Acute lymphoblastic leukemia differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Acute lymphoblastic leukemia must be differentiated from other diseases such as acute myelogenous leukemia, hairy cell leukemia and malignant lymphoma.

Differential diagnosis

The following table differentiates acute lymphoblastic leukemia from other leukemias that may present with similar clinical features such as fever, fatigue, weight loss, recurrent infections and elevated leukocyte counts. The following are the differentials:

Disease	Etiology	Clinical Manifestation											Laboratory Findings			Gold standard diagnosis	Associated findings
		Demography	History	Symptoms				Signs
				Constitutional symptoms	Weight	Bleeding	Abdominal Pain	Vital sign	Jaundice	LAP	Hepatosplenomegaly	Other	CBC	Histopathology	Other
Acute myelogenous leukemia	Clonal proliferation of malignant myeloid blast cells in the marrow Genetic abnormalities t(8;21), inv(16), and t(15;17)	The most common type of acute leukemia in adults Median age of 63 years old More in congenital disorders such as Down syndrome, Bloom syndrome	Smoking, previous chemotherapy or radiation therapy, myelodysplastic syndrome, and exposure to the chemical benzene	Fatigue	↓	+	–	Fever	–	Rare	Mild and asymptomatic	Bone tenderness Dyspnea Leukemia cutis Swelling of the gums Chloroma	Anemia Thrombocytopenia Leukocytosis or leukopenia	Leukemic blasts Positive Auer rods	NA	Flow cytometry > 20% blasts of myeloid lineage	Persistent or frequent infections Fatal within weeks or months if left untreated
Acute lymphoblastic leukemia	Arrest of lymphoblasts Chromosomal translocations: t(9;22) , t(12;21), t(5;14), t(1;19)	The most common form of cancer in children Peak 2-5 years of age Boys > girls	History of cancer History of drug exposure	Generalized weakness and fatigue	↓	+	–	Fever	–	+	+	Musculoskeletal pain Dyspnea Pallor Papilledema Nuchal rigidity Cranial nerve palsy Testicular enlargement Mediastinal mass	Anemia Thrombocytopenia Normal or slightly increased WBC counts	Lymphoblasts Atypical cells	NA	Bone marrow biopsy	CNS involvement
Chronic myelogenous leukemia	Dysregulated production and uncontrolled proliferation of mature and maturing granulocytes BCR-ABL1 fusion gene Autosomal dominant mutation	Median age 50 years old		Generalized weakness and fatigue Early satiety	↓	+	Abdominal fullness	Normal	–	–	+	Asymptomatic Blast crisis resembling acute leukemia Excessive sweating Papilledema Tenderness over the lower sternum	Anemia WBC > 100,000/microL Absolute basophilia and eosinophilia Plt > 600,000 to 700,000/microL	All cells of the neutrophilic series, from myeloblasts to mature neutrophils Myelocyte bulge	Low leukocyte alkaline phosphatase High uric acid	Bone marrow biopsy	Acute gouty arthritis Venous obstruction
Disease	Etiology	Demography	History	Constitutional symptoms	Weight	Bleeding	Abdominal Pain	Vital sign	Jaundice	LAP	Hepatosplenomegaly	Other	CBC	Histopathology	Other	Gold standard diagnosis	Associated findings
Chronic lymphocytic leukemia	Progressive accumulation of monoclonal B lymphocytes	The most common leukemia in adults in western countries M > F Median age 70 years old	Positive family history Exposure to herbicides or insecticides	Generalized weakness Anorexia	↓	+	+	Fever	–	+ The most common abnormal finding	+	Skin lesions (leukemia cutis) Night sweats Muscle wasting	Anemia Thrombocytopenia Absolute lymphocytosis >5000 cells/μl Neutropenia	Presence of smudge cells Monoclonality of kappa and lambda producing B cells Express CD19, CD20, CD23, and CD5 on the cell surface	Positive direct antiglobulin (Coombs) test Hypogammaglobulinemia Elevated levels of serum lactate dehydrogenase and beta-2 microglobulin	Flow cytometry of the peripheral blood	Extranodal involvement of skin, kidney, lung, spine Membranoproliferative glomerulonephritis Autoimmune hemolytic anemia
Hairy cell leukemia	Accumulation of small mature B cell lymphoid cells with abundant cytoplasm and "hairy" projections BRAF mutation	Uncommon Median age 50 to 55 years old M >> F More common in Caucasians than Blacks	Exposures to ionizing radiation, pesticides, and farming	Weakness and fatigue	↓	+	Abdominal fullness	Normal	–	±	+ Splenomegaly	Asymptomatic Spontaneous splenic rupture Skin rash Ascites Pleural effusion	Cytopenia Leukocytosis in 10 to 20 percent	Pancytopenia with monocytopenia and circulating tumor cells characteristic of HCL Dry bone marrow	Azotemia Abnormal liver function tests Hypergammaglobulinemia	Analysis of peripheral blood + immunophenotyping by flow cytometry	Vasculitis
Large granular lymphocytic leukemia​	Clonal proliferation of cytotoxic T cells Dysregulation of apoptosis through abnormalities in the Fas/Fas ligand pathway	Rare Median age 60 years M = F	Autoimmune diseases Lymphoproliferative disorders	Weakness and fatigue	↓	–	–	Fever	–	±	+	Mostly asymptomatic	Modest lymphocytosis Neutropenia Anemia Thrombocytopenia	Large lymphocytes with a condensed round or oval nucleus, abundant pale basophilic cytoplasm, and small azurophilic granules	Multiple serological abnormalities including rheumatoid factor, antinuclear antibody, antiplatelet antibodies, antineutrophil antibodies, positive direct Coombs test, hyper- or hypogammaglobulinemia, monoclonal gammopathies, and elevated β2-microglobulin	Biopsy and flow cytometry + T-cell receptor gene rearrangement studies	Recurrent bacterial infection
Chronic neutrophilic leukemia	Mature granulocytic proliferation in the blood and marrow Point mutations in the CSF3R gene	Very rare M = F	Multiple myeloma	Weakness and fatigue	↓	–	–	Fever	–	–	+ The most common clinical finding	Pruritus Gout	Peripheral blood neutrophilia (> 25 x 109/L) with myeloid precursors (promyelocytes, myelocytes, metamyelocytes)	Toxic granulation in the neutrophils Nuclear hypersegmentation Increased myeloid:erythroid ratio > 20:1	Elevated leukocyte alkaline phosphatase	WHO diagnostic criteria include leukocytosis of ≥ 25 x 109/L More than 80% neutrophils, Less than 10% circulating neutrophil precursors with blasts	Poor prognosis Absence of the Philadelphia chromosome or a BCR/ABL fusion gene
Disease	Etiology	Demography	History	Constitutional symptoms	Weight	Bleeding	Abdominal Pain	Vital sign	Jaundice	LAP	Hepatosplenomegaly	Other	CBC	Histopathology	Other	Gold standard diagnosis	Associated findings