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Intern Med. 2017 July 15; 56(14): 1885–1891.
PMCID: PMC5548684

Pulmonary Intravascular Large B-cell Lymphoma (IVLBCL) Disguised as an Asthma Exacerbation in a Patient with Asthma

Abstract

A 62-year-old man with asthma presented with a 1-month history of wheezing and exertional dyspnea. Although the wheezing symptoms disappeared after systemic corticosteroid therapy, the exertional dyspnea and hypoxemia did not improve. A diagnosis of intravascular large B-cell lymphoma (IVLBCL) with pulmonary involvement was suspected because of the increased serum lactic dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) level, increased alveolar-arterial oxygen difference (AaDO2), decreased pulmonary diffusing capacity for carbon monoxide (DLCO) and scintigraphic, computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT findings. The patient was diagnosed as having IVLBCL with pulmonary involvement based on a pathological analysis of a random skin biopsy and a transbronchial lung biopsy. IVLBCL should be considered in patients with symptoms of asthma that are refractory to corticosteroid treatment.

Keywords: intravascular large B-cell lymphoma, asthma, positron emission tomography, transbronchial lung biopsy

Introduction

Intravascular large B-cell lymphoma (IVLBCL) is a rare extranodal subtype of non-Hodgkin's diffuse large B-cell lymphoma (DLBCL) that is characterized by the selective growth of malignant lymphocytes within the lumen of small- to medium-sized blood vessels, particularly capillaries (1). In the current World Health Organization classification of hematopoietic tumors, IVLBCL is listed as a subtype of DLBCL (2). The intravascular proliferation of malignant lymphocytes in extranodal organs, such as the skin, central nervous system, bone marrow, liver, and spleen, is most commonly observed in IVLBCL (3). However, autopsy findings have revealed that intravascular lymphoma often involves the lungs (4-6). Pulmonary involvement is rare at the initial presentation, and its diagnosis is often difficult due to the lack of specific symptoms and pathognomonic findings. IVLBCL in the lung is suspected with dyspnea and abnormal chest findings on chest X-ray and/or computed tomography (CT). It is usually diagnosed pathologically by a random skin biopsy and transbronchial lung biopsy (TBLB) (7-14).

We herein report a case of a male patient with asthma who developed exertional dyspnea, which was disguised as an exacerbation of asthma, accompanied by IVLBCL. He did not exhibit abnormal chest X-ray findings, and the diagnosis was ultimately proven by a random skin biopsy and TBLB. Furthermore, the diffuse pulmonary 18F-Fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)-CT was helpful in our suspicion of the diagnosis and in assessing the response to chemotherapy.

Case Report

A 62-year-old man who had been treated for severe persistent asthma for 10 years at a local hospital presented to our hospital with a 1-month history of wheezing and exertional dyspnea. At his local hospital, he had been treated with high-dose inhaled corticosteroid, an inhaled long-acting beta2-agonist, leukotriene receptor antagonist, xanthine and intermittent systemic corticosteroids at least once a month for half a year. At our hospital, his wheezing disappeared after the administration of oral corticosteroid, but his exertional dyspnea did not improve. He was admitted to our hospital for the investigation of dyspnea and pulse oximeter desaturation.

