Arch Gynecol Obstet DOI 10.1007/s00404-016-4035-8
NEWS AND VIEWS
The new WHO classification of ovarian, fallopian tube, and primary peritoneal cancer and its clinical implications Ivo Meinhold-Heerlein1 • Christina Fotopoulou1 • Philipp Harter1 Christian Kurzeder1 • Alexander Mustea1 • Pauline Wimberger1 • Steffen Hauptmann1 • Jalid Sehouli1
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Received: 19 January 2016 / Accepted: 2 February 2016 Ó Springer-Verlag Berlin Heidelberg 2016
Abstract Introduction Molecular pathological research has contributed to improving the knowledge of different subtypes of ovarian cancer. In parallel with the implementation of the new FIGO staging classification, the WHO classification was revised. The latter is mainly based on the histopathological findings and defines the actual type of tumor. It has, therefore, also an important impact on prognosis and therapy of the patient. Materials and methods The new WHO Classification of Ovarian Cancer published 2014 by Robert Kurman and coauthors is summarized. The major changes compared to the hitherto existing classification are presented. Results The new classification eliminates the previous focus of mesothelial origin of ovarian cancer. Instead, it features a discussion of tubal carcinogenesis of hereditary and some other high-grade serous carcinomas. The previously assumed pathogenesis pathway may be correct for some, but not for all, serous cancers. The new classification was established to classify ovarian cancer in a more consistent way. The earlier transitional cell type of ovarian cancer has been removed while seromucinous tumors have been added as a new entity. The role of some borderline tumors as one possible step in the progression from benign to invasive lesions is incorporated. The article summarizes the essential updates concerning serous, mucinous, seromucinous, endometrioid, clear-cell, and Brenner tumors.
On behalf of the Kommission Ovar of AGO. & Ivo Meinhold-Heerlein imeinhold@ukaachen.de 1
Klinik fu¨r Gyna¨kologie und Geburtsmedizin, Uniklinik RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
Conclusion The new WHO classification takes into account the recent findings on the origin, pathogenesis, and prognosis of different ovarian cancer subtypes. The tubal origin of hereditary and some non-hereditary high-grade serous cancers is mentioned in contrast to the hitherto theory of mesothelial origin of tumors. Seromucinous tumors represent a new entity. Keywords High-grade serous Low-grade serous Endometrioid Mucinous Clear cell
Introduction Voluminous scientific studies in recent years have brought a fundamentally new understanding of the tumor biology of ovarian cancer. It is no longer controversial that the term ‘‘ovarian cancer’’ subsumes a heterogeneous group of malignant tumors that differ with respect to essential features of etiology, pathogenesis, prognosis, pathology, and molecular pathology [1]. Numerous clinical studies have also identified the most important factors that determine prognosis, and their clinical relevance is now informing therapeutic decisions. In parallel with the FIGO classification for the staging of ovarian cancer [2, 3] the WHO classification was revised [4, 5] and is valid since 2014. Most of the current clinical guidelines of ovarian cancer refer to the previous FIGO and WHO classification systems, therefore we conducted this manuscript to clarify the clinical implications of the news definitions [6–11]. Both qualities—the tumor stage (according to FIGO classification) and the type of tumor (according to WHO classification)—are essential criteria for the treatment decision-making process of a differentiated therapy.
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The following sections provide an overview of changes to the WHO classification, which, like the FIGO classification, was published in 2014 and has current validity [5]. The chapter on ovarian cancer in the old classification focused on the mesothelial surface of the ovary as the point of origin of epithelial ovarian tumors. The new classification eliminates this focus. Instead, it features a discussion of tubal carcinogenesis of high-grade serous carcinomas. This is in spite of the fact that, in up to 30 % of these tumors, no tubal precancerous lesions can be found. The previously assumed pathogenesis pathway is therefore certainly correct for some but not for all serous cancers. It remains to be emphasized that it will frequently not be possible to judge the point of origin of advanced serous cancers with certainty. The new classification (see Table 1) has become more consistent. The earlier transitional cell type of ovarian cancer class has been removed, while seromucinous tumors have been added as a new entity. The role of some borderline tumors as a step in the progression from benign to invasive lesions is incorporated. The following sections summarize the essential updates pertaining to serous, mucinous, seromucinous endometrioid, clear-cell and Brenner tumors [5, 12].
frequently occur together. The former category of invasive implants is now referred to as serous low-grade cancers. However, this change in classification is based entirely on patho-morphological criteria. To date, there are lacking data for the clinical benefit of this change. The ‘‘Kommission Ovar of AGO’’ claims the pathology report should mention also the previous classification, since current recommendations for clinical management are still based on it [6–11]. Microinvasion of an SBOT is still limited metrically (at a 5 mm breadth for individual foci). Analogously to the FIGO classification, the continuous grading of serous cancer in G1–G3 has been eliminated and replaced by a sub-classification into low-grade and highgrade carcinomas. Tumors, formerly classified as grade 2 serous carcinoma are candidates for p53 immunohistochemistry. If p53 immonostaining is negative, the tumor is classified low grade. If p53 immunostaining is positive, the tumor is classified high grade. Transitional cell cancer of the ovary which may be associated with BRCA1 inhibition no longer stands as a separate entity. But the corresponding histological growth pattern is to be described as a variant of serous or (less frequently) endometrioid cancer (high-grade or G3) [5].
