Neuroendocrine gastroenteropancreatic tumors: ESMO Clinical Recommendation for diagnosis, treatment and follow-up

Abstract

Neuroendocrine gastroenteropancreatic (NE-GEP) tumors constitute a heterogeneous group of tumors with location of the primary tumors in the gastric mucosa, pancreas, small and large intestine. The incidence is ∼2.5–5 cases/100 000/year. The largest group are small intestinal neuroendocrine tumors (midgut carcinoids) with an incidence rate of 2.4/100 000/year. The incidence in autopsy series is significantly higher at 8.4/100 000/year. The incidence and prevalence of carcinoid tumors has increased substantially over the last decades, which may partly reflect better diagnosis of incidentally identified lesions due to increased availability of advanced endoscopic techniques and radiological imaging. NE-GEP tumors can appear at all ages, with the highest incidence from the fifth decade upwards. An exception is carcinoid of the appendix, which occurs with the highest incidence at <30 years of age. NE-GEP tumors may be part of multiple endocrine neoplasia type I (MEN-1) or von Hippel–Lindau's disease (vHL). Patients with MEN-I or vHL may have a clinical onset 15 years earlier than patients with the sporadic type of neuroendocrine tumors. Clinical presentations depend on the site of the primary tumor and whether they are so called functioning tumors, i.e. whether the peptide and amines secreted by the tumor produce clinical symptoms. Most NE-GEP tumors are non functioning and present fairly late with symptoms of mass effects or distant metastases. Patients with clinical symptoms suggesting a NE-GEP tumor should be referred to a center with particular interest and knowledge in these diseases. The histopathological diagnosis is performed on tissue samples obtained either by open surgery or by core needle biopsy from metastatic sites. There are three systems of nomenclature in use according to tumor cell characteristics and the comparison is presented in Table 1. The family of NE-GEP tumors constitute a heterogeneous group (summary is presented in Table 2), but all share several common immunohistochemical features (immunoreactivity for the so called ‘pan-neuroendocrine’ markers) including positivity for at least chromogranin A, synaptophysin and neuron-specific enolase (NSE). The proliferation capacity should always be evaluated with staining for the proliferation marker Ki-67 expressed as a percentage of positive cells. Depending on clinical symptoms, specific hormonal markers can be demonstrated in tissue samples, and also measured as circulating markers in serum. The most important general circulating tumor marker is chromogranin A. A specific marker for patients with carcinoid syndrome is urinary 5-HIAA, whereas for pancreatic tumors, gastrin, insulin, glucagon and vasoactive intestinal peptide (VIP) are other specific markers that should be determined according to clinical symptoms [II, B]. The genetic background is not completely clarified for most of these tumors, but tumors associated with MEN-I and some sporadic ones show specific loss of heterozygosity of the 11q13 region, which harbors the MEN-I gene, a tumor suppressor gene encoding a protein called menin. Tumors related to vHL disease show mutation of the vHL gene, which has been mapped to chromosome 3p25.3 and acts as a tumor suppressor gene.Table 1Classification according to cell characteristics: comparison of Öberg, WHO and Klöppel nomenculatureLow malignant potential Öberg: carcinoid WHO: neuroendocrine tumor (NET) Klöppel et al.: well-differentiated neuroendocrine tumor (NET) (carcinoid)Intermediate malignant potential Öberg: endocrine pancreatic tumor WHO: neuroendocrine carcinoma Klöppel et al.: well-differentiated neuroendocrine carcinoma (malignant carcinoid)High malignant potential WHO: poorly differentiated neuroendocrine carcinoma Klöppel et al.: poorly differentiated neuroendocrine carcinoma (high-grade malignant carcinoid)Mixed tumors WHO: mixed endocrine/exocrine tumorMiscellaneous WHO: rare neuroendocrine-like lesions Open table in a new tab Table 2Classification of neuroendocrine GEP tumors (NE-GEP tumors) by site of origin and by hormonal activityCarcinoids (about two-thirds of NE-GEP tumors) with carcinoid syndrome (∼10% of carcinoids) without carcinoid syndrome (∼90% of carcinoids)Pancreatic endocrine tumors (PETs) (about one-third of NE-GEP tumors) Non-functioning (15–30% of