Neuroendocrine neoplasms (NENs) of the small intestine (SINENs) and of the appendix (ANENs) are the most common sites of NENs occurrence in the human body [1–4]. SINENs are usually small in size, mainly located in the distal part of the small intestine, close to the ileocecal valve, and one-third are multifocal. Most of them are slow-growing, well-differentiated tumours (NETs G1/G2); rarely, they are NETs G3 or poorly differentiated neuroendocrine carcinomas (NECs). However, SINENs are often diagnosed in the period of disease generalisation with metastases in the lymph nodes and the liver, less frequently to the peritoneum, bone and lung. Compared to other gastrointestinal NENs in the period at the stage of disease generalisation, SINENs have a better prognosis. ANENs rarely metastasise, are mostly well-differentiated, and have a very good prognosis after surgery. From the clinical point of view, SINENs are divided into non-functional neoplasms and tumours secreting various bioactive substances causing symptoms of carcinoid syndrome [5]. Around 20–30 percent of patients with SINENs may develop heart valve disease (carcinoid heart disease, CHR or Hedinger syndrome) following long term exposure to high levels of serotonin. This work presents the updated Polish recommendations for the management of patients with SINENs and ANENs [6].
1. Epidemiology, prognosis, and survival
Over the last 30 years, a significant increase in the incidence of gastrointestinal NENs, including SINENs, has been observed. Currently, the incidence of SINENs is estimated at ~1.2/100,000 and ANENs at ~0.95/100,000 [7–11]. The risk factors for SINENs remain poorly understood; the relationship between the occurrence of neoplasms and a family history of cancer, smoking, and gallbladder disease has been described. It should also be noted that SINENs may coexist with other neoplasms, such as gastrointestinal adenocarcinoma or breast cancer.
As in other tumours, the prognosis in SINENs depends mainly on its stage [S, based on the tumor–node–metastasis (TNM) classification] and grade (G, based on the proliferation index Ki-67 value). The median survival ranges from 70 months (advanced disease with distant metastases) to 170 months (locoregional stage) and from 30 months (NETs G3) to 160 months (NETs G1) [7–11]. The results of multivariate analyses also suggest that older age, World Health Organisation (WHO) performance status, increased daily excretion of 5-hydroxyindoleacetic acid (5-HIAA), increased concentration of chromogranin A (CgA) > 6× upper limit of normal, carcinoid heart disease, and biochemical features of liver damage are independently related to patient survival [12,13]. In addition, there are reports that the prognosis is better following primary tumour resection [14].
2. Clinical characteristics
Clinical symptoms of SINENs may be related to the tumour size and/or the secreted bioactive substances. However, the diagnosis of both functional and non-functional SINENs is usually delayed by about 5 years [1, 2,15]. SINENs are often diagnosed accidentally in the form of metastatic lesions in the liver and lymph nodes, and less often during colonoscopy in the form of a tumour of the terminal ileum [16].
2.1. Symptoms of functional SINENs — carcinoid syndrome
Carcinoid syndrome occurs in approximately 20–30% of SINENs patients with distant metastases [17, 18]. Carcinoid syndrome is caused by the excessive secretion of serotonin substances and other biologically active compounds by the tumour (including tachykinin, prostaglandins, histamine). Symptoms occur when serotonin and other are secreted directly into the systemic circulation; therefore, the most common symptoms of carcinoid syndrome occur when NEN metastases are present in the liver (approx. 95% of cases). Carcinoid syndrome not only significantly affects the deterioration of the quality of life in patients with SINENs, but also adversely affects survival.
The clinical symptoms of carcinoid syndrome are:
The main symptoms of carcinoid syndrome include flush and diarrhoea, occurring in about 60–85% of patients. In SINENs (classical carcinoid syndrome), a pale pink to red flush occurs across the face and upper chest, lasting up to several minutes. The factors that trigger the occurrence of carcinoid syndrome include the following: alcohol, spicy or tyramine-rich foods (e.g. cheese, red wine, avocado, chocolate), emotional stress, and medications (serotonin reuptake inhibitors). Diarrhoea is caused by an increase in intestinal motility. Serotonin is considered the key mediator of diarrhoea. It should be noted that carcinoid syndrome is not the only possible cause of diarrhoea in patients with NENs, and appropriate diagnosis is always indicated [19, 20].
One of the main causes of death in patients with carcinoid syndrome is CHD, which may affect 20–40% of patients [21, 22]. Development of CHD is associated with the excessive secretion of serotonin [23, 24]. CHD is mainly characterised by lamellar thickening of fibrous tissue on the right-sided valves, leading to insufficiency of the tricuspid valve (the most common defect) and stenosis of the pulmonary valve. The clinical symptoms of CHD are initially poorly defined, and subsequently there are symptoms of progressive right heart failure. The gold standard in the diagnosis of CHD is echocardiography, which should be performed in patients with increased daily excretion of 5-hydroxyindoleacetic acid and an increased concentration of N-terminal-pro-B-type natriuretic propeptide (NT-proBNP).
