Lymphomatoid Granulomatosis

Background

This is a rare lymphoproliferative disorder. For many years, it was thought to be a disorder of T-lymphocytes. With more sophisticated examination, this disorder is currently believed to be a T-cell rich B-cell lymphoproliferative disorder, with many cases caused by neoplastic transformation of B-lymphocytes by Epstein-Barr virus infection.

The lung is the most frequently involved organ affected in nearly all patients. Other organs involved in LYG include skin, kidneys, central nervous system, upper respiratory tract, and gastrointestinal tract. Surprisingly, the lymphoid organs are spared. The clinical behavior of LYG varies widely from an indolent process to an aggressive large cell lymphoma.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/Immunohistochemistry/Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

AGE RANGE-MEDIAN 4-6 decades

SEX (M:F)
2.5:1

PATHOGENESIS CHARACTERIZATION

Angiocentric T-cell rich B-cell disorder

Lymphomatoid granulomatosis of the skin and lung: an angiocentric T-cell-rich B-cell lymphoproliferative disorder.

McNiff JM, Cooper D, Howe G, et al.
Arch Dermatol 1996;132:1464–70.

Localization of Epstein-Barr viral genomes in angiocentric immunoproliferative lesions.

Medeiros LJ, Jaffe ES, Chen YY, et al.
Am J Surg Pathol 1992;16:439–47.

CYTOLYTIC LYMPHOCYTE-ASSOCIATED ANTIGENS

Expression of cytolytic lymphocyte-associated antigens in pulmonary lymphomatoid granulomatosis.

Morice WG, Kurtin PJ, Myers JL.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Am J Clin Pathol 2002 Sep;118(3):391-8 Abstract quote
Paraffin-embedded lung wedge biopsy specimens from 14 patients with pulmonary lymphomatoid granulomatosis (LYG) were analyzed using immunoperoxidase stains specific for T cell- and natural killer cell-associated antigens.

Nine cases had a minor population of CD20+ large B-cells (B-cell LYG) amidst a background of CD3- and betaF1-immunoreactive T cells. In 8 of the 9 B-cell LYG cases, the majority of the background T lymphocytes had a cytotoxic phenotype as defined by the expression of CD8 and the cytotoxic granule proteins TIA-1 (granule membrane protein 17) and granzyme B. Five cases lacked CD20+ large cells and, instead, showed predominantly CD3+ and betaF1 + T cells (T-cell LYG). Whereas the small, medium, and large atypical lymphocytes were all positive for CD3 and betaF1 in the T-cell LYG cases, immunoreactivity for CD8, TIA-1, and granzyme B was limited to the small lymphocytes, with a distribution indistinguishable from that seen in B-cell LYG.

These findings indicate that LYG is composed of a heterogeneous group of lymphoproliferative disorders that share, as unifying features, a relative paucity of neoplastic cells and a prominent reactive infiltrate rich in cytolytic lymphocytes.

EPSTEIN-BARR VIRUS
EBV RNA has been localized to small numbers of B-cells in the pulmonary lesions, and clonal rearrangements of the immunoglobulin heavy chain (IgH) gene also have been detected, especially in more high-grade lesions

Localization of Epstein-Barr viral genomes in angiocentric immunoproliferative lesions.
Am J Surg Pathol 1992;16:439–47.

HISTOLOGICAL TYPES CHARACTERIZATION

General

VARIANTS

LUNG
Blood 1988;5:1674–81.

Grade 1 lesions have a polymorphous angiocentric infiltrate without cellular atypia and with minimal to absent necrosis. EBV+ cells were infrequent (<5/high power field [HPF]) or absent.

Grade 2 lesions have angioinvasion and/or angiodestruction, with or without associated necrosis. These are grade 1 lesions were comprised of a Grade 2 lesions contained scattered large and sometimes hyperchromatic lymphoid cells with <20 EBV+ cells/HPF in the background of a polymorphous angiocentric and angiodestructive lymphoid infiltrate. Necrosis was nearly always present but was not extensive.

Grade 3 lesions contained frequent large atypical lymphoid cells (usually >20 EBV+ cells/HPF) in a polymorphous background. Large confluent areas of coagulative necrosis were often seen.

SKIN Involved in 40-50% of cases

Cutaneous lesions of lymphomatoid granulomatosis: comparison with lymphomatoid papulosis.

Kessler S, Lund HZ, Leonard DD.
Am J Dermatopathol 1981;3:115–27.

Cutaneous Lymphomatoid Granulomatosis Correlation of Clinical and Biologic Features

Michael W. Beaty, M.D.; Jorge Toro, M.D.; Lynn Sorbara, Ph.D.; Jere B. Stern, M.D.; Stefania Pittaluga, M.D.; Mark Raffeld, M.D.; Wyndham H. Wilson, M.D., Ph.D.; Elaine S. Jaffe, M.D.

