Lymphomatoid granulomatosis masquerading as interstitial pneumonia in a 66-year-old man: a case report and review of literature
- 9.9k Downloads
Lymphomatoid granulomatosis (LG) is a rare, Epstein-Barr virus (EBV)-associated systemic angiodestructive lymphoproliferative disorder that may progress to a diffuse large B cell lymphoma. Pulmonary involvement may mimic other more common lung pathologies including pneumonias. Therapeutic standards have not been established for LG, but rituximab, interferon-α2b (INF-α2b), and chemotherapy have shown to improve symptoms and long term prognosis.
We report a case of rapid respiratory deterioration in a 66-year-old man with clinical presentation, chest radiography, pulmonary function testing and high resolution computed tomography (HRCT) findings consistent with idiopathic interstitial pneumonia, but very poor response to antibiotics and low dose steroids. Lung biopsy showed histopathology consistent with LG that was confirmed by a positive in situ hybridization for Epstein - Barr virus encoded RNA (EBER). The patient was treated with rituximab and combination chemotherapy and showed significant initial clinical improvement with gradual resolution of abnormal findings on imaging. However, the patient developed pancytopenia as a complication of chemotherapy and died secondary to septic shock and renal failure that were refractory to medical management. Autopsy showed diffuse alveolar damage but no evidence of any residual LG within the lungs.
This case demonstrates that an open lung biopsy or video-assisted thoracoscopic surgical (VATS) biopsy is often necessary to rule out the presence of LG in order to determine the appropriate therapeutic strategy early in the course of illness to improve prognosis.
KeywordsInterstitial Lung Disease High Resolution Compute Tomography Diffuse Alveolar Damage Open Lung Biopsy Idiopathic Interstitial Pneumonia
High Resolution Computed Tomography
Video Assisted Thoracoscopic surgery
Epstein-Barr Virus encoded RNA
Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone combination chemotherapy
Diffuse large B cell lymphoma
Idiopathic Interstitial Pneumonia.
Lymphomatoid granulomatosis (LG) was first described as a clinicopathological entity in 1972 by Liebow et al . It is a rare, angiocentric and angiodestructive, Epstein-Barr virus (EBV)-driven, T cell rich- B cell lymphoproliferative disorder (LPD) with clinical presentation varying widely from an indolent process to an aggressive B cell lymphoma. It usually presents in the fifth-sixth decade of life and is often associated with immunosuppression or immunodeficiency states. Men are affected twice as often as women (2:1) .
Clinical presentation of Lymphomatoid Granulomatosis-a review of literature
Organ System Involved
Treatment and Prognosis
1. Pulmonary (lung and mediastinal lymph nodes)
-Dyspnea, Cough, Chest pain, Fatigue, Non-productive cough
-Underlying Immunodeficiency e.g. AIDS
- may clinically mimic pneumonia or interstitial lung disease 
-Chest Radiograph-non specific Differential Diagnosis: Pseudolymphoma, Interstitial Pneumonia, Wegener's Granulomatosis, Sarcoidosis, Metastasis 
-High Resolution CT chest-peribronchovascular distribution of nodules and coarse irregular opacities, small thin walled cysts, and conglomerating small nodules 
- Gold standard-Histopathology and Immuno-histochemical staining with EBV RNA in situ hybridization.
2. Central Nervous System
(in 20% cases)
-Central Diabetes Insipidus
-Concomitant Pulmonary involvement
-Elevated soluble IL-2 receptor level (normal 167-497 U/ml)
-CSF-elevated protein, lymphocytic pleocytosis
-MRI-spotty high intensity lesions on T2 imaging and enhancement with gadolinium contrast
-PET scan-increased uptake of FDG
-Gold standard-Biopsy and immuno-histochemical staining studies, EBV RNA in situ hybridization.
No well established treatment.
CNS involvement is a marker of poor prognosis.
Whole brain irradiation, chemotherapy, stem cell transplantation tried without much efficacy.
Rituximab monotherapy demonstrating efficacy .
