Two cases of Waldenstrӧm macroglobulinemia along with brief disease pathology. Waldenstrӧm macroglobulinemia is a rare B cell lymphoma involving bone marrow with IgM monoclonal gammopathy of any concentration

1. WALDENSTRӦM MACROGLOBULINEMIA

2.  LAKSHMI NARAYANAN G. , 78 Years, Male
 blurring of vision since 2 months,
 no h/o loss of appetite/ weight loss;
 Ashok Rao, 65 Years, M
 Presented with c/o severe anaemia, not responding to treatment.
 Investigations revealed pancytopenia.

4. Laksmi –
Hb% - 7 g/dl, rest Ok, S. Creatinine 1.2 mg/dl, LFT- Ok,
except T. Protein
11.8g/dl, S. Albumin -2.7g/dl, globulin - 9.1 g/dl.
Beta 2 microglobulin - 8520 ng/ml.
S. Protein Electrophoresis
Monoclonal (M spike band value 6.23 g/di) seen in
gamma region.
Immunofixation: IgG - 10.6g/L,
IgA <0.25 g/L,
IgM - 0.74 g/L.
Free Kappa - 59.1 mg/L,
Free lambda - 20.8 mg/L, Ratio - 2.84.
Chromosomal analysis normal karyotype.

5. CBC Hb - 5.9 gm/dl, TC 1932 cells/ cumm, Platelet - 40000 cells/ cumm.; S
Creatinine, LFT normal.
Immunoglobulin quantitative assay: IgA-144 mg/d (90-410).
IgG-1070mg/dl (600 - 1560), IgM
6370mg/di (30-360).
ESR-120 mm/hr, Sr. Beta 2 Microglobulin 3.53 mg/L (0.8-2.1).
LDH-136 UIL.

6. Laksmi Narayan G Ashok Rao
IgA

9. CD20 CD138

10. Kappa
Lambda
CD3

11. WHAT IS WALDENSTRӦM MACROGLOBULINEMIA ?
 WM is defined as LPL with bone marrow involvement and an IgM monoclonal
gammopathy of any concentration.
 To establish the diagnosis of WM, it is necessary to demonstrate an IgM monoclonal
protein, along with histologic evidence of infiltration of the BM by lymphoplasmacytic
cells (there is no minimal percentage of BM infiltration or a minimal serum IgM level).

12. OFTEN CONFUSED
 Not synonymous with Lymphoplasmacytic Lymphoma.
 Other causes of WaldenstrӦm Macroglobulinemia like clinicopathological
feature –
 Marginal zone lymphoma (Splenic > Nodal > Extranodal)
 CLL / SLL

13. BONE MARROW AND PERIPHERAL BLOOD PICTURE
Bone marrow involvement –
 nodular,
 diffuse, and/or
 interstitial infiltrate.
 sometimes even with Para trabecular aggregates
 The plasma cells may also form distinct clusters separate from the lymphoid component.
The infiltrate is
 usually composed predominantly of small lymphocytes
 admixed with variable numbers of plasma cells,
 plasmacytoid lymphocytes, and often increased mast cells

14. DIAGNOSTIC APPROACH TO SUSPECTED WALDENSTRӦM
MACROGLOBULINEMIA
• Serum protein electrophoresis
• Serum immunofixation – for the validation of the immunoglobulin M (IgM) heavy chain
and the type of light chain
• Quantitative test for immunoglobulin G, immunoglobulin A, and IgM
• 24-Hour urine collection – protein electrophoresis; monoclonal light chains detection.
• Immunoglobulin free light chain assay
• Serum β2 microglobulin evaluation for prognosis;
• Bone marrow biopsy

15. • Cytogenetic studies with optional fluorescence in situ hybridization and MYD88
mutational analysis.
• Computed tomography of abdomen and pelvis to detect organomegaly and
lymphadenopathy
(a skeletal survey and radiographic imaging of the bones are unnecessary in the
absence of symptoms; lytic bone lesions are unusual)
• Serum viscosity [ required when signs and symptoms of hyper viscosity syndrome are
present or when IgM >4,000 mg/dL]
• On the basis of clinical presentation, analysis involves Coombs test (cold autoantibody)
and cryoglobulin or tissue stains for amyloid deposits.
• Of myeloma patients, 1% have IgM, and their disorder behaves like other multiple
myeloma.
• Hepatitis B and C screening is necessary if rituximab therapy is planned

16. IMMUNOPHENOTYPE
 LPLs are typically IgD-negative;
 express B-cell–associated antigens – CD19, CD20, CD22, and CD79a
 Typically negative for CD5, CD10, CD103, and CD23
 frequent CD25 and CD38 expression.
 However, a minority of cases are positive for CD5 or CD10 (but BCL6-negative), and
 CD23 expression is not at all uncommon in some studies
 The plasma cells are CD138-positive;
 The CD138+ plasma cells in LPL, although usually positive for IRF4 / MUM1, are more
likely to be IRF4 / MUM1-negative and PAX5-positive compared with normal plasma cells
or those in MZL
 polytypic plasma cells may also be present.

17.  No specific chromosomal abnormalities are recognized in LPL;
 however, > 90% of cases have MYD88 L265P mutation, and
 approximately 30% have truncating CXCR4 mutations (most frequently CXCR4 S338X or
frameshift mutations)

18. PATHOGENESIS

19. 1. Younger age
2. Hemoglobin
>12gm/dL
3. Low β2-microglobulin
Prognostic Factors
1. Advanced patient age,
2. Cytopenias (especially anaemia),
3. Poor performance status,
4. high β2-microglobulin
5. Increased numbers of transformed
cells/​immunoblasts
6. del(6q)

20. INTERNATIONAL PROGNOSTIC SCORING SYSTEM FOR
WM
Factor associated with prognosis Value
Age , Years > 65
Haemoglobin, g/dL ≤11.5
Platelet count, per μL ≤100000
β2-microglobulin, mg/L >3
Monoclonal IgM, g/dL >7
Risk stratum and survival
Risk category Score Median survival, in months
Low 0 or 1 (except age) 142.5
Intermediate 2 or age > 65 y 98.6
High >2 43.5

21. PREDICTIVE FACTORS
1. Cases lacking MYD88 L265P mutation – reported to have a lower response to
ibrutinib;
2. CXCR4-mutation (particularly nonsense mutations) – greater resistance to
ibrutinib and possibly other therapeutic agents.
[ Transformation to diffuse large B-cell lymphoma may and is associated with poor survival. ]

22. THANK YOU