ANTICANCER RESEARCH 33: 2135-2138 (2013)

Synchronous Quadruple Primary Tumors of Thyroid, Breast, , and : a

JONG-SUN KIM1, CHO-YUN CHUNG1, HYUNG-CHUL PARK1, DAE-SEONG MYUNG1, SUNG-BUM CHO1, WAN-SIK LEE1, JUNG-JOON MIN2 and YOUNG-EUN JOO1

Departments of 1Internal Medicine and 2Nuclear Medicine, Medical School, Chonnam National University, Gwangju, Republic of Korea

Abstract. We herein present the first case to be reported of dyspepsia of one month. She suffered from essential synchronous quadruple primary of the thyroid, breast, hypertension and hyperlipidemia, but there was no previous pancreas and stomach in a 70-year-old female. Fluorine-18- history of peptic ulcer diseases, cholecystitis with , fluorodeoxyglucose (FDG)-positron-emission tomography/ smoking, any ingestion, or abdominal . Her computed tomography (PET/CT) revealed increased FDG family history was non-contributory. On admission, she was activity in the thyroid, left breast, pancreatic body and afebrile, with normal blood pressure and pulse, and she antrum of the stomach. To make a definitive diagnosis of appeared well-nourished. Anemic conjunctiva and scleral synchronous quadruple primary tumors, -guided icterus were not present. Her abdomen was not tender. There fine-needle aspiration (FNA) cytology and of the was no ; the , , and thyroid, breast, pancreas and stomach were performed. FNA were not palpable, and bowel sounds were normoactive. All cytology and biopsy findings showed papillary of laboratory examinations, including complete peripheral the thyroid, invasive ductal of the breast, blood counts, blood biochemistry and tumor markers, adenocarcinoma of the pancreas and gastrointestinal stromal were within normal range. tumor. To the best of our knowledge, this combination of Esophagogastroduodenoscopy showed a protruding synchronous multiple primary tumors has not been reported. about 5 cm in size, covered with normal mucosa in the antrum of the stomach, suggesting gastric submucosal tumor. Recently, reports of multiple primary tumors occurring in the Abdominal computed tomography (CT) revealed an same patient have gradually been published. The majority of approximately 5.0×4.0 cm sized mass in the antrum of the multiple primary tumors are metachronous, while multiple stomach and a 1.5 × 1.8 cm sized ill-defined mass with synchronous primary tumors in the same patient are dilation of the main in the pancreatic body. extremely rare (1, 2). Recently, we experienced a case of Endoscopic ultrasonography (EUS) showed a homogeneous synchronous quadruple primary cancer of the thyroid, breast, hypoechoic mass originating from the proper muscle layer in pancreas and stomach in a 70-year-old female. As far as we the antrum, indicating gastrointestinal stromal tumor (GIST). know, there has been no such case reported in the English Magnetic resonance imaging (MRI) showed an ill-defined language literature. We report the first case of synchronous inhomogeneous mass with invasion of celiac axis and quadruple primary tumors involving the thyroid, breast, dilation of the main pancreatic duct in the body, indicating pancreas and stomach, and a review of the medical literature. . We performed fluorine-18-fluorodeoxyglucose (FDG)- Case Report positron-emission tomography/computed tomography (PET/CT) to stage the pancreatic cancer and GIST. FDG- A 73-year-old female was admitted to Chonnam National PET/CT revealed increased FDG activity in both thyroid University Hwasun Hospital (Jeonnam, Korea) with lobes, left breast, pancreatic body and antrum of the stomach (Figure 1). Neck US revealed a 1.1×1.0-cm sized speculated isoechoic mass in the left lobe and a 1.3×1.5-cm sized speculated hypoechoic mass in the right lobe of the thyroid. Correspondence to: Young-Eun Joo, MD, Ph.D., Department of Breast US revealed several irregular hypoechoic masses in Internal Medicine, Chonnam National University Medical School, 8 Hak-Dong, Dong-ku, Gwangju, 501-757, Korea. Tel: +82 the upper inner portion of the left breast. 622206296, Fax +82 622258578, e-mail: [email protected] To make the histological diagnosis of synchronous quadruple primary tumors, US-guided fine-needle aspiration Key Words: Synchronous cancer, thyroid, breast, stomach, pancreas. (FNA) cytology and biopsy of the thyroid, breast, pancreas

