| Article Access Statistics | | | Viewed | 1570 | | | Printed | 44 | | | Emailed | 0 | | | PDF Downloaded | 4 | | | Comments | [Add] | | |
|
Click on image for details.
|
|
 |
| EDITORIAL |
|
|
|
| Year : 2023 | Volume
: 69
| Issue : 2 | Page : 65-67 |
Neuroendocrine neoplasm: Current understanding
AR Lila, SS Memon
Department of Endocrinology, Seth G. S. Medical College and K. E. M. Hospital, Mumbai, Maharashtra, India
| Date of Submission | 21-Jan-2023 |
| Date of Decision | 30-Jan-2023 |
| Date of Acceptance | 09-Feb-2023 |
| Date of Web Publication | 22-Mar-2023 |
Correspondence Address:
Dr. A R Lila
Department of Endocrinology, Seth G. S. Medical College and K. E. M. Hospital, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jpgm.jpgm_51_23
How to cite this article:
Lila A R, Memon S S. Neuroendocrine neoplasm: Current understanding. J Postgrad Med 2023;69:65-7 |
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]
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 | |  |
| 1. | Grahame-Smith DG. Progress report: The carcinoid syndrome. Gut 1970;11:189-92.  |
| 2. | Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev 2004;25:458-511. |
| 3. | de Herder WW, Lamberts SWJ. Gut endocrine tumours. Best Pract Res Clin Endocrinol Metab 2004;18:477-95. |
| 4. | Klöppel G, Couvelard A, Kasajima A. Histopathological classification of gastroenteropancreatic and bronchopulmonary neuroendocrine neoplasms. Curr Opin Endocr Metab Res 2021;18:76-82. |
| 5. | Das S, Dasari A. Epidemiology, incidence, and prevalence of neuroendocrine neoplasms: Are there global differences? Curr Oncol Rep 2021;23:43. |
| 6. | 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. |
| 7. | 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. |
| 8. | 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. |
| 9. | Çakir M, Grossman AB. The diagnosis of neuroendocrine tumours: An endocrine perspective. Turk J Endocrinol Metab 2018;22:117-44. |
| 10. | Hofland J, Zandee WT, de Herder WW. Role of biomarker tests for diagnosis of neuroendocrine tumours. Nat Rev Endocrinol 2018;14:656-69. |
| 11. | Hofland J, Herrera-Martínez AD, Zandee WT, de Herder WW. Management of carcinoid syndrome: A systematic review and meta-analysis. Endocr Relat Cancer 2019;26:R145-56. |
| 12. | Modlin IM, Shapiro MD, Kidd M. Carcinoid tumors and fibrosis: An association with no explanation. Am J Gastroenterol 2004;99:2466-78. |
| 13. | Lomte N, Kumar S, Sarathi V, Pandit R, Goroshi M, Jadhav S, et al. Genotype phenotype correlation in Asian Indian von Hippel-Lindau (VHL) syndrome patients with pheochromocytoma/paraganglioma. Fam Cancer 2018;17:441-9. |
| 14. | Goroshi M, Bandgar T, Lila AR, Jadhav SS, Khare S, Shrikhande SV, et al. Multiple endocrine neoplasia type 1 syndrome: Single centre experience from western India. Fam Cancer 2016;15:617-24. |
| 15. | Anlauf M, Garbrecht N, Bauersfeld J, Schmitt A, Henopp T, Komminoth P, et al. Hereditary neuroendocrine tumors of the gastroenteropancreatic system. Virchows Arch 2007;451(Suppl 1):S29-38. |
| 16. | Marotta V, Zatelli MC, Sciammarella C, Ambrosio MR, Bondanelli M, Colao A, et al. Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: More flaws than fame. Endocr Relat Cancer 2018;25:R11-29. |
| 17. | Geijer H, Breimer LH. Somatostatin receptor PET/CT in neuroendocrine tumours: Update on systematic review and meta-analysis. Eur J Nucl Med Mol Imaging 2013;40:1770-80. |
| 18. | Barrio M, Czernin J, Fanti S, Ambrosini V, Binse I, Du L, et al. The impact of somatostatin receptor-directed PET/CT on the management of patients with neuroendocrine tumor: A systematic review and meta-analysis. J Nucl Med 2017;58:756-61. |
| 19. | Goroshi MR, Jadhav SS, Lila AR, Kasaliwal R, Khare S, Yerawar CG, et al. Comparison of 68Ga-DOTANOC PET/CT and contrast-enhanced CT in localisation of tumours in ectopic ACTH syndrome. Endocr Connect 2016;5:83-91. |
| 20. | Patil VA, Goroshi MR, Shah H, Malhotra G, Hira P, Sarathi V, et al. Comparison of 68Ga-DOTA-NaI3-Octreotide/tyr3-octreotate positron emission tomography/computed tomography and contrast-enhanced computed tomography in localization of tumors in multiple endocrine neoplasia 1 syndrome. World J Nucl Med 2020;19:99-105. [Full text] |
| 21. | Shah R, Garg R, Majmundar M, Purandare N, Malhotra G, Patil V, et al. Exendin-4-based imaging in insulinoma localization: Systematic review and meta-analysis. Clin Endocrinol (Oxf) 2021;95:354-64. |
| 22. | Modlin IM, Kidd M, Bodei L, Malczewska A, Kitz A, Oberg K. Circulating biomarkers of gastroenteropancreatic and lung neuroendocrine neoplasms: “The times they are a changin.” Curr Opin Endocr Metab Res 2021;18:243-53. |
| 23. | Hofland J, Feelders RA, Brabander T, Franssen GJH, de Herder WW. Recent developments in the diagnosis and therapy of well-differentiated neuroendocrine tumours. Neth J Med 2018;76:100-8. |
| 24. | Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, et al. 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 (PROMID): Results of long-term survival. Neuroendocrinology 2017;104:26-32. |
| 25. | Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, Grozinsky-Glasberg S, Arnold R, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasia: Peptide receptor radionuclide therapy with radiolabeled somatostatin analogues. Neuroendocrinology 2017;105:295-309. |
| 26. | Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar AE, et al. Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors. J Clin Oncol 2021;39 (15 Suppl):4112. |
| 27. | Ballal S, Yadav MP, Bal C, Sahoo RK, Tripathi M. Broadening horizons with 225Ac-DOTATATE targeted alpha therapy for gastroenteropancreatic neuroendocrine tumour patients stable or refractory to 177Lu-DOTATATE PRRT: First clinical experience on the efficacy and safety. Eur J Nucl Med Mol Imaging 2020;47:934-46. |
| 28. | Herrera-Martínez AD, Hofland J, Hofland LJ, Brabander T, Eskens FALM, Gálvez Moreno MA, et al. Targeted systemic treatment of neuroendocrine tumors: Current options and future perspectives. Drugs 2019;79:21-42. |
| 29. | Bouvier C, Jervis N. Patient perspectives, from diagnosis through treatments and beyond. Curr Opin Endocr Metab Res 2021;18:254-7. |
[Table 1]
|
