Abstract
More than 25 years after the last revision, in 2012 the FIGO Oncology Committee began revising the FIGO classification for staging ovarian, Fallopian tube and primary peritoneal cancers. The new classification has become effective with its publication at the beginning of 2014. Following recent findings on the pathogenesis of ovarian, Fallopian tube and primary peritoneal cancer and reflecting standard clinical practice, the three entities have now been classified uniformly. The histological subtype is included (high-grade serous – HGSC; low-grade serous – LGSC; mucinous – MC; clear cell – CCC; endometrioid – EC). Stages III and IV have been fundamentally changed: stage IIIA now refers to a localized tumor limited to the pelvis with (only) retroperitoneal lymph node metastasis (formerly classified as IIIC). Stage IV has been divided into IVA and IVB, with IVA defined as malignant pleural effusion and IVB as parenchymatous or extra-abdominal metastasis including inguinal and mediastinal lymph node metastasis as well as umbilical metastasis. A new WHO classification was published almost concurrently. The classification of serous tumors addresses the issue of the tubal carcinogenesis of serous ovarian cancer, even if no tubal precursor lesions are found for up to 30 % of serous high-grade cancers. The number of subgroups was reduced and subgroups now include only high-grade serous, low-grade serous, mucinous, seromucinous, endometrioid, clear cell and Brenner tumors. The category “transitional cell carcinomas” has been dropped and the classification “seromucinous tumors” has been newly added. More attention has been focused on the role of borderline tumors as a stage in the progression from benign to invasive lesions.
Key words: borderline tumor, FIGO stage, ovarian cancer subtypes
Abstract
Zusammenfassung
Nach über 25 Jahren hat das FIGO Oncology Committee 2012 in Rom eine Überarbeitung der FIGO-Klassifikation zur Stadieneinteilung des Ovarialkarzinoms vorgenommen. Mit der Publikation Anfang 2014 ist die neue Klassifikation gültig. Den Erkenntnissen über die Pathogenese sowie der klinischen Praxis folgend werden das Ovarial-, das Tuben und das primäre Peritonealkarzinom einheitlich klassifiziert. Der histologische Subtyp wird angegeben (high grade serös – HGSC, low grade serös – LGSC, muzinös – MC; klarzellig – CCC und endometrioid – EC). Wesentliche Änderungen beziehen sich auf die Stadien III und IV: Stadium IIIA definiert nun einen auf das Becken beschränkten Tumor mit (ausschließlich) retroperitonealen Lymphknotenmetastasen (früher IIIC). Stadium IV wird in IVA und IVB aufgeteilt: IVA definiert einen malignen Pleuraerguss, IVB parenchymatöse oder extraabdominale Metastasen, zu denen auch die inguinalen und mediastinalen Lympknoten und die Nabelmetastasen zählen. Nahezu zeitgleich wurde auch eine neue WHO-Klassifikation publiziert. Bei den serösen Tumoren wurde auf die tubare Karzinogenese des serösen Ovarialkarzinoms eingegangen, wenn auch in bis zu 30 % der serösen High-Grade-Karzinome keine tubare Vorläuferläsion gefunden werden. Die Zahl der Subgruppen wurde auf High-grade seröse, Low-grade seröse, muzinöse, seromuzinöse, endometrioide, klarzellige Karzinome und Brenner-Tumoren reduziert. Das Transitionalzellkarzinom ist weggefallen, die seromuzinösen Tumoren sind neu. Der Rolle der Borderline-Tumoren als Progressionsstufe zwischen benignen und invasiven Läsionen wird mehr Raum gegeben.
Schlüsselwörter: Borderline-Tumoren (LMP), FIGO-Stadium, Ovarialkarzinom-Subtypen
Introduction
Extensive research in recent years have led to a fundamentally new understanding of the tumor biology of ovarian cancer. It is now generally accepted that the term “ovarian cancer” covers a heterogeneous group of malignant tumors which differ significantly in their etiology, pathogenesis, prognosis, pathology and molecular pathology 1. Numerous clinical studies have identified the most important prognostic factors whose clinical relevance also affects therapeutic decisions. The FIGO Oncology Committee has revised the previous FIGO classification of 1988 over a period of several years, publishing the new classification in 2014 2. Since the publication of the revised classification, only the new classification is considered valid; the new categories should therefore be used in clinical and scientific practice. The currently available S3-guideline (www.ago-online.org) refers to the “old” FIGO classification (1988) 3, 4, 5. With this statement we provide a guide which may prove useful until the S3-guideline has been officially updated.
