Sandbox:Hannan1

Neuroendocrine tumor		Clinical manifestations		Dianosis						Gold standard	Other features
		Symptoms	Signs	Blood & Urine	Gross	Histology	Immunohistochemistry	Imaging	Others
Medullary thyroid carcinoma		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		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		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		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		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		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		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		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		Asymptomatic Acute appendicitis localized pain shifting pain nausea, vomiting, anorexia rectal bleeding Carcinoid syndrome	Asymptomatic Acute appendicitis localized or generalized abdominal tenderness fever abdominal distension Carcinoid syndrome	Normal ↑ WBCs (appendicitis) ↑ Bilirubin (appendicitis) ↑ Urinary 5-hydroxyindole-acetic acid ↑ chromogranin A	Ill-defined Firm Nodular	Infiltrates muscularis propria & periappendiceal fat Solid clusters resembling goblet cells or signet ring cells & eosinophilic cytoplasm Scattered Paneth cells Single cells	Synaptophysin Chromogranin A CK CEA CDX-2 CAM 5.2	Thickened appendix wall (U/S and CT) Appendicitis (U/S and CT) inflamed appendix peri-appendicular fluid	Chromogranin A enzyme linked immunoassay FDG-PET 111In-labelled octreotide scintigraphy	Histopathology	N/A
Colon neuroendocrine tumors		Abdominal pain Diarrhea Hematochezia Nausea Asymptomatic Carcinoid syndrome	Abdominal tenderness Weight loss Anemia related	↑ chromogranin A ↑ Urinary 5-hydroxyindole-acetic acid (rare) ↓ Hb	Flat or depressed lesion Plaque or polypod	Islands, glandular or trabeculae Granular cytoplasm salt and pepper chromatin Lymphovascular invasion	Synaptophysin Chromogranin	Wall thickening Lumen narrowing	Colonoscopy Chromogranin A enzyme linked immunoassay PET scan SSTR (somatostatin receptors) scintigraphy	Biopsy and histopathology	Cecum is most common location ↑ prevalence in IBD patient population
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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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