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Neuroendocrine tumor Clinical manifestations Dianosis Gold

standard

Other features
Symptoms Signs Blood & Urine Gross Histology Immunohistochemistry Imaging Others
Medullary thyroid carcinoma[1][2][3]
  • Dysphagia
  • Hoarseness
  • Respiratory difficulty
  • Flushing
  • Diarrhea
  • Weight loss
  • Palpable neck mass
  • Signs of Cushing syndrome
  • ↑ Calcitonin
  • ↑ Serum calcium
  • ↑ or - Cortisol
  • ↑ CEA level
  • White or gray in color
  • Firm to palpation
  • Nests of uniform cells
  • Deposition of stromal amyloid
  • Granular chromatin
  • C-cell hyperplasia
  • Calcitonin
  • Chromogranin A
  • Carcinoembryonic antigen (CEA)
  • Solid thyroid nodule (US)
  • CT scan/MRI and PET scan for metastatis
  • Genetic testing
  • FNA cytology with immunohisto-

chemistry and

calcitonin levels

  • Associated with MEN 2A and 2B
  • Familial association with RET mutations
  • May present as Cushing syndrome
Pheochromocytoma[4][5][6][7][8]
  • Headaches
  • Palpitations
  • Excessive sweating
  • Anxiety
  • Pallor
  • Pain in chest/abdomen
  • Weakness, fatigue
  • Nausea/vomiting
  • Dizziness
  • Paresthesias
  • Constipation (rarely diarrhea)
  • Visual disturbance
  • Hypertension
  • Postural hypotension
  • Tachycardia or reflex bradycardia
  • Tremulousness
  • Pallor
  • Flushing (rare)
  • Weight loss
  • Fasting hyperglycaemia
  • Decreased GI motility
  • Pallor
  • ↑ Respiratory rate
  • Psychosis
  • ↑ Plasma and urine catecholamines
  • ↑ Plasma and urine metanephrines
  • ↑ Chromogranin A
  • ↑ Plasma methoxytyramine
  • N/A
  • Loosely cohesive clusters
  • Scattered tumor cells with prominent anisokaryosis, abundant eosinophilic granular cytoplasm and indistinct cell borders
  • Occasional binucleate cells
  • Chromogranin A (CGA)
  • Protein gene product (PGP) 9.5
  • Synaptophysin (SYN)
  • CD56 (also known as neural cell adhesion molecule or N-CAM)
  • Glial fibrillary acidic protein (GFAP)
  • Heterogeneous appearance, often with some cystic areas. Calcifications or hemorrhage may also be present (CT)
  • T2-bright lesions, with/without cystic or necrotic components (MRI)
  • Cystic or solid with necrotic areas or hemorrhages (U/S)
  • Genetic testing
  • Provacative glucagon test
  • Clonidine suppression test
  • Metaiodobenzyl-guanidine scintigraphy
  • PET scan
  • Octereoscan
  • Plasma and urine catecholamines & metanephrines combined with clinical findings
  • May mimic panic attack
  • May be associated with Von Hippel-Lindau disease, MEN type 2 and Neurofibromatosis type 1.