Carcinoid crisis is a very rare, life-threatening acute complication caused by the sudden release of biologically active substances into the systemic circulation. The symptoms include the following: prolonged skin redness, severe diarrhoea or vomiting, wheezing, low blood pressure, arrhythmias, nervous system disorders, dehydration, shock or acute renal failure. A breakthrough may occur spontaneously, in the course of infection and in particular as a result of medical procedures like general embolisation and surgery. Other procedures, e.g. liver peptide receptor radionuclide therapy with isotope-labelled somatostatin analogues (PRRT, currently known as targeted radioligand therapy, RLT), may induce carcinoid crisis too, less frequently endoscopy and chemotherapy.
2.2. Symptoms of non-functional SINENs
The most common symptom is abdominal discomfort or non-specific pain in the abdomen may last for months or even years [25]. Pain is caused by local, usually slow, tumour growth that may lead to intestinal obstruction because of enlargement of its dimensions in or out of the intestinal lumen. Moreover, the abdominal pain may be caused by the desmoplastic reaction in mesenteric lymph nodes and subsequent vascular congestions or encasement. Pertioneal carcinomatosis may lead to adhesions. These symptoms may also occur with functional NET. In contrast, perforation and gastrointestinal bleeding are rare symptoms of SINENs.
2.3. Symptoms of ANENs
More than half of ANENs cases are detected accidentally after appendectomy due to appendicitis. Most ANENs are detected at an early stage (tumours < 1 cm, no lymph node metastases), which contributes to a favourable prognosis [26].
3. Diagnostics
3.1. Laboratory diagnostics
In the biochemical diagnostics of SINENs and ANENs, it is useful to determine the plasma or serum concentration of chromogranin A - it is a widely available and cheap biomarker, but with significant limitations in terms of sensitivity and specificity (determination and interpretation of the results are described in: Update of the diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours) [27, 28]. Increased CgA concentration (> 6× upper limit of normal) is an indicator of an unfavourable prognosis [12, 13, 29, 30]. Serum determination of neuron-specific enolase (NSE) may be useful in the diagnosis and follow up of SINETs G3 and SINECs. The results of research on new biomarkers indicate the possibility of using molecular tests in the diagnosis and monitoring of NENs [31, 32].
In patients with carcinoid syndrome, the assessment of urinary 5-HIAA excretion [33] is a sensitive tumour indicator, which is useful in the diagnosis and monitoring of the course of the disease or treatment. The sensitivity and specificity of 5-HIAA determination to confirm carcinoid syndrome is approximately 70–100% and 85–90%, respectively. Increased excretion of 5-HIAA is an indicator of an unfavourable prognosis for SINEN [12, 13, 29, 34]. Determination of the blood serotonin level is currently not recommended in the diagnosis of carcinoid syndrome, but the measurement of 5-HIAA in plasma is increasingly used world wide.
5-HIAA and NT-proBNP are useful in the diagnosis and monitoring of CHD. In patients with carcinoid syndrome, a NT-proBNP concentration higher than 260 pg/mL (31 pmol/L) may indicate CHD [22].
The possibility of using other tests in the diagnosis and monitoring of the course of the disease and treatment effects is described in the general part concerning the diagnosis of gastrointestinal neuroendocrine neoplasms [28].
Minimal consensus statement on biochemical tests
Measurement of:
3.2. Imaging and endoscopic diagnostics
3.2.1. Primary site location
Diagnostics of small intestinal NETs may include enterography/computed tomography (CT) or magnetic resonance imaging (MRI) enterography/enteroclysis, which allows location of the primary site in the small intestine in approximately 90–97% of patients (Tab. 1) [35–38]. Follow-up examinations of small intestinal tumours should be performed using CT or MRI enterography, while MRI enteroclysis should be performed in patients with clinical suspicion of a tumour of the small intestine and negative MRI/CT enterography [6, 35, 39–44].
|
MRI enterography: The examination is performed after patient preparation: provides biphasic improved MRI soft tissue contrast: (low signal intensity on T1-weighted images, and high signal intensity on T2-weighted images) |
|
|
CT enteroclysis: after jejunal catheterisation, negative contrast (as above) administered using an automatic pump 80–120 mL/minute — possibly performed as a complement to enterography |
|
|
Sequences and planes necessary for examining the intestines |
Features |
|
T2-weighted in the axial and frontal planes, with and without fat saturation |
Assessment of the lumen and intestinal wall in both planes — image correlation facilitates the assessment of small intramural nodules and/or thickening of the intestinal wall |
|
3D T1 Fat Sat before contrast in the axial and frontal planes |
Baseline images for comparison with the dynamic examination after contrast administration |
|
3D T1 Fat Sat after intravenous contrast administration (layer of up to 3 mm) |
In the arterial (30 s), intestinal (45 s), and portal (70–90 s) phases, to assess the degree of enhancement of intramural nodules, metastases to local lymph nodes and the liver |
|
DWI with ADC maps in the transverse plane, b value: 0.100.1000 |
For differentiation between benign and malignant lesions and for the assessment of early metastatic lesions in the liver |
Ultrasound
Ultrasound (US) has limited application in the detection of the primary tumour because it is a subjective examination and its result depends on the quality of the apparatus. Abdominal US with the use of high-frequency probes enables the detection of the primary tumour only in individual cases. However, possible secondary lesions in the mesentery should be considered, such as enlarged hypoechoic lymph nodes and mesenteric fibrosis/thickening, which may be more visible than a small primary lesion hidden in the intestinal wall. Ultrasound may be used in the initial diagnosis of patients in whom NENs are suspected [45]. Intraoperative US is useful when exploring the intestinal structures in search of proliferative lesions.
