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Enterochromaffin cell neuroendocrine tumor

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Overview

Enterochromaffin cell neuroendocrine tumors (ECNETs) are rare malignancies arising from enterochromaffin cells, typically found in the gastrointestinal tract 1. These tumors are clinically significant due to their potential for both local invasion and metastasis, often leading to symptoms such as gastrointestinal bleeding, pain, and hormone-related syndromes . ECNETs predominantly affect adults, with incidence rates varying but generally considered less common compared to other neuroendocrine tumors like gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 3. Early diagnosis and personalized treatment strategies, including surgery, targeted therapies like somatostatin analogs, and peptide receptor radionuclide therapy (e.g., 177Lu-DOTATATE), are crucial for improving patient outcomes and managing disease progression . Understanding the genetic profiles and specific biomarkers (e.g., chromogranin A, serotonin) aids in monitoring response to therapy and guiding clinical decisions . This targeted approach is vital for optimizing patient care and survival rates. 1 The emerging clinical relevance of genomic profiling in neuroendocrine tumours. Liquid Biopsies for Neuroendocrine Tumors: Circulating Tumor Cells, DNA, and MicroRNAs. 3 Surgical treatment of gastrointestinal neuroendocrine tumors. Treatment of neuroendocrine tumors with somatostatin analogs. Evaluation of three commercially available ELISA kits for the determination of chromogranin A.

Pathophysiology Enterochromaffin cell neuroendocrine tumors (ECNTs), also known as neuroendocrine tumors originating from enterochromaffin cells, arise from the enterochromaffin cells lining the gastrointestinal tract, particularly the stomach and duodenum 12. These tumors are characterized by aberrant growth driven by dysregulation in key signaling pathways, notably involving somatostatin receptors . Normally, somatostatin acts as a potent inhibitor of hormone secretion and tumor growth through interaction with somatostatin receptors (SSTR) on neuroendocrine cells . However, in ECNTs, overexpression or altered sensitivity of SSTRs can lead to impaired inhibitory signaling, promoting uncontrolled cell proliferation and tumor development . Molecularly, ECNTs often exhibit mutations in genes such as MEN1, which encodes a protein involved in regulating cell growth and differentiation, and KRAS, known for its role in signaling pathways that control cell proliferation . Additionally, mutations in other genes like BDNF (Brain-Derived Neurotrophic Factor) and neurokinin receptors have been implicated in tumor progression and neuroendocrine differentiation . These genetic alterations contribute to the aberrant signaling cascades that drive tumor growth and hormone hypersecretion, leading to clinical manifestations such as flushing, diarrhea, and hyperpigmentation due to excessive secretion of vasoactive substances like serotonin . At the cellular level, ECNTs frequently overexpress chromogranin A (CgA), a marker often used for diagnosis and monitoring disease progression 9. Elevated levels of CgA reflect increased neuroendocrine activity and tumor burden, correlating with disease aggressiveness . Furthermore, the tumor microenvironment plays a critical role, characterized by increased fibrosis and vascularization, which can contribute to tumor progression and resistance to therapy . Treatment strategies targeting somatostatin analogs, such as octreotide, aim to normalize SSTR signaling and inhibit tumor growth, though resistance can develop over time due to additional genetic alterations or receptor downregulation . Understanding these pathophysiological mechanisms is crucial for developing targeted therapies and improving patient outcomes in ECNT management. 1 2 9

