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T-Cell lymphoproliferative disorders

T-cell lymphoproliferative disorders


Post thymic (tdt -ve) as compared to pre-thymic disorders (T-ALL = tdt positive)


WHO Classification

§        Leukaemia (arise in bone marrow with a leukaemic picture)

§        T-cell prolymphocytic leukaemia

§        T-cell large granular lymphocyte leukaemia (CD3 +)

§        Aggressive NK cell  leukaemia (CD3 -)

§        ATLL

§        Systemic EBV positive T cell LPD of childhood

§        Chronic LPD of NK cells

§        Extranodal lymphoma

§        Extranodal T/NK, nasal type

§        Enteropathy T-NHL

§        Hepatosplenic gamma/delta T-NHL

§        Cutaneous

§        Sezary syndrome / Mycosis fungoides

§        Primary cutaneous CD30+

§        Priamary cutaneous anaplastic large cell lymphoma

§        Lymphomatoid papulosis

§        Subcutaneous panniculitis like T-NHL

§        Primary cutaneous gamma delta T cell lymphoma

§        Primary cutaneous epidermotropic CD8+ cytotoxic T cell lymphoma

§        Primary cutaneous epidermotropic CD4+ cytotoxic T cell lymphoma

§        Nodal

§        Unspecified

§        Angioimmunoblastic

§        Anaplastic large cell lymphoma

§        ALK +

§        ALK -

§        Uncertain lineage

§        Blastic NK



T-prolymphocytic leukaemia

§        More frequent than B-cell PLL but rare (combined B&T account for 2% of mature lyphoid leukaemias)

§        Association with ataxia telangiectasia

§        Median age 65years

§        M>F

§        Clinical features

§        Hepatosplenomegaly

§        Lymphadenopathy

§        Skin involvement in one third

§        Effusions in 15%

§        CNS rare

§        Diagnosis

§        Prominent nucleolus

§        Deeply basophilic cytoplasm and protrusion of blebs

§        Lymphocyte count usually >100

§        Small cell variant

§        Nucleolus may not be visible by light microscopy

§        Cerebriform variant

§        Cerebriform nucleus

§        Immuno and cytogenetics similar to T-PLL

§        Aggressive

§        Spleen

§        Expansion of white pulp extending to the red pulp

§        Skin

§        Dermal infiltration preferentially around the appendages without epidermotropism

§        Immuno

§        Tdt and CD1a negative

§        CD2, CD3 (weak), CD5, CD7 positive

§        60% = CD4+ CD8-

§        25% = CD4+ CD8+ (almost unique to T-PLL)

§        15% = CD4- CD8+

§        CD52 (campath) is strongly expressed

§        Genetics

§        Antigen receptor genes

§        T cell receptor gamma and bet chains are clonally rearranged

§        Cytogenetics

§        Inv 14

§        Abnormalities of chromosome 11 and 8

§        Disease course

§        Generally aggressive with short survival (7 months)

§        Now improved with Campath

§        Treatment

§        Good responses to Campath 2/3 achieve CR

§        Needs to be consolidated by stem cell transplant


Large granular lymphocyte leukaemia (T-cell)

§   Previously T (CD3+) and NK (CD3-) cell LGL leukaemia considered together but now NK classified with NK cell neoplasms (NK aggressive course)

§        Association with autoimmune diseases (DR4 haplotype) – particularly rheumatoid with Felty’s

§        Clinical features

§        Adults, F>M

§        Recurrent infections due to cytopenias

§        Autoimmune disease

§        Hepatosplenomegaly

§        Lympadenopathy rare

§        Lymphocyte count uusually <15

§        Diagnosis

§        Morphologically, cannot be distinguished from normal circulating LGLs

§        Spleen

§        Expansion of red pulp with atrophic white pulp

§        Similar to HCL but no pseudolakes

§        Sarcoid like granulomas

§        Immuno

§        CD2, CD3, TCRa/b +

§        CD5, CD7 –

§        Most common is CD8+, CD4-, CD57+, CD16+, TIA-1+

§        TCR gene rearrangement studies are the key diagnostic test

§        Prognosis

§        Slowly progressive (median overall survival >10 years)

§        Watch and wait unless infections, progressive lymphocytosis or organomegaly

§        Symptoms may be controlled by immunosuppressive agents

§        CsA, low dose cyclophosphamide, pulsed MTX

§        Splenectomy not normally helpful at improving count and increases circulating LGLs



Adult T-cell leukaemia lymphoma


§        HTLV-1 is universally detected

§        Occurs in HTLV-1 endemic areas

§        Japan, Caribbean, Africa, S America, Middle East

§        Only 0.5% of carriers develop the disease

§        Familial cases of ATLL have been reported


Clinical features

§        2 thirds present with leukaemic form

§        Leukaemic form

§        Acute

§        Most common 65%

§        Widespread disease

§        Opportunistic infections (eg PCP, strongyloides)

