Cutaneous manifestations as initial presentation of Waldenstrom’s macroglobulinemia

ARTICLE

Waldenström’s Macroglobulinemia (WM) is a rare low grade B-cell lymphoproliferative disorder. It is characterized by the monoclonal proliferation of lymphoplasmocytes in the bone marrow and/or lymph nodes and/or spleen associated with a monoclonal peak of immunoglobulin M on serum protein electrophoresis [1]. Cutaneous manifestations are rare. We describe a woman who presented specific cutaneous lesions.

Case report

A 73 year old Caucasian woman presented at hospital in December 1997 for oedema and erythema of the face with burning sensation. The cutaneous lesions had been present for 4 months. Her medical history revealed a rosacea for 30 years, treated by electrocoagulation; a colic diverticulosis; a thyroidectomy for toxic nodule. Her familial medical history was remarkable for multiple cancers of the larynx, kidney, breast, liver and melanoma. On clinical examination, we noticed violaceous oedema of the cheeks and the nose. Her general condition was good. The rest of the examination was normal, especially the orthorhino and stomatological examination. Peripheral lymphadenopathy and splenomegaly were absent. Biological data, including blood cell count, erythrocyte sediment rate (ESR), C reactive protein, antinuclear factors (ANF), were normal or negative, except a decrease of C4 complement level 0.04 g/L (normal > 0.16 g/L). Chest Xray was normal. The deep skin biopsy showed a non specific pattern: an atrophic epidermis with an actinic elastosis and few lymphocytes in the dermis, without any lymphoproliferative disorder. Diagnosis of rosacea was made and topical treatment was used.

In July 2000, she presented with extensive violaceous infiltrated plaques on the cheeks (Fig. 1). The lesions were variable with the ambiant temperature. Physical examination revealed voluminous cervical and axillary adenopathies. The rest of the examination was normal. The following data were normal or negative: blood cell count, ANF, anti DNA and antineutrophil cytoplasmic antibodies, hemostatic studies. C4 complement rate was subnormal 0.12 g/L (normal > 0.16 g/L). ESR was increased to 62 mm at first hour (normal < 20). The serum protein immunoelectrophoresis showed a monoclonal peak of IgM kappa 22 g/L (normal < 1.53 g/L) with decrease of IgA rate, 4.9 g/L (normal > 7 g/L) and normal IgG rate. Cryoglobulinemia type II was strongly positive with the same IgM as monoclonal component found in the serum (quantification was not made). Cerebral and thoracic computed tomographic scans were normal, such as abdominal echotomography.

Node biopsy was performed. Histological examination revealed that the nodal architecture was completely effaced by a proliferation of small round lymphocytes with little cytoplasm, associated with plasmacytoid lymphocytes with slightly excentric nuclei and well-developed plasma cells. The immunohistochemical study showed the following pattern: CD20+, CD79a+, CD10—, CD5— and CD23—.

The diagnosis of low grade non Hodgkin B cell lymphoma was made and according to the Revised European-American Classification of Lymphoid Neoplasms, we considered it as lymphoplasmacytoid lymphoma (immunocytoma). There was no argument for follicle center cell lymphoma, mantle cell lymphoma or B cell small lymphocytic lymphoma. We excluded the diagnosis of marginal zone lymphoma because the first skin biopsy did not show any lymphoma at all.

Histological examination of the bone marrow biopsy showed a widespread lymphoid infiltrate with identical pattern of the node. The skin biopsy revealed a prominent lymphoid infiltrate of the dermo-hypodermal junction and of the deep dermis (Fig. 2a and 2b). The epidermis and the papillary dermis were normal. The immunohistochemical studies of bone marrow and skin biopsies were exactly the same as the node.

These histological findings were consistent with Waldenström’s Macroglobulinemia. Oral treatment with Chlorambucil (4 mg a day) was started. Two months after the initiation of the therapy, a decrease of the IgM rate (15 g/L) was noted as well as the skin infiltration of the face.

Discussion

Initially described in 1944 [1], WM is a rare chronic lymphoproliferative disorder of unknown etiology. It is observed with a little predominance in males and usually occurs in the elderly, especially in the sixth or seventh decade [2]. The biological characteristic is a monoclonal IgM peak produced by a neoplasic proliferation of lymphocytes and plasmocytes in the bone marrow. Excessive production of IgM leads to hyperviscosity of the blood and the interaction of IgM with coagulation factors is responsible for a bleeding syndrome. Weakness and weight loss are usually the early symptoms, but our patient was in excellent condition. Later, lymphadenopathies and hepatosplenomegaly may develop. Some symptoms such as headache or ocular disturbance are secondary to hyperviscosity or bleeding syndrome. Others result from the involvement by the lymphoproliferative infiltration of several organs including the lung, gastrointestinal tract and central nervous system. Peripheral neuropathy has been reported in WM resulting from cryoglobulinemia. Cutaneous manifestations are rare and occur in only 5 % of WM [3]. They include non specific and specific lesions.

Non specific cutaneous lesions are polymorphic with urticaria, purpura, ulcers or purple discoloration of toes, fingers and ear lobes. They are sometimes the result of a cryoglobulinemia [4]. Several specific manifestations are
also described. Violaceous skin induration is the most common cutaneous lesion [5, 6]. When symetrical and located on the face, it is very suggestive of WM as it was in our patient. However, it may appear on the trunk or the proximal extremities. Violaceous firm nodules, sometimes ulcerated, may grow on the same areas [7, 8]. Histologically, violaceous infiltration and nodules result from the direct lympho-plasmacytoid infiltrate of the reticular dermis and the hypodermis. The epidermis and usually the papillary dermis are not involved. Sometimes, cells contain intranuclear periodic acid-schiff (PAS) positive inclusions which correspond to IgM deposits. Clinical variants include IgM storage papules which are flesh colored papules located on the face, the extensor surfaces of extremities, the trunk and the buttocks [9, 10]. They are usually asymptomatic, sometimes pruritic. Histologically, storage papules reveal homogeneous eosinophilic material in the dermis which is PAS positive and result from direct depositions of IgM in the dermis [11]. More recently, vesiculobullous eruptions have been described [12, 13]. The skin biopsies of blisters revealed subepidermal separation and immunofluorescent techniques demonstrated deposits of IgM along the basement membrane zone which could be responsible for the blister formation.

Cutaneous manifestations may appear at the beginning of the disease [14] as described in this case report or later, when WM diagnosis is confirmed and the disease treated. There is no correlation between the onset of skin manifestations and the blood level of IgM or the disease activity. Cutaneous lesions are not correlated with a poor prognosis [7]. Our patient was treated with chlorambucil which is the the drug of choice for WM in the literature. Chlorambucil may be associated or not with corticosteroids. Melphalan, cyclophosphamide may be alternative therapies. These treatments have variable efficacity on cutaneous lesions. Some isolated skin lesions have been treated successfully with radiotherapy [4, 15].

This report may be interesting for the prominent specific cutaneous involvement as the initial manifestation of a WM.

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