Ovarian Carcinoma Histotypes: Their Emergence as Important Prognostic and Predictive Markers

Oncology (Williston Park). 30(2):178–179.

In this issue of ONCOLOGY, Dr. Ramalingam reviews clinicopathologic features of the ovarian carcinoma histotypes.[1] To appreciate her article fully, it is useful to consider how the current era of ovarian cancer management differs from our approach of 15 years ago. As the author discusses, ovarian carcinoma was formerly considered to be a single disease, with treatment decisions based solely on grade and stage; in contrast, the ovarian carcinoma histotypes are now considered to be distinct diseases, differing with respect to precursor lesions, molecular events during oncogenesis, pattern of spread, response to chemotherapy, and clinical outcome. It is worth noting that this shift in approach, in which cancers arising in a given organ are routinely classified into reproducibly diagnosable subtypes, is not unique to ovarian carcinoma. For example, breast carcinoma can be divided into molecular subtypes (luminal A, luminal B, basal-like, positive or negative for human epidermal growth factor receptor 2 [HER2]),[2] and head and neck and vulvar squamous cell carcinomas can be categorized as human papillomavirus (HPV)-associated or HPV-independent.[3,4] In each of these malignancies, the subclassification reflects differences in molecular abnormalities and has treatment implications. Diagnosis of ovarian carcinoma histotype is based largely on routine morphologic examination, without molecular testing such as immunostaining; however, diagnosis has been driven by a better understanding of the molecular pathology of the different histotypes.

It would be easy for a casual observer to fail to notice the very significant changes that have occurred in ovarian carcinoma histotype diagnosis over the past 15 years, given that the broad histotype categories (serous, mucinous, endometrioid, clear cell, transitional/Brenner) have not changed. The basis for this more finely tuned diagnostic process in ovarian cancer is our improved understanding of the molecular abnormalities associated with each histotype, which has allowed development of molecular markers, such as Wilms tumor 1 (WT1) as an immunomarker for serous carcinoma; this, in turn, has led to refined criteria for histotype diagnosis. As Dr. Ramalingam notes, we are moving away from treating ovarian carcinoma as a single disease and moving towards histotype-specific management. This is perhaps best seen in how we assess risk of inherited cancer susceptibility syndromes. There are only two common autosomal dominant inherited cancer susceptibility syndromes, hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), both of which are associated with increased risk of developing ovarian carcinoma. The ovarian carcinoma histotypes associated with HBOC and LS, however, are mutually exclusive: High-grade serous carcinoma is the predominant expression of HBOC,[5] while LS is associated with increased risk of the endometriosis-associated histotypes (endometrioid and clear cell carcinomas), and not with high-grade serous carcinoma.[6] This has immediate implications for identification of hereditary cancer syndromes in patients presenting with ovarian carcinoma; in our center, all patients with high-grade serous carcinoma are eligible for testing for germline BRCA1 and BRCA2 mutations, and more than 20% of patients tested to date have been mutation carriers.[7] Affected relatives may then undergo highly effective risk-reducing surgery. Newly diagnosed endometrioid or clear cell carcinomas of the ovary are, in many areas, subject to reflex testing for expression of mismatch repair (MMR) protein expression by immunostaining, to identify possible LS cases.[8] The likelihood of these patients having LS is similar to that of patients with colorectal carcinoma or endometrial carcinoma, for whom reflex MMR testing is routinely performed, and supports expansion of reflex MMR protein testing to patients with these histotypes of ovarian carcinoma.

For a diagnosis to be used in guiding patient management, it must be reproducible; a patient should receive the same diagnosis, and therefore the same treatment, consistently, irrespective of the diagnosing pathologist. Although histotype diagnosis was formerly plagued by high levels of interobserver variation, there is now excellent interobserver agreement using current diagnostic criteria.[9,10] This mainly is reflective of two changes in diagnostic practice. As Dr. Ramalingam describes, the high-grade carcinomas formerly diagnosed as endometrioid carcinoma are now mostly classified as high-grade serous carcinoma, with WT1 immunostaining serving as a helpful guide to correct diagnosis. The other significant change, not emphasized by the author, is that the incidence of diagnosis of mixed carcinoma (ie, tumors consisting of more than one histotype) has dropped precipitously, with mixed carcinoma now accounting for less than 1% of cases.[11] The so-called “mixed” carcinomas of the past are now recognized to be of a single histotype in most cases, with intratumoral morphologic variation that should not influence histotype diagnosis. Currently, most mixed carcinomas are admixtures of histotypes associated with endometriosis (eg, endometrioid and clear cell carcinomas).

