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Gastro-Enteropancreatic Neuroendocrine Tumor

Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are rare and complex neoplasms. The term comprises pre-neoplastic lesions, well-differentiated tumors, and poorly differentiated carcinomas - all of them originating from neuroendocrine cells -, as well as mixed neoplasms of variable malignancy. They may develop anywhere along the gastrointestinal tract and differ in the release of biologically active substances. Accordingly, the clinical presentation is highly heterogeneous, ranging from local mass effects to carcinoid syndromes.


Presentation

The clinical presentation largely depends on the site of the tumor and the functionality of tumor cells. Most GEP-NET are non-functional, with affected individuals remaining asymptomatic for prolonged periods of time. The majority of GEP-NET are slowly growing neoplasms, but mass effects may eventually be exerted by the primary tumor or by metastases. Non-specific gastrointestinal disorders such as abdominal pain, nausea, vomiting, diarrhea, and constipation are most commonly reported to this end, and they may be misrelated to irritable bowel syndrome [1] [2]. In the long term, patients tend to lose their appetite and weight. Gastrointestinal hemorrhages may lead to melena, hematochezia, and anemia, but these are rare occurrences. Masses interfering with bile secretion into the duodenum may induce jaundice. Larger GEP-NET may be palpable [3].

Those tumors that do release mediators may provoke early complaints comprising the so-called carcinoid syndrome [4]. These are due to the systemic effects of the substances released by the tumor cells, which vary according to their secretion profile. Diarrhea, hot flushes, bronchoconstriction, and palpitations are most frequently described. Palpitations are suggestive of cardiac damage, and endomyocardial fibrosis and/or tricuspid and pulmonary insufficiency - commonly referred to as "carcinoid heart disease" - may indeed have fatal consequences [5] [6].

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  • While sunitinib has already been approved for the treatment of GEP-NET, a plethora of other tyrosine kinase inhibitors are currently tested in clinical trials.[symptoma.com]
  • PI3K/AKT/mTOR is the central regulator of a plethora of downstream events, including cell proliferation, apoptosis, cell survival, differentiation, angiogenesis, and cell migration.[frontiersin.org]
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  • Patients with baseline renal impairment may be at greater risk of toxicity. Perform more frequent assessments of renal function in patients with mild or moderate impairment.[novartis.com]
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Workup

Diagnostic imaging is the basis of GEP-NET detection. Indeed, these tumors are regularly identified during imaging procedures realized for unrelated reasons. Endoscopy, endoscopic ultrasonography, abdominal ultrasound, contrast-enhanced computed tomography or magnetic resonance imaging, and octreotide scintigraphy are most commonly employed to this end. The latter techniques are very useful for tumor staging, too. While GEP-NET initially metastasize to the regional lymph nodes, the liver, lungs, and bones should be examined for distant metastases [3].

Tissue samples have to be obtained to confirm the diagnosis of GEP-NET and to proceed with tumor grading. The microscopic examination of hematoxylin and eosin-stained sections allows for the morphological characterization of tumor cells and the evaluation of the tumor's demarcation to healthy tissue. Furthermore, the mitotic index may be determined in this step. Immunohistochemical analyses should then be carried out to assess the expression of proliferation marker Ki67 and to check for pan-neuroendocrine markers like chromogranin A, neuron-specific enolase, and synaptophysin [4].

According to the WHO classification of digestive neuroendocrine neoplasms, either one of three grades may be assigned to the tumor: Well-differentiated tumors with low expression of Ki67 and few mitotic figures are classified as G1, GEP-NET of intermediate differentiation are classified as G2, and G3 corresponds to poorly differentiated carcinomas with Ki67 and mitotic indices of >20%. Finally, mixed tumors with neuroendocrine and non-neuroendocrine components as well as hyperplastic or dysplastic pre-neoplastic lesions are defined separately [7].

Of note, the mediators released by functional GEP-NET, or the corresponding metabolites, may be detected in blood and urine samples. For instance, serotonin may be produced by GEP-NET and may be metabolized to 5-hydroxyindoleacetic acid. Increased levels of urinary 5-hydroxyindoleacetic acid have been stated to be diagnostic for neuroendocrine tumors. While all patients diagnosed with GEP-NET should undergo a thorough cardiological examination, this is particularly true when functional tumors release serotonin [1].

Treatment

Management strategies include surgery, radiotherapy, and cytotoxic chemotherapy, as well as the administration of somatostatin analogs and novel biological agents such as sunitinib and everolimus [1] [8]:

