Lymphomatoid granulomatosis

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Lymphomatoid granulomatosis
SpecialtyHematology and oncology

Lymphomatoid granulomatosis (LYG or LG) is a very rare lymphoproliferative disorder first characterized in 1972.[1] Lymphomatoid means lymphoma-like and granulomatosis denotes the microscopic characteristic of the presence of granulomas with polymorphic lymphoid infiltrates and focal necrosis within it.

LG most commonly affects middle aged people,[2] but has occasionally been observed in young people.[3] Males are found to be affected twice as often as females.[4]

Symptoms and signs

Presentation entails skin lesions such as -erythematous, macules, papules.The condition also affects the lungs, hence cough, shortness of breath is present.[5]


Lymphomatoid granulomatosis involves malignant B cells and reactive, non-malignant T cells and is almost always associated with infection of the malignant B cells by the Epstein-Barr virus; it is therefore considered to be a form of the Epstein-Barr virus-associated lymphoproliferative diseases.[6] The disease is believed to be induced by a combination of Epstein Barr virus infection and immunosuppression through immunosuppressive drugs (with case reports of methotrexate[7][8][9][10][11][12][13][14][15] and azathioprine[16][17]), infections such as HIV or chronic viral hepatitis or endogenous T cell defects.[18]


The onset of the disease results in proliferation of EBV-infected malignant B-cells and a cytotoxic T-cell response which in turn leads to organ infiltration and dysfunction of the affected organs. The disease typically always relapse after successful treatment due to inability of the immune system and current viral drugs to eliminate an EBV-infection. If the onset of the disease can be linked to use of immunosuppressive drugs then discontinuation of these drugs may hinder a relapse. Organs usually affected are the skin, lungs, central nervous system while liver and kidney are affected to lesser extent. The pulmonary complications are usually what leads to death, however, CNS involvement that affects up to one third of the patients can be very severe with mental status changes, ataxia, hemiparesis, seizures, unconsciousness and death, typically followed in that order.[18]

The disease has been seen to transform to diffuse large B-cell lymphoma[19] and while LG is graded I-III based on the number of large EBV-positive B-cells, grade II and III can be considered as a variant of T-cell rich diffuse large B-cell lymphoma.[4][20]


Treatment depends on the grade (I-III) but typically consist of cortisone, rituximab and chemotherapy (etoposide, vincristine, cyclophosphamide, doxorubicin). Methotrexate has been seen to induce LG.[7][8] Interferon alpha has been used by the US National Cancer Institute with varying results.[21] In recent years hematopoietic stem cell transplantation has been performed on LG-patients with relative good success; a 2013 study identifying 10 cases found that 8 patients survived the treatment and were disease free several years later. Two of the disease free patients later died, one from suicide and one from graft versus host disease after a second transplantation 4 years later. The remaining two patients died from sepsis after the transplantation.[22]


The current mortality is over 60% after 5 years. However, due to hematopoietic stem cell transplantation being performed only in recent years, this number could potentially be lowered in the future. In people with CNS involvement, treatment with Interferon alpha at the US National Cancer Institute resulted in complete remission in 90% of patients.[21]

