Giardiello et al. were the first to demonstrate that patients with PJS have an extremely high risk of cancer (approximately 90%) during their lifetime [1, 2]. There are several reports of cases involving double cancer with PJS; however, to the best of our knowledge, metachronous triple primary cancer associated with PJS treated with curative surgery has not yet been reported [6, 7]. These patients are at increased risk from a range of gastrointestinal cancers, including the esophagus, stomach, small intestine, colon, and pancreas [1, 8, 9]. Non-gastrointestinal cancers have also been reported to occur in a high proportion of PJS patients, including cancer of the breast, ovary, cervix, and sex cord [1, 9].
Surveillance programs for malignant tumors have been proposed by several clinical guidelines or recommendations [1, 3, 10]. However, surveillance strategies can vary according to organ-specific cancer occurrence [1]. The approximate lifetime risk of uterine and cervical cancer in PJS patients is 9 and 10%, respectively. Screening by pelvic examination using the Papanicolaou test every year, beginning at the age of 21 years, is strongly recommended, not only in ordinal females but also in PJS patients. In addition, adenoma malignum, which has a dismal prognosis, is more likely to occur in patients with PJS than in healthy females. In addition, transvaginal ultrasound, with the carbohydrate antigen 125 test, is recommended for ovarian cancer screening, beginning at the age of 25 years [1, 11]. Pancreatic cancer is one of the most common tumors affecting PJS patients, with a lifetime risk of approximately 30% [4, 10, 12]. A recent consensus conference of the International Hereditary Pancreatitis Study Group recommended screening for pancreatic neoplasms, especially in patients with PJS. EUS, CT, and MRI are the most commonly used techniques for pancreatic cancer screening. Recent reports have stated that EUS is the most reliable technique for detecting early pancreatic cancer [13]. Pancreatic cancer surveillance, on an annual or biennial basis, between the ages of 25 and 30 years is recommended by several reports [14, 15]. Although the lifetime risk for carcinoma of the biliary tract has not yet been clarified, some important reports have documented these carcinomas and estimated their frequency to be about one-quarter of that of pancreatic carcinoma [1]. Surveillance of the biliary tract has rarely been documented, but radiographic surveillance, performed synchronously with tests for the pancreas, seems to be a good practical option [9].
Current evidence for appropriate surveillance guidelines is not sufficient, largely because of the rarity of this disease and the lack of accumulated data addressing the efficacy and outcomes of surveillance for patients with PJS. In our particular case, tumor markers were checked every 3 months, and CT was performed every 6 months, as a follow-up schedule following cholangiocellular carcinoma resection. Annual gastrointestinal endoscopy and the Papanicolaou test were performed every 6 months as a follow-up after cervical cancer resection. However, the optimal form of surveillance still remains unclear. The CAPS 3 study and other reports have advocated that patients with PJS should begin surveillance at least by 40 years of age and that patients without PJS, but with high risk for pancreatic ductal adenocarcinoma (PDAC) should begin surveillance by at least 50 years of age [16, 17]. PDAC is one of the most lethal malignancies; as such, special attention should be paid to the detection of PDAC at an early stage. In order to detect cases of early stage PDAC, Hanada et al. recommended that EUS and Magnetic resonance cholangiopancreatography should play an important role, rather than dynamic CT [13].
Multiple primary malignancy (MPM) is defined as two or more malignancies, without any relationship between the tumors, occurring in the same individual either simultaneously or metachronously [18]. Several factors could lead to a deterioration in host immune function, such as chemotherapy or radiotherapy after the first primary malignancy. However, not only host immune deficiency can lead to cancer; it is possible that environmental factors leading to carcinogen exposure could also lead to cancer. This may lead to the development of MPM at some point during the lifetime [19,20,21,22]. Multiple metachronous malignancies are frequently detected in hematological, lung, thyroid, breast, skin, and genitourinary malignancies [23, 24]. Liu et al. investigated the etiological factors, clinical characteristics, diagnosis, treatment strategies, and prognosis of MPM and demonstrated that curative surgery has a strong impact on long-term prognosis [22].
Our current patient had hilar cholangiocarcinoma and pancreatic cancer; these are conditions that are known to have a poor prognosis, although patients have survived for more than 9 years after surgery for hilar cholangiocarcinoma. Regardless of the dismal prognosis after curative surgery for biliary and pancreatic cancer, good long-term prognosis was achieved in our case. Repeat curative surgery could therefore have a strong impact on the long-term prognosis of patients with PJS. There are no standard guidelines for the management of PJS and MPM at present. However, we recommend that physicians take into consideration the type of malignancies, progression of disease, response to therapy, and the general condition of patients.