PETs) Functioning (70–85% of PETs) • Gastrinoma, producing excessive gastrin and causing Zollinger–Ellison syndrome • Insulinoma, producing excessive insulin • Glucagonoma, producing excessive glucagon • Vasoactive intestinal peptideoma (VIPoma), producing excessive vasoactive intestinal peptide (VIP) • PPoma, producing excessive pancreatic polypeptide (often classed with non-functioning PETs) • Somatostatinoma, producing excessive somatostatin • Watery diarrhea, hypokalemia–achlorhydria • CRHoma, producing excessive corticotropin-releasing hormonse (CRH) • Calcitoninoma, producing excessive calcitonin • GHRHoma, producing excessive growth hormone-releasing hormone (GHRH) • Neurotensinoma, producing excessive neurotensin • ACTHoma, producing excessive adrenocorticotropic hormone (ACTH) • GRFoma, producing excessive growth hormone-releasing factor (GRF) • Parathyroid hormone-related peptide tumor Open table in a new tab In the UICC-TNM staging system, there is no specific TNM staging for NE-GEP tumors, and they should be staged according to the organ they arise from. Recently a TNM staging of foregut neuroendocrine tumors (Table 1) including a proposal for a grading system has been established by the European Neuroendocrine Tumor Society. TNM stages for gastric, duodenojejunal, pancreatic and jejunoileal NE-GEP tumors are presented in Table 3, Table 4, Table 5, Table 6. The grading system (grades I, II and III) is related to the proliferation capacity of the tumor measured by Ki-67 staining of the tumor specimens. The grade I tumor shows Ki-67 in <2%, grade II tumor in 2–20% and grade III tumor in >20% of tumor cells.Table 3TNM classification for gastric endocrine tumors (European Neuroendocrine Tumor Society)TPrimary tumorTXPrimary tumor cannot be assessedT0No evidence of primary tumorTisIn situ tumor/dysplasia (<0.5 mm)T1Tumor invades lamina propria or submucosa and ≤1 cmT2Tumor invades muscularis propria or subserosa or >1 cmT3Tumor penetrates serosaT4Tumor invades adjacent structuresFor any T, add (m) for multiple tumorsNRegional lymph nodesNXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Regional lymph node metastasisMDistant metastasisMXDistant metastasis cannot be assessedM0No distant metastasesM1Distant metastasis Open table in a new tab Table 4TNM classification for endocrine tumors of the duodenum/ampulla/proximal jejunum (European Neuroendocrine Tumor Society)TPrimary tumorTXPrimary tumor cannot be assessedT0No evidence of primary tumorT1Tumor invades lamina propria or submucosa and size ≤1 cmaT2Tumor invades muscularis propria or size >1 cmT3Tumor invades pancreas or retroperitoneumT4Tumor invades peritoneum or other organsFor any T, add (m) for multiple tumorsNRegional lymph nodesNXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Regional lymph node metastasisMDistant metastasesMXDistant metastasis cannot be assessedM0No distant metastasesM1Distant metastasis Open table in a new tab Table 5TNM classification for endocrine tumors of the pancreas (European Neuroendocrine Tumor Society)TPrimary tumorTXPrimary tumor cannot be assessedT0No evidence of primary tumorT1Tumor limited to the pancreas and size <2 cmT2Tumor limited to the pancreas and size 2–4 cmT3Tumor limited to the pancreas and size >4 cm or invading duodenum or bile ductT4Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or superior mesenteric artery)For any T, add (m) for multiple tumorsNRegional lymph nodesNXRegional lymph node cannot be assessedN0No regional lymph node metastasisN1Regional lymph node metastasisMDistant metastasesMXDistant metastasis cannot be assessedM0No distant metastasesM1Distant metastasis Open table in a new tab Table 6TNM classification for endocrine tumors of lower jejunum and ileum (European Neuroendocrine Tumor Society)TPrimary tumorTXPrimary tumor cannot be assessedT0No evidence of primary tumorT1Tumor invades mucosa or submucosa and size ≤1 cmT2Tumor invades muscularis propria or size >1 cmT3Tumor invades subserosaT4Tumor invades peritoneum/other organsFor any T add (m) for multiple tumorsNRegional lymph nodesNXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Regional lymph node metastasisMDistant metastasisMXDistant metastasis cannot be assessedM0No distant metastasesM1Distant metastasis Open table in a new tab NE-GEP tumors should be further characterized by specific marker determination in biopsy samples and by determination of specific tumor markers