A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
Abstract
:1. Introduction
2. Classification and Staging
3. Carcinoid Tumor NETs
4. Pulmonary NENs
5. Gastric Carcinoids: Gastric NETs Account for Approximately 7% of All Carcinoids and 1.8% of All Gastric Neoplasms [28] and Are further Divided into Four Subtypes
5.1. Duodenal NETs
5.2. Appendiceal NETs
5.3. Rectal NETs
6. Genitourinary NEN
7. Pancreatic NENs
7.1. Insulinomas
7.2. Glucagonomas
7.3. Gastrinoma
7.4. Somatostatinoma
7.5. VIPoma
7.6. Other Pancreatic NENs
8. Adrenocortical Tumors
9. Other Rare NENs
10. Genetics and Syndromes
10.1. Multiple Endocrine Neoplasia 2 (MEN 2)
10.2. Multiple Endocrine Neoplasia 4 (MEN 4)
10.3. Von Hippel–Lindau Syndrome
10.4. Neurofibromatosis 1 (NF 1)
10.5. Tuberous Sclerosis
10.6. Pheochromocytoma and Paraganglioma
11. Diagnosis
11.1. Imaging
11.1.1. CT
11.1.2. MRI
11.1.3. Ultrasonography and Related Applications
11.2. Tumor Markers
11.2.1. Specific Tumor Markers
11.2.2. Non-Specific Tumor Markers and Immunohistochemistry (IHC)
12. Management
12.1. Gastroenteropancreatic NETs (GEP NETs)
12.2. Pulmonary NETs
12.3. Evolving Therapy Targets for Other NETs and Future Perspectives
12.4. Supportive Management
13. Conclusions and Future Direction
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Neuroendocrine Neoplasm | Classification Category | Mitotic Count | Ki-67 Index | Other Features |
---|---|---|---|---|
1. Gastrointestinal tract and pancreato-biliary tract neoplasms | ||||
a. Well-differentiated neuroendocrine neoplasm (NET) | Grade 1, NET | Less than 2 mitoses/2 mm2 | Less than 3% | - |
Grade 2, NET | 2 to 20 mitoses/2 mm2 | 3 to 20% | - | |
Grade 3, NET | More than 20 mitoses/2 mm2 | More than 20% | - | |
b. Poorly differentiated neuroendocrine carcinoma (NEC) | Small cell NECs | More than 20 mitoses/2 mm2 | More than 20% (often more than 70%) | Small cell cytomorphology |
Large cell NECs | More than 20 mitoses/2 mm2 | More than 20% (often more than 70%) | Large cell cytomorphology | |
2. Upper airway, digestive tract and salivary gland neoplasms (head and neck) | ||||
a. Well-differentiated neuroendocrine neoplasm (NET) | Grade 1, NET | Less than 2 mitoses/2 mm2 | Less than 20% | No necrosis |
Grade 2, NET | 2–10 mitoses/2 mm2 | Less than 20% | Necrosis | |
Grade 3, NET | More than 10 mitoses/2 mm2 | More than 20% | - | |
b. Poorly differentiated neuroendocrine carcinomas (NECs) | Small cell NECs | More than 10 mitoses/2 mm2 | More than 20% (often more than 70%) | Small cell cytomorphology |
Large cell NECs | More than 10 mitoses/2 mm2 | More than 20% (often more than 55%) | Large cell cytomorphology | |
3. Thymus and lung neoplasms | ||||
a. Well-differentiated neuroendocrine tumor (NET) | Grade 1, typical carcinoid/NET | Less than 2 mitoses/2 mm2 | - | No necrosis seen |
Grade 2, atypical carcinoid/NET | 2 to 10 mitoses/2 mm2 | - | Necrosis (usually punctate) | |
Carcinoids/NETs with mitotic counts and/or Ki-67 proliferation index on the higher side | More than 10 mitoses per 2 mm2 | More than 30% | Atypical carcinoid morphology | |
b. Poorly-differentiated neuroendocrine carcinomas (NECs) | Small cell (lung) carcinomas | More than 10 mitoses/2 mm2 | - | Necrosis and small cell cytomorphology often seen |
Large cell NECs | More than 10 mitoses/2 mm2 | - | Virtually almost always large cell cyto-morphology and necrosis seen | |
4. Thyroid neoplasms | ||||
a. Medullary thyroid carcinomas (MTCs) | MTC, low-grade | Less than 5 mitoses/2 mm2 | - | No necrosis seen |
MTC, high-grade | More than or equal to 5 mitoses/2 mm2 | More than or equal to 5% OR | Necrosis |
S.N. | Type of NEN | Clinical Diagnosis | Lab Diagnosis | Imaging | Treatment Options | Upcoming Evidence/Clinical Trials/Evolving Drug Targets |
---|---|---|---|---|---|---|
1. | Pulmonary NENs | Central tumors: cough, hemoptysis and recurrent pneumonia. Peripheral tumors: non-specific symptoms and complications including, dysphagia, SVC syndrome and hoarseness of voice [4,30,34,35,36]. | High levels of ACTH or ADH AND 5 HT [153]. | CT scan: lesions around the central bronchi in typical carcinoids and SCLC, and peripheral lesions in atypical carcinoids and LCNEC. Calcifications present. Octreotide scan (111In-pentetreotide) detects both TC and AC [33]. | Medical: with somatostatin analogs(SSA), everolimus, PRRT, and chemotherapy [147,192,193,194,195]. Surgical: with bronchial resection plus LND [33]. | Identification of newer targets including the stimulator of interferon gene (STING) pathway [196], mutations in the epithelial growth factor receptor (EGFR), Phosphoinositol-3 kinase (PI3K), mTOR, VEGF and human epidermal growth factor receptor 2 (HER-2) [197]. |
