Pulmonary lymphomatoid granulomatosis
- Talmadge E King, Jr, MD
Talmadge E King, Jr, MD
- Editor-in-Chief — Pulmonary and Critical Care Medicine
- Section Editor — Interstitial Lung Disease
- Dean, School of Medicine
- Vice Chancellor, Medical Affairs
- University of California San Francisco
Pulmonary lymphomatoid granulomatosis (PLG) is an uncommon pulmonary disorder characterized by multiple pulmonary nodular lesions with lymphocytic invasion of vascular walls on biopsy. Averill Liebow and colleagues first described PLG as a clinicopathologic entity in 1972 . Since that time, the clinical implications of this lesion have remained controversial, as evidenced by a long list of competing synonyms including angiocentric immunoproliferative lesion and angiocentric lymphoma [2-4]. Some have argued that the histopathologic pattern of lymphomatoid granulomatosis, which can occur in pulmonary and extrapulmonary tissue, is a nonspecific manifestation of diverse pathogenetic conditions, including autoimmunity, infection, and malignancy .
It is generally believed that PLG represents a form of lymphoproliferative disorder. The World Health Organization (WHO) classification scheme places lymphomatoid granulomatosis under the generic heading of B cell proliferations of uncertain malignant potential . These lymphoproliferative disorders are in the family of Epstein-Barr virus (EBV)-associated B cell lymphomas [5-8]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Lymphoproliferative disorders' and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Lymphomatoid granulomatosis'.)
In addition to PLG, the lung is the primary organ of involvement in a spectrum of lymphocytic and lymphoproliferative disorders. These include lymphoid interstitial pneumonia, plasma cell interstitial pneumonia, angioimmunoblastic lymphadenopathy, and primary pulmonary lymphoma [9,10]. Pulmonary lymphomatoid granulomatosis will be reviewed here. Clinical aspects of other pulmonary lymphocytic and lymphoproliferative disorders are discussed separately. (See "Lymphoid interstitial pneumonia in adults" and "Inflammatory myofibroblastic tumor (plasma cell granuloma) of the lung" and "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified", section on 'Angioimmunoblastic T cell lymphoma' and "Clinical manifestations, pathologic features, and diagnosis of extranodal (MALT) and nodal marginal zone lymphomas".)
Pulmonary lymphomatoid granulomatosis generally presents between the ages of 30 and 50, although patients can be affected at any age [4,11-17]. It is predominantly seen in men, with an estimated male to female ratio of at least 2:1 [5,18]. The effects of race and geography on disease incidence are not known, although a higher diagnosis rate is reported in Western countries .
Pulmonary lymphomatoid granulomatosis (PLG) appears to be associated with Epstein-Barr virus (EBV) infection in most if not all cases [5,6]. A small number of cases show no demonstrable evidence of EBV infection, and may represent a distinct form of peripheral T cell lymphoma . Alternatively, these cases may reflect grade 1 disease with infrequent EBV-positive cells that were not detected [19-21]. (See 'Grading' below and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Lymphomatoid granulomatosis'.)
- Liebow AA, Carrington CR, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol 1972; 3:457.
- Jaffe ES, Wilson WH. Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. Cancer Surv 1997; 30:233.
- Myers JL. Lymphomatoid granulomatosis: past, present, ... future? Mayo Clin Proc 1990; 65:274.
- Pisani RJ, DeRemee RA. Clinical implications of the histopathologic diagnosis of pulmonary lymphomatoid granulomatosis. Mayo Clin Proc 1990; 65:151.
- Pittaluga S, Wilson WH, Jaffe ES. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
- Nicholson AG, Wotherspoon AC, Diss TC, et al. Lymphomatoid granulomatosis: evidence that some cases represent Epstein-Barr virus-associated B-cell lymphoma. Histopathology 1996; 29:317.
- Myers JL, Kurtin PJ, Katzenstein AL, et al. Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol 1995; 19:1300.
- Guinee D Jr, Jaffe E, Kingma D, et al. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 1994; 18:753.
- Cosgrove GP, Schwartz MI. Lymphocytoplasmic infiltrations of the lung. In: Interstitial Lung Disease, 5th ed, Schwarz MI, King TE Jr. (Eds), People’s Medical Publishing House - USA, Hamilton 2011. p.1053.
- Cadranel J, Wislez M, Antoine M. Primary pulmonary lymphoma. Eur Respir J 2002; 20:750.
- Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 1979; 43:360.
- Sordillo PP, Epremian B, Koziner B, et al. Lymphomatoid granulomatosis: an analysis of clinical and immunologic characteristics. Cancer 1982; 49:2070.
- Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid Granulomatosis. Prospective clinical and therapeutic experience over 10 years. N Engl J Med 1982; 306:68.
- Koss MN, Hochholzer L, Langloss JM, et al. Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients. Pathology 1986; 18:283.
- Wilson WH, Kingma DW, Raffeld M, et al. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood 1996; 87:4531.
- Oren H, Irken G, Kargi A, et al. A pediatric case of lymphomatoid granulomatosis with onset after completion of chemotherapy for acute myeloid leukemia. J Pediatr Hematol Oncol 2003; 25:163.
- Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol 2010; 34:e35.
- Lee JS, Tuder R, Lynch DA. Lymphomatoid granulomatosis: radiologic features and pathologic correlations. AJR Am J Roentgenol 2000; 175:1335.
- Morice WG, Kurtin PJ, Myers JL. Expression of cytolytic lymphocyte-associated antigens in pulmonary lymphomatoid granulomatosis. Am J Clin Pathol 2002; 118:391.
- Lucantoni C, De Bonis P, Doglietto F, et al. Primary cerebral lymphomatoid granulomatosis: report of four cases and literature review. J Neurooncol 2009; 94:235.
