Lymphomatoid granulomatosis is a rare Epstein-Barr virus-driven B-cell lymphoproliferative disease in which EBV-positive atypical B cells accumulate in extranodal tissue - always the lung, often skin, central nervous system, liver and kidney - inside a dense, angiocentric and angiodestructive reactive T-cell infiltrate. Nodal and bone marrow involvement is so rare that finding it argues for a different diagnosis. The disease is understood as a failure of EBV immunosurveillance rather than as a conventional oncogenic-driver malignancy: no recurrent chromosomal lesion has been identified, patients have measurably depressed circulating T cells with the deficit falling mainly on the CD8-positive compartment, and the vascular damage and necrosis that give the disease its name are attributed to the host response to EBV rather than to the neoplastic cells. Histologic grade, defined by the number and density of EBV-positive atypical B cells, tracks clonality and is the axis on which treatment turns: low-grade disease is treated as immune-dependent with interferon alfa-2b, high-grade disease as immune-independent with chemoimmunotherapy.
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Conditions with similar clinical presentations that must be differentiated from Lymphomatoid Granulomatosis:
name: Lymphomatoid Granulomatosis
creation_date: "2026-08-29T16:00:00Z"
category: Cancer
categories:
- Hematologic Malignancy
- B-cell Neoplasm
- EBV-Associated Lymphoproliferative Disorder
synonyms:
- LYG
- angiocentric immunoproliferative lesion
- Liebow granulomatosis
description: >-
Lymphomatoid granulomatosis is a rare Epstein-Barr virus-driven B-cell
lymphoproliferative disease in which EBV-positive atypical B cells accumulate
in extranodal tissue - always the lung, often skin, central nervous system,
liver and kidney - inside a dense, angiocentric and angiodestructive reactive
T-cell infiltrate. Nodal and bone marrow involvement is so rare that finding
it argues for a different diagnosis. The disease is understood as a failure of
EBV immunosurveillance rather than as a conventional oncogenic-driver
malignancy: no recurrent chromosomal lesion has been identified, patients have
measurably depressed circulating T cells with the deficit falling mainly on
the CD8-positive compartment, and the vascular damage and necrosis that give
the disease its name are attributed to the host response to EBV rather than to
the neoplastic cells. Histologic grade, defined by the number and density of
EBV-positive atypical B cells, tracks clonality and is the axis on which
treatment turns: low-grade disease is treated as immune-dependent with
interferon alfa-2b, high-grade disease as immune-independent with
chemoimmunotherapy.
disease_term:
preferred_term: lymphomatoid granulomatosis
term:
id: MONDO:0019466
label: lymphomatoid granulomatosis
mappings:
mondo_mappings:
- term:
id: MONDO:0019466
label: lymphomatoid granulomatosis
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: Primary MONDO disease identifier for this entry.
parents:
- Epstein-Barr virus-associated lymphoproliferative disorder
- Diffuse large B-cell lymphoma
classifications:
harrisons_chapter:
- classification_value: ONCOLOGY_HEMATOLOGY
notes: >-
A WHO-recognised mature B-cell neoplasm whose management is grade-stratified
lymphoma therapy.
- classification_value: RESPIRATORY
notes: >-
The lung is involved in essentially every patient and is the usual biopsy
site.
icdo_morphology:
classification_value: Lymphoma
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease (LPD)."
explanation: >-
Places LYG in the B-cell lymphoproliferative family, supporting the
ICD-O lymphoma morphology bucket.
infectious_agent:
- name: Epstein-Barr virus
description: >-
EBV is present in the atypical B cells in essentially every case and is
treated as the transforming agent rather than a bystander. Patients have
serologic evidence of past exposure but not of acute infection, and the
measured viral load is low - the abnormality is control of a common latent
infection, not an unusual exposure.
infectious_agent_term:
preferred_term: Epstein-Barr virus
term:
id: NCBITaxon:10376
label: human gammaherpesvirus 4
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients had past EBV exposure by serology but with a low median EBV viral load."
explanation: >-
Shows that the relevant abnormality is EBV control rather than an acute or
high-burden infection.
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease (LPD). This disease is hypothesized to result from defective immune surveillance of EBV, with most patients showing evidence of immune dysfunction, despite no known primary immunodeficiency."
explanation: >-
States both the causal role of EBV and the immune-surveillance model this
entry is built around.
has_subtypes:
- name: Grade 1
display_name: Grade 1 (low grade)
description: >-
Polymorphous infiltrate with rare atypical medium-to-large lymphoid cells and
a paucity of EBV-positive cells, fewer than five per high-power field.
Necrosis is focal or absent and the infiltrate is usually polyclonal - only
about 8% of grade 1 lesions carry a clonal immunoglobulin rearrangement. This
is the grade treated as immune-dependent, and the grade hardest to diagnose
because the EBV-positive cells can be sparse or absent.
subtype_term:
preferred_term: grade I lymphomatoid granulomatosis
term:
id: MONDO:0859747
label: grade I lymphomatoid granulomatosis
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunoglobulin gene rearrangement studies were performed, and a higher percentage of clonal rearrangements were seen in LYG grade 2 (50%) and grade 3 (69%) as compared with grade 1 (8%)."
explanation: >-
Gives the grade 1 clonality figure that distinguishes it from the higher
grades.
- name: Grade 2
display_name: Grade 2 (low grade)
description: >-
More numerous large atypical cells, sometimes reminiscent of
Hodgkin/Reed-Sternberg cells, with near-universal EBER positivity at five to
twenty cells per high-power field and more necrosis than grade 1. Half of
grade 2 lesions are clonal. Grouped with grade 1 as low-grade,
immune-dependent disease for treatment purposes.
subtype_term:
preferred_term: grade II lymphomatoid granulomatosis
term:
id: MONDO:0859748
label: grade II lymphomatoid granulomatosis
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "In accordance with the World Health Organization classification, grade 1 lesions were associated with rare atypical medium-to-large lymphoid cells, whereas a greater number of large atypical cells, occasionally reminiscent of Hodgkin/Reed-Sternberg cells, were frequently seen in grade 2 and 3 lesions."
explanation: >-
Describes the cytologic difference between grade 1 and the higher grades.
- name: Grade 3
display_name: Grade 3 (high grade)
description: >-
Sheets of large atypical EBV-positive B cells, more than fifty and often more
than a hundred per high-power field, with extensive coagulative necrosis.
About 69% are clonal. This grade behaves as, and is treated as, an aggressive
EBV-positive large B-cell lymphoma - immune-independent disease.
subtype_term:
preferred_term: grade III lymphomatoid granulomatosis
term:
id: MONDO:0859749
label: grade III lymphomatoid granulomatosis
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "In contrast, near universal expression of EBER was seen in grade 2 (5-20 and occasionally up to 50 cells per high-power field) and grade 3 (>50 and often >100 cells per high power field) lesions"
explanation: >-
Gives the EBER density thresholds that define grade 2 and grade 3.
prevalence:
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: ULTRA_RARE
notes: >-
No incidence or prevalence estimate has been published. Cohort size is the
only available proxy: the largest single-institution pathology series covers
55 patients referred to one national centre over 15 years, and the pivotal
prospective trial accrued 67 patients over 28 years.
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We reviewed the biopsies of 55 patients with LYG who were referred for a prospective trial at the National Cancer Institute (1995 to 2010) and evaluated the histologic, immunohistochemical, in situ hybridization, and molecular findings of these biopsies in conjunction with clinical information."
explanation: >-
Establishes the scale of the largest available series, which is the only
quantitative handle on how rare the disease is.
progression:
- phase: Untreated or steroid-treated natural history
notes: >-
Historically poor. Before grade-stratified therapy, patients treated with
steroids and/or chemotherapy had a median survival of about 14 months, and
median overall survival across the disease was under two years.
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In regards to treatment, historical outcomes of patients treated with steroids and/or chemotherapy have been poor (median survivals of 14 months)"
explanation: >-
Gives the historical median survival figure for the pre-stratification era.
- reference: PMID:37011643
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Lymphomatoid granulomatosis is a rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder with a median overall survival of less than 2 years."
explanation: >-
The trial's own statement of the survival baseline it set out to improve.