Below we present the most important aspects of the new FIGO classification of ovarian, Fallopian tube and primary peritoneal cancer. To highlight the differences between the old and the new classification, we have compiled tables contrasting the differences.
Around 90 % of all malignant tumors of the ovaries, Fallopian tubes and peritoneum are epithelial tumors (carcinomas). Morphological, genetic, epigenetic investigations and expression analyses have led to the realization that ovarian carcinomas consist of a heterogeneous group of tumors which can present as ovarian, Fallopian tube or peritoneal carcinomas. Serous carcinomas, which constitute around 80 % of all tumors, are the most studied type. They are no longer graded on a continuum (i.e., G1, 2, 3). Instead they are differentiated into two basic pathological, molecular and prognostically different types – “low grade” and “high grade” – and should only be classified as such in pathology reports. Serous low-grade carcinomas are well differentiated and develop out of benign cystadenomas through serous borderline tumors and their micropapillary variants. Serous high-grade carcinomas are poorly differentiated. They have no known ovarian precursor lesions. However, there are some indications that a large number of high-grade carcinomas originate in the Fallopian tubes, as serous tubal intraepithelial carcinomas – so-called STICS – have been detected in macroscopically unremarkable Fallopian tubes in connection with high-grade carcinomas 6, 7. A tubal origin has been proven for the majority of hereditary carcinomas 8, 9. Low-grade carcinomas are associated with KRAS, BRAF, PIK3CA, CTNNB1 and PPP2R1A mutations, whereas high-grade carcinomas are typically associated with TP53 mutations, and BRCA mutations or inactivation (Table 1) 10, 11, 12.
Table 1 Subtypes of ovarian carcinoma and associated genetic changes 12.
| Histological subtype | High-grade serous | Low-grade serous | Endometrioid | Clear cell | Mucinous |
| Mutations | p53, BRCA 1/2 | KRAS/BRAF, Erbb2, PIK3CA | ARID1A, CTNNB1, PTEN, PIK3CA, PPP2RIA | ARID1A, PIK3CA, ZNF217, PPP2RIA | KRAS |
Although still a topic of scientific study and controversially discussed, the five morphological subtypes also appear to represent the five most common subtypes of epithelial ovarian carcinoma: low-grade serous (5 %): LGSC; high-grade serous (70 %): HGSC; mucinous (3 %): MC; endometrioid (10 %): EC; clear cell (10 %): CCC 13. The new classification therefore requires that the histological subtype is included together with the stage: HGSC, EC, CCC, MC, LGSC; “other” or “cannot be classified” 2.
The findings outlined above have been reflected in the new FIGO staging system which is used to classify ovarian, Fallopiann tube and primary peritoneal carcinomas. The location of the primary tumor is also included in the classification as follows: OV for ovary, FT for Fallopian tube and P for peritoneum. The classification must include an X if the primary site cannot be determined 2. For convenienceʼ sake we have used the term ovarian carcinoma for all types below.
The New FIGO Classification
The meaning of all staging is to categorize tumors and patients into prognostically specific groups based on the determination of tumor stage and the stage-appropriate therapy. Ensuring the comparability of groups in scientific studies also depends on being able to classify lesions into specific groups.
Careful clinical, surgical and pathological staging is necessary to correctly classify ovarian carcinomas. Surgery consists of longitudinal laparatomy, peritoneal cytology, biopsies of both suspicious and unremarkable areas of the peritoneum, hysterectomy, bilateral salpingo-oophorectomy, (infragastric) omentectomy as well as systematic pelvic and paraaortal lymphadenectomy in patients free of macroscopic tumors or the removal of enlarged (“bulky”) lymph nodes in patients with macroscopically visible tumors (S3-guideline on ovarian carcinoma, www.ago-online.org). In patients with advanced carcinoma, all visible tumor manifestations should be removed as postoperative tumor remnants are an important prognostic factor. Optimal debulking is achieved if all macroscopically visible tumor manifestations have been resected 14. At the subsequent histopathological examination it is important to indicate the tumor grade in addition to the above-mentioned primary tumor location and histological subtype. Differentiating carcinomas into low grade and high grade is particularly important for serous carcinomas. The differentation can have an important impact on future therapy as low-grade carcinomas have a more favorable prognosis and there are also indications that – in contrast to high-grade carcinomas – low-grade tumors have only a poor response to chemotherapy 15, 16. There is no prognostically relevant grading system for mucinous tumors 17.
