Waldenstroem's disease C88.0

Rare low-malignant, clonal, lymphoplasmocytic B-cell non-Hodgkin's lymphoma (NHL) in the bone marrow with formation of a monoclonal IgM serum protein. Waldenström's disease belongs to the group of indolent B-cell non-Hodgkin's lymphomas.

The very rare primary cutaneous immunocytoma represents a neoplasia of clonal lymphoplasmocytic or plasmacytic cells and cytoplasmic production of monoclonal immunoglobulin (class IgM). The population of origin of the neoplastic cells is in the follicular mantle cell.

Waldenström's disease comprises 1-2% of all hematologic neoplasms(Grunenberg A et al. 2017).

Incidence in the USA is 0.38/100,000 persons (Wang H et al. 2012). No epidemiological data are available on primary cutaneous Waldenström's disease.

Genetically heterogeneous disease. The most common mutation affects the MYD88 gene, which is mutated in >90%. The second most frequent mutation (in about 30% of patients) affects the CXCR4 gene. Based on these mutations, 3 genotypes have been described:

• Genotype1: MYD88 gene mutated/CXCr4 wild type (see below macroglobulinemia Waldenström 1)
• Genotype2: MYD88 gene mutated/CXCr4 mutated
• Genotype3: MYD88 wild type/CXCr4 wild type

Other mutations affect the genes: SDC1, PAX5, HAS1,CD40LG.

The proliferated B cells produce IgM and infiltrate mainly the bone marrow as well as other tissues, including the skin. The increase of IgM concentration in the blood leads to increased viscosity of the blood and consequently to circulatory disturbances in the smaller vessels (Raynaud's phenomenon).

Furthermore, macroglobulins bind coagulation factors so that increased skin bleeding (purpura) can occur. Immunoglobulin masses can also be deposited homogeneously in the dermis.

In contrast to plasmocytoma, osteolysis and hypercalcemia are not observed.

In Waldenstrom's disease, the frequency is about 1/4 of multiple myeloma. In most studies the median age is 65-66 (43-76) years. Rarely are patients younger than 40 years observed.

Men are more frequently affected than women.

The cutaneous manifestations are divided into:

• Specific lesions:
  • Infiltration of the bone marrow by lymphoplasmacytic lymphoma.
  • Cutaneous infiltration by neoplastic cells: Chronic, solitary or disseminated, red or brown, usually asymptomatic papules, plaques or nodules with a smooth surface (usually on the face or trunk).
  • Lymph nodes or spleen are enlarged in about 20-40% of patients.
  • Renal involvement(myeloma kidney, cast nephropathy).
  • Macroglobulinemia (see also MGUS) may be absent at an early stage of development. These clinical phenomena become clinically evident only at a critical tumor mass.
  • Cutaneous lesions due to homogeneous IgM deposits: formation of vesicles and blisters and, less frequently, of small, asymptomatic skin-colored papules on the buttocks and trunk (macroglobulinosis cutis).
• Nonspecific lesions:
  • Paraprotein may cause hyperviscosity syndrome with purpura, cyanotic discoloration of the acras (fingers, toes, earlobes), Raynaud's phenomenon, dizziness, mucosal hemorrhages, and visual disturbances.
  • Other clinical symptoms include:
    • Symptoms due to cold agglutinins (anemia, livedovasculitis, Raynaud's syndrome, acrocyanosis, digital ulcers).
    • Polyneuropathy
    • secondary IgM amyloidosis in prolonged disease course, occasionally renal dysfunction.
    • vasculitic ulcers and livedovasculopathy.

In addition to the blood count including differential blood count and reticulocytes, immunoelectrophoresis and immunoglobulins should be determined quantitatively, Coombs tests and cold agglutinins.

IgM > 70g/l

ESR is extremely elevated and usually already > 100 mm after 30 minutes.

Beta-2 microglobulin elevated (>3mg/l)

The blood count often shows anemia, HB <11.5 g/dl) and other cytopenias (thrombocytopenia <100,000/ul), a leukemic blood count is very rarely found.

Severe antibody deficiency, often found in multiple myeloma, is absent in most cases.

The bleeding tendency is usually associated with hyperviscosity syndrome.

