Majority (>90%) subjects depict pulmonary lesions. Besides, lesions may appear within the brain, renal parenchyma, hepatic parenchyma and cutaneous surfaces. Uncommonly, upper respiratory tract and gastrointestinal tract may be implicated. Exceptionally, regional lymph nodes and spleen may demonstrate the neoplasm [1,2]. Lymphomatoid granulomatosis expounds a preponderance of T lymphocytes and was initially contemplated to configure as a T cell disorder. Subsequently, lymphomatoid granulomatosis was posited to represent as a B cell lymphoproliferative disorder arising secondary to Epstein Barr virus (EBV) infection associated with prominent T cell infiltrate with angiocentric dissemination [1,2]. Lymphomatoid granulomatosis is postulated to be concordant with immune function of the host along with defective immune surveillance of Epstein Barr virus (EBV) infected B cells, especially functional derangement of CD8+ cytotoxic T cells. Pertinent immunological deficits may pre-exist and quantitative or qualitative disorder within CD8+ cytotoxic T cells appears as a prerequisite for disease emergence [1,2]. Majority of grade II and III neoplasms exhibit clone specific immunoglobulin (IG) genes. However, clone specificity of grade I tumours may be minimally consistent, in contrast to grade II neoplasms. Few lesions of lymphomatoid granulomatosis appear polyclonal. T cell receptor (TCR) genes appear non concurrent to clonal distinction.

Lymphomatoid granulomatosis may simulate lymphoproliferative disorder induced by Epstein Barr virus (EBV) infection. Neoplasm may commonly appear within immunodeficiency states as autoimmune deficiency syndrome (AIDS), allogenic organ transplant, Wiskott-Aldrich syndrome or X linked lymphoproliferative syndrome. Mature B lymphocytes transformed by EBV may concur [2,3].

Commonly, lymphomatoid granulomatosis represents with cough, dyspnoea and chest pain. Besides, pyrexia, malaise, loss of weight, neurological symptoms, arthralgia, myalgia or gastrointestinal symptoms may be observed [2,3]. Central nervous system disease is accompanied by symptoms as diplopia, deafness, dysarthria, ataxia or altered mental status. Asymptomatic lesions may concur. Cutaneous lesions as subcutaneous nodules, dermal nodules, maculopapular eruptions, macular erythema or ulcerations may be painful [2,3].

Grossly, lesions confined to pulmonary parenchyma are preponderantly nodular and emerge within middle and inferior pulmonary fields. The lesions may exhibit centric necrosis and cavitation. Lesions confined to brain or renal parenchyma appear nodular and demonstrate centric necrosis [3,4]. Cutaneous lesions appear as nodules within subcutaneous tissue to dermal ulcers with necrosis. Occasionally, plaques or maculopapular rash-like presentation may ensue [3,4].

Upon microscopy, tumefaction is comprised of polymorphous lymphoid infiltrate with angiocentric and angio-destructive predilection. Foci of lymphocytic vasculitis demonstrate infiltration of vascular articulations with infarct-like tissue necrosis or fibrinoid necrosis of vessel wall. The polymorphous infiltrate is preponderantly comprised of small, mature lymphocytes commingled with plasma cells, immunoblasts and histiocytes. Intervening small lymphocytes may depict atypia although significant neoplastic alterations appear absent [3,4]. Lesions of lymphomatoid granulomatosis demonstrate quantifiably variable B cells immune reactive to Epstein Barr virus (EBV) intermingled with inflammatory cell component. EBV+ B cells simulate immunoblasts or appear as multinucleated cells. The B cell lymphocytic component may depict cellular and nuclear atypia. Classic Reed Sternberg cells appear to be lacking. Characteristically, lesion is devoid of well-formed granulomas, especially within pulmonary parenchyma and majority of extra-nodal sites. However, precise granulomatous reactions may ensue within the subcutaneous tissue [3,4]. Lymphomatoid granulomatosis may be graded contingent to quantifiably specific EBV+ B cells concordant to intermingled reactive lymphocytes which is designated as ~grade I comprised of EBV+ B cells < 5 per high power field with absent to exceptional enlarged, transformed cells on light microscopy. Focal necrosis may be present ~grade II comprised of EBV+ B cells varying from 5 cells to 50 cells per high power field. Few enlarged, transformed cells may be discerned upon light microscopy. Tumour necrosis is common ~grade III comprised of EBV+ B cells > 50 cells per high power field. Enlarged, transformed cells are frequently observed upon light microscopy. Enlarged zones of tumour necrosis are commonly observed [3,4].