- Nishihara H, Tateishi U, Itoh T, et al. Immunohistochemical and gene rearrangement studies of central nervous system lymphomatoid granulomatosis. Neuropathology 2007; 27:413.
- Váróczy L, Gergely L, Szakáll S, Illés A. Angiocentric lymphomatoid granulomatosis and severe hypogammaglobulinaemia. Haematologia (Budap) 2002; 32:535.
- Sebire NJ, Haselden S, Malone M, et al. Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy. J Clin Pathol 2003; 56:555.
- Song JY, Pittaluga S, Dunleavy K, et al. Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations. Am J Surg Pathol 2015; 39:141.
- Katherine Martin L, Porcu P, Baiocchi RA, et al. Primary central nervous system lymphomatoid granulomatosis in a patient receiving azathioprine therapy. Clin Adv Hematol Oncol 2009; 7:65.
- Joseph R, Chacko B, Manipadam MT, et al. Pulmonary lymphomatoid granulomatosis in a renal allograft recipient. Transpl Infect Dis 2008; 10:52.
- Pfistershammer K, Petzelbauer P, Stingl G, et al. Methotrexate-induced primary cutaneous diffuse large B-cell lymphoma with an 'angiocentric' histological morphology. Clin Exp Dermatol 2010; 35:59.
- Kameda H, Okuyama A, Tamaru J, et al. Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis. Clin Rheumatol 2007; 26:1585.
- Yazdi AS, Metzler G, Weyrauch S, et al. Lymphomatoid granulomatosis induced by imatinib-treatment. Arch Dermatol 2007; 143:1222.
- Barakat A, Grover K, Peshin R. Rituximab for pulmonary lymphomatoid granulomatosis which developed as a complication of methotrexate and azathioprine therapy for rheumatoid arthritis. Springerplus 2014; 3:751.
- Oiwa H, Mihara K, Kan T, et al. Grade 3 lymphomatoid granulomatosis in a patient receiving methotrexate therapy for rheumatoid arthritis. Intern Med 2014; 53:1873.
- Connors W, Griffiths C, Patel J, Belletrutti PJ. Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease. BMC Gastroenterol 2014; 14:127.
- Shanti RM, Torres-Cabala CA, Jaffe ES, et al. Lymphomatoid granulomatosis with involvement of the hard palate: a case report. J Oral Maxillofac Surg 2008; 66:2161.
- Pereira AC, Oliveira TM, Nomelini RS, et al. Lymphomatoid granulomatosis of the vulva: case report with immunohistochemical analysis. J Obstet Gynaecol 2009; 29:255.
- Melegh Z, Sutak J, Whiteway A, et al. Lymphomatoid granulomatosis of the uterine cervix. Pathol Res Pract 2009; 205:371.
- Kappen JH, van Zaanen HC, Snelder SM, et al. Lymphomatoid granulomatosis with pulmonary and gastrointestinal involvement. BMJ Case Rep 2017; 2017.
- Mizuno T, Takanashi Y, Onodera H, et al. A case of lymphomatoid granulomatosis/angiocentric immunoproliferative lesion with long clinical course and diffuse brain involvement. J Neurol Sci 2003; 213:67.
- Collins S, Helme RD. Lymphomatoid granulomatosis presenting as a progressive cervical cord lesion. Aust N Z J Med 1989; 19:144.
- Bolaman Z, Kadiköylü G, Polatli M, et al. Migratory nodules in the lung: lymphomatoid granulomatosis. Leuk Lymphoma 2003; 44:197.
- McCloskey M, Catherwood M, McManus D, et al. A case of lymphomatoid granulomatosis masquerading as a lung abscess. Thorax 2004; 59:818.
- Arai H, Oshiro H, Yamanaka S, et al. Grade I lymphomatoid granulomatosis with increased uptake of [18F] fluorodeoxyglucose in positron emission tomography: a case report. J Clin Exp Hematop 2009; 49:39.
- Kawai N, Miyake K, Nishiyama Y, et al. FDG-PET findings of the brain in lymphomatoid granulomatosis. Ann Nucl Med 2006; 20:683.
- Erickson BW, Cripe L, Rieger K, et al. A woman with facial papules and pulmonary nodules. Respiration 2007; 74:471.
- Nichols PW, Koss M, Levine AM, Lukes RJ. Lymphomatoid granulomatosis: a T-cell disorder? Am J Med 1982; 72:467.
- Lipford EH Jr, Margolick JB, Longo DL, et al. Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 1988; 72:1674.
- Medeiros LJ, Peiper SC, Elwood L, et al. Angiocentric immunoproliferative lesions: a molecular analysis of eight cases. Hum Pathol 1991; 22:1150.
- Colby TV. Current histological diagnosis of lymphomatoid granulomatosis. Mod Pathol 2012; 25 Suppl 1:S39.
- James WD, Odom RB, Katzenstein AL. Cutaneous manifestations of lymphomatoid granulomatosis. Report of 44 cases and a review of the literature. Arch Dermatol 1981; 117:196.
- Roschewski M, Wilson WH. Lymphomatoid granulomatosis. Cancer J 2012; 18:469.
- Richter C, Schnabel A, Müller KM, et al. [Lymphomatoid granulomatosis--remission induction with interferon-alpha 2b]. Dtsch Med Wochenschr 1997; 122:1106.
- CLINICAL PRESENTATION
- Symptoms and signs
- Physical examination
- Laboratory studies
- Lung function testing
- Imaging studies
- Genetic features
- DIFFERENTIAL DIAGNOSIS
- NATURAL HISTORY AND PROGNOSIS
- SUMMARY AND RECOMMENDATIONS