Table 2 shows the new FIGO staging system and contrasts it with the older version of 1988; Table 3 shows the corresponding TNM stages. An update of the TNM classification is planned for 2016 18.
Table 2 FIGO staging of ovarian, Fallopian tube and primary peritoneal cancer (FIGO 2013 vs. FIGO 1988) – differences highlighted in bold.
| FIGO (1988) | FIGO (2013) |
|---|---|
| * There is no stage I peritoneal carcinoma.** Thick adhesions with histologically verified tumor metastases require upstaging from stage I to II.*** Extraabdominal metastases includes transmural intestinal infiltration and umbilical metastases. | |
| I: tumor confined to the ovaries | I: tumor confined to the ovaries or tube(s)* |
| IA: tumor confined to 1 ovary (capsule intact), no tumor on ovarian surface, no malignant cells in the ascites or peritoneal cytology | IA: tumor confined to 1 ovary or tube (capsule intact), no tumor on ovarian surface, no malignant cells in the ascites or peritoneal cytology |
| IB: tumor involves both ovaries (capsule intact), no tumor on ovarian surface, no malignant cells in the ascites or peritoneal cytology | IB: tumor involves both ovaries or tubes (capsule intact), no tumor on the ovarian or tubal surface, no malignant cells in the ascites or peritoneal cytology |
| IC: tumor limited to 1 or both ovaries together with one of the following: capsule rupture; tumor on ovarian surface; malignant cells in the ascites or peritoneal cytology | IC: tumor limited to 1 or both ovaries or tube(s) together with one of the following: |
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| II: tumor in 1 or both ovaries with pelvic involvement | II: tumor in 1 or both ovaries or tube(s) with pelvic involvement or primary peritoneal carcinoma** |
| IIA: extension and/or implant on uterus and/or Fallopian tube(s); no malignant cells in the ascites or peritoneal cytology | IIA: extension and/or implant on uterus and/or Fallopian tube(s) and/or ovar(ies) |
| IIB: extension to other pelvic tissue; no malignant cells in the ascites or peritoneal cytology | IIB: extension to other pelvic intraperitoneal tissue |
| IIC: IIA or IIB plus malignant cells in the ascites or peritoneal cytology | |
| III: tumor in 1 or both ovaries with microscopic extrapelvic peritoneal metastases and/or regional lymph node metastases | III: tumor in 1 or both ovaries or tube(s) or primary peritoneal carcinoma with cytologically or histologically verified peritoneal metastases outside the pelvis and/or retroperitoneal lymph node metastases. |
| IIIA: microscopic extrapelvic peritoneal metastases | |
| IIIA1: positive retroperitoneal lymph nodes only (verified cytologically or histologically) | |
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| IIIA2: microscopic extrapelvic peritoneal metastases with or without positive retroperitoneal lymph nodes | |
| IIIB: macroscopic extrapelvic peritoneal metastases of up 2 cm | IIIB: macroscopic peritoneal pelvic metastases of up to 2 cm, with or without retroperitoneal lymph node metastases (including the capsule of the liver/spleen but excluding parenchymatous metastasis) |
| IIIC: macroscopic extrapelvic peritoneal metastases larger than 2 cm and/or regional lymph node metastases | IIIC: macroscopic extrapelvic peritoneal metastases larger than 2 cm with or without retroperitoneal lymph node metastases (including capsule of the liver/spleen but excluding parenchymatous metastases) |
| IV: distant metastases excluding peritoneal metastases | IV: distant metastasis excluding peritoneal metastases |
| IVA: pleural effusion with positive cytology | |
| IVB: parenchymatous metastases and metastases to extraabdominal organs (including inguinal lymph node metastases and extraabdominal lymph node metastases)*** | |
Table 3 FIGO stages and TNM stages.
