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Year : 2023  |  Volume : 69  |  Issue : 2  |  Page : 65-67

Neuroendocrine neoplasm: Current understanding

Department of Endocrinology, Seth G. S. Medical College and K. E. M. Hospital, Mumbai, Maharashtra, India

Date of Submission21-Jan-2023
Date of Decision30-Jan-2023
Date of Acceptance09-Feb-2023
Date of Web Publication22-Mar-2023

Correspondence Address:
Dr. A R Lila
Department of Endocrinology, Seth G. S. Medical College and K. E. M. Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpgm.jpgm_51_23

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How to cite this article:
Lila A R, Memon S S. Neuroendocrine neoplasm: Current understanding. J Postgrad Med 2023;69:65-7

How to cite this URL:
Lila A R, Memon S S. Neuroendocrine neoplasm: Current understanding. J Postgrad Med [serial online] 2023 [cited 2023 May 29];69:65-7. Available from:

An article titled “Progress report: The carcinoid syndrome” by Grahame-Smith, published in 1970, starts with a quote by an English chemist John Mayow “As a rule, the disease can scarcely keep pace with the itch to scribble about it.”[1] In the last decade, there have been significant advances in the field of neuroendocrine neoplasms (NENs) that range from its nomenclature to liquid biopsy and randomized controlled trial-driven evidence on their management. This editorial describes the understanding of NENs [principally on gastroenteropancreatic (GEP)-NENs] management from an endocrinologist's perspective and is targeted to create awareness on NENs among medical professionals across specialties.

Neuroendocrine cells share a number of antigens with neural elements (synaptophysin and chromogranin) and are scattered throughout the body. NENs can arise from neuroendocrine cells of endocrine glands [anterior pituitary, parathyroid, thyroid (parafollicular C cells), or adrenal (chromaffin cells)] or the dispersed neuroendocrine cells in the digestive or respiratory tracts.[2] The epithelial NENs of the digestive or respiratory tracts were traditionally described as carcinoid tumors. They were classified as arising from the embryonic foregut (lung, thymus, stomach, duodenum, and pancreas), midgut (small intestine distal to the duodenojejunal flexure, appendix, and ascending colon), or hindgut (distal colon or rectum).[3] More recently, NENs originating from the gastrointestinal tract are called GEP-NENs, and those from the respiratory tract are called pulmonary NENs (P-NENs).[4]

GEP/P-NENs are uncommon tumors but are more often recognized as incidentaloma discovered due to the frequent use of imaging (radiology/endoscopic) tests in recent years. Increased health-care utilization is one of the reasons for the increase in the global increase in GEP-NEN incidence (2.5–8.3 cases/100,000).[5] Though population-based analysis data of NENs in India are unavailable, a multicenter longitudinal NEN registry shows a trend of rising GEP-NEN patients in the last decade.[6] As NENs can arise from multiple primary sites, they can initially present to various specialties: gastroenterology, surgery, pulmonology, radiology, medicine, or pathology. These patients are usually referred to endocrinologists or oncologists and need coordinated multispecialty care at a specialized center for further management.

To ensure precision and uniformity, WHO has proposed a standard histopathological classification of digestive NENs and P-NENs.[4],[7] The critical feature of the latest classification is a distinction between differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinoma based on p53 and Rb1 markers. NETs are further graded as G1, G2, or G3 based on mitotic count (2–20 per 2 mm2, G2) and Ki67 index (3–20%, G2). The staging of the NENs, localized (stages I and II), regional spread (stage III), and advanced with distant metastasis (stage IV), dictates its overall prognosis. Nevertheless, most NENs have indolent nature, and even with stage IV GEP-NEN, a study reported a fair prognosis with a median overall survival for low, intermediate, and high-grade differentiated tumors of 8.1, 3.2, and 1.4 years, respectively.[8]

GEP-NEN presentation depends on its site, size, and its secretory nature and can present at varied disease stages. The presentation can be divided into two broad subcategories: where we seek the NENs (based on hormone-related symptoms, physician orders test to find out NENs) or NEN seeks us (incidentally discovered when a radio-imaging or endoscopy is done for some other indication, where NEN was not the primary suspect).[9] The latter situation is far more common as most GEP-NENs are indolent and nonfunctional. However, few of them can present with local mass effect-related features like gut obstruction or bleeding. The functional GEP-NEN, which may secrete various amines or peptides, may have specific presentations [Table 1]. These tumors can present to varying specialties with concerns ranging from flushing and diarrhea to dyspepsia or heart failure. Hence, clinical suspicion and judgment are necessary. The predominant hormonal secretion is usually site-specific: duodenum (gastrin), pancreas (gastrin, insulin, glucagon, ACTH, GHRH, PTHrP, VIP, or somatostatin), and midgut (serotonin).[10] The typical symptoms of carcinoid syndrome (primarily due to serotonin secreting advanced stage midgut NEN) are diarrhea, flushing, and carcinoid heart disease, and biochemically characterized by elevated urinary 5-hydroxy-indoleacetic acid.[11] Notably, these midgut NENs also lead to local peritumoral and peritoneal fibrosis and may have related symptoms.[12] Approximately 5–10% of GEP-NENs may be a part of familial/syndromic inherited disorders like multiple endocrine neoplasia type 1 or von Hippel–Lindau disease.[13],[14],[15]
Table 1: Clinically presentation and prevalence of functioning GEP-NETs