in the plasma (depending on the associated clinical syndrome). Dynamic stimulation tests may be required in specific cases (fasting test for insulinomas, secretin test for gastrinomas, etc). Determination of non-specific markers such as chromogranin A, NSE, urinary 5-HIAA and serotonin are of clinical value in many NE-GEP tumors including apparently non-functioning tumors [II, B]. Preoperative staging procedures should always include somatostatin receptor scintigraphy (octreoscan) [II, B], although it is not equally sensitive for all NE-GEP tumors, as well as single photon emission tomography (SPECT) [II, B]. This technique should always be complemented with CT or MRI (depending on the tumor location), which offers a more precise anatomical definition. 18FDG-PET can be useful for staging in less differentiated NE-GEP tumors, but seems to offer no advantages in well-differentiated tumors. 5-HTP and L-DOPA-PET appear to have increasing utility in the management of these tumors. Patients with neuroendocrine pancreatic tumors often present with metastatic disease (>70% of patients) except for insulin-producing tumors, which are benign in 85–90% of cases [II, A]. The largest group of NE-GEP tumors are the so-called midgut carcinoids or classical carcinoids. About 40% of these present with a carcinoid syndrome including flushing, diarrhea and endocardial fibrosis. The 5-year survival rate for patients with neuroendocrine pancreatic tumors is estimated to be 60–100% for localized disease, 40% for regional, 29% for metastatic and 80% for all stages. Similarly, for classical midgut carcinoids the 5-year survival rate has been reported to be 60% for all stages, 64% for localized disease, 72% for locoregional disease and 50% for metastatic disease. The new grading system indicates significantly better survival for grade I tumors compared with grade II or III tumors [II, A]. Surgery is the primary treatment for localized tumors and might be curative, giving 5-year survival rates of 80–100% [II, A]. The majority of patients present with metastatic disease. Even in metastatic disease, surgery plays an important role in reducing tumor mass and can be performed before or concomitantly with medical treatment. Other means of cytoreductive procedures are available, such as radiofrequency ablation, laser therapy and embolization of liver metastases [III, B]. Cytotoxic treatment has been the standard for advanced neuroendocrine pancreatic tumors, but is of limited value for the treatment of low proliferating NE-GEP tumors (response rates 30–50% compared with <10%). The standard combination chemotherapy regimens include the following:•5-FU, dacarbazine and epirubicin in standard or intensified dosage with a prospect of 20–30% response rate with a median response duration of 38 months;•lomustine and 5-FU combination with a similar response pattern;•streptozoocin ± 5-FU ± doxorubicin combinations with a prospect of 40–60% response rate and a median survival of ∼2 years;•cisplatinum and etoposide combination, which may be used in poorly differentiated endocrine pancreatic tumors. Biological treatment, such as somatostatin analogues and α interferons has proved effective in control of associated clinical syndromes related to hormone production and release (carcinoid syndrome, gastrinoma, glucagonoma, etc.) in up to 60% of patients. Their use in non-functioning tumors is still not widely accepted [IV, B]. Tumor-targeted radioactive treatment is an option in the selected group of patients with tumors that present a high grade of uptake of [111In]pentaoctreotide (octreoscan) scintigraphy. Biological treatments with a promising prospect include sunitinib, everolimus and bevacizumab when associated with capecitabine and oxaliplatin. These treatments should be applied only in the setting of clinical trials. Patients should be followed at 3-monthly intervals during treatment with cytotoxic agents or biological therapy in order to assess response to treatment. Patients undergoing curative surgery should be followed every 3–6 months for at least 5 years in order to detect eventual surgically removable recurrences. Examination should include specific or non-specific biochemical markers depending on the associated (or lack of) clinical syndrome. Imaging is based on CT or MRI every 6 months. The role of octreoscan in follow-up is under evaluation. Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO Faculty.