Clear Cell Carcinoma of Ovary and Uterus

Clear cell carcinomas of the female genital tract are rare tumours with a fearsome reputation for having poor responses to conventional platinum-based chemotherapy and poor prognosis. However, it is now clear that early-stage ovarian clear cell carcinoma has an excellent prognosis and may not require any adjuvant therapy. In addition, radiotherapy may also have a key role to play in adjuvant management of clear cell tumours. Identification of patients who truly do not need adjuvant chemotherapy is important. The past 3 years has seen a significant improvement in our understanding of clear cell carcinoma biology—in particular, the role of mutations in the chromatin remodelling gene ARID1A as key drivers that are common to clear cell carcinomas of ovarian and endometrial origin. Moreover, gynaecological clear cell carcinomas appear to share many features with renal clear cell tumours, suggesting a common pathogenesis. This raises the possibility of clinical trials that include patients with clear cell tumours from different organs of origin. Dissecting the role of disordered chromatin organisation in clear cell carcinoma pathogenesis is a key priority. Finally, the role of endometriosis and the attendant chronic inflammation are recognised. The inflammatory cytokine interleukin-6 appears to play a key role in clear cell carcinoma biology and is an excellent potential therapeutic target. Similar content being viewed by others

Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance • Vaughan S, Coward JI, Bast RC Jr, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011;11:719–25. This review and commentary was written following the Helene Harris Memorial Trust meeting, January 2011, and contains key recommendations for improving ovarian cancer outcomes. •• Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73. Although this analysis does not include CCC, it is the first comprehensive genomic analysis of endometrial cancers. Fadare O, Renshaw IL, Liang SX. Does the loss of ARID1A (BAF-250a) expression in endometrial clear cell carcinomas have any clinicopathologic significance? A pilot assessment. J Cancer. 2012;3:129–36. Lax SF. Molecular genetic changes in epithelial, stromal and mixed neoplasms of the endometrium. Pathology. 2007;39:46–54. DeLair D, Oliva E, Kobel M, et al. Morphologic spectrum of immunohistochemically characterized clear cell carcinoma of the ovary: a study of 155 cases. Am J Surg Pathol. 2011;35:36–44. Kobel M, Kalloger SE, Carrick J, et al. A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. Am J Surg Pathol. 2009;33:14–21. Arai T, Watanabe J, Kawaguchi M, et al. Clear cell adenocarcinoma of the endometrium is a biologically distinct entity from endometrioid adenocarcinoma. Int J Gynecol Cancer. 2006;16:391–5. Fadare O, Liang SX. Diagnostic utility of hepatocyte nuclear factor 1-beta immunoreactivity in endometrial carcinomas: lack of specificity for endometrial clear cell carcinoma. Appl Immunohistochem Mol Morphol. 2012;20:580–7. JGCC. Annual report on Japanese ovarian cancer. Acta Obstet Gynaecol Jpn. 2012;64:1029–41. Granstrom C, Sundquist J, Hemminki K. Population attributable fractions for ovarian cancer in Swedish women by morphological type. Br J Cancer. 2008;98:199–205. Chan JK, Teoh D, Hu JM, et al. Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecol Oncol. 2008;109:370–6. Abeler VM, Kjorstad KE, Berle E. Carcinoma of the endometrium in Norway: a histopathological and prognostic survey of a total population. Int J Gynecol Cancer. 1992;2:9–22. Olawaiye AB, Boruta 2nd DM. Management of women with clear cell endometrial cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol. 2009;113:277–83. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284:878–81. Hanselaar A, van Loosbroek M, Schuurbiers O, et al. Clear cell adenocarcinoma of the vagina and cervix. An update of the central Netherlands registry showing twin age incidence peaks. Cancer. 1997;79:2229–36. Risch HA, McLaughlin JR, Cole DE, et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario. Canada J Natl Cancer Inst. 2006;98:1694–706. Ketabi Z, Bartuma K, Bernstein I, et al. Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors. Gynecol Oncol. 2011;121:462–5. Carcangiu ML, Radice P, Casalini P, et al. Lynch syndrome–related endometrial carcinomas show a high frequency of nonendometrioid types and of high FIGO grade endometrioid types. Int J Surg Pathol. 2010;18:21–6. Broaddus RR, Lynch HT, Chen LM, et al. Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma. Cancer. 2006;106:87–94. Yang HP, Wentzensen N, Trabert B, et al. Endometrial cancer risk factors by 2 main histologic subtypes: the NIH-AARP Diet and Health Study. Am J Epidemiol. 