MPC, first reported by Billroth in 1879, refers to the simultaneous or subsequent occurrence of two or more cancers unrelated to each other in one patient, which may occur in different parts of the same organ or the same system or in different organs or systems (1). In recent research, MPC was defined by Moertel as two or more malignant tumors occurring within 6 months (2). The burden of MPCs is rising as the aging population has increased over the last decades (2). Several studies have retrospectively investigated the incidence of MPCs. For example, the study of Alexia et al. showed that the incidence of MPCs in a cancer population varies between 2.4% and 8% within 20 years of follow-up (3). Moreover, another study from data of European cancer registries reported an overall incidence of multiple primary cancers of 6.3% (range, 0.4–12.9%) (4).

With the advancement of medical technology and improvements in comprehensive clinical diagnosis and treatment, previously difficult-to-find tumor lesions can now be detected easily, thereby increasing the chance of detecting multiple primary cancers. Nevertheless, owing to its low prevalence, many clinicians are not sufficiently aware of this disease and lack therapeutic experience. To date, the pathogenesis of this rare disease remains to be elucidated. MPC is clinically often confused with the recurrence or metastasis of malignant tumors which might greatly change the formula of patients. In view of above situation, we decided to report our recent observation and treatment of a female patient with synchronous primary esophagogastric junction adenocarcinoma, duodenal adenocarcinoma and PDAC. To the best of our knowledge, this combination has not yet been reported in the literature.

On January 23, 2019, a 77-year-old female patient was admitted to the Cancer Hospital, Chinese Academy of Medical Sciences, because of mild abdominal pain and intermittent fever (with a maximum temperature of 39°C) for more than 3 months, and a duodenal mass was detected 2 weeks prior. Moreover, she presented with transient jaundice and skin itching that lasted for approximately 5 days. She did not complain of any other discomfort and did not report any relevant family history, and she had not been treated at a nearby clinic or hospital. Because of the noninvasive, radiation-free, and convenient characteristics of abdominal ultrasound, the patient had a habit of regular medical examination with abdominal ultrasound every year. The patient’s duodenal mass was diagnosed by ultrasound during her annual physical examination two weeks prior, then she came to our hospital for further tests and treatment.

Gastroscopy revealed superficial ulceration at the esophagogastric junction with irregular protrusion and a polypoidal protuberant mass in the duodenal papilla protruding into the lumen ( Figure 1 ). Pancreatic magnetic resonance cholangiopancreatography (MRCP) reported soft tissue nodules at the end of the common bile duct approximately 2.6x1.7 cm in size that were prone to malignancy, with low biliary tract obstruction ( Figure 2A ). Another pancreatic somatic nodule was found in the body of the pancreas that was approximately 2.0x2.3 cm in size and poorly defined, so the possibility of malignancy could not be excluded ( Figure 2B ). The pathological results of endoscopic biopsy revealed adenocarcinoma in both lesions of the esophagogastric junction and duodenal papilla ( Figure 3A ). Hematologic examination revealed the following: ALT(88 U/L), ALP(280 u/L), DBIL(5.7 µmol/L), CA199(551 U/ml), and CA242(107.190 U/ml).

The patient was 159 cm tall and weighed 70.0 kg, and her body mass index (BMI) was 27.7. She had a past history of hypertension, type-2 diabetes mellitus, and osteoarthritis. More than 20 years ago, she underwent thyroid surgery, and the pathology was benign. After the operation, the patient was treated with oral thyroid hormone drugs.

Although the definition and criteria for the diagnosis of MPC have changed many times over the years, it is typically based on the criteria described by Warren and Gates (5): (a) each tumor must have a clear pathological diagnosis; (b) each tumor must have an independent initial site of disease; and (c) the lesions must be nonmetastatic tumors. We initially determined that this case fulfilled the diagnostic criteria for MPC by the above medical examinations, and then the case was discussed by a multidisciplinary team before treatment was initiated. Since the patient’s family refused pancreatoduodenectomy due to the high risk associated with the operation, our multidisciplinary team recommended that the tumors of the gastroesophageal junction be treated by endoscopic submucosal dissection because of the relatively early disease stage. For the pancreatic lesions and duodenal mass, the team recommended abdominal section exploration combined with intraoperative puncture biopsy of the pancreatic tumor, intraoperative radiotherapy, and gallbladder jejunostomy and gastrojejunostomy due to the high risk of radical surgery and to respect the wishes of the patient and her family.