From the Laboratory of Pathology (M.W.B., L.S., J.B.S., S.P., M.R., E.S.J.), Medicine Branch (W.H.W.), and Dermatology Branch (J.T.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.

Am J Surg Pathol 2001;25:1111-1120 Abstract quote

Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein–Barr virus-associated B-cell lymphoproliferative disorder (EBV-BLPD), varying widely from an indolent process to an aggressive large cell lymphoma. The skin is the extrapulmonary organ most commonly involved in LYG.

We studied 32 skin lesions from 20 patients with known pulmonary LYG, using immunohistochemistry, in situ hybridization for EBV, and polymerase chain reaction for the presence of antigen receptor gene rearrangements (IgH and TCR) to better define both the clinicopathologic spectrum and pathogenesis of the cutaneous lesions.

We describe two distinct patterns of cutaneous involvement. Multiple erythematous dermal papules and/or subcutaneous nodules, with or without ulceration, were present in 17 patients (85%). These lesions demonstrate a marked angiocentric lymphohistiocytic infiltrate, composed predominantly of CD4-positive T-cells, with a high propensity for involving the subcutaneous tissues, and exhibiting angiodestruction, necrosis, and cytologic atypia. EBV-positive B-cells were detected in the nodules from five patients; clonal immunoglobulin heavy chain gene (IgH) rearrangements were detected by polymerase chain reaction in two patients. Multiple indurated, erythematous to white plaques were present in three patients (15%). The plaque lesions were negative for EBV and clonal IgH gene rearrangements in all cases studied. The clinical course of overall disease was variable, ranging from spontaneous regression without treatment (1 of 13; 7%), resolution with chemo/immunomodulatory therapy (8 of 13; 62%), and progression (4 of 13; 31%).

The clinical and histopathologic features of cutaneous LYG are extremely diverse. However, the majority (85%) of the cutaneous lesions mirrors to some extent LYG in the lung, although EBV+ cells are less frequently identified. This subset of cases shows the histopathologic triad of angiodestruction with associated necrosis, panniculitis, and in some cases atypical lymphoid cells.The commonality of the histologic features in this group suggests a common pathophysiologic basis, possibly mediated by cytokines and chemokines induced by EBV. A small percentage of the lesions (15%) presented as indurated and atrophic plaques, and EBV was not identified in the small number of cases studied. The relationship of the plaque-like lesions to LYG remains uncertain. Whereas some cases of LYG regress spontaneously, most require therapy.

PROGNOSIS AND TREATMENT CHARACTERIZATION

Prognostic Factors

Survival Multiple organ involvement usually leads to death within a year of 2/3 of patients

Katzenstein AA, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 1979;43:360–73.
Liebow AA, Carrington CRB, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol 1972;3:457–558.

Commonly Used Terms

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences

Internet Links

Pathologists Who Make A Difference
Search for a Physician Specialist

Last Updated 5/24/2004

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
AGE RANGE-MEDIAN	4-6 decades
SEX (M:F)	2.5:1

PATHOGENESIS	CHARACTERIZATION
Angiocentric T-cell rich B-cell disorder
Lymphomatoid granulomatosis of the skin and lung: an angiocentric T-cell-rich B-cell lymphoproliferative disorder. McNiff JM, Cooper D, Howe G, et al.	Arch Dermatol 1996;132:1464–70.
Localization of Epstein-Barr viral genomes in angiocentric immunoproliferative lesions. Medeiros LJ, Jaffe ES, Chen YY, et al.	Am J Surg Pathol 1992;16:439–47.
CYTOLYTIC LYMPHOCYTE-ASSOCIATED ANTIGENS
Expression of cytolytic lymphocyte-associated antigens in pulmonary lymphomatoid granulomatosis. Morice WG, Kurtin PJ, Myers JL. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.	Am J Clin Pathol 2002 Sep;118(3):391-8 Abstract quote Paraffin-embedded lung wedge biopsy specimens from 14 patients with pulmonary lymphomatoid granulomatosis (LYG) were analyzed using immunoperoxidase stains specific for T cell- and natural killer cell-associated antigens. Nine cases had a minor population of CD20+ large B-cells (B-cell LYG) amidst a background of CD3- and betaF1-immunoreactive T cells. In 8 of the 9 B-cell LYG cases, the majority of the background T lymphocytes had a cytotoxic phenotype as defined by the expression of CD8 and the cytotoxic granule proteins TIA-1 (granule membrane protein 17) and granzyme B. Five cases lacked CD20+ large cells and, instead, showed predominantly CD3+ and betaF1 + T cells (T-cell LYG). Whereas the small, medium, and large atypical lymphocytes were all positive for CD3 and betaF1 in the T-cell LYG cases, immunoreactivity for CD8, TIA-1, and granzyme B was limited to the small lymphocytes, with a distribution indistinguishable from that seen in B-cell LYG. These findings indicate that LYG is composed of a heterogeneous group of lymphoproliferative disorders that share, as unifying features, a relative paucity of neoplastic cells and a prominent reactive infiltrate rich in cytolytic lymphocytes.
EPSTEIN-BARR VIRUS	EBV RNA has been localized to small numbers of B-cells in the pulmonary lesions, and clonal rearrangements of the immunoglobulin heavy chain (IgH) gene also have been detected, especially in more high-grade lesions
Localization of Epstein-Barr viral genomes in angiocentric immunoproliferative lesions.	Am J Surg Pathol 1992;16:439–47.

