EBV-positive T cell and NK cell LPD of Childhood Flashcards
What are the 2 categories of
EBV associated LPDs in pediatrics ?
- systemic EBV-positive T cell lymphoma of childhood
- Chronic active EBV infection
- significant overlap in these entities morphologically so the clinical features are very helpful in differentiating them
*both are more common in Asians and in Native Americans from central and South America as well as Mexico
What is true about EBV positive HLH in
pediatrics/adolescents ?
- it can be benign and/or self limited in some cases
What are the sub-categories of
systemic chronic active EBV LPDs?
- cutaneous CAEBV, hydroa-vacciniforme-like LPD
- cutaneous CAEBV, severe mosiquito bite allergy
- systemic CAEBV
What are the EBV related disorders
identified in adults ?
- aggressive NK-cell leukemia
- extranodal NK/T cell lymphoma, nasal type
- nodal peripheral T cell lymphoma, EBV positive
What is the definition of systemic
EBV-positive T cell lymphoma of childhood ?
- life threatening illness
- clonal proliferation of EBV-infected T cells with an activated cytotoxic phenotype
- occurs
- right after acute EBV infection OR
- in the setting of chronic active EBV
- rapid progression
- multiorgan failure, HLH is almost always present
- sepsis and death
- days to weeks
- overlapping features with aggressive NK-cell leukemia
What is the definition of Chronic active
EBV infection ?
- infectious-mononucleosis like syndrome persisting for at least 6 months and associated with high titers of IgG antibodies against EBV viral capsid antigen and early antigen
- no association with malignancy, autoimmune diseases or immunodeficiency
- primarily affects T cells and NK cells
- progression to EBV+ T cell lymphoma is not uncommon
What are the epidemiology and
etiology of systemic EBV+
T cell lymphoma of childhood ?
- most prevalent in Asia, primarily Japan, Taiwan and China
- it has been reported in central and south America as well as Mexico
- occurs most often in children and young adults
- unknown true etiology of the disease but:
- association with primary EBV infection
- racial predisposition
- suggests a genetic defect in the host immunne response
What is the localization of systemic
EBV+ T cell lymphoma of childhood ?
- liver and spleen are most common sites
- followed by:
- LN
- bone marrow
- skin
- lungs
What are the clinical features of systemic
EBV T cell lymphoma of childhood ?
- previously healthy patients
- acute viral respiratory illness occurs: fever general malaise
- over weeks to months develop hepatosplenomegaly and liver failure sometimes with LN
- pancytopenia with abnormal LFTs and abnormal EBV serology with low or absent IgM antibodies against viral capsid antigen
- complications:
- HLH, coagulopathy
- multiorgan failure
- sepsis
- disease can spread anywhere but CNS involvement is rare
What are the microscopic features of
Systemic EBV+ T cell lymphoma of childhood ?
- usually the infiltrating T cells are small and lack substantial cytologic atypia
- cases with medium to large pleomorphic, irregular nuclei and frequent mitoses have been described
- liver and spleen
- mild to marked sinusoidal infiltration
- striking HLH
- splenic white pulp is depleted
- liver with marked portal infiltrates, cholestasis, steatosis and necrosis
- LN
- open sinuses with partial preserved architecture
- expanded paracortical areas with erythrophagocytosis
- BM
- histiocytic hyperplasia with prominent erythrophagocytosis
What is the immunophenotype of
Systemic EBV+ T cell lymphoma of childhood ?
- CD3, CD2, CD8 and TIA1+
- EBV +
- CD56-
- rare cases show both CD4 and CD8 positivity
- both are positive for EBV in this case
What is the postulated normal counterpart
for Systemic EBV+ T cell lymphoma
of Childhood?
- a cytotoxic CD8+ T cell or activated CD4+ T cell
What is the genetic profile of Systemic
EBV+ T cell lymphoma of childhood ?
- monoclonally rearranged TR genes
- all cases harbour EBV in a clonal episomal form
- No consistent chromosomal aberrations have been identified
What are the prognostic and predictive
factors for systemic EBV+ T cell lymphoma of childhood ?
- most cases have a fulminant clinical course resulting in death
- usually within days to weeks of diagnosis
- most pts develop HLH
- the clinical course is similar to NK cell leukemia
What is the definition of CAEBV of
T and NK cell type, systemic form ?
- polyclonal, oligoclonal or often monoclonal LPD with fever, persistent hepatitis, hepatosplenomegaly and lymphadenopathy
- severity varies based on host immunity and EBV viral load
- Diagnostic Criteria:
- infectious mono sx > 3 months
- increased EBV DNA ( > 10.5 copies/mg)
- in peripheral blood
- histologic evidence of organ disease
- demonstration of EBV RNA or viral protein in tissues
- no known immunodeficiency, malignancy or autoimmune disorder
What is the epidmiology of CAEBV of NK and T cell
type, systemic ?