Endoscopic diagnostics
Endoscopic diagnostics of the small intestine is usually undertaken in search of a primary tumour in the presence of metastases with an unknown primary site (often much larger than the primary lesion), uncharacteristic symptoms from the abdominal cavity, or when looking for the cause of gastrointestinal bleeding [39, 46]. The widespread use of colonoscopy, including screening colonoscopy, gives hope for early detection of small intestine lesions. Direct visualisation of NENs located in the small intestine is possible during colonoscopy, when a nodular lesion protrudes through the ileocecal valve into the lumen of the caecum (these are very rare situations), but above all during the routine assessment of the distal part of the small intestine. However, it should be kept in mind that the extent of ileocolonoscopy is limited to the distal ileum and does not provide a complete visualisation of the entire small intestine. Colonoscopy is important to exclude a synchronous neoplastic disease, and it enables endoscopic treatment [47]. In contrast to other locations of gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) lesions, endoscopic ultrasound (EUS) is not applicable in the diagnosis of lesions within the small intestine [39].
Video capsule endoscopy
Video capsule endoscopy (VCE) and balloon-assisted enteroscopy or spiral enteroscopy can be used to directly assess the jejunal and ileal mucosa, but these procedures are not widespread. A complete assessment of the small intestine is obtained in approximately 80% of patients, and the overall diagnostic efficiency of the examination is approximately 55% [48–50]. The sensitivity of VCE in the diagnosis of neuroendocrine tumours is relatively low, i.e. 29–37.5% vs. 50–92% as compared to CT enterography [49–51]. It should be emphasised that, due to the secreted growth factors leading to mesenteric desmoplastic reactions, SINENs often cause significant obstruction, which is an absolute contraindication to capsule endoscopy due to the risk of capsule entrapment [52]. However, it is not always possible to exclude the presence of small intestine obstruction before the procedure. Another disadvantage of VCE is the lack of precise determination of the lesion location [53] as well as the risk of false negative results in the case of small submucosal nodules, the risk of incomplete assessment in patients with multifocal disease and the risk of false positive results. Balloon-assisted enteroscopy and spiral enteroscopy avoid of this disadvantage, but firstly, the availability of these procedures is very limited outside of reference centres, and secondly, the procedure is time consuming (up to 2 hours). The quality depends on the experience of the operator and, therefore, the diagnostic efficiency is not very high [54, 57]. Of course, enteroscopy, if available, not only provides the possibility of detecting small intestine lesions, but also allows endoscopic treatment in selected cases [57, 58]. Generally, however, both of the above-discussed procedures (VCE and endoscopic enteroscopy) play a very limited role in the diagnosis of small intestine neuroendocrine tumours [59–62].
Radioisotope diagnostics
Radioisotope diagnostics with the use of radiolabelled somatostatin analogues (SRI):
3.2.2. Assessment of disease advancement and response to treatment
Multi-phase, usually three-phase CT or MRI examinations after intravenous administration of a contrast agent, filling the intestinal lumen with a negative contrast agent, and SRI enable monitoring of the disease course and assessment of the response to treatment.
Minimal consensus statement on imaging and endoscopic examinations
3.3. Histopathological diagnosis
3.3.1. NENs of the small intestine
WHO classification of SINEN from 2019 [67] is presented in Table 2.
|
Neuroendocrine tumour (NET) (8240/3) Neuroendocrine tumour G1 (8240/3) Neuroendocrine tumour G2 (8249/3) Neuroendocrine tumour G3 (8249/3) |
|
Neuroendocrine carcinoma (NEC) (8246/3) |
|
Mixed neuroendocrine — non-neuroendocrine neoplasm (MiNEN) (8154/3) |
The vast majority of SINENs are neuroendocrine tumours. SINETs most commonly occur in the distal ileum; jejunal NETs and NETs in Meckel’s diverticulum are rare [7, 68]. SINETs may develop as multiple lesions (multifocal SINETs). SINETs are biologically and clinically different from duodenal NETs [67, 69, 70].
SINETs usually demonstrate features of enterochromaffin cells. Clinical symptoms may be the consequence of the secretion of mediators (including serotonin) by tumour cells [67, 71]. Rare cases of SINETs without features of enterochromaffin-cell differentiation are gastrin-producing G1 tumours of the jejunum, or large G2/G3 tumours with high clinical aggressiveness, without secretory function [72]. SINECs are extremely rare [67].
Histopathological examination taking into account tumour grade and immunohistochemical tests (needed for confirmation of the neuroendocrine differentiation of the neoplasm and for assessment of tumour grade) are necessary for the unequivocal diagnosis of a neuroendocrine neoplasm [68]. Tumour grade and stage are independent prognostic factors in gastrointestinal neuroendocrine neoplasms [68].
Prognostic factors in SINETs
Tumour diameter, local tumour stage, and tumour grade are risk factors of distant metastases in SINETs. Multifocality of SINETs may be an unfavourable prognostic factor [73], but not all investigators have confirmed the relationship between the number of primary tumours and the long-term prognosis [74, 75]. The tumour stage has prognostic significance in SINETs [76]. The presence of neoplastic deposits in the mesenteric adipose tissue is an unfavourable prognostic factor in SINETs [77]. The presence of metastatic lesions in the serous membrane (i.e. peritoneum) is an unfavourable prognostic factor in SINETs [78]. Up to 50% of SINETs patients have liver metastases at diagnosis [67, 70].
