Dual Cancer: Papillary and Signet Ring Cell Carcinoma, Arising in a Patient Operated for Choledochal Cyst: an Unusual Histological Finding

Introduction

Choledochal cysts are cystic dilatations of parts of the biliary ducts, most commonly involving the extrahepatic bile ducts with varying amounts of intrahepatic involvement. Incidence is higher in Asian countries (1 in 1000) with two-thirds of all cases reported in Japan, as compared with the western countries having a relatively low incidence [1, 2].

Though choledochal cysts are known to be a disorder of childhood and infancy, 25–40% of patients are initially diagnosed in adulthood [3]. There is a female predominance with a male:female ratio of 1:3 to 1:4 [4]. Choledochal cysts are recognized to be a premalignant condition with an estimated incidence of malignancy, which is 20 times higher compared with healthy population. In general, malignancies occur in patients with choledochal cysts at a younger age, 10–15 years earlier, as compared with the general population [5, 6]. The risk of malignancy increases with increasing age; it is 23% at 20–30 years and can increase up to 75% at 70–80 years [7]. Hence, the recommended treatment, even in asymptomatic patients, includes a complete excision of the choledochal cyst with Roux-en-Y hepatico-jejunostomy, in most cases. The incidence of malignant transformation after cyst excision, though is significantly reduced, is still approximately 9.9%, warranting a life-long follow-up [8].

The most common histological types are adenocarcinoma (73–84%), anaplastic carcinoma (10%), undifferentiated carcinoma (5–7%), and squamous cell carcinoma (5%) [9, 10]. Rare type like botryoid sarcoma has also been reported [11]. There has been only one reported case of signet ring cell carcinoma arising 25 years after choledochal cyst excision [12]. We hereby report a unique histopathological finding of a dual cancer, papillary as well as signet ring cell carcinoma, arising 14 months after choledochal cyst excision along with right hepatectomy done for type IVA choledochal cyst.

Case Report

A 65-year-old gentleman presented at a local hospital in Japan with complaints of intermittent pain in right hypochondriac region, since few months. The history of previous diseases or operations was negative. He reported about occasional alcohol (beer) consumption. In the clinical examination, he was vitally stable. There was mild tenderness in the right hypochondriac region. An ultrasound examination revealed grossly distended extrahepatic bile duct with multiple cystic dilatations of the intrahepatic portion of the right-sided bile duct system suggestive of type IVA choledochal cyst (although only the right biliary system was involved). A CT scan and ERCP confirmed this diagnosis (Fig. 1). The tumor markers CEA and CA 19.9 were within normal range, and the rest of the hematologic and biochemical parameters was also noted to be normal. He was managed with antibiotics and analgesics and planned for surgery after 2–3 weeks.

Fig. 1.

CT scan suggestive of Choledochal Cyst (type IVA, involving right liver lobe, intrahepatic with extrahepatic duct system)

A right hepatectomy with excision of the extrahepatic bile duct and removal of the gall bladder was performed in October 2017. Biliary reconstruction was achieved through a hepatico-jejunostomy. The patient had an uneventful postoperative recovery and was discharged 2 weeks after surgery. Histopathological examination revealed intraductal papillary neoplasm of the bile duct with mild to moderate atypia and a chronic cholecystitis. The resection margins and four lymph nodes were negative. Follow-up was recommended with clinical examination, ultrasound and tumor markers with ultrasound every 3–4 months.

In December 2018, 14 months after surgery, during his regular follow-up, an increase in tumor markers was noted (CEA 6.3 ng/ml and CA 19.9 196.8 u/ml). The patient was otherwise asymptomatic. A MRI scan revealed a hilar mass with thickening of the right diaphragm, suspicious for malignancy (Fig. 2). He was, hence, referred to our hospital for further management. In January 2019, he underwent an exploratory laparotomy. Intraoperatively, tumor was noted in the liver hilar region with multiple nodules in the right diaphragmatic peritoneum and in the Morrison’s pouch (Fig. 3a, b). The rest of the peritoneal cavity did not show any signs of metastasis. An intraoperative frozen section of the right diaphragmatic nodule revealed a signet ring cell carcinoma. Cytology from peritoneal washing was reported as negative. Considering the limited disease burden (peritoneal carcinomatosis index of 6), cytoreductive surgery (CRS) with hyperthermic intra-peritoneal chemotherapy (HIPEC) was performed. HIPEC was carried out using mitomycin C 20 mg/m², at 43 °C for 60 min. A complete cytoreduction (CC0 resection) could be achieved (Fig. 3c).

