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
LEUKAEMIA 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 Aetiology § 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
Diagnosis § 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
Pathogenesis § 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)
CUTANEOUS 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 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
Enteropathic § 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
NODAL 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
Cytogenetics § Complex
Prognosis § New prognostic model – PIT incorporates features of IPI but also BM involvement § Identifies patients with different % year survival ranging form 18 to 62%
Treatment § 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.
Treatment § 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 |
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