§        Hypercalcaemia

§        Lymphadenopathy, skin lesions +/- hepatosplenomegaly

§        Lymphomatous form

§        Prominent lympadenopathy without peripheral blood involvement

§        Chronic             

§        5%

§        Stable or slowly progressive lympocytosis

§        Minor or no LAP, skin lesions

§        Smouldering

§        5%

§        Normal blood counts

§        Recurrent skin lesions or lung infiltrates

§        Chronic and smouldering progress over months or years into acute


§        HTLV-1

§        Retrovirus

§        May cause tropical spastic parapareis, arthritis, uveitis



§        Morphology

§        Pleomorphic cells with irregular nuclei and ‘flower’ cells

§        Immunology

§        CD2, CD3, CD5 +

§        CD4+, CD8-

§        Strong expression of IL-2 receptor CD25

§        Bone marrow

§        Mild or no infiltration

§        Bone resorption and proliferation of osteoclasts if calcium high

§        ? secondary to a PTH-like hormone

§        Serology

§        Demonstrate HTLV-1 positivity



§        Cytogenetics

§        Complex and may show clonal evolution as disease progresses


Differential diagnosis

§        Distinction between smouldering ATLL and carriers of the virus may be difficult

§        DNA analysis will show a monoclonal pattern of retroviral integration in smouldering ATLL versus a polyclonal pattern in the carrier


Clinical course

§        Acute

§        5-13 months

§        Transient response to chemotherapy

§        Chronic and smouldering

§        Indolent course until progression

§        CHOP

§        Alpha-interferon and zidovudine is effective

§        ? trial of chemo and dacluzimab (anti-CD25 MAB)



Sezary’s syndrome / Mycosis fungoides

§        SS Rare (incidence 4/1000,000)

§        Cutaneous T-cell lymphomas

§        Sezary’s syndrome considered to be the leukaemic manifestation of MF

§        Aetiology

§        Unknown

§        May progress from lymphomatoid papulosis (a recurrent skin eruption with Reed-Sternberg like cells infiltrating the skin, which may also progress to anaplastic lymphoma and Hodgkin’s)

§        Both MF and SS tend to affect the elderly (M>F)

§        Clinical features

§        Pruritus

§        Nodules and plaques

§        Diagnosis

§        Circulating atypical lymphocytes in SS

§        Variable size, hyperchromatic nucleus with scant cytoplasm

§        Prominent vacuolation in some cases

§        Serpentine nucleus with multiple narrow indentations = cerebriform

§        Lymphoid infiltrates in the dermis

§        Pautrier microabscesses

§        Negative for HTLV-1

§        Lymph node biopsy (may show reactive lymphadenitis rather but may be lymphoma)

§        Bone marrow shows mild interstitial infiltration when involved

§        Immunophenotyping

§        CD2, CD3 and CD5 and TCR beta positive

§        CD7-

§        CD25 rarely expressed (in contrast to ATLL)

§        Cytogenetics

§        Variable – often hyperploidy but no recurrent chromosomal abnormalities

§        Chromosome 17 abnormalities frequent (p53)

§        Differential diagnosis

§        Reactive dermatitis

§        T-PLL with skin involvement

§        ATLL

§        Cutaneous B-cell lymphomas


§        Clinical course

§        MF 87% survive 5 years

§        SS more rapidly progressive

§        10% transform into large T-cell NHL

§        Treatment

§        Topical

§        PUVA

§        Topical BCNU

§        Steroids

§        Local radiotherapy

§        Systemic

§        Single agent (eg methotrexate, cyclophosphamide)

§        Combination (eg CHOP)

§        Purine analogues

§        Interferon

§        Immunotherapy (anti IL2 MAB) conjugated with diphtheria toxin

§        Campath

§        (Allografting)


Priamry cutaneous anaplastic large cell lymphoma/ Lymphomatoid papulosis

§   CD30 positive cutaneous T cell lymphomas

§   Distinguuished for systemic anaplastic LCL be being limited to the skin

§   ALK negative

§   May be spontaneous regression

§   5 year survival of 90%

§   Treatment should be targeted at the skin lesions (eg. Surgery/ radiotherapy)

§   Over aggressive systemic treatment should be avoided/ reserved for disseminated disease.


Subcutaneous panniculitis-like T-NHL

§        Skin nodules resembling benign panniculitis

§        Haemophagocytic syndrome may be fatal

§        Marked prognostic difference between the more common  TCRa/b and TCR g/d ( 5 year survival 82 v 11%) so that now g/d classified seperately

§        Skin histology

§        Lymphoid infiltrates admixed with adipocytes in subcutaneous tissue; with sparing of the dermis and epidermis

§        Granulomas and tissue necrosis are common

§        Mitotic rate is high

§        CD2, CD3, CD8 +

§        Granzyme B, perforins and TIA-1 positive

§        Molecular analysis

§        Rearrangement of TCR-beta

§        Limited data on outcome or response to therapy but it seems poor



Extranodal T/NK lymphoma, nasal type

§   Common in China and S America – often related to EBV infection

§   Clonal T-cell nature not always confirmed but the clinical course suggests that it is a malignant disease