The patient underwent two operations in our hospital. The first operation was endoscopic submucosal dissection (ESD) performed under general anesthesia on February 19, 2019. The final pathological result showed moderately differentiated adenocarcinoma (Lauren classification: intestinal type) ( Figure 3B ). It had invaded the submucosa at a depth of 1550 microns (1650 microns) and was staged as pT1b. Immunohistochemical results showed the following: AFP (-), CD10 (intramucosal +, submucosal region +, glandular surface +, partial intramucosal -), cdx-2 (2+), c-met (2+), EGFR(2+), GPC3(-), HER2(2+), MLH1(+), MSH2(+), MSH6(+), MUC2(surface 1+, deep -), MUC5AC(1+), MUC6(1+), P53(90%+, missense mutated expression), SALL4(-), CD31, D2-40 (vascular staining), and Desmin (muscularis mucosa staining). Special staining results were observed for elastic fiber staining (showing veins). Gene detection did not show mutations in KRAS gene exons 2, 3 and 4, NRAS gene exons 2, 3 and 4, PIK3CA gene exons 9 and 20, or BRAF gene exons 11 and 15. On March 4, 2019, abdominal exploration was performed under general anesthesia. Intraoperative exploration revealed an unresectable tumor (the tumor was closely adhered to the mesenteric vasculature, and their separation was not possible) approximately 3x4 cm in size in the pancreatic body. The intraoperative pancreatic biopsy result was suggestive of adenocarcinoma ( Figure 3C ). Therefore, intraoperative radiotherapy with a dosage of 1500 cGy was delivered to the pancreatic mass. Gallbladder jejunostomy and gastrojejunostomy were also performed to relieve the obstruction of the biliary and gastrointestinal tracts. The final results of biopsy immunohistochemistry showed the following: braf-v600e (-), c-met (2+), HER2(1+), MLH1(+), MSH2(+), MSH6(+), PMS2(+), AE1/AE3(3+), CK18(3+), ChrA(-), Syno(-), and Ki-67 (30%+). In combination with the immunohistochemistry results, it was suggested that there was little infiltration of poorly differentiated adenocarcinoma into the fibrous adipose tissue with mucous secretion.

The patient recovered well, and she was discharged on the 14th postoperative day after the second operation. The first month after surgery, the patient had resumed her preoperative diet, her abdominal pain significantly improved, and no fever was reported. From June 10 to October 21, 2019, the patient underwent six cycles of chemotherapy (Abraxane combined with S-1) at the internal medicine department of our hospital. S-1, also known as Tegafur, Gimeracil and Oteracil Porassium Capsules, is a fluorouracil derivative oral anticancer agent that includes tegafur and the following two classes of modulators: gimeracil and oteracil. This medicine is mainly used for the treatment of unresectable locally advanced or metastatic gastric cancer and pancreatic cancer, etc. (6). After six courses of chemotherapy, her tumor markers were still not normalized (CEA, 15.25 ng/ml; CA199, 580.6 U/ml; CA242, >200 U/ml). However, no evidence of tumor progression or distant metastasis was found on multiple follow-up chest and abdominal CT and MRI scans during the entire period of chemotherapy. Four months later, the patient’s level of CA199 increased to 20000 U/ml, and thoracic MRI revealed metastasis in the thoracic spine. Then, she received for further treatment in the form of proton radiation therapy at another hospital in February 2020. Radiotherapy achieved some encouraging treatment outcomes, and the patient’s CA199 level decreased to 700 U/ml. Unfortunately, pulmonary metastasis was detected in June 2020, and the patient’s level of CA199 had increased again. The patient ultimately died of cancer cachexia on August 27, 2020 ( Figure 4).

Liu reported that MPC most commonly occurs in the respiratory system and gastrointestinal tract, while intracranial origin is rare (1). Utada stated that esophageal cancer and oral/pharyngeal cancer are the most common types of MPC (5). Other studies have reported that the incidence of multiple primary cancers in the digestive system is 2% ~ 17%, and that of multiple primary cancer patients with pancreatic cancer is 5.2% ~ 23% (7–12). To gain further insights into the occurrence of pancreatic cancer with multiple primary cancers, we carried out a critical review of the literature. A summary of the previous studies describing MPC is shown in Table 1 .

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethics Committee of the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The patients/participants provided their written informed consent to participate in this study.

YXD, YJD, and LZ wrote this paper. LZ and ZG collected relevant data of this patients. XZ and ZL followed up the patient. YXD, LZ, and CW managed the patient. CW and YXD revised this paper. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (81972314 and 81802463).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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