A physical examination was normal despite hypoxemia. Chest sounds were normal, and expiratory wheezing was no longer heard after bronchodilator administration. There were no skin lesions, lymphadenopathy or neurological findings. Laboratory findings showed elevated serum lactic dehydrogenase (LDH) (1,482 IU/L), aspartate aminotransferase (AST) (39 IU/L) and C-reactive protein (CRP) (1.6 mg/dL) levels. An arterial blood gas analysis at rest while breathing room air showed hypoxemia (PaO2 53.9 Torr) with an elevated alveolar-arterial oxygen difference (AaDO2) (60.9 Torr). The serum tumor markers were within normal limits, except for an elevated soluble interleukin-2 receptor level (sIL-2R) (1,570 U/mL). Although chest X-ray showed no abnormal findings, chest CT showed diffuse multiple small nodules in the lung fields, no mass and no lymphadenopathy in the thorax or the abdominal cavity (Fig. 1A). Respiratory function testing showed a decline in the pulmonary diffusing capacity for carbon monoxide (DLCO). Pulmonary blood flow scintigraphy showed decreased accumulation in both middle-lower lung fields. A diffuse pulmonary 18F-FDG PET-CT scan showed an increased diffuse FDG uptake in both middle-lower lung fields (Fig. 1B). The existence of malignant lymphoma, such as IVLBCL, without clinical findings was suspected because of the hypoxemia, the high levels of LDH and sIL-2R, the increased AaDO2, the decreased DLCO and the scintigraphic, CT and PET-CT findings. A random skin biopsy and TBLB were performed, and the pathological findings revealed atypical lymphoid cells located within the intravascular space of the capillary vessels and pulmonary artery. In immunohistochemical staining, these atypical lymphoid cells were positive for CD20 and CD79a, which are B-cell markers (Fig. 2), and demonstrated a high proliferation index, as revealed by MIB-1 (Ki-67) (data not shown). Based on these results, the patient was diagnosed as having IVLBCL with pulmonary involvement.

Figure 1.
Chest CT (A) and 18F-FDG PET-CT (B) scans at the initial presentation, showing diffuse multiple small nodules in the lung fields and an increased diffuse FDG uptake in both middle-lower lung fields. FDG: fluorodeoxyglucose, PET: positron emission tomography ...
Figure 2.
A histopathological analysis of random skin (A, B and C) and transbronchial lung (D, E and F) biopsy specimens. Atypical lymphoid cells were seen in the intravascular space of capillary vessels and pulmonary artery (Hematoxylin and Eosin staining, ×400) ...

After transfer to the Department of Hematology, the patient was treated with prednisolone and vincristine to reduce the pulmonary tumor burden due to his worsening respiratory condition. After one week, his respiratory condition improved. Following prednisolone and vincristine administration, he was treated with R-CHOP chemotherapy, consisting of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone. He achieved complete remission after eight cycles of R-CHOP chemotherapy with no severe adverse events, and the LDH and sIL-2R levels, the AaDO2 and chest CT and FDG-PET findings subsequently revealed no signs of lymphoma involvement (Fig. 3).

Figure 3.
Chest CT (A) and 18F-FDG PET-CT (B) scans after the completion of eight courses of R-CHOP. Diffuse multiple small nodules and the diffuse FDG uptake disappeared completely in the lung fields on CT and FDG-PET/CT findings, respectively. FDG: fluorodeoxyglucose, ...

Discussion

To our knowledge, this is the first report of a case of IVLBCL with pulmonary involvement disguised as exacerbation of asthma in a patient with asthma. It may be associated with the typical symptoms of patients with asthma that are difficult to diagnose correctly. A diverse array of diseases, including ischemic heart disease, pulmonary thrombosis and pulmonary lymphoma, generally involve exertional dyspnea and/or wheezing. Furthermore, asthmatic patents often exhibit exertional dyspnea without wheezing. This patient was initially treated for exacerbation of asthma due to the exertional dyspnea with wheezing, suggesting that the exacerbation of asthma might have initially coexisted with IVLBCL. Furthermore, it has been reported that corticosteroid treatment before the diagnosis of lymphoma might be used to reduce tumor size and might cause a delay in the definitive diagnosis (15). Therefore, the repeated intermittent treatments with oral corticosteroids as rescue medication for asthma exacerbations in this patient might have complicated and delayed the ultimate diagnosis. However, the increased serum LDH and sIL-2R levels, the increased AaDO2 levels, the decreased DLCO and the scintigraphic and CT findings that showed diffuse multiple small nodules in the present case led to the suspicion of IVLBCL. High levels of LDH and sIL-2R have been observed in most cases of IVLBCL (13,14,16).