Serous tumors Mucinous tumors The dividing line between adenomas and borderline tumors (SBOTs) has been sharpened in the new WHO classification. Cystic serous tumors with [10 % BOT architecture are now classified as SBOTs. If the lesion shows a BOT fraction smaller than 10 %, the term ‘‘serous cystadenoma with focal epithelial proliferation’’ applies. The diagnostic criteria of SBOTs have remained essentially the same. Emphasis with respect to SBOTs lies on the lack of p53 mutations and the absence of diffuse p53 immunostaining. The frequency of KRAS/BRAF mutations is set at 50 %. The progression rate of an SBOT to an LGSC is reported at 5 %. The micropapillary SBOT variant is featured pointedly and afforded comprehensive description. The higher risk of peritoneal implants associated with it (27 vs 13 % associated with the conventional variant) is emphasized, as is the 50 % probability that the peritoneal hearth of a micropapillary SBOT variant corresponds to a serous lowgrade cancer. Micropapillary SBOTs exhibit the same frequency of KRAS/BRAF mutations as common SBOTs, but their gene expression profile is different and similar to that of a serous low-grade cancer [1, 13–17]. Every sub-classification of peritoneal implants has been dispensed with. The term ‘‘implant’’ does not refer to any form of the former non-invasive implant category (e.g. epithelial and desmoplastic) because a further subclassification has no assured prognostic value and both forms
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The subcategorization of mucinous borderline tumors (MBOTs) into an intestinal and an endocervical type has been dispensed with. What formerly were endocervical MBOTs are now found in the newly-created seromucinous tumor group; MBOT therefore now applies to the former intestinal variety. The new WHO classification emphasizes the consideration of metastasis of an extragenital malignancy even in cases of MBOT. Bilaterality, small tumors and a peritoneal involvement are particularly suspicious with respect to metastasis. Diagnostic categories in between MBOT and mucinous invasive carcinoma are MBOT with intraepithelial cancer, microinvasive MBOT, and microinvasive mucinous cancer, respectively. Even so, the new classification puts forth no satisfactory solution to the problem of defining invasion in cases of mucinous cancer. The sub-classification of mucinous cancer into an expansive and a destructive-invasive type has been kept [5].
Seromucinous tumors This group of tumors is a new entity among ovarian cancer within the new WHO classification. Essentially, it comprises the former endocervical-type mucinous BOT,
Arch Gynecol Obstet Table 1 Previous and actual WHO classification [4] Previous
New (2014)
Serous tumors Benign 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 Adenocarcinoma Papillary surface carcinoma
Serous low-grade carcinoma Serous high-grade carcinoma
Adenocarcinofibroma Mucinous tumors Benign Cystadenoma
Cystadenoma
Adenofibroma and cystadenofibroma 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 Adenocarcinoma
Mucinous carcinoma
Adenocarcinofibroma (malignant adenofibroma) Endometrioid tumors Benign Endometriosis cyst Cystadenoma
Endometrioid cystadenoma
Adenofibroma and cystadenofibroma
Endometrioid cystadenofibroma
Borderline (EBOT) Cystic tumor
Endometrioid BOT/atypical proliferating endometrioid tumor
Adenofibroma and cystadenofibroma Malignant Adenocarcinoma NOS
Endometrioid carcinoma
Adenocarcinofibroma (malignant adenofibroma) Malignant Mu¨llerian mixed tumor (carcinosarcoma) Adenosarcoma Endometrioid stromal sarcoma (low grade) Undifferentiated ovarian sarcoma Clear cell tumors Benign Cystadenoma
Cystadenoma
Adenofibroma and cystadenofibroma
Adenofibroma
Borderline (CBOT) Cystic tumor
CCBOT/atypical proliferating clear cell tumor
Adenofibroma and cystadenofibroma
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Arch Gynecol Obstet Table 1 continued Previous
New (2014)
Malignant Adenocarcinoma
Clear cell carcinoma
Adenocarcinofibroma (malignant adenofibroma) Transitional cell tumors
Brenner tumors
Benign Brenner tumor
Brenner tumor
Metaplastic type Borderline Borderline Brenner tumor
Borderline Brenner-tumor/atypical proliferating Brenner tumor
Proliferating type Malignant Transitional cell carcinoma Malignant Brenner Tumor
Malignant Brenner tumor Seromucinous tumors Benign Seromucinous cystadenoma Seromucinous adenofibroma Borderline tumor Seromucinous borderline tumor/atypical proliferating seromucinous tumor Seromucinous carcinoma
Squamous epithelial tumors Mixed epithelial tumors Undifferentiated and unclassifiable tumors
Undifferentiated carcinoma
although the WHO now requires at least two types of Muellerian differentiation for the diagnosis. The architecture of the seromucinous BOTs resembles that of the SBOTs; but one-third of them are associated with endometriosis, and by virtue of the ARID1A-mutations they are closer on the molecular level to endometrioid tumors than to the serous tumors. In this category, too, there are both microinvasive and micropapillary SMBOTs; in contrast to SBOTs, which never contain areas of intraepithelial carcinoma, seromucinous BOTs may present with intraepithelial cancer. Because no one has amassed extensive experience with this group of tumors, it remains to be seen what its clinical significance will be [5, 18].
