Endoscopic Diagnosis of Gastrointestinal and Pancreatic Neuroendocrine Tumors

 

Type 1

Type 2

Type 3

Type 4

Frequency (%)

70–80

5–6

14–25

6–8

Age of occurrence

40–60

45

50

>60

Dimensions (mm)

<10

<15

>20

>20

Features

Multiple

Multiple

Single

Single

Histology

Well-differentiated

Well-differentiated

Well-differentiated

Poorly differentiated

Proliferation rate (%)

<2

<2

>2

20–30

Gastrinemia

High

High

Normal

Mostly normal

pH

Anacidic

Hyperacidic

Normal

Mostly normal

Metastases (%)

<10

10–30

50–100

80–100

Associated diseases

CAG

MEN1, ZES

No

No


CAG, chronic atrophic gastritis; MEN1, multiple endocrine neoplasia type 1 ; ZES, Zollinger-Ellison syndrome.



Type 1 lesions represent up to 80% of gastric NETs, appear multifocal on endoscopy, develop in the gastric corpus and fundus, and are small (<10 mm) [11, 12]. These lesions are often associated with fundic chronic atrophic gastritis. In up to 90% of cases they are limited to the mucosa or submucosa and infiltration of the muscularis propria can be observed only when their size is greater than 10–20 mm [12, 13]. Metastases to loco-regional lymph nodes can be found in up to 9%, and this usually occurs in lesions >20 mm that often infiltrate the muscularis propria and also become angioinvasive [11, 14, 15].

Type 2 gastric NETs are similar to type 1 (Fig. 6.1). These NETs usually present in up to 30% of patients after a long course (up to 20 years) of MEN1 or Zollinger-Ellison syndrome (ZES) [1619]. As in type 1, lymph node metastases in type 2 are found in tumors >20 mm, which infiltrate the muscularis propria and are angioinvasive [11, 14, 15].

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Fig. 6.1
Endoscopic image and endoscopic ultrasound image of a type 2 gastric neuroendocrine tumor

Type 3 gastric NETs endoscopically can be found in any part of the stomach as solitary polypoid lesions, and they are not associated with other diseases or conditions (Table 6.1). When diagnosed, these lesions are often >20 mm in dimensions, infiltrate the muscularis propria and are angioinvasive, and have a 75% rate of metastases at presentation [20].

Type 4 gastric NETs are poorly differentiated solitary carcinomas that can be found anywhere in the stomach. These lesions on endoscopy are usually ulcerated, big and adenocarcinoma-like. The prognosis is very bad since more than 50% of the patients die within 12 months [7, 2123].

Type 1 and 2 NETs that are confined to the mucosa can be resected en bloc by EMR [11]. EUS can be useful in these lesions for staging. ESD is the treatment of choice for bigger NETs confined to the mucosa or infiltrating the submucosa, but without lymph node involvement confirmed at EUS [24, 25].

Type 3 gastric NETs confirmed by EUS-guided fine-needle aspiration (FNA) or EUS-guided fine-needle biopsy (FNB) should be evaluated for locoregional lymph node metastases and distal metastases, even when these lesions are small [20].

A follow-up, with repeat gastroscopy every 1 to 2 years is recommended, especially for type 1 gastric NETs, due to their tendency to recur.

Multiple random biopsies and biopsies of the antrum, fundus and gastric body and of any suspected lesion and/or polyp is recommended in this setting.

Surgery with or without neoadjuvant chemotherapy is indicated for all types of NETs that are associated with high rates of lymph node metastases.



6.2.3 6.2.3 Duodenum


Primary duodenal NETs represent about 2% of all gastrointestinal NETs [26] (Fig. 6.2). Duodenal NETs are classified into five types based on their pathohistological characteristics: gastrinomas, somatostatinomas, non-functioning NETs, poorly differentiated neuroendocrine carcinomas, and duodenal gangliocytic paragangliomas (predominantly located in the ampulla of Vater).

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Fig. 6.2
Large duodenal neuroendocrine tumor

The diagnosis is often incidental during upper endoscopy for unrelated symptoms. Jaundice is the more frequent presentation of ampullary NETs.

