THE FISHY PANCREAS

By Monzur Ahmed
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A 68 year old man was admitted with a 2 week history of painless jaundice, dark urine, 2-3 stone weight loss and poor appetite. Initial investigations were as follows:
- Bilirubin 330 umol/L, ALT 230, Alk Phosp 420 (NR < 130)
- Hb15.3 g/dL, WBC 14, platelets 210
A CT scan showed a 5cm tumour in head of the pancreas with a dilated pancreatic duct (14mm) and dilated common hepatic duct and intrahepatic ducts. There was no evidence of metastasis or vascular invasion. It was thought that the appearances were compatible with pancreatic adenocarcinoma. He was discussed with the local HPB unit. In view of the COVID-19 pandemic, surgery was deferred and the recommendation was an ERCP with biliary stenting with subsequent “downstaging” chemotherapy as a prelude to surgery once the COVID situation improves! Hence the patient attended for ERCP. There was a surprise finding (see video)...

Intraductal papillary mucinous neoplasms (IPMNs) result from the intraductal proliferation of mucin producing neoplastic epithelium, leading to hypercellular outgrowths that secrete frank, mucinous fluid. IPMNs were first described in 1982 by Ohhashi et al, who described four patients with successfully resected main duct IPMN (MD-IPMN) [1]. The 1996 World Health Organization (WHO) classification designated these tumours as intraductal papillary mucinous tumors [2] and this was revised to intraductal papillary mucinous neoplasm in the 2010 publication [3].

IPMNs are classified as main duct (MD-IPMN), branch duct (BD-IPMN) or mixed type according to the anatomic involvement of the pancreatic ductal system. MD-IPMN have a higher risk of malignant transformation; the risk of malignancy has been found to range from 19% to 30% in BD-IPMNs and as high as 40% to 60% in MD-IPMN [4-7].

Histologically, IPMNs can be classified into four subtypes based on morphological and immunohistochemical characteristics: gastric, intestinal, pancreatobiliary and oncocytic [8]. While not always the case, gastric type IPMNs typically displays low-grade dysplasia, intestinal type often displays moderate to high-grade dysplasia, while the less common pancreatobiliary type and oncocytic type often display high-grade dysplasia. The two main histopathological types of invasive IPMN are colloid carcinoma, which typically arises from intestinal type IPMN, and tubular carcinoma, which arises from pancreatobiliary type IPMN. Histologic subtypes are typically only determined following surgical resection and currently may not be used to dictate clinical management.

Endoscopic ultrasound (EUS) should be considered as a ‘second-level’ diagnostic modality after CT and MRI. EUS is an invasive, operator-dependent imaging technique with the possibility of performing fine-needle aspiration (FNA) for cyst fluid analysis. EUS is useful in differentiating IPMNs from other pancreatic cysts, including macrocystic serous cystadenomas (SCAs), mucinous cystic neoplasms (MCNs) or pseudocysts. By analysing CEA level, amylase/lipase, glucose as well as cytology in the cyst fluid, it may be possible to increase the diagnostic yield in their differential diagnosis. A cut-off ≥192 ng/ml of cyst fluid carcinoembryonic antigen (CEA) has been suggested for distinguishing mucinous from non-mucinous cysts, with a sensitivity of 38–78% and specificity of 63–99%, but it is not helpful in distinguishing between benign and malignant mucinous cysts. Similar results are reported for cytological examination. At ERCP, IPMNs are characterised by the "fish mouth papilla” which is said to be diagnostic.

The management of IPMNs is dependent on the accurate assessment of the risk of malignant transformation. Surgical resection remains the best treatment to avoid this unfavourable outcome. However, two major problems remain: first, many BD IPMN (75–82%) will never progress to malignancy; and second, pancreatic surgery inherent morbidity is not negligible. Therefore, it is crucial to identify the patients who will actually need surgical resection. Several guidelines have been established to define the surgery criteria, depending on the presence or not of “worrisome signs” and “high risk stigmata of malignancy” (i.e., high grade dysplasia and invasive carcinoma [4,5,6,7,9,10]. In these algorithms, the patient’s performance status is taken into account to determine the surgery benefit/risk ratio.

The Sendai and Fukuoka consensus conferences of 2006 and 2012 / 2017 respectively [9,4,5], established some baseline clinical and radiological criteria, especially in terms of tumour size and associated lesions (lymphadenopathy), to guide the decision concerning the patient management (surveillance or surgical treatment). This consensus separated criteria in “worrisome” and “high-risk stigmata” that allow or not the surgical option. The Sendai guidelines [9], recommended resection for all MD-IPMNs and mixed type IPMNs if patients are good surgical candidates. Resection was also recommended for symptomatic patients with BD-IPMNs, or BD-IPMNs with main duct dilatation > 6mm or the presence of mural nodules. It was also recommended that lesions > 3 cm be resected, with the caveat that more data was required to determine whether all BD-IPMNs > 3 cm should be resected immediately.

The revised Fukuoka guidelines of 2012 [4] decreased the threshold of main duct dilatation for characterisation of MD-IPMN to > 5 mm without other causes of obstruction. Resection was recommended for all surgically fit patients with MD-IPMN. Both “high risk stigmata” and “worrisome features” were defined, with surgical resection recommended for high-risk stigmata, namely obstructive jaundice in a patient with a cystic lesion in the head of the pancreas, enhancing mural nodules and main pancreatic duct diameter ≥ 10 mm.

The above Japanese guidelines are complemented by the European and American guidelines as important decision-making aids [6,7,10]. In the latest update of the European guidelines of 2018, recommendations include a conservative approach for asymptomatic IPMN measuring <40 mm without an enhancing nodule [10]. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter ≥40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule >5 mm, and MPD diameter >10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery.
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REFERENCES
1. Ohhashi K. Four cases of mucous secreting pancreatic cancer. Prog Digest Endosc. 1982;20:348–351.
2. Klöppel GSE, Longnecker DS, et al., editors. Histologic Typing of Tumours of the Exocrine Pancreas. 2. New York, NY: Springer-Verlag; 1996.
3. Bosman FTCF, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010. Tumours of the Pancreas.
4.Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M, Jang J-Y, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatol Off J Int Assoc Pancreatol IAP Al. 2012;12:183–97.
5. Tanaka M, Fernández-Del Castillo C, Kamisawa T, Jang JY, Levy P, Ohtsuka T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatol Off J Int Assoc Pancreatol IAP Al. 2017;17:738–53
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8. Furukawa T, Klöppel G, Volkan Adsay N, et al. Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Archiv. 2005;447:794–799.
9. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17–32.
10. European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018;67:789–804.