Pulmonary manifestations of peripheral T‐cell lymphoma: case report and review of the literature

Introduction: Peripheral T‐cell lymphomas (PTCL) represent approximately 10% of non‐Hodgkin's lymphomas. Pulmonary involvement is an uncommon manifestation of this heterogeneous group of malignancies. Methods: Report of a case. Results: This case report describes a 75‐year‐old man with fever, weight loss, anemia, enlargement of spleen and liver, atypical lymphocytes and pulmonary nodules. Lung biopsy showed lymphocytic infiltration of the lung parenchyma. T‐cell receptor gamma gene rearrangement by polymerase chain reaction confirmed the diagnosis of peripheral T‐cell lymphoma. Unfortunately, the patient died because of refractory and aggressive disease. Conclusion: Pulmonary and pleural involvement are seen in patients with PTCL and usually carry a poor prognosis. The subject of pulmonary involvement in peripheral T‐cell lymphoma is discussed. Please cite this paper as: Vahid B, Machare‐Delgado E and Marik PB. Pulmonary manifestations of peripheral T‐cell lymphoma: case report and review of the literature. The Clinical Respiratory Journal 2007; 1:114–117.     

Peripheral T‐cell lymphoma gene expression profiling and potential therapeutic exploitations

Peripheral T‐cell lymphomas constitute a heterogeneous group with regard to diagnosis, treatment and prognosis. Efforts have been made to combine novel techniques with cytology and immunochemistry in order to more precisely define these entities. Molecular profiling has contributed to novel insights in the biology of T‐cell lymphoma. Regarding anaplastic large cell lymphoma, low expression T‐cell receptor signalling and high STAT3 target signatures have been associated with the ALK‐positive subgroup. Gene expression profiling differentiates angioblastic T‐cell lymphoma from other T‐cell malignancies, suggests that the normal counterpart of lymphoma cells are follicular helper T cells, and supports the involvement of vascular endothelial growth factor deregulation in its physiopathology. In peripheral T‐cell lymphoma unspecified, gene profiling suggests the normal counterpart of tumour cells are activated CD4⁺ or CD8⁺ T‐lymphocytes, delineates prognostic groups depending on the proliferative signature, and suggests therapeutic options aimed at regulating nuclear factor‐κB and platelet‐derived growth factor receptor‐α phosphorylation. Gene expression profiling of primary cutaneous T cell lymphomas highlighted the importance of abnormal methylation patterns, suggested a pivotal role for JUNB/AP‐1, and defined a predictive model for response to interferon‐α. In conclusion, gene expression profiling is beginning to change the pathological classification, the prognosis profiles and the therapeutic approach in T‐cell lymphomas.     

Upfront VIP‐reinforced‐ABVD (VIP‐rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS‐LTP95

Peripheral T‐Cell lymphomas (PTCL) are relatively rare diseases but appear to be highly aggressive and display worse remission and survival rates than B‐cell lymphomas. Despite unsatisfactory results with the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen, it remains the reference front‐line therapy in these diseases, but has not been challenged in phase III trials. The Groupe Ouest Est d’Etude des Leucémies et Autres Maladies du Sang (GOELAMS) devised an alternative therapeutic schedule including etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (VIP‐reinforced‐ABVD; VIP‐rABVD) and compared it to CHOP/21 as front‐line treatment in non‐cutaneous PTCL. All newly diagnosed patients were eligible. The primary objective was to improve the 2‐year event‐free survival (EFS) rate. Secondary objectives were to compare the response rate, overall survival, and toxicities as well as identify prognostic factors. Eighty‐eight patients were identified between 1996 and 2002 . Both arms were well balanced for patients’ characteristics in terms of histological and clinical presentation. No significant difference was observed between the two arms in terms of 2‐year EFS. Anaplastic large cell lymphoma type and Ann Arbor stage I–II were identified as two independent favourable prognostic factors influencing survival. VIP‐rABVD was not superior to CHOP/21 in terms of EFS as first‐line treatment of PTCL, confirming that CHOP/21 remains the reference regimen in these lymphomas.     