- definite racial predilection:
- Japan, Korea, Taiwan, China
- South America
- Africa
- occurs in children and adolescents
- if it occurs in adults it is rapidly progressive
What is the etiology of CAEBV,
T and NK cell type, systemic ?
- etiology is not quite known
- racial predilection in immunocompetent individuals suggests:
- genetic polymorphisms in genes related to EBV immune response
- EBV specific cytotoxic T lymphocyte activity is impaired
What is the localization of CAEBV
T and NK cell type, systemic ?
- Most common sites of involvement:
- liver
- spleen
- lymph nodes
- bone marrow
- skin
- systemic disease so can affect any organ
What are the clinical features of CAEBV
T and NK cell type, systemic ?
- 50% of patients present with IM-like symptoms as well as other manifestations:
- skin rash
- hydroa-vacciniforme-like eruptions
- mosquito bite allergy
- uveitis
- abnormal LFTs
- high titers of EBV IgG antibodies against viral capsid are seen
- all patients have increased EBV DNA in the PB
- protracted clinical course without progression for many years
- patients with T cell disease have shorter survival than those with Nk cell disease
What are the complications that arise
from CAEBV T and NK cell type,
systemic ?
- HLH (20%)
- coronary aneurysm
- hepatic failure (15%)
- interstitial pneumonia
- CNS involvement
- myocarditis
- GI perforation
IMP: 16% progress to NK/T cell lymphoma or aggressive NK-cell leukemia
What are the microscopic features of
CAEBV infection, T and NK cell type,
systemic form ?
- IMP: the infiltrating cells do not show changes suggestive of neoplastic infiltration
- Liver: portal infiltrate suggestive of viral hepatitis
- Spleen: atrophy of white pulp and congested red pulp
- LN: variable morphology including paracortical and follicular hyperplasia, focal necrosis and epithelioid granulomas
- BM: usually appear normal
What is the immunophenotype of
CAEBV infection, T and NK cell type,
systemic form ?
- variable immunophenotype
- T and NK cells
- IMP: unlike EBV+ T cell lymphoma the T cells in CAEBV are CD4+
- rarely (2%) of cases are B cell phenotype
- EBV RNA (EBER) is positive
What is the cell of origin for
CAEBV infection, T and NK cell type,
systemic form ?
What is the genetic profile of
CAEBV infection, T and NK cell type,
systemic form ?
- chromosomal aberrations are seen in a small number of cases
- some reports of polyclonal, oligoclonal and monoclonal TCR gene but these may include cases of EBV T cell lymphoma
What is the prognostic and predictive factors
of CAEBV infection, T and NK cell types,
systemic form ?
- prognosis is variable with some cases having an indolent clinical course and others more aggressive
- Risk factors for mortality:
- patient age > 8 years old
- liver dysfunction
- Adults with CD4+ disease have more aggressive clinical course
- IMP:
- monoclonality does not correlate with increased mortality
- does NOT warrant a diagnosis of lymphoma
- Bone marrow transplantation improves prognosis
What is the definition of Hydroa-vacciniforme-like
LPD (HV-LPD) ?
- chronic EBV+ LPD
- associated with a risk of developing systemic lymphoma
- primarily cutaneous
- can be polyclonal
- usually monoclonal T or NK cells
- broad spectrum of aggressiveness and long clinical course
- severe and extensive skin lesions develop as disease progresses
- develop systemic symptoms
- Spectrum of disease includes:
- Classic HV, severe HV, and HV-like T cell lymphoma
What is the epidemiology of
HV-like LPD ?
- more common in Asian, South and Central American and Mexican
- seen in children and adolescents
- rare in adults
- median patient age: 8
- slightly more common in males
What is the etiology of HV-like
LPD ?
- etiology is unknown
- likely a genetic predisposition given the distribution of the disease
What is the localization of
HV-like LPD ?
- cutaneous condition that affects sun-exposed and non-sunexposed areas
- Early phase:
- affects mainly face, dorsal surface of the hands and earlobes
- Late phase:
- can be generalized
What are the clinical features
of HV-like LPD ?
- severity and presenation vary amongst patients
- starts with a papulovesicular rash that then proceeds to ulceration and scarring
- Classic HV
- indolent course
- localized skin lesions in sun-exposed areas
- no systemic symptoms
- spontaneous remission may occur with photoprotection but usually a long clinical course with progression
- Seasonal variation:
- increased in spring and summer
- Severe HV
- systemic symptoms (fever, wasting, hepatosplenomegaly and LN)
- extensive skin diseases
What are the macroscopic features
of HV-like LPD ?