- phase: Grade transformation in both directions
notes: >-
Grade is not a fixed property of a patient. Low-grade disease can progress to
high-grade disease after immune modulation, and high-grade disease can recur
as low-grade disease after immunochemotherapy. Both directions are managed by
crossing over to the other arm of therapy, which is a direct clinical
consequence of the shared underlying defect in EBV surveillance.
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Given the underlying defective immune surveillance of EBV, patients with high-grade disease may have a recurrence in the form of low-grade disease after immunochemotherapy, and those with low-grade disease may progress to high-grade disease after immune modulation, which can be effectively managed with crossover treatment."
explanation: >-
States the bidirectional grade shift and its mechanistic explanation.
- phase: Progression to overt EBV-positive lymphoma or organ failure
notes: >-
Without recognition and grade-appropriate treatment the disease can progress
to pulmonary failure, central nervous system disease, or frank EBV-positive
lymphoma.
evidence:
- reference: PMID:23006954
reference_title: "Lymphomatoid granulomatosis."
supports: SUPPORT
evidence_source: OTHER
snippet: "Lymphomatoid granulomatosis can lead to progressive pulmonary failure, central nervous system disease, or progression to overt EBV-positive lymphoma without appropriate recognition and management."
explanation: >-
Names the three endpoints of untreated progression.
pathophysiology:
- name: Defective EBV Immunosurveillance
biological_scale: ORGANISM
conforms_to: "viral_oncogenesis#Persistent Oncogenic Virus Infection"
description: >-
Latent EBV, carried by most of the adult population, escapes control in a
host whose cell-mediated surveillance of EBV-infected B cells is
quantitatively or qualitatively impaired. Every patient treated at the
reporting national centre had moderately to severely reduced circulating
CD3-positive T cells with the deficit falling more heavily on the
CD8-positive compartment, and none had a recognised primary immunodeficiency
- so the defect is inferred to be pre-existing and subtle rather than
syndromic. Recognised syndromic and iatrogenic causes of the same defect
exist and predispose to the disease.
cell_types:
- preferred_term: CD8-positive, alpha-beta T cell
term:
id: CL:0000625
label: CD8-positive, alpha-beta T cell
biological_processes:
- preferred_term: viral latency
modifier: INCREASED
term:
id: GO:0019042
label: viral latency
- preferred_term: T cell mediated immunity
modifier: DECREASED
term:
id: GO:0002456
label: T cell mediated immunity
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Taken together, these results suggest that the immunologic deficits are likely preexistent and that a quantitative and/or qualitative defect in mainly CD8+cytotoxic T cells may be a prerequisite for disease."
explanation: >-
States the CD8-centred surveillance defect and its position upstream of
disease.
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "More recently, it has been hypothesized that patients with LYG have defective immune surveillance of EBV-infected B cells particularly by the CD8-positive T cells"
explanation: >-
Independent statement of the same model from the pathology series.
downstream:
- target: Outgrowth of EBV-Positive Atypical B Cells
description: >-
Loss of cytotoxic control permits EBV-infected B cells to expand rather
than be cleared.
- name: Outgrowth of EBV-Positive Atypical B Cells
biological_scale: CELLULAR
description: >-
EBV-infected B cells expressing latent viral proteins proliferate and
accumulate in extranodal tissue. Their number and density per high-power
field is precisely what histologic grade measures, so this node is the one
the grading system quantifies. Nodal and bone marrow compartments are spared,
which is one of the features that separates the disease from other
EBV-positive B-cell lymphoproliferations.
cell_types:
- preferred_term: EBV-positive atypical B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
locations:
- preferred_term: lung
term:
id: UBERON:0002048
label: lung
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Pathologically, LYG is graded by the number and density of EBV+ atypical B cells, and other characteristic findings include an angioinvasive/angiodestructive reactive T-cell infiltrate and various degrees of necrosis."
explanation: >-
Identifies the EBV-positive atypical B-cell population as the graded
quantity.
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Clinically, LYG universally involves the lungs with other common extranodal sites, including skin, central nervous system, liver, and kidneys. Nodal and/or bone marrow involvement is extremely rare and, if present, suggests an alternative diagnosis."
explanation: >-
Establishes the extranodal distribution and the diagnostic weight of nodal
sparing.
downstream:
- target: Ineffective Angiocentric Reactive T-cell Response
description: >-
The expanding EBV-positive population recruits a large but ineffective
reactive T-cell infiltrate.
- target: Clonal Selection and High-Grade Transformation
description: >-
Continued proliferation under persistent immune failure selects for
transformed clones.
- name: Ineffective Angiocentric Reactive T-cell Response
biological_scale: TISSUE
description: >-
A dense reactive T-cell infiltrate, CD4-predominant rather than CD8, gathers
around and invades vessel walls without clearing the EBV-positive B cells.
The interferon-inducible chemokines CXCL9 and CXCL10 localise to reactive
cells in viable tissue at the edge of necrotic areas rather than to the
malignant cells, which is the basis for attributing the vascular damage to
the host response rather than to the tumour. The vascular injury is
angiocentric and angiodestructive but is not a primary vasculitis - the
vessel wall is damaged by lymphocytic invasion, not by an immune-mediated
attack on the wall itself.
cell_types:
- preferred_term: CD4-positive, alpha-beta T cell
term:
id: CL:0000624
label: CD4-positive, alpha-beta T cell
biological_processes:
- preferred_term: chemokine-mediated signaling pathway
modifier: INCREASED
term:
id: GO:0070098
label: chemokine-mediated signaling pathway
- preferred_term: inflammatory response
modifier: INCREASED
term:
id: GO:0006954
label: inflammatory response
locations:
- preferred_term: blood vessel
term:
id: UBERON:0001981
label: blood vessel
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "CXCL9 and CXCL10 localize to the reactive cells in the viable tissue surrounding areas of necrosis, suggesting that cells in the tumor microenvironment and not the malignant cells themselves are the principal source of chemokines, resulting in vascular damage and necrosis."
explanation: >-
Locates the chemokine source in the reactive microenvironment, which is
what makes this node distinct from the B-cell node upstream of it.
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Thus, the host immune response to EBV is a principal cause of the vasculitic changes that are such a typical feature of the disease."
explanation: >-
States directly that the host response, not the neoplastic clone, drives
the vascular pathology.
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Most of the angiocentric lymphocytes are CD3+T cells, with CD4+cells representing the predominant subtype in most cases."
explanation: >-
Establishes the CD4-predominant composition of the angiocentric infiltrate.
downstream:
- target: Coagulative Necrosis and Multi-organ Tissue Destruction
description: >-
Vascular invasion and destruction produce ischaemic coagulative necrosis in
the involved tissue.
- name: Coagulative Necrosis and Multi-organ Tissue Destruction
biological_scale: TISSUE
description: >-
Coagulative necrosis follows the vascular damage and is present at every
grade, focal in grade 1 and often extensive in grades 2 and 3. In the lung
this produces the bilateral nodules, sometimes cavitating, that define the
radiologic picture; in skin, central nervous system, liver and kidney it
produces the corresponding extranodal lesions.
biological_processes:
- preferred_term: cell death
modifier: INCREASED
term:
id: GO:0008219
label: cell death
locations:
- preferred_term: lung
term:
id: UBERON:0002048
label: lung
- preferred_term: brain
term:
id: UBERON:0000955
label: brain
- preferred_term: skin of body
term:
id: UBERON:0002097
label: skin of body
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Necrosis was seen in all grades, with a greater degree in high-grade lesions."
explanation: >-
Establishes necrosis as a feature of every grade with a grade-dependent
extent.
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We reviewed 122 biopsies; the most common site was lung (73%), followed by skin/subcutaneous tissue (17%); other sites included kidney, nasal cavity, gastrointestinal tract, conjunctiva, liver, and adrenal gland."
explanation: >-
Documents the organ distribution of biopsy-proven tissue destruction.
downstream:
- target: Bilateral Pulmonary Nodules
description: >-
Necrotic angiocentric lesions in the lung are what imaging shows as
bilateral nodules.
- name: Clonal Selection and High-Grade Transformation
biological_scale: CELLULAR
description: >-
With continued proliferation under a persistent surveillance defect, the
EBV-infected B-cell population shifts from polyclonal to monoclonal.