| FIGO stage | T | N | M |
|---|---|---|---|
| * Extraabdominal metastases includes transmural intestinal infiltration and umbilical metastases as well as inguinal lymph node metastases and extraabdominal lymph node metastases. | |||
| IA | T1a | N0 | M0 |
| IB | T1b | N0 | M0 |
| IC | T1c | N0 | M0 |
| IIA | T2a | N0 | M0 |
| IIB | T2b | N0 | M0 |
| IIIA | T3aT3a | N0N1 | M0M0 |
| IIIB | T3bT3b | N0N1 | M0M0 |
| IIIC | T3cT3c | N0N1 | M0M0 |
| IVA | Any T | Any N | M1 (malignant pleural effusion) |
| IVB | Any T | Any N | M1 (parenchymatous and extraabdominal metastases)* |
Stage I
Stage I includes tumors limited to the ovary or Fallopian tube, although tumor cells may be present in peritoneal fluids. An important difference between the old and the new classification is the explicit reference to the Fallopian tubes as a potential site of origin and the differentation of stage IC to indicate the time and cause of capsule rupture into intraoperative (IC1), preoperative (IC2) or atypical cells in ascites or rinse cytology (IC3). It is important to avoid intraoperative rupture, although it is not possible to definitively state that this will worsen prognosis. This is an issue that will require further scientific study. The new classification clearly categorizes iatrogenic rupture of what is actually FIGO stage IA as FIGO stage IC1, and treatment needs to be adjusted accordingly 19. If tumor cells are detected in adhesions in a patient with presumed stage I carcinoma, then the patient must be upstaged to stage II 2. The IC1–IC3 classification does not yet have any therapeutic relevance. A consistent subdivision of stage I is the prerequisite for developing further risk-adapted therapeutic strategies.
Stage II
Stage II includes the small group of tumors whose spread is limited to the pelvis below the pelvic brim. Sigma metastasis and infiltration of the sigma in the pelvis are also included in stage II. All malignant peritoneal metastases of the lesser pelvis are classified as stage II. There are therefore no stage I peritoneal carcinomas. The stage formerly known as stage IIc no longer exists 2.
Stage III
Stage III is the largest group of advanced cancers and includes tumors outside the pelvis in the peritoneum, the omentum, the renal fascia, the hepatic capsule, the splenic capsule (excluding parenchymatous metastases) and/or lymph node metastases. The prognosis for patients with isolated (paraaortal) lymph node metastases is better when the tumor is limited to the pelvic cavity compared to intraperitoneal tumor sites outside the pelvis. This has lead to a new subdivision of stage III: stage IIIA1 includes pelvic tumors with retroperitoneal lymph node metastases up to 1 cm (IIIA1i) or larger than 1 cm (IIIA1ii). Stage IIIA2 includes microscopically visible tumors outside the pelvis irrespective of the presence or absence of lymph node metastases. Stage IIIB includes tumors < 2 outside the pelvis with or without retroperitoneal lymph node metastases. In the old classification, all tumors with retroperitoneal lymph node metastases were classified as stage IIIC, meaning that tumors previously staged as IIIC may now correspond to stage IIIA (“only positive lymph nodes”) or IIIB (tumors < 2 cm). it is important to be aware of this when considering the indication for therapy with bevacizumab (approved for stages IIIB–IV in the old FIGO classification, which correspond to stages IIIA–IV in the new FIGO classification). It may be necessary to explain to health insurance companies that current stage IIIA was formerly classifed as stage IIIC and that approval is based on the old classification. Enlarged lymph nodes detected on palpation alone are not sufficient for classification as metastasis; lymph node metastases must be verified cytologically or histologically 2.
Stage IV
Stage IV includes all tumors with distant metastases – with the exception of peritoneal metastasis which is included in stages II and III. Stage IV is subdivided into stages IVA and IVB. Stage IVA only includes malignant pleural effusion. Stage IVB includes parenchymatous metastases or extra-abdominal metastases (including lymph nodes outside the abdominal cavity, tumors of the umbilicus or umbilical wall, intestinal infiltration with mucosal involvement). In the new classification, inguinal lymph nodes are no longer classified as stage IIIC but as stage IVB, although the usefulness of this classification has not been conclusively demonstrated in scientific studies. The question whether resectable tumors of the umbilicus, the intestinal mucosa and the liver or spleen should, in future, be classified as stage IIIC is still controversially discussed. They are currently classifed as FIGO IVB. The differentiation of FIGO IV into IVA and IVB also remains controversial 2.