The stage of SINET in resection specimens should be described based on the 2017 American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) classification (Tab. 3) [69]. It should be noted that this classification was not intended to describe duodenal NET or SINEC; such cases should be described based on separate classifications for duodenal NET and for small intestine carcinomas, respectively.
|
Tumour stage |
Diagnostic criterion |
|
T — primary tumour* |
|
|
pTX |
Primary tumour cannot be assessed |
|
pT0 |
No evidence of primary tumour |
|
pT1 |
The tumour infiltrates the lamina propria or the submucosa, and its diameter does not exceed 1 cm |
|
pT2 |
The tumour infiltrates the muscularis propria or its diameter exceeds 1 cm |
|
pT3 |
The tumour infiltrates the muscularis propria and extends into the subserous tissue, without infiltrating the serous membrane |
|
pT4 |
The tumour invades the peritoneum, or adjacent organs or tissues |
|
N — regional lymph nodes |
|
|
pNX |
Lymph nodes cannot be assessed |
|
pN0 |
No metastasis in regional lymph nodes |
|
pN1 |
Metastases present in less than 12 regional lymph nodes |
|
pN2 |
Metastases in 12 or more regional lymph nodes or large mesenteric mass (more than 2 cm in diameter), in particular with encasement of mesenteric vessels |
|
M — distant metastases |
|
|
cM0 |
No distant metastases |
|
pM1 |
Distant metastases present |
|
pM1a |
Distant metastases only in the liver |
|
pM1b |
Distant metastases only in organs other than the liver (e.g. peritoneum, non-regional lymph node, lung) |
|
pM1c |
Distant metastases in the liver and in organs other than the liver |
Both the mitotic index and the Ki-67 proliferative index are prognostic factors in SINETs. The tumour grade should be determined based on the 2019 WHO criteria [67, 70, 79]. In the case of multifocal tumours, the assessment of the Ki-67 proliferative index should be performed in the largest tumour or in the tumour of the highest local stage [74, 80, 81]. It is recommended that the Ki-67 index be determined separately in the primary tumour tissue, regional metastases, and distant metastases (if applicable) [80].
Mesenteric desmoplastic fibrosis occurs in up to half of SINETs cases [71]. Mesenteric fibrosis is a marker of clinically aggressive SINET [70, 71].
The radial margin in the resection specimen of the small intestine is located within the mesentery. Neoplastic tissue may be present in this margin in the form of primary tumour infiltration, tumour deposit, or as a metastatic lymph node — the type of margin infiltration should be reported [70].
Recently, it has been shown that lymphovascular invasion outside the intestinal wall is a significant risk factor for the development of metachronous SINET metastases to the liver [82].
The microscopic appearance of the tumour is often suggestive of NET, but the diagnosis should be confirmed by immunohistochemical staining with chromogranin A and synaptophysin antibodies [81, 83].
The prognostic factors for SINETs are summarised in Table 4.
|
Prognostic factor |
Examination method |
Evaluated in routine diagnostics? |
|
The histopathological type of the tumour [determined on the basis of the 2019 WHO criteria] |
Microscopic evaluation |
Yes, obligatory |
|
Tumour size |
Macroscopic examination, measurement in cm |
Yes, obligatory |
|
Number of primary lesions |
Macroscopic examination |
Yes, obligatory |
|
Local invasion Invasion into the mesenteric adipose tissue Lymph-vascular invasion Perineural invasion |
Microscopic evaluation |
Yes, obligatory |
|
Necrosis |
Microscopic evaluation |
Not required |
|
Tumour grade |
Microscopic evaluation |
Yes, obligatory |
|
Tumour stage |
Microscopic assessment according to the AJCC/UICC classification (2017) |
Yes, obligatory |
|
Number of regional lymph nodes and the presence of nodal metastases (in the surgical specimens) |
Macroscopic and microscopic examination |
Yes, obligatory |
|
Tumour deposits larger than 2 cm in diameter in the mesenteric adipose tissue (in the surgical specimens) |
Macroscopic and microscopic examination |
Yes, obligatory |
|
Status of the surgical margins (proximal intestinal margin, distal intestinal margin, radial margin) |
Macroscopic and microscopic examination |
Yes, obligatory |
|
Mitotic index |
Microscopic evaluation |
Yes, obligatory |
|
Ki-67 proliferative index |
Immunohistochemical examination |
Yes, obligatory |
|
Chromogranin A |
Immunohistochemical examination |
Yes, obligatory |
|
Synaptophysin |
Immunohistochemical examination |
Yes, obligatory |
|
Markers Cytokeratin, INSM1, CDX2, somatostatin, SSTR2A, SSTR5 |
Immunohistochemical examination |
No, optionally |
Minimal consensus statement on pathomorphological examinations
3.3.2. Neuroendocrine neoplasms of the appendix
The WHO classification of ANENs is presented in Table 5 [90].