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Serum chromogranin A (CgA) is the most commonly used GEP-NEN biomarker. Besides concerns related to the lack of standardization of its assays, serum CgA has limited diagnostic accuracy as its levels are within the normal range in 30–50% of NENs and may be elevated in various oncological and non-oncological conditions (e.g., due to proton pump inhibitors use).[16] CgA has some value in disease prognosis in advanced disease, but as a tumor follow-up marker, it has limited utility, as the trend of rise in CgA does not represent a valid indicator of morphological evolution. GEP-NEN expresses large numbers of high-affinity somatostatin receptors, and somatostatin receptor positron emission tomography/computed tomography (PET/CT) imaging has good diagnostic performance (sensitivity 93%, specificity 96%) for the evaluation of GEP/P NEN and is the most valuable available investigation today.[17] These imaging modalities also help in disease mapping.[18] In our experience, in MEN1 syndrome and ectopic ATCH syndrome, overall sensitivity for NEN diagnosis was around 70%, but it was less sensitive for P-NEN and insulinomas.[19],[20] Notably, glucagon-like peptide-1 receptor-based nuclear imaging scans are beneficial in accurately locating insulin-secreting pancreatic NEN.[21] NETest (liquid biopsy) analyzing mRNAs (multi-transcriptome) in the blood to detect, track, and assess treatment outcomes in GEP-NETs seems very promising.[22] With further validation and easy and affordable availability, such tests may soon become the standard of care in GEP-NET management.

The treatment approach in GEP-NEN differs based on stage, grade, secretary status, and disease progression. The general principle of “primum non nocere” (“first, do no harm”) applies to these tumors with a highly variable natural history. For a localized/regional disease, either close observation (especially for asymptomatic incidentalomas) or surgical resection (especially for symptomatic/larger lesions) can be considered.[23] Anesthesia and tumor handling during surgery can lead to carcinoid crisis (in midgut tumors) and the treating team should be equipped to manage it. For an advanced disease with inoperable patients, biotherapy with somatostatin analogs and/or peptide receptor radionuclide therapy are an effective and relatively safe option.[24],[25] They help to reduce hormone-related symptoms and have some antiproliferative effects. The results of the NETTER-1 study (advanced midgut NETs) demonstrated that 177Lu-DOTATATE yielded a significant improvement in progression-free survival and a clinically meaningful trend toward improvement in median overall survival of 11.7 months.[26] 225Ac-DOTATATE-targeted alpha therapy for GEP-NET refractory to 177Lu-DOTATATE has shown promising results and needs further studies.[27] In advanced disease (lacking somatostatin expression) or progressive diseases, various medical lines of treatment like everolimus, sunitinib (specifically for pancreatic NEN), capecitabine-temozolomide, or other cytotoxic chemotherapy can be planned with palliative intent in consultation with a medical oncologist.[28] A team approach is needed to achieve a balanced opinion on the different therapeutic options in patients with these tumors. Patients should be part of decision-making in care, as emotional and quality of life considerations should be of equal importance.[29]

Recent advances in the field of NENs, including a better understanding of the underpinning genetics, availability of accurate diagnostic modalities, and treatment outcome data from multicentric RCTs, help tailor the treatment plan of NEN. Hopefully, uniform adoption of NEN classification and a better understanding of tumor biology will lead to its future translation into better diagnostics and therapeutics. Last but not least, the physician dealing with NENs with heterogeneous behavior and prognosis has a crucial role in accurately counseling the patient, and the balancing act of neither ignoring nor indulging is of utmost importance.

 :: References Top

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Klöppel G, Couvelard A, Kasajima A. Histopathological classification of gastroenteropancreatic and bronchopulmonary neuroendocrine neoplasms. Curr Opin Endocr Metab Res 2021;18:76-82.  Back to cited text no. 4
Das S, Dasari A. Epidemiology, incidence, and prevalence of neuroendocrine neoplasms: Are there global differences? Curr Oncol Rep 2021;23:43.  Back to cited text no. 5
Palepu J, Shrikhande SV, Bhaduri D, Shah RC, Sirohi B, Chhabra V, et al. Trends in diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in India: A report of multicenter data from a web-based registry. Indian J Gastroenterol 2017;36:445-51.  Back to cited text no. 6
Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, et al. A common classification framework for neuroendocrine neoplasms: An International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 2018;31:1770-86.  Back to cited text no. 7
Formica V, Wotherspoon A, Cunningham D, Norman AR, Sirohi B, Oates J, et al. The prognostic role of WHO classification, urinary 5-hydroxyindoleacetic acid and liver function tests in metastatic neuroendocrine carcinomas of the gastroenteropancreatic tract. Br J Cancer 2007;96:1178-82.  Back to cited text no. 8
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