With its new classification the FIGO Oncology Committee has attempted to take account of recent clinical and translational studies. The first studies have been published comparing the old and the new classifications with regard to disease-free and overall survival. The studies showed that, overall, the new classification results in a better differentiation between prognostically different (sub-)stages 20, 21.
The New WHO Classification
While the FIGO classification focuses on the differentiation into tumor stages, the WHO classification indicates the histopathological and molecular tumor type. Both aspects – tumor stage and tumor type – are already important criteria as they form the basis of a differentiated therapeutic approach.
The following sections provide an overview of the changes in the WHO classification, which was also published in 2014 and is therefore also already valid 22.
In the old classification, the chapter on ovarian cancers focused on the mesothelial layer of the ovary as the place of origin for epithelial ovarian tumors. This has been abandoned in the new classification. Instead, the tubal carcinogenesis of ovarian cancers is already addressed in the introduction to serous tumors, even though no tubal precurson lesions have been found in up to 30 % of serous high-grade carcinomas; the originally assumed pathogenesis would therefore still appear to apply for a certain percentage of serous cancers. The new classification also emphasizes that reliable determination of the place of origin of advanced serous carcinomas is often not possible. The new classification (Table 4) has become more consistent due to the reduction in the number of subgroups. The term “transitional cell carcinoma” has been dropped; the classification “seromucinous tumor” has been added. The role of borderline tumors as a progression stage between benign and invasive lesions in various histological subtypes has been addressed in more detail. The sections below summarize the most important changes in the classification of serous, mucinous, seromucinous, endometrioid, clear cell and Brenner tumors 22.
Table 4 Previous and new WHO classification.
| Previous | New (2014) |
|---|---|
| Serous tumors | |
| Benign type | |
| Cystadenoma | cystadenoma |
| Papillary cystadenoma | adenofibroma |
| Surface papilloma | surface papilloma |
| Adenofibroma and cystadenofibroma | |
| Borderline (SBOT) | |
| Papillary cystic BOT | serous BOT/atypical proliferating tumor |
| Papillary surface BOT | SBOT, micropapillary type/non-invasive, serous low-grade carcinoma |
| Adenofibromatous and cystadenofibromatous BOT | |
| Malignant type | |
| Adenocarcinoma | serous low-grade carcinoma |
| Papillary surface carcinoma | serous high-grade carcinoma |
| Adenocarcinofibroma | |
| Mucinous tumors | |
| Benign type | |
| Cystadenoma | cystadenoma |
| Adenofibroma and cystadenofibroma | adenofibroma |
| Mucinous cystic tumor with mural nodules | |
| Mucinous cystic tumor with pseudomyxoma peritonei | |
| Borderline (MBOT) | |
| Intestinal type | mucinous BOT/atypical proliferating mucinous tumor |
| Endocervical type | |
| Malignant type | |
| Adenocarcinoma | mucinous carcinoma |
| Adenocarcinofibroma (malignant adenofibroma) | |
| Endometrioid tumors | |
| Benign type | |
| endometriosis cyst | |
| Cystadenoma | endometrioid cystadenoma |
| Adenofibroma & cystadenofibroma | endometrioid cystadenofibroma |
| Borderline (EBOT) | |
| Cystic tumor | endometrioid EBOT/atypical proliferative endometrioid tumor |
| Adenofibroma and cystadenofibroma | |
| Malignant type | |
| Adenocarcinoma NOS | endometrioid carcinoma |
| Adenocarcinofibroma (malignant adenofibroma) | |
| Malignant Müllerian mixed tumor (carcinosarcoma) | |
| Adenosarcoma | |
| Endometrioid stromal sarcoma (low-grade) | |
| Undifferentiated ovarian sarcoma | |
| Clear cell tumors | |
| Benign type | |
| Cystadenoma | cystadenoma |
| Adenofibroma and cystadenofibroma | |
| Borderline (KBOT) | |
| Cystic tumor | CBOT/atypical proliferating clear cell tumor |
| Adenofibroma and cystadenofibroma | |
| Malignant type | |
| Adenocarcinoma | clear cell tumor |
| Adenocarcinofibroma (malignant adenofibroma) | |
| Transitional cell tumors | Brenner tumors |
| Benign type | |
| Brenner tumor | Brenner tumor |
| Metaplastic type | |
| Borderline | |
| Borderline Brenner tumor | borderline Brenner tumor/atypical proliferating Brenner tumor |
| Proliferative type | |
| Malignant type | |
| Transitional cell carcinoma | |
| Malignant Brenner tumor | malignant Brenner tumor |