HISTOLOGICAL TYPES	CHARACTERIZATION
General
VARIANTS
LUNG	Blood 1988;5:1674–81. Grade 1 lesions have a polymorphous angiocentric infiltrate without cellular atypia and with minimal to absent necrosis. EBV+ cells were infrequent (<5/high power field [HPF]) or absent. Grade 2 lesions have angioinvasion and/or angiodestruction, with or without associated necrosis. These are grade 1 lesions were comprised of a Grade 2 lesions contained scattered large and sometimes hyperchromatic lymphoid cells with <20 EBV+ cells/HPF in the background of a polymorphous angiocentric and angiodestructive lymphoid infiltrate. Necrosis was nearly always present but was not extensive. Grade 3 lesions contained frequent large atypical lymphoid cells (usually >20 EBV+ cells/HPF) in a polymorphous background. Large confluent areas of coagulative necrosis were often seen.
SKIN	Involved in 40-50% of cases
Cutaneous lesions of lymphomatoid granulomatosis: comparison with lymphomatoid papulosis. Kessler S, Lund HZ, Leonard DD.	Am J Dermatopathol 1981;3:115–27.
Cutaneous Lymphomatoid Granulomatosis Correlation of Clinical and Biologic Features Michael W. Beaty, M.D.; Jorge Toro, M.D.; Lynn Sorbara, Ph.D.; Jere B. Stern, M.D.; Stefania Pittaluga, M.D.; Mark Raffeld, M.D.; Wyndham H. Wilson, M.D., Ph.D.; Elaine S. Jaffe, M.D. From the Laboratory of Pathology (M.W.B., L.S., J.B.S., S.P., M.R., E.S.J.), Medicine Branch (W.H.W.), and Dermatology Branch (J.T.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.	Am J Surg Pathol 2001;25:1111-1120 Abstract quote Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein–Barr virus-associated B-cell lymphoproliferative disorder (EBV-BLPD), varying widely from an indolent process to an aggressive large cell lymphoma. The skin is the extrapulmonary organ most commonly involved in LYG. We studied 32 skin lesions from 20 patients with known pulmonary LYG, using immunohistochemistry, in situ hybridization for EBV, and polymerase chain reaction for the presence of antigen receptor gene rearrangements (IgH and TCR) to better define both the clinicopathologic spectrum and pathogenesis of the cutaneous lesions. We describe two distinct patterns of cutaneous involvement. Multiple erythematous dermal papules and/or subcutaneous nodules, with or without ulceration, were present in 17 patients (85%). These lesions demonstrate a marked angiocentric lymphohistiocytic infiltrate, composed predominantly of CD4-positive T-cells, with a high propensity for involving the subcutaneous tissues, and exhibiting angiodestruction, necrosis, and cytologic atypia. EBV-positive B-cells were detected in the nodules from five patients; clonal immunoglobulin heavy chain gene (IgH) rearrangements were detected by polymerase chain reaction in two patients. Multiple indurated, erythematous to white plaques were present in three patients (15%). The plaque lesions were negative for EBV and clonal IgH gene rearrangements in all cases studied. The clinical course of overall disease was variable, ranging from spontaneous regression without treatment (1 of 13; 7%), resolution with chemo/immunomodulatory therapy (8 of 13; 62%), and progression (4 of 13; 31%). The clinical and histopathologic features of cutaneous LYG are extremely diverse. However, the majority (85%) of the cutaneous lesions mirrors to some extent LYG in the lung, although EBV+ cells are less frequently identified. This subset of cases shows the histopathologic triad of angiodestruction with associated necrosis, panniculitis, and in some cases atypical lymphoid cells.The commonality of the histologic features in this group suggests a common pathophysiologic basis, possibly mediated by cytokines and chemokines induced by EBV. A small percentage of the lesions (15%) presented as indurated and atrophic plaques, and EBV was not identified in the small number of cases studied. The relationship of the plaque-like lesions to LYG remains uncertain. Whereas some cases of LYG regress spontaneously, most require therapy.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
Prognostic Factors
Survival	Multiple organ involvement usually leads to death within a year of 2/3 of patients