A case of nasal‐type NK/T cell lymphoma in a patient with dermatomyositis

The association of malignancy with dermatomyositis is well known, and the frequency is reported to be up to 30%. However, cutaneous lymphoma associated with dermatomyositis has rarely been reported. We experienced a case of nasal‐type NK/T‐cell lymphoma in a 40‐year‐old woman with a 2‐year history of dermatomyositis. To our knowledge, this is the first report of cutaneous involvement of nasal‐type NK/T‐cell lymphoma developing in a dermatomyositis patient. When skin lesions are resistant to aggressive conventional treatment in dermatomyositis patients, we should consider the possibility of malignancy, especially cutaneous lymphoma.     

Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma)

The peripheral T-cell neoplasms are a biologically and clinically heterogeneous group of rare disorders that result from clonal proliferation of mature post-thymic lymphocytes. Natural killer (NK) cell neoplasms are included in this group. The World Health Organization classification of haemopoietic malignancies has divided this group of disorders into those with predominantly leukaemic (disseminated), nodal, extra-nodal or cutaneous presentation. They usually affect adults and are more commonly reported in males than in females. The median age at diagnosis is 61 years with a range of 17-90 years. Although some subtypes may follow a relatively benign protracted course most have an aggressive clinical behaviour and poor prognosis. Excluding anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), which has a good outcome, 5-year survival for other nodal and extranodal T-cell lymphomas is about 30%. Most patients present with unfavourable international prognostic index scores (>3) and poor performance status. The rarity of these diseases and the lack of randomized trials mean that there is no consensus about optimal therapy for T- and NK-cell neoplasms and recommendations in this guideline are therefore based on small case series, phase II trials and expert opinion.     

Ethnic disparity in primary cutaneous CD30+ T‐cell lymphoproliferative disorders: an analysis of 1496 cases from the US National Cancer database

Primary cutaneous CD30⁺ T cell lymphoproliferative disorders (PCLPD), the second most common type of primary cutaneous T cell lymphomas, accounts for approximately 25–30% of cutaneous T‐cell lymphoma cases. However, only small retrospective studies have been reported. We aimed to identify prognostic factors and evaluate the overall survival (OS) of patients with PCLPD stratified by ethnicity. We identified 1496 patients diagnosed with PCLPD between 2004 and 2014 in the US National Cancer Database. Chi‐square test and anova were used to evaluate differences in demographic and disease characteristics, socioeconomic factors and treatments received. OS was evaluated with the log‐rank test, Cox proportional hazard regression analysis, and propensity score matching. The study included 1267 Caucasians, 153 African Americans (AA), 43 Asians, and 33 of other/unknown ethnicity. Older age, higher Charlson‐Deyo score, higher clinical stage and receipt of chemotherapy were predictors of shorter OS. Primary disease site on a lower extremity was associated with shorter OS, while a head and neck location was associated with longer OS. AA patients had shorter OS when compared to Caucasian patients on multivariate analysis. This ethnic disparity persisted on propensity‐score matched analysis and after matching Caucasian and AA patients on demographic and disease characteristics, socioeconomic factors and treatments received, and age and gender‐matched relative survival analyses.     

Allogeneic haematopoietic cell transplantation after nonmyeloablative conditioning in patients with T‐cell and natural killer‐cell lymphomas

Patients with T‐cell and natural killer‐cell lymphomas have poor outcomes. This study examined the role of allogeneic haematopoietic cell transplantation (allo‐HCT) after nonmyeloablative conditioning in this setting. Seventeen patients with T‐cell lymphoma or NK‐cell lymphoma, including three patients in first complete remission, received allo‐HCT after 2 Gy total‐body irradiation and fludarabine. The median age was 57 (range, 18–73) years. The median number of prior therapies was 3 (range, 1–7), six patients (35%) had failed prior autologous HCT, and five patients (29%) had refractory disease at the time of allograft. Postgrafting immunosuppression was provided with mycophenolate mofetil with ciclosporin or tacrolimus. After a median follow‐up of 3·3 (range, 0·3–8·0) years among surviving patients, the estimated probabilities of 3‐year overall and progression‐free survival were 59% and 53%, respectively, while the estimated probabilities of non‐relapse mortality and relapse at 3 years were 19% and 26%, respectively. Sixty‐five percent of patients developed grades 2–4 acute graft‐versus‐host disease and 53% of patients developed chronic graft‐versus‐host disease. Allo‐HCT after nonmyeloablative conditioning is a promising salvage option for selected patients with T‐cell and NK‐cell lymphomas. These results suggest that graft‐versus‐T‐cell lymphoma activity is responsible for long‐term disease control.     

