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Lymphoma - Non B cell neoplasms

T/NK cell disorders

EBV+ T cell lymphoproliferative disorders of childhood


Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 8 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Two major types: system and Hydroa Vacciniforme-like
● Increased frequency in Asians and Native Americans from Central and South America, and Mexico


Systemic EBV+ T cell Lymphoproliferative Disease of Childhood (S-EBV-TLPD)

General
=========================================================================

● Life-threatening illness of children and young adults characterized by a clonal proliferation of EBV infected T cells with an activated cytotoxic phenotype (WHO 2008)

Terminology
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● Overlapping clinicopathologic features with aggressive NK cell leukemia
● Historical terms: fulminant EBV+ T cell lymphoproliferative disorder of childhood, sporadic fatal infectious mononucleosis, fulminant hemophagocytic syndrome in children (Taiwan, Am J Pathol 1994;144:1219), fatal EBV associated hemophagocytic syndrome (Japan), severe chronic active EBV infection
● Severe chronic active EBV infection: infectious mononucleosis-like syndrome persisting for at least 6 months and associated with high titers of VCA-IgG and EA-IgG but no association with malignancy, autoimmune disease or immunodeficiency

Epidemiology
=========================================================================

● Most prevalent in Asia, primarily Japan and Taiwan; also reported in Mexico and rarely in West
● Children and young adults, no sex predilection
● Western version of chronic active EBV infection - progression to EBV-TLPD uncommon
● Japanese version of chronic active EBV infection - more severe with high fever, hepatosplenomegaly, extensive lymphadenopathy, pancytopenia, higher viral copy numbers in peripheral blood T cells or NK cells, monoclonal proliferation, usually progresses to malignancy (Blood 2001;98:280)

Etiology
=========================================================================

● Develops shortly after primary EBV infection or in the setting of chronic active EBV infection
● Etiology unknown, but association with EBV and racial predisposition strongly suggest genetic immune defect

Postulated normal counterpart
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● Cytotoxic CD8+ T lymphocytes or activated CD4+ T cells

Sites
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● Systemic: liver, spleen, lymph nodes, bone marrow, skin, lung

Clinical features
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● Previously healthy, then acute onset with fever and general malaise suggestive of viral syndrome, hepatosplenomegaly and liver failure and variable lymphadenopathy
● Aphthous stomatitis, ulcerative gingivitis, vesiculopapular and papulonecrotic mucocutaneous eruptions
● Very fulminant clinical course
● Rapid progression with multiple organ failure, sepsis and death, usually occuring in days to weeks
● Lab: pancytopenia, abnormal liver function tests, abnormal EBV serology with low or absent anti-VCA IgM antibodies
● Imaging: interstitial pneumonia, basal ganglia calcifications, coronary aneurysms
● Complications: hemophagocytic syndrome (Leuk Lymphoma 1995;19:401), coagulopathy, GI ulcers, coronary aneurysms, CNS involvement, multiorgan failure and sepsis

Treatment and prognosis
=========================================================================

● No standard treatment
● Usually resistant to conventional chemotherapy; hematopoietic stem cell transplant has been introduced
● Fulminant course in most cases with death within days or weeks
● Subacute course of several months to a year also possible

Micro description
=========================================================================

● Infiltrating, usually small T cells with no significant atypia; may have pleomorphic medium to large lymphoid cells, irregular nuclei and frequent mitoses
● Marked sinusoidal infiltration and hemophagocytosis in liver and spleen, splenic white pulp depletion, hepatic portal and sinusoidal infiltration, cholestasis, steatosis and necrosis
● Lymph nodes: preserved architecture, open sinuses, variable sinus histiocytosis with erythrophagocytosis
● Bone marrow: lymphohistiocytic hyperplasia with prominent erythrophagocytosis
● Lung: necrosis and peri-bronchial infiltration, sometimes angiocentricity and angioinvasion
● Skin: extension from epidermis to subcutis, necrosis, angiocentricity, angioinvasion, periappendageal infiltration, epidermal ulceration

Micro images
=========================================================================


   
Bone marrow

       
Liver and lung


Liver with CD3 and CD20


Liver double staining with CD4/EBER and CD8/EBER

   
Lymph nodes and skin

       
Spleen


Various images


Left: bone marrow-EBER1; Right: liver-CD45 RO

Positive stains
=========================================================================

● CD2, CD3, CD8 (acute primary EBV infection), CD4 (severe CAEBV), CD4/CD8 double positive rarely, TIA1, granzyme B, EBER-ISH

Negative stains
=========================================================================

● CD56

Molecular
=========================================================================

● Clonal TCR gene rearrangements
● Clonal episomal form of EBV type A (wild type or the 30bp deleted product of LMP1) in all cases
● No consistent chromosomal abnormalities, but often 6q deletion

Molecular images
=========================================================================



PCR for TCR-gamma gene


Hydroa Vacciniforme-like Lymphoma (HVL)

General
=========================================================================

● HVL is an EBV+ cutaneous T cell lymphoma occurring in children and associated with sun sensitivity (WHO 2008)

Epidemiology
=========================================================================

● Mainly children and adolescents from Asia, or Native Americans from Central and South America, and Mexico
● Rare in adults

Etiology
=========================================================================

● EBV transformed neoplastic cells (usually T but sometimes NK cells)
● Hypersensitivity to sunlight
● Related condition: mosquito bite hypersensitivity (the EBV+ cells are NK cells)

Postulated normal counterpart
=========================================================================

● Skin homing cytotoxic T cell or NK cell

Sites
=========================================================================

● Sun exposed skin, particularly the face (cheeks, nose, lower lip) but also ears and dorsum of hands

Clinical features
=========================================================================

● Papulovesicular eruption usually followed by ulceration and scarring (mimics herpes)
● Edema of face, eyelids and lips
● Systemic symptoms (fever, wasting, lymphadenopathy, hepatosplenomegaly, myocarditis) may occur, particularly late in course of disease

Treatment and prognosis
=========================================================================

● Variable clinical course with recurrent skin infections for up to 10-15 years before progression to systemic involvement
● Much more aggressive once systemic spread has occurred
● Mosquito bite allergy: clinically more aggressive and often associated with a hemophagocytic syndrome

Micro description
=========================================================================

● Small to medium neoplastic cells without significant atypia
● Infiltrates extend from epidermis to subcutis with necrosis, angiocentricity, angioinvasion, epidermal ulceration

Micro images
=========================================================================



Various images

Positive stains
=========================================================================

● Cytotoxic T cell phenotype; less often NK cell phenotype with CD56 expression
● EBER-ISH

Negative stains
=========================================================================

● EBV-LMP1

Genetics and molecular
=========================================================================

● Clonal TCR gene rearrangements in most cases (except some NK cell cases)
● EBV is monoclonal

Additional references
=========================================================================

Cancer 1991;68:1954, Blood 2000;96:443, Ann Oncol 2009;20:1472

End of Lymphoma - Non B cell neoplasms > T/NK cell disorders > EBV+ T cell lymphoproliferative disorders of childhood


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