Immunoglobulin gene rearrangement is clonal in 8% of grade 1, 50% of grade 2
and 69% of grade 3 lesions - a monotonic gradient that is the molecular
reading of the grading system. At grade 3 the lesion is no longer separable
from an EBV-positive large B-cell lymphoma, which is why the treatment
strategy switches from restoring immunity to killing the clone. No recurrent
chromosomal abnormality has been found, so this transformation is not
anchored to a known cytogenetic driver.
cell_types:
- preferred_term: EBV-positive atypical B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
mechanism_confidence: PROVISIONAL
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunoglobulin gene rearrangement studies were performed, and a higher percentage of clonal rearrangements were seen in LYG grade 2 (50%) and grade 3 (69%) as compared with grade 1 (8%)."
explanation: >-
Provides the grade-clonality gradient that this node describes.
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "This shift in clonality from polyclonal to monoclonal disease seen with increased histologic grade most likely represents the selective transformation of EBV-infected B-cell clones"
explanation: >-
States the clonal-selection interpretation of that gradient, hedged by its
authors as the likely explanation, which is why this node is provisional.
phenotypes:
- category: Respiratory
name: Bilateral Pulmonary Nodules
description: >-
Bilateral pulmonary nodules or masses, often peribronchovascular and
lower-lobe predominant and sometimes cavitating. Lung involvement is
essentially universal, and its absence should prompt reconsideration of the
diagnosis.
phenotype_term:
preferred_term: Pulmonary nodule
term:
id: HP:0033608
label: Pulmonary nodule
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinically, all patients had lung involvement (100%), with the next most common site being the central nervous system (38%). No patient had nodal or bone marrow disease."
explanation: >-
Gives the 100% lung involvement figure in the largest pathology series.
- reference: PMID:23006954
reference_title: "Lymphomatoid granulomatosis."
supports: SUPPORT
evidence_source: OTHER
snippet: "It is usually a progressive disorder that virtually always involves the lung and characteristically presents as bilateral pulmonary nodules."
explanation: >-
Confirms bilateral nodules as the characteristic pulmonary presentation.
- category: Nervous System
name: Central Nervous System Involvement
description: >-
Parenchymal brain lesions, with cranial neuropathies, seizures and focal
deficits as their clinical expression. The central nervous system is the
second most common site of disease after the lung and is an adverse
prognostic feature.
review_notes: >-
The bound term covers the structural lesion, which is what the cited cohort
counted. The individual neurologic symptoms are not separately enumerated in
that source, so no narrower term is used.
phenotype_term:
preferred_term: Morphological central nervous system abnormality
term:
id: HP:0002011
label: Morphological central nervous system abnormality
frequency: FREQUENT
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinically, all patients had lung involvement (100%), with the next most common site being the central nervous system (38%). No patient had nodal or bone marrow disease."
explanation: >-
Gives the 38% frequency of central nervous system involvement supporting
the FREQUENT band.
- category: Integument
name: Cutaneous Nodules and Plaques
description: >-
Dermal papules and subcutaneous nodules, plaques or a patchy erythematous
rash, present in roughly a sixth of biopsied sites. Cutaneous lesions show a
dense lymphohistiocytic infiltrate with nonnecrotizing granulomatous
inflammation and only sparse EBV-positive cells, so skin lesions alone cannot
establish the diagnosis.
review_notes: >-
No frequency is recorded. The available figure, 17%, is a share of 122
biopsies rather than of patients, and the FrequencyEnum bands are defined
over patients.
phenotype_term:
preferred_term: Skin nodule
term:
id: HP:0200036
label: Skin nodule
diagnostic: false
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We reviewed 122 biopsies; the most common site was lung (73%), followed by skin/subcutaneous tissue (17%); other sites included kidney, nasal cavity, gastrointestinal tract, conjunctiva, liver, and adrenal gland."
explanation: >-
Gives skin and subcutaneous tissue as the second most frequently biopsied
site.
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "For this reason, skin lesions alone are inadequate to establish a definitive diagnosis of LYG."
explanation: >-
Supports marking the cutaneous phenotype as non-diagnostic on its own.
- category: Respiratory
name: Dyspnea
description: >-
Breathlessness from progressive pulmonary infiltration; part of the
presenting respiratory syndrome along with cough and chest pain.
phenotype_term:
preferred_term: Dyspnea
term:
id: HP:0002094
label: Dyspnea
evidence:
- reference: PMID:23006954
reference_title: "Lymphomatoid granulomatosis."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "Lymphomatoid granulomatosis can lead to progressive pulmonary failure, central nervous system disease, or progression to overt EBV-positive lymphoma without appropriate recognition and management."
explanation: >-
Supports progressive pulmonary compromise as a disease consequence. The
review does not enumerate individual respiratory symptoms, so breathlessness
follows by inference and the item is marked INDIRECT.
histopathology:
- name: Angiocentric and angiodestructive polymorphous infiltrate
description: >-
A polymorphous lymphoid infiltrate centred on and invading vessels, rich in
reactive T cells, containing large atypical EBV-positive B cells, with
coagulative necrosis. This combination is the diagnostic finding and is what
separates the disease from other EBV-positive B-cell lymphoproliferations.
diagnostic: true
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Histologically, the lesions showed angiocentricity, were rich in T cells, had large atypical B cells, and were positive for EBV."
explanation: >-
States the four features that together define the diagnostic histology.
- name: Grade assignment by EBER-positive B-cell density
description: >-
Grade is assigned from the number and density of EBER-positive atypical B
cells and the extent of coagulative necrosis, predominantly on the diagnostic
lung biopsy. In the reference series grades were distributed 30% grade 1, 22%
grade 2 and 48% grade 3. Grading is acknowledged to be inconsistent and
poorly reproducible between observers, which matters because it selects the
treatment arm.
diagnostic: true
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Grading was performed predominantly on the lung biopsy at diagnosis; they were distributed as follows: LYG grade 1 (30%), grade 2 (22%), and grade 3 (48%)."
explanation: >-
Gives the grade distribution and confirms the lung biopsy as the grading
substrate.
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, in practice, the grading can be inconsistent and poorly reproducible among observers."
explanation: >-
Records the reproducibility limitation of the grading system that drives
therapy.
diagnosis:
- name: Tissue biopsy with EBER in situ hybridization
description: >-
Definitive diagnosis needs tissue, usually a lung biopsy, showing the
angiocentric polymorphous infiltrate with EBER-positive atypical B cells.
Immunohistochemistry for CD20, CD3, CD4, CD8 and LMP1 and immunoglobulin gene
rearrangement studies support the diagnosis and set the grade.
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "LYG is a distinct entity that can usually be differentiated from other EBV-associated B-cell lymphoproliferative disorders on the basis of the combination of clinical presentation, histology, and EBV studies."
explanation: >-
States that the diagnosis rests on the combination of clinical picture,
histology and EBV studies.
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Grading of these lesions is important because it dictates the treatment choice."
explanation: >-
Explains why grading, and therefore adequate tissue, is a diagnostic
requirement rather than an academic exercise.
- name: Recognition of diagnostic delay
description: >-
The combination of rarity and a nonspecific presentation - cough,
breathlessness, fever, pulmonary nodules - routinely delays diagnosis, and
the differential includes both infection and vasculitis.
evidence:
- reference: PMID:23006954
reference_title: "Lymphomatoid granulomatosis."
supports: SUPPORT
evidence_source: OTHER
snippet: "The rareness of LYG in conjunction with its nonspecific presentation contributes to delays in diagnosis in many situations."
explanation: >-
Documents diagnostic delay as a recognised feature of the disease.
differential_diagnoses:
- name: Other EBV-positive B-cell lymphoproliferative disorders
description: >-
EBV-positive diffuse large B-cell lymphoma and the post-transplant
lymphoproliferative disorders share EBV positivity and large atypical B
cells. The separating features are the angiocentric architecture, the
obligatory pulmonary involvement, and the absence of nodal and bone marrow
disease.
distinguishing_features:
- Angiocentric and angiodestructive architecture with a reactive T-cell-rich background
- Lung involvement in essentially every patient
- Nodal or bone marrow involvement argues for an alternative diagnosis
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Clinically, LYG universally involves the lungs with other common extranodal sites, including skin, central nervous system, liver, and kidneys. Nodal and/or bone marrow involvement is extremely rare and, if present, suggests an alternative diagnosis."
explanation: >-
Gives the distribution rule used to separate this disease from other
EBV-positive B-cell lymphoproliferations.
