A Female With Synchronous Multiple Primary Malignant Tumors in the Esophagogastric Junction, Duodenum and Pancreas: Case Report and Review of the Literature

The incidence of multiple primary carcinomas (MPCs), which are defined as two or more malignancies detected in an individual person, is gradually increasing around the world. According to the timing of diagnosis for each constituent tumor, MPCs are classified into 2 categories: synchronous MPCs if constituent tumors emerge simultaneously or within 6 months or metachronous MPCs otherwise. In this report, we describe our recent observation and treatment of a female patient with synchronous primary esophagogastric junction adenocarcinoma, duodenal adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). To the best of our knowledge, this combination has not yet been reported in the literature. A crucial aspect is the decision regarding which tumor to treat initially and how to schedule further treatments according to individual tumor hazards. Our multidisciplinary team devised an individualized treatment regimen for this patient. The patient ultimately achieved an overall survival time of 18 months, which was much longer than the median survival time (6~11 months) of patients with locally advanced pancreatic cancer. Moreover, treating this rare combination raised a series of diagnostic, etiological and therapeutic questions, motivating us to carry out a critical review of the literature. In summary, an individualized treatment strategy with input from a dedicated multidisciplinary team and consideration of all options at different points along the disease trajectory is essential to optimize outcomes for patients with MPC.

INTRODUCTION 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.

CASE REPORT
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.

DIAGNOSTIC INVESTIGATION AND TREATMENT
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 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).

DISCUSSION AND LITERATURE REVIEW
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)(8)(9)(10)(11)(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.

Pancreatic Carcinoma and Hepatocellular Carcinoma
We retrieved two articles focusing on primary pancreatic carcinoma combined with hepatocellular carcinoma, and all cases were synchronous MPCs (13,14) Sasaki and Zhang performed both hepatectomy and pancreaticoduodenectomy during the course of therapy. In the case report of Zhang, the patient received chemotherapy with gemcitabine combined with tegafur gimeracil oteracil potassium and anti-hepatitis C virus (HCV) therapy after the operation. Zhang investigated the possibility that HCV infection could increase the incidence of pancreatic cancers, but the biological mechanism underlying HCV-induced pancreatic cancers has not been fully elucidated. Finally, he highlighted the critical role of PET-CT as a tumorrelated systemic examination method in the diagnosis and treatment of MPC.

Pancreatic Carcinoma and Biliary Carcinoma
Eight articles on synchronous pancreatic and biliary carcinomas were retrieved (15)(16)(17)(18)(19)(20)(21)(22). Nishihara performed total pancreatectomy and extended cholecystectomy with regional lymph node dissection. The follow-up results showed that the patients survived for 3 years, and the recurrence-free survival time was 11 months without any adjuvant therapy after surgery. Sato adopted pancreaticoduodenectomy to treat MPC. Interestingly, the overexpression of p53 in the tumors observed in the present case was also reported by Nishihara, and he speculated that the oncogenic mechanisms of multiple synchronous cancers were caused by mutation of the p53 gene and abnormal DNA reparative mechanisms.

Pancreatic Carcinoma and Gastric Carcinoma
We retrieved seven articles on synchronous pancreatic and gastric carcinomas (23)(24)(25)(26)(27)(28)(29). The FOLFIRINOX chemotherapy regimen was adopted to treat synchronous pancreatic and gastric cancers in the study by Kouria. He planned to reevaluate the surgical feasibility after two months of treatment.
Meanwhile, Kourie emphasized that multiple tumors demonstrated loss of protein expression of mismatch repair genes and were associated with microsatellite instability (MSI). Therefore, MSI testing may be reasonable for patients with synchronous pancreatic and gastric cancers. For patients with synchronous pancreatic carcinoma and gastrointestinal stromal tumor (GIST), pancreatectomy combined with postoperative concurrent chemoradiotherapy was performed in the study by Dasanu, and the patient was free of recurrence for 18 months following comprehensive treatment. Moreover, Dasanu suggested that screening for second cancers was warranted in patients with gastrointestinal stromal tumor (GIST) and early diagnosis of these cancerous lesions. A thorough search for second cancers, along with a multidisciplinary treatment approach, could further prolong patient survival and improve quality of life.