Uncommon non‐Hodgkin lymphomas of childhood: pathological diagnosis,clinical features and treatment approaches

We provide a review of the pathological and clinical features for uncommon B‐cell and T‐cell lymphomas of childhood with a specific focus on advances in treatment approaches and outcomes. There is clearly a need for prospective investigation of both the clinical and biological features of the uncommon non‐Hodgkin lymphoma subtypes in childhood. These results should lead to more uniform and more effective treatment approaches.     

THP‐COP regimen for the treatment of peripheral T‐cell lymphoma and adult T‐cell leukemia/lymphoma: a multicenter phase II study

Objective: The efficacy of pirarubicin (THP)‐COP was previously compared with cyclophophamide + doxorubicin + vincristine + prednisolone (CHOP) in elderly patients with lymphoma. The subset analysis showed that T‐cell lymphoma had a significantly better response with THP‐COP, whereas no such difference was observed in B‐cell lymphoma. The aim of this study is to confirm the efficacy of THP‐COP in the treatment of T‐cell lymphoma. Methods: We underwent a multicenter phase II study of THP‐COP as a first‐line treatment for T‐cell lymphoma. The overall response rate, survival period, and toxicity were analyzed. Results: Fifty‐three patients were enrolled in this study. Seventeen patients had peripheral T‐cell lymphoma (PTCL), including nine of PTCL not otherwise specified (PTCL‐NOS) and eight of angioimmunoblastic T‐cell lymphoma (AITL). Thirty‐six patients had adult T‐cell leukemia/lymphoma (ATLL), including 20 of acute type and 16 of lymphoma type. A treatment response was obtained in 35 (66%) patients, including 17 (32%) complete responses. Median overall survival (OS) and progression‐free survival (PFS) times were 14.3 months and 5.2 months, respectively. Patients with ATLL showed a tendency to obtain low response rate (61% vs. 77%, P = 0.27) and had a significantly inferior OS (13.3 vs. 28.6 months, P = 0.04) and PFS (4.6 vs. 8.1 months, P = 0.01) in comparison with PTCL. Grade 3 to 4 neutropenia, anemia, and thrombocytopenia occurred in 72%, 34%, and 58% of the patients, respectively. Febrile neutropenia was observed in 51% and grade 3 non‐hematological toxicities in 2–9% of the patients. Conclusion: The efficacy of THP‐COP is equivalent to that of CHOP for the first‐line therapy in T‐cell lymphoma.     

Non‐anaplastic peripheral T‐cell lymphoma in children and adolescents – a retrospective analysis of the NHL‐BFM study group

Mature (peripheral) T‐cell lymphoma (PTCL) other than anaplastic large cell lymphoma is a heterogeneous group of diseases and exceedingly rare in children and adolescents. Survival rates range between 46% and 85%. This study reports the disease characteristics, treatment and outcome of all patients with the diagnosis of mature TCL registered in the Berlin‐Frankfurt‐Munster non‐Hodgkin lymphoma database between 1986 and 2012. All diagnoses were centrally reviewed and revised by clinico‐pathological correlation according to the criteria of the current World Health Organization classification. Of the 69 patients originally registered as having PTCL, the diagnosis was confirmed in 38 of them. Most patients were treated with an anaplastic large cell lymphoma (ALCL)‐like therapy regimen. Patients with PTCL‐not otherwise specified comprised the largest group and showed a 5‐year event‐free survival rate of 61 ± 11%. Patients suffering from Natural Killer/T‐cell‐ and hepatosplenic TCL had the poorest outcome. Our results suggest that the outcomes of children with mature TCL other than ALCL depend on the subtype and are worse than in all other paediatric lymphomas. The clinical experience presented in this largest study on paediatric mature TCL may serve as basis for future collaborative international prospective clinical trials.     

Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte rich large B cell lymphoma (THRLBCL) usually affect middle‐aged men, show tumour cells with a B cell phenotype and a low tumour cell content. Whereas the clinical behaviour of NLPHL is indolent, THRLBCL presents with advanced stage disease and an aggressive behaviour. In the present study, array comparative genomic hybridization was performed in seven typical NLPHL, four THRLBCL‐like NLPHL variants, six THRLBCL and four diffuse large B cell lymphomas (DLBCL) derived from NLPHL. The number of genomic aberrations was higher in THRLBCL compared with typical and THRLBCL‐like variant of NLPHL. Gains of 2p16.1 and losses of 2p11.2 and 9p11.2 were commonly observed in typical and THRLBCL‐like variants of NLPHL as well as THRLBCL. Gains of 2p16.1, affecting the REL locus were confirmed in an independent cohort. Expression of the REL protein was observed at similar frequencies in typical and THRLBCL‐like variant of NLPHL as well as THRLBCL (33–38%). In conclusion, the present study reveals further similarities between NLPHL and THRLBCL on the genomic level, confirming that these entities are part of a pathobiological spectrum with common molecular features, but varying clinical presentations.     

Time to treatment is an independent prognostic factor in aggressive non‐Hodgkin lymphomas

In aggressive lymphomas, discrepancies in survival reported from experimental and observational studies may reflect selective non‐enrolment of high‐risk patients in trials. We examined the association between time from diagnosis to chemotherapy and overall survival in diffuse large B‐cell (DLBCL), Burkitt (BL), mantle cell (MCL) and peripheral T‐cell lymphoma (PTCL), using National Cancer Data Base records of 130 549 patients treated in 2004–2014. Across the histologies, patients who started chemotherapy within 7 days of diagnosis had more often high International Prognostic Index (IPI) or advanced‐stage disease. The discrepancy in 3‐year survival between groups treated within 7 or >30 days from diagnosis ranged from 14% in BL to 30% in MCL. After adjusting for the IPI, time to treatment was significantly associated with shorter overall survival. Using the group treated >30 days from diagnosis as reference, patients treated within 7 days had a hazard ratio of 1·38 [95% confidence interval (CI), 1·28–1·48] in DLBCL, 1·42 (95% CI, 1·22–1·66) in BL, 2·23 (95% CI, 1·79–2·78) in MCL and 1·46 (95% CI, 1·18–1·81) in PTCL. Time from diagnosis to treatment may reflect high‐risk features uncaptured by standard prognostic assessments. Clinical trials should accommodate patients who need urgent therapy to improve external validity and detect treatment effects in high‐risk groups.     

Efficacy and safety of pegylated liposomal doxorubicin in primary cutaneous B‐cell lymphomas and comparison with the commonly used therapies

Objectives: The therapy of advanced, relapsed or refractory primary cutaneous lymphomas is often unsatisfactory. Recent data indicate a favourable pharmacokynetic, pharmacodynamic and toxicity profile of pegylated liposomal doxorubicin (Peg‐Doxo) in primary cutaneous T‐cell lymphomas, while in primary cutaneous B‐cell lymphomas (PCBCLs), the drug efficacy has never been assessed so far. Methods: We performed a prospective phase II pilot clinical trial of Peg‐Doxo monotherapy (20 mg/m²) in PCBCLs. One patient had a marginal zone B‐cell lymphoma and four were affected by diffuse large B‐cell lymphoma‐leg type, all with widespread nodular lesions. Results: All the patients achieved a complete response (CR = 100%) in a short period of time (median 3 months), even when pretreated with radio‐chemotherapy. Two experienced a relapse. At follow‐up, one patient died for progressive disease; four are in CR after 5, 52, 63 and 69 months. As concerning the toxicity profile, the treatment was well‐tolerated, no one decreased or delayed the dose. The haematological toxicity was mild with only one case of grade III neutropenia; a patient showed a grade I neurotoxicity. Dermatological toxicity, in particular the palmar–plantar erythrodysesthesia, did not occurred, probably because of both the low dosages of Peg‐Doxo monotherapy and the oral prophylaxis with pyridoxine. Conclusions: In spite of the small number of patients, it emerges that monochemotherapy with Peg‐Doxo has a significantly high clinical activity and a good safety profile in PCBCLs, even in aggressive forms, compared with other therapeutic regimens, which are completely reviewed. It suggests the need of further investigations in this field.     

