1. Epidemiology and pathogenesis
1.1. Gastric neuroendocrine neoplasms
Neuroendocrine neoplasms (NENs) account for less than 2% of all gastric tumours [1, 2]. In the years 1973–2012, on the basis of the American Surveillance, Epidemiology, and End Results (SEER) database, a 15-fold increase in the incidence of gastric neuroendocrine neoplasms (GNENs) was observed, which is mainly related to more frequent application of endoscopic examinations [3–6]. According to the same source, the prevalence of all neuroendocrine neoplasms in the USA is 6.98 per 100,000 inhabitants, which is a 6.4-fold increase since 1973 [7].
The gastric location constitutes 5.6–8.7% of all NENs of the gastrointestinal system and depends on the study site [1, 6]. Reports on the percentage of GNENs in relation to all NENs are similarly variable, and, depending on the study population, range from 5 to 23% [8, 9]. These differences indicate the need for multi-centre, prospective studies with long-term analysis to obtain better characteristics of the epidemiology of these neoplasms in Europe.
There are 3 types of GNENs, differing in their clinical symptoms and histopathology, as well as in their diagnostic and therapeutic management. Two additional types are currently being discussed, namely type 4 and type 5, the frequencies of which have not yet been estimated [10, 11], and have not yet been reflected in the World Health Organization (WHO) and North American Neuroendocrine Tumor Society (NANETS) recommendations [12, 13] (Tab. 1).
|
Gastric NET type |
Recommended action |
|
Type 1 |
|
|
Lesion < 1 cm |
Lesion follow-up or endoscopic removal |
|
Lesion ≥ 1 cm, submucosal lesions |
Lesion removal: endoscopic submucosal dissection (ESD) endoscopic mucosal resection (EMR) local removal |
|
Lesion ≥ 1 cm, muscularis propria infiltration or the presence of positive margins after endoscopic resection or suspicion of metastatic lymph nodes |
Lesion removal: local excision or partial gastrectomy |
|
Type 2 |
Gastrinoma resection, each case should be considered individually, treatment principles as in type 1 |
|
Type 3 |
Partial or complete gastric resection with the removal of lymph nodes |
1.1.1. Pathogenesis
Type 1 and type 2 tumours develop from enterochromaffin-like (ECL) cells in the gastric mucosa in response to chronic oversecretion of gastrin. Secondary hypergastrinaemia — caused by achlorhydria in the course of chronic atrophic gastritis (CAG) –– is responsible for the development of GNEN type 1. Primary hypergastrinaemia — in Zollinger-Ellison syndrome (ZES), sporadic or associated with multiple endocrine neoplasia 1 (MEN-1) –– is responsible for GNEN type 2. Gastrin and its derivatives stimulate the proliferation, migration, and differentiation of ECL cells, which in turn leads to their hyperplasia and dysplasia. Hypergastrinaemia, without the interaction of the transforming factor/factors, does not cause the development of GNEN [4]. Menin dysfunction may constitute a transforming factor in patients with MEN-1. The literature also mentions other factors including the following: BCL2 apoptosis inhibiting protein, p53 protein, fibroblast growth factor (FGF), transforming growth factor (TGF), Regla protein dysfunction (inhibiting the proliferation of ECL cells) [14].
1.1.2. Type 1
Gastric neuroendocrine neoplasms type 1 (70–80% GNEN) occur in patients with atrophic gastritis. They occur in less than 1% of patients, more often in women, most commonly between the 5th and 7th decade of life. It is expected that the increased availability of endoscopic examinations will reduce the age of patients diagnosed with gastric neuroendocrine tumour (GNET) type 1 in the future [8, 9]. Because they are rarely clinically evident, they are diagnosed during endoscopy due to dyspeptic symptoms or anaemia, more often macrocytic than resulting from iron deficiency [15]. They are most commonly small (< 1–2 cm), multiple (65%), and polypoid (78%) [5]. NETs G1 constitute 70–85% according to WHO [15, 16]. They are rarely invasive. Metastases occur in 2–5% of cases, and the ability to metastasise increases with the tumour size [5]. They are almost always slow-growing neoplasms with a good prognosis — no mortality has been described despite the advancement of the disease (up to 100% of patients with 10-year survival). They are non-functional: less than 1% of patients with GNET type 1 present symptoms of atypical carcinoid syndrome. The serum gastrin concentration is significantly increased, as well as the gastric juice pH.
1.1.3. Type 2
It is the least common (5–6%) form of GNET. It occurs only in the course of gastrinoma: in 23–29% of patients with ZES/MEN-1 and in 1–3% of sporadic cases [4, 17, 18]. Zollinger-Ellison syndrome is clinically present. Tumours are usually small (< 1–2 cm) and often multiple and polypoid in nature. They are usually located in the fundus and body of the stomach, occasionally in the cardia. They are classified as well-differentiated NETs (G1/G2 according to 2019 WHO classification), with a good prognosis despite the presence of metastases in up to 30% of patients at the time of diagnosis [12, 19]. Disease-related mortality is less than 10% [5]. The serum gastrin concentration is significantly increased and accompanied by very low gastric juice pH.
1.1.4. Type 3
This type accounts for 14–25% of GNEN cases. It is more often diagnosed in men over 50 years old. No predisposing factors have been identified. Tumours are single, usually large (> 2 cm in diameter), polypoid, with ulceration on the surface, located in the fundus and body of the stomach. They are usually G3 tumours classified as gastric neuroendocrine carcinomas (GNEC) according to 2019 WHO classification. They metastasise to the lymph nodes and the liver in 50–100% of cases. Death due to GNEC occurs in 25–30% of patients, depending on the degree of cancer differentiation and the presence of metastases [5]. Serum gastrin levels and gastric pH values are normal.