Figure 1: Lymphomatoid Granulomatosis Depicting a Polymorphous Population of B Lymphocytes, Immunoblasts, Plasma Cells and Few Histiocytes. Reed Sternberg Cells are Absent. Focal Areas of Necrosis and Haemorrhage are Observed [7].

Figure 2 : Lymphomatoid Granulomatosis Delineating a Polymorphous Population of B Lymphocytes, Immmunoblasts, Plasma Cells and Few Histicoytes. Reed Sternberg Cells are Absent. Few Ill Formed Granulomas are Observed. Superimposed Stratified Squamous Epithelium Demonstrates Mild Acanthosis and Hyperkeratosis [8].

Table: Differentiation between Progressive Transformation of Germinal Centres and Lymphomas with Large Nodules [3,4].

PTGC: Progressively transformed germinal centre, RFH: Reactive follicular hyperplasia, GC: Germinal centre, HRS: Hodgkin’s Reed Sternberg, LP: Lymphocyte predominant, EMA: Epithelial membrane antigen.

B cell component of lymphomatoid ganulomatosis appears immune reactive to CD20, Epstein Barr virus (EBV), latent membrane protein 1(LMP1), Epstein Barr encoding region (EBER) and variably immune reactive to CD30. As encountered with latency type III, Epstein Barr virus nuclear antigen 2(EBNA2) appears immune reactive. Intervening T cells appear immune reactive to CD3, CD4 and CD8. Tumour cells appear immune non-reactive to CD15 [5,6]. Lymphomatoid granulomatosis requires distinction from neoplasms as polymorphous variant of EBV+ diffuse large B cell lymphoma, extra-nodal NK/T cell lymphoma, classic Hodgkin’s lymphoma (CHL), nodular lymphocyte predominant Hodgkin’s lymphoma(NLPHL) and polymorphous lymphoid infiltration associated with immunodeficiency or organ transplant [5,6].

Neoplasm may be appropriately discerned upon assessment of morphological features on light microscopy and cogent immunohistochemistry or in situ hybridization for Epstein Barr virus (EBV) coded small ribonucleic acids (RNAs) (EBER) [5,6]. Upon plain radiography, singular or multiple tumour nodules with inadequately defined perimeter may be discerned. Computerized tomography (CT) expounds well demarcated and inadequately defined tumour nodules disseminated within bilateral pulmonary parenchyma [5,6]. Low grade lymphomatoid granulomatosis may be subjected to primary therapy with interferon alpha (IFN-α). High grade lymphomatoid granulomatosis may be managed with primary therapy of dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) every 3 weeks for a period of up to 6 cycles [5,6].

Prognostic outcomes of the exceptionally encountered lymphomatoid granulomatosis may be challenging to ascertain [5,6].

1. Ghenbot Y, Arena J, Howard S, Wathen C, Dagli MM, Zadnik P, et al. Isolated Lymphomatoid Granulomatosis of the Central Nervous System Mimicking Trigeminal Neuropathy, Bell's Palsy, and Glioblastoma in an Epstein-Barr-Negative Immunocompetent Host: A Case Report. Cureus. 2023; 15: e45309.
2. Chen D, Zhou J, Lu W, Lu L, Chen B, Li W. Lymphomatoid granulomatosis with the central nervous system involvement as the main manifestation: a case report. BMC Neurol. 2023; 23: 208.
3. So M, Shachi T, Mudd J, Miyakawa L, Kim B. Pulmonary lymphomatoid granulomatosis in a patient with long-term use of a tumour necrosis factor-α inhibitor. BMJ Case Rep. 2023; 16: e254211.
4. Sarfraz S, Wali RM, Jameel M. Lymphomatoid Granulomatosis: A Case Report and Literature Review of a Rare Pediatric Disorder from Pakistan. J Pediatr Hematol Oncol. 2023; 45: e927-e930.
5. Patel D, Rinehart R, Abraham RG. A Case of Lymphomatoid Granulomatosis in a Lymph Node with Unique Clinical and Histopathologic Features. Am J Case Rep. 2022; 23: e936862.
6. Melani C, Dowdell K, Pittaluga S, Dunleavy K, Roschewski M, Song JY, et al. Interferon alfa-2b in patients with low-grade lymphomatoid granulomatosis and chemotherapy with DA-EPOCH-R in patients with high-grade lymphomatoid granulomatosis: an open-label, single-centre, phase 2 trial. Lancet Haematol. 2023; 10: e346-e358.
7. Image 1 Courtesy: Dermatology advisor
8. Image 2 Courtesy: Basic medical key