The aggressive peripheral T‐cell lymphomas: 2015

Background: T‐cell lymphomas make up approximately 10%–15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. Diagnosis: The diagnosis of aggressive peripheral T‐cell lymphoma (PTCL) is usually made using the World Health Organization classification. The ability of hematopathologists to reproducibly diagnosis aggressive PTCL is lower than that for aggressive B‐cell lymphomas, with a range of 72%–97% for the aggressive PTCLs. Risk Stratification: Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, positron emission tomography scans seem to be useful as they are in aggressive B‐cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large‐cell lymphoma—particularly young patients with the anaplastic lymphoma kinase positive subtype. Risk‐Adapted Therapy: Anaplastic large‐cell lymphoma is the only subgroup to have a good response to a CHOP‐like regimen. Angioimmunoblastic T‐cell lymphoma has a prolonged disease‐free survival in only ～20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL‐not otherwise specified is not one disease. Anthracycline‐containing regimens have disappointing results, and a new approach is needed. Natural killer/T‐cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy‐containing regimens. Enteropathy‐associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy‐associated PTCL seem to benefit from intensive therapy. Am. J. Hematol. 90:666–673, 2015. © 2015 Wiley Periodicals, Inc.     

B‐cell lymphoma,unclassifiable, with features intermediate between diffuse large B‐cell lymphoma and burkitt lymphoma: study of 39 cases

B‐cell lymphoma, unclassifiable (B‐UCL), with features intermediate between diffuse large B‐cell lymphoma and Burkitt lymphoma, is a poorly characterized entity. Therefore, we investigated cases of B‐UCL treated by the Nebraska Lymphoma Study Group (NLSG). We searched the NLSG registry for years 1985–2010 for cases of B‐UCL. Immunohistochemical stains and fluorescence in situ hybridization studies for MYC, BCL2 and BCL6 gene rearrangements were performed. Among the 39 cases studied, 54% were male and 46% were female, with a median age of 69 years. The majority of patients presented with advanced‐stage disease (62%) and had high (3–5) International Prognostic Index (IPI) scores (54%). The median overall survival (OS) was only 9 months and the 5‐year OS was 30%. Patients with low IPI scores (0–2) had a better survival than those with high scores (3–5). The cases were genetically heterogeneous and included 11 ‘double‐hit’ lymphomas with rearrangements of both MYC and BCL2 or BCL6. None of the immunohistochemical or genetic features was predictive of survival. This B‐cell lymphoma is a morphologically‐recognizable entity with a spectrum of genetic abnormalities. New and better treatments are needed for this aggressive lymphoma.     

Malignant lymphoma in the HIV‐positive patient

The introduction of combination antiretroviral therapy (cART) drastically improved performance status, immune function, and life expectancy of HIV‐infected individuals. In addition, incidence of opportunistic infections and of AIDS‐defining malignancies declined. Nevertheless, aggressive non‐Hodgkin’s lymphoma still remains the leading cause of AIDS‐related deaths. The availability of cART, however, significantly improved the therapeutic options for HIV‐positive patients with lymphomas. Diffuse large B‐cell lymphoma, Burkitt’s lymphoma, or Hodgkin lymphoma has increasingly become curable diseases. In light of these favorable developments in the treatment of HIV and HIV‐associated lymphomas, reduction in treatment‐associated toxicities and further improvement of outcome of patients with advanced immune suppression are major requirements for future clinical trials. This review summarizes the current treatment landscape and gives an overview on future needs in HIV‐positive patients with lymphoma.     

