Differentiating carcinoid syndrome from other diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

Overview

Carcinoid syndrome must be differentiated from systemic mastocytosis, medullary thyroid carcinoma, irritable bowel syndrome, malignant neoplasms of the small intestine, benign cutaneous flushing, and recurrent idiopathic anaphylaxis.

Differentiating Carcinoid Syndrome from other Diseases

Carcinoid syndrome must be differentiated from:

• Systemic mastocytosis
• Medullary thyroid carcinoma
• Irritable bowel syndrome
• Malignant neoplasms of the small intestine
• Benign cutaneous flushing
• Recurrent idiopathic anaphylaxis

Diseases		Clinical manifestations												Para-clinical findings										Gold standard	Additional findings
		Symptoms						Physical examination
														Lab Findings			Imaging						Histopathology
		Abdominal pain	Diarrhea	Flushing	Dyspnea	Palpitations	Other symptoms	Wheezing	Telangiectasia	Hypotension	Tachycardia	Systolic murmur of tricuspid regurgitation	Other physical findings	Urinary 5-hydroxyindoleacetic acid (5-HIAA)	Serum Chromogranin A (CgA)	Other markers	Abdominal computed tomography (CT)	Abdominal MRI	Somatostatin receptor scintigraphy [SRS], or Octreoscan	Metaiodobenzylguanidine (MIBG) scintigraphy	Other diagnostic studies	Transthoracic echocardiography
Carcinoid Syndrome	Neuroendocrine tumor of midgut	+ Mild	+ Intermittent Secretory diarrhea	+	+	+	Pellagra Dermatitis Diarrhea Dementia Metastatic tumors in the liver: Right upper quadrant pain, hepatomegaly, and early satiety	+	+/-	+/-	+	+	-	+	+	NT-proBNP Screening of carcinoid heart disease Blood Serotonin levels	Neuroendocrine tumor of midgut are difficult to identify on CT because of their small size. Findings: mass-like process with soft tissue "spokes" radiating into the mesenteric fat toward the small bowel causing retraction. Liver metastases	Sensitive for detection of liver metastases	+ Localization of carcinoid tumor	+	68-Ga DOTATATE PET scan Positron emission tomography-computed tomography (PET-CT) using 18-fluoro-dihydroxyphenylalanine Ki-67 labeling index Endoscopy for metastatic Neuroendocrine tumour with an unknown primary site.	Valve thickening with retraction and reduction in the mobility of the tricuspid valve	Enterochromaffin cells stain with potassium chromate (chromaffin). On electron microscopy ,the cells in tumors are found to contain membrane-bound secretory granules with dense-core granules in the cytoplasm.	Somatostatin receptor scintigraphy [SRS], or Octreoscan Biopsy and histopathology	Mesenteric fibrosis Pathognomonic radiological sign of midgut NET.
	Neuroendocrine tumor of lung	+	+	+	+	+	Cough Hemoptysis Chest pain Fever due to post -obstructuve pneuomnia	+	+/-	+/-	+	+	-	+	+	Immunohistochemical stains: Synaptophysin Neuron-specific enolase NT-proBNP Low serotonin content as compared to midgut tumors.	Atypical neuroendocrine tumors have a greater tendency to metastasize to liver,hypervascular, and becomies isodense relative to the liver parenchyma after contrast administration.		Sensitive for detection of liver metastases if present	+	+	Chest X ray: round or oval opacities from 2-5cm with sharp and notched margins Chest CT : Hilar or Perihilar Masses, Endobronchial Nodules,Related to bronchial Obstruction:peripheral atelectasis and postobstructive pneumonia Pulmonary funcation test Bronchoscopy 68-Ga DOTATATE PET scan Fluorodeoxyglucose PET scans for atypical lung NETs .	-	Typical low-grade:bland cells containing regular round nuclei with finely dispersed chromatin and inconspicuous small nucleoli.Mitotic figures are scarce and necrosis is absent. Intermediate-grade atypical: presence of Neuroendocrine morphology and either necrosis or 2 to 10 mitoses per 10 HPF	Biopsy and histopathology
Irritable Bowel Syndrome		+ Perioidic	Intermittent Chronic history of diarhea alternating with constipation	-	-	-	Fibromyalgia Chronic fatigue syndrome Gastroesophageal reflux disease, Functional dyspepsia Non-cardiac chest pain, Major depression ,Anxiety	-	-	-	-	-		-	-		-	-	-	-	Bristol stool form scale should to record stool consistency Abdominal radiograph to assess for stool accumulation and determine the severity. Age-appropriate colorectal cancer screening in all patients	-	-	Rome IV criteria Recurrent abdominal pain, at least 1day/week in the last 3 months, a/s with 2 or more of the following criteria: •Related to defecation •Associated with a change in stool frequency •Associated with a change in stool form (appearance)