  • The complete resection of the tumor is curative but may be difficult to achieve in the case of metastatic disease. In an effort to alleviate symptoms and increase the quality of life, cytoreductive surgery is usually recommended if a cure is deemed unattainable. Debulking may be repeated as needed, and the surgical approach may be complemented by radiofrequency ablation, laser ablation, embolization, cryotherapy, and similar techniques to decrease the tumor burden.
  • Chemotherapy comprising streptozotocin, 5-fluorouracil, and doxorubicin may be indicated to inhibit the proliferation of tumor cells. An alternative chemotherapeutic regimen includes platinum and etoposide. In general, chemotherapy is to be considered an adjuvant strategy in the treatment of poorly differentiated GEP-NET with high expression of Ki67 and high mitotic indices.
  • Treatment with radioactive octreotide derivatives has been shown to induce tumor shrinkage and clinical improvement. External radiation therapy is recommended only for metastases of the skeleton and brain.
  • Somatostatin analogs such as octreotide and lanreotide are successfully used to control carcinoid syndrome. These drugs should also be applied in preparation for interventions to avoid carcinoid crises [9]. The medical treatment of GEP-NET may be supplemented by the application of interferon-α and loperamide or diphenoxylate. While the latter mitigate diarrhea, the former exerts anti-secretory, anti-proliferation, and anti-angiogenic effects.
  • In recent years, molecular-targeted therapies have been intensively studied regarding their efficacy against GEP-NET. While sunitinib has already been approved for the treatment of GEP-NET, a plethora of other tyrosine kinase inhibitors are currently tested in clinical trials [10]. On the other hand, mTOR inhibitors like everolimus have been shown to inhibit cell growth, proliferation, and angiogenesis.
  • Those patients with bilobar liver involvement without extrahepatic disease may eventually be considered for liver transplantation. Liver transplantation may be carried out with curative or palliative intent.

Prognosis

The prognosis largely depends on the tumor grade and stage at the time of diagnosis:

  • While G1 tumors are expected to have a low malignant potential, poorly differentiated GEP-NET classified as G3 are likely to invade adjacent tissues and to form metastases [7]. Median survival times of patients with G1 tumors exceed 10 years, but those who are diagnosed with highly malignant neoplasms are likely to die within less than one [11].
  • Fortunately, more and more tumors are detected during early stages. Localized disease is associated with long-term survival; regional tumor spread more or less halves the remaining time of life, and patients who are diagnosed with distant metastases have a severely limited life expectancy [11].

Etiology

Most GEP-NET are sporadic, but increased familial incidence has been observed and the disease has been related to hereditary syndromes. In this context, multiple endocrine neoplasia type 1, neurofibromatosis type 1, and von Hippel-Lindau disease shall be mentioned as predisposing conditions [8]. Beyond that, distinct genetic polymorphisms have been speculated to modulate the individual risk for GEP-NET [12] [13], but reliable data have yet to be provided. Similarly, little is known about the possible influence of environmental factors [14].

Epidemiology

Reported incidence rates have multiplied in the last decades: In the 1970s, the annual incidence of neuroendocrine tumors had been estimated at 1 in 100,000 inhabitants, but in 2004, this number had risen to 5 in 100,000 [4] [11]. The apparent increase in incidence is likely due to the extensive implementation of preventive gastroenterology procedures and investigations [7], but the comprehensive use of proton pump inhibitors has also been discussed as a possible cause [1]. Patients may live for years with GEP-NET, which is why the prevalence is as high as 35 in 100,000 [11].

Females and males are affected equally, and the average patient presents during their seventh decade of life. The latter applies to all kinds of GEP-NET, the majority of which develop in the foregut and small intestine, except for neuroendocrine tumors of the appendix. These are more commonly diagnosed in mid-adulthood. Furthermore, early onset is characteristic of syndromic tumors [4] [11].

Sex distribution
Age distribution

Pathophysiology

GEP-NET may be functional and release a variety of peptides and amines, e.g., serotonin, histamine, gastrin, insulin, glucagon, adrenocorticotropic hormone, and growth hormone, among others [1]. Tumor cells are not part of the regulatory feedback loops, and the aforementioned mediators are usually released excessively. They may exert systemic effects or interfere with the function of determined organs, but the clinical presentation does not allow for conclusions on the localization of the primary tumor. They may suggest, however, the presence of hepatic metastases: While mediators released in the bowel may be metabolized in the liver, those secreted in the liver directly pass into the systemic circulation [6].

Beyond that, GEP-NET are known to induce mesenteric fibrosis. Interestingly, the fibroblastic reaction to be observed in the mesenterium is independent of the release of mediators as described above. It may lead to an intermittent partial obstruction of the bowel and the impingement or encasement of mesenteric vessels, and has been reported in patients with functional and non-functional GEP-NET [3]. Mesenteric metastases may be involved in the pathogenesis of this condition [15].

Prevention

The etiology and pathogenesis of GEP-NET are incompletely understood, so recommendations can hardly be given to prevent the disease. In general, treatment should be initiated as early as possible to reduce morbidity and mortality. If the patient is eligible for surgery and the tumor is considered resectable, every possible effort should be made to remove it entirely. Otherwise, local and systemic complications may be prevented following treatment strategies as described above. The risk of a carcinoid crisis should be taken into account when manipulating the tumor and/or using anesthetics, and the appropriate measures should be taken to inhibit the release of bioactive substances by the tumor cells [9].