See also


  1. Liebow, Averill A.; Carrington, Charles R.B.; Friedman, Paul J. (1972). "Lymphomatoid granulomatosis". Human Pathology. 3 (4): 457–558. doi:10.1016/S0046-8177(72)80005-4. PMC 1518397. PMID 4638966.
  2. Song, Joo Y.; Pittaluga, Stefania; Dunleavy, Kieron; Grant, Nicole; White, Therese; Jiang, Liuyan; Davies-Hill, Theresa; Raffeld, Mark; Wilson, Wyndham H.; Jaffe, Elaine S. (2015). "Lymphomatoid Granulomatosis—A Single Institute Experience". The American Journal of Surgical Pathology. 39 (2): 141–56. doi:10.1097/PAS.0000000000000328. PMC 4293220. PMID 25321327.
  3. Tacke, Zwanique C. A.; Eikelenboom, M. Judith; Vermeulen, R. Jeroen; Van Der Knaap, Marjo S.; Euser, Anne M.; Van Der Valk, Paul; Kaspers, Gertjan J. L. (2014). "Childhood Lymphomatoid Granulomatosis: A Report of 2 Cases and Review of the Literature". Journal of Pediatric Hematology/Oncology. 36 (7): e416–22. doi:10.1097/MPH.0000000000000090. PMID 24390446.
  4. 4.0 4.1 Katzenstein, Anna-Luise A.; Doxtader, Erika; Narendra, Sonia (2010). "Lymphomatoid Granulomatosis". The American Journal of Surgical Pathology. 34 (12): e35–48. doi:10.1097/PAS.0b013e3181fd8781. PMID 21107080.
  5. "Lymphomatoid Granulomatosis". NORD (National Organization for Rare Disorders). Archived from the original on 18 March 2021. Retrieved 5 July 2021.
  6. Rezk SA, Zhao X, Weiss LM (September 2018). "Epstein-Barr virus (EBV)-associated lymphoid proliferations, a 2018 update". Human Pathology. 79: 18–41. doi:10.1016/j.humpath.2018.05.020. PMID 29885408.
  7. 7.0 7.1 Ochi, N.; Yamane, H.; Yamagishi, T.; Monobe, Y.; Takigawa, N. (2013). "Methotrexate-Induced Lymphoproliferative Disease: Epstein-Barr Virus-Associated Lymphomatoid Granulomatosis". Journal of Clinical Oncology. 31 (20): e348–50. doi:10.1200/JCO.2012.46.2770. PMID 23733760.
  8. 8.0 8.1 Blanchart, K; Paciencia, M; Seguin, A; Chantepie, S; Du Cheyron, D; Charbonneau, P; Galateau-Salle, F; Terzi, N (2014). "Fatal pulmonary lymphomatoid granulomatosis in a patient taking methotrexate for rheumatoid arthritis". Minerva Anestesiologica. 80 (1): 119–20. PMID 23857444. Archived from the original on 2021-08-28. Retrieved 2021-01-13.
  9. Oiwa, Hiroshi; Mihara, Keichiro; Kan, Takanobu; Tanaka, Maiko; Shindo, Hajime; Kumagai, Kazuhiko; Sugiyama, Eiji (2014). "Grade 3 Lymphomatoid Granulomatosis in a Patient Receiving Methotrexate Therapy for Rheumatoid Arthritis". Internal Medicine. 53 (16): 1873–5. doi:10.2169/internalmedicine.53.2593. PMID 25130128.
  10. Yamakawa, T; Kurosawa, M; Yonezumi, M; Suzuki, S; Suzuki, H (2014). "メトトレキサート中止と脳病変への放射線照射が奏効したメトトレキサート関連リンパ腫様肉芽腫症" [Methotrexate-related lymphomatoid granulomatosis successfully treated with discontinuation of methotrexate and radiotherapy to brain]. Rinsho Ketsueki (in 日本語). 55 (3): 321–6. doi:10.11406/rinketsu.55.321. PMID 24681935.
  11. Kobayashi, Shinichi; Kikuchi, Yuichi; Sato, Kimiya; Matsukuma, Susumu; Matsuki, Yasunori; Horikoshi, Hideyuki; Nagumo, Morichika; Kobayashi, Ayako; Masuoka, Kazuhiro; Kimura, Fumihiko; Oshima, Satoshi; Hakozaki, Yukiya; Kondo, Toshiro (2013). "Reversible iatrogenic, MTX-associated EBV-driven lymphoproliferation with histopathological features of a lymphomatoid granulomatosis in a patient with rheumatoid arthritis". Annals of Hematology. 92 (11): 1561–4. doi:10.1007/s00277-013-1741-1. PMID 23529185.
  12. Inaba, M; Ushijim, S; Hirata, N; Saisyoji, T; Kitaoka, M; Yoshinaga, T (2011). "Methotrexate-related lymphomatoid granulomatosis in a patient with rheumatoid arthritis". Nihon Kokyuki Gakkai Zasshi. 49 (8): 597–601. PMID 21894776.