Isolated limb infusion with cytotoxic agent for treatment of localized refractory cutaneous T‐cell lymphoma

We described a 57‐yr‐old male diagnosed with cutaneous T‐cell lymphoma that had failed multiple treatment options, as his disease was mainly confined to one limb. We attempted a novel approach in this condition using a technique of intra‐arterial limb infusion with cytotoxic agent Melphalan (ILI) which has been proven beneficial in management of localised malignant melanoma. This treatment approach was well tolerated with mild myelosuppression and moderate limb toxicity. However, a significant improvement has been noted in the affected limb. This case demonstrated the successful use of isolated limb infusion with Melphalan in the management of localised cutaneous T‐cell lymphoma. However, this result needs to be confirmed and further study is recommended. We are unaware there have been similar cases reported in the literature.     

Follicular helper T‐cells: expanding roles in T‐cell lymphoma and targets for treatment

Follicular helper T‐cells (Tfh cells) are a subset of CD4⁺ T‐cells that are essential for normal production of high affinity antibodies. Tfh cells characteristically produce IL21 and IL4 and show high expression of surface markers CXCR5, ICOS, PDCD1 (PD‐1) and the chemokine CXCL13. In this review we will focus on the emerging links between Tfh cells and subtypes of T‐cell non‐Hodgkin lymphoma: angioimmunoblastic T‐cell lymphoma (AITL) and ~20% of peripheral T‐cell lymphoma not otherwise specified (PTCL‐NOS) have surface marker features of Tfh cells and share a spectrum of genetic abnormalities. The recurrent genetic abnormalities associated with AITL include mutations in epigenetic modifiers such as TET2 and DNMT3A and the motility and adhesion gene, RHOA, is mutated in up to 70% of cases. ~20% of PTCL‐NOS demonstrate RHOA mutations and have other characteristics suggesting an origin in Tfh cells. The recognition that specific genetic and surface markers are associated with malignant Tfh cells suggests that the next few years will bring major changes in diagnostic and treatment possibilities. For example, antibodies against IL21, PDCD1 and ICOS are already in clinical trials for autoimmune disease or other malignancies and antibodies against CXCL13 are in pre‐clinical development.     

Expression levels of apoptosis-related proteins and Ki-67 in nasal NK / T-cell lymphoma

Objectives: Nasal natural killer (NK)/T‐cell lymphoma is characterized by chemo‐resistance, angiodestruction, and aggressive tumor progression. Few studies exist on molecular characteristics of this disease entity. Methods: Expression levels of major apoptosis‐related proteins Bcl‐2, Bcl‐x, Mcl‐1, Bax, and a proliferative marker Ki‐67 were analyzed in 11 nasal NK/T‐cell lymphoma cases by immunohistochemical methods. Nine cases were of NK‐cell lineage and two cases were of T‐cell lineage. For comparison, 12 follicular lymphoma (FL) cases and 16 diffuse large B‐cell lymphoma (DLBCL) cases were also studied. Results and conclusions: Bax expression was low in all nasal NK‐cell lymphoma cases, which constitute the major population of nasal NK/T‐cell lymphoma. Bax expression in nasal NK‐cell lymphoma was similar to FL and significantly lower compared with DLBCL. Bcl‐2 expression was significantly lower in nasal NK/T‐cell lymphoma compared with that of FL and DLBCL. Bcl‐x expression was high in all three lymphomas. Two distinct Mcl‐1 expression groups existed for nasal NK/T‐cell lymphoma (6.2 ± 5.2% and 59.1 ± 12.3%, 95% CI). Ki‐67 expression was high in nasal NK/T‐cell lymphoma, and worse prognostic groups tended to express higher levels of Ki‐67. The results suggest a combination of impaired apoptosis and aggressive proliferation in nasal NK/T‐cell lymphoma, and may provide explanations for its poor prognosis.