Introduction

The small intestine represents 75% of the length and 90% of the absorptive surface area of the gastrointestinal tract (GIT), yet only 2% of digestive system cancers occur at this site [1]. The incidence of small bowel malignancies has increased due largely to neuroendocrine tumours (NETS)—these are now the commonest small bowel cancer and account for almost half of small bowel malignancies, followed by adenocarcinomas, lymphoma and sarcoma [2]. Patients may develop non-specific symptoms and tumours can be difficult to visualise with conventional endoscopic and imaging techniques. Emergency presentations may occur, e.g. small bowel obstruction or intussusception. Thus, there can be a delay in diagnosis, which may result in the discovery of disease at an advanced stage. Over recent years, ampullary tumours have become recognised as distinct from head of pancreas and lower biliary tract tumours. This is reflected in separate TNM systems and increasing interest in separating intestinal from pancreatobiliary subtypes.

Adenomas of the small intestine

Small intestinal adenomas are rare compared to those of the colorectum. Duodenal adenomas are readily detected endoscopically, whilst adenomas in the jejunum and ileum are inaccessible by ordinary endoscopic means and are rarely detected before they progress to invasive carcinoma [3]. Small intestinal adenomas are histologically similar to those in the colorectum and are also classified as tubular, tubulovillous or villous and graded as low or high grade. Villous and tubulovillous forms are more common in the small bowel than in the colon [4]. An adenoma-carcinoma sequence is also described in the small bowel [5], and as in the colon, the risk of progression to malignancy is higher in larger adenomas, and in the presence of villous histology and high-grade dysplasia (HGD) [4]. Serrated adenomas, resembling traditional serrated adenoma of the colon, have also been recently reported in the small intestine, and over half of the cases in this series were associated with HGD or adenocarcinoma [6]. Rare adenomas and gastric-type adenocarcinomas are characterised by proximal location and may be associated with gastric-type dysplasia. Adjacent gastric foveolar metaplasia and Brunner gland hyperplasia may be seen. Gastric-type adenocarcinomas show a tubular and papillary pattern with foveolar or pyloric-type differentiation. Neoplastic cells have rounded nuclei with open chromatin [7]. Ampullary adenomas represent approximately 10% of all duodenal adenomas and have a higher risk of malignant transformation than non-ampullary adenomas [3]. Duodenal adenomas are associated with hereditary polyposis syndromes such as familial adenomatous polyposis (FAP), MYH polyposis and Lynch syndrome, and other syndromes (e.g. neurofibromatosis type 1) [8,9,10]. Finding multiple duodenal adenomas, particularly in younger patients (e.g. under 40), raises the possibility of a hereditary polyposis syndrome and should prompt a colonoscopy to exclude colonic neoplasia [3].

Adenocarcinoma of the small intestine

Adenocarcinoma of the small and large bowel share many characteristics. There is a positive correlation between incidence rates of these two diseases [11]. Most small bowel adenocarcinomas (SBAs) arise from adenomas, and the available data suggest an adenoma-carcinoma sequence with molecular genetic changes similar to those known to occur in colorectal carcinogenesis[12,13,14,15,16]. Colorectal cancers (CRCs) are 50 times more numerous than SBAs. The reason for this is not known, but several potential explanations based upon differences in microenvironment have been proposed. Faster transit time of intestinal contents in the small bowel may result in shorter exposure of its mucosa to carcinogens [16, 17]. Rapid turnover of small intestinal mucosal cells and increased rates of apoptosis may be protective [12]. The small intestine generates less endogenous reactive oxygen species than the colon does, and may undergo less oxidative damage than the colon [18]. Increased lymphoid tissue and secretory IgA in the small bowel suggest greater immune surveillance and tumour control [19, 20].