- name: T-cell and NK-cell lymphomas of the angiocentric group
description: >-
Extranodal NK/T-cell lymphoma of nasal type and peripheral T-cell lymphoma
were historically pooled with this disease under the label angiocentric
immunoproliferative lesion, and misclassification confounded the older
literature. On expert re-review of cases referred as possible lymphomatoid
granulomatosis, a fifth turned out to be something else.
distinguishing_features:
- The neoplastic population is B-cell, not T-cell or NK-cell
- Expert re-review reclassified 14 of 69 referred cases, including NK/T-cell lymphoma, peripheral T-cell lymphoma and classical Hodgkin lymphoma
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnoses on review were: NK/T cell lymphoma, nasal type (1 case), peripheral T-cell lymphoma, not otherwise specified (1 case), classical Hodgkin's lymphoma (4 cases), and EBV positive polymorphic or monomorphic B-cell lymphoma, lacking features of LYG (8 cases)."
explanation: >-
Enumerates what referred cases actually turned out to be, which is the
practical content of this differential.
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Earlier studies were likely confounded by the inclusion of T and NK cell lymphomas (formerly included in the diagnosis of angiocentric immunoproliferative lesion) with cases of LYG"
explanation: >-
Records the historical conflation that makes this differential important
when reading older literature.
treatments:
- name: Interferon Alfa-2b
description: >-
Dose-escalated subcutaneous interferon alfa-2b, from 7.5 million
international units three times weekly and continued for up to a year past
best response, for low-grade disease. The rationale is explicitly
mechanistic: low-grade disease is treated as immune-dependent, so the
intervention augments the host response to EBV rather than killing the clone.
In the phase 2 trial it produced complete responses in 61% of evaluable
patients and was substantially better tolerated than chemotherapy.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: recombinant interferon alfa-2b
term:
id: NCIT:C1953
label: Recombinant Interferon Alfa-2b
target_mechanisms:
- target: Defective EBV Immunosurveillance
description: >-
Augments the host immune response to EBV, which is the defect this node
records.
evidence:
- reference: PMID:37011643
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "After initial treatment with interferon alfa-2b, the overall response was 64% (28 of 44 evaluable patients) with 61% (27 of 44) having a complete response"
explanation: >-
Gives the response rates from the pivotal prospective trial.
- reference: PMID:37011643
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Interferon alfa-2b is efficacious for treating low-grade lymphomatoid granulomatosis and hence reducing progression to high-grade disease, whereas patients with high-grade lymphomatoid granulomatosis showed expected responses to chemotherapy."
explanation: >-
The trial's own conclusion, including the claim that treating low-grade
disease reduces progression to high grade.
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Methods of augmenting the immune response to EBV in low-grade LYG include treatment with interferon-α2b, whereas high-grade disease requires immunochemotherapy."
explanation: >-
States the mechanistic rationale that makes this an immune-directed rather
than cytotoxic treatment.
- name: DA-EPOCH-R
description: >-
Six three-weekly cycles of dose-adjusted etoposide, prednisone, vincristine,
cyclophosphamide, doxorubicin and rituximab for high-grade disease, which is
treated as immune-independent. Complete responses were seen in 47% of
evaluable patients. Toxicity is the trade-off: serious adverse events
occurred in 64% of chemotherapy-treated patients against 25% of those on
interferon alfa-2b.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: chemotherapy
term:
id: NCIT:C15632
label: Chemotherapy
therapeutic_agent:
- preferred_term: etoposide
term:
id: CHEBI:4911
label: etoposide
- preferred_term: prednisone
term:
id: CHEBI:8382
label: prednisone
- preferred_term: vincristine
term:
id: CHEBI:28445
label: vincristine
- preferred_term: cyclophosphamide
term:
id: CHEBI:4027
label: cyclophosphamide
- preferred_term: doxorubicin
term:
id: CHEBI:28748
label: doxorubicin
- preferred_term: rituximab
term:
id: NCIT:C1702
label: Rituximab
regimen_term:
preferred_term: dose-adjusted EPOCH-R regimen
term:
id: NCIT:C140097
label: Dose-adjusted EPOCH-R Regimen
target_mechanisms:
- target: Clonal Selection and High-Grade Transformation
description: >-
Cytotoxic and anti-CD20 therapy directed at the transformed clone that
defines high-grade disease.
evidence:
- reference: PMID:37011643
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "After initial treatment with DA-EPOCH-R, the overall response was 76% (13 of 17 evaluable patients) with 47% (eight of 17) having a complete response"
explanation: >-
Gives the response rates for the high-grade arm of the trial.
- reference: PMID:37011643
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Serious adverse events occurred in 13 (25%) of 51 patients receiving treatment with interferon alfa-2b and 21 (64%) of 33 patients receiving DA-EPOCH-R, with five treatment-related deaths: one thromboembolic, one infection, and one haemophagocytic syndrome with interferon alfa-2b, and one infection and one haemophagocytic syndrome with DA-EPOCH-R."
explanation: >-
Quantifies the toxicity difference between the two arms, including
treatment-related deaths in both.
- name: Crossover Between Treatment Arms
description: >-
Patients with residual or progressive disease after initial therapy cross
over to the other arm. This is not a salvage improvisation but a designed
consequence of the model: the underlying EBV surveillance defect persists
through chemotherapy, so high-grade disease can recur as low-grade disease
and be treated with interferon, and low-grade disease can transform under
immune modulation and need chemotherapy.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Therapeutic Procedure
term:
id: NCIT:C49236
label: Therapeutic Procedure
evidence:
- reference: PMID:37011643
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with residual or progressive disease after initial therapy crossed over to alternative therapy."
explanation: >-
Documents crossover as part of the prospective trial design.
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: OTHER
snippet: "Given the underlying defective immune surveillance of EBV, patients with high-grade disease may have a recurrence in the form of low-grade disease after immunochemotherapy, and those with low-grade disease may progress to high-grade disease after immune modulation, which can be effectively managed with crossover treatment."
explanation: >-
Gives the mechanistic reason crossover is expected rather than
exceptional.
- name: Hematopoietic Stem Cell Transplantation
description: >-
Considered for primary refractory disease or multiple relapses. Its efficacy
in this disease is explicitly described as not well established, so it is
recorded here as an option rather than a standard.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: Hematopoietic Cell Transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: OTHER
snippet: "In patients with primary refractory disease or in those with multiple relapses, hematopoietic stem cell transplantation may be considered, but its efficacy is not well established."
explanation: >-
Supports transplantation as a considered option while explicitly declining
to claim established efficacy.
clinical_trials:
- name: NCT00001379
phase: PHASE_II
status: COMPLETED
description: >-
Treatment and Natural History Study of Lymphomatoid Granulomatosis. The
single-centre trial that established grade-stratified therapy: interferon
alfa-2b for grade 1 and 2 disease, DA-EPOCH-R for grade 3, with crossover for
residual or progressive disease. Its results are the evidence base for the
treatments recorded in this entry.
target_phenotypes:
- preferred_term: Pulmonary nodule
term:
id: HP:0033608
label: Pulmonary nodule
evidence:
- reference: clinicaltrials:NCT00001379
reference_title: "Treatment and Natural History Study of Lymphomatoid Granulomatosis"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "If patients have grade 3 disease, they will usually receive etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH)-rituximab (EPOCH-R) chemotherapy (each letter representing a drug). If patients have grade 1 or 2 disease, they will usually receive alpha interferon."
explanation: >-
The trial record states the grade-stratified allocation this entry's
treatment section is built on.
discussions:
- discussion_id: lyg_immune_defect_unidentified
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
What is the specific immune defect that permits lymphomatoid granulomatosis
in patients with no recognised primary immunodeficiency?
attaches_to:
- pathophysiology#Defective EBV Immunosurveillance
rationale: >-
The upstream node of this entry is a defect that has been measured only as an
aggregate: reduced circulating T cells, falling more on the CD8 compartment,
in patients who have no diagnosed immunodeficiency syndrome. It is inferred
to be pre-existing and is described by its own authors as hypothesised. No
causal gene, no functional assay and no biomarker identifies it in an
individual patient, so the entry has a trigger node it cannot yet
characterise molecularly.
evidence:
- reference: PMID:32107539
reference_title: "Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Taken together, these results suggest that the immunologic deficits are likely preexistent and that a quantitative and/or qualitative defect in mainly CD8+cytotoxic T cells may be a prerequisite for disease."
explanation: >-
The hedged language is the point: this is the strongest available
characterisation of the defect.
