April - June 2008: 
Volume 21, Issue 2

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Waldenström’s macroglobulinaemia:chest involvement as the first manifestation of the disease
Waldenstrφm’s macroglobulinemia (WM) is a neoplastic lymphoproliferative disease, characterized by clonal expansion of B-lymphocytes, which produce monoclonal immunoglobulin of the IgM type. A 77 year-old female presented with shortness of breath and a dry cough. Physical examination revealed absence of breath sounds over the base of the right lung. Blood tests showed anaemia, raised ESR and a monoclonal IgM protein. On chest X-ray right pleural effusion was found, and chest CT scan revealed multiple nodules of about 1cm in diameter in the lung parenchyma, mediastinal lymph node enlargement, and right-sided pleural effusion. Examination of the pleural fluid showed lymphoplasmacytic infiltration. Bronchoscopy and bronchoalveolar lavage were normal. Investigation for autoimmune disease and specific bacterial and viral diseases was negative. The bone marrow aspirate (BMA) showed diffuse infiltration by lymphoplasmacytoid cells (45%-50%) expressing CD20, CD19 and IgM, consistent with a diagnosis of WM. The patient underwent chemotherapy, which produced complete haematological remission and normalization of the chest CT scan. There was no evidence of disease one year later. The lungs are affected only 3%-5% of cases of WM. Pleuropulmonary involvement as the first manifestation of WM is extremely rare and only few cases have been reported in the literature. Pneumon 2008; 21(2):181–184
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Waldenstrφm\'s macroglobulinaemia (WM) is categorized as a low-grade non-Hodgkin\'s lymphoma. It was first reported by Waldenstrφm in 1944 and is characterized by a monoclonal proliferation of B-lymphocytes expressing CD19, CD20 and IgM.1-4 The etiology of WM is unknown, but chronic antigenic stimuli, infections, dioxins, solvents and other toxic agents, ionizing radiation and genetic fac tors have been implicated. The paraprotein macroglobulin usually has no specific antibody activity, although it may coat the cells, producing functional alterations and secondary immunological phenomena.3,4 The clinical manifestations and laboratory findings of the disease are related either to direct infiltration of various organs by the tumour, or to the high concentration and specific properties of the IgM. The bone marrow is always infiltrated in WM, while the lymphoplasmacytic lymphoma secreting IgM may be limited to the lymphoid tissue5,6. The large size of the molecule of the circulating IgM results in an increase in the osmotic pressure, which leads to increased blood flow resistance and microcirculation impairment. In addition, the IgM can cause symptoms due to amyloid deposition, or from its tendency to precipitate upon cooling, behaving as a cryoglobulin.7-13 The diagnostic criteria for WM were defined at the Second International Workshop on Waldenstrφm\'s Macroglobulinaemia.10 The treatment of patients varies from \"watch and wait\" to chemotherapy of varying intensity, administration of monoclonal antibodies or immunomodulatory drugs, and bone marrow transplantation. In hyperviscosity syndrome plasmapheresis is effective for rapid reduction of circulating IgM.11 Alkylating agents (chlorambucil), nucleoside analogues (fludarabine) and the monoclonal antibody rituximab (anti-CD20) or the radioactive zevalin are reasonable choices for first line therapy12-15. For relapses or refractory disease autologous stem cell transplantation has been used16,17. Corticosteroids have been given in combination with other drugs. New agents, such as thalidomide and its more potent analogue lenalidomide, bortezomib and deacetylase inhibitors are used with success in various combinations with the older drugs12-17