Malignant neoplasms of small intestine		+/-	+/-	-	-	+/-	Constipation Fatigue Early satiety	-	-	+/-	-	* Abdominal mass Ascites	-	+	Abdominal CT scan may be diagnostic of small intestine cancer. Findings on CT scan suggestive of small intestine cancer include intrinsic mass with a short segment of bowel wall thickening	MRI and MRI enteroscopy are other advance modalities to diagnose and stage small intestinal cancers	-	-	Enteroscopy, capsule endoscopy and double balloon enteroscopy		Adenocarcinomas may be polypoid, infiltrating, or as annular constricting lesions is small intestine. Polyps and adenomas of small intestine are considered precursor lesions of adenocarcinoma. Lymphomas of small intestine present with suspicious growths in submucosa with normal appearing muscosa. Endoscopic evaluation may show multifocal involvement and large biopsies are required for diagnoses	Biopsy and histopathology
Crohn disease		Right lower quadrant pain	+/-	-	-	-	Gross bloody diarrhea +/- Weight loss Fatigue	-	-	-	-	-	Weight loss Pallor Oral lesions Odynophagia Dysphagia Perianal skin tags Sinus tracts Gallstones Extraintestinal manifestations Arthritis Uveitis, Iritis, and Episcleritis Erythema nodosum and Pyoderma gangrenosum Primary sclerosing cholangitis Secondary amyloidosis Thromboembolism Renal stones Osteoporosis Vitamin B12 deficiency	-	-	CRP may be high p-ANCA and ASCA	CT enterography Small bowel inflammation by displaying mural hyperenhancement and thickening; engorged vasa recta; and perienteric inflammatory changes.		-	-	CBC Blood chemistry including electrolytes Renal function tests liver enzymes Blood glucose ESR CRP Serum iron Vitamin D & vitamin B12 levels Stool D/R and culture for ova and parasites, C. difficile toxin	-	Focal ulcerations and acute and chronic inflammation Granulomas	Colonoscopy:focal ulcerations adjacent to areas of normal appearing mucosa along with polypoid mucosal,skip lesions,pseudopolyps,
Benign cutaneous flushing		-	-	+	-	-		-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Systemic mastocytosis		+	+	+	+	-	Maculopapular rash Pruritus	+/-	+/-	+	-	-	Diffuse musculoskeletal pain Neuropsychiatric symptoms	-	-	Activating mutations of KIT Serum Tryptase levels			-	-
Asthma exacerbation		-	-	-	+	+		+	-	-	+	-	Tachypnea Prolonged expiratory phase of respiration (decreased I:E ratio) Seated position with use of extended arms to support the upper chest (tripod position) +/- Pulsus paradoxus	-	-	-	--	-	-	-	Chest X ray	-	Loss of the normal pseudostratified structure of airway epithelium Increase in the proportion of goblet cells Fibrotic thickening of the sub-epithelial reticular basement membrane Increased numbers of myofibroblasts Increased vascularity Increased airway smooth muscle mass Increased extracellular matrix
Anaphylaxis		+	-/+	+	+	+	Vomiting Generalized hives, Pruritus Itching	+/-	-	+	+	-	Swollen lips-tongue-uvula Periorbital edema, Conjunctival swelling	-	-	-	-	-	-	-	plasma tryptase Plasma histamine levels Take proper clinical history and medication history specially beta blockers,ACE-inhibitors,opioids Skin testing with allergen extracts enzyme-linked immunosorbent assays (ELISAs) for quantification of allergen-specific IgE levels	-	-		History of exposure to insect stings,food alllergy,rubber latex,food additives,,allergy to medications,physical factors such s excercise and cold
Histaminergic Angioedema		+/-	+/-	+	+	+	Generalized pruritus Throat tightness Hoarse voice Difficulty swallowing	+	-	+	+	-	Urticaria Localized swelling of skin	-	-	-	Bowel wall edema Circumferential thickening of the small bowel wall with ascites or incomplete obstruction	-	-	-	CBC with differential, Electrolytes Liver function tests C-reactive protein Erythrocyte sedimentation rate Levels of the complement protein C4 Serum total tryptase Allergen-specific IgE immunoassays	-	-	-	Take proper clinical history of previous similar episodes Medication history Any allergy to insects stings , foods or any ingestion within previous 24 hours
Medullary Thyroid Carcinoma		-	+/-	+/-	+/-	-	Neck pain Hoarseness Cough Difficulty swallowing Difficulty breathing Lethargy Bone pain from metastasis	-	-	-	-	-	Solitary thyroid nodule Cervical lymph node involvement Weight loss	-	-	Basal serum calcitonin concentrations Carcinoembryonic antigen (CEA) concentration Thyroid function tests: normal Germline RET testing Serum calcium Plasma fractionated metanephrines	-	-	-	-	Ultrasonography of the neck For metastasis Chest computed tomography Neck CT Three-phase contrast-enhanced liver CT Axial MRI Bone scintigraphy.	-	Immunohistochemical staining for calcitonin Spindle-shaped and frequently pleomorphic cells without follicle development	Fine-needle aspiration (FNA) biopsy TNM staging American Thyroid Association (ATA) Guidelines for Management and evaluation of Medullary Thyroid Cancer