  • Arise from the chromaffin cells
Merkel cell carcinoma[9][10][11]
  • Asymptomatic red-to-violet nodules
  • Violaceous nodule
  • Ulcerated Nodule
  • Lympadenopathy
  • Seropositivity for Merkel cell polyomavirus
  • Anti-ST antibodies
  • Dermal and subcutaneous nodule
  • Monomorphic cells with 3 main types — small-cell, trabecular and intermediate
  • May show necrosis & pleomorphism
  • Epidermotropism
  • Chromogranin-A
  • Synaptophysin
  • Cytokeratin 20 (CK20)
  • Merkel cell polyomavirus (MCPyV) large T antigen
  • U/S, CT scan, MRI and PET scan for metastasis
  • N/A
  • Biopsy with immunohisto-chemistry
  • Higher mortality than melanoma
  • ↑ Risk in immun-compromised
Parathyroid adenoma[12][13][14]
  • Depression
  • Memory loss
  • Fatigue
  • Sleep problems
  • Bone or muscle pains
  • GERD
  • ↓ concentration
  • Renal colic
  • Constipation
  • Nephrolithiasis
  • Nephrocalcinosis
  • osteopenia
  • osteoporosis
  • ↑ Serum and urinary Calcium
  • ↑ or N/L PTH
  • Enlarged
  • smooth
  • Soft
  • Reddish brown in color
  • Discrete with thin fibrous capsule
  • May be multinodular and irregular
  • Proliferation of a single cell type with solid to pseudo-glandular, follicular, and acinar structure
  • Chromogranin
  • Parathyroid hormone
  • Enlarged gland on U/S and 99mTc-sestamibi scintigraphy
  • Single photon emission computed tomography
Staining for
  • bcl-1
  • Ki67
  • p27
  • parafibromin
  • Biopsy
  • Associated with MEN
  • Associated with HPRT
Paraganglioma[15][16][17][18]
  • Headaches
  • Palpitations
  • Tinnitus
  • Decreased hearing
  • Localized pain
  • GI & intracranial hemorrhage
  • Cardiomyopathy Generalized weakness
  • Pallor
  • Hypertension
  • Localized mass
  • Orthostasis
  • Incidentalomas
  • Cranial nerve palsies
  • ↑ Plasma and urine catecholamines
  • ↑ Plasma and urine metanephrines
  • ↑ Chromogranin A
  • ↑ Plasma methoxytyramine
  • Clear margins
  • Encapsulated
  • Honeycomb or nests patterns separated by broad bands of fibrous tissue
  • Prominent vascularization
  • Argyrophilic fibers
  • Chromogranin A
  • Synaptophysin
  • CD56
  • S-100
  • Cytokeratin
  • Mass with an un-enhanced density
  • Internal Hemorrhage
  • Cystic changes
  • Necrosis
  • Internal calcifications
  • Genetic testing
  • Provacative glucagon test
  • Clonidine suppression test
  • Metaiodobenzyl-guanidine scintigraphy
  • PET scan
  • Octereoscan
N/A
  • Paragangliomas are similar to pheochromo-cytomas but arise outside adrenal medulla
Pituitary gland tumors
Neuroendocrine tumors of the testicles[19][20][21]
  • Painless scrotal mass & swelling
  • Scrotal pain
  • Carcinoid syndrome
  • Firm painless or painful scrotal mass & swelling
  • Flushing
  • Hydrocele
  • ↑ Serum NSE
  • ↑ Serum vanillylmandelic acid
  • ↑ Serum serotonin and serotonin metabolites
  • Well-defined
  • Non-capsulated
  • Calcified cyst
  • Hemorrhage & necrosis
  • Presence of argentaffin and argyrophilic cells
  • Monomorphous polygonal cells
  • Eosinophilic cytoplasm
  • Finely dispersed chromatin
  • Cytokeratin
  • Chromogranin
  • Synaptophysin
  • Serotonin
  • NSE
  • Vimentin
  • Well-defined solid hypoechoic mass (U/S)
  • Dense punctate calcifications (U/S)
For metastasis and grading:
  • CT scan
  • Octreotide scintigraphy
  • Pan GI endoscopy
  • Scrotal U/S with immunohisto-chemistry
  • May be associated with testicular teratoma
  • Normal serum levels of testicular tumor markers
Neuroendocrine tumors of the ovaries[22][23][24]