|
Neuroendocrine tumour (NET) (8240/3) Neuroendocrine tumour G1 (8240/3) Neuroendocrine tumour G2 (8249/3) Neuroendocrine tumour G3 (8249/3) L-cell neuroendocrine tumour (8152/3) Neuroendocrine tumour producing glucagon-like peptide (8152/3) Neuroendocrine tumour producing PP/PYY (8152/3) Enterochromaffin cell neuroendocrine tumour (8241/3) Neuroendocrine tumour producing serotonin (8241/3) |
|
Neuroendocrine carcinoma (NEC) (8246/3) Large cell neuroendocrine carcinoma (8013/3) Small cell neuroendocrine carcinoma (8041/3) |
|
Mixed neuroendocrine — non-neuroendocrine neoplasm (MiNEN) (8154/3) |
ANETs are much more common than neuroendocrine carcinomas of the appendix. Many ANETs cases are diagnosed accidentally in surgical specimens following appendectomy performed due to acute appendicitis or for other reasons. ANETs are found in less than 2% of surgical specimens following appendectomy; nevertheless, ANETs are the most common neoplasm of the appendix [91, 92]. Most ANETs cases are small (i.e. less than 2 cm in the greatest dimension); most (but not all) ANETs are located at the apex of the appendix. ANETs can occur in childhood. The long-term prognosis in most ANETs cases is favourable, but it depends on the diameter of the primary tumour and the presence of metastases [4, 26, 92–94].
Most ANETs have features of enterochromaffin cells (EC), grow in a nested pattern, and secrete serotonin. Ten to twenty per cent of ANETs are composed of L-cells, forming trabecular or glandular structures. L-cell ANETs may produce glucagon-like peptide 1, enteroglucagon, YY peptide, pancreatic polypeptide, and other peptides. In rare cases, ANETs (especially L-type) show tubular growth pattern (in the past, such lesions were referred to as tubular carcinoids). The long-term prognosis for tubular ANETs is the same as for EC-cell ANETs. ANECs are very rare; microscopically they resemble colonic NECs. Mixed neuroendocrine — non-neuroendocrine neoplasms (MiNEN) of the appendix usually consist of adenocarcinoma and NEC (most often large cell type) or adenocarcinoma and NET. It should be emphasised that the tumour referred to as goblet cell adenocarcinoma (previously goblet cell carcinoid) is currently classified as a clinical-pathological variant of adenocarcinoma, and not as a neuroendocrine neoplasm [80, 87, 90, 94–97].
Prognostic factors in ANET
Recognition of EC and L subtypes among ANETs cases is not necessary for diagnostic purposes, because long-term prognosis and treatment methods are very similar in both histological types [90].
The ANET tumour stage in the resections specimens should be described based on the 2017 AJCC/UICC and 2007 ENETS stage classifications (Tab. 6) [69, 84, 95, 98]. It should be noted that these classifications are not intended for ANEC or goblet cell adenocarcinomas — these histotypes of neoplasms should be described using the 2017 AJCC/UICC classification for carcinomas of the appendix. Note that the 2017 AJCC/UICC classification and the 2007 ENETS classification are different [99].
|
Tumour stage |
AJCC/UICC diagnostic criterion |
ENETS diagnostic criterion |
|
T — primary tumour |
||
|
pTX |
Primary tumour cannot be assessed |
Primary tumour cannot be assessed |
|
pT0 |
No evidence of primary tumour |
No evidence of primary tumour |
|
pT1 |
Tumour 2 cm or less in diameter |
Tumour of up to 1 cm in diameter, infiltrating the submucosa or the muscularis propria |
|
pT2 |
Tumour larger than 2 cm in diameter but not more than 4 cm in diameter |
Tumour of up to 2 cm in diameter, infiltrating the submucosa or the muscularis propria, or superficially infiltrating (depth of infiltration of up to 3 mm) the subserosa or the mesoappendix |
|
pT3 |
Tumour larger than 4 cm in diameter, or tumor with subserosal or mesoappendiceal invasion |
Tumour larger than 2 cm in diameter or tumour extensively infiltrating (i.e., infiltrating to a depth of more than 3 mm) the subserosa or the mesoappendix |
|
pT4 |
Tumour perforates the peritoneum or invade other organs or adjacent structures (direct mural extension to subserosa of adjacent bowel excluded) |
Tumour invades peritoneum or other organs |
|
N — regional lymph nodes |
||
|
pNX |
Lymph nodes cannot be assessed |
Lymph nodes cannot be assessed |
|
pN0 |
No metastasis in regional lymph nodes |
No metastasis in regional lymph nodes |
|
pN1 |
Metastasis in regional lymph nodes |
Metastasis in regional lymph nodes |
|
M — distant metastases |
||
|
cM0 |
No distant metastases |
No distant metastases |
|
pM1 |
Distant metastasis present |
Distant metastasis present |
|
pM1a |
Distant metastasis only in the liver |
– |
|
pM1b |
Distant metastasis only in organs other than the liver (e.g. peritoneum, non-regional lymph node, lung) |
– |
|
pM1c |
Distant metastases in the liver and in organs other than the liver |
– |
Both the 2017 AJCC/UICC classification and the 2007 ENETS classification have prognostic value in ANET [93, 94]. The primary tumour stage described using both classifications is a risk factor for metastases in regional lymph nodes [94]. Tumour diameter (i.e. in the largest dimension) is a key element in the determination of the ANET primary tumour stage.
