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1. GENERAL INFORMATION
1.1 Definition
In the current WHO Classification (Swerdlow 2008), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) does correspond to a heterogeneous group of nodal and extranodal mature T-cell lymphomas, which does not fit with any of the specifically defined entities derived from mature T lymphocytes. This is a group of lymphomas uncommon in Western countries, whose classification is very difficult because of the lack of reliable immunophenotypic markers of T-cell malignancies. Some distinct clinical syndromes with recognizable morphologic features of T-cell malignancies have been described, and they should be considered separately. Peripheral T-cells in various stages of transformation have been postulated as the normal-cell counterparts for peripheral T-cell lymphomas (PTCL).
1.2 Incidence and Risk factors
PTCL constitute less than 15% of all NHLs in the United States and Europe but they are more common in the Far East. In a recent international collaborative effort, the most common diagnoses by the World Health Organization classification for lymphomas (Swerdlow 2008) are (PTCL-NOS) (25.9%), angioimmunoblastic T-cell lymphoma (18%), systemic anaplastic large cell lymphoma (12.1%) and extranodal NK/T-cell lymphoma, nasal type (10.4%) (Vose 2008). The present article will focus on PTCL-NOS.
No risk factors have been clearly identified in PTCL, including PTCL-NOS. Epstein-Barr virus (EBV) is positive in approximately 30% of cases of PTCL-NOS, although the role in pathogenesis is unknown. No particular correlation between PTCL-NOS and inherited immunological deficiency disease, or other immunological disorders has been reported. There are no convincing data regarding the role of chronic antigenic stimulation in the genesis of PTCL. However, the inflammatory background and the follicular dendritic cell proliferation observed in these malignancies suggest a pathogenesis mediated by different chemokines. Several chemical substances, such as solvents, pesticides and fertilizers as well as dusts and particles, hair, smoking and diet, have been suggested as possible aetiological factors in general for non-Hodgkin lymphoma (NHL) (
Weisenburger 1985). Among other pesticides, 2,4-D (Zahm 1990), organophosphate insecticides (Woods 1987) and phenoxy herbicides (La Vecchia 1989) have been suggested as aetiological agents. Although the highest risk is related to the occurrence of large-cell lymphomas, all histotypes of NHL occur in individuals whose work involves application of pesticides (Scherr 1992; Weisenburger 1990).
2. PATHOLOGY and BIOLOGY
2.1 Morphology
In the lymph node, PTCL-NOS shows paracortical or diffuse infiltrates with effacement of the normal architecture. The cytological spectrum is extremely broad, from highly polymorphous to monomorphous. Clear cells and Reed-Sternberg-like cells can also be seen. High endothelial venules may be increased. An inflammatory background is often present. The differential diagnosis with angioimmunoblastic T-cell lymphoma (AITL) may require extensive immunophenotyping. In the new WHO Classification, some morphological variants have been included: lympho-epithelioid or Lennert’s type, T-zone and follicular. In particular, the latter consists of atypical clear cells forming intrafollicular aggregates (mimicking follicular lymphoma), small nodular aggregates in a background of progressively-transformed germinal centres (mimicking nodular lymphocyte-predominant Hodgkin lymphoma) or enlarged perifollicular zones/nodular aggregates surrounding hyperplastic follicles (mimicking nodal marginal zone lymphoma). Although this variant shows a follicular T helper derivation, it has not been included in the AITL chapter because of limited disease extent, frequent partial organ involvement and lack of hyperplasia of both follicular dendritic cells and high endothelial venules. The lymphoepithelioid variant (so-called Lennert lymphoma) shows a diffuse or, more rarely, interfollicular growth of small CD8+ cells with slight nuclear irregularities, clusters of epithelioid lymphocytes and some atypical proliferating blasts (
Geissinger 2004). The T-zone variant was proposed in the Kiel Classification {Lennert, 1978 1465 /id} and a relationship to AITL has been postulated. However, this morphological pattern may be found in different entities.
