What are the diagnostic procedures for Splenic Marginal Zone Lymphoma (SMZL)?

Diagnostic Procedures for Splenic Marginal Zone Lymphoma (SMZL)

The diagnosis of SMZL can typically be established without splenectomy through a combination of peripheral blood/bone marrow examination and imaging studies, though in some cases splenectomy may be necessary for definitive diagnosis. 1

Initial Diagnostic Approach

Clinical and Laboratory Evaluation

• Thorough physical examination with special attention to:
  • Splenomegaly (most common finding)
  • Lymph node regions
  • Liver examination
• Complete blood count with differential
  • Look for moderate lymphocytosis
  • Presence of villous lymphocytes in peripheral blood (though not seen in all cases)
• Flow cytometry of peripheral blood (mandatory)
• Biochemistry panel:
  • Renal and liver function tests
  • Lactate dehydrogenase (LDH)
  • β2-microglobulin (B2M)
• Protein electrophoresis
• Direct antiglobulin (Coombs) test (optional)
• Serum and urine immunofixation
• Viral serology:
  • Hepatitis C virus (HCV) - if positive, perform HCV-RNA PCR and virus genotyping
  • Hepatitis B virus (HBV)
  • HIV serology
• If HCV positive: check for cryoglobulins and cryocrit 1

Bone Marrow Examination

• Bone marrow aspirate with morphology and flow cytometry
• Bone marrow biopsy with histology and immunohistochemistry (IHC)
• Look for:
  • Intrasinusoidal infiltration pattern by CD20+ cells
  • Characteristic immunophenotype 1, 2

Imaging Studies

• Complete chest and abdominal CT scan or MRI
• Special attention to spleen size and architecture
• PET-CT may be considered when:
  • Transformation to high-grade histology is suspected
  • Guiding decisions on which lymph node to target for biopsy 1

Immunophenotypic and Molecular Analysis

Essential Immunophenotypic Markers

• Positive markers: CD19, CD20, CD22, CD79a, surface immunoglobulin (usually IgM±IgD)
• Negative markers: CD5, CD10, CD23, CD43, cyclin D1
• Variable expression: CD103, CD11c, CD25 1

Molecular and Genetic Studies

• MYD88 mutation testing (should be negative in SMZL)
• FISH studies for:
  • Deletion of 7q (characteristic of SMZL)
  • NOTCH2 mutations (almost specific for SMZL)
• These genetic markers can serve as diagnostic biomarkers 1, 3

Differential Diagnosis

SMZL must be differentiated from:

• Splenic diffuse red pulp small B-cell lymphoma (SDRL)
• Hairy cell leukemia variant
• Lymphoplasmacytic lymphoma (LPL)
• Chronic lymphocytic leukemia (CLL)
• Mantle cell lymphoma 1, 2

Diagnostic Challenges and Pitfalls

1. Splenectomy vs. Non-invasive Diagnosis:

   • While splenectomy has traditionally been considered the gold standard for diagnosis, it is now performed less frequently 2
   • Bone marrow histopathology can confirm SMZL but may not always distinguish it from SDRL 2

2. Villous Lymphocytes:

   • Though characteristic of SMZL, villous lymphocytes are not seen in all cases
   • Technical issues may prevent their visualization
   • Not all lymphomas with villous lymphocytes are SMZL 1

3. Bone Marrow Pattern:

   • Intrasinusoidal infiltration is characteristic but not pathognomonic
   • Expert hematopathologist review is essential 1, 2

Diagnostic Algorithm

1. Initial presentation (typically splenomegaly with or without lymphocytosis)
2. First-line investigations:
   • Complete blood count with peripheral blood smear
   • Flow cytometry of peripheral blood
   • Comprehensive laboratory workup as outlined above
   • CT/MRI imaging
3. Second-line investigations:
   • Bone marrow aspirate and biopsy with immunophenotyping
   • Molecular testing for MYD88 mutation and FISH for 7q deletion
4. If diagnosis remains uncertain:
   • Consider splenectomy for definitive diagnosis
   • Particularly important to differentiate from SDRL when treatments may differ 1, 2, 4

Conclusion

While splenectomy was historically considered mandatory for SMZL diagnosis, advances in diagnostic techniques now allow for diagnosis in most cases without splenectomy. The combination of peripheral blood morphology, flow cytometry, bone marrow histology with immunohistochemistry, and molecular studies can establish the diagnosis in the majority of cases. However, in a minority of patients, splenectomy may still be required for definitive diagnosis, particularly to differentiate SMZL from other splenic lymphomas 1, 2, 4.