- discussion_id: lyg_grading_reproducibility
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
How should treatment be allocated when the grading that selects the treatment
arm is not reproducible between observers?
attaches_to:
- histopathology#Grade assignment by EBER-positive B-cell density
- treatments#
rationale: >-
Grade decides whether a patient receives interferon alfa-2b or
chemoimmunotherapy, and the toxicity difference between those arms is large -
serious adverse events in 25% against 64%. The pathologists who defined the
grading system record in the same paper that it is inconsistent and poorly
reproducible between observers, with grade 1 the hardest because the
EBV-positive cells can be sparse or absent. No reproducibility study,
quantitative EBER threshold or adjunct molecular assay has been published to
close the gap.
evidence:
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, in practice, the grading can be inconsistent and poorly reproducible among observers."
explanation: >-
States the reproducibility problem directly.
- reference: PMID:25321327
reference_title: "Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The greatest difficulty for the diagnosis of LYG has been with grade 1 lesions because of the possible absence or paucity of EBV-positive atypical B cells."
explanation: >-
Identifies grade 1 as the specific point of failure, which is also the
grade that selects the low-toxicity arm.
- discussion_id: lyg_no_model_system
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Do humanized-mouse models of EBV lymphoproliferation actually model
lymphomatoid granulomatosis, or only the generic EBV-plus-immunosuppression
axis?
attaches_to:
- pathophysiology#Ineffective Angiocentric Reactive T-cell Response
rationale: >-
No animal or in vitro model of this disease exists. Humanized mice
reconstituted with human haematopoietic cells develop EBV-associated B-cell
lymphoproliferation, and immunosuppression increases its frequency, so they
model the upstream axis. They do not reproduce what actually defines the
disease - the angiocentric and angiodestructive architecture, the
lung-skin-CNS distribution, or the CD4-predominant reactive microenvironment.
The entry therefore records no animal_models, and the tissue-level node has
no experimental system behind it. This is flagged as a model mismatch rather
than a plain knowledge gap because evidence exists in a model system whose
fidelity to the human tissue phenotype is the open question.
evidence:
- reference: PMID:25436886
reference_title: "Humanized mouse models of epstein-barr virus infection and associated diseases."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Thus, many aspects of human EBV infection, including associated diseases (e.g., lymphoproliferative disease, hemophagocytic lymphohistiocytosis and erosive arthritis resembling RA), latent infection, and T-cell-mediated and humoral immune responses have been successfully reproduced in humanized mice."
explanation: >-
Establishes what the available models do reproduce - generic EBV-driven
lymphoproliferation and immune control - which is the upstream axis of
this disease and not its defining tissue phenotype.
- reference: PMID:32251475
reference_title: "Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We found that FK506 treatment of EBV-infected mice led to an elevated viral burden, more frequent tumor formation and diminished EBV-induced T cell responses, indicative of reduced EBV-specific immune control."
explanation: >-
Shows that the immunosuppression-plus-EBV axis is modellable, and that the
modelled endpoint is post-transplant-style lymphoproliferation rather than
an angiocentric, lung-predominant lesion.
notes: >-
Entity identity was checked manually because `just preflight-dr` returned SKIP:
MONDO records no causal gene for MONDO:0019466, so its gene-identity check
cannot discriminate. The MONDO term's own Orphanet-sourced definition matches
the research report on every point checked - EBV-driven, fourth to sixth
decade, lung, skin, central nervous system and kidney, with lymph nodes and
spleen only very rarely involved.
Grades 1, 2 and 3 are curated as `has_subtypes` rather than as `stages`
because MONDO models them as three distinct disease children
(MONDO:0859747/8/9) and because they select different treatment arms rather
than marking sequential points in one course. Grade is not fixed for a
patient, though: it moves in both directions under treatment, which the
`progression` section records.
No `genetic` section is curated. Germline immunodeficiency genes - DOCK8, WAS,
SH2D1A - are reported as predisposing conditions in case reports, but they
cause their own syndromes, of which this disease is one manifestation among
several; folding them in here would misrepresent them as causal genes for a
disease that has none. No recurrent chromosomal abnormality has been
identified either.
Scope calls made deliberately. No `environmental:` section: the recognised
predisposing conditions are iatrogenic immunosuppression, HIV and germline
immunodeficiency syndromes, none of which is an ECTO-style exposure acting on
a named mechanism node, and the one thing that would qualify - EBV - is
curated as `infectious_agent` instead. No separate molecular or viral-latency
node: the mechanism this disease turns on is the host's failure to control a
latent infection that is otherwise near-universal, so latency is annotated on
the immunosurveillance node (GO:0019042) rather than given a node of its own,
and no LYG-specific data on EBV latent gene programs was found to support one.
No `animal_models`: see the HUMAN_MODEL_MISMATCH discussion.
Most of the reference cache added alongside this entry comes from the
deep-research run's own citation-validation pass rather than from curation.
Those files are committed because the report that cites them is committed;
they are not evidence for anything in the entry.
Historical caution when reading pre-2001 literature: T-cell and NK-cell
lymphomas were pooled with this disease under the label "angiocentric
immunoproliferative lesion", and the confounding is explicitly noted by the
reference pathology series.
Overview. Lymphomatoid granulomatosis (LYG) is a rare, Epstein-Barr virus (EBV)–driven, angiocentric and angiodestructive B-cell lymphoproliferative disease that arises against a background of defective host immune surveillance of EBV. First described by Averill Liebow in 1972, it is now recognized in the WHO classification as a distinct entity most closely related to a T-cell/histiocyte-rich large B-cell lymphoma variant, formally classified since 2015 within the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, and retained in the 2016/2022 WHO classifications of mature lymphoid neoplasms (Melani et al., Blood 2020, PMID 32107539; PathologyOutlines). Histologically it is defined by an angiocentric, angioinvasive, extranodal, polymorphous lymphoid infiltrate containing variable numbers of large, atypical, EBV-positive B cells set in a dense background of reactive, predominantly CD4+ T lymphocytes, with associated coagulative ("tumor") necrosis (PMID 25321327).
Key identifiers: - MONDO: MONDO:0019466 - Orphanet: ORPHA:86869 - ICD-10-CM: C83.8 (Other non-follicular lymphoma) - ICD-O: 9766/1 - OMIM: No dedicated single-gene OMIM entry exists for sporadic LYG (it is not a classic monogenic Mendelian disorder); related immunodeficiency-associated lymphoproliferative OMIM entries exist for specific germline predisposition syndromes (e.g., OMIM #613011, Lymphoproliferative syndrome 1)
Synonyms: angiocentric immunoproliferative lesion (AIL); "LG"/"LYG"; historically grouped with (though not identical to) polymorphic reticulosis/lethal midline granuloma and angiocentric lymphoma under the older umbrella term "angiocentric immunoproliferative lesions," though modern classification distinguishes LYG (B-cell driven, EBV+, multi-organ) from nasal NK/T-cell lymphoma (formerly "polymorphic reticulosis") (GARD; PMID 7281476).
Evidence basis: Information is derived almost entirely from aggregated case series, single-institution retrospective cohorts, and one prospective NCI phase 2 interventional trial — not large-scale EHR/claims data — reflecting the disease's rarity.
Primary causal driver — EBV plus host immune dysfunction. LYG is hypothesized to result from defective cell-mediated immune surveillance of EBV-infected B cells, permitting outgrowth of EBV-driven B-cell clones amid a robust but ineffective reactive T-cell response ("hyperimmune" reaction), rather than from any single germline oncogenic driver (PMID 32107539). A functional defect, primarily in CD8+ cytotoxic T-cell immunosurveillance, is hypothesized as a prerequisite; notably, the reactive infiltrate itself is CD4-predominant (CD4:CD8 ratio favoring CD4 in 95% of cases, 20/21) rather than CD8-predominant, consistent with an ineffective/dysregulated rather than absent T-cell response (PMID 25321327).