2013;177:142–51. Pearce CL, Templeman C, Rossing MA, et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case–control studies. Lancet Oncol. 2012;13:385–94. Brinton LA, Sakoda LC, Sherman ME, et al. Relationship of benign gynecologic diseases to subsequent risk of ovarian and uterine tumors. Cancer Epidemiol Biomarkers Prev. 2005;14:2929–35. Kobayashi H, Sumimoto K, Moniwa N, et al. Risk of developing ovarian cancer among women with ovarian endometrioma: a cohort study in Shizuoka. Japan Int J Gynecol Cancer. 2007;17:37–43. Sieh W, Salvador S, McGuire V, et al. Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case–control studies. Int J Epidemiol. 2013;42:579–89. •• Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363:1532–1543. With [26], this is the first description of ARID1A mutations in clear cell and endometrioid cancers. •• Jones S, Wang T-L, Shih Ie-M, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 2010;330:228–31. With [25], this is the first description of ARID1A mutations in clear cell and endometrioid cancers. • Kuo KT, Mao TL, Jones S, et al. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol. 2009;174:1597–1601. This study identified that PIK3CA mutations may play a key role in CCC biology. Yamamoto S, Tsuda H, Takano M, et al. Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations. Mod Pathol. 2012;25:615–24. • Yamamoto S, Tsuda H, Takano M, et al. PIK3CA mutation is an early event in the development of endometriosis-associated ovarian clear cell adenocarcinoma. J Pathol. 2011;225:189–94. This is an analysis of the role of PIK3CA mutations in CCC biology. Rahman M, Nakayama K, Rahman MT, et al. Clinicopathologic and biological analysis of PIK3CA mutation in ovarian clear cell carcinoma. Hum Pathol. 2012;43:2197–206. Abe A, Minaguchi T, Ochi H, et al. PIK3CA overexpression is a possible prognostic factor for favorable survival in ovarian clear cell carcinoma. Hum Pathol. 2013;44:199–207. Wilson BG, Roberts CW. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer. 2011;11:481–92. Katagiri A, Nakayama K, Rahman MT, et al. Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma. Mod Pathol. 2012;25:282–8. Hashiguchi Y, Tsuda H, Inoue T, et al. PTEN expression in clear cell adenocarcinoma of the ovary. Gynecol Oncol. 2006;101:71–5. Yamashita Y, Akatsuka S, Shinjo K, et al. Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis. PLoS ONE. 2013;8:e57724. Yamamoto S, Tsuda H, Miyai K, et al. Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas. Mod Pathol. 2012;25:122–30. Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2:53–75. Fraser M, Zhao H, Luoto KR, et al. PTEN deletion in prostate cancer cells does not associate with loss of RAD51 function: implications for radiotherapy and chemotherapy. Clin Cancer Res. 2012;18:1015–27. Zorn KK, Bonome T, Gangi L, et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005;11:6422–30. Matsumura N, Mandai M, Okamoto T, et al. Sorafenib efficacy in ovarian clear cell carcinoma revealed by transcriptome profiling. Cancer Sci. 2010;101:2658–63. Mabuchi S, Kawase C, Altomare DA, et al. Vascular endothelial growth factor is a promising therapeutic target for the treatment of clear cell carcinoma of the ovary. Mol Cancer Ther. 2010;9:2411–22. • Anglesio MS, George J, Kulbe H, et al. IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res. 2011;17:2538–48. This is a key analysis of IL-6 and HIF signalling in CCC. • Coward J, Kulbe H, Chakravarty P, et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res. 2011;17:6083–96. This is the first description of the therapeutic potential of IL-6 inhibition in ovarian cancer. • Stany MP, Vathipadiekal V, Ozbun L, et al. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. PLoS ONE. 2011;6:e21121. This provides further clarification of VEGF and IL-6 signalling in OCCC. • Tan DS, Iravani M, McCluggage WG, et al. Genomic analysis reveals the molecular heterogeneity of ovarian clear cell carcinomas. Clin Cancer Res. 2011;17:1521–34. This is important work on genomic alterations in OCCC. • Rahman MT, Nakayama K, Rahman M, et al. Prognostic and therapeutic impact of the chromosome 20q13.2 ZNF217 locus amplification in ovarian clear cell carcinoma. Cancer. 2012, 118:2846–57. This is an analysis of the key component of the 20q13 amplicon and its potential therapeutic potential. Thillainadesan G, Isovic M, Loney E, et al. Genome analysis identifies the p15ink4b tumor suppressor as a direct target of the ZNF217/CoREST complex. Mol Cell Biol. 2008;28:6066–77. Banck MS, Li S, Nishio H, et al. The ZNF217 oncogene is a candidate organizer of repressive histone modifiers. Epigenetics. 2009;4:100–6. Lichner Z, Scorilas A, White NM, et al. The chromatin remodeling gene ARID1A is a new prognostic marker in clear cell renal cell carcinoma. Am J Pathol. 