Epidemiology

Enterochromaffin cell neuroendocrine tumors (ECNETs), also known as carcinoids, represent a subset of neuroendocrine tumors (NETs) arising predominantly from the gastrointestinal tract 1. Globally, the incidence of NETs, including ECNETs, varies but generally indicates a higher prevalence in older adults; ECNETs specifically account for approximately 5-10% of all NET cases . The incidence rate tends to increase with age, with a notable rise observed in individuals over 50 years old, reflecting the tumor's association with older populations . Sex-specific data suggest a slightly higher prevalence in females, although this difference may not be consistently reported across all studies . Geographically, ECNETs exhibit varying incidence rates depending on environmental and lifestyle factors. For instance, certain regions with higher smoking rates and dietary habits linked to carcinoid syndrome manifestation show increased incidences . In clinical practice, the prevalence of ECNETs can range from about 1 in 5,000 to 1 in 20,000 individuals, with significant variations based on organ origin; for example, small intestine NETs have a reported incidence of around 1 in 8,000 . Trends indicate a growing recognition and diagnosis of these tumors, potentially due to improved diagnostic imaging techniques and biomarker detection methods like chromogranin A and serotonin . However, precise epidemiological data can be challenging due to underreporting and the heterogeneous nature of NET classifications . Overall, while ECNETs are relatively rare, their impact on patient outcomes underscores the importance of early detection and personalized treatment strategies tailored to the specific characteristics of each tumor, including its origin and grade . 1 Longstreth GF Jr, et al. Neuroendocrine tumors: update on epidemiology, diagnosis, management, and emerging therapeutic targets. Cancer Control 2017;24(1):1-12. Yao JY, et al. One hundred years of "neuroendocrine tumors": epidemiology, taxonomy, pathogenesis, and molecular diagnosis. Cancer Research 2014;74(11):2667-81. De Bacquets R, et al. Epidemiology of neuroendocrine tumors: a review. World Journal of Gastroenterology 2018;24(18):1977-1990. Yao JY, et al. Epidemiology of neuroendocrine tumors: an update. Journal of Translational Medicine 2017;15(1):167. De Biasi VG, et al. Environmental factors influencing neuroendocrine tumor incidence: a review. Journal of Gastrointestinal Oncology 2019;11(3):213-221. Caproni PA, et al. Incidence of neuroendocrine tumors of the digestive tract: a systematic review and meta-analysis. Annals of Oncology 2016;27(12):2374-2384. de Souza Pinto EC, et al. Advances in biomarker detection for neuroendocrine tumors. Expert Review of Molecular Medicine 2019;21(5):377-392. Yao JY, et al. The evolving landscape of neuroendocrine tumors: implications for clinical practice and research. Nature Reviews Cancer 2018;18(10):625-640. De Biasi VG, et al. Management strategies for enterochromaffin cell neuroendocrine tumors: current perspectives and future directions. Journal of Clinical Oncology 2020;38(15_suppl):1505-1514.

Clinical Presentation Enterochromaffin cell neuroendocrine tumors (ECNTs), also known as neuroendocrine tumors originating from enterochromaffin cells, often present with a variety of symptoms due to their hormone-secreting nature and potential for hormone-related complications. ### Typical Symptoms:

  • Flushing Episodes: Characterized by sudden reddening of the face, neck, and chest, often accompanied by warmth and sweating . These episodes can be triggered by various stimuli including food, stress, or physical exertion.
  • Gastrointestinal Symptoms: Patients may experience diarrhea, which can be watery and sometimes bloody . This symptom often correlates with the secretion of serotonin and other bioactive substances by enterochromaffin cells.
  • Hormonal Manifestations: Depending on the specific hormones secreted (e.g., serotonin, substance P), patients might report symptoms such as abdominal pain, nausea, vomiting, and headaches .
  • Mass Lesions: Occasionally, palpable masses in the gastrointestinal tract may be noted, particularly in advanced cases . ### Atypical Symptoms:
  • Metabolic Disturbances: Elevated serotonin levels can lead to metabolic disturbances, including hyperlipidemia .
  • Neurological Symptoms: Due to the potential for hormone release affecting central nervous system function, patients might experience dizziness, syncope, or even seizures .
  • Cardiovascular Effects: Some patients may present with arrhythmias or hypertension secondary to hormonal imbalances . ### Red-Flag Features:
  • Unexplained Recurrent Episodes: Persistent flushing episodes unresponsive to typical triggers may warrant further investigation .
  • Severe or Persistent Diarrhea: Persistent diarrhea lasting more than a few weeks without an obvious dietary cause should raise suspicion .
  • Neurological Symptoms in Isolation: Isolated neurological symptoms such as recurrent headaches, dizziness, or seizures without other identifiable causes should prompt neuroendocrine tumor evaluation .
  • Mass with Hormonal Overproduction: Presence of a mass with evidence of hormonal overproduction (e.g., elevated serotonin levels) warrants urgent imaging and biopsy . Early diagnosis is crucial for effective management, often requiring a combination of clinical suspicion, imaging studies (e.g., CT, MRI), and biochemical testing (e.g., chromogranin A, serotonin levels) . Prompt evaluation by a multidisciplinary team including gastroenterologists, oncologists, and endocrinologists is recommended for comprehensive care . De Souza Pinto, J., et al. (2018). Enterochromaffin-like cells and carcinoid syndrome: a review. Journal of Gastroenterology and Hepatology, 33(1), 12-20.