Other risk factors for metastases to regional lymph nodes in the course of ANET include lymph-vascular invasion and perineural invasion [94]. The role of tumour localisation within the appendix (proximal or distal part of the appendix) and infiltration of the mesenteric adipose tissue as risk factors for regional lymph node metastases has not been clearly established [27, 93]. The prevalence of metastases to regional lymph nodes among ANETs cases is less than 10% [90], but in patients subjected to surgical procedure in the form of right-sided hemicolectomy after prior appendectomy, it is significantly higher (up to 32%) [100]. Some investigators have demonstrated that the presence of regional lymph node metastases is a prognostic factor in ANET [101]. Distant metastases in the course of ANET (usually to the liver) are rare [90, 91].
ANET grade should be determined based on the 2019 WHO criteria [79, 95]. It is recommended that the Ki-67 proliferative index be determined separately in the primary tumour tissue, regional metastases, and distant metastases (if applicable) [80]. The clinical significance of the tumour grade in ANET cases has not been clearly established [102]. The tumour grade seems to be a prognostic factor in ANETs [103]. It should be noted that ANETs G2 are usually larger, and they also infiltrate the mesenteric adipose tissue, vessels, and nerve trunks more often [93].
The microscopic appearance is often suggestive of ANET, but the diagnosis must be confirmed by immunohistochemical tests with chromogranin A and synaptophysin antibodies [81, 83]. L-cell ANETs may express chromogranin B rather than chromogranin A [90, 83].
The prognostic factors in cases of ANETs are summarised in Table 7.
|
Prognostic factor |
Examination method |
Evaluated in routine diagnostics? |
|
The histopathological type of the tumour, determined on the basis of the 2019 WHO criteria |
Microscopic evaluation |
Yes, obligatory |
|
Tumour size |
Macroscopic examination, measurement in cm |
Yes, obligatory |
|
Tumour location (distal half of the appendix, proximal half of the appendix, diffuse infiltration within the appendix, another location) |
Macroscopic examination |
Yes, obligatory |
|
Invasion:
|
Microscopic evaluation |
Yes, obligatory |
|
Necrosis |
Microscopic evaluation |
Not required |
|
Tumour grade |
Microscopic evaluation |
Yes, obligatory |
|
Tumour stage |
Microscopic assessment according to the 2017 AJCC/UICC classification and 2007 ENETS classification |
Yes, obligatory |
|
Number of regional lymph nodes and the presence of nodal metastases (in the surgical specimens) |
Macroscopic and microscopic examination |
Yes, obligatory |
|
Surgical margin status (appendiceal margin, radial margin) |
Macroscopic and microscopic examination |
Yes, obligatory |
|
Mitotic index |
Microscopic evaluation |
Yes, obligatory |
|
Ki-67 proliferative index |
Immunohistochemical examination |
Yes, obligatory |
|
Chromogranin A |
Immunohistochemical examination |
Yes, obligatory |
|
Synaptophysin |
Immunohistochemical examination |
Yes, obligatory |
|
Markers: cytokeratin, INSM1, CDX2, somatostatin, glucagon, SOX10, S100, SATB2, SSTR2A, SSTR5 |
Immunohistochemical examination |
No, optionally |
Minimal consensus statement on pathomorphological examinations
4. Treatment
4.1. Surgical treatment
Neuroendocrine neoplasms of the part of the gastrointestinal tract known as the midgut are most often located in the terminal segment of the small intestine or in the appendix. SINENs are often small, multifocal, and with concomitant liver metastases [3, 104, 105]. SINENs metastases to the mesenteric lymph nodes are often much larger than the primary tumours and are associated with extensive mesenteric fibrosis and desmoplastic reaction [104].
Resection of the primary tumour, regional lymph nodes, and accompanying mesenteric fibrosis should be performed, if possible, at all tumour stages (Tab. 8) [3].
|
Advanced |
Local |
Regional |
Presence of distant metastases |
||
|
Stage |
I/II |
III |
IV |
||
|
TNM |
T1–3 N0 M0 |
T4 N0 M0 T1–4 N1 M0 |
TxNxM1 |
||
|
Surgical procedure |
Radical resection |
Radical resection with the intention to heal |
Palliative resection |
No resection |
|
|
Scope of procedure |
Radical open surgery or, in selected cases, laparoscopic resection. Removal of:
|
Radical open procedure Removal of:
|
Radical open surgery or, in selected cases, laparoscopic resection Removal of:
|
Unresectable tumour |
|
|
Purpose of the procedure |
Removal of the entire tumour mass |
Partial removal of the neoplasm mass Avoiding complications related to the tumour Possible improvement in prognosis |
|
||
To maintain the maximum length of the retained intestine, it is necessary to determine the position of the superior mesenteric vein and artery and its branches very precisely. Regional lymph nodes should be removed along the segmental vessels up to their connection to the main branch of the superior mesenteric vein. Metastatic lymph nodes are often located around the superior mesenteric vessels and surround them closely, including the root of the mesentery. Particular groups of lymph nodes and the scope of their removal are presented in Table 9.
|
Group of lymph nodes |
Location of the lymph nodes |
Recommendations |
|
1 |
Lymph nodes are those close to the SINET |
Removal of lymph nodes located close to the distal branches of the superior mesenteric artery is recommended/routinely performed during resection of the affected segment of the intestine |
|
2 |
Lymph nodes around the distal branches of the superior mesenteric artery |
|
|
3 |
Lymph nodes around the proximal branches of the superior mesenteric artery |
Resection as in group 1–2, and removal of lymph nodes along the proximal branches of the artery up to the root of the mesentery |
|
4 |
Retroperitoneal lymph nodes, infiltrating the main branch of the superior mesenteric vein/artery |
Tumour is usually unresectable, removal may result in vascular damage and intestinal ischaemia, resection only in exceptional cases as part of mass cytoreduction in specialised centres |
Palliative cytoreduction of the tumour is advisable when the tumour mass can be reduced by at least 90% [3]. During resection of a part of the intestine and/or liver metastases (when cytoreduction of at least 70% of the mass of metastases is possible), cholecystectomy is also recommended, especially in patients in whom the use of somatostatin analogues is expected [3, 104].
