Gastroenteropancreatic neuroendocrine tumours: an overview Louise Davies and Martin O Weickert
Incidence and prevalence
Gastroenteropancreatic neuroendocrine tumours (GEP-NET) represent a heterogeneous family of diseases of often challenging clinical management. Although many GEP-NET are slow progressing and frequently less aggressive than neoplasms of other origin, they can metastasise and reduce the life span of the patient. GEP-NET can be functioning (secreting hormones that may cause symptoms and organ damage), but some 60% are non-functioning. Thorough clinical assessment including family history, biochemical tests, radiology and nuclear medicine scans, and histological confirmation are important to tailor the optimal treatment of GEP-NET, which should be managed with a multidisciplinary approach and mainly guided by tumour grading and staging, functioning status, and location of the primary lesion. Key words: Neuroendocrine tumour ■ Grading ■ Staging ■ Biomarkers Somatostatin
■
G
astroenteropancreatic neuroendocrine tumours (GEP-NET) are often slow growing neoplasms that may produce hormones causing functioning symptoms (caused by secreting hormones) (Rossana et al, 2016). GEP-NET include neuroendocrine tumours of the stomach, pancreas, small bowel, appendix, colon and rectum (Vinik et al, 2014). Neuroendocrine tumours of pulmonary origin often need different management (Caplin et al, 2015) and are not included in this review. GEP-NET can spread, if not diagnosed early; and therefore show cancer-like behaviour. Most GEP-NET are well differentiated, whereas poorly differentiated GEP-NET are rare (5% of all GEP-NET) and usually more aggressive (Vinik et al, 2014).Treatment options for GEP-NET have significantly improved recently and patients may survive for many years with good symptom control (Rossana et al, 2016). Louise Davies, Neuroendocrine Specialist Nurse, ARDEN NET Centre, European Neuroendocrine Tumour Society Centre of Excellence, University Hospitals Coventry and Warwickshire NHS Trust Martin O Weickert, Lead The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence, University Hospitals Coventry & Warwickshire NHS Trust (UHCW); and Centre for Applied Biological and Exercise Sciences, Coventry University Accepted for publication: February 2016
S12
The incidence of GEP-NET has more recently been reported to be 5.25/100 000 (Vinik et al, 2014). Therefore, in the UK some 3000 newly diagnosed patients each year can be expected. Prolonged survival further contributes to a raising prevalence. Median survival in metastatic NET of pancreatic origin has been reported to be between 4.7 and 7.4 years (Jann et al, 2011;Ter-Minassian et al, 2013). In well-differentiated midgut NET, even with metastatic liver disease, survival appears to be even better, in some of the studies over 10 years (Jann et al, 2011; Ter-Minassian et al, 2013). Prime age for developing a GEP-NET is the sixth and seventh decade, with the exception of often benign-behaving, well-differentiated NET of the appendix, most frequently incidentally diagnosed following appendectomy (3-5/1000 appendectomies) (Pape et al, 2016) (a condition that often presents also in young patients). In paediatric patients with appendiceal NET, long-term outcomes are excellent, even in higher stages, with the reasons for better prognosis not being completely understood (Pape et al, 2016). Apart from tumours of rectum origin, GEP-NET appear to be less common in South Asian and Afro-Caribbean populations (Vinik et al, 2010). The frequency of occurrence of GEPNET according to the location of the primary tumour is shown in Table 1.
Clinical presentation Many GEP-NET are clinically silent for many years, often presenting for the first time after they have metastasised.As many as 71% of patients have metastatic disease when diagnosed (Vinik et al, 2014). Aside from the liver, common sites of metastases include the regional lymph nodes and, less frequently, the bones. The likelihood of metastases directly relates to tumour size, with a less than 15% likelihood of a metastatic tumour in a small bowel NET, that is 2 cm (Vinik et al, 2014).The average time from first onset of tumour-related symptoms to diagnosis is approximately 5–7 years and likely to be longer in non-functioning GEP-NET (Vinik et al, 2010). Symptoms are often unspecific and can mimic various other disorders including irritable bowel syndrome, coeliac disease, food intolerance, or inflammatory bowel disorders. Behaviour is not predictable and can change into more aggressive types with poor prognosis (Ahlman et al, 2008). Functioning symptoms are related to excess secretion of hormones by the GEP-NET that can cause symptoms such as flushing and diarrhoea. ‘Carcinoid crisis’ represents severe
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ABSTRACT
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CLINICAL
and possibly life-threatening features of carcinoid syndrome (Massimino et al, 2013) and may include flushing, diarrhoea, bronchospasm, changes in the heart rate, hyperthermia, and blood pressure fluctuations with predominance of hypotension (Massimino et al, 2013). Triggers for carcinoid crisis include emotional stress, pharmacologic agents, especially catecholamines, angiography, induction of anaesthesia; and sometimes even minor surgical procedures (Massimino et al, 2013). Treatment with somatostatin analogues including intravenous infusion, especially in functioning GEP-NET may reduce the risk of carcinoid crisis i.e. when manipulating the tumour during surgery, although efficacy of this measure has been questioned more recently (Massimino et al, 2013).
