Mast cell tumor differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2] Zahir Ali Shaikh, MD[3] Suveenkrishna Pothuru, M.B,B.S. [4]

Overview

Mast cell tumor must be differentiated from other diseases that cause flushing,such as: phaeochromocytoma and carcinoid syndrome. Mast cell tumor must be differentiated from other diseases that cause elevated serum tryptase levels and cytopenia, such as: myelodysplastic syndrome, primary myelofibrosis, essential thrombocythemia, and chronic eosinophilic leukemia.

Differential Diagnosis

Mast cell tumor must be differentiated from other diseases that cause flushing:

• Phaeochromocytoma
• Carcinoid syndrome

Mast cell tumor must be differentiated from other diseases that cause abdominal pain and discomfort:

• Irritable bowel syndrome
• Inflammatory bowel disease
• Zollinger-Ellison syndrome

Mast cell tumor must be differentiated from other diseases that cause elevated serum tryptase levels and cytopenia, such as:

• Myelodysplastic syndrome
• Primary myelofibrosis
• Essential thrombocythemia
• Chronic eosinophilic leukemia
• Chronic myeloid leukemia
• Myelomastocytic leukemia
• Malignant lymphoma

Differentiating Myeloproliferative Disorders

ABBREVIATIONS

N/A: Not available, NL: Normal, FISH: Fluorescence in situ hybridization, PCR: Polymerase chain reaction, LDH: Lactate dehydrogenase, PUD: Peptic ulcer disease, EPO: Erythropoietin, LFTs: Liver function tests, RFTs: Renal function tests, LAP: Leukocyte alkaline phosphatase, LAD: Leukocyte alkaline dehydrgenase, WBCs: White blood cells.