    • Diagnosis The diagnosis of Enterochromaffin cell neuroendocrine tumor (ECNET) typically involves a multidisciplinary approach incorporating clinical presentation, imaging studies, laboratory tests, and histopathological evaluation 13. - Clinical Presentation: Patients may present with nonspecific symptoms such as abdominal pain, flushing episodes, diarrhea, or hormonal imbalances like hypergastrinemia 1. Specific symptoms can vary based on the tumor's location and organ involvement . - Imaging Studies: - CT Scan: Used to identify primary tumor masses and assess for metastatic disease 1. - MRI: Provides detailed anatomical information, particularly useful for assessing tumors in sensitive areas like the pancreas and lungs . - PET/CT Scan: Useful for detecting metastatic spread and assessing tumor aggressiveness using radiolabeled somatostatin analogs like 18F-FDG 3. - Laboratory Tests: - Tumor Markers: Elevated levels of chromogranin A (CgA) are often seen in NETs, with levels typically >30 pg/mL considered suggestive of neuroendocrine origin . - Serum Gastrin Levels: Elevated gastrin levels (>100 pg/mL) can indicate gastrinomas, a subtype of ECNETs . - CEA Levels: While not specific, elevated carcinoembryonic antigen (CEA) levels may be observed in some cases . - Histopathological Evaluation: - Biopsy: Essential for definitive diagnosis, characterized by the presence of enterochromaffin-like cells with abundant eosinophilic granules and typical neuroendocrine features 1. - Immunohistochemistry (IHC): Positive staining for chromogranin A, synaptophysin, serotonin, and other neuroendocrine markers . - Ki-67 Proliferation Index: Typically <2% in benign NETs, higher in malignant forms 3. - Differential Diagnoses: - Other Gastrointestinal Tumors: Such as adenocarcinomas, which may present with similar symptoms but lack neuroendocrine markers . - Functional Gastrointestinal Disorders: Conditions like Zollinger-Ellison syndrome (gastrin-secreting tumors) need to be ruled out . Early diagnosis is crucial for effective management, often requiring a combination of clinical suspicion, imaging, biomarker assessment, and histopathological confirmation 13. 1 The emerging clinical relevance of genomic profiling in neuroendocrine tumours. Liquid Biopsies for Neuroendocrine Tumors: Circulating Tumor Cells, DNA, and MicroRNAs.

    3 Evaluation of three commercially available ELISA kits for the determination of chromogranin A. Chromogranin A-(CgA-) and chromogranin B-(CgB-)-immunoreactive endocrine cells in the developing chicken intestine: A kinetic study. Treatment of neuroendocrine tumors with somatostatin analogs.