| seromucinous tumors | |
| benign tumors | |
| seromucinous cystadenoma | |
| seromucinous adenofibroma | |
| borderline tumors | |
| seromucinous borderline tumor/atypical proliferating seromucinous tumor | |
| malignant disease | |
| seromucinous carcinoma | |
| Squamous epithelial tumors | |
| Mixed epithelial tumors | |
| Undifferentiated and unclassifiable tumors | Undifferentiated carcinoma |
Serous tumors
The difference between adenomas and borderline tumors (SBOTs) has become more sharply demarcated in the new WHO classification. Cystic serous tumors with > 10 % BOT structures are classified as SBOT. If the BOT percentage in the lesion is below 10 %, the term “serous cystadenoma with focal epithelial proliferation” is used to describe the entity. The diagnostic criteria for SBOT have largely remained the same. The lack of p53 mutations and the absence of diffuse p16-staining in SBOTs is emphasized. The incidence of KRAS/BRAF mutations is reported to be 50 %. The progression from SBOT to LGSC is given as 5 %. The micropapillary SBOT variant is expressly mentioned and described in detail. The higher risk of peritoneal disease associated with micropapillary SBOT (27 compared to 13 % for the conventional type) and the 50 % probability that the peritoneal origin of a micropapillary SBOT corresponds to that of serous low-grade carcinoma are emphasized. Micropapillary SBOTs have the same incidence of KRAS/BRAF mutation as normal SBOTs but their gene expression profile is different and resembles that of serous low-grade carcinomas.
If invasive implants are present, the tumor is referred to as serous low-grade carcinoma. However, this change of classification is based exclusively on pathological and morphological criteria. There are currently no clinical data which suggest that this step is necessary. In these cases it is suggested that pathological reports also include the old classification on which the current recommendations for clinical management are based.
The definition of SBOT with microinvasion is limited to single lesions with a maximum diameter of 5 mm. Analogously to the FIGO classification, the continuous grading of serous carcinoma into G1–G3 has been dropped and replaced by the subdivision into low-grade und high-grade carcinoma. Immunohistochemical staining for p53 is recommended for the morphological differentiation of tumors on the border to high-grade carcinoma.
Transitional cell carcinoma of the ovary no longer exists as a separate entity in the new classification. The corresponding histological growth pattern is now described as a variant of serous or (more rarely) endometrioid carcinoma (high-grade or G3) 22.
Mucinous tumors
The differentiation of mucinous borderline tumors (MBOT) into intestinal type and endocervical type has been abandoned. What was formerly classified as an endocervical MBOT is now part of the newly created category of seromucinous tumors; the current definition of MBOT corresponds to the former intestinal type MBOT. In particular, the new classification highlights the importance of considering metastasis if an MBOT is present, even if no primary (extragenital) tumor has been identified. Bilateral MBOT, small tumor size and peritoneal foci are particularly suspicious for metastasis of an extragenital (gastrointestinal) malignancy. The definition of MBOT to include intraepithelial carcinoma was retained, along with the terms “microinvasive MBOT” and “microinvasive mucinous carcinoma”. Nevertheless, the new classification does not offer a satisfactory resolution of the problem of defining invasion for mucinous carcinoma. The subdivision of mucinous carcinomas into expansile type and infiltrative-invasive type was retained 22.
Seromucinous tumors
This group represents a new entity among the epithelial ovarian tumors in the new WHO classification. Basically, this group of tumors includes cancers formerly classified as endocervical-type mucinous BOT, although the WHO requires at least two degrees of Müllerian differentiation for a diagnosis. The structures of seromucinous BOTs resemble those of SBOTs; however, up to one third of them are associated with endometriosis, and because of ARID1A mutations their molecular structures suggest that they are closer to endometrioid tumors than to serous tumors. This category includes both microinvasive and micropapillary BOTs and – in contrast to SBOTs – BOTs with intraepithelial carcinoma. As the findings for this tumor group are still limited, their clinical importance remains to be seen 22, 23.
