Papillary serous carcinoma in situ in ovarian endometriosis in an MSH2 mutation carrier

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Papillary serous carcinoma in situ in ovarian endometriosis in an MSH2 mutation carrier Zvi Vaknin a,b, Walter H. Gotlieb a,b, Jocelyne Arseneau a,c, Alex Ferenczy a,b,c,d,⁎ a b c d

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada Jewish General Hospital, Montreal, Quebec, Canada Department of Pathology, McGill University, Montreal, Quebec, Canada Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada

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Article history: Received 27 March 2009 Received in revised form 21 April 2009 Accepted 15 May 2009 Keywords: Endometriosis Hereditary nonpolyposis colorectal cancer (HNPCC) Lynch syndrome Ovarian cancer Prophylactic surgery Serous carcinoma in situ

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant cancer caused by a germline mutation of mismatch repair (MMR) genes [1]. It is characterized by an early onset of colorectal, endometrial, and ovarian cancer as well as cancers of the gastrointestinal and upper urinary tracts, brain, and skin. The risk of gynecologic cancer in women with HNPCC equals or even exceeds that of colorectal cancer [1]. Typically, HNPCC-associated ovarian cancers are of nonserous histologies, such as endometrioid, mucinous, and clear cell types [1]. We report a unique case of noninvasive serous carcinoma that developed in an endometriotic cyst of the ovary in an MSH2 mutation carrier. A 47-year-old woman (G3P3) with a strong family history of cancer underwent surgery and adjuvant chemotherapy at age 42 for a welldifferentiated adenocarcinoma of the colon (stage pT3 pN1). This was subsequently identified to be HNPCC with an MSH2 mutation. An endometrial biopsy was negative for cancer. Pelvic sonography suggested ovarian endometriosis, CA125 level was 86 U/mL (normal b35 U/mL), CEA was 0.6 ng/mL (normal b3.0 ng/mL), and the patient's Pap test was normal. At pathological inspection of the hysterectomy and bilateral salpingo-oophorectomy specimens, the adnexae and uterus appeared normal. The right ovary (4 × 2 × 2 cm) contained a 2.3 × 2.0 × 1.8 cm cyst filled with bloody fluid. The left ovary (2 × 1 × 0.8 cm) contained a few minute cystic structures filled with blood. Microscopically, both ovaries contained several foci of endometriosis. The cystic structure in the right ovary was lined by tuboendometrial type epithelium and focally displayed a papillary growth pattern and severe cytonuclear and nucleolar atypia, in all respects similar to high grade serous papillary carcinoma of the ovary or endometrium (Fig. 1). There was no invasion of the underlying endometrial type cellular stroma. By immunohistochemistry, the serous carcinoma in situ cells stained for p53 (30% of cells), p16 (90% of cells), and Ki-67, but not for estrogen/progesterone (ER/PR)

⁎ Corresponding author. Department of Pathology, Jewish General Hospital, 3755 Cote Sainte-Catherine Road, Montreal, Quebec, Canada H3T 1E2. Tel.: +1 514 340 7526; fax: +1 514 340 7542.

and Wilms tumor 1 (WT1). The fimbriated segment of both tubes contained p53-negative epithelial hyperplasia without atypia. To the authors' knowledge, this is the first reported case of occult serous carcinoma in situ arising in cystic ovarian endometriosis in an HNPCC patient who underwent risk-reducing robotic hysterectomy and salpingo-oophorectomy. Both the light microscopic and immunophenotypic characteristics supported a serous rather than an endometrioid histotype of the atypical cells. Furthermore, consistent with the histological origin of the lesion together with positive immunoreactivity for p53 and p16 but not for WT1, the malignant cells were presumably of endometrial rather than ovarian serous phenotype. According to current concept, WT1 is a more reliable immunomarker of ovarian serous differentiation than p16 [2]. Also, WT1 is generally negative in serous carcinoma of the endometrium. The association of serous carcinoma in situ within endometriosis presents a management challenge. On the one hand, similar lesions in the endometrium are treated with chemoradiation for they are known to carry a potential for disseminated malignant disease [3]. On the other hand, there is no information on the clinical behavior of a case like ours, and preoperative cytology was negative for malignant cells. Hence, we elected a tight surveillance scheme rather than postoperative chemotherapy. The patient is well, without disease clinically, radiologically,

Fig. 1. Papillary structures lined by highly atypical gland cells with enlarged, pleomorphic nuclei and nucleoli consistent with high-grade serous type adenocarcinoma. Endometriotic stroma in lower right (hematoxylin-eosin x450).

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and biochemically (CEA and CA125 within normal limits) 13 months after surgery. Conflict of interest The authors declare that there are no conflicts of interest. Acknowledgments

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References [1] Watson P, Bützow R, Lynch HT, Mecklin JP, Järvinen JH, Vasen HG, et al. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2001;82(2):223–8. [2] Phillips V, Kelly P, McCluggage WG. Increased p16 expression in high-grade serous and undifferentiated carcinoma compared with other morphologic types of ovarian cancer. Int J Gynecol Pathol 2009;28:179–86. [3] Santin AD, Bellone S, O'Brien TJ, Pecorelli S, Cannon MJ, Roman JJ. Current treatment options for endometrial cancer. Expert Rev Anticancer Ther 2004;4(4):679–89.

This work and some of the authors were in part supported by grants from the Israel Cancer Research Foundation, Dr Sima Visman fund – Sackler Faculty of Medicine, Tel Aviv University, Dr Alvin Hoffman fund – American Physicians Fellowship, The Israel Cancer Association.

0020-7292/$ – see front matter © 2009 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2009.05.017