Screening for GEP-NET Initial assessment for GEP-NET includes a full clinical and family history.Although most GEP-NET appear spontaneously, the presence of genetic syndromes such as multiple endocrine neoplasia type-1 (MEN-1) needs to be excluded (Vinik et al, 2014). It is important to keep in mind that absence of functioning symptoms is not reliable to exclude the presence of a GEP-NET. If there is reasonable suspicion for a GEP-NET, biomarkers in circulating blood and urine should be sampled under standardised conditions, for example urine sampling under restricted diet to improve the sensitivity of the test (Oberg et al, 2015), and imaging can be considered (Boudreaux et al, 2010; Ramage et al, 2012).
Biomarkers
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Biomarkers in blood and urine are important tools for screening, as well as monitoring of treatment success and possible progression (Oberg et al, 2015). Measurement of 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine sample was the initially established biochemical screening test, but sensitivity is poor and sampling requires various dietary restrictions (Oberg et al, 2015). Fasted ‘gut hormones’ in circulating blood are now routinely used both in screening and follow-up. The most commonly used marker is chromogranin A (CgA), a glycoprotein that can provide information about neuroendocrine differentiation, functionality and tumour burden (Oberg et al, 2015). Plasma CgA is elevated in 50% to 100% of patients with GEP-NET and can also often be raised in non-functioning GEP-NET (Campana et al, 2007). Other markers include chromogranin B and C, gastrin, pancreatic polypeptide, somatostatin, glucagon, neurotensin and others, which may be useful as monitoring tools in specific circumstances and types of GEP-NET (Oberg et al, 2015). More recently, the ‘NETest’ represents a molecular measurement of a variety of different gene transcripts in the blood which may indicate the biological nature of the tumour and the extent of its progression (Modlin et al, 2015).
Table 1. Frequency of occurrence of NET primaries in a European cohort (Norwegian Registry of Cancer, NEC; n = 2013)* Primary (% of occurrence) Gastroenteropancreatic neuroendocrine tumours Small intestine
25.5
Colon
8
Rectum
7.2
Pancreas
6.9
Stomach
5.7
Appendix
4.8
Other primaries Unknown primary
13.7
Lung
21 * Data
Source: from a larger cohort in the US (Surveillance, Epidemiology, and End Results program, SEER; n = 17 312) showed comparable distribution, apart from increased frequency of rectum NET mainly in Afro-Caribbean (27%) people; and a higher frequency of pulmonary NET in white caucasian people (31.9%). Adapted from Hauso et al, 2008; Ramage et al, 2012 Other rare NET primaries include female gonads (2.4%), prostrate (1.5%), breast (1.6%), liver and biliary (1%)
Table 2. Grading for GEP NET according to ENETS criteria (Capelli et al, 2012) Grade
Mitotic count/10 HPF
Ki-67 index*
1
1
≤2
2
2–20
3–20
3
> 20
> 20
HPF: high-power field = 2 mm2, at least 40 fields at x 40 magnification evaluated in areas at highest mitotic density. *Percent of 2000 tumour cells in areas of highest nuclear labelling. Adapted from (Rindi et al, 2006). Further sub-division of G2 into G2/1 (Ki-67 < 10%) and G2/2 (Ki-67 10 –20%) has been proposed (12th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Barcelona, 2015), related to different and often more aggressive behaviour of higher grade G2 GEP-NET.
scan) (Boudreaux et al, 2010). These tests can give valuable information about the location of the primary tumour and presence and extent of systemic involvement; and also can help assessing the possible treatment response to somatostatin-related treatment modalities (Boudreaux et al, 2010). Nuclear medicine scans can also provide hints about the differentiation of a GEPNET, with somatostatin receptors being typically expressed in more well differentiated GEP-NET. If a poorly differentiated NET is suspected, fluorodeoxy-glucose (FDG) positron emission tomographic (PET) scans are superior (Rossana et al, 2015). For imaging of the liver, contrast magnet resonance imaging (MRI) is advised and should be especially added if surgical intervention is planned (Boudreaux et al, 2010; Ramage et al, 2012).