Recent studies have indicated that the G3 neoplasms can be divided into prognostic groups based on the degree of morphological differentiation and the Ki-67 value. Therefore, there is a division into well-differentiated NETs G3 and poorly differentiated NECs [1, 3, 9, 19]. The division according to the proliferation index (Ki-67 > 55%) has clinical implications in terms of response to chemotherapy (ChT) and prognosis: NECs with a Ki-67 value of over 55% demonstrated a better response to platinum-based ChT, but they had a 4-month lower median survival time than NETs G3 in the lower range of the proliferative index values (20–55%) [20].
According to the new literature data, some researchers currently distinguish type 4 and type 5 gastric neuroendocrine neoplasms [10, 11].
1.1.5. Type 4
The incidence of this type has not yet been established. Patients are diagnosed with achlorhydria, gastric wall cell hyperplasia and hypergastrinaemia. This type of pathogenesis is associated with abnormal secretion of hydrochloric acid from functionally damaged parietal cells; there is a mutation of the a subunit of the gastric proton pump, antral G-cell hyperplasia, and hypergastrinaemia [10, 11].
1.1.6. Type 5
The incidence of this type has not been established either. It is found in patients with moderate hypergastrinaemia treated for a long time (at least one year) with proton pump inhibitors, in whom chronic autoimmune gastritis, gastrinoma, and MEN-1 syndrome have been excluded. In patients with this type of tumour, the gastric mucosa around the lesion is normal or slightly hyperplastic; therefore, the lesion may be similar to GNET type 3. Differentiation of GNET type 5 from type 3 is very important due to its less aggressive surgical treatment and better prognosis than in type 3 [10, 11].
Well-differentiated GNETs with various degrees of malignancy (G1–G3) not associated with chronic atrophic gastritis have been described. Gastric tumours of mixed nature — mixed neuroendocrine — non-neuroendocrine neoplasms (MiNENs) — have also been described [17]. So far, 68 such cases have been reported in the literature, but no data on survival are available [5].
1.2. Duodenal neuroendocrine neoplasms
According to American statistics, they account for 2–3% of all cancers of the gastrointestinal system [4, 8, 21]. In 50–70% of cases, they belong to well-differentiated NETs G1 (according to 2019 WHO classification). There are 5 types of duodenal neuroendocrine neoplasms (DNENs) [12, 19]:
Some researchers exclude from the classification tumours located in the papilla of Vater and its vicinity (approx. 20% of NENs), because their clinical course is more similar to pancreatic neoplasms and they often coexist with Recklinghausen’s disease (neurofibromatosis 1, NF-1) [21].
Some authors classify neuroendocrine tumours of the papilla of Vater as neuroendocrine neoplasms of the bile ducts (in addition to neuroendocrine neoplasms of the gallbladder and extrahepatic bile ducts). They account for approximately 60% of these neoplasms. 50–70% of the neuroendocrine neoplasms of the papilla of Vater are well-differentiated NENs (G1 and G2), in contrast to neuroendocrine neoplasms of the gallbladder, 90–100% of which are neuroendocrine carcinomas [22, 23].
Less than 10% of patients with NF-1 develop NEN, which is almost always a duodenal somatostatinoma, most often without clinical symptoms. Recently, the actual existence of a separate clinical somatostatinoma syndrome has been questioned, because none of the 46 patients with histopathologically diagnosed somatostatinoma described by Garbrecht et al. presented the full symptoms proposed for this syndrome [24].
Over 90% of DNENs are located in the duodenal bulb (58%) and the descending part (33%) of the duodenum. DNENs are usually small (> 75% are < 2 cm in diameter), limited to the mucosa and submucosa, but at diagnosis 40–60% of cases demonstrate metastases to the regional lymph nodes. Liver metastases occur in less than 10% of patients. Multiple DNENs suggest MEN-1 [18].
2. Clinical characteristics
2.1. Gastric neuroendocrine neoplasms
Type 1 GNENs do not have characteristic clinical symptoms. They are usually diagnosed during upper gastrointestinal endoscopy due to dyspeptic symptoms. The disease is usually mild and requires only periodic endoscopic follow-up after endoscopic or surgical treatment. Its characteristic feature is its recurrence — the mean time to relapse is 24 months [15].
The symptoms of ZES (described in gastrinoma) dominate in type 2 GNENs. It is necessary to perform the examinations described in the first part of the Recommendations — in the article Update of the diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours) [25].
The clinical presentation of GNECs includes abdominal pain, anaemia, and weight loss. They are characterised by a malignant course and are most often disseminated at the time of diagnosis [14, 16].
Gastric neuroendocrine neoplasms very rarely (< 1%) cause atypical carcinoid syndrome (in case of concomitant liver metastases). Paroxysmal facial flushing usually lasts longer and is associated with lacrimation, often with a drop in arterial blood pressure. Unlike typical carcinoid syndrome, the excess of histamine can cause overgrowth of the facial skin (“lion’s face”) and its bruising. There is also endocardial damage [26].
2.2. Duodenal neuroendocrine neoplasms
2.2.1. Gastrinoma
Gastrinomas are neuroendocrine neoplasms located in the duodenum (70%), pancreas (25%), and rarely in other locations (5%: stomach, liver, ovary, lungs), secreting gastrin and causing clinical ZES. Hypergastrinaemia causes hypersecretion of gastric acid and, as a result, peptic ulcer disease and severe reflux disease [27, 28].
Gastrinomas are well-differentiated NENs G1/G2. These tumours are malignant in 60–90% of cases.
Recently, it has been noticed that 81% of patients with ZES caused by a duodenal tumour (i.e. 60–95% of all patients with ZES) have a history of long-term alcohol abuse (> 50 g/24 h). Therefore, it may constitute a significant ZES risk factor [29].
The features of gastrinoma dependent on the location and coexistence with MEN-1 are noteworthy [19, 28, 30, 31].
