Pathology International 2013; 63: 611–614


Case Report

KRAS mutation positive mucinous adenocarcinoma originating in mature ovarian teratoma: Case report and review of literature

Dov Hershkovitz,1,2 Euvgeni Vlodavsky,1,2 Einav Simon2 and Ofer Ben-Izhak1,2 Institute of Pathology, Rambam Health Care Campus and 2B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel


Mature ovarian teratomas rarely undergo transformation into malignancy. Carcinomas, mostly squamous cell carcinoma, are the most common malignancy arising in mature cystic teratoma. In the present report we describe a 13-yearold girl who developed a large mass in her ovary. Fine needle biopsy identified intestinal type mucinous adenocarcinoma, which was also identified in the full surgical specimen. Extensive sampling of the surgical specimen also identified areas of mature cystic teratoma. Interestingly, molecular analysis of DNA extracted from various components of the lesion identified KRAS mutation in the carcinoma, borderline mucinous tumor and benign intestinal-type epithelium but not in the epidermal component of the teratoma. To the best of our knowledge this is the first report of KRAS mutation in mucinous carcinoma originating in mature cystic teratoma. We discuss the importance of extensive tissue sampling to differentiate between carcinoma originating in teratoma and metastatic colorectal carcinoma to the ovary. Additionally, the identification of KRAS mutation in the morphologically benign intestinaltype epithelium indicated that it is an early event in the carcinogenic sequence and that the molecular pathway of carcinogenesis in teratoma is similar to that in the carcinogenic process of somatic tissue. Key words: Adenoma-Carcinoma sequence, KRAS mutation, mucinous carcinoma, teratoma

Teratoma is a germ cell tumor composed of derivates of two or all three germ cell layers (endoderm, mesoderm and ectoderm). Teratomas commonly occur in sacrococcygeal, mediCorrespondence: Dov Hershkovitz, MD, PhD, Institute of Pathology, Rambam Health Care Campus, PO Box 9602, Haifa 31096, Israel. Email: [email protected] Declaration of interest: None declared. Received 12 September 2013. Accepted for publication 27 November 2013. © 2013 The Authors Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

astinal, retroperitoneal, cervicofacial and intracranial areas as well as the gonads, including ovary. Within the ovaries, teratomas are the most common germ cell tumor and the most common neoplasm in patients younger than 20 years. Teratomas are mostly a benign neoplasia but there are several types of malignant teratomas, including immature teratoma, mixed germ cell tumor and malignant transformation of mature teratoma. In the present report we describe a young patient with mucinous adenocarcinoma developing in mature cystic teratoma of the ovary. Interestingly, molecular analysis of the sample identified KRAS mutation in the carcinoma and the benign intestinal-type epithelium.

CLINICAL SUMMARY A 13-year-old, previously healthy girl from an Arab Muslim family was referred to our hospital due to abdominal pain and large ovarian mass. Sonographic examination of pelvis demonstrated a well-circumscribed heterogeneous solid mass, measuring 7 × 10 cm, attached to the right ovary. Serum levels of CA-19-9 (162 U/mL), CEA (5.5 ng/mL) and CA-125 (268 U/mL) were elevated. Serum beta-HCG (human chorionic gonadotropin) and alpha fetoprotein levels were within the normal limits. The patient underwent resection of the tumor. Surgery and post-surgical course were unremarkable. Five months after discharge the patient is with no clinical evidence of disease.

PATHOLOGICAL FINDINGS The patient underwent ultrasound-guided fine needle biopsy. Histological examination revealed intestinal-type adenocarcinoma, that was immunohistochemically positive for CDX2 and cytokeratin 20, and negative for cytokeratin 7 and PAX 8,


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Figure 1 Histological and immunohistochemical analysis of the fine needle biopsy. Microscopic examination showed mucous adenocarcinoma, intestinal type (a) that was immunohistochemically positive for CDX2 (b) and cytokeratin 20 (c). The sample was negative for cytokeratin 7 (d).