Imaging
Histological grading and tumour staging
Various imaging methods have been proposed for initial tumour detection and follow up (Vinik et al, 2010). Useful initial scans include dual phase (arterio-venous) computer tomographic (CT) scans of the thorax, abdomen and pelvis; and nuclear medicine scans (i.e. somatostatin receptor scintigraphy (SRS) ‘Octreotide’ scan, or, if available, the more advanced 68-Gallium
One of the most important aspects to tailor the optimal treatment for the GEP-NET patient is information about tumour grading, based on the Ki-67 proliferation index and the mitotic rate (Table 2). Patients with well-differentiated (grade 1 or grade 2) GEP-NET are usually managed with treatment with somatostatin analogues and further treatment such as
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■■
GEP-NET comprise a complex group of rare disorders with increasing incidence
■■
Symptoms are often non-specific and diagnosis is typically delayed by 5–7 years. Fewer than 50% of patients with GEP-NET show functioning symptoms
■■
Histological grading is a key step to allocate the patient to tailored and optimised treatment; fewer than 5% of the patients have a poorly differentiated neuroendocrine carcinoma
■■
Treatment with somatostatin analogues has been licensed for both control of functioning symptoms and to delay tumour progression in welldifferentiated GEP-NET
■■
The prognosis of patients with well-differentiated GEP-NET is often more favourable compared with other neoplasms and can exceed 10 years even in metastatic disease
surgery or peptide receptor radionuclide therapy (PRRT) can be considered (Rossana et al, 2016). Patients with poorly differentiated (grade 3) neuroendocrine carcinoma (NECA) should be referred to the oncology department with no delay. There are ongoing efforts to further improve the grading system of GEP-NET, which includes proposals to further subdivide grade 2 tumours, given the differences in behaviour of tumours within the currently wide range of the grade (Pelosi et al, 2014; Rindi et al, 2014). The TNM system stands for: ‘tumour’, related to the size and extent of the primary mass; ‘node’, related to metastatic involvement of the regional lymph nodes; and ‘metastasis’, related to metastatic spread elsewhere (Capelli et al, 2012). This system is the most widely used cancer staging system and also used for the staging of GEP-NET (Capelli et al, 2012). Several slightly differing staging systems are in use for GEPNET of different primaries, with varying cut-offs according to tumour size in midgut as compared with pancreatic NET (Capelli et al, 2012).
Immunostaining Important neuroendocr ine markers for histological immunostaining include CgA, synaptophysin and neural cell adhesion molecule (CD56).Additional staining for markers such as caudal-related homeobox transcription factor 2 (CDX-2; indicating a gastrointestinal NET) or thyroid transcription factor-1 (TTF-1; indicating a bronchopulmonary NET) can give valuable hints if the location of a small primary NET is not obvious. Others such as glucagon can be useful in specific circumstances. It is important to keep in mind that positive expression of these markers in the histological sample is useful for the diagnosis of a GEP-NET, but does not give information about the functioning status, which is defined by clinical symptoms and supported by raised levels of GEP-NET biomarkers in circulating blood and urine samples (Vinik et al, 2014).
Treatment
Once a GEP-NET has been diagnosed and the grading and staging has been complete, along with biochemistry testing and imaging, a tailored treatment plan can be discussed (Rossana S14
et al, 2016). In localised disease, surgical removal should be considered, regardless of the grade of the GEP-NET. In welldifferentiated GEP-NET, there often are surgical options even if the GEP-NET has spread to the liver (Boudreaux et al, 2010). If the patient is symptomatic related to a functioning GEP-NET, treatment with long-acting somatostatin analogues should be initiated. Somatostatin analogues are now also being used and licensed in an attempt to slow tumour progression (Rinke et al, 2009; Caplin et al, 2014). PRRT, which uses radiolabelled somatostatin to target the GEP-NET, is another established treatment modality for well differentiated GEP-NET (Rossana et al, 2016).Various further treatment modalities are available, which include trans-arterial embolisation or chemoembolisation for hepatic metastases, biological treatment modalities such as mammalian target of rapamycin (mTOR) inhibitors or Sunitinib (mainly used in patients with well-differentiated pNET; (Raymond et al, 2011,Yao et al, 2011)); or oncological treatment options, i.e. Streptozocin in well and moderately differentiated pNET (Falconi et al, 2006); and platinum-based chemotherapy in poorly differentiated NECA and goblet cell carcinomas of the appendix (Ahlman et al, 2008).