The histological pattern is characterized by a dense, diffuse or (more rarely follicular) arranged lymphoplasmocytoid infiltrate with a free border zone towards the epidermis. In addition to small lymphocytes, mature plasma cells are also found. The tumor cells express immunoglobulins (IgM and IgG) in different densities. they are positive for the B-cell markers CD20 and Bcl-2.

Findings of macroglobulinosis cutis: Scaly, extravascular, eosinophilic and PAS-positive homogeneous deposits in the entire dermis (partly also perifollicular) which are traversed and bordered by a sparse lymphocytic accompanying infiltrate.

• Amyloidosis, systemic: Generalized; but often the head (with tongue) is affected; petechiae on skin and mucous membranes, frequently on the flexion sides and eyelids (so-called raccoon-sign = raccoon-sign). Wax-like papules and painless knots. Possibly scleroderma-like.
• Colloidalmilium (very rare): Juvenile form (cheeks, nose, perioral); adult form (face, ears, neck, back of the hand); papules the size of a glass pinhead, transparent in appearance, exceptionally yellowish-brownish or skin-coloured, soft, grouped papules; after a stab incision a gelatinous mass empties under pressure. In the adult form: occurrence in combination with other actinic changes.
• Hyalinosis cutis et mucosae: Head (eyelids), neck, extremities are affected. The first impression is a rigid facial expression with pronounced perioral and frontal furrow formation. Yellow-white, pinhead-sized nodules, confluence with plate-like, coarse plaques, some with a brownish, verrucous or crusty surface.
• Erythropoietic protoporphyria: Face and back of the hands are affected; appearing in early youth. Acute burning and itching after exposure to the sun. Formation of a severe dermatitis solaris with extensive, sharply defined erythema and oedema of the skin. Possible formation of blisters and crusts which heal with small, varioliform scars.

As in chronic lymphocytic leukemia (CLL), the therapy is influenced by the course of the disease.

Rituximab (in case of intolerance: Ofatumumab) Mono- or combination therapy with the chemotherapeutic agent Bendamustin or with cyclophosphamide+dexamethasone.

Alternative: bud scheme (chlorambucil and prednisolone).

In case of recurrence, the therapy is switched to the COP-scheme or CHOP-scheme.

Hyperviscosity can be reduced for a short time by plasmapheresis, osteoporosis by bisphosphonates.

The administration of contrast media containing iodine can lead to acute kidney failure.

The diagnosis is saved by:

• skin biopsy
• Bone marrow biopsy (>10% lymphoplasmocytic bone marrow infestation)
• Serum electrophoresis/immune electrophoresis (>30g/l IgM MGUS )

put. The blood count often shows anemia and leukopenia due to the displacement of the normal bone marrow. Further imaging procedures are routinely required to assess the type of spread and stage.

• X-rays of the thorax (widening of the mediastinum?)
• Sonographs of the abdomen (spleen size?, lymphomas?).

If necessary, the sonography can be supplemented by an abdominal CT. An MRI of the entire spinal column has proved particularly effective. Skeletal x-rays often show severe osteoporosis; osteolytic foci are rarely found. A bone density measurement using QDR is recommended to assess the bone mass.

1. Autier J et al (2005) Cutaneous Waldenström`s macroglobulinemia with "deck-chair" sign treated with cyclophosphamide. J Am Acad Dermatol 52: 45-47
2. Bartl R et al (1983) Bone marrow histology in Waldenström's macroglobulinaemia. Scand J Haematol 31: 359-375
3. Child FJ et al (2000) Multiple cutaneous immunocytoma with secondary anetoderma: a report of two cases. Br J Dermatol 143:165-170
4. Dimopoulos MA et al (1994) Waldenström's macroglobulinemia. Blood 83: 1452-1459
5. Grunenberg A et al (2017) monoclonal IgM gammopathy and Waldenström's disease. German medical journal 114: 745-751
6. Lüftl M et al (2010) Macroglobulinosis cutis in IgM paraproteinemia/induced Waldenstrom's disease. JDDG 8: 1000-1003
7. Magro CM et al (2004) Cutaneous immunocytoma: a clinical, histologic, and phenotypic study of 11 cases. Appl Immunohistochem Mol Morphol 12: 216-224
8. Wang H et al.(2012)Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a
   large population-based study. Cancer 118:3793-3800.