In the skin, the tumor population infiltrates the dermis and subcutis, often forming nodules, sometimes with central ulceration (Paulli 2004). In the spleen, infiltration varies from nodules to diffuse infiltration of the white pulp, in some cases, with colonization of the periarteriolar shealth or predominant infiltration of the red pulp (Chan 2003).
2.2 Immunophenotype
PTCL-NOS is usually characterized by an aberrant T-cell phenotype with frequent loss of CD5 and CD7 (Went 2006). A CD4+/CD8- phenotype predominates in nodal cases. CD4/CD8 double-positivity or double-negativity is at times seen, as is CD8, CD56 and cytotoxic granule expression. TCR -chain (antibody βF1) is usually expressed. CD52 has been reported to be absent in 60% of cases (
Piccaluga 2007). CD30 can be expressed, exceptionally with CD15, but the global phenotypic profile and morphology allow the distinction from anaplastic large-cell lymphoma (ALCL) and Hodgkin lymphoma (HL). In particular, CD30 staining is typically focal and more heterogeneous than that observed in ALCL. Aberrant expression of CD20 and/or CD79a is occasionally encountered (Swerdlow 2008). Unlike AITL, PTCL-NOS usually lacks a follicular T helper phenotype (CD10+, Bcl6+, PD1+, CXCL13+) with the exception of the follicular variant (Attygalle 2007; Dorfman 2006; Grogg 2006; Went 2006). Proliferation is usually high and Ki-67 rates exceeding 80% are associated with a worse prognosis (Went 2006).
2.3 Genetic features
TCR genes are clonally rearranged in most cases {Swerdlow 2008
). Cytogenetic data on PTCL are still limited because of the rarity of these malignancies in Western countries and the use of different histological classifications. Deletions of 6q, total or partial trisomies of 7q and monosomy 13 or changes 13q14 are significantly more common in tumours consisting of large cells (Schlegelberger 1994). Chromosomally abnormal clones were identified in 71% of PTCL cases, 1p36 breakpoints in half of them {Inwards 1990). Chromosome abnormalities previously attributed to B-cell malignancies are infrequent. Genetic imbalances and gene expression profiles observed in PTCL differ from those of the AILT and anaplastic large cell lymphoma (Thorns 2007; Zettl 2004; Piccaluga 2007; de Leval 2007; Cuadros 2007). In comparison to normal T lymphocytes, PTCLs-NOS show a gene signature characterized by the recurrent deregulation of genes involved in relevant cell functions, e.g. matrix deposition, cytoskeleton organization, cell adhesion, apoptosis, proliferation, transcription and signal transduction (Piccaluga 2007). The products of these genes might have therapeutic relevance (
Piccaluga 2007). EBV integration has been reported in a variable percentage of cases (Dupuis 2006; Went 2006).
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3. DIAGNOSIS
3.1 Clinical presentations
PTCL-NOS typically occurs in adults, with a median age of 55-60 years, with a higher prevalence observed in males (Campo 1998). This clinically heterogeneous group of malignancies presents more often as disseminated disease (stage III or IV disease), occasionally with eosinophilia, pruritis or hemophagocytic syndromes (Falini 1990). Patients often have B symptoms, generalized lymphadenopathy and extranodal involvement is common, with the skin and gastrointestinal tract representing the most commonly affected sites (Swerdlow 2008
). Bone marrow involvement is more frequent than that observed in diffuse large B-cell lymphoma (20-30%) ( Vose 2008; Gallamini 2004). Approximately 50-70% present with a high or high-intermediate International Prognostic Index (IPI) score (Vose 2008; Gallamini 2004).