Myeloproliferative neoplasms (MPN)		Clinical manifestations		Diagnosis											Other features
		Symptoms	Physical examination	CBC & Peripheral smear									Bone marrow biopsy	Other investigations
				WBCs							Hb	Plat- elets
				Leuko-cytes	Blasts	Left shift	Baso- phils	Eosino- phils	Mono- cytes	Others
Chronic myeloid leukemia (CML), BCR-ABL1+		Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<2%	+	↑	↑	↑	N/A	↓	NL	Hypercellurarity with ↑ granuloscytosis and ↓ erythrocytosis Fibrosis	FISH for t(9;22)(q34;q11.2) Reverse transcriptase quantitative PCR (RQ-PCR) for BCR-ABL	Granulocytic dysplasia is minimal/absent May present with blast crisis Absolute leukocytosis (median of 100,000/µL) Classic myelocyte bulge thrombocytopenia indicates advanced stage
Chronic neutrophilic leukemia (CNL)		Asymptomatic Constitutional symptoms Bleeding Infection	Splenomegaly Heptomegaly Purpura Anemia related	↑	Minimal	+	NL	NL	NL	↑ LDH ↑ B12 levels	↓	↓	Uniforme and intense hypercellularity with minimal to none fibrosis Neutrophil toxic granulations and Dohle bodies	FISH Imaging for hepatosplenomegaly	Associationed with polycythemia vera and plasma cell disorders Leukocytosis with chronic neutrophilia
Polycythemia vera (PV)		Constitutional Thromboembolism and bleeding Pruritus after a warm bath PUD related	Facial ruddiness Related to underlying cause Splenomegaly Renal bruit	NL or ↑	None	-	↑ or ↓	NL or ↑	NL	↓ Serum ferritin ↓ Folate levels ↑↑ B12 levels	↑↑	NL	Hypercellularity for age with tri-lineage growth Myelofibrosis (in up to 20% of patients)	Radioisotope studies Serum EPO levels LFTs RFTs Imaging studies	May transform into myelofibrosis or leukemia
Primary myelofibrosis (PMF)		Constitutional Anemia related Bleeding Infection Abdominal Pain	Hepatosplenomegaly Petechiae & ecchymoses Abdominal distension Lymphadenopathy	↓	Erythroblasts	-	Absent	NL	NL	↑ LAP ↑ LAD ↑ Uric acid ↑ B12 levels	↓	↓	Variable with fibrosis or hypercellularity	JAK2 mutation CALR mutation MPL mutation	Bone marrow aspiration shows a dry tap Variable with leukocytosis or leukopenia
Essential thrombocythemia (ET)		Headache Dizziness Visual disturbances Priapism Acute chest pain	Splenomegaly Skin bruises	NL or ↑	None	-	↓ or absent	NL	NL	N/A	↓	↑↑	Normal/Hypercellular	JAK2 mutation CALR mutation MPL mutation	Thrombosis Hemorrhage Pregnancy loss
Chronic eosinophilic leukemia, not otherwise specified (NOS)		Constitutional Rash Rhinitis Gastritis Thromboembolism related	Hypertension Eczema, mucosal ulcers, erythema Angioedema Ataxia Anemia Lymphadenopathy Hepatosplenomegaly	↑	Present	+	↑	↑↑	↑	↑ B12 levels ↑ LDH	↓	↓	Hypercelluar with ↑ eosinophilic precursors, ↑ eosinophils, and atypical mononuclear cells	FISH Cytogenetic analysis of purified eosinophils and X-chromosome inactivation analysis	Heart failure Lung fibrosis Encephalopathy Erythema annulare centrifugam
MPN, unclassifiable		Similar to other myeloproliferative neoplasms	Similar to other myeloproliferative neoplasms	↑	Variable	±	↑ or ↓	↑ or ↓	↑ or ↓	May resemble other myeloproliferative neoplasms	↓	↑	↑ megakaryocyte proliferation with variable hypercellularity in granulocytic or erythrocytic cell lines	N/A	Similar to other myeloprolifeartive neoplasms but do not fulfil the criteria to be classified to a specific type
Mastocytosis		Constitutional Pruritus & Flushing Urticaria & Blisters Hypotension & PUD Bleeding Bronchoconstriction	Mastocytosis exanthema Blistering Swelling Lymphadenopathy Bleeding Fibrosis	↑	None	-	NL	↑	NL	↑ Alkaline phosphatase ↑ LDH	↓	↓ or ↑	Multifocal dense infiltrates of mast cells with atypical morphology in >25 %	Cytogenetic analysis for c-KIT receptor mutations Serum tryptase levels 24-hour urine test for N-methyl histamine and 11-beta-prostaglandine	Skin most commonly involved Susceptibility to anaphylaxix Osteoporosis
Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2		Asymptomatic Constitutional Rash Cough & breathlessness Peripheral neuropathy/ encephalopathy	Fever Lymphadenopathy	↑	NL	-	NL	↑	↑	None	NL	↓	Myeloid expansion with eosinophilia	FISH shows t(8;13) and t(8;22)	May present or evolve into acute myeloid or lymphoblastic leukemia Leukocytosis (30 - 59 × 109/L