Endometrioid tumors
ARID1A and PIK3CA mutations and PTEN loss of heterozygosity (LOH) occur with similar frequency in endometriosis cysts and endometrioid cystadenomas, suggesting they may share a pathogenic connection. Similar mutations are also found with endometrioid ovarian carcinomas. Atypical lesions of endometriosis are also associated with the development of endometrioid (but also clear cell) ovarian carcinomas 24, 25.
Because ARID1A and PIK3CA mutations and LOH of PTEN occur with the same incidence in endometriosis cysts as in endometrioid cystadenomas, the new WHO classification places endometriosis cysts in a neoplastic context. The endometrioid borderline category has been broken down further, differentiating between adenofibromatous (originating from an endometrioid adenofibroma) und intracystic (originating from an endometrioid cystadenofibroma/from an endometrioid cyst) EBOTs. In analogy to MBOTs, the diagnostic addendum “with intraepithelial carcinoma” is recommended when describing EBOTs with high-grade nuclear atypia. As with mucinous tumors, the problem of differentiating these entities from carcinomas in the differential diagnosis has not yet been satisfactorily resolved. There are many types of endometrioid carcinomas (with squamous differentiation, with secretory changes, with mucinous differentation, oxyphile type or with similar patterns to germ cell-stromal tumors). It is important to consider the possibility of metastasis when evaluating lesions presenting as endometrioid tumors 22.
Clear cell tumors
The new WHO classification has not resulted in any significant changes in the classification of clear cell tumors. Clear cell BOTs are very similar to clear cell adenomas and parts of both entities are usually present in tumors. In contrast, clear cell carcinomas are irregular, with papillary structures, solid parts with desmoplastic hyalinized stroma, and high-grade nuclear atypia 22. Clear cell carcinomas may be associated with Lynch syndrome but also with endometriosis and are the most common ovarian carcinoma with paraneoplastic symptoms (thromboembolism and hypercalcemia) 24, 25.
Brenner tumors
The former chapter on transitional cell tumors is now entitled “Brenner tumors”. Around 25 % of Brenner tumors are associated with other epithelial tumors. Brenner tumors consist of cell nests of varying sizes and can be differentiated immunohistochemically from transitional cell tumors. The differentiation between Brenner tumors and borderline tumors is not defined precisely or in terms of size. Epithelial proliferation in Brenner BOTs is significantly higher, resulting in considerably larger lesions (mean diameter 18 cm) with a significantly higher epithelial percentage. This BOT category also includes a subgroup “intraepithelial carcinoma”. Malignant Brenner tumors are characterized by destructive stromal invasion of unspecified morphology. These tumors additionally present with focal, high-grade nuclear atypia 22.
Supporting Information
References
- 1.Meinhold-Heerlein I, Hauptmann S. The heterogeneity of ovarian cancer. Arch Gynecol Obstet. 2014;289:237–239. doi: 10.1007/s00404-013-3114-3. [DOI] [PubMed] [Google Scholar]
- 2.Prat J. FIGO Committee on Gynecologic Oncology . Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014;124:1–5. doi: 10.1016/j.ijgo.2013.10.001. [DOI] [PubMed] [Google Scholar]
- 3.Shepherd J H. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol. 1989;96:889–892. doi: 10.1111/j.1471-0528.1989.tb03341.x. [DOI] [PubMed] [Google Scholar]
- 4.Pecorelli S, Benedet J L, Creasman W T. et al. FIGO staging of gynecologic cancer. 1994–1997 FIGO Committee on Gynecologic Oncology. International Federation of Gynecology and Obstetrics. Int J Gynaecol Obstet. 1999;65:243–249. doi: 10.1016/s0020-7292(99)00070-3. [DOI] [PubMed] [Google Scholar]
- 5.Pecorelli S, Benedet J L, Creasman W T. et al. FIGO staging of gynecologic cancer. 1994–1997 FIGO Committee on Gynecologic Oncology. International Federation of Gynecology and Obstetrics. Int J Gynaecol Obstet. 1999;64:5–10. doi: 10.1016/s0020-7292(98)00234-3. [DOI] [PubMed] [Google Scholar]