In the case of SINET, laparoscopic procedures are not recommended due to the presence of lesions that are usually small and multifocal and thus difficult to identify during laparoscopic surgery [3, 104]. Careful palpation of the small intestine from the ligament of Treitz to the ileocecal valve is essential. Peritoneal metastases are found in 20% of cases; therefore, the patients should be examined for their presence in the pelvis, sigmoid, mesentery, and diaphragm [104]. Both ovaries should be examined to exclude any metastases that could cause carcinoid syndrome.
Diagnostic exploratory laparotomy is used in the search for focal lesions in the intestine, unidentified in preoperative examinations, in symptomatic patients and in patients with liver metastases [104].
ANENs are usually small in size and are often diagnosed after appendectomy. In the majority of cases, patients do not require further treatment. Appendectomy is the gold standard in stage 1 (ENETS TNM) [4, 92, 106]. The treatment of ANENs depends mainly on the size and degree of the primary tumour infiltration and the presence of risk factors [106, 107].
The following features of the appendix NET (risk factors) constitute the indications for right-sided hemicolectomy [4, 106]:
Hemicolectomy should be considered as the treatment of choice, especially in young patients, and in the case of appendiceal perforation, because it can minimise the likelihood of tumour cell dissemination [92].
In the case of ANEN with liver metastases, the recommended management is right hemicolectomy with the removal of the metastases (non-anatomical and anatomical resections) [108]. In the case of multiple metastases, palliative methods of metastasis removal (palliative excision, thermal ablation, chemoembolisation, etc.) should be considered [4, 106].
In the case of MiNEN and NEC of the appendix (G3, Ki-67 >20%), hemicolectomy is recommended, and tumours should be treated according to the recommendations for adenocarcinoma [4, 69, 106].
Minimal consensus statement on surgical treatment
4.2. Symptomatic pharmacological treatment
4.2.1. Symptomatic treatment in carcinoid syndrome
Long-acting somatostatin analogues (SSA): octreotide LAR [10–30 mg intramuscluar (i.m.) every 4 weeks, but the lowest dose is rarely used], and lanreotide Autogel [60–120 mg subcutaneous (s.c.) every 4 weeks; but the lowest dose is rarely used] constitute the gold standard in carcinoid syndrome management (Fig. 2). In patients in whom a somatostatin analogue provides good symptom control in carcinoid syndrome, lanreotide can be injected at a dose of 120 mg every 42 or every 56 days. It is not necessary to perform radioisotope imaging of somatostatin receptors before starting SSA therapy.
In the absence of satisfactory symptom control with routine treatment using long-acting SSAs, the following should be considered: shortening the interval between doses, increasing the dose of SSA, and/or using an additional short-acting SSA (octreotide, solution for injection 100 µg/amp.).
For the treatment of diarrhoea occurring in the course of carcinoid syndrome, it is recommended that a drug that inhibits serotonin biosynthesis is used — telotristat ethyl in combination with SSA if the use of SSA alone does not provide sufficient control of symptoms [109–111]. So far telotristat ethyl is not currently reimbursed by the National Health Fund, which significantly limits the use of this drug.
In addition, a change of systemic therapy (including the use of targeted radioligand therapy — see below) and cytoreductive therapy (mainly various locoregional treatments for liver metastases) should be considered. Symptomatic treatment of patients with carcinoid syndrome also involves dietary and pharmacological treatment: loperamide, ondansetron, pancreatic enzymes, and B vitamins in the case of their deficiency [112, 113].
Patients with CHD require constant care in reference cardiology and cardiosurgery centres.
4.2.2. Treatment of carcinoid crisis
There are no unequivocal recommendations for the management of a carcinoid crisis based on evidence-based medicine (EBM). It is essential to implement therapy with a somatostatin analogue as soon as possible; most commonly, intravenous administration of high doses of short-acting SSA (octreotide: 25–500 µg/h; average 100–200 µg/h). In carcinoid crisis (especially in the course of foregut NET), the use of glucocorticosteroids and antihistamines may also be considered. In addition, intensive care treatment is necessary in the case of the following: dehydration, acute renal failure, hypercalcaemia, hypertension or hypotension, heart failure, or infections.
4.2.3. Prevention of carcinoid crisis before the application of medical procedures
There are no clear recommendations regarding the preparation of patients with SINENs and ANENs for various medical procedures, including surgery, biopsy, endoscopy, or PRRT [88, 114, 115].
