Lymphomatoid Granulomatosis



Lymphomatoid Granulomatosis


Francisco Vega, MD, PhD










The morphologic hallmark of LYG is the presence of vessel walls with a transmural infiltrate of small lymphocytes, large atypical lymphoid cells, and histiocytes with angiodestruction image.






Case of LYG with numerous EBV(+) cells as shown by in situ hybridization for EBV-encoded RNA. The number of EBV(+) cells correlates with prognosis. This case was LYG grade 3.


TERMINOLOGY


Abbreviations



  • Lymphomatoid granulomatosis (LYG)


Synonyms



  • Angiocentric lymphoma


Definitions



  • Extranodal angiocentric &/or angiodestructive B-cell lymphoproliferative disorder composed of numerous T cells and a variable number of neoplastic EBV(+) B cells


ETIOLOGY/PATHOGENESIS


Infectious Agents



  • LYG presumably arises from EBV-immortalized B cells that have escaped immune surveillance


  • Relationship between LYG and post-transplant lymphoproliferative disorders is unclear


Clinical Associations



  • Congenital and acquired immunodeficiencies



    • Wiskott-Aldrich syndrome


    • HIV infection


    • High-dose chemotherapy


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Rare


  • Age



    • Wide age range


    • Most frequent in young adults (˜ 30-40 years)


  • Gender



    • M:F ratio = > 2:1


  • Ethnicity



    • No clear ethnic susceptibility; more common in Western countries


Presentation



  • Generalized symptoms that suggest infection


  • Lung is most frequent site of involvement



    • Multiple bilateral pulmonary nodules (most frequent)



      • Lower lobes involved most often


      • Cavitation in large nodules; ˜ 25% of cases


    • Rare forms of lung involvement



      • Interstitial &/or reticulonodular patterns


      • Single &/or unilateral nodules


    • Lesions can disappear or migrate spontaneously (“wax and wane”)


  • Other sites of involvement



    • Skin (˜ 40-50%); particularly lower extremities


    • Central nervous system (˜ 30%)


    • Kidney (˜ 30%) and liver (˜ 30%)


    • Upper aerodigestive and gastrointestinal tracts uncommonly involved


    • Lymph nodes and spleen are involved rarely


Laboratory Tests



  • Peripheral blood



    • High levels of EBV DNA


Treatment



  • Interferon-α 2b is reported to be effective for LYG with few EBV(+) large cells (low-grade)


  • Aggressive chemotherapy plus rituximab for LYG with numerous EBV(+) large cells


Prognosis



  • Number of large EBV(+) B cells correlates with prognosis



    • Also influences choice of therapy


  • Most patients have progressive course



    • Median survival: 14 months



  • Up to ˜ 25% of patients may have spontaneous remission(s)


MICROSCOPIC PATHOLOGY


Histologic Features



  • Angiocentric & angiodestructive lymphohistiocytic infiltrate



    • Invasion of blood vessel walls



      • Lymphocytic “vasculitis” with transmural invasion


  • Small lymphocytes admixed with histiocytes, plasma cells, and variable numbers of large atypical lymphoid cells



    • Granulocytes are rare or absent


  • Variable areas of necrosis



    • Vascular occlusion


    • Fibrinoid necrosis of blood vessels mediated by chemokines


  • Granulomas or multinucleated giant cells are not usually seen



    • Except in skin


  • Grading is based on number of EBV(+) large B cells and extent of necrosis



    • Grade 1 and 2 are considered B-cell lymphoproliferative disorder of uncertain malignant potential



      • Some cases may regress spontaneously or respond to interferon-α 2b therapy


    • Grade 3 is equivalent to diffuse large B-cell lymphoma (DLBCL)


Cytologic Features



  • Larger atypical cells have round to oval nuclei and prominent nucleoli


  • Binucleated cells are commonly seen


ANCILLARY TESTS


Immunohistochemistry



  • Positive for common pan-B-cell markers



    • CD19, CD20, CD22, CD79a, pax-5


  • CD45/LCA(+), CD30(+/−)


  • EBV-LMP1(+/−), CD15(−)


  • Rarely can show cytoplasmic monotypic Ig light chain in large B cells


  • Smaller reactive cells are T cells: CD3(+), CD4 > CD8


In Situ Hybridization



  • Large B cells are EBER(+)


Molecular Genetics



  • Monoclonal IgH gene rearrangements in grade 2 and 3 cases of LYG


DIFFERENTIAL DIAGNOSIS


Fungal or Mycobacterial Infections



  • Pulmonary histoplasmosis



    • Acute form



      • Flu symptoms, pulmonary infiltrates, and serologic evidence of Histoplasma infection


      • Lymphohistiocytic infiltrate with parenchymal necrosis and vasculitis (differential diagnosis with LYG grade 1)


      • Small necrotizing granulomas; granulocytes(+)


      • GMS(+), EBER(−)


    • Chronic form and histoplasmoma



      • Well-formed necrotizing granulomas; granulocytes(+)


  • Tuberculosis



    • Granulomatous inflammation with caseating necrosis; variable number of Langhans giant cells


    • M. tuberculosis organisms can be found in areas of necrosis



      • Acid-fast by Ziehl-Neelsen stain


  • Atypical mycobacteriosis



    • Immunocompromised patients &/or preexisting lung disease


    • Granulomatous inflammation with caseating necrosis; variable number of Langhans giant cells


    • Culture is required for diagnosis



Necrotizing Sarcoidosis



  • Adult females; frequently asymptomatic


  • Unilateral or bilateral lung lesions


  • Histologic features



    • Vascular granulomas surrounding, infiltrating, and destroying pulmonary arteries and veins; necrosis(+)


Wegener Granulomatosis



  • Systemic necrotizing vasculitis that primarily involves upper and lower respiratory tracts and kidneys


  • Clinical criteria



    • Nasal or oral inflammation


    • Pulmonary nodules, infiltrates, or cavities


    • Abnormal urinary sediment (usually microscopic hematuria)


    • Necrotizing granulomatous inflammation involving small arteries (by biopsy)


  • Limited Wegener granulomatosis



    • Female predominance; disease confined to lungs


  • Hallmark histologic features



    • Liquefactive &/or coagulative necrosis, geographic-shaped


    • Eosinophils(+); multinucleated giant cells without forming well-defined granulomas


    • Destructive, leukocytolytic angiitis involving arteries and veins


Diffuse Large B-cell Lymphoma



  • Primary DLBCL of lung represents < 1% of all lung neoplasms


  • Histologic features



    • Sheets of large neoplastic cells (centroblasts &/or immunoblasts)


    • ± areas of coagulative necrosis


    • Invasion of normal pulmonary structures, such as bronchial wall and pleura, is common


  • Immunophenotype



    • B-cell antigens(+), CD10(+/−), Bcl-6(+/−), EBV(−)


  • DLBCL differs from grade 3 LYG in 2 ways



    • Grade 3 LYG resembles DLBCL but usually maintains some inflammatory background


    • Grade 3 LYG is EBV(+) unlike most cases of DLBCL


Primary Mediastinal Large B-cell Lymphoma (PMLBCL)

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lymphomatoid Granulomatosis
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