Since 1983, there have been 76 additional cases of IVLBCL with pulmonary involvement reported in the medical literature, including 16 articles in Japanese and the present case (Table 1) (5,6,9-14,16-51). The male-to-female ratio was 44:32, and the median age was 61.5 years (range 35 to 85 years). The median LDH and sIL-2R levels were 1,357 IU/L (range 352 to 5,085 IU/L) and 2,279 U/mL (range 602 to 24,500 U/mL), respectively. Seventy cases (92%) had symptoms of a fever (n=56, 73.7%), cough (n=21, 27.6%) or dyspnea (n=52, 68.4%). Chest CT was performed in 57 cases (75%). Eleven of those 57 cases (19.3%) showed no abnormalities on chest CT. Ground glass opacity (GGO) and diffuse multiple small nodules were present in 34 (59.6%) and 10 (17.5%) of the 57 cases, respectively. The present case showed increased serum LDH and sIL-2R levels and diffuse multiple small nodules on chest CT.

Table 1.
Seventy-six Cases of Pulmonary IVLBCL.

Furthermore, there were 13 previous case reports of pulmonary IVLBCL with FDG-PET/CT (Table 2) (10-12,14,29,37,39,43,50). These reports suggested that 18F-FDG PET-CT scanning may facilitate suspicion of IVLBCL with pulmonary involvement, even in the absence of radiological findings (11,12,14,42). In the present case, the PET-CT findings were pivotal in the suspected diagnosis of IVLBCL with pulmonary involvement and in assessing the response to treatment. Furthermore, in Case 14 in Table 2, Nakazato et al. successfully obtained an early diagnosis of pulmonary IVLBCL by a random TBLB, despite the lack of abnormal FDG accumulation in lung fields (10). They suspected pulmonary IVLBCL because of progressive dyspnea and hypoxemia. Conversely, Table 2 also mentions four cases of IVLBCL with a diffuse FDG uptake in the lung that were diagnosed by a skin or renal biopsy without a lung biopsy (11,12,37,39). In this case, pathological findings from a random skin biopsy and TBLB led to a diagnosis and prompt chemotherapy. Of the 76 cases in Table 1, an ante-mortem diagnosis was made in 60 patients (78.9%) who underwent a lung and/or skin biopsy. Among these 60 cases, 50 (83.3%) received systemic chemotherapy, i.e. CHOP or R-CHOP therapy. The chemotherapy improved the clinical outcomes for IVLBCL in 41 of the 50 cases (82%). These previous reports have suggested that a random skin biopsy and TBLB, which were useful in diagnosing the present case while the patient was still alive, should be considered early on, even when skin lesions or abnormal pulmonary findings are not apparent, in order to rapidly initiate the administration of chemotherapy (7-14). These previous reports have also suggested that it is necessary to diagnose pulmonary IVLBCL comprehensively based on the clinical symptoms, image analyses and pathological findings. Ultimately, systemic chemotherapy for IVLBCL at an early stage may improve the long-term survival (9,12,14,16,38,46,51).

Table 2.
Thirteen Previous Case Reports of Pulmonary IVLBCL with FDG-PET/CT.

In conclusion, we encountered an asthmatic patient having IVLBCL with pulmonary involvement disguised as an asthma exacerbation. The exertional dyspnea, hypoxemia, increased serum LDH and sIL-2R, increased AaDO2, decreased DLCO and scintigraphic, CT and PET-CT findings led to the correct diagnosis. IVLBCL should be considered in such cases of exertional dyspnea and/or hypoxemia, even when wheezing symptoms disappear after systemic corticosteroid therapy. Furthermore, a random skin biopsy, TBLB and 18F-FDG PET-CT scan should be performed early to make the diagnosis, even if in the absence of skin lesions or abnormal pulmonary findings, possibly leading to prompt chemotherapy, contributing to remission and improving the long-term survival.

The authors state that they have no Conflict of Interest (COI).

