What are the common causes of massive splenomegaly (spleen >20 cm or >1000 g)?

Massive Splenomegaly: Common Causes

Massive splenomegaly (spleen >20 cm or >1000 g) is most commonly caused by myeloproliferative neoplasms in developed countries, with chronic myeloid leukemia and primary myelofibrosis being the leading etiologies, while infectious diseases—particularly malaria, visceral leishmaniasis, and schistosomiasis—predominate in tropical and endemic regions. 1

Primary Etiologic Categories

Myeloproliferative Neoplasms (Leading Cause in Developed Countries)

Myeloproliferative disorders represent the most predominant cause of massive splenomegaly in Western populations. 2

• Primary myelofibrosis is the most common hematologic cause of massive splenomegaly, frequently producing enlargement exceeding 10 cm below the left costal margin 1
• Chronic myeloid leukemia (CML) characteristically presents with splenomegaly that can extend massively below the costal margin, particularly in children where splenomegaly is more pronounced than in adults 3, 1
• Chronic myelomonocytic leukemia (CMML) can progress to massive splenomegaly requiring intervention with splenectomy, splenic irradiation, or JAK-inhibitor therapy 3, 1
• Post-polycythemia vera and post-essential thrombocythemia myelofibrosis are defined by increasing splenomegaly ≥5 cm from the left costal margin 1

Infectious Diseases (Leading Cause in Endemic Regions)

• Hyperreactive malarial splenomegaly (HMS) is the leading cause of massive splenomegaly in malaria-endemic areas, driven by chronic antigenic stimulation 1
• Visceral leishmaniasis (kala-azar) presents with chronic fever, weight loss, massive splenomegaly, pancytopenia, hypoalbuminemia, and elevated inflammatory markers 4, 1
• Schistosomiasis is a common infectious cause of significant splenomegaly in tropical regions 3, 4

Lysosomal Storage Disorders

• Gaucher disease (type 1) results in significant splenomegaly in approximately 90% of patients and is the most common lysosomal storage disorder causing massive splenomegaly 4, 1
• Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) typically causes massive hepatosplenomegaly, often exceeding 10 times normal organ size 1
• Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) are also associated with notable splenomegaly 4

Lymphoproliferative Disorders

• Hairy cell leukemia characteristically presents with splenomegaly in approximately 90% of patients, and resolution of palpable splenomegaly is required for complete remission 1
• B-cell lymphoma can cause massive splenomegaly, with documented cases of spleens weighing over 5000 g 5

Hepatic Diseases with Portal Hypertension

• Idiopathic non-cirrhotic portal hypertension (INCPH) causes significant splenomegaly more commonly than other causes of portal hypertension 4, 1
• Cirrhosis with portal hypertension from any cause commonly leads to splenomegaly, though massive enlargement is less frequent than with myeloproliferative disorders 4, 6
• Wilson's disease may manifest with isolated splenomegaly due to clinically inapparent cirrhosis 4

Critical Diagnostic Algorithm

Initial Assessment

When encountering massive splenomegaly, immediately order JAK2 V617F, CALR, and MPL mutation testing, as myeloproliferative neoplasms can present with normal complete blood counts due to splenic sequestration masking the underlying proliferation. 1

• Obtain complete blood count, peripheral blood smear, and liver function tests as first-line laboratory studies 4, 1
• Perform abdominal ultrasound to confirm splenomegaly and measure spleen size (>13 cm vertical length defines splenomegaly; >20 cm defines massive splenomegaly) 4, 1
• Assess geographic exposure history for malaria, schistosomiasis, or leishmaniasis in patients from or traveling to endemic regions 4, 1

Second-Line Testing Based on Initial Results

• If molecular testing for myeloproliferative neoplasms is negative, proceed to bone marrow examination, particularly in patients ≥60 years or those with systemic symptoms 1
• Flow cytometry (CD19, CD20, CD11c, CD25, CD103, CD123, CD200) for suspected hairy cell leukemia or other lymphoproliferative disorders 4, 1
• Genetic testing for SMPD1 gene when acid sphingomyelinase deficiency is suspected, particularly if mixed dyslipidemia is present 4, 1

Critical Clinical Pitfalls

Moderate or massive splenomegaly essentially excludes idiopathic thrombocytopenic purpura (ITP) as a diagnosis; palpable splenomegaly exceeding 3% of the abdominal examination mandates investigation of alternative etiologies. 4, 1

• Normal peripheral blood counts do not exclude myeloproliferative neoplasms, as splenic sequestration can mask underlying marrow proliferation 1
• Pancytopenia with massive splenomegaly requires urgent evaluation for acute complications, including splenic infarction, rupture, or hemorrhagic shock, particularly in CML where these complications are more common in children 3
• Splenomegaly with weight loss and malaise is highly suggestive of underlying neoplastic conditions and requires immediate diagnostic investigation 5

Management Considerations

• For patients with massively enlarged spleens (>20 cm below costal margin) and CMML, splenectomy, splenic irradiation, or JAK-inhibitor therapy should be performed before proceeding to allogeneic hematopoietic cell transplantation 1
• Splenectomy for massive splenomegaly carries an 11.1% 30-day mortality rate, with sepsis being the major cause of death; preoperative coagulopathy requires correction with an average of 10 units of blood products 2
• Elective splenectomy in patients with smaller spleens has significantly lower morbidity (3%) and no operative mortality compared to massive splenomegaly cases 2