br Discussion Over the past two decades the incidence of
Discussion Over the past two decades, the incidence of second primary malignancy has progressively risen among cancer survivors and is an issue of increasingly greater concern in oncology. The increasing incidence may be due to the elevated rate of early cancer detection, improved cancer treatment and better supportive care with longer survivor life expectancy. The synchronous occurrence of multiple cancers, although rare, has been reported sporadically in the previous literature. Our own data from a single Taiwan cancer center institute (Chang Gung Memorial Hospital, CGMH, Taoyung, Taiwan) showed that from 2002 to 2012, 1413 patients (0.64%) were diagnosed with triple primary cancers and 305 patients (0.13%) were diagnosed with multiple malignancies of more than 3 cancers. From our data, a total of 7825 patients were diagnosed with gastric cancer and 14,941 patients were diagnosed with breast cancer in the same catalase inhibitor of time. Among those gastric cancer patients, 534 patients (6.8%) had second primary cancers, including 100 patients (1.28%) with colon cancer and 11 patients (0.14%) with breast cancer as a second primary neoplasm. Among breast cancer patients, 1437 patients (9.6%) had second primary cancer, including 52 patients (3.5%) with cervical cancer and 47 patients (3.1%) with colon cancer as second primary neoplasm (unpublished data from CGMH cancer registry). Therefore, cases with triple primary malignancies are extremely rare. Therefore, the limited knowledge to be derived from such a rare experience contributes to the challenge upon clinical diagnosis despite detailed history-taking, physical examination, thorough imaging check-up and advanced immunohistochemical stain techniques. Yet knowledge gained from these rare cases, however limited, may aid in the diagnosis of future cases. Clinically, we observed typically multicentric tumors involved with shared risk factor exposure and/or genetic predisposition with the phenomenon called “field cancerization”, especially in the head and neck area, and colorectal and urinary tract cancers. Conversely, the situation of multiple tumors involving diverse sites commonly has occurred by coincidence; however, it is also possible that field cancerization plays a role in their development. In addition, chemotherapy and radiotherapy may also contribute to the development of neoplasms, such as secondary leukemia and sarcoma. Hereditary cancer syndrome accounts for only 5% of all malignancies and usually presents with the following characteristics: 1) strong family history with high penetrance genotypes, such as hereditary breast and ovarian cancer syndrome with BRCA-1 gene and familial adenomatous polyposis with FAP gene; 2) multiple primary cancers with or without specific tissue type, such as Li-Fraumeni syndrome with early onset sarcoma, adrenocortical carcinoma, brain tumor, leukemia or premenopausal breast cancer; hereditary diffuse gastric cancer with diffuse gastric cancer and invasive lobular breast carcinoma; 3) unusual clinical presentation, such as early onset in hereditary diffuse gastric cancer, Lynch syndrome, and FAP (or multicentric tumors with Von Hippel-Lindau syndrome, heritable retinoblastoma, FAP); or 4) associated non-malignant disease, such as mucocutaneous pigmentation in Peutz-Jeghers syndrome or ataxia telangiectasia with cerebellar ataxia, telangiectasia, or vitiligo. In Taiwan, breast cancer is the most prevalent type of cancer for females, with up to 10% of the breast cancers associated with specific hereditary mutations in single-acting genes. Hereditary breast cancer may be present with the following syndromes: hereditary breast and/or ovarian cancer syndrome (HBOC syndrome) linked to mutation in BRCA1 or BRCA2 gene; Li-Fraumeni syndrome with a germline TP53 gene mutation; and Cowden syndrome/PTEN hamartoma syndrome, an autosomal disorder associated with germline mutations in the PTEN tumor suppressor gene. There are some additional genetic mutations associated with breast/ovarian cancer risk, such as CDH1 gene noted in hereditary diffuse gastric cancer syndrome, STK11/LKB1 gene shown in Peutz-Jeghers syndrome, and MMR (Mismatch repair) gene including MLH1, MSH2, MSH6 and PMS2 or EPCAM gene deletion expressed in Lynch syndrome. According to the National Comprehensive Cancer Network (NCCN) guidelines, the criteria for which further genetic risk evaluation should be considered in breast cancer patients includes a known mutation in a breast cancer susceptibility gene within the family, early-age-onset breast cancer, triple negative (ER-, PR-, Her2-) breast cancer, two breast cancer primaries in a single individual, invasive ovarian cancer, male breast cancer, and breast cancer at any age with a) ≥ 1 close blood relative with breast cancer at ≤ 50 years of age; b) ≥ 1 close blood relative with ovarian cancer at any age; c) ≥ 2 close blood relative with breast cancer and/or pancreatic cancer at any age; d) combination of ≥1 of the following malignancies: pancreatic cancer, prostate cancer (Gleason score ≧ 7), sarcoma, adrenocortical carcinoma, brain tumors, endometrial cancer, thyroid cancer, kidney cancer, hamartomatous polyps of the gastrointestinal tract, and diffuse gastric cancer.