Duodenal gastrinoma:
Pancreatic gastrinoma:
Gastrinoma in the course of MEN-1/ZES:
In sporadic ZES, gastrin tumours occasionally occur in the liver (< 1%) and the liver/bile ducts [28, 33–35], which has also been recently demonstrated in patients with MEN-1/ZES [36].
Zollinger-Ellison syndrome should be suspected in patients with peptic ulcer disease [28] and the following:
The most common symptoms are the following: persistent abdominal pain (79–100%), nausea (38%), vomiting (24%), diarrhoea (30–75%), resolution with proton pump inhibitors (PPI) — which is a very characteristic feature — weight loss (in 12%), and gastrointestinal bleeding. The clinical symptoms do not differ between the pancreatic and duodenal gastrinoma location [28].
H. pylori infection is less common in patients with ZES (24–48%) compared to peptic ulcer disease which is not caused by excessive gastrin secretion (90%). For this reason, a negative H. pylori test result in patients with recurrent ulcer disease who do not take non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid should raise suspicion of gastrinoma [37].
The clinical course is aggressive in about 25% of patients with sporadic gastrinoma and in 15% of patients with ZES/MEN-1. The unfavourable prognostic factors are as follows [38]:
2.2.2. Other duodenal neuroendocrine neoplasms
The clinical symptoms of non-functioning DNENs include the following: abdominal pain (in 9–64% of patients), bleeding from the upper gastrointestinal tract (in 11–28%), jaundice (in 7–32%), anaemia (in 11–28% of patients), vomiting (4–8%), and duodenal stenosis (1%). Jaundice, bile duct dilatation, vomiting, and diarrhoea often accompany NENs located around the papilla of Vater [38]. Duodenal neuroendocrine neoplasms very rarely cause carcinoid syndrome. It is almost always an atypical syndrome (previously described in gastric carcinoids) [27].
Ectopic hormone secreting duodenal neuroendocrine neoplasms
In the literature, there are descriptions of DNEN cases accompanied by Cushing’s syndrome (5–15% of patients), with acromegaly (ectopic secretion of growth hormone-releasing hormone, GHRH), symptoms of insulinoma, glucagonoma, and polycythaemia vera [39].
2.2.3. Non-functioning duodenal neuroendocrine neoplasms
They do not cause hormonally dependent clinical symptoms, but the presence of gastrin, serotonin, calcitonin, and somatostatin in the tumour is detected in the immunohistochemistry. These neoplasms account for 70–98% of duodenal tumours. They include gangliocytic paragangliomas, which are most often located in the periampullary region. These are usually large tumours infiltrating the muscular layer, and their course is mild [40].
3. Diagnostics
3.1. Biochemical diagnostics
3.1.1. Gastric neuroendocrine neoplasms
In GNETs type 1, biochemical diagnostics includes determination of the concentration of the following parameters:
The determination of beta-human chorionic gonadotropin (beta-hCG) may be helpful in the diagnosis (its presence in tumour cell granularities, with possible ectopic secretion) [41].
To confirm the diagnosis of ZES in NET type 2 through biochemical diagnostics, the following steps are necessary:
ZES diagnostics
The diagnosis of ZES requires the determination of fasting hypergastrinaemia in the presence of hypersecretion of hydrochloric acid or low pH (pH < 2) of the gastric environment. In practice, the diagnostic process begins with determination of the fasting gastrin concentration in the serum, which is increased in 98% of patients with ZES. The identification of hypergastrinaemia is not sufficient for the diagnosis of ZES because there are other causes of increased gastrin concentration apart from gastrinoma [4, 43]:
In 40–60% of patients with ZES, the FSG value is less than 10 times the normal fasting gastrin concentration and is comparable to its concentration in the course of H. pylori infection. For this reason, among others, effective eradication of H. pylori is necessary before the implementation of diagnostics for gastrinoma [43].
Proton pump inhibitors and histamine H2 receptor antagonists increase the blood gastrin and CgA levels, so it was previously recommended that PPIs should be discontinued 10–14 days before scheduled blood gastrin measurements. In patients with suspected gastrinoma, PPI can be replaced with oral preparations of H2 receptor antagonists during this period, but it is advisable to discontinue them 48 hours before the examination [43]. Because sudden discontinuation of PPI in a patient with ZES may cause complications resulting from a rapid increase in hydrochloric acid secretion, currently some experts recommend carrying out diagnostics without discontinuing PPI or only with an attempt to reduce the dose. In doubtful cases, the patient should be referred to a reference centre, and if this is not possible, a cautious attempt can be made to discontinue PPI (in an asymptomatic patient with no active ulcer) and administer H2 receptor antagonists.
Gastrinoma is diagnosed when the fasting gastrin concentration is more than 10-fold higher and the gastric pH is less than 2. In most cases, increased gastrin levels are accompanied by increased serum CgA levels. A fasting blood test should be performed for gastrin determination. When measuring gastrin levels on consecutive days, less than 0.5% of patients with ZES have values within the reference range. On the other hand, gastric pH above 3 excludes the existence of gastrinoma with high probability. Because 20–25% of gastrinoma cases are part of MEN-1 syndrome, every patient with ZES should undergo screening for MEN-1 as described in the first part of the Recommendations — in the article Update of the diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours) [25].
In a small percentage of patients with clinical symptoms of ZES resulting from excessive secretion of gastric juice, the fasting gastrin concentration is normal. In this case, the plasma concentration of cholecystokinin (CCK) should be assessed because it may be caused by a CCK-secreting pancreatic neuroendocrine neoplasm (PanNEN) [44]. This situation may cause diagnostic difficulties because few laboratories are able to reliably assess the CCK concentration.
