Peripheral T-Cell and Anaplastic Large Cell Lymphoma

Anaplastic large cell lymphoma

• ALK-positive ALCL is defined by translocation of the ALK gene at 2p23, most often t(2;5)(p23;q35) creating the NPM1-ALK fusion. The fusion protein dimerizes constitutively, producing ligand-independent tyrosine kinase activity that drives STAT3, PI3K/AKT and RAS/MAPK signalling
• A single dominant driver, in a young patient with an otherwise intact genome, explains both the chemosensitivity and the excellent prognosis — and provides a target for ALK inhibitors
• ALK-negative ALCL is genetically heterogeneous. DUSP22 rearrangement marks a favourable subgroup with outcomes approaching ALK-positive disease; TP63 rearrangement marks a distinctly poor one. Both should be tested
• Breast implant-associated ALCL is ALK-negative and arises in the chronic inflammatory milieu of the fibrous capsule surrounding textured implants, with JAK/STAT activation. It is typically confined to the effusion and capsule

Angioimmunoblastic T-cell lymphoma (AITL)

• Derived from T follicular helper (TFH) cells, retaining their phenotype — CD4, CD10, BCL6, PD-1 and CXCL13 positive
• Characteristic mutation sequence: early TET2 and DNMT3A mutations (often present in haematopoietic stem cells as clonal haematopoiesis), followed by IDH2 R172 and the near-specific RHOA G17V
• The tumour cells retain TFH function and drive B-cell proliferation and antibody production, producing polyclonal hypergammaglobulinaemia and autoimmune phenomena. EBV-positive B-cell blasts proliferate in the background under this drive — a feature that can mislead toward an EBV-driven B-cell process

Other subtypes

• PTCL, not otherwise specified — the largest group, a diagnosis of exclusion without unifying genetics
• Enteropathy-associated T-cell lymphoma (EATL) — arises from intraepithelial lymphocytes in coeliac disease, typically after refractory coeliac disease type II
• Hepatosplenic T-cell lymphoma — a gamma-delta T-cell neoplasm with isochromosome 7q, infiltrating hepatic and splenic sinusoids and marrow, characteristically sparing lymph nodes
• Extranodal NK/T-cell lymphoma, nasal type — EBV-driven in essentially all cases, angiocentric and angiodestructive, causing ischaemic necrosis. Expresses P-glycoprotein, a multidrug efflux pump, which is why anthracycline-based therapy fails

• Age — most subtypes present in the sixties; ALK-positive ALCL is a disease of children and young adults
• Geography and ethnicity: extranodal NK/T-cell lymphoma is far more common in East Asia and Latin America; PTCL overall is more common in Asia
• Coeliac disease, particularly refractory coeliac disease type II, for enteropathy-associated T-cell lymphoma. Poor dietary adherence increases risk
• Chronic immunosuppression, notably thiopurines and anti-TNF agents in inflammatory bowel disease, for hepatosplenic T-cell lymphoma — classically a young man on long-term combination therapy
• EBV infection for extranodal NK/T-cell lymphoma and for the background B cells of AITL
• HTLV-1 causes adult T-cell leukaemia/lymphoma, a separate entity that must be excluded serologically
• Textured breast implants for breast implant-associated ALCL, with risk rising with time since implantation (median around 8-10 years); the absolute risk is low
• Prior chemotherapy or autoimmune disease, weakly

Common to the group

• Advanced stage at diagnosis in most, with B symptoms in a majority — more frequent than in B-cell lymphoma
• Extranodal involvement is frequent: skin, gastrointestinal tract, liver, spleen, marrow, lung
• Elevated LDH and poor performance status
• Haemophagocytic lymphohistiocytosis may complicate NK/T-cell and other T-cell lymphomas, presenting with fever, cytopenias, ferritin elevation and organ failure