Conclusion The clinical management of GEP-NET can be challenging and typically involves a multidisciplinary approach, with endocrinology, histopathology, radiology, nuclear medicine, surgeons, gastroenterology and oncology being core members of the team. Patients will usually remain under the care of endocrinology, but should be referred to oncology with no delay if a poorly differentiated NECA has been diagnosed. It should be highlighted that in many GEP-NET even the presence of liver metastases may have no immediate effects on the short-term prognosis of the patient and should not directly influence possible end-of-life decisions in inpatients. Overall 5-year survival in all patients with GEP-NET was reported as 77.5% more than 10 years ago (Panzuto et al, 2005), with powerful additional treatment options being available since the publication of these results (Caplin et al, 2014; Rinke et al, 2009, Raymond et al, 2011; Yao et al, 2011). Physicians and nurses who have limited experience with the management of NET and their respective treatment modalities are also encouraged to seek advice from one of the eight ENETS Centres of Excellence in the UK. BJN Declaration of interest: none Ahlman H, Nilsson O, McNicol AM et al (2008) Poorly-differentiated endocrine carcinomas of midgut and hindgut origin. Neuroendocrinology 87(1): 40–6. doi: 10.1159/000109976 Boudreaux JP, Klimstra DS, Hassan MM et al (2010) The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: welldifferentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 39(6): 753–66. doi: 10.1097/MPA.0b013e3181ebb2a5 Campana D, Nori F, Piscitelli L et al (2007) Chromogranin A: is it a useful marker of neuroendocrine tumors? J Clin Oncol 25(15): 1967–73. doi: 10.1200/JCO.2006.10.1535 Capelli P, Fassan M, Scarpa A (2012) Pathology - grading and staging of GEPNETs. Best Pract Res Clin Gastroenterol 26(6): 705–17. doi: 10.1016/j. bpg.2013.01.003 Caplin ME, Baudin E, Ferolla P et al (2015) Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert
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KEY POINTS
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consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol 26(8): 1604–20. doi: 10.1093/annonc/ mdv041 Caplin ME, Pavel M, Cwikła JB et al (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371(3): 224–33. doi: 10.1056/NEJMoa1316158 Falconi M, Plockinger U, Kwekkeboom DJ et al (2006) Well-differentiated pancreatic nonfunctioning tumors/carcinoma. Neuroendocrinology 84(3): 196–211. doi: 10.1159/000098012 Hauso O, Gustafsson BI, Kidd M et al (2008) Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer 113(10): 2655–64. doi: 10.1002/cncr.23883 Jann H, Roll S, Couvelard A et al (2011) Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. Cancer 117(15): 3332–41. doi: 10.1002/cncr.25855 Massimino K, Harrskog O, Pommier S, Pommier R (2013) Octreotide LAR and bolus octreotide are insufficient for preventing intraoperative complications in carcinoid patients. J Surg Oncol 107(8): 842–6. doi: 10.1002/jso.23323 Modlin IM, Kidd M, Bodei L, Drozdov I, Aslanian H (2015) The clinical utility of a novel blood-based multi-transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract. Am J Gastroenterol 110(8): 1223–32. doi: 10.1038/ajg.2015.160 Oberg K, Modlin IM, De Herder W et al (2015) Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol 16(9): e435–46. doi: 10.1016/ S1470-2045(15)00186-2 Panzuto F, Nasoni S, Falconi M et al (2005) Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 12(4): 1083–92. doi: 10.1677/ erc.1.01017 Pape U-F, Niederle B, Costa F et al (2016) Consensus Guidelines for Neuroendocrine Neoplasms of the Appendix (Excluding Goblet Cell Carcinomas). Neuroendocrinology. doi: 10.1159/000443165 Pelosi G, Papotti M, Rindi G, Scarpa A (2014) Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. Endocr Pathol 25(2): 151–64. doi: 10.1007/s12022-014-9320-0 Ramage JK, Ahmed A, Ardill J et al (2012) Guidelines for the management