Biochemical diagnosis in type 3 NENs:
3.1.2. Duodenal neuroendocrine neoplasms
The biochemical diagnosis of duodenal endocrine neoplasms requires determination of the concentration of the following parameters:
Minimal consensus statement on biochemical tests
The minimal histopathological report regarding gastric NEN should include the following:
3.2. Pathomorphological diagnosis
3.2.1. Gastric neuroendocrine neoplasms
2019 WHO histopathological classification
The 2019 classification of gastric neuroendocrine neoplasms according to the WHO is presented in Table 2 [12].
|
Neuroendocrine tumour (NET) (8240/3) |
|
Histamine-producing enterochromaffin-like-cell (ECL-cell) NET Type 1 ECL-cell NET (8242/3) Type 2 ECL-cell NET (8242/3) Type 3 NET (8240/3) NET G1 (8240/3) NET G2 (8249/3) NET G3 (8249/3) Somatostatin-producing D-cell NET (8156/3) Gastrin-producing G-cell NET (8156/3) Serotonin-producing enterochromaffin-cell (EC-cell) NET (8156/3) |
|
Neuroendocrine carcinoma (NEC) (8246/3) Small cell neuroendocrine carcinoma (SCNEC) (8041/3) Large cell neuroendocrine carcinoma (LCNEC) (8013/3) |
|
Mixed neuroendocrine — non-neuroendocrine neoplasm (MiNEN) (8154/3) Mixed adenocarcinoma — NEC, mixed adenoneuroendocrine carcinoma (MANEC) (8244/3) Mixed adenocarcinoma — NET 2 (8244/3) |
The precursor to type 1 gastric NETs is linear or nodular ECL cell hyperplasia, which is defined as 2 groups of at least 5 ECL cells arranged in the gland, while micronodular hyperplasia is a tiny cluster of at least 5 ECL cells. Continued growth leads to the formation of a macroscopically visible nodule [45]. Larger tumours may invade the muscularis propria. Gastric NETs are composed of well-differentiated, monotonous cells without distinct nucleoli, with eosinophilic cytoplasm forming micro-lobular and/or trabecular systems. Mitotic activity and necrosis are almost always absent. The morphological features of type 1 ECL-cell NET overlap with types 2 and 3; hence, the appearance of the mucosa around the tumour is a significant differentiating feature [46].
The clinical and pathological characteristics of each type of NET, NEC, and MiNEN are presented in Table 3.
|
Feature |
Type 1 ECL-cell NET |
Type 1 ECL-cell NET |
Type 3 NET |
NEC |
MiNEN ADC/SCC-NEC |
MiNEN ADC/SCC-NET |
|
F:M |
0.4 |
1:1 |
2.8:1 |
2:1 |
2:1 |
Unknown |
|
Incidence |
80–90% |
5–7% |
10–15% |
6–20% |
20% |
|
|
Hypergastrinaemia |
Present |
Present |
Absent |
Absent |
Absent |
Absent |
|
Antral G-cell hyperplasia |
Present |
Absent |
Absent |
No data |
No data |
No data |
|
Acid secretion |
Low or absent |
High |
Normal |
Normal |
Normal |
Normal |
|
Surrounding mucosa |
Atrophic inflammation |
Parietal cell hyperplasia |
No specific lesions |
Chronic inflammation |
Chronic inflammation |
Chronic inflammation |
|
ECL-cell proliferation |
Present |
Present |
Absent |
Absent |
Absent |
Absent |
|
Degrees of Differentiation |
G1 |
G1 |
G1 (rare) |
G3 |
G in both compounds acc. to WHO 2019 |
G in both compounds acc. to WHO 2019 |
|
Staging |
I–II: 95% |
I–II:70% |
I–II: 38% |
No data |
No data |
No data |
|
Metastases |
1–3% |
10–30% |
50% |
70% |
55% |
Unknown |
|
5-year survival |
~100% |
60–90% |
< 50% |
10% |
10% |
Unknown |
In the literature, based on the description of individual cases, 2 provisional types of ECL-cell NET have been proposed: type 4 and type 5. They are not yet fully characterised in terms of clinical symptoms, pathology, and biochemistry [11]. Provisional type 4 NET includes tumours associated with hypergastrinaemia, achlorhydria, and parietal cell hyperplasia without the presence of gastrinoma or MEN-1 syndrome [47]. Provisional type 5 ECL-cell NET includes tumours arising in patients with moderate hypergastrinaemia treated with proton pump inhibitors for at least one year without autoimmune atrophic gastritis, gastrinoma, and MEN-1 syndrome. These tumours may resemble type 3 but have an excellent prognosis and do not require such an aggressive surgical approach, although they may metastasise to the lymph nodes in about 15% of cases [11].
Prognostic factors of gastric neuroendocrine neoplasms
The prognosis in gastric neuroendocrine neoplasms largely depends on the tumour type, degree of differentiation, and pathological stage of advancement [12]. Lower differentiation and higher severity are associated with higher mortality. The prognosis in type 1 ECL-cell NET is excellent, but in type 3 NET it is distinctly worse.
Gastric NECs and MiNENs are characterised by an unfavourable prognosis, with short survival times calculated in months [12]. Table 4 presents the pathological stages of gastric neuroendocrine neoplasms.
|
pT tumour feature |
|
|
TX |
Main tumour has not been assessed |
|
T0 |
Primary tumour absent |
|
T1 |
The tumour invades the lamina propria or the submucosa and is less than or equal to 1 cm in diameter |
|
T2 |
The tumour invades the muscularis propria or has a diameter greater than 1 cm |
|
T3 |
The tumour crosses the muscularis propria and spreads to the subserous tissues without crossing the sera |
|
T4 |
The tumour crosses the visceral peritoneum or invades other organs and structures |
|
Condition of the lymph nodes, pN |
|
|
NX |
Regional lymph nodes have not been assessed |
|
N0 |
No regional lymph node involvement |
|
N1 |
Regional lymph node involvement |
|
Distant metastases, pM |
|
|
M0 |
No distant metastases |
|
M1 |
The presence of distant metastases
|
The diagnostics of gastric NENs is based on the histopathological examination of the polyps after their endoscopic excision in the case of type 1 and 2 (NET G1/G2) or the surgical material following resection of the stomach and lymph nodes in the case of type 3 (NET G3, NEC) (Tab. 5).