Summary

GEP-NET is a very broad term comprising distinct neoplasms to be found along the gastrointestinal tract. GEP-NET have traditionally been divided according to tumor locations [8]:

  • GEP-NET of the foregut may develop in the esophagus, stomach, proximal duodenum, liver, or pancreas.
  • GEP-NET of the midgut may be detected in the distal duodenum, ileum, jejunum, ascending colon and proximal two-thirds of the transverse colon.
  • Tumors of the distal third of the transverse colon, descending colon, sigmoid colon, and rectum are referred to as GEP-NET of the hindgut.

GEP-NET originate from neuroendocrine cells, i.e., tumor cells may be able to produce and release mediators and to induce characteristic hormonal syndromes. Because GEP-NET have formerly been referred to as carcinoids, the respective syndromes are usually called carcinoid syndromes. However, GEP-NET may be non-functional, and the clinical presentation may be limited to local mass effects. What's more, the relatively high incidence of GEP-NET in autopsy specimens suggests that many of these tumors never cause clinical disorders [3].

Patient Information

Gastroenteropancreatic neuroendocrine tumors (GEP-NET) is a generic term referring to a heterogeneous group of neoplasms originating from neuroendocrine cells in the digestive system. Neuroendocrine cells are able to release mediators and hormones, such as serotonin, histamine, gastrin, insulin, and glucagon. Accordingly, GEP-NET may secrete these biologically active substances into the circulation. Patients may then develop symptoms like diarrhea, hot flushes, dyspnea, cough, and palpitations. These symptoms don't allow for conclusions regarding the localization and size of the causative tumor, which are usually determined employing diagnostic imaging techniques. Indeed, imaging procedures carried out fo unrelated reasons may reveal the presence of non-functional GEP-NET: These tumors don't release any of the aforementioned substances and tend to grow slowly. They may cause non-specific gastrointestinal disorders such as abdominal pain, nausea, vomiting, diarrhea, and constipation, but they tend to go unnoticed for prolonged periods of time.

Regardless of the functionality of the tumor, surgery is the only potentially curative therapeutic strategy. The complete removal of the tumor may not be feasible if metastases are encountered, and patients diagnosed with advanced-stage GEP-NET may be considered for surgical debulking, molecular radiotherapy, or chemotherapy to decrease the tumor burden. Additionally, medical therapy may help to inhibit tumor growth and the secretion of mediators and hormones. The patient's quality of life may be increased this way.

In sum, the outcome largely depends on the tumor's properties - GEP-NET may be benign or malignant - and the tumor stage at the time of diagnosis. Patients with benign GEP-NET who are diagnosed early have a favorable prognosis; those who are found to suffer from metastatic, malignant GEP-NET have a poor prognosis.

References

Article

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  2. Plöckinger U, Rindi G, Arnold R, et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology. 2004; 80(6):394-424.
  3. Plöckinger U, Wiedenmann B. Diagnosis of non-functioning neuro-endocrine gastro-enteropancreatic tumours. Neuroendocrinology. 2004; 80 Suppl 1:35-38.
  4. Oberg K, Jelic S. Neuroendocrine gastroenteropancreatic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up. Ann Oncol. 2009; 20 Suppl 4:150-153.
  5. Hayes AR, Davar J, Caplin ME. Carcinoid Heart Disease: A Review. Endocrinol Metab Clin North Am. 2018; 47(3):671-682.
  6. Pasricha G, Padhi P, Daboul N, Monga DK. Management of Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEPNETs): A Review. Clin Ther. 2017; 39(11):2146-2157.
  7. Rindi G, Petrone G, Inzani F. The 2010 WHO classification of digestive neuroendocrine neoplasms: a critical appraisal four years after its introduction. Endocr Pathol. 2014; 25(2):186-192.
  8. Díez M, Teulé A, Salazar R. Gastroenteropancreatic neuroendocrine tumors: diagnosis and treatment. Ann Gastroenterol. 2013; 26(1):29-36.
  9. Woltering EA, Wright AE, Stevens MA, et al. Development of effective prophylaxis against intraoperative carcinoid crisis. J Clin Anesth. 2016; 32:189-193.
  10. Grillo F, Florio T, Ferraù F, et al. Emerging multitarget tyrosine kinase inhibitors in the treatment of neuroendocrine neoplasms. Endocr Relat Cancer. 2018; 25(9):R453-r466.
  11. Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008; 26(18):3063-3072.
  12. Dumanski JP, Rasi C, Björklund P, et al. A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors. Endocr Relat Cancer. 2017; 24(8):427-443.
  13. Karakaxas D, Gazouli M, Coker A, et al. Genetic polymorphisms of inflammatory response gene TNF-alpha and its influence on sporadic pancreatic neuroendocrine tumors predisposition risk. Med Oncol. 2014; 31(10):241.
  14. Hallet J, Law CH, Karanicolas PJ, Saskin R, Liu N, Singh S. Rural-urban disparities in incidence and outcomes of neuroendocrine tumors: A population-based analysis of 6271 cases. Cancer. 2015; 121(13):2214-2221.
  15. Rodríguez Laval V, Pavel M, Steffen IG, et al. Mesenteric Fibrosis in Midgut Neuroendocrine Tumors: Functionality and Radiological Features. Neuroendocrinology. 2018; 106(2):139-147.

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Last updated: 2019-07-11 19:55