There has been an important shift in ovarian cancer management over the past 15 years, with evidence of some dramatic and clinically significant changes in the diagnostic approach. Consider, for example, the histotype of ovarian carcinomas associated with HBOC. In studies in which histotype has not been based on pathology slide review or use of current diagnostic criteria, there is a wide range of histotypes associated with HBOC. For example, in the recently published CIMBA study of ovarian carcinomas arising in patients with BRCA1 or BRCA2 mutations, only 67% of cancers were high-grade serous type,[12] a rate similar to that reported for sporadic ovarian carcinomas. While histotype assignment in CIMBA was based on the original pathology report, in studies of ovarian carcinomas arising in patients with HBOC in which the pathology slides have been reviewed and modern diagnostic criteria applied, these carcinomas have consistently been shown to be almost exclusively high-grade serous carcinoma.[5] Another more direct demonstration of the change in ovarian carcinoma diagnosis over time comes from a recent review we did of cases from a historic, large chemotherapy trial of patients with primary advanced-stage ovarian carcinomas,[13] the original diagnoses of which had been reviewed by one of us (FK).[14] Upon re-review of the original slides 12 years later, only 52% of histotype diagnoses were confirmed by the same gynecologic pathologist applying current World Health Organization (WHO) diagnostic criteria, clearly indicating how much change there has been. Interestingly, there was also very high interobserver agreement in histotype diagnosis, when the re-review results were compared with the results of independent review by a second gynecologic pathologist (BG), with 98% concordance of histotype diagnosis (Kommoss S, Kommoss F, and Gilks CB, unpublished data).

In summary, Dr. Ramalingam provides a thoughtful review of the current state of our understanding of ovarian carcinoma histotypes. We have attempted to provide context by demonstrating how the current approach to diagnosis of ovarian cancer has changed significantly from our understanding as recently as 15 years ago. The movement of ovarian carcinoma histotypes from ill-defined and poorly reproducible clusters of cases to distinct disease entities clearly has beneficial implications for patient management.

Financial Disclosure:The authors have no significant financial relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Ramalingam P. Morphologic, immunophenotypic, and molecular features of epithelial ovarian cancer. Oncology (Williston Park). 2016;30:166-76.

2. Chia SK, Bramwell VH, Tu D, et al. A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen. Clin Cancer Res. 2012;18:4465-72.

3. Ang KK, Sturgis EM. Human papillomavirus as a marker of the natural history and response to therapy of head and neck squamous cell carcinoma. Semin Radiat Oncol. 2012;22:128-42.

4. Ueda Y, Enomoto T, Kimura T, et al. Two distinct pathways to development of squamous cell carcinoma of the vulva. J Skin Cancer. 2011;2011:951250.

5. Schrader KA, Hurlburt J, Kalloger SE, et al. Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy. Obstet Gynecol. 2012;120:235-40.

6. Lu FI, Gilks CB, Mulligan AM, et al. Prevalence of loss of expression of DNA mismatch repair proteins in primary epithelial ovarian tumors. Int J Gynecol Pathol. 2012;31:524-31.

7. McAlpine JN, Porter H, Köbel M, et al. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod Pathol. 2012;25:740-50.

8. Chui MH, Ryan P, Radigan J, et al. The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy. Am J Surg Pathol. 2014;38:1173-81.

9. Köbel M, Kalloger SE, Baker PM, et al. Diagnosis of ovarian carcinoma cell type is highly reproducible: a transCanadian study. Am J Surg Pathol. 2010;34:984-93.

10. Köbel M, Bak J, Bertelsen BI, et al. Ovarian carcinoma histotype determination is highly reproducible, and is improved through the use of immunohistochemistry. Histopathology. 2014;64:1004-13.

11. Mackenzie R, Talhouk A, Eshragh S, et al. Morphologic and molecular characteristics of mixed epithelial ovarian cancers. Am J Surg Pathol. 2015;39:1548-57.

12. Mavaddat N, Barrowdale D, Andrulis IL, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers; results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 2012;21:134-7.

13. du Bois A, Lück HJ, Meier W, et al; Arbeitsgemeinschaft Gynäkologische Onkologie Ovarian Cancer Study Group. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003;95:1320-9.

14. Kommoss F, Kommoss S, Schmidt D, et al; Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom. Survival benefit for patients with advanced-stage transitional cell carcinomas vs. other subtypes of ovarian carcinoma after chemotherapy with platinum and paclitaxel. Gynecol Oncol. 2005;97:195-9.