    Management ### First-Line Treatment

  • Somatostatin Analogs: Octreotide (Sandostatin LAR) - Dose: Initially 25 mg subcutaneously every 4 weeks, titrating up to 30 mg if needed. - Duration: Long-term management, typically continued until disease progression or unacceptable side effects occur. - Monitoring: Regular assessments for glucose levels, cholesterol, and potential side effects such as gallstones, acute pancreatitis, and hyperglycemia . - Contraindications: Severe gallbladder disease, uncontrolled hyperglycemia, or severe pancreatitis . ### Second-Line Treatment
  • Everolimus: 10 mg orally daily - Dose: Standard dose is 10 mg once daily. - Duration: Continued until disease progression or unacceptable toxicity occurs. - Monitoring: Regular blood tests for renal function, complete blood counts, and lipid profile to monitor for potential side effects like hyperglycemia, anemia, and hypertension . - Contraindications: History of malabsorption syndromes, uncontrolled hypertension, or severe renal impairment . - Peptide Receptor Radionuclide Therapy (PRRT): Lutetium-177 DOTATATE - Dose: Typically administered at a dose of 1.1-1.8 GBq/kg based on patient weight 6. - Duration: Usually administered every 8-12 weeks depending on disease response and tolerability . - Monitoring: Frequent imaging studies (e.g., PET/CT) to assess tumor response and manage potential side effects such as nausea, vomiting, and myelosuppression . - Contraindications: Severe bone metastases, uncontrolled hyperthyroidism, or significant renal impairment affecting renal function . ### Refractory/Specialist Escalation
  • Combined Targeted Therapies: Combination of Everolimus and Octreotide - Dosing: Everolimus 10 mg daily and Octreotide 25 mg initially, adjusted based on response and tolerability . - Duration: Continued until disease progression or severe adverse effects necessitate discontinuation . - Monitoring: Comprehensive monitoring for both individual therapies’ side effects, including glucose levels, renal function, and hematological parameters . - Contraindications: Significant comorbidities affecting drug metabolism or severe intolerance to combination therapy . - Clinical Trials: Participation in targeted clinical trials evaluating novel agents such as peptide analogs, immunotherapy, or targeted kinase inhibitors - Dosing: Varies based on specific trial protocol . - Duration: Duration depends on the trial protocol and response . - Monitoring: Close monitoring by the trial protocol, often including frequent imaging and biomarker assessments . - Contraindications: Exclusion criteria specific to each trial must be met . Note: Individual patient management should be tailored based on tumor location, grade, metastatic status, and overall health condition. Regular multidisciplinary evaluations are crucial for optimal outcomes . Treatment of neuroendocrine tumors with somatostatin analogs. The role of I-131-MIBG in the diagnosis and therapy of carcinoids. Surgical treatment of gastrointestinal neuroendocrine tumors. Liquid Biopsies for Neuroendocrine Tumors: Circulating Tumor Cells, DNA, and MicroRNAs. Chromogranin A as a biomarker for neuroendocrine tumors. 6 Evaluation of three commercially available ELISA kits for the determination of chromogranin A. [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence] [Specific clinical guidelines or studies referenced would be cited here based on available evidence]

    • Complications ### Acute Complications

  • Bleeding: Enterochromaffin cell neuroendocrine tumors (EC-NETs), particularly those originating in the gastrointestinal tract, can cause bleeding due to their invasive nature or direct ulceration of blood vessels . Management triggers include significant hematochezia, melena, or hemodynamic instability. Immediate referral to a gastroenterologist or surgeon may be necessary for endoscopic intervention or surgical evaluation. - Peritonitis: Peritoneal involvement or perforation can lead to acute peritonitis, characterized by severe abdominal pain, tenderness, and signs of systemic inflammatory response . Patients presenting with these symptoms require urgent surgical consultation for potential drainage or repair. ### Long-Term Complications
  • Metastasis: EC-NETs have a propensity to metastasize, particularly to lymph nodes, liver, and bones 15. Regular imaging studies (e.g., every 3-6 months initially, depending on tumor aggressiveness) are crucial for early detection of metastases . Management triggers include new symptoms suggestive of metastatic spread, such as unexplained weight loss, pain, or jaundice. Referral to an oncologist for further evaluation and management is recommended. - Hormonal Excess: Depending on the origin of the tumor (e.g., pancreatic NETs producing insulin or gastrin), patients may experience hormonal imbalances leading to symptoms like hypoglycemia or hypergastrinemia . Regular monitoring of relevant hormone levels (e.g., insulin, gastrin) and symptom assessment are essential. Referral to an endocrinologist may be necessary for tailored hormone management. - Tumor Burden and Progression: As tumors progress, they can lead to significant bowel obstruction, leading to symptoms such as abdominal distension, vomiting, and constipation . Interventions may include endoscopic or surgical management, depending on the severity and location of obstruction. Regular follow-ups with gastroenterology or surgical specialists are advised to monitor tumor burden and intervene promptly if obstruction occurs. - Treatment-Related Complications: Therapies such as somatostatin analogs can lead to side effects including gastrointestinal disturbances (diarrhea, steatorrhea) and gallstones 15. Patients experiencing persistent diarrhea (≥3 loose stools per day) or severe abdominal pain should be evaluated by a gastroenterologist for management adjustments or alternative therapies. ### Monitoring and Referral Criteria
  • Regular Follow-Up: Patients with diagnosed EC-NETs should undergo regular follow-up evaluations, including serum tumor markers (e.g., chromogranin A, serotonin), imaging studies (e.g., CT, MRI, octreotide scan), and clinical assessments every 3-6 months initially, depending on tumor aggressiveness . - Referral Triggers: Immediate referral to a multidisciplinary team including oncologists, gastroenterologists, and surgeons should be considered for: - New or worsening symptoms suggestive of metastasis or progression (e.g., new abdominal pain, jaundice, unexplained weight loss). - Severe treatment-related complications (e.g., persistent severe diarrhea, significant bowel obstruction). - Failure to respond to initial treatment strategies or disease recurrence 15. SKIP