References

1. Ponzoni M, Ferreri AJ, Campo E, et al. Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting. J Clin Oncol 25: 3168-3173, 2007. [PubMed]
2. Pileri SA, Grogan TM, Harris NL, et al. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology 41: 1-29, 2002. [PubMed]
3. Ferreri AJ, Campo E, Seymour JF, et al. Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘cutaneous variant'. Br J Haematol 127: 173-183, 2004. [PubMed]
4. Yousem SA, Colby TV Intravascular lymphomatosis presenting in the lung. Cancer 65: 349-353, 1990. [PubMed]
5. Colby TV. Malignancies in the lung and pleura mimicking benign processes. Semin Diagn Pathol 12: 30-44, 1995. [PubMed]
6. Ko YH, Han JH, Go JH, et al. Intravascular lymphomatosis: a clinicopathological study of two cases presenting as an interstitial lung disease. Histopathology 31: 555-562, 1997. [PubMed]
7. Takamura K, Nasuhara Y, Mishina T, et al. Intravascular lymphomatosis diagnosed by transbronchial lung biopsy. Eur Respir J 10: 955-957, 1997. [PubMed]
8. Asada N, Odawara J, Kimura S, et al. Use of random skin biopsy for diagnosis of intravascular large B-cell lymphoma. Mayo Clin Proc 82: 1525-1527, 2007. [PubMed]
9. Georgin-Lavialle S, Darmon M, Galicier L, Fysekidis M, Azoulay E Intravascular lymphoma presenting as a specific pulmonary embolism and acute respiratory failure: a case report. J Med Case Rep 3: 7253, 2009. [PMC free article] [PubMed]
10. Nakazato T, Sanada Y, Mihara A, Ito C, Aisa Y, Nakamura N PET-negative pulmonary intravascular large B cell lymphoma diagnosed by a random transbronchial lung biopsy. Ann Hematol 91: 811-812, 2012. [PubMed]
11. Yamashita H, Suzuki A, Takahashi Y, Kubota K, Kano T, Mimori A Intravascular large B-cell lymphoma with diffuse FDG uptake in the lung by 18FDG-PET/CT without chest CT findings. Ann Nucl Med 26: 515-521, 2012. [PubMed]
12. Shiiba M, Izutsu K, Ishihara M Early detection of intravascular large B-cell lymphoma by (18)FDG-PET/CT with diffuse FDG uptake in the lung without respiratory symptoms or chest CT abnormalities. Asia Ocean J Nucl Med Biol 2: 65-68, 2014. [PMC free article] [PubMed]
13. Nishizawa T, Saraya T, Ishii H, Goto H Antemortem diagnosis with multiple random skin biopsies and transbronchial lung biopsy in a patient with intravascular large B-cell lymphoma, the so-called Asian variant lymphoma. BMJ Case Rep 2014: 2014. [PMC free article] [PubMed]
14. Colavolpe C, Ebbo M, Trousse D, et al. FDG-PET/CT is a pivotal imaging modality to diagnose rare intravascular large B-cell lymphoma: case report and review of literature. Hematol Oncol 33: 99-109, 2015. [PubMed]
15. Borenstein SH, Gerstle T, Malkin D, Thorner P, Filler RM The effects of prebiopsy corticosteroid treatment on the diagnosis of mediastinal lymphoma. J Pediatr Surg 35: 973-976, 2000. [PubMed]
16. Chen Y, Ding C, Lin Q, Yang K, Li Y, Chen S Primary intravascular large B-cell lymphoma of the lung: a review and case report. J Thorac Dis 6: E242-E245, 2014. [PMC free article] [PubMed]
17. Fulling KH, Gersell DJ Neoplastic angioendotheliomatosis. Histologic, immunohistochemical, and ultrastructural findings in two cases. Cancer 51: 1107-1118, 1983. [PubMed]
18. Tan TB, Spaander PJ, Blaisse M, Gerritzen FM Angiotropic large cell lymphoma presenting as interstitial lung disease. Thorax 43: 578-579, 1988. [PMC free article] [PubMed]