|
Prognostic factor |
Examination method |
Is it assessed in routine diagnostics? |
|
Tumour size |
Macroscopic examination, measurement in cm |
Yes, obligatory |
|
Invasiveness Vessel invasion Nerve invasion Infiltration of tissues outside the stomach |
Microscopic assessment |
Yes, obligatory |
|
Necrosis |
Microscopic assessment |
Not required |
|
Grade of histological maturity |
Microscopic assessment, NET G1, NET G2, NET G3, NEC |
Yes, obligatory |
|
Surgical margins in biopsy material Deep Mucosal |
Microscopic assessment |
Yes, obligatory |
|
Surgical margins in biopsy material Proximal Distal Radial |
Macroscopic and microscopic examination |
Yes, obligatory |
|
Stage of advancement (Tab. 4) |
Microscopic assessment according to 2017 AJCC/UICC pTNM classification |
Yes, obligatory |
|
Number of mitotic figures per 2 mm² |
Microscopic assessment |
Yes, obligatory |
|
Ki-67 proliferation index |
Immunohistochemical examination |
Yes, obligatory |
|
Chromogranin A |
Immunohistochemical examination |
Yes, obligatory |
|
Synaptophysin |
Immunohistochemical examination |
Yes, obligatory |
|
Markers NSE, CD56, CDX2, serotonin |
Microscopic assessment |
No, conditionally |
|
Lesions in the gastric mucosa outside the tumour Presence/absence of atrophic inflammation Presence of ECL cell hypertrophy Other lesions |
Microscopic assessment |
Yes, obligatory |
|
Number and size of lymph nodes in the surgical specimen |
Macroscopic and microscopic examination |
Yes, obligatory |
Minimal consensus statement on pathomorphological examinations
3.2.2. Duodenal neuroendocrine neoplasms
2019 WHO histopathological classification
The 2019 WHO classification of duodenal neuroendocrine neoplasms is presented in Table 6.
|
Neuroendocrine tumour (NET) (8240/3) |
|
NET G1 (8240/3) NET G2 (8249/3) NET G3 (8249/3) Gastrinoma (8153/3) Somatostatinoma (8156/3) Extra-adrenal paraganglioma (8693/3) |
|
Neuroendocrine carcinoma (NEC) (8246/3) Small cell neuroendocrine carcinoma (SCNEC) (8041/3) Large cell neuroendocrine carcinoma (LCNEC) (8013/3) |
|
Mixed neuroendocrine — non-neuroendocrine neoplasm (MiNEN) (8154/3) |
The characteristics of the main histopathological subtypes are presented in Table 7.
|
Features |
Subtype |
||||
|
Gastrinoma |
Somatostatinoma |
Neuroendocrine tumour non-functional |
Gangliocytic paraganglioma |
Neuroendocrine carcinoma |
|
|
Patient’s age at the time of diagnosis |
5th decade |
5th decade |
6th decade |
6th decade |
7th decade |
|
Functional |
Always |
Rarely |
No |
No |
Rarely (paraneoplastic syndromes) |
|
Hereditary predisposition syndromes |
MEN-1 (< 50%) |
Neurofibromatosis type 1, Pacak-Zhuang syndrome (rarely) |
MEN-1 (rarely) |
Neurofibromatosis type 1 (rarely) |
no |
|
Location |
1 part of the duodenum |
Bulb region |
1 part of the duodenum |
Bulb region |
Bulb region |
|
Microscopic picture |
Trabecular |
Tubulo-lobular/glandular |
Nest/trabecular |
Triphase: paraganglioid + spindle cells + ganglion-like cells |
Solid/diffused (poorly differentiated) |
|
Tumour size > 1 cm |
Rarely |
Common |
Rarely |
Common |
Common |
|
Metastases to lymph nodes |
Common |
Common |
Rarely |
Rarely |
Very common |
|
Distant metastases |
Rarely |
Rarely |
Rarely |
Extremely rare |
Common |
|
Prognosis after resection |
Good |
Good |
Good |
Good |
Unfavourable |
Prognostic factors of duodenal neuroendocrine neoplasms
Duodenal neuroendocrine tumours of less than 2 cm in diameter or limited to the duodenal bulb have a better prognosis [23]. NEN metastases to the lymph nodes do not affect the prognosis or disease-free survival [51]. After duodenal NET resection, the liver is the most common site of metastases [52].
Gangliocytic paraganglioma is usually mild. However, it has been observed that this type of tumour with a diameter greater than 2 cm spreads to regional lymph nodes [53].
Table 8 presents the pathological stages of duodenal neuroendocrine neoplasms.
|
pT tumour feature |
|
|
TX |
Main tumour has not been assessed |
|
T1 |
The tumour invades the lamina propria or the submucosa and is less than or equal to 1 cm in diameter, limited to the duodenal bulb sphincter |
|
T2 |
The tumour infiltrates the duodenal bulb sphincter to the submucosa or the muscularis propria, or tumour with a diameter of more than 1 cm in the case of bulbar tumours |
|
T3 |
The tumour invades the pancreas or peripancreatic adipose tissue |
|
T4 |
The tumour infiltrates the visceral peritoneum or invades other organs and structures |
|
Condition of the lymph nodes, pN |
|
|
NX |
Regional lymph nodes have not been assessed |
|
N0 |
No regional lymph node involvement |
|
N1 |
Regional lymph node involvement |
|
Distant metastases, pM |
|
|
M0 |
No distant metastases |
|
M1 |
The presence of distant metastases
|
Gastrin-secreting neuroendocrine tumours associated with Zollinger-Ellison syndrome have a less favourable prognosis and metastasise to a larger extent than non-secreting tumours [54].