§   Patients present with extranodal disease, particularly nasal masses (skin, testes, CNS, lung, bowel and bone)

§   Histology shows lymphoid infiltrates with histiocytes and a marked angiocentricity and angiodestruction (necrosis probably relates to EBV driven release of TNF)

§   Immunophenotype either CD4+CD8- or NK phenotype (EBV+, CD56+)

§   Positive for cytotoxic granules ( perforin, granzyme)

§   LMP-1 + in most cells – latent membrane protein of EBV

§   Only a minority have TCR gene rearrangement

§   Prognosis variable, but disease occurring outside the nasal cavity is very aggressive

§   Best treatment is probably primary radiotherapy +/- chemo



§   T cell tumour of intra-epithelia lymphocytes

§   More common in areas with a high prevalence of celiac disease

§   Most commonly present in jejunum/ ileum

§   Presenting feature may be abdominal pain or perforation

§   Prognosis is poor, death frequently results from abdominal complications in patients already weakened by malabsorption.


Hepatosplenic gamma delta T-NHL

§        Young males

§        More common in immunocompromised (esp following solid organ transplants)

§        Hepatosplenomegaly without lymphadenopathy

§        Thrombocytopenia

§        Intrasinusoidal pattern of involvement in all tissues

§        CD2+, CD7+, CD3+-, TCR-gd+, TIA-1

§        TIA-1 is a MAb that identifies cytotoxic granule-associated proteins

§        TCR-ab-, CD4-, CD5-, CD8-

§        Molecular studies show rearrangement of the TCR-gd chain genes

§        Cytogenetics

§        Iso7q

§        Aggressive with median survival <2 years




Peripheral T NHL unspecified

§        Non-lymphoblastic tdt negative T NHL


Clinical features

§        Organomegaly, B-symptoms +/- extranodal disease

§        65% have stage 4 disease

§        May have eosinophilia, pruritus, haemophagocytosis or immune impairment

§        Aggressive with frequent relapses and poor outcome (5 year survival 20-30%)


Lymph node histology

§        Diffuse effacement of architecture by atypical lymphocytes

§        Or infiltration confined to interfollicular +/- paracortical zone

§        Background of eosinophilas and histiocytes

§        Neoplastic cells express T markers, although abberant phentyopes lacking pan T markers are common


Bone marrow

§        Rarely involved



§        Complex



§   New prognostic model – PIT incorporates features of IPI but also BM involvement

§   Identifies patients with different % year survival ranging form 18 to 62%



§        CHOP normal or intensified followed by SCT = gold standard



Angioimmunoblastic (AIL) T-NHL

§        Clinical features

§        Elderly adults

§        Acute onset

§        ‘B’ symptoms and lymphadenopathy

§        Skin rash and arthralgia

§        Immune disturbances common (immunodeficiency, autoimmune phenomena eg. AIHA, dysproteinaemia)

§        80% stage 3 or 4 at diagnosis

§        Diagnosis

§        Lymph node histology

§        Pleomorphic infiltrate compose of lymphocyts, plasma cells, immunoblasts and eosinophils with proliferation of epithelioid post-capillary venules.

§        CD2, CD5, CD3 and often CD10 +ve

§        TCR gene rearrangement confirms clonality

§        Treatment

§        Poor prognosis (survival <3 years)

§        Some patients respond to combination chemotherapy or steroids but most relapse

§        Likely that anti-T cell monoclonal Abs and SCT may improve the outcome


Anaplastic Large Cell Lymphoma

§   Lymphadenopathy

§   Extarnodal involvement common

§   B symptoms

§   >50% stage 3 or 4 at diagnosis

§   55-85% ALK + (t(2;5) ALK - nuclephosmin) and have good response to chemo and good prognosis

§   Hallmark cells – eccentric horse shoe shaped nucleus and a prominent eosinophilic golgi region

§   CD30+, TCR beta gamma rearrangements


§   ALK – occurs in older patients, extranodal involvement is less common

§   Prognosis worse compared to ALK+, but better than PTCL NOS.



§   CHOP widely used in PTCLs

§   With the exception of ALK pos ALCL, outcomes with CHOP are poor

§   Outcome of more intensive regimens not been proven

§   The need for anthracyclines, esp in PTCL NOS is controversial – may be anthracycline resistance secondary to p- GP expression.

§   New possibilities include combining chop with:

o        alemtuzumab (anti CD52)  - profoundly immunosupresssive and not all PTCLs express CD52

o        denileukin difitox – diphtheria – IL2 (CD25) fusion protein – no increased toxicity

o        bevacizumab

o        gemcitabine

§   Alternative include HDT and ASCT in first remission and allogeneic transplant at relapse

§   Novel agents

o        Pralatrexate; antifolate resulting in increased internalization and retention of the drug in tumours. Reults of a phase 2 study pending.

o        Depsipeptide; histone deacetylase inhibitor

o        Zanolimumab – anti CD4