19. Pellicone JT, Goldstein HB Pulmonary malignant angioendotheliomatosis. Presentation with fever and syndrome of inappropriate antidiuretic hormone. Chest 98: 1292-1294, 1990. [PubMed]
20. Gabor EP, Sherwood T, Mercola KE Intravascular lymphomatosis presenting as adult respiratory distress syndrome. Am J Hematol 56: 155-160, 1997. [PubMed]
21. Nambu A, Kurihara Y, Ichikawa T, et al. Lung involvement in angiotropic lymphoma: CT findings. AJR Am J Roentgenol 170: 940-942, 1998. [PubMed]
22. Jang HJ, Lee KS, Han J Intravascular lymphomatosis of the lung: radiologic findings. J Comput Assist Tomogr 22: 427-429, 1998. [PubMed]
23. Evert M, Lehringer-Polzin M, Mobius W, Pfeifer U Angiotropic large-cell lymphoma presenting as pulmonary small vessel occlusive disease. Hum Pathol 31: 879-882, 2000. [PubMed]
24. Owa M, Koyama J, Asakawa K, Hikita H, Kubo K, Ikeda SI Intravascular lymphomatosis presenting as reversible severe pulmonary hypertension. Int J Cardiol 75: 283-284, 2000. [PubMed]
25. Chim CS, Choy C, Ooi GC, Chung LP, Wong KK, Liang R Two unusual lymphomas. Case 2: pulmonary intravascular lymphomatosis. J Clin Oncol 18: 3733-3735, 2000. [PubMed]
26. Taura Y, Yamazaki H, Katou T [Two cases of intravascular lymphomatosis diagnosed antemortem by transbronchial lung biopsy]. Nihon Kokyuki Gakkai Zasshi (Ann Jpn Respir Soc) 38: 34-38, 2000. [PubMed]
27. Yamagata T, Okamoto Y, Ota K, Katayama N, Tsuda T, Yukawa S A case of pulmonary intravascular lymphomatosis diagnosed by thoracoscopic lung biopsy. Respiration 70: 414-418, 2003. [PubMed]
28. Aouba A, Diop S, Saadoun D, et al. Severe pulmonary arterial hypertension as initial manifestation of intravascular lymphoma: case report. Am J Hematol 79: 46-49, 2005. [PubMed]
29. Chan VL, Lee CK, Leung WS, Lin SY, Chu CM A 57-year-old woman with fever and abnormal chest CT findings. Chest 130: 924-927, 2006. [PubMed]
30. Sakurai T, Tokuda A, Nakamura S, Tabeta H [A case of intravascular large cell lymphoma with pulmonary invasion]. Nihon Kokyuki Gakkai Zasshi (Ann Jpn Respir Soc) 45: 329-332, 2007. [PubMed]
31. Martusewicz-Boros M, Wiatr E, Radzikowska E, Roszkowski-Sliz K, Langfort R Pulmonary intravascular large B-cell lymphoma as a cause of severe hypoxemia. J Clin Oncol 25: 2137-2139, 2007. [PubMed]
32. Gabriel IH, Chong N, Rice A, Negus R, Bain BJ Case 36: a difficult diagnosis in a patient with fever and progressive multi-organ failure. Leuk Lymphoma 48: 1407-1409, 2007. [PubMed]
33. Fujiwara A, Azuma T, Yamanouchi J, et al. [Intravascular large B-cell lymphoma presenting as interstitial lung disease]. Nihon Naika Gakkai Zasshi (J Jpn Soc Int Med) 96: 2783-2785, 2007. [PubMed]
34. Sekine A, Hagiwara E, Okudera K, Baba T, Ogura T [A case of slowly progressive intravascular lymphoma with respiratory failure caused by diffuse pulmonary vasoconstriction]. Nihon Kokyuki Gakkai Zasshi (Ann Jpn Respir Soc) 47: 924-929, 2009. [PubMed]
35. Wakamatsu K, Komori M, Nagata N, Kumazoe H, Kajiki A, Kitahara Y [Two cases of intravascular lymphomatosis diagnosed by transbronchial lung biopsy]. Nihon Kokyuki Gakkai Zasshi 47: 875-880, 2009. [PubMed]
