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Journal of Clinical Oncology, Vol 25, No 15 (May 20), 2007: pp. 2137-2139 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.7201
Pulmonary Intravascular Large B-Cell Lymphoma As a Cause of Severe HypoxemiaThird Lung Diseases Department, National TB & Lung Diseases Research Institute, Warsaw, Poland
Department of Pathology, National TB & Lung Diseases Research Institute, Warsaw, Poland A 35-year-old never-smoking woman was admitted to our hospital because of severe hypoxemia of unknown origin. She presented a 10-month history of progressive dyspnea on exertion, intermittent fevers (about 39°C), and nonproductive cough. She was treated with oral antibiotics (clarythromycin) without any improvement. She had no prior history of lung disease, and no exposure to occupational, dust, or animal hazards. Laboratory examination results revealed a hemoglobin (Hb) of 11.5 g/100 mL and erythrocyte sedimentation rate (ESR) of 67 mm/h. Throughout observation the chest x-ray was normal. Bronchoscopy and bronchioalveolar lavage were nondiagnostic. Echocardiographic (ECHO) examination did not show any abnormalities with normal pulmonary pressures in Doppler studies. Three months before admission increased liver enzymes: glutamic oxoloacetic transaminase (GOT) 406 U/I, glutamic pyruvic transferase (GPT) 845 U/I, and total bilirubin –4.92 mg/100 mL were detected. Hepatosplanomegaly without lymphadenopathy was observed at that time. Hepatitis type B and type C virus, as well as HIV infections, were ruled out. Bone marrow aspiration and trephine biopsy were performed and revealed normal hematopoesis with no abnormal infiltrates (included lymphocytes infiltration; CD20 [negative]). Blind groin lymph node biopsy showed no neoplasmatic infiltrates. Contraceptive treatment with estrogen, which was taken by patient for the past 9 years was stopped. Thereafter, liver tests normalized. Due to the aforementioned risk factor (estrogen therapy), progressing hypoxemia with normal chest radiography and nonspecific patchy, spheric pulmonary perfusion defects seen at the same time on perfusion scintigraphy, at first, thromboembolism was suspected. Low fraction heparin treatment did not lessen her symptoms and was without influence on blood gases. At the time of admission to our ward she appeared unwell, but no focal findings were noted on examination. Her temperature was 36.6°C, blood pressure 120/60, pulse 110 per minute, respiratory rate 22 per minute. She had no peripheral lymphadenopathy, skin lesions, nor signs of neurological deficit. On abdominal examination, liver and spleen tip was not palpable. Arterial blood gases drawn on room air showed a PaO2 –48.8 mmHg (normal, 80 to 100), PaCO2 –31.8 mmHg (normal, 35 to 45), pH –7.48 (normal, 7.35 to 7.45), HCO3 –24.1 mmol/L (normal, 21 to 25), BE 1.3 mmol/L (normal, –0.3 to 0.3), saturation of Hb –88% (normal, > 98). In our laboratory findings, anemia was not detected (Hb –13.3 g/100 mL), ESR was 28 mm/h, electrolytes, renal and liver function studies were normal (GOT, –17 U/L; GPT, –22 U/L; total bilirubin, –0.9 mg/100 mL). A serum lactate dehydrogenase activity was markedly elevated to 1,018 U/L (normal, < 480 U/L), C-reactive protein (CRP) –17 mg/L (normal, < 5). Antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies were not detected. Repeated culture of blood, sputum, urine, and stool were negative for possible pathogens. Chest radiography was stable, without any notable changes, however high-resolution computed tomography (CT) revealed bilateral minimal nonspecific ground-glass appearance in upper-middle lobes. An angio-CT scan showed no signs of pulmonary thromboembolism or lymphadenopathy in chest and abdomen examination. In pulmonary function tests there were no signs of airflow limitation or volume restriction, however, severe reduction of diffusing lung capacity for carbon monoxide was observed (37.5% of predicted). The patient was placed on supplemental oxygen therapy (nasal catheter, O2 flow –4 l/min) which normalized her PaO2. For the purpose of diagnosis, open lung biopsy was performed. The specimen consisting of two fragments of lung tissue was obtained for microscopic examination; the first biopsy from the apical part of the lung (dimensions, 3.0 x 2.5 x 1.0 cm) and the second biopsy was from the medial lobe (dimensions 3.5 x 2.5 x 2.0 cm). In both tissue specimens, no significant pathological changes were found. Tissue was fixed in 10% neutral buffered formalin, embedded in paraffin, and stained with hematoxylin and eosin. Immunohistochemical