. The term HGSC of ovary should be kept until the different origins of ovarian tumors are better understood. Terms such as “Müllerian” or “pelvic serous carcinoma” are not recommended because they create confusion for patients, physicians, and medical investigators .

The process of the proposed changes to the staging of ovarian, fallopian tube, and primary peritoneal cancer started in 2011 under the leadership of the Chair of the FIGO Committee on Gynecologic Oncology, Professor Lynette Denny. The proposal was sent to all relevant gynecologic oncology organizations and societies worldwide. The new staging was reached by consensus of those participating in the FIGO meeting held in Rome, Italy, on October 7, 2012, some of whom were representatives of their organizations. The new staging was presented to the FIGO Executive Board on October 12, 2012, and was approved 2 weeks later. Subsequently, the proposal was presented to and approved by the American Joint Commission on Cancer and the International Union Against Cancer, the latter in May 2013. It was reported on January 1, 2014 . The following is the consensus agreement that resulted from these efforts and represents new criteria for staging of these gynecologic cancers.

Stage I: tumor confined to ovaries or fallopian tube(s)

Stage I: tumor confined to ovaries or fallopian tube(s)

Controversial issues

Recommendations

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  Histologic type, which in most cases includes grade, should be recorded.

  
  
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  All individual subsets of stage IC disease should be recorded.

  
  
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  Dense adhesions with histologically proven tumor cells justify upgrading to stage II.

  
  
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  If rupture is noted, peritoneal washing and cytology study are indicated.