Details of the histopathological report on the assessment of endoscopic and surgical specimens of duodenal neuroendocrine neoplasms are presented in Table 9 [12].
|
Prognostic factor |
Examination method |
Evaluated in routine diagnostics? |
|
Tumour size |
Macroscopic examination, measurement in cm |
Yes, obligatory |
|
Invasiveness Vessel invasion Nerve invasion Infiltration of tissues outside the duodenum |
Microscopic assessment |
Yes, obligatory |
|
Necrosis |
Microscopic assessment |
Not required |
|
Grade of histological maturity |
Microscopic assessment, NET G1, NET G2, NET G3, NEC |
Yes, obligatory |
|
Surgical margins in biopsy material Deep Mucosal |
Microscopic assessment |
Yes, obligatory |
|
Surgical margins in biopsy material Proximal Distal Radial |
Macroscopic and microscopic examination |
Yes, obligatory |
|
Stage of advancement |
Microscopic assessment according to 2017 AJCC/UICC pTNM classification |
Yes, obligatory |
|
Number of mitotic figures per 2 mm² |
Microscopic assessment |
Yes, obligatory |
|
Ki-67 proliferation index |
Immunohistochemical examination |
Yes, obligatory |
|
Chromogranin A |
Immunohistochemical examination |
Yes, obligatory |
|
Synaptophysin |
Immunohistochemical examination |
Yes, obligatory |
|
Markers: NSE, CD56, CDX2, gastrin, somatostatin |
Immunohistochemical examination |
No, conditionally |
|
S-100 in gangliocyte paraganglioma |
Immunohistochemical examination |
Yes, obligatory |
|
Number and size of lymph nodes in the surgical specimen |
Macroscopic and microscopic examination |
Yes, obligatory |
|
Presence of other changes in the duodenal wall |
Macroscopic and microscopic examination |
Yes, obligatory |
Minimal consensus statement on pathomorphological examinations
3.3. Location diagnostics of gastric and duodenal neuroendocrine neoplasms
3.3.1 Gastric neuroendocrine neoplasms
Gastric neuroendocrine neoplasms type 1
Type 1 gastric neuroendocrine neoplasms are most often small, multiple polypoid lesions, usually up to 1–2 cm, occurring in the course of atrophic gastritis. The examination of choice in this case is endoscopy with biopsy or removal of the largest lesions followed by histopathological examination. Additionally, 2 specimens should be collected from the pre-antral part and 4 specimens from the fundus/body of the stomach for histopathological examination [5]. It is also recommended that specimens be collected from the pre-antral part and body of the stomach for a rapid urease test.
If the lesions are larger than 1–2 cm and/or multiple, endoscopic ultrasonography (EUS) should be performed prior to a possible polypectomy to assess the depth of the intramural infiltrate [16].
In some cases, to determine the stage of the disease, contrast-enhanced computed tomography (CT) after the stomach is fully filled with water may be considered as an initial examination [55].
Gastric neuroendocrine neoplasms type 2
As in the case of type 1 lesions, they are usually small (< 1–2 cm), often multiple, polypoid in nature, and located in the fundus and body of the stomach. As they develop in the course of gastrinoma, they may be associated with other lesions, such as severe reflux oesophagitis or thickening of the gastric mucosal folds. Endoscopic examination of the upper gastrointestinal tract with biopsy and/or removal of the entire lesion is of primary diagnostic importance, and in the case of major and/or multiple lesions, specimens from the lesion should be collected for histopathological examination including 2 specimens from the antrum and 4 specimens from the fundus/body of the stomach and tests performed to determine H. pylori infection [5].
In the case of lesions exceeding 1–2 cm and/or multiple lesions, EUS should be performed to assess the depth of the intramural infiltration [16, 55].
As in the case of type 1 lesions, in order to exclude metastases, further consideration should be given to performing 3-phase computed tomography as the initial (baseline) examination and then every 6 months or, depending on the clinical symptoms, as a follow-up examination during clinical follow-up [56].
Radioisotope somatostatin receptor imaging (SRI) should be performed to assess the stage of the disease and to monitor its course. This examination is required for qualification for peptide receptor radionuclide therapy with isotope-labelled somatostatin analogues (PRRT) and for the anti-proliferative treatment with somatostatin analogue (SSA) [1, 3, 9].
Gastric neuroendocrine neoplasms type 3 (sporadic)
The lesions are usually located in the fundus and body of the stomach, single, large, over 2 cm in diameter, with ulcerations on the surface. An endoscopic examination of the upper gastrointestinal tract should be performed with the collection of specimens from the lesion in order to establish the diagnosis.
Endoscopic ultrasonography can be used to assess the depth of the intramural infiltration and the presence of metastases to regional lymph nodes [5].
Transabdominal ultrasonography (US) of the abdominal cavity enables the identification of metastases to the liver and lymph nodes under optimal conditions for examining the abdominal cavity or superficial nodes and other tissues affected by the neoplastic process.
Three-phase CT examination after maximal filling of the stomach with water and after intravenous administration of a contrast agent according to the protocol as in the case of type 1 gastric neuroendocrine neoplasms should be performed every time as an initial (baseline) examination for assessment the stage of the tumour. Follow-up examination usually should be performed every 3–6 months or depending on the histopathological diagnosis, baseline staging, and ongoing active anti-neoplastic treatment in the case of advanced, unresectable neoplasms, with or without progression, and depending on the coexisting symptoms of local advancement or clinical and biochemical symptoms, such as carcinoid syndrome [56, 57].
If it is not possible to perform CT (allergy to iodine agents is not an absolute contraindication to the examination, which can be performed after appropriate premedication), magnetic resonance imaging (MRI) of the abdominal cavity should be performed before and after intravenous administration of the contrast medium. The diffusion-weighted imaging (DWI) and 3D, T1 sequence before and after contrast administration using a dynamic test is particularly useful in the assessment of metastatic lesions in the liver [57, 58].