Fig. 2.

MRI scan showing recurrent disease at liver hilar region as well as right diaphragmatic region

Fig. 3.

a Intraoperative view of recurrent disease. b Postoperative view after disease complete cytoreductive surgery. c Specimen after complete cytoreductive surgery (right diaphragmatic peritonectomy; black arrow, hilar disease with distal gastrectomy; orange arrow, total omentectomy; yellow arrow and falciform ligament; gray arrow)

The patient developed a postoperative pancreatic fistula, which was managed conservatively by retaining the drain for a longer period of time and he was discharged well on postoperative day 45. The definitive histopathological result showed primary tumor consisting of two components: papillary carcinoma and signet ring cell carcinoma; the signet ring carcinoma probably arising from the transformation from papillary carcinoma. The peritoneal metastasis showed signet ring cell carcinoma component alone.

The panel of immunohistochemical (IHC) markers (Figs. 4a, b, 5a, b, and 6) which was performed confirmed the presence of two different histopathological entities with different proliferation indices (Table 1).

Fig. 4.

a Primary tumor showing both papillary and signet ring cell carcinoma. b Higher magnification of papillary carcinoma seen in primary tumor

Fig. 5.

a IHC staining of CK7 in papillary carcinoma in primary tumor. b IHC staining of CK7 in signet ring cell in peritoneal metastasis, showing no positivity

Fig. 6.

Ki67 staining in papillary carcinoma in primary tumor

Table 1.

IHC markers in the two components: papillary carcinoma and signet ring cell carcinoma

Histopathological type	CK7	CK 20	MUC5AC	MUC2	CDX2	MIB index (%)
High/low grade Papillary adenocarcinoma	+	+	+	+	+	35
Signet ring cell carcinoma in peritoneal metastasis	Partially +	_	_	_	_	< 1

Discussion

An abnormal pancreaticobiliary duct junction (APBDJ) is present in 70–90% of the cases of choledochal cysts and has been postulated to be the etiological factor in most cases of choledochal cyst [13, 14]. The APBDJ results in a common channel between the bile duct and the pancreatic duct before entering into the duodenal wall, allowing mixing of the biliary and the pancreatic juices, thus activating the pancreatic enzymes and causing inflammation and weakening of the bile duct wall [15]. The increased incidence of malignant transformation has also been proposed to be due to this bile stasis, irritation, and chronic inflammation occurring within the dilated duct wall [16, 17].

Though the most commonly reported histological type is adenocarcinoma, occurring in 73–84% of these patients, rare types like anaplastic carcinoma (10%), undifferentiated carcinoma (5–7%), and squamous cell carcinoma (5%) have also been reported [9, 10]. Our case has a unique histopathological finding with the primary tumor being composed of both papillary and signet ring cell carcinoma cells. Though the margins of the previous choledochal cyst excision were negative, papillary carcinoma did arise from the remaining part of the bile duct, with the previous histology being intraductal papillary neoplasm. The signet ring cell carcinoma has probably originated from transformation from papillary carcinoma. It has been reported that highly differentiated carcinomas are able to transform into signet ring cell carcinomas by the loss of adherence and tight junctions [18]. The peritoneal metastasis developing only from signet ring cell carcinomas can also be explained by this loss of cell adherence, causing an epithelial-mesenchymal transition, increasing their motility and hence ability to metastasize [19].

Though peritoneal metastasis was noted, a complete cytoreduction was possible due to the limited disease spread (peritoneal cancer index 6). Though there is some evidence for CRS and HIPEC in few selected patients of peritoneally metastasized gall bladder and pancreatic cancer, one has to be highly selective considering the overall poor prognosis of these patients [20]. Additionally, though signet ring cell cancers have been known to have poor prognosis, there have been reports of improved survival in highly selected patients with CRS and HIPEC [21]. In our case, owing to the limited nature of peritoneal disease and patient’s good general condition, a decision was taken to proceed with CRS and HIPEC in this rare disease. These decisions have to be individualized, and surgery with curative intent should be carried out only when a complete cytoreduction is possible and, in a specialized center, focused on the treatment of peritoneal metastasis patients.

Conclusion

Dual cancer arising in a previously treated case of choledochal cyst is a rare occurrence. Treatment has to be individualized and with involvement of multidisciplinary team, to ensure the appropriate treatment decision.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.