Genetic/immunologic risk factors: - Underlying primary or acquired immunodeficiency is documented in a substantial fraction of cases even without a formally diagnosed syndrome. Recognized associated conditions include: - Wiskott–Aldrich syndrome (X-linked; marked predisposition to EBV-associated lymphoma) - X-linked lymphoproliferative syndrome (XLP) - Common variable immunodeficiency (CVID) - DOCK8 deficiency — a combined immunodeficiency in the hyper-IgE spectrum; a 2017 report described EBV+ LYG as a previously unreported presentation of DOCK8 deficiency, with resolution of LYG following hematopoietic stem cell transplantation in affected relatives (PMID from Frontiers report, DOCK8/LYG) - HIV/AIDS — via CD4+ T-cell depletion and loss of EBV control - Solid organ transplantation (iatrogenic immunosuppression) — placing LYG within the broader post-transplant lymphoproliferative disease (PTLD) spectrum in transplant recipients - No recurrent chromosomal abnormalities have been reported in LYG, and no single causal driver gene/variant analogous to a classic Mendelian mutation has been established (PMID 32107539). - Sporadic disease without recognized immunodeficiency is also common — most affected adults have no formally diagnosed primary immunodeficiency syndrome, suggesting a subtler or acquired immune surveillance defect specific to EBV.
Environmental/infectious factor — EBV is central and essentially obligate. EBV (a γ-herpesvirus) genomes and gene products (EBER, LMP1) are demonstrable in the neoplastic B cells of the great majority of cases across grades (EBER positivity: ~46% in grade 1, 100% in grade 2, 94% in grade 3 lesions per PMID 25321327), supporting EBV as the direct causal/transforming agent rather than a bystander.
Protective factors: No specific genetic or environmental protective factor has been established in the literature; intact cell-mediated (particularly CD8+ cytotoxic T-lymphocyte) immunosurveillance of EBV is implicitly protective, as evidenced by disease remission following immune reconstitution (e.g., antiretroviral therapy in newly diagnosed HIV, or reduction of immunosuppression in transplant recipients) (PMC11829542).
Gene-environment interaction: The disease represents a paradigmatic gene(immune)-environment(EBV) interaction: a host with a quantitative or qualitative T-cell surveillance defect (genetic/immunodeficiency-related or acquired) fails to control EBV-driven B-cell proliferation, and progressive genetic/clonal evolution of the EBV+ B-cell population (increasing clonality with grade) leads to transformation toward overt lymphoma.
LYG is multisystemic, with organ involvement documented in a 55-patient single-institution series (Song et al., Am J Surg Pathol 2015, PMID 25321327):
| Organ | Frequency | HPO term (suggested) |
|---|---|---|
| Lung | ~90–100% (near-universal) | HP:0006536 (Pulmonary infiltrates) / HP:0032230 (Pulmonary nodule) |
| CNS | 20–38% | HP:0002316 (CNS neoplasm) / HP:0007281 |
| Skin | 17–55% | HP:0011355 (Skin nodule) / HP:0100310 (Skin ulcer) |
| Liver | 19–29% | HP:0001392 (Abnormal liver morphology) |
| Kidney | 15–40% | HP:0000077 (Abnormality of the kidney) |
Pulmonary phenotype (near-universal, ~90–100% of cases): Presenting symptoms include cough, dyspnea, chest pain, and fever; imaging shows bilateral, peribronchovascular, lower/peripheral-lung-predominant nodules or masses in 80–100% of cases, with cavitation, small thin-walled cysts, atelectasis/lobar obstruction, and occasional pneumothorax (AJR, PMID 11044036).
Cutaneous phenotype (~17–55%; second most common site): Multiple erythematous dermal papules and/or subcutaneous nodules, plaques, or a patchy erythematous rash, with ulceration in up to ~30% of affected patients; distribution favors extremities over head/neck (only ~10% head/neck) (Dermatology Advisor; PMC6110445).
CNS phenotype (20–38%): Parenchymal brain lesions, cranial neuropathies, seizures, and focal neurologic deficits; CT shows high-density lesions. CNS involvement is a major adverse prognostic factor — one CNS-focused cohort reported overall mortality of 63.5% in LYG generally versus 86.0% in CNS-LYG specifically, with 5-year mortality of 38–88% and median survival 14–72 months in CNS-involved disease (PMC7516720).
Hepatic and renal phenotype: Often asymptomatic or detected on imaging/labs; renal involvement can present with hematuria or renal impairment without overt vasculitic glomerulonephritis (distinguishing it from ANCA-associated vasculitis).
Constitutional/laboratory phenotypes: Fever, weight loss, malaise; laboratory abnormalities may include cytopenias, and rare cases present with hemophagocytic lymphohistiocytosis (HLH) as an initial manifestation (Frontiers, PMC) or paraneoplastic polymyositis (PMC4757691).
Onset/course: Typically insidious onset in adults (fourth–sixth decade), though a chronic, indolent ("smoldering") cutaneous-only course has also been reported (PMC8841505); grade generally correlates with disease pace, with low-grade disease often smoldering/relapsing-remitting and high-grade disease behaving as an aggressive lymphoma.
Quality of life impact: Not systematically studied via standardized instruments (EQ-5D/SF-36) in this rare disease; qualitatively, pulmonary and CNS involvement drive the greatest functional morbidity.
Causal genes: No single germline causal gene for sporadic LYG exists; it is not a classic monogenic disorder. However, LYG has been reported as a rare secondary manifestation of several germline primary immunodeficiency genes: - DOCK8 (hgnc:19191) — autosomal recessive combined immunodeficiency (hyper-IgE syndrome spectrum); reported cause of EBV+ LYG with intrafamilial phenotypic variation (PMC5328973) - WAS — Wiskott-Aldrich syndrome gene, X-linked - Genes underlying XLP (SH2D1A, XIAP) and CVID
Somatic/molecular features of the neoplastic clone: - Clonality: Immunoglobulin heavy-chain gene rearrangement studies show grade-dependent clonality — grade 1: ~8% clonal (1/12); grade 2: ~50% clonal (4/8); grade 3: ~69% clonal (11/16) — consistent with progressive selection/transformation of an EBV-infected B-cell clone with increasing grade (Song et al. 2015, PMID 25321327). - No recurrent cytogenetic abnormalities (translocations, aneuploidy) have been established, unlike most other B-cell lymphomas (PMID 32107539). - EBV gene expression: Neoplastic B cells express EBER (EBV-encoded small RNA, detected by in situ hybridization) and latent membrane protein 1 (LMP1) by immunohistochemistry, consistent with a latency II/III-like expression program; EBER positivity rises from ~46% (grade 1) to 100% (grade 2) to 94% (grade 3) (PMID 25321327). - Immunophenotype of neoplastic cells: CD20+, CD45+, LMP1+ large atypical B cells; background reactive infiltrate is CD3+ T cells, CD4-predominant in 95% of cases (20/21) (PMID 25321327).
Variant classification/allele frequency: Not applicable in the classic ClinVar/gnomAD sense for sporadic LYG, since it is a somatic/EBV-driven lymphoproliferation rather than a germline variant-caused disease; where associated germline immunodeficiency genes (DOCK8, WAS) are implicated, standard ACMG/AMP pathogenic-variant classification applies to those underlying conditions rather than to LYG itself.
Epigenetics: No LYG-specific DNA methylation/histone-modification studies were identified in the search; EBV latency programs themselves involve epigenetic (CpG methylation, histone) regulation of the viral genome, a mechanism general to EBV-associated lymphoproliferations.
Infectious trigger — EBV (Epstein-Barr virus, human gammaherpesvirus 4; NCBITaxon:10376): The central and essentially obligate etiologic agent; EBV genomes are detectable by PCR/in situ hybridization in the overwhelming majority of cases (PMID 2170969).
Iatrogenic/exposure factors: - Immunosuppressive medication — solid organ transplantation, TNF-α inhibitor therapy (a 2023 case report describes pulmonary LYG in a patient on long-term TNF-α inhibitor use, PMID 37160375), and other immunosuppressive regimens for autoimmune disease can precipitate LYG by impairing EBV surveillance. - HIV infection — a well-documented environmental/infectious risk factor via CD4+ T-cell depletion; case reports document LYG remission after immune reconstitution with antiretroviral therapy.
Lifestyle factors: No specific lifestyle risk factor (smoking, diet, alcohol) has been established in the literature as a driver of LYG.