Some duodenal NETs can present in the setting of Zollinger-Ellison or Cushing syndrome and, rarely, acromegaly. Duodenal NETs generally arise in the submucosa (third layer) and on EUS appear as hypoechoic, rounded and with a characteristic salt-and-pepper appearance. These lesions are usually small (<10 mm), but when their size is >10 mm they have a very high metastatic potential.

When less than 10 mm in diameter, these lesions can be removed by EMR, after careful EUS evaluation for adjacent lymph node metastasis [27, 28]. Independent factors for metastases are invasion of the muscularis propria, tumor size (>20 mm) and the presence of mitotic figures on histology [29].

According to the ENETS guidelines for the management of duodenal NETs, endoscopic resection can be done for lesions smaller than 10 mm, located outside the ampulla of Vater, without signs of invasion of the muscularis propria and with no evidence of lymph node metastases on EUS [20]. Several studies have reported no correlation between tumor size and the presence of malignancy and/or metastases in ampullary and periampullary NETs; therefore, surgical resection with lymphadenectomy is the best treatment of choice of these lesions [3034].

Endoscopic papillectomy is an option in high-risk surgical candidates and in the case of small ampullary NETs without local angioinvasion and lymph node metastases confirmed by EUS, and EUS-FNA or EUS-FNB showing high differentiation [31].


6.2.4 6.2.4 Small Intestine


The small intestine should be investigated in all patients with neuroendocrine metastases of unknown origin. Endoscopic options for investigation of the small intestine are videocapsule endoscopy (VCE) and enteroscopy. Fig. 6.3 shows a small NET of the small intestine found on VCE.

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Fig. 6.3
Neuroendocrine tumor found in the small intestine during videocapsule endoscopy (Courtesy of Dr. Cristiano Spada)

Computed tomography enteroclysis seems to be superior to VCE in the detection of the primary neoplasm and also in the evaluation of extraluminal invasion [35, 36]. Furthermore, in cases of mesenteric involvement, almost always there is a significant stricture in the intestine that can block the capsule progression [37].

Enteroscopy (single or double balloon) has low diagnostic potential, and should be performed in selected cases after positive previous non-invasive investigations [38]. Other indications for enteroscopy are preoperative tattooing of operable NET lesions and endoscopic removal of small incidental NETs.


6.2.5 6.2.5 Colon and Rectum


NETs of the colon originate from the enterochromaffin cells in the crypts of Lieberkühn. Clinically they can present with abdominal pain, change in bowel habits, anorexia, bleeding, weight loss and weakness, but can also be asymptomatic. The most frequent localizations are the cecum and the ascending colon. Generally, colonic NETs tend to present later especially if located in the cecum and ascending colon, due to the bigger diameter of this part of the colon, which is probably the reason why more than 60% are metastatic at the time of diagnosis [39, 40]. The 5-year survival rate is about 60% [41].

It is important to underline that colonic NETs bigger than 20 mm have almost always regional lymph node metastases; therefore the recommended treatment in these patients is surgery combined or not with chemotherapy [42, 43].

EMR is the best treatment modality for lesions <20 mm, involving the mucosa and/or submucosa, without distant metastases, while ESD bears major perforation risks in the colon.

As far as NETs of the rectum are concerned, these lesions are often small (<10 mm) and with polypoid appearance. As a result, in clinical practice, most of these lesions are removed routinely by snare polypectomy and only after histological examination are they reclassified as NETs [44]. The need for additional investigations in these lesions is driven by the status of the resection margins and tumor grading. However, complete colonoscopy should always be performed in order to exclude other synchronous lesions [45]. In Fig. 6.4 a small NET of the rectum involving the muscularis mucosae is shown.

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Fig. 6.4
Small neuroendocrine tumor of the rectum involving the muscularis mucosae

EUS for staging is indicated for rectal lesions larger than 20 mm. Rectal NETs bigger than 20 mm with invasion of the muscularis propria or aggressive histological features should undergo surgery.

The ENETS guidelines treatment algorithm for rectal NETs is based on EUS findings and suggests exclusion of pararectal lymph node metastases before endoscopic removal [20].

Standard polypectomy compared to EMR or ESD for rectal NETs has shown to be less effective in terms of complete resection (31% vs. 72%) [46]. A combination of EUS and ESD for rectal NETs larger than 10 mm is the best approach in this setting [47].