Pancreatic Carcinoma and Breast Carcinoma
Two articles on synchronous pancreatic and breast carcinomas were retrieved (27,30). Among the cases previously reported, O'Brien performed modified radical mastectomy and palliative bypass procedures to treat breast carcinoma and pancreatic carcinoma, respectively. In his case report, he implied that high dietary intake of unsaturated fats was a carcinogenic factor for both carcinomas. If there is an association between breast and pancreatic adenocarcinomas, it may provide further evidence for the significance of dietary factors in the carcinogenesis of these two neoplasms in humans.

Etiologies of MPCs
Some studies have speculated that the development of MPCs is associated with an unhealthy lifestyle, genetic susceptibility, side effects of chemotherapy and radiotherapy, weak immunity, etc. Moreover, as a tumor suppressor gene, inactivation of the TP53 gene plays a crucial role in the formation of tumors, and mutations in this gene exist in many solid tumors. Gerdes (11) reported that mutations of p16INK4a in the TP53 gene may be related to the occurrence of pancreatic cancer with multiple primary cancers. The patient in our case was overweight, with a BMI of 27.7, and high BMI is a well-known risk factor for the occurrence of malignant tumors, especially tumors of the digestive system (12). In addition, this patient had previously undergone partial thyroidectomy. Hormonal dysregulation may also be a risk factor for tumor development (12). Besides, another factor that could not be neglected is the weakened immunity associated with aging and increased tumor susceptibility (12).

Therapeutic Options for MPCs
Most MPCs are found in the same pipeline system. In the diagnosis and treatment of multiple primary cancers, surgical exploration or biopsy should be used as soon as possible to make a clear diagnosis. When primary cancer or metastatic cancer cannot be distinguished, as long as the tumor is limited or isolated and the patient's body condition allows, surgical resection should be performed to allow for the chance of cure. However, pancreatic cancer is an aggressive tumor with high mortality and poor prognosis. When pancreatic cancer patients have multiple primary cancers, priority should be given to a multidisciplinary combined treatment approach for pancreatic cancer. In this case, ESD was performed first to excise the esophagogastric junction lesions because this treatment was relatively easy to provide. Although we did not treat the tumor of the duodenal papilla or pancreatic tumor with surgery because pancreaticoduodenectomy could not be performed, intraoperative radiotherapy combined with postoperative adjuvant chemotherapy was used in a timely manner. Encouragingly, tumor progression or distant metastasis was not observed during the period of six cycles of chemotherapy, illustrating that intraoperative radiotherapy combined with postoperative adjuvant chemotherapy can effectively suppress advanced pancreatic cancer growth. Furthermore, this treatment result exemplifies the significant advantages of using multidisciplinary combined therapy for certain cancer patients.
The patient in our case received proton radiotherapy when she developed distant metastasis, and the level of CA199 presented a significant decrease (from 20000 U/ml to 700 U/ ml). Proton radiotherapy is a type of external beam radiation therapy modality for the treatment of local disease that uses a proton beam to deliver a highly focused radiation dose to the tumor. In 1979, the University of Tsukuba began using proton cancer therapy with a booster accelerator for liver cancer, esophageal cancer, lung cancer, and brain tumors and achieved good curative effects (48). Proton radiotherapy has also gained popularity for the treatment of pancreatic cancer in recent years. Romaine, Michael and Dongha studied the efficacy of proton radiotherapy for the treatment of pancreatic cancer and found that patient survival was prolonged by this treatment (49)(50)(51). Here, our patient also exhibited a good treatment response. Although she ultimately passed away after an overall survival time of 18 months, this is much longer than the median survival time (6~11 months) of patients with locally advanced pancreatic cancer (52). The above evidence suggests that timely and effective multidisciplinary combined treatment for pancreatic cancer should be favored when pancreatic cancer patients are found to have multiple primary cancers. In a retrospective study of 147 cases of pancreatic resection for pancreatic cancer in Kumamoto University of Japan (53), it was found that when treating multiple primary cancers in patients with pancreatic cancer, priority should be given to pancreatic cancer treatment, and the postoperative outcomes and survival conditions were similar to those of pure pancreatic cancer patients. This also supports the validity of giving clinical priority to pancreatic cancer treatment.
In conclusion, the treatment of malignant tumors needs to adhere to the concept of multidisciplinary comprehensive treatment, and individualized precision therapy is especially valuable for patients with multiple primary cancers. Our experience and further accumulation of these cases will provide guidance and a reference for clinicians.

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

ETHICS STATEMENT
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.

AUTHOR CONTRIBUTIONS
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.