In radioisotope diagnostics, both SRI and positron emission tomography/computed tomography (PET/CT) examinations with radiolabelled 18F-fluorodeoxyglucose ([18F]FDG) [1, 3, 9] should be performed (currently, the examination with [18F]FDG is not reimbursed for this indication in Poland).
Magnetic resonance imaging of the spine or bone scintigraphy with technetium 99m-methyl diphosphonate (99mTc MDP) should be performed in the case of clinical suspicion of bone metastases or metastases visible in CT examination [59].
3.3.2. Duodenal neuroendocrine neoplasms
SRI should be performed to assess the stage of the disease and to monitor its course. This examination is required to qualify a patient for PRRT and for anti-proliferative treatment with SSA [1, 3, 9].
Magnetic resonance imaging of the spine or bone scintigraphy with 99mTc-MDP should be performed in the case of clinical suspicion of bone metastases or metastases visible in CT examination [16].
Minimal consensus statement on localisation examinations
4. Treatment
4.1. Endoscopic and surgical treatment
4.1.1. Gastric neuroendocrine neoplasms (type 1–3)
Treatment of gastric NETs depends on the clinical and pathogenetic type.
Type 1
In type 1 GNETs, conservative management is preferred in most cases. The eligibility criteria for surgical treatment include the size of the tumour and the depth of invasion into the muscularis propria [60]. The principles of management of individual types of gastric NETs are presented in Table 1 [5]:
Type 2
Because type 2 GNETs occur in the course of gastrinoma in patients with MEN-1 or, much less frequently, in the sporadic form, surgical treatment includes gastrinoma resection [5, 61]. The principles of endoscopic treatment are based on the principles of GNET type 1 treatment; however, due to the coexistence of gastrinoma, each case should be considered individually by an experienced team of experts [5, 61, 62].
Type 3
Type 3 GNETs should be treated surgically by performing a partial or complete gastrectomy with the removal of lymph nodes [5, 60, 62]. According to some authors, in selected cases (tumour < 2 cm, limited to the submucosa, no nodal or vascular invasion, no other malignancy) resection may be performed endoscopically [5, 63, 64].
4.1.2. Duodenal neuroendocrine neoplasms
For tumours located outside the papilla and < 1 cm in size, without invasion confined to the submucosa, in the absence of suspicion of distant and lymph node metastases, endoscopic treatment is recommended [5, 61].
The treatment of 1–2 cm large tumours is controversial [61, 62]. In this group, endoscopic resection is considered (the preferred method is ESD, used in the absence of suspicion of metastatic lymph nodes and other malignant features) or surgical resection (the location is very important) [61, 62].
Tumours > 2 cm in size, tumours with malignant features (metastatic lymph nodes, invasion beyond the submucosa), and peripapillary tumours require surgical resection. These include local tumour resection or pancreaticoduodenectomy with lymph node removal [60].
In the case of DNET with liver metastases, if surgical resection or ablation of the metastases is possible, radical duodenal surgery should be considered [62, 64].
4.1.3. Gastrinoma
A detailed description of gastrinoma treatment is included in the article: Pancreatic neuroendocrine neoplasms — update of the diagnostic and therapeutic guidelines (recommended by the Polish Network of Neuroendocrine Tumours) [65].
Because sporadic gastrinomas are most often malignant tumours with lymph node involvement, radical surgical removal of the lesions is recommended. The scope of the procedures depends on the location and size of the tumour.
Since these tumours are often multiple and occur in the duodenum, a thorough examination of the abdominal cavity, especially the pancreatic-duodenal area, using intraoperative ultrasound is recommended during surgery [17, 66, 67]. Currently, routine duodenotomy is not recommended [67].
In MEN-1 syndrome, in the case of gastrinomas with diameter ≤ 2 cm, surgical treatment is not recommended as standard treatment. Surgical treatment is recommended when the tumour is > 2 cm in size [66–68].
Minimal consensus statement on endoscopic/surgical treatment
4.2. Pharmacological treatment
4.2.1. Gastric neuroendocrine neoplasms
GNET type 1
As a rule, patients with type 1 gastric NETs do not require pharmacological treatment, but in the case of H. pylori infection, eradication therapy should be started [40]. Sometimes individual attempts of treatment with somatostatin analogues are made because they inhibit hypergastrinaemia, prevent the proliferation of ECL cells, and lead to tumour regression [5]. However, it should be emphasised that SSAs were not compared with follow-up strategies and therefore cannot be recommended for use in the early stages of the disease. Somatostatin analogues may be useful in the treatment of patients with multiple minor lesions that are difficult to remove endoscopically [69]. Their use may be an appropriate option for patients with metastatic disease and proven somatostatin receptor type 2 (SSTR2) expression, as well as a low Ki-67 value. Non-controlled studies have demonstrated that the gastrin and cholecystokinin receptor antagonist netazepide has antiproliferative properties in GNENs [70, 71]. Its use cannot be universally recommended either, and it is necessary to study this drug in randomised controlled trials.
GNET type 2
Zollinger-Ellison syndrome
ZES therapy is aimed at the following:
The excessive secretion of gastric acid in gastrinomas must be pharmacologically controlled in all patients with gastrinomas in order to prevent complications.