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of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 61(1): 6–32. doi: 10.1136/gutjnl-2011-300831 Raymond E, Dahan L, Raoul J-L et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6): 501–13. doi: 10.1056/NEJMoa1003825 Rindi G, Klöppel G, Alhman H et al (2006) TNM staging of foregut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449(4): 395–401. doi: 10.1007/s00428-006-0250-1 Rindi G, Petrone G, Inzani F (2014) The 2010 WHO classification of digestive neuroendocrine neoplasms: a critical appraisal four years after its introduction. Endocr Pathol 25(2): 186–92. doi: 10.1007/s12022-014-9313-z Rinke A, Müller H-H, Schade-Brittinger C et al (2009) Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 27(28): 4656–63. doi: 10.1200/JCO.2009.22.8510 Rossana B, Silvia R, Mariangela T et al (2016) Gastrointestinal neuroendocrine tumors: searching the optimal treatment strategy-A literature review. Crit Rev Oncol Hematol 98: 264–74. doi: 10.1016/j.critrevonc.2015.11.003 Ter-Minassian M, Chan JA, Hooshmand SM et al (2013) Clinical presentation, recurrence, and survival in patients with neuroendocrine tumors: results from a prospective institutional database. Endocr Relat Cancer 20(2): 187–96. doi: 10.1530/ERC-12-0340 Vinik A, Feliberti E, Perry RR (2014) Carcinoid Tumors. In: De Groot LJ BeckPeccoz P, Chrousos G et al (eds) Endotext. South Dartmouth (MA) Vinik AI, Woltering EA, Warner RR et al (2010) NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas 39(6) 713-34 Yao JC, Shah MH, Ito T et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6): 514–23. doi: 10.1056/ NEJMoa1009290
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Incidence and prevalence
Gastroenteropancreatic neuroendocrine tumours (GEP-NET) represent a heterogeneous family of diseases of often challenging clinical management. Although many GEP-NET are slow progressing and frequently less aggressive than neoplasms of other origin, they can metastasise and reduce the life span of the patient. GEP-NET can be functioning (secreting hormones that may cause symptoms and organ damage), but some 60% are non-functioning. Thorough clinical assessment including family history, biochemical tests, radiology and nuclear medicine scans, and histological confirmation are important to tailor the optimal treatment of GEP-NET, which should be managed with a multidisciplinary approach and mainly guided by tumour grading and staging, functioning status, and location of the primary lesion. Key words: Neuroendocrine tumour ■ Grading ■ Staging ■ Biomarkers Somatostatin
■
G
astroenteropancreatic neuroendocrine tumours (GEP-NET) are often slow growing neoplasms that may produce hormones causing functioning symptoms (caused by secreting hormones) (Rossana et al, 2016). GEP-NET include neuroendocrine tumours of the stomach, pancreas, small bowel, appendix, colon and rectum (Vinik et al, 2014). Neuroendocrine tumours of pulmonary origin often need different management (Caplin et al, 2015) and are not included in this review. GEP-NET can spread, if not diagnosed early; and therefore show cancer-like behaviour. Most GEP-NET are well differentiated, whereas poorly differentiated GEP-NET are rare (5% of all GEP-NET) and usually more aggressive (Vinik et al, 2014).Treatment options for GEP-NET have significantly improved recently and patients may survive for many years with good symptom control (Rossana et al, 2016). Louise Davies, Neuroendocrine Specialist Nurse, ARDEN NET Centre, European Neuroendocrine Tumour Society Centre of Excellence, University Hospitals Coventry and Warwickshire NHS Trust Martin O Weickert, Lead The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence, University Hospitals Coventry & Warwickshire NHS Trust (UHCW); and Centre for Applied Biological and Exercise Sciences, Coventry University Accepted for publication: February 2016
S12
The incidence of GEP-NET has more recently been reported to be 5.25/100 000 (Vinik et al, 2014). Therefore, in the UK some 3000 newly diagnosed patients each year can be expected. Prolonged survival further contributes to a raising prevalence. Median survival in metastatic NET of pancreatic origin has been reported to be between 4.7 and 7.4 years (Jann et al, 2011;Ter-Minassian et al, 2013). In well-differentiated midgut NET, even with metastatic liver disease, survival appears to be even better, in some of the studies over 10 years (Jann et al, 2011; Ter-Minassian et al, 2013). Prime age for developing a GEP-NET is the sixth and seventh decade, with the exception of often benign-behaving, well-differentiated NET of the appendix, most frequently incidentally diagnosed following appendectomy (3-5/1000 appendectomies) (Pape et al, 2016) (a condition that often presents also in young patients). In paediatric patients with appendiceal NET, long-term outcomes are excellent, even in higher stages, with the reasons for better prognosis not being completely understood (Pape et al, 2016). Apart from tumours of rectum origin, GEP-NET appear to be less common in South Asian and Afro-Caribbean populations (Vinik et al, 2010). The frequency of occurrence of GEPNET according to the location of the primary tumour is shown in Table 1.