suggesting intestinal differentiation of the tumor (Fig. 1). Nevertheless, a subsequent colonoscopic examination was unremarkable. The patient then underwent complete surgical resection of the ovarian mass. Macroscopic examination of the surgical specimen revealed a tumor measuring 13 × 11 × 10 cm. The sectioned surfaces showed solid and cystic tumor with massive necrosis and occasional gelatinous content. Microscopic examination demonstrated extensive areas of mucinous adenocarcinoma, intestinal type, with widespread necrosis. The carcinoma component showed extensive invasive pattern and necrosis and was mostly composed of glandular and cribriform structures. Cytologically, tumor cells demonstrated prominent atypia, pseudostratification, mitosis and karyorrhexis. Extensive sampling of the tissue demonstrated a few foci of residual mature teratoma, composed of cysts, lined by mature squamous epithelium simulating skin, with adnexa (Fig. 2), as well as foci of benign intestinal-type epithelium. Additionally, areas of borderline mucinous tumor were identified, in continuity with benign mucinous epithelium and invasive carcinoma. DNA was extracted from the various components of the tumor mass and scrutinized for KRAS exon 2 mutations using direct sequencing, as previously described.1 Briefly, DNA was polymerase chain reaction (PCR) amplified using primers forward 5′-GGCCTGCTG AAAATGACTGAA-3′ and reverse 5′-GGTCCTGCACCAG TAATATGCA-3′ and amplicons were subjected to direct DNA sequencing using the BigDye Terminator v1.1 Cycle Sequencing kit (Applied Biosystems, Foster City, CA, USA) on an automated sequencer (ABI Prism 3130xl Genetic Analyzer; Applied Biosystems). Molecular analysis identified KRAS mutation c.35G>A in the carcinoma, borderline mucinous

tumor and benign intestinal-type epithelium. The mutation was not present in the epidermal component of the teratoma (Fig. 2). The final diagnosis was KRAS mutation positive intestinal-type mucinous adenocarcinoma arising in mature teratoma.

DISCUSSION Ovarian mature cystic teratomas are usually benign; however, malignancy arises in 1–2% of them, mostly in postmenopausal women. Squamous and adenocarcinomas are the most common malignancies arising in teratomas, but rare cases such as pulmonary type small cell carcinoma, angiosarcoma and clear cell carcinoma have been described.2,3 Among the carcinomas squamous cell carcinoma (SCC) account for 80% of cases.4 SCC in mature teratoma occurs most commonly in women older than 50 and are usually larger than 10 cm.4 Complete resection with hysterectomy and salphingo-oophorectomy followed by adjuvant chemotherapy was shown to improved survival.4 Adenocarcinoma is the second most common malignancy arising in mature cystic ovarian teratomas, accounting for only 6% of cases.5 Several cases of intestinal type adenocarcinoma originating in teratoma have been described in the literature. A study of 42 cases of mucinous epithelial neoplasms arising in mature teratoma demonstrated a CK7-/ CK20+ and CDX2+ immunophenotype in all the cases of invasive carcinoma,6 as with our patient. In the present case, the fine needle biopsy contained only carcinoma, therefore raising a differential diagnosis between

© 2013 The Authors Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

KRAS positive carcinoma in teratoma

Figure 2 Histologic and molecular analysis of the surgical specimen. Extensive sampling of the surgical specimen showed areas of mature cystic teratoma, with a group of glands (arrowheads), suggestive of sweat gland type adnexa (a). Other areas showed foci of benign intestinal-type epithelium (b) and borderline mucinous tumor showing nuclear enlargement and hyperchromasia as well as cellular stratification (c) in addition to the extensive intestinal carcinoma (d). Molecular analysis identified KRAS codons 12, c.35G > A mutation in the carcinoma as well as the benign intestinal-type epithelium and the borderline mucinous tumor (b–d, insets). No mutation could be demonstrated in the squamous epithelium of the mature cystic teratoma (a, inset).





metastatic colonic carcinoma to the ovary, primary ovarian carcinoma and malignant transformation of mature teratoma. Making the distinction between these entities is important not only due to differences in treatment and prognosis, but because the diagnosis of colonic carcinoma in a young patient requires work-up for Lynch syndrome and genetic counseling for the patient and her family.7 This is especially important considering the recent reports of familial DNA mismatch repair gene mutations8 and the high frequency of consanguineous marriage in the patient’s population. Clinical evaluation and extensive sampling of the tumor identified mature teratoma elements and allowed us to make the correct diagnosis. Another diagnostic possibility that should be considered is a collision tumor of mucinous adenocarcinoma and mature teratoma. However, the patient’s age, the normal colonoscopic findings and the presence of benign intestinal-type epithelium, continuous with borderline changes and carcinoma, admixed with the mature teratoma, make this diagnosis less likely. KRAS mutation is very rarely reported in ovarian teratomas, like in the case of Sedivi et al. describing KRAS mutation in mature teratoma from archived tissue from the Viennese Museum of Pathological Anatomy.9 To the best of our knowledge, this is the first report of KRAS mutation in mucinous carcinoma originating in mature teratoma. KRAS mutation may play an important role in malignant transformation of mature teratoma, which might simulate the molecular events underlying the carcinogenic process of colorectal carcinoma.10 Additional support for this assumption can be found in a recent report of malignant struma ovarii originating in mature teratoma with identified KRAS mutation in the sample, a mutation that is also present in some cases of thyroid carci-