2. | GIT NENs | Gastric: heartburn, peptic ulcers and diarrhea [28,29]. Duodenal: abdominal pain, diarrhea, gastrointestinal bleeding and jaundice [43]. Appendiceal: abdominal pain [46]. Rectal: abdominal pain, hematochezia, change in bowel movements and pruritis [49,50]. | Gastrin/somatostatin/histamine/peptide YY positive [153]. | Endoscopy with biopsy and endoscopic ultrasound are required for diagnosis and staging. CT scan and MRI are performed to identify distant metastasis [208]. | Medical: with SSA, PRRTs, everolimus, IFN alpha chemotherapy [131,157,161,167,168,169]. Surgical: with bowel resection + LND, hemicolectomy if ileal involvement [165,166]. | Currently, registered clinical trials are aimed at understanding the efficacy of already available treatments in different combinations and comparisons between them, for instance, PRRT vs. temozolomide/capecitabine or everolimus, or sunitinib. Sequential treatments are also being compared [202]. |
3. | Genitourinary NENs | Females: abnormal uterine bleeding is seen in cervical and endometrial tumors [57,58,59,60,61]. Males: urinary frequency, urgency and hematuria in prostate tumors. Testicular mass with or without pain. Bladder tumors: cause hematuria or urinary obstruction [55,56,60]. Renal NENs: Flank pain and hematuria [56,57]. | CgA or Synaptophysin or NSE positive [153]. | CT scan, MRI and octreotide scan are required for diagnosis and surveillance of lesions. FDG-PET is useful for staging [61]. | Medical: unresectable tumors are treated with radiotherapy and platinum-based chemotherapy. Surgical: for resectable tumors, oncological resection with neoadjuvant chemotherapy [56,57,60,61]. | A new combination of chemotherapy agents, BXCL701-Pembrolizumab, is being studied for efficacy in small cell NETs of prostate and adenocarcinoma phenotype (phase Ib/II—NCT03910660) [204]. |
4. | Pancreatic NENs | Insulinomas: tremors, palpitations, diaphoresis, syncope, confusion, anxiety, visual changes and coma [62,76]. Glucagonomas: migratory erythema diarrhea, weight loss, diabetes mellitus, DVT, anemia, and stomatitis [83,85]. Gastrinoma: Heartburn, abdominal pain, diarrhea and weight loss. Strictures, bleeding and perforation [93]. Somatostatinomas: Weight loss, abdominal pain, diarrhea or statorrhea, diabetes mellitus and cholelithiasis [100]. VIPomas: Watery diarrhea, hypocalcemia, flushing and glucose intolerance [103]. | Insulin levels in the blood must be greater than or equal to 36 pmol/L [78]. Glucagon level of more than 500 to 1000 pg/mL (normal 50 to 150 pg/mL) [62]. Fasting serum gastrin level of 1000 pg/mL [93]. A fasting plasma hormone concentration of more than 3-fold the normal [62]. VIP elevations (>200 pg/dL) are present [104]. | Demarcated hyper or hypovascular homogenous tumor on CT scan and endoscopic ultrasound [70]. | Medical: with SSA, everolimus, sunitinib and chemotherapy [157,181,184]. Surgical: G1 via pancreaticoduodenectomy, pancreatectomy + splenectomy pr debulking surgery [176,177,178]. | Research is being performed to determine the efficacy of 177Lu-DOTATOC (Lutathera), a new therapeutic agent for PRRT in gastroenteropancreatic NETs. Various phase 2 and phase 3 clinical trials for different combination therapies for pancreatic NETs are also in place [204]. The presence of tumor-infiltrating lymphocytes (TILs) in pancreatic NETs is thought to be a predictor of survival; hence, modulating the TIL density may be another treatment option [204]. |
5. | Rare NENs | Head and neck NENs: dysphagia, hoarseness of voice and epistaxis [114]. Thymus NENs: cough, dyspnea, chest pain, weight loss and chronic fever [116]. Thyroid NENs: thyroid nodule and cervical lymphadenopathy [117]. Breast NENs: solitary breast nodule, axillary lymphadenopathy, nipple discharge and retraction [118]. Skin NENs: Warts or blister [119]. | CgA or Synaptophysin or NSE positive [153]. | CT scan and MRI help identify adrenal lesions and FDG-PET scan distinguishes malignant from benign lesions. | Based on the site of involvement the tumor is managed and some tumors can also present as part of genetic syndromes and are treated with them. | Newer targets: programmed death ligand-1 (PDL1) expression and cytotoxic T lymphocyte antigen-4 are being reported in SCLC and melanoma [20,205,206,207]. |
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Sultana, Q.; Kar, J.; Verma, A.; Sanghvi, S.; Kaka, N.; Patel, N.; Sethi, Y.; Chopra, H.; Kamal, M.A.; Greig, N.H. A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management. J. Clin. Med. 2023, 12, 5138. https://doi.org/10.3390/jcm12155138
Sultana Q, Kar J, Verma A, Sanghvi S, Kaka N, Patel N, Sethi Y, Chopra H, Kamal MA, Greig NH. A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management. Journal of Clinical Medicine. 2023; 12(15):5138. https://doi.org/10.3390/jcm12155138
Chicago/Turabian StyleSultana, Qamar, Jill Kar, Amogh Verma, Shreya Sanghvi, Nirja Kaka, Neil Patel, Yashendra Sethi, Hitesh Chopra, Mohammad Amjad Kamal, and Nigel H. Greig. 2023. "A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management" Journal of Clinical Medicine 12, no. 15: 5138. https://doi.org/10.3390/jcm12155138