Endometrioid tumors Because ARID1A and PIK3CA gene mutations as well as loss of heterozygosity (LOH) of PTEN occur with similar frequency in endometrioid cysts and endometrioid cystadenoma, one might postulate that they are pathogenetically related. Similar mutations appear in
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endometrioid ovarian cancer and in endometrioid BOTs. Atypical endometrioses may also be associated with developing endometrioid (and clear-cell) ovarian cancer [19, 20]. The new WHO classification, therefore, places endometrioid cysts in the same neoplastic context as endometrioid cystadenomas. Two different subtypes of endometrioid borderline tumors (intracystic and adenofibromatous) have been defined more exactly, the former evolving from an endometrioid adenofibroma, the latter from an endometrioid cystadenoma or endometrioid cyst. The diagnostic term ‘‘with intraepithelial carcinoma’’ is recommended for EBOTs with high-grade nuclear atypia, analogously as with the MBOTs. Again, the problem of differential diagnosis between EBOT and invasive endometrioid carcinoma has not be solved satisfactory, an analogous situation to the mucinous tumors. Endometrioid invasive carcinoma is morphological heterogeneous with areas of squamous differentiation, secretory modifications, mucinous differentiation, oxyphile variants, or sex cord stromal pattern. Endometrioid ovarian tumors are also suspicious to be metastases instead of primary tumors [5].
Arch Gynecol Obstet
Clear cell tumors
References
The new WHO classification has not brought any essential changes pertaining to the clear cell tumors. Clear cell BOTs are very similar to clear cell adenomas, and both components are regularly found within one tumor. By contrast clear cell carcinomas have a different architecture, characterized by papillary structures, and solid components with desmoplastic and hyalinized stroma and high-grade nuclear atypia [5]. Clear cell carcinoma may be associated with Lynch syndrome or endometriosis and is the most common ovarian cancer with paraneoplastic symptoms (thrombembolies or hypercalcemia) [19, 20].
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Brenner tumors The previously named ‘‘transitional cell tumors’’ is now entitled ‘‘Brenner Tumors.’’ Brenner tumors, associated with other epithelial tumors in up to 25 % of cases, are composed of cell nests whose sizes vary and are characterized by transitional cell differentiation. Brenner BOTs have in contrast to Brenner tumors a much more extensive epithelial proliferation. Therefore, they are significantly larger (mean 18 cm) and (b) having a much higher epithelial volumes than benign Brenner tumors. This BOT category now also contains an ‘‘intraepithelial carcinoma’’. Invasive malignant Brenner tumors are characterized by a destructive stroma invasion, but the morphology is not further specified. As in the previous classification, these tumors display at least focal highgrade nuclear atypia [5]. Any classification of ovarian cancers and its precursor lesions remains imperfect and has to be renewed as scientific knowledge progresses. Thus, further molecular, histopathological, and clinical investigations will enlighten the character of the different ovarian cancer subtypes and will necessitate the actualization of the current WHO classification. The latter will contribute to an even better prognosis of serous ovarian borderline tumors, since the cases with invasive implants are no longer considered borderline tumors but low-grade serous cancers. Since the histopathological assessment of borderline tumors is difficult and contains incorrect diagnoses up to 15 % and more, the German Ovary Board (AGO) recommends to involve an assessment by a reference pathologist [10, 21]. Compliance with ethical standards This article does not contain any studies with human participants or animals performed by any of the authors. Conflict of interest of interest.
The authors declare that they have no conflict
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