Clinical presentation Many GEP-NET are clinically silent for many years, often presenting for the first time after they have metastasised.As many as 71% of patients have metastatic disease when diagnosed (Vinik et al, 2014). Aside from the liver, common sites of metastases include the regional lymph nodes and, less frequently, the bones. The likelihood of metastases directly relates to tumour size, with a less than 15% likelihood of a metastatic tumour in a small bowel NET, that is 2 cm (Vinik et al, 2014).The average time from first onset of tumour-related symptoms to diagnosis is approximately 5–7 years and likely to be longer in non-functioning GEP-NET (Vinik et al, 2010). Symptoms are often unspecific and can mimic various other disorders including irritable bowel syndrome, coeliac disease, food intolerance, or inflammatory bowel disorders. Behaviour is not predictable and can change into more aggressive types with poor prognosis (Ahlman et al, 2008). Functioning symptoms are related to excess secretion of hormones by the GEP-NET that can cause symptoms such as flushing and diarrhoea. ‘Carcinoid crisis’ represents severe
© 2016 MA Healthcare Ltd
ABSTRACT
British Journal of Nursing, 2016, (Oncology Supplement) Vol 25, No 4
British Journal of Nursing. Downloaded from magonlinelibrary.com by 129.096.252.188 on February 29, 2016. For personal use only. No other uses without permission. . All rights reserved.
CLINICAL
and possibly life-threatening features of carcinoid syndrome (Massimino et al, 2013) and may include flushing, diarrhoea, bronchospasm, changes in the heart rate, hyperthermia, and blood pressure fluctuations with predominance of hypotension (Massimino et al, 2013). Triggers for carcinoid crisis include emotional stress, pharmacologic agents, especially catecholamines, angiography, induction of anaesthesia; and sometimes even minor surgical procedures (Massimino et al, 2013). Treatment with somatostatin analogues including intravenous infusion, especially in functioning GEP-NET may reduce the risk of carcinoid crisis i.e. when manipulating the tumour during surgery, although efficacy of this measure has been questioned more recently (Massimino et al, 2013).
Screening for GEP-NET Initial assessment for GEP-NET includes a full clinical and family history.Although most GEP-NET appear spontaneously, the presence of genetic syndromes such as multiple endocrine neoplasia type-1 (MEN-1) needs to be excluded (Vinik et al, 2014). It is important to keep in mind that absence of functioning symptoms is not reliable to exclude the presence of a GEP-NET. If there is reasonable suspicion for a GEP-NET, biomarkers in circulating blood and urine should be sampled under standardised conditions, for example urine sampling under restricted diet to improve the sensitivity of the test (Oberg et al, 2015), and imaging can be considered (Boudreaux et al, 2010; Ramage et al, 2012).
Biomarkers
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Biomarkers in blood and urine are important tools for screening, as well as monitoring of treatment success and possible progression (Oberg et al, 2015). Measurement of 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine sample was the initially established biochemical screening test, but sensitivity is poor and sampling requires various dietary restrictions (Oberg et al, 2015). Fasted ‘gut hormones’ in circulating blood are now routinely used both in screening and follow-up. The most commonly used marker is chromogranin A (CgA), a glycoprotein that can provide information about neuroendocrine differentiation, functionality and tumour burden (Oberg et al, 2015). Plasma CgA is elevated in 50% to 100% of patients with GEP-NET and can also often be raised in non-functioning GEP-NET (Campana et al, 2007). Other markers include chromogranin B and C, gastrin, pancreatic polypeptide, somatostatin, glucagon, neurotensin and others, which may be useful as monitoring tools in specific circumstances and types of GEP-NET (Oberg et al, 2015). More recently, the ‘NETest’ represents a molecular measurement of a variety of different gene transcripts in the blood which may indicate the biological nature of the tumour and the extent of its progression (Modlin et al, 2015).
Table 1. Frequency of occurrence of NET primaries in a European cohort (Norwegian Registry of Cancer, NEC; n = 2013)* Primary (% of occurrence) Gastroenteropancreatic neuroendocrine tumours Small intestine
25.5
Colon
8
Rectum
7.2
Pancreas
6.9
Stomach
5.7
Appendix
4.8
Other primaries Unknown primary
13.7
Lung
21 * Data
Source: from a larger cohort in the US (Surveillance, Epidemiology, and End Results program, SEER; n = 17 312) showed comparable distribution, apart from increased frequency of rectum NET mainly in Afro-Caribbean (27%) people; and a higher frequency of pulmonary NET in white caucasian people (31.9%). Adapted from Hauso et al, 2008; Ramage et al, 2012 Other rare NET primaries include female gonads (2.4%), prostrate (1.5%), breast (1.6%), liver and biliary (1%)
Table 2. Grading for GEP NET according to ENETS criteria (Capelli et al, 2012) Grade
Mitotic count/10 HPF
Ki-67 index*
1
1
≤2
2
2–20
3–20
3
> 20
> 20
HPF: high-power field = 2 mm2, at least 40 fields at x 40 magnification evaluated in areas at highest mitotic density. *Percent of 2000 tumour cells in areas of highest nuclear labelling. Adapted from (Rindi et al, 2006). Further sub-division of G2 into G2/1 (Ki-67 < 10%) and G2/2 (Ki-67 10 –20%) has been proposed (12th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Barcelona, 2015), related to different and often more aggressive behaviour of higher grade G2 GEP-NET.