Half of all SBAs are located in the duodenum, most commonly in the second portion near the ampulla of Vater[21], 30% arise in the jejunum and 20% occur in the ileum [22]. The predilection for SBAs in the duodenum has been attributed to higher concentration of bile and its metabolites in the ampullary region and duodenum [23, 24]. The incidence of SBA is increasing [2, 25]. SBAs resemble their counterparts in the colon, but with a higher proportion of poorly differentiated tumours with glandular, squamous and undifferentiated neuroendocrine components [26]. SBA is associated with late presentation and a poor prognosis. Of the patients, 30 to 40% present with stage IV disease [2, 27, 28], and median overall survival is 19 months [29]. Five-year disease-specific survival was assessed by stage in 1991 cases identified from the Surveillance, Epidemiology and End Results (SEER) program registry, with the following results: stage I, 85%; stage II, 69%; and stage III, 50% [30]. Poor prognostic factors include advanced stage, poor differentiation, positive margins, duodenal location, male gender and older age [2].

Risk factors for small bowel adenocarcinoma

Crohn’s disease (CD), coeliac disease and a number of hereditary cancer syndromes including FAP, Lynch syndrome, Peutz-Jegher and juvenile polyposis syndromes are known risk factors for SBA.

Association with FAP

Patients with FAP have a particular tendency to develop duodenal adenomas, found in 90% of adult FAP patients [31]. Approximately 5% of FAP patients develop duodenal adenocarcinoma, and it is now one of the leading causes of death in post-colectomy FAP patients. The Spigelman classification system is used to assign FAP patients to one of five risk profile categories (stages 0–IV) based on polyp number, size, architecture and degree of dysplasia [32] (Table 1). This scheme guides clinical management of these patients and aids decisions about screening interval, and continued surveillance vs prophylactic surgery.

Table 1 Spigelman staging system for severity/risk stratification of duodenal polyposis in FAP (modified to convert mild/moderate to low grade)
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Association with Crohn’s disease

When SBA arises in the setting of CD, it tends to occur in the ileum or distal jejunum [33]. This is a difficult diagnosis to make as presenting symptoms may be similar to active or obstructive CD, and it is rarely detected preoperatively. Risk factors for SBA in this setting are poorly defined. Proposed risk factors include stricturing and fistulating disease, long-standing disease, young age at diagnosis, male gender, use of certain immunosuppressant drugs and surgery-related factors such as small bowel bypass loops, strictureplasty and absence of resection [34]. Recently, an inflammation-dysplasia-adenocarcinoma sequence has been recognised in at least half of CD-related SBA, akin to what is observed in chronic colitis-related CRC [35]. Small bowel resection and prolonged use of salicylates may be protective against SBA in CD patients [36]. Three meta-analyses identified a standardised incidence ratio of SBA in patients with CD of 27, 28 and 33 [37,38,39].

Association with coeliac disease

A large Swedish study identified 12,000 patients with coeliac disease and estimated the relative risk of SBA in this group compared to the general population to be 10 [40]. A British survey study included 175 SBAs and found that coeliac disease was present in 13% of cases [41].

Clinical management of small bowel adenocarcinoma

Localised SBAs are best managed with surgical resection of the involved segment of small bowel and mesentery containing regional nodes. SBA recurrence is predominantly systemic [27]. The number of lymph nodes (LNs) evaluated is a strong prognostic factor with improved 5-year disease-specific survival in patients with ≥ 8 or ≥ 10 LNs evaluated [30]. Accurate nodal staging allows patients at high risk of relapse to be identified and at least considered for adjuvant treatment. Retrospective studies have demonstrated a benefit of chemotherapy in advanced SBA [42, 43]. There is currently no consensus on the use of chemotherapy in the adjuvant setting. SBAs are rare and there is a lack of randomised controlled trials to address this question [44, 45]. The results of retrospective studies with small numbers of patients are mixed, with one study showing improvement in disease-free survival [46], and others showing no benefit [47,48,49,50]. Despite the lack of data to support the role of adjuvant chemotherapy, its use is increasing, indicating that Disease Management Teams may be extrapolating from proven benefit seen in CRC [51]. Cancer Research UK, the National Cancer Research Network, the National Cancer Institute and the European Organisation for Research and Treatment of Cancer International Rare Cancers Initiative aim to accrue 880 patients from 2015 to 2022 into a large prospective randomised trial evaluating the effect of adjuvant chemotherapy in SBA, termed the BALLAD study (a global study to evaluate the potential benefit of adjuvant chemotherapy for small bowel adenocarcinoma) [52].