6.3 6.3 Pancreatic NETs


The pancreas can be entirely studied with EUS through the stomach and the duodenum obtaining high-resolution images. EUS can precisely visualize small anatomical structures that cannot be studied by other imaging modalities. These features, together with the possibility to perform tissue sampling (EUS-FNA and/or EUS-FNB) makes EUS the best diagnostic tool for pancreatic NETs [48, 49]. In Fig. 6.5 a small NET of the pancreatic isthmus and in Fig. 6.6 a NET in the pancreatic tail are shown.

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Fig. 6.5
Small neuroendocrine tumor in the pancreatic isthmus


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Fig. 6.6
Neuroendocrine tumor in the pancreatic tail

Pancreatic NETs appear on EUS as rounded, hypoechoic lesions with clear and regular margins and a homogeneous pattern. In cases of advanced lesions, pancreatic NETs can also appear irregular, with the same features as pancreatic adenocarcinoma. EUS can also establish the localization and the distance from the tumor of the main pancreatic duct, which can indicate the best surgical approach: enucleation versus resection [50]. Furthermore, EUS-guided fine needle tattooing (EUS-FNT) is a valid technique that helps surgeons in the precise localization of small pancreatic NETs, especially when laparoscopic surgery is planned [51].

NETs of the pancreas are rare tumors and represent about 1% of all pancreatic neoplasms [7, 52]. As for other gastrointestinal NETs, the incidence of pancreatic NETs has significantly increased in recent decades, mostly due to the wide availability of EUS. The clinical course of pancreatic NETs is generally indolent [7, 52]. As mentioned in previous chapters, pancreatic NETs are classified into functioning and non-functioning lesions based on the presence or absence of a clinical hormonal hypersecretion syndrome [53]. Pancreatic functioning NETs are mainly insulinomas, which in 50% of the cases are less than 1 cm in diameter, and therefore sometimes very difficult to detect [53].

The sensitivity of EUS in pancreatic NETs is up to 94% [5460]. The ENETS consensus guidelines classify EUS as the imaging study of choice for these patients. [20]. EUS combined with FNA can predict the 5-year survival of these patients through determination of malignant potential [61]. Today, determining the tumor proliferation index Ki-67 of pancreatic NETs is an essential step in the choice of the best patient-tailored treatment [62]. This is important both for operable and non-operable patients. For instance, the degree of proliferation index can lead to the choice of different targeted therapies, such as everolimus and sunitinib, peptide receptors targeted therapy, etc. [6264].

The role of EUS in pancreatic NETs is not only diagnostic, but also therapeutic. EUS-guided fine-needle injections and tumor ablation therapies are both possible [65, 66]. This minimally invasive approach can be done in selected, mostly non-operable or high-risk surgical patients, and consists in radiofrequency and cryotherapy tumor ablation, fine-needle injection of ethanol, antitumor agents [66]. The long-term efficacy of these treatments is currently not known. Serious adverse events such as portal vein thrombosis and large pancreatic tissue necrosis have been reported [67, 68].


6.4 6.4 Conclusions


Upper and lower endoscopy have an essential role in the diagnosis and treatment of gastrointestinal NETs. VCE and enteroscopy are suboptimal modalities for the study of the small bowel, and other diagnostic modalities should be preferred in this setting. EUS has a critical role in the diagnosis of NETs of the gastrointestinal wall and gives precise information about localization within the intestinal wall, size, depth of invasion, and it is essential for staging (alone or in combination with other diagnostic modalities). EUS is also essential in the selection of the best endoscopic resection approach: EMR versus ESD versus surgery. EUS combined with FNA and/or FNB has a pivotal role in the setting of diagnosis and treatment of pancreatic NETs. EUS-guided tattooing of pancreatic NETs is another important approach that helps surgeons to avoid destructive surgery. Finally, EUS-guided tumor ablation and fine-needle injections in selected patients are becoming promising treatment modalities, but more investigation is required in this field.

Jan 5, 2018 | Posted by in ABDOMINAL MEDICINE | Comments Off on Endoscopic Diagnosis of Gastrointestinal and Pancreatic Neuroendocrine Tumors

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