  • Lower abdominal pain & swelling
  • Carcinoid syndrome
  • Abdominal and/or pelvic mass
  • Ascites
  • Flushing
  • ↑ Urinary 5-hydroxyindole-acetic acid
  • ↑ Chromogranin A
  • ↑ or - CA 125
  • Well-defined
  • Smooth
  • Solid with cystic areas
  • Insular pattern with nested areas
  • Cells in groups and trabeculae arrangement
  • Mild to moderate nuclear pleomorphism
  • CD 56
  • Synaptophysin
  • Chromogranin
  • Solid ovarian mass with significant enhancement (MRI)
  • Ovarian solid mass (U/S)

For metastasis and grading:

  • CT scan
  • Octreotide scintigraphy
  • Pan GI endoscopy
  • N/A
  • CDX2 may distinguish primary ovarian NET from metastatic NET from GI tract
Thymic neuroendocrine cancer[25][26][27][28]
  • Chest pain
  • Cough
  • Respiratory distress
  • Cushing’s syndrome
  • Carcinoid syndrome (rare)
  • ↓ Breath sounds
  • Flushing
  • Cushing’s syndrome
  • Hypercalcemia
  • Usually normal
  • May see
    • ↑ Serum calcium & ACTH
    • ↑ Serum serotonin and its metabolites
  • Solid mass
  • Hemorrhage & necrosis
  • Calcification
  • Gross invasion
  • Small cells with scant cytoplasm
  • Trabeculae
  • Solid nests
  • Vascular invasion
  • Fine granular or vesicular chromatin
  • Keratins (AE1/AE3, CAM5.2)
  • Synaptophysin
  • Chromogranin
  • NSE
  • CD 56
  • Mediastinal mass
  • Necrotic areas
  • Unclear margins
  • Adjacent compression

For metastasis and grading:

  • PET scan
  • Endoscopy
  • H & E morphology
  • May co-exist with thymoma
  • Associated with MEN-1
Jejuno-Ileal neuroendocrine tumors
Appendix neuroendocrine tumors
Colon neuroendocrine tumors
Rectum neuroendocrine tumors
  • Asymptomatic
  • Rectal pain
  • Pruritus
  • Hematochezia
  • Constipation
  • Carcinoid syndrome (rare)
  • Abdominal tenderness
  • Weight loss
  • Carcinoid signs (rare)
  • ↑ chromogranin A
  • ↑ Urinary 5-hydroxyindole-acetic acid (rare)
  • ↓ Hb
  • Small and multiple
  • Nodules or polypoid
  • Islands, glandular or trabeculae
  • Granular cytoplasm
  • salt and pepper chromatin
  • Mucin secretion (rare)
  • Synaptophysin
  • Chromogranin
  • Neuron-specific enolase
  • CD56
  • Rectal mass or nodule
  • Ulcerative mass (high grade)
  • Hemorrhage
  • Liver mass (metastatic)
  • Colonoscopy
  • Chromogranin A enzyme linked immunoassay
  • PET scan
  • SSTR (somatostatin receptors) scintigraphy
  • Biopsy and histopathology
  • May exist with adenocarcinoma
  • Exhibits malignant potential
Gastric neuroendocrine tumors Type I GNET[29][30][31]
  • Dyspepsia
  • Abdominal discomfort and/or pain
  • Anemia related
  • Neurological symptoms
  • Weight loss
  • Pallor
  • Neurological signs
  • ↑ Gastrin level
  • ↑ chromogranin A
  • ↓ Hb
  • ↓ Serum iron
  • ↓ Serum B12 levels
  • Flattened gastric folds
  • Multiple polyps or nodules
  • Dense core granules
  • Glandular or trabecular
  • Salt and pepper chromatin
  • Keratins
  • Chromogranin
  • NSE
  • Synaptophysin
  • VMAT 2
  • Well demarcated hypoechoiec lesions
  • Mucosal / submucosal
  • Regular borders
  • Gastroscopy
  • pH on gastric aspirate
  • Axial CT
  • Somatostatin receptor imaging
  • N/A
  • Chronic atrophic gastritis → gastric achlorhydria and hypergastrinaemia → proliferation of ECL cells → type 1 G-NETs
Type II GNET[29][30][32]
  • Abdominal pain and/or discomfort
  • Severe watery diarrhea
  • GI bleed
  • Anemia related
  • GERD
  • Abdominal tenderness
  • Hypercalcemia
  • Anemia related
  • ↑ Gastrin or gastrin precursors