nomas.11 This indicates that the common mutational drivers of various malignancies are also present in their somatic analogues in teratomas. In our case we identified KRAS mutation in the intestinal carcinoma component but a small peak of the mutant allele could be traced in the borderline mucinous tumor component and the benign intestinal-type epithelium, suggesting that KRAS mutation occurred before the morphological changes of dysplasia could be seen. Indeed, in the colon, previous reports have indicated that KRAS mutation is present in up to 18% of hyperplastic polyps.12 Interestingly, a recent analysis of microsatellite polymorphism in mucinous ovarian carcinomas and associated teratomas showed a clonal match between the samples, suggesting that a subset of mucinous ovarian carcinoma actually arise from mature teratomas.13 The absence of KRAS mutation in the mature teratoma element in our sample suggests that this mutation occurred later in the carcinogenic process. In conclusion, we described a patient with KRAS mutation positive mucinous carcinoma arising in mature teratoma. It might be possible that future, more extensive evaluation of KRAS mutation in cases of ovarian and other teratomas will improve our understanding of molecular mechanisms, regulating growth and malignant transformation of these tumors, with possible effect on targeted treatment decisions.

REFERENCES 1 Efrati E, Elkin H, Peerless Y, Sabo E, Ben-Izhak O, Hershkovitz D. LNA-based PCR clamping enrichment assay for the identification of KRAS mutations. Cancer Biomark 2010; 8: 89–94.

© 2013 The Authors Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd


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2 Ikota H, Kaneko K, Takahashi S et al. Malignant transformation of ovarian mature cystic teratoma with a predominant pulmonary type small cell carcinoma component. Pathol Int 2012; 62: 276–80. 3 Takahashi H, Chaopotong P, Kajita S, Hashimura M, Yamazaki H, Saegusa M. Mixed angiosarcoma, clear cell adenocarcinoma and mature teratoma elements in an ovarian tumor: A case report and literature review. Pathol Int 2012; 62: 538–42. 4 Hackethal A, Brueggmann D, Bohlmann MK, Franke FE, Tinneberg HR, Munstedt K. Squamous-cell carcinoma in mature cystic teratoma of the ovary: Systematic review and analysis of published data. Lancet Oncol 2008; 9: 1173–80. 5 Comiter CV, Kibel AS, Richie JP, Nucci MR, Renshaw AA. Prognostic features of teratomas with malignant transformation: A clinicopathological study of 21 cases. J Urol 1998; 159: 859– 63. 6 McKenney JK, Soslow RA, Longacre TA. Ovarian mature teratomas with mucinous epithelial neoplasms: Morphologic heterogeneity and association with pseudomyxoma peritonei. Am J Surg Pathol 2008; 32: 645–55. 7 Herkert JC, Niessen RC, Olderode-Berends MJ et al. Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations:







Case series, review and follow-up guidelines. Eur J Cancer 2011; 47: 965–82. Tomsic J, Senter L, Liyanarachchi S et al. Recurrent and founder mutations in the PMS2 gene. Clin Genet 2013; 83: 238–43. Sedivy R, Kalipciyan M, Patzak B, Mader RM. KRAS mutations in historical tumour specimens of the Viennese Museum of pathological anatomy. Histopathology 2011; 58: 792–6. Leslie A, Carey FA, Pratt NR, Steele RJ. The colorectal borderline mucinous tumor-carcinoma sequence. Br J Surg 2002; 89: 845–60. Stanojevic B, Dzodic R, Saenko V et al. Unilateral follicular variant of papillary thyroid carcinoma with unique KRAS mutation in struma ovarii in bilateral ovarian teratoma: A rare case report. BMC Cancer 2012; 12: 224. Chan TL, Zhao W, Leung SY, Yuen ST. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated borderline mucinous tumors. Cancer Res 2003; 63: 4878–81. Kerr SE, Flotte AB, McFalls MJ, Vrana JA, Halling KC, Bell DA. Matching maternal isodisomy in mucinous carcinomas and associated ovarian teratomas provides evidence of germ cell derivation for some mucinous ovarian tumors. Am J Surg Pathol 2013; 37: 1229–35.

© 2013 The Authors Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

KRAS mutation positive mucinous adenocarcinoma originating in mature ovarian teratoma: case report and review of literature.

Mature ovarian teratomas rarely undergo transformation into malignancy. Carcinomas, mostly squamous cell carcinoma, are the most common malignancy ari...
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