Lymphomatoid granulomatosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

Lymphomatoid granulomatosis is a neoplastic disease.

It is a lymphoproliferative disorder (lymphomatoid means lymphoma-like). The word granulomatosis denotes one of its microscopic character, polymorphic lymphoid infiltrates and focal necrosis within it.

It usually involves lung, skin, and central nervous system.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

In 1972, Averill Liebow, a clinico-pathologist, discovered lymphamatoid granulomatosis

• In 1972, Averill Liebow, a clinico-pathologist, discovered lymphamatoid granulomatosis.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

Lymphomatoid granulomatosis may be classified according to a grading system into low grade and high grade.

Lymphomatoid granulomatosis may be classified according to a grading system which denotes the amount of EBV positive large B-cell malignant cells that are present. Deciphering the severity of the disease is crucial in determining which treatment options to pursue. The condition is classified into two subtypes:^[1]

• Low grade:
  • Small amount of large atypical cells
  • Few mitotic figures
  • Minute amount of necrosis
  • Some cases resolve on there own

• High grade:
  • Preponderant population of large atypical cells
  • Profuse necrosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

Lymphomatoid granulomatosis arises from T cells infused with EBV, which are lymphoid cells that are normally involved in Immunity.As a result patients typically resent with pulmonary symptoms (cough, dyspnea, chest tightness).Patients with lymphomatoid granulomatosis tend to have low CD4 counts usually due to infection (EBV, hep c, and hiv) and/or immunospression( immunosuppressive drugs, and Inherited immunodeficiency diseases).On microscopic pathology inflammation of micro vessels are seen or angitis is seen and t cells containing EBV.On gross pathology nodules are seen mostly in the lung.

• The normal physiology of cell mediated immunity can be understood as follows:
• Historically, the immune system was divided into two branches:
  • Humoral immunity, for which the defending function of immunization could be seen in the humor (cell-free bodily fluid or serum)
  • Cellular immunity or Cell mediated immunity , for which the defending function of immunization was associated with cells. The cell involved in cell mediated immunity are the following:
    • CD4 cells or Helper T cells provide defense against varying pathogenic organisms.
    • Naive T cells
• Mature T cells that have yet to come upon an antigen, and are transformed into activated effector T cells after coming across an antigen-presenting cells (APCs)
  • These APCs, are the following
    • Macrophages
    • Dendritic cells
    • B cells
• The cells listed above in some cases, pack antigenic peptides onto the MHC of the cell, in turn introducing the peptide to receptors on T cells. The most important of these APCs are highly specialized dendritic cells; conceivably operating solely to ingest and present antigens.^[1]

• It is understood that Lymphomatoid granulomatosis is seen in extranodal sites, most commonly the lung
• Other recurrent sites of involvement include the following:
  • Kidney
  • Skin
  • Central nervous system
  • Liver
• The pattern of necrosis in both Lymphomatoid granulomatosis and T/Natural killer cell lymphoma are very similar, accentuating the probable importance of EBV in interceding the vascular damage
• Recent studies shows that the chemokines IP-10 and monoclonal immunoglobilins are indicated in the pathogenesis of the vascular damage
• Although the most common infiltrating cells are T cells, the T cell receptor genes are not clonally rearranged. However, by VDJ polymerase chain reaction, approximately 60% of cases contain clonal rearrangements
• EBV sequences can be confined to B cells and are clonal in most cases
• Most patients with Lymphomatoid granulomatosis carefully evaluated clinically have irregularities in there cytotoxic T cell function and low levels of CD8+ T cells^[2][3]

Other systems of the body which are affected in Lymphomatoid granulomatosis include:^[4]

• Pulmonary^{[5] [6]}
• CNS^[7][8]
• Skin^[9][10]

On gross pathology, the following is seen:^[9]

• Lung nodules up to 10 cm with central necrosis and cavitation^[11][12]
• 15% of patients with skin lesions have indurated and atrophic plaques^[13][14]

On microscopic histopathological analysis, the presence of an angiocentric and angiodestructive accumulation of differing numbers of T cells with varying numbers of atypical clonal EBV-positive B cells in a polymorphous inflammatory background is seen in Lymphomatoid granulomatosis. This is what is seen in the different organ systems that Lymphomatoid granulomatosis affects:^[15][12]

• Lung:
  • Nodular and disseminated lymphoid infiltrates alongside lymphatics and bronchovascular bundles^[16]
  • Centers of nodules have large vessels with lymphatic infiltration^[16]
  • Typically high grade
  • Small lymphocytes, plasma cells and histiocytes are also present, seldomly accompanied by neutrophils, granulomas are mostly seen with cutaneous involvement^[17]
• Skin:
  • Usually multiple erythematous dermal papules or subcutaneous nodules with an angiocentric lymphohistiocytic infiltrate of CD4+ T cells and angiodestruction, necrosis, panniculitis, atypia^[18]
• Grading:^[9][15] Relates to the proportion of EBV+ B cells relative to the reactive background lymphocytes
  • Grade 1:
    • infrequent EBV positive cells (< 5/HPF)
    • No large atypical cells
    • Small amount of necrosis
    • Some cases resolve immediately
  • Grade 2:
    • EBV positive large lymphoid cells or immunoblasts (5 – 50/HPF)
    • Intermittent large atypical cells
    • Modest amount of necrosis
    • Some cases spontaneously resolve
  • Grade 3:
    • large atypical CD20+ B cells with extensive necrosis and > 50/HPF EBV positive cells
    • Prevalent population of large atypical cells
    • May be coalescent
    • Diffuse necrosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

The exact cause of Lymphomatoid granulomatosis is unknown. Lymphomatoid granulomatosis occurs with more in people with some form of immune system disability including individuals with Sjogren syndrome, rheumatoid arthritis or chronic viral hepatitis.