  • ↑ Serum calcium
  • ↑ Chromogranin A
  • N/A
  • Dense core granules
  • Glandular or trabecular
  • Salt and pepper chromatin
  • Keratins
  • Chromogranin
  • NSE
  • Synaptophysin
  • Hypertrophied gastric mucosal folds
  • Well demarcated hypoechoiec lesions
  • Secretin test
  • pH on gastric aspirate
  • 111Indium Octreotide scintigraphy
  • 68Gallium-DOTATOC/DOTATATE PET/CT
  • N/A
  • Caused by gastrinoma
  • Most patient have MEN-1 syndrome → evaluate
Type III GNET[33][34][35]
  • Dyspepsia
  • Abdominal discomfort and/or pain
  • May present with carciniod syndrome
  • Weight loss
  • Anaemia related
  • Flushing
  • ↓ Hb
  • ↑ Urinary 5-hydroxyindole-acetic acid (rare)
  • Large lesion with poor margins
  • Ulcerated appearance
  • High grade
  • Invasive
  • Dense core granules
  • Glandular or trabecular
  • Keratins
  • NSE
  • Synaptophysin
  • Absence of surface villiform architecture
  • Single large lesion
  • Ulcerated appearance
  • Gastroscopy
  • CT
  • 111Indium octreotide scintigraphy
  • Biopsy and histopathological studies
  • Early involvement of regional lymph nodes
  • May present with metastatic disease at diagnosed
Type IV GNET[36][37][38]
  • Dyspepsia
  • Abdominal discomfort and/or pain
  • Weight loss
  • Anaemia related
  • ↑ Gastrin or gastrin precursors
  • ↑ Serum calcium
  • Invasion of adjacent structures
  • Large solid lesion
  • Solid structure
  • Necrosis
  • Atypia
  • Invasive
  • Synaptophysin
  • NSE
  • PGP9.5 positive
  • N/A
  • Gastroscopy
  • CT
  • 111Indium octreotide scintigraphy
  • Biopsy and histopathological studies
Structural abnormality → no HCL secretion → achlorhydria →

hypergastrinemia → hyperplasia

Duodenal neuroendocrine tumors Gastrinoma[39][40][41][42]
  • Atypical PUD
  • Abdominal pain and/or cramps
  • Esophagitis
  • GERD
  • Upper GI blee
  • Secretory diarrhea
  • Abdominal tenderness
  • Hypercalcemia
  • ↑ Gastrin or gastrin precursors
  • ↑ Serum calcium
  • ↑ Chromogranin A
  • N/A
  • Trabeculae
  • Solid nests
  • Presence of argentaffin and argyrophilic cells
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • Gastrin
  • Diffuse erosive esophagitis, gastric and duodenal ulcer (Endoscopic gastroduo-denoscopy)
  • Enhancing lobulated lesion (CT)
  • Gastrin levels
  • Pancreatic polypeptide levels
  • Insulin levels
  • Glucagon levels
  • VIP levels
  • PET with gallium 68–labeled octreotide
  • Provocative secretin test & biopsy
  • Associated with MEN-1
Somatostatinomas[43][44][45][46]
  • Abdominal pain
  • Jaundice
  • Gastrointestinal bleeding
  • Diarrhea
  • Weight loss
  • Hypoglycemia related
  • Jaundice
  • Diabetes mellitus
  • Gallstones
  • Hypochlorhydria
  • Hypoglycemia related
  • ↑ Somatostatin
  • Anemia
  • Hyper or hypoglycemia
  • N/A
  • Acinar structures
  • Trabeculae
  • Psammoma body
  • Abundant fine granular cytoplasm
  • Salt and pepper chromatin
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • Leu-7
  • Isodense
  • Hypervascular lesion
  • Dual phase CT
  • MRI
  • Endoscopic ultrasonography
  • 68Ga-DOTATATE
  • Octreoscan
  • Gastrin levels
  • Pancreatic polypeptide levels
  • Insulin levels
  • Glucagon levels
  • N/A
  • Associated with NF-1
Gangliocytic paraganglionomas[47][48][49][50]
  • GI bleed
  • Abdominal pain
  • Anemia related
  • Carcinoid syndrome (rare)
  • Anemia related
  • May mimic other neuroendocrine tumors such as somatostatinoma
  • ↓ Hb
  • ↑ Chromogranin A
  • May have ↑ urinary 5-hydroxyindole-acetic acid or serum somatostatin