Causal chain (upstream → downstream): 1. Trigger: EBV infection of B lymphocytes (nearly universal in the population; EBV seroprevalence >90% in adults) combined with a host defect in cell-mediated EBV immunosurveillance (constitutional immunodeficiency, HIV, iatrogenic immunosuppression, or an unidentified subtler defect). 2. Molecular/cellular consequence: Failure of cytotoxic (largely CD8+) T-cell control permits outgrowth of EBV-infected B cells expressing latent viral oncoproteins (LMP1, EBNA), which drive B-cell proliferation and survival signaling (NF-κB activation downstream of LMP1, analogous to other EBV+ lymphoproliferations). 3. Tissue-level consequence: A robust reactive, predominantly CD4+ T-cell response is recruited but is immunologically ineffective at eliminating the EBV+ B-cell population; the mixed infiltrate shows a striking tropism for blood vessel walls (angiocentricity) and vessel destruction (angioinvasion/angiodestruction), producing ischemic coagulative ("tumor") necrosis in affected tissue. 4. Organism-level consequence: Multi-organ tissue destruction (lung nodules/cavitation, cutaneous ulceration, CNS lesions, hepatic/renal involvement) and, with clonal evolution/selection of the EBV+ B-cell population (rising Ig-clonality across grades 1→3), progression from a polyclonal/oligoclonal low-grade lymphoproliferation to a clonal, aggressive B-cell lymphoma indistinguishable from EBV+ diffuse large B-cell lymphoma at grade 3.
Cellular processes involved: Chronic inflammation, angiocentric/angiodestructive vasculopathy (not a true vasculitis, since there is no primary destruction of the vessel wall by an immune-mediated vasculitic process — vessel damage is secondary to lymphocytic infiltration), ischemic/coagulative necrosis, and B-cell clonal selection/malignant transformation.
Grading as a mechanistic readout: The three-tier histologic grading system directly operationalizes the pathobiology — grade is defined by the number/density of large EBV+ B cells and extent of necrosis: - Grade 1: Polymorphous infiltrate, few/no large atypical cells, scant EBV+ B cells (EBER+ ~46%), no or minimal necrosis, low/no clonality (8% clonal) — indolent, "immune-dependent" biology. - Grade 2: Increased large EBV+ B cells (EBER+ 100%), more necrosis, intermediate clonality (50%). - Grade 3: Sheets of large atypical EBV+ B cells resembling conventional EBV+ diffuse large B-cell lymphoma, extensive necrosis, high clonality (69%) — "immune-independent," frankly malignant biology (PMID 25321327; Nakamura/Nature Modern Pathology review).
This grade-dependent biology is the direct rationale for the NCI's differentiated treatment strategy (immunotherapy for immune-dependent low-grade disease vs. cytotoxic chemoimmunotherapy for immune-independent high-grade disease — see Treatment section).
Suggested GO terms: GO:0006955 (immune response), GO:0002432 (granuloma formation), GO:0031295 (T cell costimulation) [context], GO:0043065 (positive regulation of apoptotic process) [reactive T cell attack on infected cells], GO:0001525 (angiogenesis)/GO:0032102 (negative regulation of response to wounding) not directly established. Suggested CL terms: CL:0000236 (B cell) — specifically EBV-transformed large B cell; CL:0000624 (CD4-positive, alpha-beta T cell) for the reactive infiltrate; CL:0000625 (CD8-positive, alpha-beta T cell) for the hypothesized deficient surveillance population.
Advanced/omics profiling: No large-scale transcriptomic, proteomic, single-cell, or spatial transcriptomic dataset specific to LYG was identified in this search — consistent with its rarity and the field's reliance on immunohistochemistry/ISH-based diagnostic pathology rather than genomic profiling to date. This represents a knowledge gap relative to better-characterized B-cell lymphomas.
Epidemiology: - LYG is an exceedingly rare disease of unknown precise population prevalence/incidence — described as "a disease of unknown prevalence" with no dedicated national registry figures identified. - Sex ratio: Male predominance, approximately 2:1 male:female. - Age distribution: Most common in the fourth to sixth decades of adult life; can occur at any age, including rare pediatric cases. - Race/ethnicity: No known racial predilection reported.
Inheritance pattern: LYG itself is not inherited in a classic Mendelian sense — it is a sporadic, EBV-driven lymphoproliferation. However, when it arises secondary to a germline primary immunodeficiency (e.g., DOCK8 deficiency — autosomal recessive; Wiskott-Aldrich syndrome — X-linked recessive), the underlying predisposing condition follows that syndrome's inheritance pattern, and intrafamilial variation in LYG presentation among relatives sharing the same germline DOCK8 mutation has been documented (PMC5328973).
Penetrance/expressivity: Not classically applicable, given the sporadic/acquired nature of most cases; where a germline immunodeficiency is causal, penetrance for LYG specifically (versus other EBV-driven manifestations) is incomplete and variable even within families.
Founder effects/consanguinity/carrier frequency: Not established for LYG itself, though relevant to the rare recessive immunodeficiency syndromes (e.g., DOCK8 deficiency) that can predispose to it.
Tissue diagnosis is required and central. Definitive diagnosis requires tissue biopsy (open lung biopsy or video-assisted thoracoscopic surgery [VATS] for pulmonary disease, or biopsy of an accessible extrapulmonary site such as skin) demonstrating the characteristic angiocentric/angioinvasive polymorphous infiltrate with EBV+ atypical B cells (emedicine Workup).
Ancillary pathology studies: - In situ hybridization for EBER (EBV-encoded RNA) — the key diagnostic test confirming EBV positivity in the atypical B-cell population. - Immunohistochemistry: CD20 (neoplastic B cells), CD3/CD4/CD8 (background reactive T cells, CD4-predominant), LMP1 (latent EBV protein). - Molecular clonality studies: Immunoglobulin heavy-chain gene rearrangement (PCR-based) to assess clonality, correlating with grade.
Imaging: - Chest CT — bilateral, peribronchovascular, lower/peripheral-lung nodules or masses, sometimes with cavitation; the primary modality for detecting and monitoring pulmonary disease. - Brain MRI/CT — for suspected CNS involvement; CT shows high-density lesions. - F18-FDG PET/CT — used to assess multisystem disease distribution, guide high-yield biopsy site selection, and monitor treatment response.
Laboratory studies: No LYG-specific serum biomarker exists; EBV serology/PCR (plasma EBV DNA load) may support the diagnosis and can be used for monitoring, though it is not diagnostic in isolation given high background EBV seroprevalence.
Genetic testing: Not part of routine LYG diagnostic workup unless an underlying primary immunodeficiency is clinically suspected (e.g., recurrent infections, eczema, and elevated IgE suggesting DOCK8 deficiency; recurrent infections/thrombocytopenia/eczema suggesting Wiskott-Aldrich syndrome), in which case targeted gene panel or exome sequencing for primary immunodeficiency genes would be pursued.
Differential diagnosis: - Granulomatosis with polyangiitis (GPA/Wegener's) — distinguished by true necrotizing vasculitis (destruction of the vessel wall itself by the inflammatory process) and typically ANCA positivity, versus LYG's angiocentric/angioinvasive-but-not-classically-vasculitic pattern and EBV positivity. - Sarcoidosis / necrotizing sarcoid granulomatosis — distinguished by well-formed granulomas with giant cells, more frequent mediastinal adenopathy, and absence of EBV+ atypical B cells (LYG characteristically lacks well-formed granulomas or multinucleated giant cells). - Other entities in the differential: pseudolymphoma, other malignant lymphomas (including EBV+ diffuse large B-cell lymphoma, into which grade 3 LYG merges diagnostically), lymphocytic interstitial pneumonia, metastatic disease, cryptogenic organizing pneumonia, infectious granulomatous disease (fungal, mycobacterial).
Screening: No population-level screening program exists given the disease's rarity and lack of an identifiable pre-symptomatic screening marker; surveillance in known immunodeficiency syndromes (DOCK8 deficiency, Wiskott-Aldrich) for EBV-driven lymphoproliferative complications is a reasonable clinical practice, though not formally codified as LYG-specific screening.
Historical (pre-risk-stratified-therapy) outcomes: Median overall survival was poor, historically cited as 14 months (steroid/chemotherapy era) to under 2 years, with 5-year mortality around 50%.
