Long-Term Survival by Resection and Adjuvant Chemotherapy With S-1 in Pancreatic Signet Ring Cell Carcinoma: a Case Report With Literature Review

Background: Signet ring cell carcinoma (SRCC) of the pancreas is a very rare histologic variant of pancreatic carcinoma with very poor prognosis. We present a case of pancreatic SRCC with good prognosis achieved by resection and adjuvant chemotherapy with S-1 one year, which is the standard treatment for advanced resected gastric cancer in Japan. The stomach carried a higher incidence of SRCC than other sites. Case presentation: A 70-year-old man presented with abdominal discomfort, and ultrasonography revealed a mass in the pancreas. Computed tomography showed a hypovascular tumor in the head of the pancreas, 51 mm in diameter, with invasion to the portal vein and duodenum. The patient underwent pancreaticoduodenectomy (PD) with portal vein resection and reconstruction. The pathological diagnosis was SRCC of the pancreas without invasion to the portal vein, pT3N1M0 Stage IIB (UICC classication). Subsequently, postoperative adjuvant chemotherapy with S-1 was initiated to prevent recurrence. The patient has remained recurrence-free for 2 years and 6 months after PD. Conclusion: Adjuvant chemotherapy with S-1 may be an important factor for improving the prognosis of patients with resectable SRCC of the pancreas.


Background
Signet ring cell carcinoma (SRCC) of the pancreas is extremely rare, representing < 1% of pancreatic cancers [1]. The prognosis of this tumor has been reported to be very poor [2]. Among a few reported cases of pancreatic SRCC in the literature, there is no case with long-term survival. The e cacy of adjuvant chemotherapy improving the prognosis has been reported in pancreatic ductal adenocarcinoma. Herein, we present a case of pancreatic SRCC with over 2-years recurrence-free survival achieved by resection and 1 year adjuvant chemotherapy with S-1.

Case Presentation
A 70-year-old man visited at a local clinic with abdominal discomfort. Ultrasonography revealed a hypoechoic mass in the head of the pancreas; thus, he was referred to our department. The laboratory test results showed markedly elevated level of carcinoembryonic antigen (CEA) at 1,706.0 ng/ml (reference range < 5.0 ng/ml). The level of carbohydrate antigen 19 − 9 (CA 19 − 9) was 8 U/ml (reference range < 37 U/ml) within normal imit. Serum amylase, bilirubin, and hepatobiliary enzymes were also in normal range. Abdominal computed tomography (CT) revealed a hypovascular tumor lesion, 51 × 50 × 39 mm in diameter, with invasion to the portal vein and duodenum (Fig. 1). Positron emission tomography-CT showed high uorodeoxyglucose accumulation in the tumor (SUV max 10.8) and no evidence of regional lymph node metastasis or distant metastasis in the liver or lungs. The tumor was considered resectable by portal vein resection. Based on the clinical diagnosis, we performed pancreaticoduodenectomy (PD) with portal vein resection and reconstruction. The macroscopic ndings of the resected specimen revealed a nodular tumor in the pancreatic head sized 63 × 50 × 40 mm. Pathological examination revealed SRCC ( Fig. 2) with direct invasion in the duodenum and no invasion in the portal vein. There were multiple lymph node metastases in lesion of #5, #8 and peritumor. The pathological diagnosis according to the UICC classi cation was T3N1M0 Stage IIB, R0 resection. We consulted a medical oncologist and initiated 1-year adjuvant chemotherapy with S-1 according to the Japanese guideline of gastric cancer. Thirty months after the surgery, the patient is well and without recurrence. There were no grade 3/4 adverse events according to the CTCAE classi cation. At 21 months after surgery, hepatoma that was enhanced in the early phase and washed out in the late phase was detected, with elevated PIVKA-II, a tumor maker of hepatocellular carcinoma (HCC). Diagnosis of HCC was made, and hepatectomy was performed. Intraoperatively, there were no ndings of recurrence of the pancreatic cancer. In addition to the regular examination, the pathologist performed an immunohistochemical study; the pathological diagnosis was HCC. After PD for pancreatic SRCC, the levels of the tumor makers of pancreatic cancer, CEA and CA19-9, have remained within normal limits (Fig. 3).

Discussion And Conclusions
SRCC is composed almost exclusively of poorly cohesive neoplastic epithelial cells containing intracytoplasmic mucin that displaces the nuclei towards the periphery. SRCC of the pancreas is extremely rare and has a very poor prognosis [3]. According to the study using the Surveillance, Epidemiology, and End Results database from 2000 to 2014, the incidence of pancreatic SRCC is 0.4-0.5% among all cases of pancreatic carcinoma [1]. Among the eight cases reported thus far (Table 1) [4][5][6][7][8][9][10][11], surgical treatment with radical resection, pancreatoduodenectomy, and/or total pancreatomy could be performed in four cases, and there was only one case of borderline-resectable tumor treated with neoadjuvant chemotherapy with gemcitabine.
Two studies have reported on the prognosis of patients with pancreatic SRCC. In the rst, where the prognosis was investigated according to the tumor location (esophagus, stomach, small intestine, appendix, colon, and rectum), the group with pancreatic SRCC had the worst median overall survival (3.4 months) [1]. The second study evaluated the predictive effects of epidemiological factors and treatment interventions on the overall survival. The 1-, 2-, and 5-year overall survival rates were 17%, 9%, and 4%, respectively, and surgical interventions (pancreatectomy and pancreatomy with radiation therapy, no case with adjuvant therapy) were associated with improved overall survival [2].
To the best of our knowledge, the present is the rst report of adjuvant chemotherapy and long-term postoperative survival in pancreatic SRCC. We performed adjuvant chemotherapy with S-1, which is an oral uoropyrimidine that contains tegafur, a prodrug of 5-uorouracil, gimeracil, and oteracil potassium. The e cacy of S-1 for improving the postoperative survival has been reported in gastric cancer [12], which has the highest incidence of SRCC among gastroenterological tumors [1], and pancreatic cancer [13]. According to the Japanese guidelines, adjuvant chemotherapy with S-1 is recommended for gastric and pancreatic cancer [14][15]. The difference in the therapeutic regimens for the two types of cancer is the length of drug administration; 1 year for gastric and 6 months for pancreatic cancer. However, SRCC of the pancreas has a higher risk of recurrence and poorer survival rates than those of typical ductal adenocarcinoma [2]; therefore, we scheduled and performed 1-year adjuvant therapy.
In summary, we report a rare case of pancreatic SRCC with long-term survival. This case indicates that radical resection and adjuvant chemotherapy with S-1 may be an important treatment strategy for resectable pancreatic SRCC.

Consent for publication
Written informed consent was obtained from the patient for publication of this case report.

Availability of data and material
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Competing interests
The authors declare that they have no competing interests.