Subtype-specific pictures

• ALK-positive ALCL: a young patient with lymphadenopathy, prominent B symptoms and high fever, frequent skin, bone, soft tissue and marrow involvement. Can be mistaken clinically for infection
• AITL: generalized lymphadenopathy with hepatosplenomegaly, skin rash, arthralgia, pleural effusions and oedema, plus polyclonal hypergammaglobulinaemia, Coombs-positive haemolytic anaemia, circulating immune complexes and autoantibodies. It is very commonly mistaken for a systemic autoimmune disease, a drug reaction or an infection, and patients often receive steroids — which transiently improve everything and delay diagnosis
• EATL: abdominal pain, weight loss and diarrhoea in a patient with coeliac disease, frequently presenting acutely with small bowel perforation or obstruction
• Hepatosplenic T-cell lymphoma: marked hepatosplenomegaly with cytopenias and characteristically no lymphadenopathy, in a young man, often on thiopurines for inflammatory bowel disease. Aggressive and frequently fatal
• Extranodal NK/T-cell lymphoma, nasal type: a destructive midline facial lesion — nasal obstruction, epistaxis, then progressive destruction of the nasal septum, palate and orbit ("lethal midline granuloma"). Perforation of the hard palate is characteristic
• Breast implant-associated ALCL: a late peri-implant seroma, typically more than a year after implantation, sometimes with a capsular mass or contracture. It is not a breast parenchymal tumour

• Excisional biopsy with expert haematopathology review. T-cell lymphomas are among the hardest lymphomas to classify, and reactive processes mimic them closely
• Comprehensive immunophenotyping: pan-T markers (CD2, CD3, CD5, CD7 — with aberrant loss supporting neoplasia), CD4 and CD8, and CD30 on every case, since CD30 positivity opens the door to brentuximab vedotin
• ALK immunohistochemistry and FISH in any CD30-positive large cell lymphoma. "Hallmark cells" — large cells with eccentric, horseshoe- or kidney-shaped nuclei and a paranuclear eosinophilic region — are characteristic of ALCL and present in all its variants
• DUSP22 and TP63 FISH in ALK-negative ALCL, because they define favourable and unfavourable subgroups
• TFH markers (CD10, BCL6, PD-1, CXCL13, ICOS) where AITL is suspected, plus EBER in situ hybridization, which will highlight background B cells rather than the tumour
• T-cell receptor gene rearrangement to demonstrate clonality — supportive, not by itself diagnostic
• EBER in suspected NK/T-cell lymphoma, with CD56 positivity and cytotoxic markers; circulating EBV DNA is useful for monitoring
• HTLV-1 serology to exclude adult T-cell leukaemia/lymphoma
• Coeliac serology and duodenal biopsy where EATL is considered
• Staging: PET-CT, bone marrow biopsy, LDH, and the IPI or the PIT (Prognostic Index for T-cell lymphoma: age, performance status, LDH, marrow involvement)
• For suspected breast implant-associated ALCL: aspirate the seroma and send fluid for cytology, CD30 immunostaining and flow cytometry — the diagnosis is usually made on effusion fluid, and a plain "seroma" should not be discarded without testing

Nodal PTCL and ALCL

• CHOP or CHOEP (adding etoposide, which benefits younger patients with normal LDH) has been the historical backbone, with unsatisfactory results in most subtypes
• Brentuximab vedotin with CHP (A+CHP), replacing vincristine, is standard for CD30-positive disease — the ECHELON-2 trial showed improved progression-free and overall survival versus CHOP, with the benefit driven largely by ALCL
• Autologous stem cell transplantation in first remission is widely used as consolidation for most subtypes, though not for ALK-positive ALCL in low-risk patients, whose outcomes with chemotherapy alone are good
• CNS prophylaxis in high-risk disease

Extranodal NK/T-cell lymphoma — do not use CHOP

• P-glycoprotein expression confers anthracycline resistance, so CHOP performs poorly. Treatment uses asparaginase-containing regimens such as SMILE or P-GEMOX
• Concurrent or sequential radiotherapy is essential for localized nasal disease and contributes substantially to cure
• PD-1 inhibitors are active in relapsed disease, reflecting the EBV-driven immune biology

Subtype-specific management

• Breast implant-associated ALCL: complete surgical excision — total capsulectomy with implant removal — is curative in the majority of patients with disease confined to the capsule and effusion. Chemotherapy is reserved for a mass lesion, nodal involvement or incomplete excision. This is the one lymphoma primarily managed by a surgeon
• ALK-positive ALCL relapse: crizotinib and other ALK inhibitors are highly active
• EATL: strict gluten-free diet, surgical management of perforation, then chemotherapy with transplant consolidation; outcomes remain poor
• Hepatosplenic T-cell lymphoma: intensive induction followed by allogeneic transplantation, which offers the only realistic chance of cure