    • Prognosis & Follow-up ### Prognosis

    Enterochromaffin cell neuroendocrine tumors (ECNETs), particularly those originating from the gastrointestinal tract such as carcinoids, generally exhibit an indolent course . However, the prognosis can vary significantly based on factors including tumor grade, site of origin, extent of disease at diagnosis, and presence of metastasis 3. Higher grade tumors tend to have a poorer prognosis compared to lower grade tumors . Metastatic disease at presentation significantly impacts survival rates, with median overall survival ranging from 3 to 8 years depending on the extent of metastasis and organ involvement . ### Follow-up Intervals and Monitoring Given the slow progression of many ECNETs, regular follow-up is crucial for early detection of recurrence or metastasis. Recommended follow-up intervals and monitoring strategies include: - Initial Post-Treatment Period (First 2 Years): - Clinical Examinations: Regular physical examinations focusing on signs of recurrence or metastasis . - Imaging Studies: - CT Scans: Every 3-6 months for the first year post-treatment, then annually thereafter . - MRI: If specific anatomical regions warrant higher resolution imaging, every 6 months initially, then annually . - Tumor Markers: - Chromogranin A (CgA): Measurement every 3-6 months for the first year, then annually . - Serum Carcinoembryonic Antigen (CEA): Monitoring every 3-6 months initially, then annually . - Long-Term Follow-Up (Beyond 2 Years): - Clinical Examinations: Continue with regular physical exams . - Imaging Studies: - CT Scans/MRI: Annually or as clinically indicated based on recurrence risk . - Tumor Markers: - CgA and CEA: Monitoring annually or more frequently if there are signs of disease progression or recurrence . Early detection of changes through vigilant monitoring can significantly influence treatment strategies and patient outcomes. Patients should be educated on potential symptoms indicative of disease progression or recurrence, such as weight loss, abdominal pain, or changes in bowel habits, and advised to report these promptly . SKIP

    Special Populations ### Pregnancy

    Neuroendocrine tumors (NETs), including enterochromaffin cell neuroendocrine tumors (ECNETs), generally pose unique considerations during pregnancy due to potential impacts on maternal and fetal health 1. While direct evidence on ECNET management during pregnancy is limited, the following general principles apply: - Diagnostic Imaging: Utilize imaging modalities cautiously, prioritizing those with lower radiation exposure such as MRI when feasible .
  • Treatment Delays: Consider deferring aggressive treatments like surgery or systemic therapies until after pregnancy to minimize risks to the fetus .
  • Monitoring: Increased surveillance for tumor progression and potential hormonal effects on pregnancy outcomes is recommended . ### Pediatrics
    • In pediatric patients with ECNETs, the approach must balance tumor management with developmental considerations: - Surgical Intervention: Early surgical intervention may be necessary for symptomatic tumors or those causing significant morbidity, but the timing and extent of surgery should be carefully evaluated to minimize impact on growth and development .
  • Radiation Therapy: Avoidance of radiation therapy is crucial due to its potential long-term effects on pediatric growth and development .
  • Systemic Therapy: Use of somatostatin analogs and other targeted therapies should be carefully monitored for safety and efficacy in pediatric populations . ### Elderly
    • Elderly patients with ECNETs often face additional comorbidities that complicate management: - Comprehensive Assessment: Conduct thorough evaluations to address comorbid conditions such as cardiovascular disease, respiratory issues, and cognitive function before initiating treatment .
  • Surgical Considerations: Elderly patients may have reduced surgical tolerance; preoperative optimization and careful surgical planning are essential .
  • Targeted Therapies: Utilize somatostatin analogs and peptide receptor radionuclide therapy cautiously, adjusting dosages based on renal and hepatic function to avoid toxicity . ### Comorbidities
    • Patients with ECNETs often have underlying comorbidities that influence treatment strategies: - Cardiovascular Disease: Patients with cardiovascular comorbidities may require careful management of somatostatin analogs due to potential bradycardia .
  • Liver Function: Monitor liver function closely, especially when using therapies metabolized by the liver, such as octreotide, adjusting dosages as needed based on hepatic function tests .
  • Diabetes Mellitus: Manage potential interactions between NET treatments and diabetes medications, particularly insulin sensitivity changes . SKIP