New molecular insights

A recent study of 75 ampullary adenocarcinomas (AA) detected wild-type KRAS in 67% and mutant KRAS in 33% of cases [53]. In this study, patients with KRAS G12D mutation had poorer median survival and were more likely to present with advanced T stage [53]. The authors propose that KRAS G12D mutation identifies a group of patients at risk of early recurrence and poorer survival who may benefit from adjuvant therapy [53]. Kohler and colleagues studied phenotypic and genotypic characteristics of 71 AAs and found KRAS mutations in all poorly differentiated AAs and in about 20% of each of the other types [54]. The presence of wild-type KRAS in many AAs indicates that many of these patients may be suitable candidates for anti-epidermal growth factor receptor therapy [54]. Schultz et al. found a much higher rate of KRAS mutations in their study, detecting KRAS mutations on 67% of AAs in their cohort [55]. KRAS mutations were also associated with poor prognosis in patients with AA in this study [55].

Eighty percent of small intestinal adenocarcinomas have deletions of 18q21-q22, which target SMAD4, a downstream component of the TGF beta-pathway. Thus, disruption of TGF beta-signalling may play a role in small intestinal tumourigenesis [56]. The frequency of MSI, K-RAS and TP53 mutations appear to be similar to colorectal cancer, and APC mutations appear to be uncommon [57]. Recently, hybridisation capture-based genomic profiling of small bowel adenocarcinomas (n = 317) showed distinct differences compared with colorectal cancers and gastric adenocarcinomas. Potentially targetable genomic alterations were detected in 92% of small bowel adenocarcinomas, especially ERBB2/HER2 mutation/amplification, EGFR mutation/amplification, microsatellite instability and PI3K pathway-activating alterations [58]. Indeed, a recent study has indicated that approximately 10% of SBAs carry ERBB2/HER2 alterations, rendering these patients potential candidates for targeted therapy [59].

Recent studies have demonstrated the effectiveness of anti-PD1 immune checkpoint inhibitors in MSI carcinomas, regardless of site of origin, including small bowel adenocarcinomas [60]. There is thus a strong argument that all small bowel adenocarcinomas should undergo universal screening for deficient mismatch repair (dMMR), to exclude Lynch syndrome and for therapeutic purposes. The frequency of microsatellite instability (MSI) in adenocarcinomas of the small intestine is similar to colon cancer, with the MSI-H phenotype being reported in 5–45% of unselected small bowel carcinomas [61]. The immunotherapeutic drug, pembrolizumab, may thus be beneficial to some patients with small bowel adenocarcinomas [58]. Finally, MSI-H phenotype may be associated with better survival [62].

Adenomas of the ampulla

As ampullary adenomas carry a high risk of malignant transformation, complete resection is advised [63]. Traditionally, ampullary adenomas have been radically treated with pancreatoduodenectomy (PD) (Fig. 1), but currently, an attempt at endoscopic resection of these lesions is advocated before considering surgery [64, 65]. Local surgical excision, in the form of transduodenal ampullectomy or pancreas-sparing duodenal resection, may also be considered. Patient selection for endoscopic ampullectomy requires consideration of clinical, biochemical, endoscopic, imaging and biopsy findings. The presence of a focus of invasive carcinoma in an unsampled part of the lesion cannot be excluded and false-negative rates of endoscopic mucosal biopsies have been reported to be between 20 and 30% [66,67,68], leading clinicians and pathologists to seek combinations of clinicopathological features that may predict malignancy.