  • Solid tumor
  • Ulceration
  • Sessile or polypod
  • Covered by the smooth
  • Spindle cells, ganglion-like cells and epithelioid cells
  • Nests and trabeculae
  • Chromogranine
  • AE1–3
  • Cytokeratins
  • S100
  • Neuron-specific enolase
  • Synaptophysin
  • CD56
  • Ampullary smooth mass (CT scan and endoscopic ultrasonography)
  • Endoscopic ultrasonography-guided FNA
  • Serum serotonin assay
  • Biopsy with immunohisto-chemistry
  • Associated with NF-1
Nonfunctioning NET[51]
  • Asymptomatic
  • GI bleed
  • Abdominal pain
  • Anemia related
  • Anemia related
  • ↓ Hb
  • Solid tumor
  • Trabecular or microlobular structure
  • Mucosal-submucosal tumor
  • Chromogranin A
  • Synaptophysin
  • Hormones such as gastrin, somatostatin, serotonin
  • CT scan
  • Endoscopic ultrasonography
  • Endoscopic ultrasonography-guided FNA
  • Biopsy with immunohisto-chemistry
  • May produce hormones but do not secrete
neuroendocrine carcinomas[52][53][54][55]
  • Upper abdominal pain
  • Abdominal Discomfort
  • Obstruction
  • Gastrointestinal bleeding
  • Constitutional
  • Anemia related
  • ↑ Chromogranin A
  • Progastrin-releasing peptide (pro-GRP)
  • Cytokeratin fragments (CKfr, CK8, 18, 19)
  • Solid tumor
  • Ulceration
  • Poorly differentiated
  • Necrosis
  • Lymphovascular invasion
  • Marked pleomorphism
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • Protein-gene-product 9.5 (PGP 9.5)
  • CD56 (N-CAM)
  • Polypoid intraluminal mass (CT scan)
  • MRI
  • FDG-PET
  • Somatostatin receptor imaging (SRI)
  • Biopsy with immunohisto-chemistry
  • Typically non-functioning
  • May exist with adenocarcinoma
Pancreatic neuroendocrine tumours Gastrinoma[39][40][41][42]
  • Atypical PUD
  • Abdominal pain and/or cramps
  • Esophagitis
  • GERD
  • Upper GI blee
  • Secretory diarrhea
  • Abdominal tenderness
  • Hypercalcemia
  • ↑ Gastrin or gastrin precursors
  • ↑ Serum calcium
  • ↑ Chromogranin A
  • N/A
  • Trabeculae
  • Solid nests
  • Presence of argentaffin and argyrophilic cells
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • Pancreastatin
  • Gastrin
  • Diffuse erosive esophagitis, gastric and duodenal ulcer (Endoscopic gastroduo-denoscopy)
  • Enhancing lobulated lesion (CT)
  • Gastrin levels
  • Insulin levels
  • Glucagon levels
  • VIP levels
  • PET with gallium 68–labeled octreotide
  • Indium-labelled octreotide (111In-octreotide)
  • Provocative secretin test & biopsy
  • Associated with MEN-1
Insulinoma[56][57][58][59]
  • Visual disturbances
  • Weakness
  • Seizures
  • Palpitations
  • Sweating
  • Hyperphagia/obesity
  • Tachycardia
  • Altered mental state
  • Amnesia
  • Confusion
  • Coma
  • Tremors
  • ↓ Blood sugar level
  • ↑ or inappropriately normal insulin level
  • ↑ Plasma proinsulin
  • Firm
  • Well-circumscribed nodule
  • Encapsulated mass
  • Solid or gyriform patterns
  • May be associated with nesidioblastosis
  • Amyloid
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • CD56
  • Insulin
  • Hypervascular lesion (CT)
  • Calcification (malignant)
  • Homogeneously hypoechoic (endoscopic U/S)
  • MRI
  • Transabdominal U/S
  • C peptidelevel
  • Urinary Sulfonylurea
  • Pancreatic angiography
  • Transhepatic portal venous sampling (THPVS)
  • Intraoperative U/S
  • Intra-arterial calcium stimulation (IAC)
  • Associated with MEN-1
Glucagonoma[60][61][62][63]
  • Rash
  • Weight loss
  • Anemia
  • Diarrhea
  • Abdominal pain
  • Nausea or anorexia