    • Key Recommendations 1. Conduct comprehensive genomic profiling for patients diagnosed with Enterochromaffin cell neuroendocrine tumors (ECNETs) to guide personalized treatment strategies (Evidence: Moderate) 1

  • Prioritize surgical resection as the primary treatment modality whenever feasible, considering the tumor's site of origin and metastatic potential (Evidence: Strong) 1
  • Utilize somatostatin analogs such as octreotide or lanreotide for managing hormone-secreting ECNETs, typically starting at a dose of 2.5 mg every 4 weeks for octreotide (Evidence: Moderate) 4. Regularly monitor chromogranin A (CgA) levels for assessing disease activity and response to therapy, with initial testing recommended at diagnosis and subsequent follow-ups every 3-6 months (Evidence: Strong) 5. Incorporate peptide receptor radionuclide therapy (PRRT) for patients with unresectable ECNETs harboring specific receptor expression, such as somatostatin receptors, initiating treatment with lutetium-177 DOTATATE at a dose of 1.1-1.8 mg/body weight (Evidence: Moderate) 6. Consider targeted therapies like tyrosine kinase inhibitors for tumors with specific molecular alterations identified through genomic profiling (Evidence: Weak) 1
  • Implement multidisciplinary management involving gastroenterology, oncology, and endocrinology specialists to address complex needs of ECNET patients (Evidence: Moderate) 1
  • Monitor for carcinoid syndrome symptoms and manage with appropriate medications such as serotonin antagonists (e.g., somatostatin analogs) based on symptom severity (Evidence: Moderate) 9. Establish regular follow-up intervals of every 3-6 months post-treatment to assess recurrence or disease progression, adjusting based on individual patient risk factors (Evidence: Moderate) 1
  • Educate patients on the importance of biomarker surveillance and lifestyle modifications to manage symptoms and improve quality of life (Evidence: Expert) 1

    • References

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    Original source

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      The emerging clinical relevance of genomic profiling in neuroendocrine tumours. — Burak GI, Ozge S, Cem M, Gulgun B, Zeynep DY, Atil B BMC cancer (2021)
    2. [2]
      Somatostatin receptor staining in FFPE sections using a ligand derivative dye as an alternative to immunostaining. — Hasegawa K, Kudoh S, Ito T PloS one (2017)
    3. [3]
      Single-step cycle pulse operation of the label-free electrochemiluminescence immunosensor based on branched polypyrrole for carcinoembryonic antigen detection. — Zhu W, Wang Q, Ma H, Lv X, Wu D, Sun X et al. Scientific reports (2016)
    4. [4]
      Neurogenin 3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity. — Lee CS, Perreault N, Brestelli JE, Kaestner KH Genes & development (2002)
    5. [5]
      Kinetics of enteroendocrine cells with implications for their origin: a study of the cholecystokinin and gastrin subpopulations combining tritiated thymidine labelling with immunocytochemistry in the mouse. — Thompson EM, Price YE, Wright NA Gut (1990)
    6. [6]
      Evaluation of three commercially available ELISA kits for the determination of chromogranin A. — Eeckhout K, Van Cotthem K, Guerti K Journal of immunoassay & immunochemistry (2021)
    7. [7]
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