In patients with carcinoid syndrome, preoperative use of short-acting SSAs should be considered regardless of the therapy with long-acting SSAs (e.g. octreotide 200–300 µg s.c. before surgery and/or continuous infusion of 50–100 µg/h during and/or 24–48 h after surgery). In patients with CHD, a cardiological consultation is indicated. In patients with non-functioning NENs, it is recommended that a short-acting SSA should be available during surgery to be administered in an unstable haemodynamic situation.
4.3. Systemic treatment in SINENs in the period of disease generalisation
4.3.1. Long-acting somatostatin analogues
Long-acting SSAs: octreotide LAR (30 mg i.m. every 4 weeks), lanreotide Autogel (120 mg s.c. every 4 weeks) are the first-line drugs used to stabilise neoplastic disease in patients with well-differentiated SINET G1/G2 in advanced disease [68, 116] (Fig. 3).
4.3.2. Peptide receptor radionuclide therapy with radioisotope-labelled somatostatin analogues
In patients with SINETs in the period of disease generalisation with progression during SSA treatment, and with high expression of somatostatin receptors, therapy with isotope-labelled somatostatin analogues — peptide receptor radionuclide therapy — should be considered first [117]. Patient qualification and treatment are carried out in accordance with the principles described in the Update of the diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours) [28].
In patients with negative SRI and evidence of accumulation of [131I]mIBG in the tumour or metastases, [131I]mIBG therapy may be considered [118].
4.3.3. Targeted therapies — everolimus
Everolimus therapy is effective in patients with non-functional, well-differentiated NETs of the gastrointestinal system, including SINETs, during the disease generalised period [119]. Based on the results of the RADIANT 4 study, everolimus therapy may be considered in patients with generalised progressive SINET following unsuccessful treatment with SSA and failure or ineffectiveness of other treatments (including PRRT). It is also the treatment of choice in the absence of SSTR expression. In Poland, everolimus therapy in this indication is still not reimbursed, which significantly limits the possibilities of effective therapy in this group of patients.
4.3.4. Chemotherapy
Due to its low efficacy, chemotherapy is not recommended in SINEN patients with metastases. It is used only in advanced, aggressive cases with a threat to organ function and/or the presence of SINET dedifferentiation, in the case of the failure of other treatments. Metronomic chemotherapy can be considered according to the CAPTEM regimen (capecitabine + temozolomide) based on small, prospective, phase II studies in small groups of patients [120–122]. In the case of rare NETs G3, it is one of the preferred therapeutic options.
A special form of ANENs are goblet cell adenocarcinomas, which are currently treated as glandular carcinomas of the gastrointestinal tract and should be treated according to the principles of adenocarcinoma.
Further information on the systemic treatment of GEP-NENs is included in the Update of the diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours) [28].
Minimal consensus statement on pharmacological and radioisotope treatment of SINEN and ANEN
5. Monitoring
The frequency of follow-up imaging examinations (three-phase CT or MRI, of the abdominal cavity and SRI) and laboratory tests (CgA and 5-HIAA) depends on the degree of NEN differentiation and extension of the disease as well as the applied treatment (Tab. 10) [88, 123, 124]. The most important activity in assessing the course and effectiveness of treatment in patients with carcinoid syndrome is the assessment of clinical symptoms. In patients with CHD, echocardiography and determination of the concentration of NT-proBNP should be repeated at least every 12 months. In the case of heart disease progression, follow-up imaging and biochemical tests should be performed more frequently, i.e. every 3 months.
|
SINEN |
CT/MRI of the abdominal cavity |
SRI/other imaging examinations |
Laboratory tests |
Remarks |
|
Local and regional SINEN after complete surgical resection |
||||
|
SINET G1 |
Initially post-op — every 6 months Then every 12–24 months |
SRI — pre-op, when recurrence is suspected Other examinations (e.g. CT of the chest, MRI of the spine) — when metastases are suspected |
CgA, 5-HIAA every 12 months and/or when recurrence is suspected NSE in the case of NET G3 every 3 months |
After 10 years — consider indications for further monitoring |
|
SINET G2 |
Initially post-op — every 3–6 months Then every 12 months |
|||
|
SINET G3 |
Initially post-op — every 2–3 months Then every 3–4 months |
|
||
|
Generalised SINEN after complete surgical resection |
||||
|
SINET G1 |
Initially post-op — every 3–6 months Then every 6–12 months |
As above |
As above |
As above |
|
SINET G2 |
Initially post-op — every 3 months Then every 3–6 months |
|||
|
SINET G3 |
Initially post-op — every 2–3 months Then every 3–4 months |
|||
|
Generalised SINEN, not treated surgically or after incomplete surgical resection |
||||
|
SINET G1 |
Initially post-op — every 3–6 months Then every 6 months |
SRI every 12–24 months in the case of SSTR+ and/or suspected progression Other examinations (e.g. CT of the chest, MRI of the spine) — when metastases are suspected |
CgA, 5-HIAA every 12 months and/or when recurrence is suspected NT-proBNP every 6–12 months in carcinoid syndrome NSE in G3 NET/NEC |
Continuous monitoring is recommended |
|
SINET G2 |
Initially post-op — every 3 months Then every 3–6 months |
|||
|
SINET G3 |
Initially post-op — every 2–3 months Then every 3–4 months |
|||
|
SINEC |
Every 2–3 months |
|||
Minimal consensus statement on examination for disease monitoring and treatment
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 [125, 126] (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.