- 6.Przybycin C G, Kurman R J, Ronnett B M. et al. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol. 2010;34:1407–1416. doi: 10.1097/PAS.0b013e3181ef7b16. [DOI] [PubMed] [Google Scholar]
- 7.Zeppernick F, Meinhold-Heerlein I, Shih Ie M. Precursors of ovarian cancer in the fallopian tube: serous tubal intraepithelial carcinoma—an update. J Obstet Gynaecol Res. 2015;41:6–11. doi: 10.1111/jog.12550. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Benedet J L, Bender H, Jones H 3rd. et al. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 2000;70:209–262. [PubMed] [Google Scholar]
- 9.Piek J M, van Diest P J, Zweemer R P. et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001;195:451–456. doi: 10.1002/path.1000. [DOI] [PubMed] [Google Scholar]
- 10.Meinhold-Heerlein I, Bauerschlag D, Hilpert F. et al. Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential. Oncogene. 2005;24:1053–1065. doi: 10.1038/sj.onc.1208298. [DOI] [PubMed] [Google Scholar]
- 11.Shih Ie M, Kurman R J. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol. 2004;164:1511–1518. doi: 10.1016/s0002-9440(10)63708-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kurman R J, Shih Ie M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm. Hum Pathol. 2011;42:918–931. doi: 10.1016/j.humpath.2011.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Prat J. New insights into ovarian cancer pathology. Ann Oncol. 2012;23 10:x111–x117. doi: 10.1093/annonc/mds300. [DOI] [PubMed] [Google Scholar]
- 14.du Bois A, Reuss A, Pujade-Lauraine E. et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe dʼInvestigateurs Nationaux Pour les Etudes des Cancers de lʼOvaire (GINECO) Cancer. 2009;115:1234–1244. doi: 10.1002/cncr.24149. [DOI] [PubMed] [Google Scholar]
- 15.Gershenson D M, Sun C C, Bodurka D. et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol. 2009;114:48–52. doi: 10.1016/j.ygyno.2009.03.001. [DOI] [PubMed] [Google Scholar]
- 16.Gershenson D M, Sun C C, Iyer R B. et al. Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2012;125:661–666. doi: 10.1016/j.ygyno.2012.02.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Hauptmann S, du Bois A, Meinhold-Herlein I. et al. [Histological grading of epithelial ovarian cancer. Review and recommendation] Der Pathologe. 2014;35:497–503. doi: 10.1007/s00292-014-1948-5. [DOI] [PubMed] [Google Scholar]
- 18.Hohn A K, Einenkel J, Wittekind C. et al. [New FIGO classification of ovarian, fallopian tube and primary peritoneal cancer] Der Pathologe. 2014;35:322–326. doi: 10.1007/s00292-014-1908-0. [DOI] [PubMed] [Google Scholar]
- 19.Vergote I, De Brabanter J, Fyles A. et al. Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet. 2001;357:176–182. doi: 10.1016/S0140-6736(00)03590-X. [DOI] [PubMed] [Google Scholar]
- 20.Paik E S, Lee Y Y, Lee E J. et al. Survival analysis of revised 2013 FIGO staging classification of epithelial ovarian cancer and comparison with previous FIGO staging classification. Obstet Gynecol Sci. 2015;58:124–134. doi: 10.5468/ogs.2015.58.2.124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Suh D H, Kim T H, Kim J W. et al. Improvements to the FIGO staging for ovarian cancer: reconsideration of lymphatic spread and intraoperative tumor rupture. J Gynecol Oncol. 2013;24:352–358. doi: 10.3802/jgo.2013.24.4.352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kurman R J, Carcangiu M L, Herrington C S, Lyon: WHO Press; 2014. WHO Classification of Tumours of female reproductive Organs. [Google Scholar]
- 23.Hauptmann S. Die neue WHO-Klassifikation des Ovarial-, Tuben- und primären Peritonealkarzinoms. 2015. [DOI] [PubMed]
- 24.Chene G, Ouellet V, Rahimi K. et al. The ARID1A pathway in ovarian clear cell and endometrioid carcinoma, contiguous endometriosis, and benign endometriosis. Int J Gynaecol Obstet. 2015;130:27–30. doi: 10.1016/j.ijgo.2015.02.021. [DOI] [PubMed] [Google Scholar]
- 25.Wiegand K C, Shah S P, Al-Agha O M. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363:1532–1543. doi: 10.1056/NEJMoa1008433. [DOI] [PMC free article] [PubMed] [Google Scholar]
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