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Figure 1. Fluorine-18-fluorodeoxyglucose (FDG)-positronemission tomography/computed tomography (PET/CT). Maximum intensity projection PET image shows the FDG-avid foci in both thyroid lobes, left breast, pancreatic body and antrum of the stomach (arrows) (A). PET/CT shows multiple masses with increased FDG uptake in both thyroid lobes, left breast, pancreatic body and antrum of the stomach (arrows) (B).

Figure 2. Microscopic examinations. Papanicolaou staining shows the characteristic Orphan Annie eye nuclear inclusions, intranuclear grooves and pseudoinclusion, indicating papillary carcinoma of the thyroid (A, ×400). Routine , stained using hematoxylin-eosin (H&E), shows moderately differentiated invasive of the breast (B, ×200). Routine histology, stained using H&E, shows moderately differentiated adenocarcinoma of pancreas (C, ×200). Immunohistochemical staining of tumor cells is strongly positive for cluster of differentiation antigen 117 (CD117), indicating gastrointestinal stromal tumor (D, ×100).

2136 Kim et al: Synchronous Quadruple Primary Tumors and stomach were performed. Microscopic examinations mutations occur in a considerable proportion of pancreatic revealed papillary carcinoma of the thyroid (Figure 2A), and colon cancer cases (13, 14). Further investigations invasive ductal adenocarcinoma of the breast (Figure 2B), focusing on oncogenes are necessary to clarify the etiology adenocarcinoma of the pancreas (Figure 2C) and GIST of development of multiple synchronous primary tumors. positive for cluster of differentiation antigen 117 (CD117) Previous studies reported that about 25% of patients with (Figure 2D), respectively. The patient refused further GIST were found to have at least one additional malignant evaluation and aggressive treatment such as surgery. We tumor due to as increase in of patients with decided to treat the and GIST by GIST (15). Several studies have reported that carcinoma in therapy and , and provide supportive treatment the was the most common additional for the thyroid and pancreatic cancer. Therefore, the patient in GIST (15, 16). However, concurrent was given letrozole (Femara® Tab 2.5 mg) and imatinib occurrence of non-familial GISTs with extra-gastrointestinal (Glivec® Tab 2.5 mg). The patient’s condition was getting tract is a very rare episode, such as in our case worse, and she eventually died 8 months after the diagnosis. (17). Taken together, since synchronous quadruple primary Discussion tumors of the thyroid, breast, pancreas and stomach have not been reported, we suggest that the association between such The of synchronous and metachronous multiple tumors may not be one of these, and further studies are primary tumors has increased in recent decades (1, 2). There warranted to clarify the relationship between multiple are several possible explanations for this change. Firstly, primary tumors, including common etiological factors. recent improvements in the survival of patients with tumor References have led to an increase in the incidence of second primary tumors, and the frequency of multiple primary tumors is 1 Axelrod JH, Fruchter R and Boyce JG: Multiple primaries expected to increase as the population ages. Secondly, changes among gynecologic malignancies. Gynecol Oncol 18: 359-372, of therapeutic modality and constant follow-up examinations 1984. for the primary tumor can affect the incidence of synchronous 2 Watanabe S, Kodama T, Shimosato Y, Arimoto H, Sugimura T, or metachronous multiple primary tumors (1, 2). Suemasu K and Shiraishi M: Multiple primary in 5,456 The criteria for multiple primary tumors were those cases in the National Cancer Center of Japan. J Natl proposed earlier (3), i.e. that each of the tumors should have Cancer Inst 72: 1021-1027, 1984. 3 Warren S and Gates O: Multiple primary malignant tumors. A a distinctively-different histology and the probability of one study of the literature and a statistical study. Am J Cancer 16: being a of the other must be excluded. The term 1358-1414, 1932. synchronous is used in various ways, with an interval of two 4 Howe HL: A review of the definition for multiple primary months, six months, one year, and two years in different cancers in the United States. Workshop Proceedings from studies (4). Our case had tumors with four different December 4-6, 2002, in Princeton, New Jersey. Springfield (IL): , including the papillary carcinoma of the thyroid, North American Association of Central Cancer Registries, 2003. invasive ductal adenocarcinoma of the breast, 5 Soliman PT, Slomovitz BM, Broaddus RR, Sun CC, Oh JC, Eifel PJ, Gershenson DM and Lu KH: Synchronous primary adenocarcinoma of the pancreas and GIST, coincidently. cancers of the endometrium and ovary: A single institution The etiologies and epidemiologies of multiple primary review of 84 cases. Gynecol Oncol 94: 456-462, 2004. tumors are under investigation, and relationships between 6 Axelrod JH, Fruchter R and Boyce JG: Multiple primaries some tumors are well-established. Multiple primary tumors among gynecologic malignancies. Gynecol Oncol 18: 359-372, are predominantly seen in both the genitourinary and 1984. gastrointestinal tracts (1, 3). Because breast, ovarian, and 7 Reimer RR, Hoover R, Fraumeni JF Jr and Young RC: Second endometrial tissues are all hormonally-responsive, there are primary following ovarian cancer. J Natl Cancer Inst 61: 1195-1197, 1978. increased risks of synchronous primary tumors among 8 Eriguchi N, Aoyagi S, Hara M, Okuda K, Tamae T, Fukuda S, tumors at these sites (5-7). Patients with ovarian cancer have Hashino K, Sato S, Fujiki K, Furukawa S and Jimi A: a significant risk for synchronous breast cancer (5-7). Synchronous or metachronous double cancers of the pancreas Pancreatic cancer was associated with tumors of the and other organs: Report on 12 cases. Surg Today 30: 718-721, gastrointestinal tract, especially of the stomach (8-10). Some 2000. studies suggested that gastrectomy may be a 9 Dasanu CA, Mesologites T and Trikudanathan G: Synchronous predisposing a patient to the development of pancreatic tumors: of pancreas and GIST of stomach. J Gastrointest Cancer 42: 186-189, 2011. cancer (11, 12). However, there was no clinical evidence to 10 Miyaguni T, Muto Y, Kusano T, Yamada M, Matsumoto M and suggest that gastrectomy is associated with the development Shiraishi M: Synchronous double cancers of the remnant of pancreatic cancer. Previous studies also reported that v- stomach and pancreas: Report of a case. Surg Today 25: 1038- Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) 1042, 1995.