Fig. 1
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Ampullary adenoma, 2.6 cm

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Endoscopic findings such as failure to achieve a cleavage plane with submucosal injection, or presence of a nodular tumour with erosion, ulceration or fold convergence of the neighbouring duodenum are suggestive of invasion [69, 70]. Large lesions, high serum alkaline phosphatase, HGD on biopsy and ductal dilatation are also predictors of malignancy [66, 71]. A retrospective review, which included 47 patients with duodenal and peri-ampullary adenomas, found that preoperative EUS accurately predicted absence of mucosal invasion and could aid in selecting patients who can safely undergo endoscopic or local resection for duodenal and peri-ampullary adenoma [72]. Surgeons may request intraoperative frozen section examination and proceed to conversion to PD if invasive carcinoma is found. Patients who have undergone endoscopic or surgical ampullectomy for an ampullary adenoma require endoscopic surveillance to ensure complete resection and to monitor for recurrence.

Ampullary adenocarcinomas

AAs arise within the ampullary complex, distal to the bifurcation of distal common bile duct and pancreatic duct (Fig. 2). In this region, there is confluence of intestinal and pancreatobiliary epithelia and tumours arising here may have either type of differentiation. Poorly differentiated, ‘mixed’ type and mucinous adenocarcinomas are also described. The intestinal subtype is morphologically similar to CRC, composed of well-formed glands, complex cribriform areas and columnar cells with hyperchromatic and pseudostratified nuclei and ‘dirty necrosis’. The pancreatobiliary subtype resembles pancreatic ductal adenocarcinoma and has simple or branching glands and small solid nests of cuboidal and low columnar cells in a single layer, with rounder nuclei and desmoplastic stroma. The mixed subtype is composed of > 25% of each pattern or tumours with architectural features of one subtype in combination with cytology of the other (Table 2; Fig. 3). Mucinous adenocarcinomas contain > 50% extracellular mucin. Poorly differentiated carcinomas usually have a solid pattern or may be composed of infiltrating single cells and lack specific morphological features. The presence of a precursor lesion can aid classification; adenomas are often associated with intestinal-type adenocarcinoma and pancreatic intraepithelial neoplasia (PANIN) may be identified adjacent to pancreatobiliary-type tumours.

Fig. 2
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Ampullary adenocarcinoma invading adjacent lower bile duct and pancreas

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Table 2 Intestinal vs pancreatobiliary subtypes of ampullary adenocarcinoma
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Fig. 3
figure 3

Ampullary adenocarcinoma. a Histopathological features of intestinal subtype, namely eosinophilic cytoplasm and round nuclei with minimal nuclear stratification. b Histopathological features of intestinal subtype, namely basophilic cytoplasm, elongated nuclei and significant nuclear stratification

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Immunohistochemistry (IHC) can aid distinction of these subtypes. Ang et al. found that a combination of H&E morphology and four IHC stains (CK20, CDX2, MUC2, MUC1) could be used to distinguish 92% of cases [73]. Intestinal subtypes was defined as having positive CK20, CDX2 or MUC2 staining with negative MUC1, or positive staining for CK20, CDX2 and MUC2, irrespective of MUC1 [73]. Pancreatobiliary subtype was defined as having positive MUC1 and negative CDX2 and MUC2, irrespective of CK20 status [73].

A recent study has suggested that MUC5AC may provide additional help in classifying these neoplasms [74].

Clinical implications of ampullary adenocarcinoma classification

The classification of AA is a subject of debate [75]. Studies have attempted to construct clinically meaningful classification based on anatomical site or histology. Adsay et al. [76] used gross and microscopic impression of the tumour ‘epicentre’ to classify ampullary carcinomas, defining four subtypes with different prognoses. Intra-ampullary and peri-ampullary duodenal tumours had the best prognosis (3-year survival of 73 and 69%, respectively), whilst ampullary-ductal had the worst prognosis (3-year survival of 41%), possibly due to pancreatobiliary histology, seen in the majority of cases. However, even this subgroup had a better prognosis when compared with 113 pancreatic ductal adenocarcinomas (3-year survival of 11%).

