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Hematopathology WHO T cell Neoplasms > EBV-positive T cell and NK cell LPD of Childhood > Flashcards

EBV-positive T cell and NK cell LPD of Childhood Flashcards

1
Q

What are the 2 categories of

EBV associated LPDs in pediatrics ?

A
  • 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

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2
Q

What is true about EBV positive HLH in

pediatrics/adolescents ?

A
  • it can be benign and/or self limited in some cases
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3
Q

What are the sub-categories of

systemic chronic active EBV LPDs?

A
  • cutaneous CAEBV, hydroa-vacciniforme-like LPD
  • cutaneous CAEBV, severe mosiquito bite allergy
  • systemic CAEBV
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4
Q

What are the EBV related disorders

identified in adults ?

A
  • aggressive NK-cell leukemia
  • extranodal NK/T cell lymphoma, nasal type
  • nodal peripheral T cell lymphoma, EBV positive
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5
Q

What is the definition of systemic

EBV-positive T cell lymphoma of childhood ?

A
  • 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
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6
Q

What is the definition of Chronic active

EBV infection ?

A
  • 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
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7
Q

What are the epidemiology and

etiology of systemic EBV+

T cell lymphoma of childhood ?

A
  • 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
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8
Q

What is the localization of systemic

EBV+ T cell lymphoma of childhood ?

A
  • liver and spleen are most common sites
  • followed by:
    • LN
    • bone marrow
    • skin
    • lungs
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9
Q

What are the clinical features of systemic

EBV T cell lymphoma of childhood ?

A
  • 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
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10
Q

What are the microscopic features of

Systemic EBV+ T cell lymphoma of childhood ?

A
  • 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
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11
Q

What is the immunophenotype of

Systemic EBV+ T cell lymphoma of childhood ?

A
  • CD3, CD2, CD8 and TIA1+
  • EBV +
  • CD56-
  • rare cases show both CD4 and CD8 positivity
    • both are positive for EBV in this case
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12
Q

What is the postulated normal counterpart

for Systemic EBV+ T cell lymphoma

of Childhood?

A
  • a cytotoxic CD8+ T cell or activated CD4+ T cell
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13
Q

What is the genetic profile of Systemic

EBV+ T cell lymphoma of childhood ?

A
  • monoclonally rearranged TR genes
  • all cases harbour EBV in a clonal episomal form
  • No consistent chromosomal aberrations have been identified
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14
Q

What are the prognostic and predictive

factors for systemic EBV+ T cell lymphoma of childhood ?

A
  • 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
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15
Q

What is the definition of CAEBV of

T and NK cell type, systemic form ?

A
  • 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
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16
Q

What is the epidmiology of CAEBV of NK and T cell

type, systemic ?

A
  • definite racial predilection:
    • Japan, Korea, Taiwan, China
    • South America
    • Africa
  • occurs in children and adolescents
    • if it occurs in adults it is rapidly progressive
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17
Q

What is the etiology of CAEBV,

T and NK cell type, systemic ?

A
  • 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
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18
Q

What is the localization of CAEBV

T and NK cell type, systemic ?

A
  • Most common sites of involvement:
    • liver
    • spleen
    • lymph nodes
    • bone marrow
    • skin
  • systemic disease so can affect any organ
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19
Q

What are the clinical features of CAEBV

T and NK cell type, systemic ?

A
  • 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
20
Q

What are the complications that arise

from CAEBV T and NK cell type,

systemic ?

A
  • 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

21
Q

What are the microscopic features of

CAEBV infection, T and NK cell type,

systemic form ?

A
  • 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
22
Q

What is the immunophenotype of

CAEBV infection, T and NK cell type,

systemic form ?

A
  • 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
23
Q

What is the cell of origin for

CAEBV infection, T and NK cell type,

systemic form ?

A
24
Q

What is the genetic profile of

CAEBV infection, T and NK cell type,

systemic form ?

A
  • 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
25
Q

What is the prognostic and predictive factors

of CAEBV infection, T and NK cell types,

systemic form ?

A
  • 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
26
Q

What is the definition of Hydroa-vacciniforme-like

LPD (HV-LPD) ?

A
  • 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
27
Q

What is the epidemiology of

HV-like LPD ?

A
  • 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
28
Q

What is the etiology of HV-like

LPD ?

A
  • etiology is unknown
  • likely a genetic predisposition given the distribution of the disease
29
Q

What is the localization of

HV-like LPD ?

A
  • 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
30
Q

What are the clinical features

of HV-like LPD ?

A
  • 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
31
Q

What are the macroscopic features

of HV-like LPD ?

A
  • prominent swelling of the face, lips, eyelids
  • mulitple vesiculopapular lesions with umbilication and crusts
32
Q

What are the microscopic features of

HV-like LPD ?

A
  • 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
33
Q

What is the immunophenotype of

HV-like LPD ?

A
  • 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
34
Q

What is the postulated normal counterpart

to HV-like LPD ?

A
  • skin-homing cytotoxic T cell or NK cell
  • G/D T cells play some role in the formation of vesicles
35
Q

What is the genetic profile of

HV-like LPD ?

A
  • 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
36
Q

What are the prognostic and predictive factors

for HV-like LPD ?

A
  • 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
37
Q

What is the definition of

Severe Mosquito Bite Allergy?

A
  • EBV+ NK LPD
    • characterized by high fever and intense local symptoms
      • erythema, bullae, ulcers, skin necrosis, deep scarring
      • all occur following a mosquito bite
  • NK cell lymphocytosis in the peripheral blood
  • Increased risk of HLH
  • can progress to over NK/T cell lymphoma or aggressive NK cell leukemia
38
Q

What is the epidemiology of

Severe mosquito bite allergy?

A
  • 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
39
Q

What is the etiology of severe mosquito

bite allergy ?

A
  • 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
40
Q

What are the clinical features of

severe mosquito bite allergy?

A
  • 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
41
Q

What are common complications of

severe mosquito bite allergy?

A
  • progression to:
    • systemic CAEBV infection of NK cell type
    • HLH
    • aggressive NK cell leukemia
    • Nasal type extranodal NK/T cell lymphoma
42
Q

What are the microscopic findings

of Severe Mosquito Bite Allergy ?

A
  • 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
43
Q

What is the immunophenotype of

severe mosquito bite allergy ?

A
  • 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
44
Q

What is the postulated normal counterpart

of severe mosquito bite allergy ?

A
  • mature activated NK cell
45
Q

What is the genetic profile of

Severe mosquito bite allergy?

A
  • 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
46
Q

What is the prognosis for

Severe mosquito bite allergy ?

A
  • 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

Hematopathology WHO T cell Neoplasms (14 decks)

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