scan) (Boudreaux et al, 2010). These tests can give valuable information about the location of the primary tumour and presence and extent of systemic involvement; and also can help assessing the possible treatment response to somatostatin-related treatment modalities (Boudreaux et al, 2010). Nuclear medicine scans can also provide hints about the differentiation of a GEPNET, with somatostatin receptors being typically expressed in more well differentiated GEP-NET. If a poorly differentiated NET is suspected, fluorodeoxy-glucose (FDG) positron emission tomographic (PET) scans are superior (Rossana et al, 2015). For imaging of the liver, contrast magnet resonance imaging (MRI) is advised and should be especially added if surgical intervention is planned (Boudreaux et al, 2010; Ramage et al, 2012).
Imaging
Histological grading and tumour staging
Various imaging methods have been proposed for initial tumour detection and follow up (Vinik et al, 2010). Useful initial scans include dual phase (arterio-venous) computer tomographic (CT) scans of the thorax, abdomen and pelvis; and nuclear medicine scans (i.e. somatostatin receptor scintigraphy (SRS) ‘Octreotide’ scan, or, if available, the more advanced 68-Gallium
One of the most important aspects to tailor the optimal treatment for the GEP-NET patient is information about tumour grading, based on the Ki-67 proliferation index and the mitotic rate (Table 2). Patients with well-differentiated (grade 1 or grade 2) GEP-NET are usually managed with treatment with somatostatin analogues and further treatment such as
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GEP-NET comprise a complex group of rare disorders with increasing incidence
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Symptoms are often non-specific and diagnosis is typically delayed by 5–7 years. Fewer than 50% of patients with GEP-NET show functioning symptoms
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Histological grading is a key step to allocate the patient to tailored and optimised treatment; fewer than 5% of the patients have a poorly differentiated neuroendocrine carcinoma
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Treatment with somatostatin analogues has been licensed for both control of functioning symptoms and to delay tumour progression in welldifferentiated GEP-NET
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The prognosis of patients with well-differentiated GEP-NET is often more favourable compared with other neoplasms and can exceed 10 years even in metastatic disease
surgery or peptide receptor radionuclide therapy (PRRT) can be considered (Rossana et al, 2016). Patients with poorly differentiated (grade 3) neuroendocrine carcinoma (NECA) should be referred to the oncology department with no delay. There are ongoing efforts to further improve the grading system of GEP-NET, which includes proposals to further subdivide grade 2 tumours, given the differences in behaviour of tumours within the currently wide range of the grade (Pelosi et al, 2014; Rindi et al, 2014). The TNM system stands for: ‘tumour’, related to the size and extent of the primary mass; ‘node’, related to metastatic involvement of the regional lymph nodes; and ‘metastasis’, related to metastatic spread elsewhere (Capelli et al, 2012). This system is the most widely used cancer staging system and also used for the staging of GEP-NET (Capelli et al, 2012). Several slightly differing staging systems are in use for GEPNET of different primaries, with varying cut-offs according to tumour size in midgut as compared with pancreatic NET (Capelli et al, 2012).
Immunostaining Important neuroendocr ine markers for histological immunostaining include CgA, synaptophysin and neural cell adhesion molecule (CD56).Additional staining for markers such as caudal-related homeobox transcription factor 2 (CDX-2; indicating a gastrointestinal NET) or thyroid transcription factor-1 (TTF-1; indicating a bronchopulmonary NET) can give valuable hints if the location of a small primary NET is not obvious. Others such as glucagon can be useful in specific circumstances. It is important to keep in mind that positive expression of these markers in the histological sample is useful for the diagnosis of a GEP-NET, but does not give information about the functioning status, which is defined by clinical symptoms and supported by raised levels of GEP-NET biomarkers in circulating blood and urine samples (Vinik et al, 2014).