3. Others-skin, liver, kidney, spleen, mesenteric lymph nodes, etc
-Rash, subcutaneous nodules, ulceration. Usually non tender but occasionally pruritic
-Usually associated with pulmonary or CNS LG
Work up as above
Treatment is along lines of systemic LG.
Chest radiographs are usually non-specific. Pulmonary nodules of varying sizes ranging from 1 to 9 cm are the most common findings (80% cases), but hilar adenopathy, pleural effusion, pneumothorax, pneumomediastinum and abscesses  also have been reported. Studies containing large radiographic series often report presence of diffuse bilateral nodules in the lower and peripheral lung fields with mass-like opacities [1, 2, 3, 6, 7, 8]. Bronchoscopic biopsy is positive in up to 27% cases, but definitive diagnosis requires tissue biopsy obtained by open lung biopsy or video assisted thoracoscopic surgery (VATS) (3). Gross pathology of the lung lesions may consist of multiple yellow-white spherical masses with central necrosis with a solid or granular cheesy appearance . Histologically, it is characterized by large atypical CD20+ B cells in a polymorphous inflammatory milieu of small lymphocytes, plasma cells, histiocytes (with karyorrhectic debris), and numerous CD3+ T cells (quantitatively outnumbering the B cells) with the infiltrate centered around bronchovascular and perivascular regions . Epithelioid granulomas and giant cells are almost always absent despite the name 'granulomatosis'. EBV is demonstrable in the large atypical B cells by in situ hybridization of EBV encoded RNA. LG has been classified into 3 histological grades depending on the number of atypical large EBV-infected cells . Grade 3 LG lesions most closely resemble clinically and pathologically the more conventional forms of diffuse large B cell lymphoma (DLBCL) and are treated in a similar manner. Most patients have grade 1-2 LG lesions at presentation.
Outcomes are variable and correlate with the histological grade. About one third of grade 1 lesions and two-thirds of grade 2 lesions progress to lymphoma . The course of LG tends to be fulminant with a median survival of 14 months and mortality of 65-90%, with death resulting from progressive pulmonary involvement, extrapulmonary disease (particularly neurological) and/or complications of therapy .
Due to its rarity, standard treatment has not been established but it is important to diagnose and intervene early because of rapid progression. Therapy has ranged from observation to treatment with steroids or aggressive chemotherapy in various case series . Low grade lesions may be treated with steroids alone. In view of similarity to EBV associated post transplant lymphoma, Interferon-α2b has often been used to treat LG due to its antiviral, antiproliferative and immunomodulatory properties, with good response . Grade 1 and 2 diseases are often treated by interferon-α2b in combination with a humanized monoclonal anti-CD20 antibody (rituximab)  while Grade 3 lesions are treated like high grade lymphomas with aggressive chemotherapy. Combination chemotherapy, usually, R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is used but response rates are poor at this grade . Autologous stem cell transplantation has also been reported to be successful in refractory cases but the clinical implications of this modality have not been reported in large studies .
A 66-year-old Caucasian man with no significant past medical history presented with flu-like symptoms, progressively worsening shortness of breath, difficulty in breathing (NYHA class III) and dry cough over the past 2 weeks prior to presentation. He denied any fever, chills, sputum production, orthopnea or paroxysmal nocturnal dyspnea, anorexia, weight loss, recent or past exposure to tuberculosis, sick contacts, pets, recent travel or past exposure to cigarette smoke (active or passive), asbestos, silica, coal dust or chemicals. He maintained an active lifestyle walking 5 miles three times a week without overt dyspnea. He had no prior history of connective tissue disease or HIV and denied any history of skin rash or joint pains. Past surgical, social and family histories were non-contributory. He also had no history of prior use of any long term medications. He had presented to the hospital 4 days prior to present admission and a provisional diagnosis of community acquired pneumonia was made based on chest radiograph findings and he was discharged home on 2L of oxygen and Levofloxacin, but came back to the hospital due to lack of obvious improvement.