  • DVT or PE related
  • Neurological symptoms
  • Weakness or fatigue
  • Necrotizing migratory erythema
  • Glossitis
  • Stomatitis
  • Cheilitis
  • Anemia related
  • DVT or PE related
  • Onychodystrophy
  • Peripheral edema
  • Depression
  • ↑ Glucagon levels
  • Diabetes or impaired fasting glucose
  • Hypoaminoacidemia
  • ↓ Serum zinc
  • ↓ Hb
  • N/A
  • Dense core granules
  • Nests pattern
  • Salt and pepper chromatin
  • Amphophilic cytoplasm
  • PGP 9.5
  • CAM 5.2
  • anti-glucagon
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • Helical multiphasic contrast-enhanced CT scan
  • MRI
  • Somatostatin receptor scintigraphy (SRS)
  • FPET imaging technique with DOTA peptides
  • Serum parathyroid hormone, gastrin, insulin, pancreatic polypeptide, serotonin, VIP, prolactin and ACTH levels
  • Skin biopsy
  • N/A
  • Associated with MEN-1
Somatostatinoma[43][44][45]
  • Abdominal pain
  • Jaundice
  • Gastrointestinal bleeding
  • Diarrhea
  • Weight loss
  • Hypoglycemia related
  • Jaundice
  • Diabetes mellitus
  • Gallstones
  • Hypochlorhydria
  • Hypoglycemia related
  • ↑ Somatostatin
  • Anemia
  • Hyper or hypoglycemia
  • N/A
  • Acinar structures
  • Trabeculae
  • Psammoma body
  • Abundant fine granular cytoplasm
  • Salt and pepper chromatin
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • Leu-7
  • Isodense
  • Hypervascular lesion
  • Dual phase CT
  • MRI
  • Endoscopic ultrasonography
  • 68Ga-DOTATATE
  • Octreoscan
  • Gastrin levels
  • Pancreatic polypeptide levels
  • Insulin levels
  • Glucagon levels
  • N/A
  • Associated with MEN-1
VIPoma[64][65][66][67]
  • Secretory diarrhea with odorless and tea colored stools
  • Lethargy
  • Nausea & vomiting
  • Muscle weakness & cramps
  • Tetany
  • Dehydration
  • Flushing
  • Cardiac arrhythmias, myopathy, tetany and hypovolemic shock (crisis)
  • ↑ VIP levels
  • ↑ Serum pancreatic polypeptide level
  • Hypokalemia
  • Hypomagnesemia
  • Hypochlorhydria
  • Hyperglycemia
  • Hypercalcemia
  • Encapsulated
  • Necrosis
  • Nested cells
  • Trabeculae
  • Secretory granules
  • Granular cytoplasm
  • Chromogrannin A
  • VIP
  • Pancreatic polypeptide
  • Encapsulated and necrotic mass (CT scan & MRI)
  • Somatostatin receptor scintigraphy
  • Endoscopic U/S
  • FPET imaging with DOTA peptides
  • VIP radioimmunoassay
  • Celiac, superior mesentericand renal angiography
  • Levels of other PNETs
  • VIP radioimmunoassay with clinical manifestations
  • Associated with MEN-1
ACTHoma[68][69][70][71]
  • Weight gain
  • Acne
  • Ophthalmologic discomfort
  • Extremity weakness
  • Hypertension
  • Moon facies
  • Easy bruising
  • Buffalo-hump
  • Abdominal striae
  • ↑ Serum ACTH
  • ↑ Serum and urinary cortisol
  • Diabetes mellitus
  • Hypokalemic alkalosis
  • Firm
  • Well circumscribed
  • Encapsulated
  • Nested cells
  • Trabeculae
  • Secretory granules
  • Lymphovascular invasion
  • Synaptophysin
  • Chromogranin A
  • ACTH
  • Hypoechoic, homogenous, solid mass (endoscopic U/S)
  • Dexamethasone suppression test
  • Somatostatin receptor scintigraphy (SRS)
  • FPET imaging
  • N/A
  • Osteoporosis
  • Menstrual irregularities
Lung neuroendocrine tumors Typical carcinoid tumours[72][73][74][75]
  • Asymptomatic
  • Constitutional
  • Cough
  • Hemoptysis
  • Recurrent pneumonia
  • Seizures
  • ↓ Breath sounds
  • Fever
  • Weight loss
  • Carcinoid syndrome related
  • Cushing's syndrome related
  • ↑ Urinary 5-hydroxyindole-acetic acid