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11 Watanapa P, Flaks B, Oztas H, Deprez PH, Calam J and 16 Wronski M, Ziarkiewicz-Wroblewska B, Gornicka B, Cebulski W, Williamson RC: Enhancing effect of partial gastrectomy on Slodkowski M, Wasiutynski A and Krasnodebski IW: Synchronous pancreatic . Br J Cancer 65: 383-387, 1992. occurrence of gastrointestinal stromal tumors and other primary 12 Offerhaus GJ, Giardiello FM, Moore GW and Tersmette AC: gastrointestinal neoplasms. World J Gastroenterol 12: 5360-5362, Partial gastrectomy: A risk factor for carcinoma of the pancreas? 2006. Hum Pathol 18: 285-288, 1987. 17 Takeuchi H, Hiroshige S, Hashimoto K, Kusumoto T, Yoshikawa 13 Flanders TY and Foulkes WD: Pancreatic adenocarcinoma: Y and Muto Y: Synchronous double tumor of breast cancer and and . J Med Genet 33: 889-898, 1996. gastrointestinal stromal tumor in a patient with neurofibro- 14 Minamoto T, Ougolkov AV and Mai M: Detection of oncogenes matosis type 1: Report of a case. Anticancer Res 31: 4481-4484, in the diagnosis of cancers with active oncogenic signaling. 2011. Expert Rev Mol Diagn 2: 565-575, 2002. 15 Liszka L, Zielinska-Pajak E, Pajak J, Golka D and Huszno J: Received March 9, 2013 Coexistence of gastrointestinal stromal tumors with other Revised April 15, 2013 neoplasms. J Gastroenterol 42: 641-649, 2007. Accepted April 17, 2013

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