It is likely that some amalgamation of Immune, genetic and familial factors all contribute a role in the causation of lymphomatoid granulomatosis. The therapy used varies, but is generally directed towards eliminating the EBV-infected B-cells or strengthening of the immune system.

Lymphomatoid granulomatosis involves malignant B cells and reactive, non-malignant T cells and is almost always associated with infection of the malignant B cells by the Epstein-Barr virus; it is therefore known to be a form of the Epstein-Barr virus-associated lymphoproliferative diseases. The disease is believed to be induced by a combination of the following:^[1][2]

• Epstein Barr virus infection^[3]
• Immunodeficiency diseases:
  • Wiskott-Aldrich syndrome^[4]
  • Common variable immunodeficiency^[5]
• Immunosuppression through immunosuppressive drugs:
  • Methotrexate^[6][7]
  • Azathioprine^[8]
• Infections such as HIV or chronic viral hepatitis or endogenous T cell defects^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

Lymphamtoid granulomatosis must be differentiated from bronchocentric granulomatosis and Churg-Strauss, necrotizing sarcoid granulomatosis, Wegeners granulomatosis, Hodgkins disease, non-Hodgkin lymphoma, and Nasal angiocentric lymphoma

As Lymphamatoid granulomatosis manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtypes pulmonary being the most common. The sub types are the following:^{[1][2][3][4][5][6]}

• Cough(non-productive, rarely hemoptysis can occur)^[7][8]
• Dyspnea^[9]
• Chest tightness^[10]

Other Symptoms that are asscociated with the pulmonary symptoms are:^[10][11][12]

• Malaise^[10]
• Weight loss^[13]
• Fatigue^[14]

From the symptoms listed above; Lymphamatoid granulomatosis is usually differtiated from the following diseases bronchocentric granulomatosis and Churg-Strauss, necrotizing sarcoid granulomatosis, Wegeners granulomatosis, Hodgkins disease, non-Hodgkin lymphoma, and nasal angiocentric lymphoma.^[15][16][17]

In contrast, CNS lymphamatoid granulomatosis must be differentiated from other diseases that cause:^{[18][19][20][21]}

• Headaches^[22]
• Seizures^[23]
• Hemiparesis^[24]
• Ataxia^[25]

The differentials are the following CVA, Brain tumors or CNS lymphoma and Parkinsonism.^[26]

Finally Cutaneous Lymphamatoid granulomatosis must also be differtiated from other diseases that cause:^[21][27][28]

• Erythematous rash^[3]
• Macules ^[29]
• Papules^[3][30]
• Plaques ^[31]
• Subcutaneous nodules^[3][32]
• Larger ulcerated nodules^[3][33]

The differentials are the following Dermatomyositis, and Psoriasis^[34][10]

On the basis of Cough, Dyspnea, and Chest tightness, Lymphamatoid granulomatosis must be differentiated from Bronchocentric granulomatosis and Churg-Strauss, Necrotizing sarcoid granulomatosis, Wegeners granulomatosis, Hodgkins disease, Non-hodgkin lymphoma, and Nasal angiocentric lymphoma.^[15][16][17]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

Lymphomatoid granulomatosis is a rare disease with which has prevalence that is not known. Its incidence is higher in males (male : female ratio 2 : 1), and it tends to occur between the 5th to 6th decade of life. It is more frequent in Europe than in Asia.^[1]

• There is no documentation on the incidence of this disease.

• Prevalence of the diseases is unknown.

• Some sources that the mortality rate can be at 50%, but the prognosis is still variable.^[2]

• Usually occurs in the 5th to 6th decade of life, but there have been cases where the condition has occurred in adolescence.^[1]

• There is no racial predilection to Lymphomatoid granulomatosis.

• Males are more commonly affected by Lymphmatoid granulomatosis than females. The male to female ratio is approximately (male : female ratio 2 : 1).

• The majority of Lymphomtoid graulomatosis cases are reported in Europe and Asia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

The risk factor this disease is commonly EBV infection . One my also develop it in a immunodeficient state, organ transplantation , and HIV infection.

• The most potent risk factor in the development of Lymphomatoid granulomatosis is EBV infection. Other risk factors include Drug induced immunodeficiency, Immunodeficient diseases, and HIV infection, and organ transplantation.^[1][2]

• Common risk factors in the development of Lymphamatoid granulomatosis include:
  • EBV infection^[3]
  • HIV infection^[4]
  • Drug induced immunodeficiency^[5]
  • Organ transplantation^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

There is insufficient evidence to recommend routine screening for Lymphomatoid granulomatosis.

• There is no evidence to recommend screening for Lymphomatoid granulomatosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

Prognosis is generally variable and the 5-year mortality rate of patients with Lymphmatoid granulomatosis is approximately 63-90%. In many instances there is totally remission of the disease

• The symptoms of Lymphomatoid granulomatosis usually develop in the fifth to the sixth decade of life, and start with symptoms such as Cough, Dyspnea , and Chest tightness. Patient mostly present with pulmonary symptoms but in 40-50% of cases patients will present with cutaneous symptoms and then 30 present of patients will present with CNS symptoms.^[1]

• The most common complication of the disease can be Lymphoma. In some cases the disease does progress to lymphoma if patient is not cared for.^[2][3]

• Depending on the extent of the disease at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor.^[4]

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