B-lymphoblastic leukemia/lymphoma		Constitutional Anemia related Bleeding Infection Bone pain	Pallor Petechiae Organomegaly Lymphadenopathy	NL or ↑	>25%	N/A	↑ or ↓	↑ or ↓	↑ or ↓	Auer bodies	↓	↓	Hypercellular with blast infilterationwith or without myelodysplasia	Cytogenetic analysis Flow cytometry FISH	May present as extramedullary disease (Myeloid sarcoma)
Myelodysplastic syndromes (MDS)		Constitutional Anemia related Bleeding Infection	Pallor Petechiae Organomegaly	↓	Variable	-	↓	↓	↓	Macro-ovalocytes Basophilic stippling Howell-Jolly body	↓	↓	Hypercellular/ normocellular bone marrow with dysplastic changes	Cytogenetic analysis Flow cytometry	Leukemia transformation Acquired pseudo-Pelger-Huët anomaly
Acute myeloid leukemia (AML) and related neoplasms		Constitutional Anemia related Bleeding Bone pain Joint pain Infections	Infection related Pallor Leukemia cutis Bruising & petechiae Lymphadenopathy Hepatosplenomegaly	NL or ↑	↑	N/A	↑ or ↓	↑ or ↓	↑ or ↓	↑ Potassium ↑ Uric acid ↑ Phosphorus ↓ Calcium ↑ LDH	↓	↓	Increased immaturemyeloid cells with dysplasia	Cytogenetic analysis Flow cytometry FISH	Common in Down syndrome
Blastic plasmacytoid dendritic cell neoplasm		Cutaneous symptoms (brown/purple nodular lesions) on face, scalp, lower limb & trunk	Brown/violaceous bruise like lesions Lymphadenopathy Splenomegaly	NL	↑		NL	NL	NL	Neutropenia	↓	↓	Malignant cells	Immunohistochemistry or flow cytometry for CD4 & CD56	TdT expression positive May develop chronic myelomonocytic leukemia (CMML)
Myelodysplastic /myeloproliferative neoplasms (MDS/MPN)	Chronic myelomonocytic leukemia (CMML)	Constitutional Anemia related Bleeding Infections Bone pain Leukemia Cutis	Organomegaly Bruising	↑	< 20%		NL	↑	↑↑	↑ LDH	↓	↓	Myelodysplastic and myeloproliferative feature	Cytogenetic analysis Flow cytometry	Overlapping of both, MDS and MPN Absolute monocytosis > 1 × 109/L (defining feature) MD-CMML:WBC ≤ 13 × 109/L (FAB)  MP-CMML:WBC > 13 × 109/L (FAB)
	Atypical chronic myeloid leukemia (aCML), BCR-ABL1-	Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<20%	+	<2% of WBCs	N/A	N/A	N/A	↓	↓	Granulocytic hyperplasia with prominent dysplasia	Cytogenetic analysis Flow cytometry	Granulocytic dysplasia is prominent Absence of BCR-ABL or PDGFRA, PDGFRB, or FGFR1 rearrangements WBC > 13 × 109/L
	Juvenile myelomonocytic leukemia (JMML)	Infections Anemia related	Hepatosplenomegaly Lymphadenopathy Rash	↑	↑	N/A	N/A	N/A	↑	↓ Serum Iron ↑ B12 levels	↓	↓	Hypercelluar with ↑ myeloid cells in stages of maturation	Cytogenetic analysis Flow cytometry	Polyclonal hypergammaglobulinemia
	MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)	Constitutional Anemia related Thrombosis	Variable	NL or ↑	NL	-	NL	N/A	N/A	↑ Serum Iron	↓	↑	Hypercellularity with dyserythropoiesis and increased megakaryocytes	Cytogenetic analysis Flow cytometry	Large atypical megakaryocytes Ringed sideroblasts SF3B1 mutation
T-lymphoblastic leukemia/ lymphoma	T-lymphoblastic leukemia/ lymphoma	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	>25% blasts (Leukemia) <25% blasts (Lymphoma)	±	↑ or ↓	↑ or ↓	↑ or ↓	↑ LDH Positive for TdT	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysisFlow cytometry FISH	May involve brain, skin, and testes.
	Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymph	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↑ LDH	↓	↓	N/A	Cytogenetic analysis FISH Flow cytometry	Similar to T-cell lymphoblastic leukemia but may have more aggressive clinical course. Diagnosis is usually based on presence of CD56 expression, and T-cell-associated markers such as CD2 and CD7. B-cell markers are absent.
	Provisional entity: Early T-cell precursor lymphoblastic leukemia	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↑ LDH	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysis FISH Flow cytometry	Similar to T-cell lymphoblastic leukemia but is more aggressive clinically and cell are characterized by cytometry as CD1a−, CD8−, CD5− (dim), and positivity for 1 or more stem cell or myeloid antigens. Gene expression indicates more immature cells as compared to other subtypes of T-cell neoplasms.

Differentiating mast cell tumor from other causes of abdominal pain and diarrhea

Mast cell tumor must be differentiated from other causes of abdominal pain and diarrhea.

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

References