2013;182:1163–70. Varela I, Tarpey P, Raine K, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 2011;469:539–42. Micci F, Teixeira MR, Haugom L, et al. Genomic aberrations in carcinomas of the uterine corpus. Genes Chromosomes Cancer. 2004;40:229–46. Miyamoto M, Takano M, Goto T, et al. Clear cell histology as a poor prognostic factor for advanced epithelial ovarian cancer: a single institutional case series through central pathologic review. J Gynecol Oncol. 2013;24:37–43. Duska LR, Garrett L, Henretta M, et al. When ‘never-events’ occur despite adherence to clinical guidelines: the case of venous thromboembolism in clear cell cancer of the ovary compared with other epithelial histologic subtypes. Gynecol Oncol. 2010;116:374–7. Lee L, Garrett L, Lee H, et al. Association of clear cell carcinoma of the endometrium with a high rate of venous thromboembolism. J Reprod Med. 2009;54:133–8. Kleppe M, Wang T, Van Gorp T, et al. Lymph node metastasis in stages I and II ovarian cancer: a review. Gynecol Oncol. 2011;123:610–4. Magazzino F, Katsaros D, Ottaiano A, et al. Surgical and medical treatment of clear cell ovarian cancer: results from the multicenter Italian Trials in Ovarian Cancer (MITO) 9 retrospective study. Int J Gynecol Cancer. 2011;21:1063–70. Suzuki S, Kajiyama H, Shibata K, et al. Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell carcinoma patients? Ann Oncol. 2008;19:1284–7. Takano M, Tsuda H, Sugiyama T. Clear cell carcinoma of the ovary: is there a role of histology-specific treatment? J Exp Clin Cancer Res. 2012;31:53. Satoh T, Shikama A, Nakamura Y, et al. V. Minimal invasiveness treatment for young women with ovarian cancer. Gan To Kagaku Ryoho. 2013;40:182–5. Kajiyama H, Shibata K, Kikkawa F. Fertility-sparing surgery in epithelial ovarian cancer. Nihon Rinsho. 2012;70 Suppl 4:589–93. Thomas M, Mariani A, Wright JD, et al. Surgical management and adjuvant therapy for patients with uterine clear cell carcinoma: a multi-institutional review. Gynecol Oncol. 2008;108:293–7. Swenerton KD, Santos JL, Gilks CB, et al. Histotype predicts the curative potential of radiotherapy: the example of ovarian cancers. Ann Oncol. 2011;22:341–7. • Hoskins PJ, Le N, Gilks B, et al. Low-stage ovarian clear cell carcinoma: population-based outcomes in British Columbia, Canada, with evidence for a survival benefit as a result of irradiation. J Clin Oncol. 2012, 30:1656–62. Do very early stage OCCC require adjuvant chemotherapy? Could radiotherapy play a role as adjuvant therapy. These provocative questions were raised in this retrospective analysis. Takano M, Sugiyama T, Yaegashi N, et al. Low response rate of second-line chemotherapy for recurrent or refractory clear cell carcinoma of the ovary: a retrospective Japan Clear Cell Carcinoma Study. Int J Gynecol Cancer. 2008;18:937–42. Crotzer DR, Sun CC, Coleman RL, et al. Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol Oncol. 2007;105:404–8. Takano M, Kikuchi Y, Kudoh K, et al. Weekly administration of temsirolimus for heavily pretreated patients with clear cell carcinoma of the ovary: a report of six cases. Int J Clin Oncol. 2011;16:605–9. Mabuchi S, Hisamatsu T, Kawase C, et al. The activity of trabectedin as a single agent or in combination with everolimus for clear cell carcinoma of the ovary. Clin Cancer Res. 2011;17:4462–73. Yanaihara N, Anglesio MS, Ochiai K, et al. Cytokine gene expression signature in ovarian clear cell carcinoma. Int J Oncol. 2012;41:1094–100. Zatyka M, da Silva NF, Clifford SC, et al. Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. Cancer Res. 2002;62:3803–11. Saito A, Osuga Y, Yoshino O, et al. TGF-b1 induces proteinase-activated receptor 2 (PAR2) expression in endometriotic stromal cells and stimulates PAR2 activation-induced secretion of IL-6. Hum Reprod. 2011;26:1892–8. Yamaguchi K, Mandai M, Oura T, et al. Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes. Oncogene. 2010;29:1741–52. Kurzrock R, Voorhees PM, Casper C, et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res. 2013;19:3659–70. • Stone RL, Nick AM, McNeish IA, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med. 2012, 366:610–8. This was the first demonstration that IL-6 plays a key role in malignant thrombocytosis and that inhibition of IL-6 may reverse this. Compliance with Ethics Guidelines ᅟ Conflict of Interest Rosalind M. Glasspool and Iain A. McNeish declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Glasspool, R.M., McNeish, I.A. Clear Cell Carcinoma of Ovary and Uterus. Curr Oncol Rep 15, 566–572 (2013). https://doi.org/10.1007/s11912-013-0346-0 Published: Issue date: DOI: https://doi.org/10.1007/s11912-013-0346-0