stains were performed. The tissue of the lung was preserved but revealed the presence of atypical lymphocytes within small pulmonary arterioles, venules, capillaries, and lymphatics. The neoplastic cells showed large, vesicular, indented nuclei, eosinophilic nucleoli, and moderate amounts of pale cytoplasm. Mitoses including atypical forms were seen. The perivascular regions contained an admixture of small lymphocytes, plasma cells, and histiocytes. There was evidence of muscular hypertrophy and intimal hyperplasia of the pulmonary arterioles. The neoplastic cells distended vessels; in particular capillaries superficially resembled an interstitial pneumonia, leukemia, or metastatic carcinoma (Fig 1, hematoxyline and eosine staining; original magnification, x400). Immunohistochemical studies demonstrated that the tumor cells were highlighted by staining for common leukocyte antigen and B-cell marker CD20 (Fig 2; original magnification, x400). The tumor cells exhibited no immunoreactivity for cytokeratin cocktail AE1/AE3 and for CD30 and for T-cell markers UCHL-1, CD3. Proliferative marker, Mib-1 showed distinctive nuclear reaction involving almost 100% neoplastic cells. Thus, microscopic features and immunohistochemical reactions allowed to establish the diagnosis of pulmonary intravacular large B-cell lymphoma. At that point treatment with combination chemotherapy and rituximab was started.
Intravascular lymphoma (IVL) is a rare and aggressive variant of intravascular proliferation of clonal lymphocytes with little to no parenchymal involvement. The B-cell immunotype is most common, although cases with T-cell receptor have been reported.1 The disease affects a wide age range with no specific predilection for sex. The clinical presentation is highly variable and the diagnosis is often difficult and delayed.2,3 Autopsy examinations revealed IVL involvement of multiple organs, even asymptomatic ante mortem.4-6 There are no pathognomonic, clinical, laboratory, or radiological signs of IVL. Patients usually present B symptoms including fever of unknown origin, night sweats, malaise, fatigue, unexplained weight loss.1,2,7-9 The most common clinical manifestations involve the skin and nervous system and some authors found that 68% of IVL patients had symptoms present in at least one of these organs.2 The cutaneous variant of IVL is recognized by the European Oncology Research and Treatment of Cancer group and may carry a more favorable prognosis.10 Diagnosis for our patient was so difficult because she did not demonstrate any cutaneous or neurological symptoms. Primary presentation of IVL in the lungs is uncommon and only a few cases have been reported in the literature to date,2,5,6,11-26 although in autopsy changes were found in approximately 60% of cases.22 Increased serum lactate dehydrogenase (presented in more than 80% of IVL cases), anemia (63%), and elevated ESR (43%), observed also in this case, are the most often of laboratory findings.2 Radiological examinations in pulmonary IVL present various findings. The majority of cases with lung involvement showed diffuse interstitial infiltrates, pleural effusion, signs of pulmonary hypertension, or consolidation (tumor like) in the lungs.12,13,16,17,20,25 Despite progressive dyspnea and hypoxemia, our patient's chest x-ray appeared normal with minimal and nonspecific high-resolution CT findings. The investigation did not reveal signs of air trapping (confirmed by the expiratory high-resolution CT) or signs of pulmonary arterial hypertension (also in Doppler-ECHO). Diagnosis can be made by lung biopsy, and in cause of lung infiltration, even using transbronchial way.24 IVL is potentially a systemic disease, therefore skin biopsy, or other surgical resection may also be diagnostic.4,19,27 Some authors have reported success in using random skin biopsy and muscle biopsy, to evaluate the possibility of IVL, in the absence of focal lesions.9 Bone marrow involvement has been reported in 33% and lymph node involvement in 11% of cases.2 Bone marrow is usually spared until late in the disease, hence, its examination is often unhelpful in the diagnosis, as it was in this case.2 There are no randomized, controlled trials comparing treatments in IVL. Most of authors recommended an anthracycline-based chemotherapy regimen, such as cyclophosphamide, doxorubicin, vincristine, and prednisone with the addition of the monoclonal antibody rituximab in cases with a B-cell immunophenotype.1,2 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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