Relapsed and refractory disease

• Pralatrexate, romidepsin and belinostat (the latter two histone deacetylase inhibitors, with particular activity in AITL and other TFH lymphomas)
• Azacitidine in TET2/DNMT3A-mutated AITL, exploiting the epigenetic biology
• Allogeneic stem cell transplantation for eligible patients, with a graft-versus-lymphoma effect
• Clinical trial enrolment should be the default given the poverty of standard options

• Refractory and relapsing disease — the dominant problem in all subtypes except ALK-positive ALCL and DUSP22-rearranged ALK-negative ALCL
• Haemophagocytic lymphohistiocytosis, particularly with NK/T-cell and gamma-delta lymphomas — fever, cytopenias, hyperferritinaemia, coagulopathy and multi-organ failure
• Bowel perforation and obstruction in EATL, sometimes as the presenting event and sometimes precipitated by treatment response
• Facial and orbital destruction, palatal perforation and disfigurement in nasal NK/T-cell lymphoma
• Autoimmune complications of AITL: haemolytic anaemia, immune thrombocytopenia, vasculitis
• Profound immunosuppression and opportunistic infection, worsened by disease-intrinsic T-cell dysfunction as well as therapy
• Secondary EBV-driven B-cell lymphoma arising from the expanded background B-cell population in AITL
• Treatment toxicity: brentuximab vedotin peripheral neuropathy (cumulative and dose-limiting), asparaginase-related pancreatitis, thrombosis, hypersensitivity and hepatotoxicity, and transplant-related mortality
• Capsular contracture, seroma recurrence and reconstructive issues after capsulectomy for implant-associated disease

• Peripheral T-cell lymphomas do worse than B-cell lymphomas — no CD20, so no rituximab. Brentuximab vedotin targets CD30 and is the closest equivalent, so check CD30 on every case
• ALK-positive ALCL is the outlier — young patients, t(2;5) NPM1-ALK, and 70-90% five-year survival, better than most B-cell lymphomas. Do not lump it with poor-prognosis PTCL
• "Hallmark cells" with eccentric horseshoe- or kidney-shaped nuclei and strong CD30 define ALCL
• In ALK-negative ALCL, test DUSP22 (favourable) and TP63 (poor) — the prognosis differs several-fold between them
• Breast implant-associated ALCL is ALK-negative, arises around textured implants, and presents as a late seroma. Complete capsulectomy with implant removal is usually curative — send any late peri-implant seroma for cytology and CD30
• AITL masquerades as autoimmune disease: lymphadenopathy, rash, hypergammaglobulinaemia, Coombs-positive haemolysis and arthralgia, with a transient response to steroids. It is of T follicular helper origin (CD10, BCL6, PD-1, CXCL13), with RHOA G17V, TET2, DNMT3A and IDH2 mutations, and EBV-positive background B cells
• Extranodal NK/T-cell lymphoma, nasal type: EBV-driven midline destructive facial lesion, CD56-positive. CHOP fails because of P-glycoprotein-mediated drug efflux — use asparaginase-based regimens plus radiotherapy
• Hepatosplenic T-cell lymphoma: young man, hepatosplenomegaly with cytopenias and no lymphadenopathy, gamma-delta phenotype, isochromosome 7q, associated with thiopurines and anti-TNF therapy in inflammatory bowel disease. Very poor prognosis
• EATL complicates coeliac disease, arises in the jejunum, and often presents with perforation
• A+CHP beat CHOP on overall survival in CD30-positive disease (ECHELON-2) — one of the few clear survival advances in this group
• Autologous transplantation in first remission is standard for most subtypes but not needed for low-risk ALK-positive ALCL
• Crizotinib for relapsed ALK-positive disease — a targeted option that follows directly from the driving translocation
• Always exclude HTLV-1 before settling on a peripheral T-cell lymphoma diagnosis