  13. Schalk, Enrico; Krogel, Christian; Scheinpflug, Katrin; Mohren, Martin (2009). "Lymphomatoid Granulomatosis in a Patient with Rheumatoid Arthritis Receiving Methotrexate: Successful Treatment with the Anti-CD20 Antibody Mabthera". Onkologie. 32 (7): 440–1. doi:10.1159/000218356. PMID 19556825.
  14. Shimada, K.; Matsui, T.; Kawakami, M.; Nakayama, H.; Ozawa, Y.; Mitomi, H.; Tohma, S. (2007). "Methotrexate‐related lymphomatoid granulomatosis: A case report of spontaneous regression of large tumours in multiple organs after cessation of methotrexate therapy in rheumatoid arthritis". Scandinavian Journal of Rheumatology. 36 (1): 64–7. doi:10.1080/03009740600902403. PMID 17454938.
  15. Kameda, Hideto; Okuyama, Ayumi; Tamaru, Jun-Ichi; Itoyama, Shinji; Iizuka, Atsushi; Takeuchi, Tsutomu (2007). "Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis". Clinical Rheumatology. 26 (9): 1585–9. doi:10.1007/s10067-006-0480-2. PMID 17200802.
  16. Barakat, Athar; Grover, Karan; Peshin, Rohit (2014). "Rituximab for pulmonary lymphomatoid granulomatosis which developed as a complication of methotrexate and azathioprine therapy for rheumatoid arthritis". SpringerPlus. 3: 751. doi:10.1186/2193-1801-3-751. PMC 4320142. PMID 25674479.
  17. Connors, William; Griffiths, Cameron; Patel, Jay; Belletrutti, Paul J (2014). "Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease". BMC Gastroenterology. 14: 127. doi:10.1186/1471-230X-14-127. PMC 4105046. PMID 25022612.
  18. 18.0 18.1 Roschewski, Mark; Wilson, Wyndham H. (2012). "Lymphomatoid Granulomatosis". The Cancer Journal (Submitted manuscript). 18 (5): 469–74. doi:10.1097/PPO.0b013e31826c5e19. PMID 23006954. Archived from the original on 2021-08-28. Retrieved 2021-01-13.
  19. Boone, J. M.; Zhang, D; Fan, F (2013). "Lymphomatoid granulomatosis: A case report with unique clinical and histopathologic features". Annals of Clinical and Laboratory Science. 43 (2): 181–5. PMID 23694794. Archived from the original on 2021-08-28. Retrieved 2021-01-13.
  20. Tagliavini, E; Rossi, G; Valli, R; Zanelli, M; Cadioli, A; Mengoli, M. C.; Bisagni, A; Cavazza, A; Gardini, G (2013). "Lymphomatoid granulomatosis: A practical review for pathologists dealing with this rare pulmonary lymphoproliferative process" (PDF). Pathologica. 105 (4): 111–6. PMID 24466760. Archived from the original (PDF) on 2017-05-10. Retrieved 2021-01-13.
  21. 21.0 21.1 Dunleavy, Kieron; Roschewski, Mark; Wilson, Wyndham H. (2012). "Lymphomatoid Granulomatosis and Other Epstein-Barr Virus Associated Lymphoproliferative Processes". Current Hematologic Malignancy Reports (Submitted manuscript). 7 (3): 208–15. doi:10.1007/s11899-012-0132-3. PMC 6317897. PMID 22814713. Archived from the original on 2021-08-28. Retrieved 2021-01-13.
  22. Siegloch, Kristina; Schmitz, Norbert; Wu, Huei-Shan; Friedrichs, Birte; Van Imhoff, Gustaaf W.; Montoto, Silvia; Holler, Ernst; Ribera, Josep Maria; Delage, Robert; Dührsen, Ulrich; Castillo, Nerea del; Harrison, Beth; Dreger, Peter; Sureda, Anna; Working Party Lymphoma of the European Group for Blood Marrow Transplantation (EBMT) (2013). "Hematopoietic Stem Cell Transplantation in Patients with Lymphomatoid Granulomatosis: A European Group for Blood and Marrow Transplantation Report". Biology of Blood and Marrow Transplantation. 19 (10): 1522–5. doi:10.1016/j.bbmt.2013.07.023. PMID 23948061.

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