Duodenal and Papillary Adenomas

Introduction

Duodenal polyps are uncommon. They can be found in 0.3%–4.6% of patients undergoing upper gastrointestinal endoscopy, and are usually an incidental finding. Adenomas account for approximately 7% of all duodenal polyps. They are most commonly found in the second part of the duodenum, and are usually solitary, flat, sessile lesions. Duodenal adenomas can be classified as papillary adenomas (PAs) when primarily involving the papilla Vateri, or duodenal adenomas (DAs) when there is no involvement of the papilla. These adenomas can be further classified as sporadic papillary adenomas (SPAs) or sporadic duodenal adenomas (SDAs), i.e., those not associated with genetic polyposis syndromes, or as those related to familial adenomatous polyposis (FAP). It is estimated that 40% of duodenal adenomas are sporadic and 60% are related to FAP.

Endoscopic resection (ER) of DA and PA is quickly becoming the treatment of choice for noninvasive lesions, even when they are very extensive. Although no systematic comparative data exist, due to the lower risks of morbidity, mortality, and long-term digestive dysfunction, ER is considered preferable to surgery. ER in the duodenum requires a diverse range of endoscopic skills. These include proficiency in advanced endoscopic resection techniques, experience with pancreaticobiliary endoscopy, and the ability to identify and manage complications. These procedures should be performed by experienced endoscopists practicing in tertiary referral centers with access to surgical and interventional radiology support. A structured approach to lesion assessment, technical aspects of resection, and postresection surveillance is required.

Epidemiology and Natural History

SDAs are rare, and most are discovered incidentally during esophagogastroduodenoscopy (EGD) performed for other indications. In a similar fashion to colonic carcinogenesis, 30%–80% of SDAs demonstrate malignant progression through the adenoma-to-carcinoma pathway. In one study, 21% of lesions with low-grade dysplasia (LGD) showed progression to high-grade dysplasia (HGD), and the presence of HGD and a lesion size of more than 20 mm were independently associated with progression to adenocarcinoma. In other studies, invasive adenocarcinomas were often found within small bowel adenomas, and residual adenomatous tissue was found adjacent to, or within, most carcinomas. It is therefore recommended that all SDAs be removed.

SPAs are also uncommon, and have been reported to occur at a rate of 0.04%–0.12% in autopsy series. Today, with the increasing performance of EGD and endoscopic retrograde cholangiopancreatography (ERCP), these adenomas are more frequently recognized at an asymptomatic stage. Similar to SDAs, SPAs appear to follow the adenoma-to-carcinoma paradigm, and should thus be removed. However, SPAs are thought to progress to cancer more rapidly than nonpapillary duodenal adenomas.

The molecular and genetic pathways of the adenoma-to-carcinoma sequence in SDA/SPA are less well established. In one study, approximately 75% of duodenal adenomas (both sporadic, FAP-related, and those involving the papilla) showed Wnt signaling pathway abnormalities. KRAS mutations were found in 18% of SDAs, 9% of FAP-related adenomas, and 44% of SPAs. No BRAF mutations were identified, and both p53 and DNA mismatch repair mutations were rare. In another study, the CpG island methylator phenotype (CIMP) was analyzed in ampullary and nonampullary SDAs. Thirty-three percent of duodenal adenomas were CIMP+, and CIMP+ status was associated with advanced age, large lesions, villous histology, MLH1 methylation, and KRAS mutations. These results suggest that duodenal adenomas develop via similar mechanisms as colonic adenomas, and that CIMP+ duodenal adenomas may have a higher risk of developing malignancy.

SDAs are also considered surrogate markers for colonic neoplasia. Several retrospective case control studies have demonstrated a significantly higher risk of colonic neoplasia in patients with sporadic duodenal adenomas when compared with their matched controls (relative risk [RR] 2.5–7.8). Thus, all patients with SDA/SPA should undergo colonoscopy at some point.

In contrast, patients with FAP have a much higher prevalence of DA or PA. Duodenal or papillary adenomas are found in more than 90% of patients with FAP, and 3%–10% will progress to malignancy over their lifetime. In patients with FAP, duodenal adenomas are usually multiple, sessile, and located in the second and third parts of the duodenum. The Spigelman staging system is used to stratify disease burden and predict the risk of malignant transformation. The risk of duodenal cancer increases with age and with progressive adenoma stage. DA may also occur in association with MYH-associated polyposis and Lynch syndrome.

Clinical Presentation

As previously mentioned, DAs are usually asymptomatic, and the majority are discovered incidentally during routine EGD performed for other indications. Rarely, very large lesions may present with gastrointestinal bleeding or obstructive features. PA may present with abdominal pain, recurrent pancreatitis, malaise, or anorexia. However, most noninvasive lesions are asymptomatic and are found incidentally during EGD or ERCP performed for other indications. Symptoms such as jaundice may result from invasive malignancy or intraductal extension, but may alternatively be caused by a concurrent benign condition such as common bile duct (CBD) stones.

Indications and Patient Selection

ER should be considered for any noninvasive DAs/PAs, because it potentially offers significant advantages over operative management. Long-term cure rates can be expected in more than 90% of patients undergoing ER. Periprocedural complications are not uncommon (bleeding up to 25%, perforation up to 3%, recurrence up to 30%); however, they are usually not severe, and are managed successfully endoscopically or with conservative management without long-term sequelae. In comparison, a conservative surgical procedure (transduodenal resection/ampullectomy) carries a morbidity rate of 20%–30%, a mortality rate of 0%–6%, and a residual disease rate of 13%–100%. The more radical pancreaticoduodenectomy has even higher rates of morbidity and mortality (25%–50% and 3%–9%, respectively).

The patient's medical history, including his or her medication list, has to be thoroughly reviewed and the patient's comorbidities constantly factored into the therapeutic process. This is especially important because, compared with similar size adenomas in the colon, the risk for malignant transformation appears to be reduced, the time course more prolonged, and the ER procedure more technically challenging and associated with greater incidence of complications.

To achieve endoscopic cure, the entire lesion must be accessible to resection, and the risk of submucosal invasive cancer (SMIC) and lymph node metastases (LNM) negligible. Lesions with LGD or HGD confined to the mucosa are considered suitable for ER. Lesions with suspected SMIC or LNM require surgery to achieve cure, and are not suitable for ER. For PA, lymphovascular invasion and moderate or poor tumor differentiation confer additional risks for LNM. T1 lesions (limited to the papilla vateri or sphincter of Oddi) harbor an appreciable rate of LNM (18%) and are best managed surgically. Papillectomy may serve as the definitive staging tool and finally determine the need for additional therapy such as surgery. On the other hand, endoscopic cure of selected well-differentiated T1 papillary carcinomas has been demonstrated in small case series, presenting a therapeutic alternative for patients unfit for surgical resection.

PA may contain an intraductal component or a lateral spreading component, or can involve the minor papilla. PA with intraductal extension limited to the papillary complex or extending 1 cm or less beyond the duodenal wall may be removed by ER. Lesions with more extensive intraductal involvement have higher failure rates with ER, and at present are best referred for surgical resection, although with expanding possibilities of cholangioscopy, such as intraductal radio frequency ablation (RFA), this may change in the future. Lateral spreading lesions of the papilla (LSL-P) may be very large (in excess of 50–60 mm) and involve the entire duodenal circumference. Although uncommon, LSL-Ps may be cured endoscopically at rates comparable to lesions confined to the papilla, albeit with an elevated risk of bleeding. Lesions involving the minor papilla are rare, hence data on resection and outcomes are limited.