What is the appropriate diagnostic and management approach for an adult patient with no known medical history presenting with splenomegaly and monocytosis?

Diagnostic and Management Approach for Splenomegaly with Monocytosis

In an adult with splenomegaly and monocytosis without known medical history, chronic myelomonocytic leukemia (CMML) must be ruled out immediately through comprehensive bone marrow evaluation, as this presentation is highly characteristic of this myelodysplastic/myeloproliferative neoplasm. 1

Immediate Diagnostic Workup

Confirm Splenomegaly and Assess Severity

• Obtain abdominal ultrasound as the first-line imaging modality to confirm splenomegaly, document exact spleen size, and evaluate for hepatomegaly and lymphadenopathy 2, 3
• Spleen size >13 cm is clinically significant and warrants aggressive workup 2, 4
• Document exact spleen size below the costal margin on physical examination 2

Essential Laboratory Testing

• Complete blood count with differential to quantify absolute monocyte count and identify cytopenias or other abnormal cell populations 1, 2, 4
• Peripheral blood smear review is critical—look specifically for dysgranulopoiesis, promonocytes, blasts, and neutrophil precursors 1, 2, 4
• Comprehensive metabolic panel to assess liver function 2, 4
• Lactate dehydrogenase (LDH) to screen for hemolysis or malignancy 2, 4

Rule Out Infectious Causes

• Test for EBV, CMV, HIV, and hepatitis viruses, as infectious causes are among the top three etiologies in developed countries 2

Bone Marrow Evaluation—The Critical Step

If monocytosis is persistent (>1×10⁹/L) with splenomegaly, proceed immediately to bone marrow aspiration and biopsy. 1 This is mandatory for CMML diagnosis and should not be delayed. 1, 2, 4

Bone Marrow Studies Must Include:

• Morphological assessment for dysplasia in one or more myeloid lineages, granulocytic hyperplasia, and blast percentage (including myeloblasts, monoblasts, and promonocytes) 1
• Bone marrow biopsy with hematoxylin-eosin staining, immunostaining for CD34+ and monocytic cells (CD68R and CD163), and Gomori's silver impregnation for fibrosis 1
• Conventional cytogenetic analysis to detect clonal abnormalities (most common: chromosome 7 abnormalities, trisomy 8, complex karyotype) 1
• Molecular assays to exclude BCR/ABL fusion gene and PDGFRA/PDGFRB rearrangements 1
• Store bone marrow cells for possible further molecular analysis if available 1

Flow Cytometry

• Perform flow cytometry immunophenotyping of peripheral blood immediately if lymphoproliferative disorder is suspected 2, 3, 4
• In CMML, flow cytometry may detect aberrancies in monocytic lineage including abnormal CD11b/HLA-DR, CD36/CD14, and overexpression of CD56, though none are specific 1

Molecular Testing Considerations

While molecular mutations (TET2, SRSF2, ASXL1, NRAS, KRAS, CBL, JAK2) are frequently found in CMML (93% carry at least one somatic mutation), the panel agreed that validation of these biomarkers is needed before routine diagnostic use. 1 However, if myeloproliferative neoplasm is suspected, test for JAK2, CALR, and MPL mutations. 2, 3, 4

Recent evidence suggests that next-generation sequencing can uncover mutations (ASXL1, SRSF2, KRAS, TET2) in cases of otherwise idiopathic splenomegaly, potentially revealing underlying myeloproliferative neoplasms. 5

CMML Diagnostic Criteria

The diagnosis requires: 1

• Persistent peripheral blood monocytosis >1×10⁹/L
• Bone marrow blasts <20%
• Dysplasia in one or more myeloid lineages OR clonal genetic abnormalities
• Exclusion of BCR/ABL (chronic myeloid leukemia) and PDGFRA/PDGFRB rearrangements

Classification and Risk Stratification

Once CMML is diagnosed, classify as: 1

• Myelodysplastic (MD-CMML): White blood cell count <13×10⁹/L
• Myeloproliferative (MP-CMML): White blood cell count ≥13×10⁹/L

This distinction is critical as it determines monitoring frequency and treatment response criteria. 1

Alternative Diagnoses to Consider

Hemophagocytic Lymphohistiocytosis (HLH)

If the patient presents with fever, organomegaly (hepatomegaly AND splenomegaly), cytopenias affecting ≥2 lineages, and elevated ferritin (≥500 mg/L), calculate the HScore. 1 Approximately 40-70% of adult HLH cases are malignancy-associated, particularly with lymphomas. 2

Lymphoproliferative Disorders

If lymphadenopathy is present or flow cytometry suggests lymphoid abnormalities, consider lymphoma. PET-guided imaging and repetitive tissue sampling may be necessary, as tumor-infiltrating reactive lymphocytes can mask underlying lymphoma. 2

Critical Pitfalls to Avoid

• Do not delay bone marrow evaluation in patients with persistent monocytosis and splenomegaly—this combination is highly suggestive of CMML 1, 2
• Do not assume reactive monocytosis without excluding infectious diseases, solid tumors, and obtaining bone marrow confirmation 1
• Do not miss malignancy-associated HLH, particularly in patients with constitutional symptoms and cytopenias 2
• In patients with splenomegaly and dysplasia, clustering of Leder-negative large cells in the spleen may correlate with increased risk of disease progression to acute leukemia 6

Immediate Hematology Referral Indicated

Refer immediately to hematology for: 2, 4

• Peripheral smear showing blasts or abnormal lymphocytes beyond typical reactive changes
• Presence of unexplained cytopenias
• Symptomatic splenomegaly without clear etiology after initial workup
• Confirmed or suspected CMML requiring risk stratification and treatment planning

Management Principles

Treatment depends on MD-CMML versus MP-CMML classification: 1

• MD-CMML: Monitor with complete blood count monthly for first month, then every three months; apply IWG 2006 response criteria for MDS if treatment initiated
• MP-CMML: Monitor monthly for first three months to exclude rapid WBC rise, then every three months; apply IWG 2009 response criteria for myelofibrosis if treatment initiated
• Cytoreduction with hydroxyurea for proliferative features 7
• Hypomethylating agents (azacitidine, decitabine) for higher-risk disease 7
• Allogeneic stem cell transplantation remains the only curative option 7

For massively enlarged spleen (>20 cm below costal margin), splenectomy, splenic irradiation, or JAK inhibitors may be considered, though splenomegaly in CMML usually reflects dyspoiesis rather than a proliferative phase. 1, 6