Treatment
Once a GEP-NET has been diagnosed and the grading and staging has been complete, along with biochemistry testing and imaging, a tailored treatment plan can be discussed (Rossana S14
et al, 2016). In localised disease, surgical removal should be considered, regardless of the grade of the GEP-NET. In welldifferentiated GEP-NET, there often are surgical options even if the GEP-NET has spread to the liver (Boudreaux et al, 2010). If the patient is symptomatic related to a functioning GEP-NET, treatment with long-acting somatostatin analogues should be initiated. Somatostatin analogues are now also being used and licensed in an attempt to slow tumour progression (Rinke et al, 2009; Caplin et al, 2014). PRRT, which uses radiolabelled somatostatin to target the GEP-NET, is another established treatment modality for well differentiated GEP-NET (Rossana et al, 2016).Various further treatment modalities are available, which include trans-arterial embolisation or chemoembolisation for hepatic metastases, biological treatment modalities such as mammalian target of rapamycin (mTOR) inhibitors or Sunitinib (mainly used in patients with well-differentiated pNET; (Raymond et al, 2011,Yao et al, 2011)); or oncological treatment options, i.e. Streptozocin in well and moderately differentiated pNET (Falconi et al, 2006); and platinum-based chemotherapy in poorly differentiated NECA and goblet cell carcinomas of the appendix (Ahlman et al, 2008).
Conclusion The clinical management of GEP-NET can be challenging and typically involves a multidisciplinary approach, with endocrinology, histopathology, radiology, nuclear medicine, surgeons, gastroenterology and oncology being core members of the team. Patients will usually remain under the care of endocrinology, but should be referred to oncology with no delay if a poorly differentiated NECA has been diagnosed. It should be highlighted that in many GEP-NET even the presence of liver metastases may have no immediate effects on the short-term prognosis of the patient and should not directly influence possible end-of-life decisions in inpatients. Overall 5-year survival in all patients with GEP-NET was reported as 77.5% more than 10 years ago (Panzuto et al, 2005), with powerful additional treatment options being available since the publication of these results (Caplin et al, 2014; Rinke et al, 2009, Raymond et al, 2011; Yao et al, 2011). Physicians and nurses who have limited experience with the management of NET and their respective treatment modalities are also encouraged to seek advice from one of the eight ENETS Centres of Excellence in the UK. BJN Declaration of interest: none Ahlman H, Nilsson O, McNicol AM et al (2008) Poorly-differentiated endocrine carcinomas of midgut and hindgut origin. Neuroendocrinology 87(1): 40–6. doi: 10.1159/000109976 Boudreaux JP, Klimstra DS, Hassan MM et al (2010) The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: welldifferentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 39(6): 753–66. doi: 10.1097/MPA.0b013e3181ebb2a5 Campana D, Nori F, Piscitelli L et al (2007) Chromogranin A: is it a useful marker of neuroendocrine tumors? J Clin Oncol 25(15): 1967–73. doi: 10.1200/JCO.2006.10.1535 Capelli P, Fassan M, Scarpa A (2012) Pathology - grading and staging of GEPNETs. Best Pract Res Clin Gastroenterol 26(6): 705–17. doi: 10.1016/j. bpg.2013.01.003 Caplin ME, Baudin E, Ferolla P et al (2015) Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert
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of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 61(1): 6–32. doi: 10.1136/gutjnl-2011-300831 Raymond E, Dahan L, Raoul J-L et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6): 501–13. doi: 10.1056/NEJMoa1003825 Rindi G, Klöppel G, Alhman H et al (2006) TNM staging of foregut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449(4): 395–401. doi: 10.1007/s00428-006-0250-1 Rindi G, Petrone G, Inzani F (2014) The 2010 WHO classification of digestive neuroendocrine neoplasms: a critical appraisal four years after its introduction. Endocr Pathol 25(2): 186–92. doi: 10.1007/s12022-014-9313-z Rinke A, Müller H-H, Schade-Brittinger C et al (2009) Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 27(28): 4656–63. doi: 10.1200/JCO.2009.22.8510 Rossana B, Silvia R, Mariangela T et al (2016) Gastrointestinal neuroendocrine tumors: searching the optimal treatment strategy-A literature review. Crit Rev Oncol Hematol 98: 264–74. doi: 10.1016/j.critrevonc.2015.11.003 Ter-Minassian M, Chan JA, Hooshmand SM et al (2013) Clinical presentation, recurrence, and survival in patients with neuroendocrine tumors: results from a prospective institutional database. Endocr Relat Cancer 20(2): 187–96. doi: 10.1530/ERC-12-0340 Vinik A, Feliberti E, Perry RR (2014) Carcinoid Tumors. In: De Groot LJ BeckPeccoz P, Chrousos G et al (eds) Endotext. South Dartmouth (MA) Vinik AI, Woltering EA, Warner RR et al (2010) NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas 39(6) 713-34 Yao JC, Shah MH, Ito T et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6): 514–23. doi: 10.1056/ NEJMoa1009290
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