A 77 year-old woman, who was a non-smoker, presented with dyspnoea on exercise which was gradually worsening, and a dry cough of one month\'s duration. She had also developed oedema and pain in the right wrist during the previous week. Her past medical history included malaria at the age of twenty and traumatic fracture of two lumbar vertebrae five years earlier. On admission her general status was good; she was afebrile, with breathing rate 16 /min, pulse rate 68/min and BP 120/80mmHg. Auscultation of the thorax revealed absence of breath sounds at the base of the right hemithorax. Her right wrist was slightly swollen. No lymph node, liver or spleen enlargement was detected, and examination of the other organs and systems was negative. Full blood count and biochemical tests were normal except for: Hct: 29.3%, Hb: 9.4g/dl, MCV 90.3fl, MCH:30.4pg, ESR: 105/1h and CRP: 6.97mg/dl. Arterial blood gas analysis revealed hypoxaemia (PaO2= 64mmHg at room air) without evidence of acid-base disorder. Chest X-ray demonstrated pleural effusion, which proved to be exudate with normal glucose level (109mg/dl) and pH (7.4), but cytological examination revealed the presence of small lymphocytes (80/ml) with plasmacytic differentiation. Fluid and sputum cultures for bacteria, fungus and β-Koch, and PCR analysis were negative and ADA 20IU/L. The purified protein          derivative (PPD) test with 0.2 TU tuberculin (mantoux) was 13 mm in diameter. Chest CT scan revealed a bilateral nodular (<1cm) pattern, a large right-sided pleural effusion and enlargement of the mediastinal and right auxiliary lymph nodes. Bronchoscopy revealed no abnormal findings and transbronchial biopsy, brushing, bronchial secretions and bronchoalveolar lavage (BAL) were negative for infection and malignancy. Abdominal US and CT scan, and X-ray of the right wrist were normal. Bone X-ray survey did not show osteolytic leasons. During hospitalization, the symptoms from the right wrist subsided. Further screening for tuberculosis, autoimmune disease and neoplasia was negative. Protein electrophoresis revealed a monoclonal increase in γ-globulins and immunofixation showed a marked increase in monoclonal IgMk. No free light chains were identified in serum or urine. The bone marrow aspiration demonstrated a diffuse infiltration (45-50%) with small B-lymphocytes with plasmacytoid differentiation and mature plasmacytes. These findings confirmed the diagnosis of lymhoplasmacytic lymphoma/WM. The patient underwent chemotherapy with 6 cycles of the COP-R regimen (Cyclophosphamide, Vincristine, Prednisone and Rituximab, anti-CD20 antibody). She was also given a 6-months\' prophylactic course of isoniazide because of the positive PPD reaction. She responded to therapy, and achieved complete remission. One year later she was disease free.



 Ιn this paper a case is presented of WM with pleuropulmonary involvement as the first manifestation of the disease. The involvement of the lung as the initial manifestation of WM is very rare and only few cases have  been reported so far (table 1). Pulmonary involvement in WM occurs in 3%-5% of cases.16-18 Symptoms at the onset include dyspnoea, nonproductive cough and chest pain, although 15% of the patients are asymptomatic. X-ray findings may include masses, diffuse or reticulonodular infiltrates, pulmonary nodules, mediastinal lymph node enlargement, and pleural effusions.18,26-28 The histological confirmation of the disease is very important . This patient presented with the non-specific symptoms of dyspnoea and cough. The differential diagnosis based on patient\'s CT pattern (nodules, pleural effusion and mediastinal lymph node enlargement) included infections (tuberculosis, bacteria and fungus), malignancies (brochoalveolar carcinoma, metastatic disease), lymphoproliferative diseases, pneumonia and amyloidosis. Symptoms suggestive of WM were not observed, possibly due to the low concentration of the monoclonal IgM, and low degree of bone marrow infiltration.1 Chest symptoms in WM are very rare, but autopsy series have shown that the lung and pleurae are affected more often than previously thought, even in the absence of clinical findings29. For this reason, in the context of confirmation of a low grade lymphoma, the clinician should consider the possibility of MW, since the correct diagnosis may lead to effective therapy.


Table 1. Previously reported cases of WM with lung involvement as the first manifestation of the disease
 Age, Sex  Symptoms  Chest X-ray pattern  Diagnosis
 62, M19
58, M20
70, F21
78, F21
79, F22
78, M23
47, F24
40, M25
Dyspnoea, cough
No symptoms
Dyspnoea, cough
Dyspnoea, haemoptysis
Dyspnoea, cough
No symptoms 
Infiltrates, Mass
Infiltrates, Mass, Effusion
Infiltrates, Mass, Effusion
Infiltrates, Effusion 
BMB, autopsy
Known WM
 Abbreviations: M: Male, F: Female, BMB: bone marrow biopsy, TBB: transbronchial biopsy, OLB: open lung biopsy, WM: Waldenstrom's macroglobulinaemia, TLB: transdermal lung biopsy



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