  • ↑ Chromogranin A
  • Central
  • Polypoid
  • Usually well defined
  • Smooth
  • No necrosis
  • Organized structure
  • <2 mitoses/2 mm2
  • No necroses
  • Nesting and/or trabecular pattern
  • Synaptophysin
  • Chromogranin A
  • CD56/NCAM
  • TTF1
  • Estrogen receptor
  • N/L
  • Coin lesion
  • Enlarged lymph nodes
  • Mass (rare)
  • Bronchoscopy (Gold standard for tumor visualization)
  • Endoscopic biopsy
  • N/A
  • 5‐year survival rate >90%
  • 12% metastasis at presentation
Atypical carcinoid tumours[72][73][74][75]
  • Asymptomatic
  • Constitutional
  • Cough
  • Hemoptysis
  • Recurrent pneumonia
  • Seizures
  • ↓ Breath sounds
  • Fever
  • Weight loss
  • Carcinoid syndrome related
  • Cushing's syndrome related
  • ↑ Urinary 5-hydroxyindole-acetic acid
  • ↑ Chromogranin A
  • Peripheral
  • Polypoid
  • Irregular margins
  • Smooth
  • Necrosis
  • More pleomorphism
  • 2–10 mitoses/2 mm2
  • Necroses
  • Nesting and/or trabecular pattern
  • Synaptophysin
  • Chromogranin A
  • CD56/NCAM
  • TTF1
  • Estrogen receptor
  • N/L
  • Coin lesion
  • Enlarged lymph nodes
  • Mass (rare)
  • Bronchoscopy (Gold standard for tumor visualization)
  • Endoscopic biopsy
  • N/A
  • 5‐year survival rate 40-75%
  • 50% metastasis at presentation
Large cell lung neuroendocrine carcinomas[76][77][78][79]
  • Asymptomatic
  • Cough
  • Hemoptysis
  • Recurrent infections
  • Seizures
  • ↓ Breath sounds
  • Fever
  • Carcinoid syndrome related (rare)
  • Cushing's syndrome related (rare)
  • ↑ Urinary 5-hydroxyindole-acetic acid (rare)
  • ↑ Serum ACTH (rare)
  • ↑ Chromogranin A
  • Less differentiated
  • Grey-white
  • Invasive
  • Hemorrhage/necrosis
  • Organoid or trabecular pattern
  • Rosette-like structures
  • Cells are ×3 the diameter of resting lymphocytes
  • Necrosis
  • Chromogranin
  • Neuron-specific enolase
  • Synaptophysin
  • Somatostatin
  • CD56
  • Peripheral lesion
  • Expansively growing
  • Irregular margins
  • Mediastinal lymph node enlargement
  • Bronchoscopy (Gold standard for tumor visualization)
  • SSTR (somatostatin receptors ) scintigraphy
  • Biopsy with immunohisto-chemistry
Associated
  • Smoking
  • Humoral hypercalcemia of malignancy
  • SIADH
  • Hypoglycemia
  • Acromegaly
  • Carcinoid syndrome
  • Neurological syndromes
  • Gynecomastia
  • Hyperthyroidism
Small cell lung neuroendocrine carcinomas[80][81][82][83]
  • Asymptomatic
  • Cough
  • Hemoptysis
  • Recurrent infections
  • Seizures
  • ↓ Breath sounds
  • Fever
  • Carcinoid syndrome related (rare)
  • Cushing's syndrome related (rare)
  • ↑ Urinary 5-hydroxyindole-acetic acid (rare)
  • ↑ Serum ACTH (rare)
  • ↑ Chromogranin A
  • Less differentiated
  • Grey-white
  • Invasive
  • Hemorrhage/necrosis
  • Diffuse sheets
  • No prominent neucleoli
  • Cells < size of three small resting lymphocytes
  • The mitotic rate averages over 60 mitoses/2 mm2
  • Extensive necrosis
  • Chromogranin
  • Neuron-specific enolase
  • Synaptophysin
  • Somatostatin
  • CD56
  • Homogeneous or noncontiguous parenchymal mass, or peripheral nodule
  • Adjacent compression
  • Atelectasis
  • Pleural effusion .
  • Intratumoral calcification
  • Lymphadenopathy
  • PET scan
  • Bronchoscopy
  • Scintigraphy
  • Biopsy with immunohisto-chemistry
Associated
  • Smoking
  • Humoral hypercalcemia of malignancy
  • SIADH
  • Hypoglycemia
  • Acromegaly
  • Neurological syndromes
  • Gynecomastia
  • Hyperthyroidism

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