- prominent swelling of the face, lips, eyelids
- mulitple vesiculopapular lesions with umbilication and crusts
What are the microscopic features of
HV-like LPD ?
- classic: epidermal reticular degeneration
- leads to epidermal spongiotic vesicle formation
- lymphoid infiltrate predominantly in the dermis but may extend into the subQ
- mostly around BV and adnexa
- angiodestructive features are present
- intensity of the infiltrate and atypia vary
- usually small to medium size lymphocytes without significant atypia
- epidermis is ulcerated in severe cases
What is the immunophenotype of
HV-like LPD ?
- cytotoxic T cell phenotype (CD8+) most common
- CD4+ in a few cases
- 1/3 cases have an NK cell phenotype with CD56+
- clonal expansion of G/D T cells has been documented in the peripheral blood in many cases but not in the skin
- CCR4 is expressed in the G/D T cells
- CD30+
- in EBV+ T cells
- LMP1
- usually negative
What is the postulated normal counterpart
to HV-like LPD ?
- skin-homing cytotoxic T cell or NK cell
- G/D T cells play some role in the formation of vesicles
What is the genetic profile of
HV-like LPD ?
- most have clonal rearrangement of TR genes
- except for those with NK cell phenotype
- EBER ISH is positive to varying degrees from case to case
What are the prognostic and predictive factors
for HV-like LPD ?
- clinical course is variable
- recurrent skin lesions for as long as 10-15 years before progressing to systemic involvement
- T cell clonality and the number of EBV positive cells do not predict the clinical course
- The disease is resistant to conventional chemotherapy and patients often die of infectious complications
What is the definition of
Severe Mosquito Bite Allergy?
- EBV+ NK LPD
- characterized by high fever and intense local symptoms
- erythema, bullae, ulcers, skin necrosis, deep scarring
- all occur following a mosquito bite
- characterized by high fever and intense local symptoms
- NK cell lymphocytosis in the peripheral blood
- Increased risk of HLH
- can progress to over NK/T cell lymphoma or aggressive NK cell leukemia
What is the epidemiology of
Severe mosquito bite allergy?
- severe mosquito bite allergy is very uncommon
- most of the cases have been reported in Japan and some other Asian countries as well as Mexico
- occurs in young patients
- from birth to 18
- no sex predilection
What is the etiology of severe mosquito
bite allergy ?
- occurs due to a CD4+ T cell proliferation responding to the salivary secretions of the mosquito
- CD4+ T cells reactivate EBV in NK cells and induce LMP1 expression
- LMP1 expression induces NK cell proliferations
- may be responsible for the development of NK cell leukemia
What are the clinical features of
severe mosquito bite allergy?
- local skin symptoms:
- erythema, bullae, ulcers, necrosis and scarring
- high fever and general malaise are common
- High serum IgE, high EBV DNA load in PB, and NK cell lymphocytosis
- after recovering patients are usually asymptomatic until the next mosquito bite
What are common complications of
severe mosquito bite allergy?
- progression to:
- systemic CAEBV infection of NK cell type
- HLH
- aggressive NK cell leukemia
- Nasal type extranodal NK/T cell lymphoma
What are the microscopic findings
of Severe Mosquito Bite Allergy ?
- epidermal necrosis, ulcceration or intraepidermal bullae
- dermis
- edema and a dense infiltrate extending into the SubQ
- angioinvasion and angiodestruction
- polymorphic infiltrate but with numerous large atypical cells, small lymphocytes, histiocytes and abundant eosinophils
- IMP:
- morphology is similar to HV-like LPD
What is the immunophenotype of
severe mosquito bite allergy ?
- NK cell immunophenotype
- CD3 epsilon and CD56+
- TIA1 and granzyme B positive
- CD4 and CD8 reactive T cells are seen in variable numbers
- CD30+ in EBV+ cells
What is the postulated normal counterpart
of severe mosquito bite allergy ?
- mature activated NK cell
What is the genetic profile of
Severe mosquito bite allergy?
- NK cells are infected with monoclonal EBV with clonal expansion
- Rare, monoclonal TR gene rearrangement can be seen
- chromosomal aberrations are rare
- EBER ISH positive in subset of NK cells
What is the prognosis for
Severe mosquito bite allergy ?
- usually a long clinical course
- increased risk of developing HLH and NK cell leukemia after 2-17 years (median 12)
- particularly in patients with chromosomal abnormalities