On examination, he appeared tired with shortness of breath. The temperature was 99.9°F, the pulse 124/min, respiratory rate 26/min and oxygen saturation of 86% on 2L. Skin was diaphoretic. There was no evidence of rash, pallor, lymphadenopathy, clubbing, joint swelling or edema. Auscultation of chest revealed diminished breath sounds with bilateral velcro-like fine inspiratory crackles. Laboratory studies showed a normal complete blood count, metabolic panel, liver function tests, cardiac enzymes, BNP, lactate, PT/INR, aPTT, fibrinogen and TSH. D-dimer was elevated at 15.4 (normal <1.6). ESR was 52 mm/hour. Rheumatoid factor was <5 (negative). ANA, p-ANCA and c-ANCA were negative. Blood cultures (bacterial/fungal/mycobacterial), urine legionella and streptococcal antigen were negative. Viral respiratory panel, including cytomegalovirus & Herpes Simplex Virus PCR were also negative. ABG showed hypoxemia with respiratory alkalosis. Pulmonary function tests showed restrictive pattern of lung disease. Transthoracic echocardiogram showed normal cardiac chamber sizes and left ventricular ejection fraction of 81%.
Immuno-histochemical studies of lung tissue showed predominance of T cells expressing CD3, CD5 and CD43 with a smaller population of large atypical cells expressing CD20 and CD79a (B cell markers) (Fig. 2B). Many CD138+ plasma cells exhibiting polyclonal staining pattern for kappa and lambda immunoglobulin light chains were also seen. Bone marrow biopsy revealed normal cellularity with no evidence of lymphoma. In situ hybridization for EBV encoded RNA (EBER) was positive within scattered large lymphoid cells throughout the biopsy specimen (Fig. 2C).
Based on the pathological and immuno-histochemical findings, a diagnosis of Lymphomatoid Granulomatosis was made. Treatment with high dose steroids and rituximab showed significant clinical improvement and he was extubated 4 days after starting therapy. Treatment was continued with cyclophosphamide, vincristine, doxorubicin and prednisolone chemotherapy and he showed gradual but slow resolution of clinical and x-ray findings. However, he subsequently developed pancytopenia consequent to chemotherapy, septic shock requiring increasing doses of pressors and acute renal failure which did not respond to aggressive management and he was terminally weaned per family wishes 4 weeks later. A chest-only autopsy revealed diffuse alveolar damage, likely secondary to sepsis or chemotherapy or both, but no evidence of residual LG was noted within the lungs (Fig. 2D).
Discussion and Conclusion
This case illustrates that LG can clinically and radiographically mimic idiopathic interstitial pneumonia on presentation. However, rapid respiratory deterioration, without any other obvious etiology as in our patient, must prompt physicians to consider additional differential diagnoses. Although HRCT is an excellent modality in diagnosing interstitial pathology, we must be aware of potential mimics and proceed with open or VATS biopsy to obtain a pathological diagnosis in all patients who do not respond to empirical therapy. Early diagnosis and aggressive intervention, with interferon therapy, rituximab and chemotherapy in high grade LG can be life-saving for a patient with this rare yet treatable disease.
AM is an Internal Medicine Resident at Michigan State University. KK is a Pulmonary and Critical Care fellow at Wayne State University. DT is a hematology/oncology professor at Michigan State University. WC and HTC are pathologists in the Department of Pathology at Sparrow Health System, and HTC and DT are also associate professors at the Michigan State University.
Written informed consent was obtained from the patient's next-of-kin for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
- 2.Jaffe ES, Wilson WH: Lymphomatoid granulomatosis. World Health Organization Classification of tumors. Pathology and Genetics of Haemotopoietic and Lymphoid Tissues. Edited by: Jaffe ES, Harris NL, Stein H, Vardiman JW. 2001, IARC Press, Lyon, 185-Google Scholar
- 7.Guinee D, Jaffe E, Kingma D, Wallberg K, Krishnan J: Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein Barr virus infected B-lymphocytes with a predominant T-cell component and vasculitis. Am J Surg Pathol. 1994, 18: 753-64. 10.1097/00000478-199408000-00001.CrossRefPubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.