Proton-pump inhibitors are the treatment of choice. All available PPIs (omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole) show similar efficacy. Once or twice daily oral administration of PPIs is effective in most patients. According to the available guidelines, high-dose PPIs (3–4 times the standard dose) are the drugs of choice [31, 38]. The recommended starting dose in sporadic forms of ZES is 60 mg once a day for omeprazole, 80 mg a day for pantoprazole, 60 mg once a day for rabeprazole, and 40 mg twice a day for esomeprazole. In patients with complications of ZES (MEN-1 with hypercalcaemia, severe symptoms of gastro-oesophageal reflux disease [GERD] preceding Billroth II resection) higher doses of antisecretory drugs are used (daily doses for omeprazole are up to 120 mg, pantoprazole 160 mg, rabeprazole up to 120 mg, esomeprazole up to 160 mg — each of them in 2 divided doses) [14]. In special cases, PPI therapy can be started by administering the drug via the intravenous route (e.g. pantoprazole 80 mg every 8 h) [72]. The intravenous route is also recommended when drugs cannot be taken orally. Good control of symptoms resulting from excess hydrochloric acid secretion obtained through PPI therapy enables surgical intervention [73]. When surgery is not possible, PPI therapy should be continued indefinitely. It should be emphasised that in patients in whom gastrinoma was successfully resected, the use of PPIs may still be necessary, because in most of them, despite surgery, hypersecretion is still observed [74]. Discontinuation of PPI treatment and, consequently, rebound hypersecretion may lead to severe complications such as gastrointestinal perforation and stricture [75]. At the same time, it is worth noting that during the follow-up, PPI doses can be reduced in some patients [71].
The efficacy and favourable safety profile of long-term therapy with high doses of PPIs has been confirmed in the conducted studies [76]. In patients with H. pylori infection, eradication therapy should be applied [40].
The results of the latest studies [77–79] do not confirm the previous reports on the influence of long-term PPI treatment on the concentration of vitamin B12 and vitamin D3. In recent years, however, there have been reports suggesting an increased risk of Clostridioides difficile infection and community-acquired pneumonia in patients taking PPI.
Histamine H2 receptor antagonists can also be used in patients with ZES. It should be kept in mind that when using H2 receptor inhibitors, a shorter period of drug action is observed compared to PPI as well as the phenomenon of tachyphylaxis, which makes these preparations second-line drugs. Patients with gastrinoma require higher and more frequent doses of histamine H2-receptor antagonists than patients with idiopathic peptic ulcer disease. It is also possible to use it in high doses by continuous intravenous infusion.
Long-acting somatostatin analogues are not first-line drugs and should only be used in cases of PPI-resistant malignant gastrinomas. Studies are currently underway on the efficacy of treating patients with GNET type 2 with a gastrin-cholecystokinin antagonist (netazepide).
In MEN-1 syndrome, surgical parathyroid resection in primary hyperparathyroidism reduces the excessive secretion of hydrochloric acid [38].
In light of the results of the RADIANT-4 study, in patients with advanced non-functional NETs G1/G2, after progression within 6 months, the recommended treatment is everolimus (currently not reimbursed in Poland) [80].
GNEN type
Gastric neuroendocrine tumours and gastric neuroendocrine carcinomas
There are no studies on perioperative treatment of resectable gastric NETs G3 and NECs; therefore, each case should be considered individually at a multidisciplinary meeting. In some NEC cases, preoperative treatment may be considered [81].
Despite ambiguous reports on adjuvant treatment after radical surgery, in the case of NETs G3 and NECs with a high proliferative index (Ki-67 > 55%), adjuvant treatment should be considered, and in some cases of SCNECs, combination therapy may be considered — radiochemotherapy or sequential treatment — chemotherapy followed by radiotherapy as an analogy to the treatment of small cell lung cancer [82–85].
Chemotherapy is the treatment of choice in gastric NET G3 or NEC in unresectable, locally advanced, or generalised disease. When qualifying patients for systemic treatment, it is necessary to take into account the patient’s performance status, as well as organ capacity and comorbidities [37].
4.2.2. Duodenal neuroendocrine neoplasms
The treatment of gastrinoma should be carried out in the same way as in type 2 gastric NETs, while in the case of other tumours — especially disseminated ones with accompanying carcinoid syndrome — treatment should be the same as in gastric tumours at the same stage of advancement.
In the treatment of poorly differentiated duodenal neuroendocrine neoplasms, systemic therapy should be used, taking into account the patient’s performance status and the state of organ capacity [37].
Minimal consensus statement on pharmacotherapy
4.3. Radioisotope therapy
4.3.1. Gastric and duodenal neuroendocrine neoplasms
Peptide receptor radionuclide therapy is a form of palliative treatment that is rarely used in gastric and duodenal NETs [60, 86–90]. Eligibility for treatment is established according to the rules presented in the first part of the Recommendations — in the article Update of the diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours) [25].
Information on the use of PRRT in gastric and duodenal NETs is sparse, and the literature data includes only single cases [60, 86–90]. PRRT in both gastric NETs and duodenal NETs can be used in the case of advanced, unresectable, and progressive tumours, after failure of previous treatment [91].
In NETs with clinical symptoms of carcinoid syndrome (gastric) and ZES (gastric and duodenal), in which symptoms cannot be controlled by other types of treatment, PRRT should be considered beforehand, often in combination with “cold” somatostatin analogues [91–94].
In the case of bone metastases and concomitant clinical symptoms, palliative radioisotope therapy (89Sr, 153Sm) should be considered, after positive verification in bone scintigraphy with [99mTc]Tc-MDP [92].
Conclusions
Radioisotope therapy — PRRT in gastric and duodenal NETs –– should be considered in NETs G1/G2 and in selected cases of NETs G3 with disease progression in the course of current therapy or intolerance to previous treatment, provided that high receptor expression is confirmed in SRI examination.
Minimal consensus statement on radioisotope therapy
5. Follow-up
5.1 Principles of biochemical monitoring
Stomach:
Duodenum:
Gastrinoma:
5.2. Principles of imaging monitoring
Stomach:
Duodenum:
In some cases, if the expression of somatostatin receptors is confirmed, radioisotope SRI imaging may be useful in monitoring.
Evidence quality and the strength of recommendations
#Evidence quality and the strength of recommendations has been established on the basis of the following tables according to ESMO and NCCN [95, 96] (Supplementary File — Tab. S1 and S2).
Conflict of interest
For the Conflict of Interest Statement, please see the Supplementary File.
Author contributions
All authors contributed to the idea, gathered the information, interpreted the data, and wrote and accepted the final version of the manuscript.
