Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (372 page)

   Immunofixation is a more definitive diagnostic assay because it identifies the M spike as a monoclonal IgM protein.

   Serum light chains: A preponderance of κ over λ light chains, with a reported 4.5:1 incidence ratio. Serum free light chain determination could be used as a surrogate tumor marker.

   A serum monoclonal IgM is not pathognomonic for WM. It may be seen in rare cases of multiple myeloma (WM can be excluded if such patients have osteolytic lesions) and splenic marginal zone lymphoma. In asymptomatic patients, a diagnosis of smoldering LPL/WM may be entertained. If the bone marrow is infiltrated with <10% clonal cells and the patient is asymptomatic, the diagnosis of IgM-MGUS should be considered.

   
Serum viscosity
: Clinical symptoms of hyperviscosity begin when serum viscosity is >4 centipoise. At a viscosity of >6 centipoise the symptoms become more severe. The frequency of hyperviscosity ranges from 6% to 20% of cases. There may be great variability in the serum viscosity level at which patients become symptomatic.

   
Bone marrow biopsy
is recommended for all patients. Bone marrow
aspirate
appears often to be hypocellular. The
biopsy
specimen, however, demonstrates hypercellularity with ≥10% infiltration by small lymphocytic and plasmacytoid or plasma cells. The intratrabecular pattern of infiltration may be nodular, interstitial, or diffuse. The abnormal cells have a nuclear spoke-wheel pattern of plasma cells but have high nuclear/cytoplasmic ratio more typical of small lymphocytes. Nevertheless, typical plasma cells with Russell and Dutcher bodies may be seen. Mast cells are frequently increased.

   
Lymph node biopsy
shows lymphoplasmacytic infiltration, but the normal architecture is preserved. Distinguishing LPL/WM from other B-cell lymphomas, especially marginal zone B-cell lymphoma, may be difficult.

   
Histologic transformation
: LPL can transform in a more aggressive form of lymphoma, similar to Richter transformation in CLL. Transformation can be demonstrated by lymph node or bone marrow biopsy. It connotes an aggressive clinical picture resistant to therapy. Occasionally, the disease may evolve into AL amyloidosis.

   
CNS infiltration
with plasma cells and lymphocytes (the Bing-Neel syndrome) has been described. Peripheral neuropathy is seen in up to 20–25% of patients. The evaluation of anti–myelin-associated glycoprotein antiganglioside MI and antisulfatide IgM antibodies may be appropriate.

   
Flow cytometry
demonstrates an earlier stage of B-cell differentiation in addition to the plasmacytic cells. The clonal cells are surface IgM
⁺
, CD19
⁺
CD20
⁺
, CD22
⁺
, CD25
⁺
, CD38
⁺
, CD79a
⁺
, FMC7
⁺
, BCL2
⁺
, PAX5
⁺
; CD3
⁻
, CD103
⁻
. A small subset of patients may express CD5 in their lymphocytic component.

   
Cytogenetics
: Cytogenetic examination may be useful in differentiating LPL/WM from IgM myeloma. Eighty-three percent of patients have chromosomal abnormalities. The most common reported recurrent abnormality is 6q deletion (encompassing 6q21-25).

   
Molecular genetics
: MYD88 L265P is a commonly recurring mutation that can be useful in differentiating LPL/WM and non-IgM LPL from B-cell disorders that have some of the same features. miRNA expression profiling reveals a specific signature, but the technology is available only in some research laboratories.