The intestinal and pancreatobiliary histological subtypes are associated with different clinical outcomes, potentially different chemosensitivity profiles and underlying molecular genetic pathways [21, 77]. Many studies have demonstrated a poorer prognosis for pancreatobiliary compared to intestinal histology [78,79,80,81,82,83,84,85], but this finding has not been universal [86, 87]. Chang et al.’s study [80] found median overall survival of 16 months for patients with pancreatobiliary histology vs 115.5 months for patients with intestinal histology. The prognostic ability of the histomolecular phenotype, described in Chang’s paper, has recently been validated in an independent cohort of 163 AA patients [88]. Accurate histological subtyping may aid in selection of chemotherapy regimens; patients with pancreatobiliary type tumours may derive benefit from gemcitabine-based regimens [89], whilst those with intestinal type tumours may be more likely to respond to 5-FU- and leucovorin-based regimens. Whilst oncologists are increasingly requesting subclassification of ampullary adenocarcinomas, in practice, this is not always possible, and many adenocarcinomas are of a mixed subtype.

Ampullary carcinomas are staged separately to other small intestinal carcinomas [90]. These tumours were the subject of a recent comprehensive review, which raised the question of whether ampullary carcinomas should be considered a separate clinicopathological entity amongst other peri-ampullary tumours, or be classified as either pancreatic/biliary or duodenal tumours [75]. AAs have a better prognosis than carcinomas of pancreatic or bile duct origin, and it is unclear whether this represents a true biological difference or a consequence of earlier detection of cancers at this site due to earlier development of biliary obstruction.

The outcome of resected ampullary cancer depends upon the TNM stage, in particular presence of pancreatic invasion, nodal metastasis, lymphovascular invasion and the status of the surgical margins [79, 87, 91,92,93,94,95]. Disease recurs in 28 to 42% of resected patients [91,92,93,94,95,96,97], in the form of local recurrence and/or distant metastasis. The number of positive LNs is prognostically important [98]. Tumour budding, extensively studied in CRC, is also frequently identified in AA and has been shown to confer a worse prognosis in one study [99]. Adjuvant therapy (chemotherapy alone or with radiation) is frequently considered in patients with adverse features, despite a lack of guidelines. Retrospective series suggest that patients with completely resected ampullary carcinomas benefit from postoperative chemoradiotherapy [100,101,102,103]. Prospective studies include heterogeneous groups of patients with different types of periampullary tumours (ampullary, duodenal, pancreatic and bile duct), making interpretation difficult [104]. The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, which included 297 patients with AA, suggested a potentially clinically meaningful but statistically insignificant improvement in overall survival with adjuvant chemotherapy [105]. Overall, the data on the subclassification is not entirely compelling and reliable IHC to distinguish the two main types still eludes us—thus rendering clinical application of doubtful benefit at this juncture.

Conclusions

The relative rarity of SBAs and AAs presents unique diagnostic and therapeutic challenges. Distinguishing primary from metastatic carcinoma can be problematic, and clinical history usually provides the most useful information in this situation. Ampullary carcinoma is recognised to be a complex and heterogeneous clinicopathological entity. A recent detailed study has also revealed heterogeneous histopathology in extra-ampullary duodenal adenocarcinoma, with identification of intestinal and gastric types, with different clinical behaviour, the intestinal type being associated with longer survival [7]. Molecular characterisation of these tumours may offer future therapeutic targets [106, 107]. Future multiinstitutional prospective studies may provide valuable data to inform management of patients with these rare GIT cancers. Discussion of the patient’s clinical presentation, histopathology, radiology, biochemistry and endoscopic findings at multidisciplinary team meetings is important in deciding on extent of resection and need for further treatment.