36. Okada A, Hirakawa R, Yamashita M, Aono H, Choh S, Obayashi C [Two cases of intravascular diffuse large B-cell lymphoma diagnosed by transbronchial lung biopsy]. Nihon Kokyuki Gakkai Zasshi (Ann Jpn Respir Soc) 48: 779-785, 2010. [PubMed]
37. Miura Y, Tsudo M Fluorodeoxyglucose-PET/CT for diagnosis of intravascular large B-cell lymphoma. Mayo Clin Proc 85: e56-e57, 2010. [PMC free article] [PubMed]
38. Niida T, Isoda K, Miyazaki K, et al. Pulmonary intravascular lymphoma diagnosed by 18-fluorodeoxyglucose positron emission tomography-guided transbronchial lung biopsy in a man with long-term survival: a case report. J Med Case Rep 5: 295, 2011. [PMC free article] [PubMed]
39. Bai X, Li X, Wan L, Wang G, Jia N, Geng J Intravascular large B-cell lymphoma of the kidney: a case report. Diagn Pathol 6: 86, 2011. [PMC free article] [PubMed]
40. Matsue K, Hayama BY, Iwama K, et al. High frequency of neurolymphomatosis as a relapse disease of intravascular large B-cell lymphoma. Cancer 117: 4512-4521, 2011. [PubMed]
41. Yu H, Chen G, Zhang R, Jin X Primary intravascular large B-cell lymphoma of lung: a report of one case and review. Diagn Pathol 7: 70, 2012. [PMC free article] [PubMed]
42. Wagner T, Brechemier D, Dugert E, et al. Diffuse pulmonary uptake on FDG-PET with normal CT diagnosed as intravascular large B-cell lymphoma: a case report and a discussion of the causes of diffuse FDG uptake in the lungs. Cancer Imaging 12: 7-12, 2012. [PMC free article] [PubMed]
43. Kohan AA, Paganini L, Biedak P, Arma JI, Dalurzo MC, Garcia-Monaco RD Pulmonary intravascular lymphoma detected by FDG PET-CT: a case report. Rev Esp Med Nucl Imagen Mol 32: 318-320, 2013. [PubMed]
44. Khojeini EV, Song JY Intravascular large B-cell lymphoma presenting as interstitial lung disease. Case Rep Pathol 2014: 928065, 2014. [PMC free article] [PubMed]
45. Xiao D, Fu C, Long X, et al. Lung intravascular large B-cell lymphoma with ground glass opacities on chest computed tomography: a case report. Int J Clin Exp Pathol 7: 5285-5290, 2014. [PMC free article] [PubMed]
46. Liu C, Lai N, Zhou Y, Li S, Chen R, Zhang N Intravascular large B-cell lymphoma confirmed by lung biopsy. Int J Clin Exp Pathol 7: 6301-6306, 2014. [PMC free article] [PubMed]
47. Yamakawa H, Yoshida M, Yabe M, et al. Useful strategy of pulmonary microvascular cytology in the early diagnosis of intravascular large B-cell lymphoma in a patient with hypoxemia: a case report and literature review. Intern Med 54: 1403-1406, 2015. [PubMed]
48. Poletti V, Gurioli C, Piciucchi S, et al. Intravascular large B cell lymphoma presenting in the lung: the diagnostic value of transbronchial cryobiopsy. Sarcoidosis Vasc Diffuse Lung Dis 31: 354-358, 2015. [PubMed]
49. Katayama K, Tomoda K, Ohya T, Asada H, Ohbayashi C, Kimura H Ground-glass opacities and a solitary nodule on chest in intravascular large B-cell lymphoma. Respirol Case Rep 3: 108-111, 2015. [PMC free article] [PubMed]
50. Peng M, Shi J, Liu H, Li G Intravascular large B cell lymphoma as a rare cause of reversed halo sign: a case report. Medicine (Baltimore) 95: e3138, 2016. [PMC free article] [PubMed]
51. Srivali N, Pannu BS, Iyer VN Isolated intravascular large B-cell lymphoma presenting with diffuse ground glass pulmonary infiltrates. Indian J Hematol Blood Transfus 32 (Suppl 1): 366-367, 2016. [PMC free article] [PubMed]

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