What are the causes of massive splenomegaly?

Causes of Massive Splenomegaly

Massive splenomegaly (spleen >20 cm below costal margin or >1000g) is most commonly caused by chronic myeloid leukemia, myelofibrosis, chronic malaria (hyperreactive malarial splenomegaly), Gaucher disease, and visceral leishmaniasis. 1, 2

Definition and Measurement

Massive splenomegaly is defined by:

• Spleen extending >20 cm below the costal margin 3, 1
• Spleen weight exceeding 1000g 2
• Vertical length >13 cm on imaging (general splenomegaly threshold) 1

Primary Causes by Category

Myeloproliferative Disorders (Most Common in Developed Countries)

• Chronic myeloid leukemia (CML) presents with splenomegaly as a defining feature, measured as distance below costal margin 1
• Myelofibrosis is particularly associated with massive splenomegaly (>10cm below costal margin) 1, 4
• Chronic myelomonocytic leukemia (CMML) frequently presents with splenomegaly; while often limited, some patients develop massive splenomegaly requiring intervention with splenectomy, splenic irradiation, or JAK inhibitor reduction 3, 1
• Polycythemia vera and essential thrombocythemia should be considered, with progression to post-PV or post-ET myelofibrosis defined by increasing splenomegaly ≥5 cm from left costal margin 1

Infectious Diseases (Most Common in Endemic Regions)

• Hyperreactive malarial splenomegaly (HMS) is a leading cause of massive splenomegaly in malaria-endemic countries, caused by chronic antigenic stimulation from malaria parasites 1, 5
• Visceral leishmaniasis (kala-azar) presents with chronic fever, weight loss, splenomegaly, pancytopenia, hypoalbuminemia, and elevated inflammatory markers 1
• Schistosomiasis is a common cause of splenomegaly in tropical regions 1
• EBV infection can rarely cause massive reactive follicular splenic hyperplasia 6

Lysosomal Storage Disorders

• Gaucher disease is the most common lysosomal storage disorder causing significant splenomegaly, with 90% of type 1 patients affected 1
• Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) commonly presents with hepatosplenomegaly, which can be massive (>10x normal size) 4, 7
• Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) are also associated with splenomegaly 1, 7

Hepatic Diseases with Portal Hypertension

• Cirrhosis with portal hypertension from any cause commonly causes splenomegaly, though rarely massive 1, 8
• Idiopathic non-cirrhotic portal hypertension (INCPH) causes significant splenomegaly more commonly than other causes of portal hypertension 1
• Wilson's disease may present with isolated splenomegaly due to clinically inapparent cirrhosis 1, 4

Lymphoproliferative Disorders

• Hairy cell leukemia characteristically presents with splenomegaly; resolution of palpable splenomegaly is required for complete remission 1
• B-cell lymphoma can cause massive splenomegaly, with spleen specimens weighing up to 5000g reported 2

Other Hematologic Causes

• Megaloblastic anemia rarely causes massive splenomegaly due to sequestration of macrocytic erythrocytes, which is reversible with treatment 9

Diagnostic Algorithm

Initial Laboratory Evaluation

• Complete blood count to assess for cytopenias (anemia, thrombocytopenia, leukopenia) 1, 4
• Peripheral blood smear to identify abnormal cells, hairy cells, or leukoerythroblastic picture 1
• Liver function tests including total bilirubin, AST, ALT, alkaline phosphatase, and GGT 1, 7
• Lipid profile may reveal mixed dyslipidemia in storage disorders 1, 7

Imaging Studies

• Abdominal ultrasound as first-line imaging to confirm splenomegaly, measure spleen size, assess for portal hypertension signs, and evaluate liver parenchyma 1
• CT or MRI for precise measurement and evaluation of associated findings 1

Specialized Testing Based on Clinical Context

• JAK2V617F, MPL, and CALR mutation testing for myeloproliferative neoplasms 1
• Flow cytometry for lymphoproliferative disorders (CD19, CD20, CD11c, CD25, CD103, CD123, CD200 for hairy cell leukemia) 1
• Genetic testing (SMPD1 gene for ASMD) for suspected storage disorders 1
• Bone marrow examination may be informative in patients older than 60 years or those with systemic symptoms 1

Critical Clinical Pitfalls

• In suspected ITP, mild splenomegaly may be found in younger patients, but moderate or massive splenomegaly suggests an alternative cause 1
• Splenomegaly greater than 3% palpability in adults essentially excludes ITP as a diagnosis 1
• For patients with massively enlarged spleen (>20 cm below the costal margin), splenectomy, splenic irradiation, or reduction of spleen size with JAK inhibitors is recommended before allogeneic hematopoietic cell transplantation in CMML 3
• HMS is fatal if left untreated; fatality rate reaches 36% in three years without treatment 5