Modern, grade-stratified therapy outcomes (NCI phase 2 trial, Lancet Haematology 2023, PMID 37011643): - Patients with low-grade disease treated with interferon alfa-2b achieved a median overall survival of approximately 20 years — a dramatic improvement over historical controls. - Progression-free survival for grades 1–2 treated with interferon-alfa was 56%, with median PFS of 5.1 years; for grade 3 treated with DA-EPOCH-R, PFS was 44%, median 32 months (PMID 25321327 reporting NCI cohort outcomes). - Complete response rates in the phase 2 trial: 61% (27/44) after initial interferon alfa-2b in low-grade disease; 47% (8/17) after initial DA-EPOCH-R in high-grade disease; with additional responses after cross-over treatment. - Serious adverse events occurred in about 25% of interferon alfa-2b-treated patients versus nearly two-thirds of chemotherapy-treated patients, favoring the tolerability of immunotherapy for low-grade disease.
Prognostic factors: - Histologic grade is the single most important prognostic factor — grade 3 (high-grade) disease behaves as an aggressive lymphoma with poorer outcomes than low-grade disease, though modern chemoimmunotherapy has substantially improved even high-grade outcomes. - CNS involvement confers markedly worse prognosis: one cohort reported 3-year overall mortality of 63.5% in LYG broadly versus 86.0% specifically in CNS-involved LYG, with 5-year mortality of 38–88% and median survival 14–72 months in CNS-LYG (PMC7516720). - Underlying immunodeficiency status and ability to achieve immune reconstitution (e.g., HIV control, reduction of iatrogenic immunosuppression) favorably affect outcome.
Complications: Progression to overt EBV+ diffuse large B-cell lymphoma (grade 3 transformation), organ failure from pulmonary/hepatic/renal destruction, secondary infections related to immunosuppressive therapy, hemophagocytic lymphohistiocytosis as a rare severe complication.
Modern risk/grade-stratified paradigm (NCI standard of care, established by the Lancet Haematology 2023 phase 2 trial, PMID 37011643):
Interferon alfa-2b — dose-escalated subcutaneous injections, starting ~7.5 million international units three times weekly, continued for up to 1 year past best response. NCIT suggestion: NCIT:C1666 (Interferon Alfa-2b); treatment_term NCIT:C15986 (Pharmacotherapy).
High-grade disease (grade 3) — chemoimmunotherapy, reflecting "immune-independent," frankly malignant biology:
DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) — six cycles every 3 weeks intravenously. NCIT suggestion: regimen conceptually analogous to standard aggressive B-cell lymphoma chemoimmunotherapy; therapeutic_agent components include rituximab (CHEBI/NCIT:C2185 or similar anti-CD20 monoclonal antibody term), doxorubicin, cyclophosphamide, vincristine, etoposide, prednisone.
Rituximab monotherapy — reported in isolated case reports (e.g., mediastinal LYG achieving complete remission after 3 months of rituximab monotherapy, PMID 15693798), but with variable/unpredictable results as monotherapy; not established as standard for high-grade disease alone.
Immune reconstitution as therapy: In cases secondary to reversible immunosuppression (e.g., newly diagnosed HIV, TNF-α inhibitor use, post-transplant), reducing/discontinuing the offending immunosuppression or initiating antiretroviral therapy has produced remission of low-grade pulmonary LYG, underscoring the immune-dependent mechanism at low grade (PMC11829542).
Emerging/experimental therapies: - PD-1 checkpoint inhibition — a case report describes successful treatment of pulmonary LYG with a PD-1 inhibitor-based regimen, suggesting a role for immune checkpoint blockade as an emerging strategy, though this is not yet standard of care and mechanistic rationale (tumor PD-L1 engagement suppressing anti-EBV T-cell responses) is inferred by analogy to other EBV+ lymphomas rather than LYG-specific mechanistic data. - Hematopoietic stem cell transplantation — curative for LYG arising in the context of an underlying correctable primary immunodeficiency (e.g., DOCK8 deficiency), where HSCT resolved both the immunodeficiency and the LYG.
Supportive care: Management of pulmonary complications (may require ventilatory support in severe disease), CNS-directed therapy (high-dose methotrexate plus rituximab reported effective for higher-grade CNS-LYG), and standard supportive oncologic care.
Treatment algorithm summary: The defining modern conceptual advance is that LYG is not treated as a single entity but is bifurcated by grade into a proposed "immune-dependent" (low-grade, treat the immune deficit) versus "immune-independent" (high-grade, treat as lymphoma) disease model — directly informing the two-arm design of the pivotal 2023 trial.
Given LYG's basis in EBV plus acquired/host immune dysfunction, prevention is indirect rather than primary (no LYG-specific vaccine or prophylactic agent exists):
No naturally occurring veterinary counterpart of lymphomatoid granulomatosis specifically was identified in this search (unlike, e.g., some EBV-associated human lymphomas that have partial analogs in Old World primate lymphocryptovirus infections). EBV itself is a human-tropic gammaherpesvirus (NCBITaxon:10376) without natural non-human hosts, though related lymphocryptoviruses infect other primates and can produce analogous lymphoproliferative disease in those species (relevant to comparative biology of gammaherpesvirus-driven lymphoproliferation broadly, though not documented as "lymphomatoid granulomatosis" by name in veterinary literature). No OMIA (Online Mendelian Inheritance in Animals) entry or zoonotic transmission pathway is applicable, since EBV is not zoonotic.
No LYG-specific animal or in vitro model was identified in the literature searched. However, the broader mechanistic paradigm — EBV infection with defective T-cell immunosurveillance driving B-cell lymphoproliferation — is modeled by:
Model limitations relevant to LYG specifically: Existing humanized-mouse EBV-lymphoproliferation models capture generic EBV+ B-cell lymphoproliferative disease and PTLD-like biology but do not recapitulate the LYG-defining angiocentric/angioinvasive tissue tropism, multi-organ pattern (lung/skin/CNS predominance), or the specific CD4-predominant reactive T-cell microenvironment — representing a clear gap between available model systems and the human disease phenotype that would need explicit flagging (e.g., a HUMAN_MODEL_MISMATCH framing) in any KB curation.
| Concept | Suggested term |
|---|---|
| Disease | MONDO:0019466 (lymphomatoid granulomatosis) |
| Causal/associated agent | EBV — NCBITaxon:10376 |
| Neoplastic cell | CL:0000236 (B cell), EBV-transformed large B cell |
| Reactive infiltrate cell | CL:0000624 (CD4+ alpha-beta T cell) |
| Lung involvement | UBERON:0002048 |
| Skin involvement | UBERON:0002097 |
| CNS involvement | UBERON:0000955 |
| Angiodestruction/necrosis | GO process terms for apoptosis/necrosis, tissue damage |
| Treatment — interferon | NCIT:C1666 (Interferon Alfa-2b) under NCIT:C15986 (Pharmacotherapy) |
| Treatment — DA-EPOCH-R | NCIT:C15632 (Chemotherapy) + therapeutic_agent list (rituximab, doxorubicin, cyclophosphamide, vincristine, etoposide, prednisone); consider regimen_term if an NCIT-coded DA-EPOCH-R identity exists |
| Genetic predisposition (when applicable) | hgnc:2993 (DOCK8), WAS gene |
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 24 |
| Resolved | 24 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 24 |
| On topic | 12 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 29 |
| Resolved | 27 |
| Unresolved (possible confabulation) | 1 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 18 |
| Terms named correctly | 11 |
| Terms named as a different term | 2 |
| Terms whose name is worth a second look | 5 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
UBERON:0000955 (2 mentions) - the report calls it "CNS involvement"; UBERON calls it brainNCIT:C1666 (2 mentions) - the report calls it "Interferon Alfa-2b"; NCIT calls it Tyrphostin A30These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
HP:0002316 (1 mention) - HP does not contain this termThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0001392 (1 mention) - the report calls it "Abnormal liver morphology"; HP calls it Abnormality of the liver, and lists "Abnormal liver" among its other namesGO:0032102 (1 mention) - the report calls it "negative regulation of response to wounding"; GO calls it negative regulation of response to external stimulusCL:0000624 (3 mentions) - the report calls it "CD4-positive, alpha-beta T cell", "CD4+ alpha-beta T cell"; CL calls it CD4-positive, alpha-beta T cellUBERON:0002048 (2 mentions) - the report calls it "lung", "Lung involvement"; UBERON calls it lungUBERON:0002097 (2 mentions) - the report calls it "Skin involvement"; UBERON calls it skin of body, and lists "entire integument" among its other namesThe report gives these identifiers more than one name of its own:
CL:0000624 - called "CD4-positive, alpha-beta T cell", "CD4+ alpha-beta T cell"UBERON:0002048 - called "lung", "Lung involvement"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.