Lymphomatoid Granulomatosis

Epidemiology and Etiology:

· rare

· EBV associated

· A minority of cases are variants of peripheral T cell lymphoma not associated with EBV

· Immunodeficiency associated

· Allogeneic organ transplantation

· Wiskott-Aldrich syndrome

· HIV infection

· X-linked lymphoproliferatie syndrome

· Spectrum of histologic grade and clinical aggressiveness related to proportion of large B cells

· May be hard to differentiate from T cell rich B cell lymphoma

· Wide age range

· Mean 50-60y

· children and adolescents with immunodeficiency disorders

· M:F >= 2:1

· Western > Asia

Common sites:

· Extranodal

· Lungs (>90%)

· CNS (26%)

· Kidney (32%)

· Liver (29%)

· Skin (25-50%)

· Peripheral nerve

· URT uncommon

· GI tract uncommon

Gross features:

· Multiple pulmonary nodules usually mistaken for mets

· Vary in size

· Bilateral usually

· Mid to lower lung fields

· Central necrosis in larger nodules frequently – may cavitate

· Solitary mass maybe

· Diffuse pneumonia-like infiltrates maybe

· Diverse skin lesions

· Subcutaneous nodules

· Dermal involvement sometimes with necrosis and ulceration

· Plaques or a maculopaupular rash less commonly

Histologic features:

· Polymorphic infiltrate

· Lymphocytes predominantly

· Heavy reactive T cell response

· CD4 > CD8

· Similar to post-transplant immunoproliferative lesions

· Variable (usually small) number of EBV-positive B cells

· Variable morphology

· Some atypia usually

· Resembling immunoblasts maybe

· Pleomorphic reminiscent of Hodgkin cells less commonly

· Classical Reed-Sternberg cells generally not present

· Multinucleated forms maybe

· Plasma cells

· immunoblasts

· histiocytes

· inconspicuous neutrophils and eosinophils

· Lymphocytic vasculitis is hallmark

· Transmural invasion

· Occlusion of vessels maybe

· Infarct-like tissue necrosis maybe

· Fibrinoid necrosis (like Wegener) is also common

· Geographic necrosis maybe

· No well-formed granulomas typically in most sites

· Skin lesions often exhibit prominent granulomatous reaction in subcutaneous tissue

· Grading:

· Proportion of EBV-positive B cells relative to the reactive lymphocyte background

· Most important to distinguish grade 3 from grade 1 or 2

· Uniform population of large atypical EBV-positive B cells without a polymorphous background should be classified as diffuse large B-cell lymphoma

· Grade 1:

· Polymorphous lymphoid infiltrate

· No cytologic atypia

· Large transformed lymphoid cells absent or rare

· Better appreciated by immunohistochemistry

· Necrosis focal when present

· Only infrequent EBV-positve cells are identified by EBER (< 5 per HPF)

· May be absent in some cases (rule out other inflammatory or neoplastic conditions)

· Grade 2:

· Occasional large lymphoid cells or immunoblasts in a polymorphous background

· Small clusters can be seen by CD20

· Necrosis more commonly seen

· EBER readily identifies EBV-positive cells (5-20 per HPF, up to 50 within a nodule)

· Grade 3:

· Inflammatory background still

· Large atypical B cells readily identified by CD20, can form larger aggregates

· Markedly pleomorphic and Hodgkin like cells often

· Necrosis extensive usually

· EVB+ cells extremely numerous (> 50 / HPF)

· Focally may form small confluent sheets

Immunophenotype and special stains:

Marker:	Sensitivity:	Specificity:
CD20
EBER
CD30	Variable
CD15 (neg)
LMP1 (large, atypical, pleomorphic cells)	Maybe
Kappa / lambda (noninformative typically)

Molecular features:

· Clonal immunoglobulin gene rearrangements in most grade 2 and 3 cases

· Different clonal populations in different anatomic sites in some cases

· Grade 1 more inconsistent

· May be related to relative rarity of EBV-positive cells

· Some may be polyclonal?

· Clonality of EBV by southern blot maybe

· TCR gene analysis no evidence of monoclonality

Other features:

· Clinical

· Fever

· Cough & other respiratory tract symptoms

· SOB

· Chest pain

· Weight loss

· Hemoptysis

· CNS symptoms depending on the site

· Aggressive in most patient

· Median survival < 2 y.

· Waxing and waning course in some

· Rare spontaneous remissions without therapy

· Response to aggressive chemo with rituximab for grade 3 lesions

· Grade 1 and 2 usually respond to interferon-alpha 2b

· May progress to EBV+ DLBCL

· Grade 3 lesions should be approached as DLBCL for clinical purposes

References:

· Silverberg SG, DeLellis RA, Frable WJ, LiVolsi VA, Wick MR. Silverberg's Principles and Practice of Surgical Pathology and Cytopathology: 2-Volume Set. 4th ed. Churchill Livingstone; 2005.

· WHO blue book (2008)