4. STAGING
4.1 Staging procedures
Complete staging work-up for PTCL-NOS is the same that used routinely for nodal NHL. It includes an accurate physical examination, complete haematological and biochemical exams, total-body computerized tomography and bone marrow aspirate and biopsy. Clinical symptoms suggestive of gastrointestinal lymphoma should also prompt an endoscopic or barium study because isolated luminal disease may not be detected by CT. Similarly, central nervous system imaging or sampling of the cerebrospinal fluid should be performed if neurological symptoms are present. FDG-PET has not been well studied in PTCLs with some studies showing avid uptake (
Kako 2007; Khong 2008) but others showing lower sensitivity compared to aggressive B-cell lymphomas (Elstrom 2003) and outside of clinical trials, it is not routinely recommended (Cheson 2007). No reliable molecular markers are available for monitoring of minimal residual disease in PTCL-NOS.
4.2 Staging system
The standard staging system used for PTCL-NOS is the same as that proposed for Hodgkin's disease at the Ann Arbor Conference in 1971 (Carbone 1971). This system is currently used for all non-Hodgkin's lymphomas, even if other staging systems are used in some extranodal lymphomas displaying particular biological behaviour. The Ann Arbor staging system reflects both the number of sites of involvement and the presence of disease above or below the diaphragm. This staging system considers four stage of disease: Stage I: involvement of a single lymph node region (I) or a single extranodal site (IE). Stage II: involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic site (IIE). Stage III: involvement of lymph node regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic site (IIIE) or spleen (IIIs) or both (IIIEs). Stage IV: diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement. Localized involvement of liver or bone marrow is also considered stage IV. Patients are divided in two subsets according to the presence (A) or absence (B) of systemic symptoms. Fever of no evident cause, night sweats and weight loss of more than 10% of body weight are considered systemic symptoms. Even though it is a frequently accompanying symptom, pruritis should not be considered as a systemic symptom. The presence of bulky mass, such as a lesion of 10 cm or more in the longest diameter is signaled as "X", while the extranodal involvement should be identified by a symbol (O: bone, L: lung, D: skin, etc.).
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5. PROGNOSIS5.1 Natural history and prognosis
Early studies based on older classification systems evaluating the prognostic significance of the T-cell phenotype were discrepant, likely due to a number of reasons: the use of older immunophenotyping techniques; the lack of molecular techniques; the evaluation of mixed populations that may have included indolent subtypes or subtypes now recognized as having a more favorable prognosis; and conversely, others may have included cases that have a fatal course with standard therapy (
Savage 2008 ). More recent large comprehensive analyses on patients diagnosed either according to the updated Kiel ( Gisselbrecht 1998 ) REAL or WHO classification ( Savage 2004 ; Melnyk 1997 ; Lopez-Guillermo 1998; Morabito 2004; Arrowsmith 2003; Kim 2002) confirm that with exception of ALK-positive ALCL, patients with PTCL have a worse outcome in comparison to their B-cell lymphoma.
PTCL-NOS represents the largest PTCL subgroup in Western populations and outcomes are poor, with a 5-y FFS and OS rates of approximately 20-30% (Vose 2008). Attempts have been made to identify biologically and prognostically distinct subgroups within the heterogeneous PTCLNOS subtype.
Most nodal cases of PTCL-NOS are T-helper (CD4+CD8-) and some studies have evaluated whether prognosis varies based on expression of TH1 and/or TH2 surface chemokine receptors (
Ishida 2004; Tsuchiya 2004). In one study, two distinct subgroups with PTCL-NOS were identified. Group 1 ‘functional’ were positive for any of ST2(L)(TH2 marker, IL-1R family member), CCR5 (TH1), CXCR3 (TH1) and had a more favorable prognosis than group 2 negative for all these markers ( Tsuchiya 2004). Group 1 cases, considered ‘functional’ based on the receptor expression had a more favorable prognosis compared to group 2 cases (Tsuchiya 2004). In a separate study, CXCR3 expression was associated with intermediate prognosis, CCR3 (TH2) expression was a favorable marker and CCR4 (TH2) expression was found to be associated with a poor outcome (Ishida 2004).
Epstein Barr Virus (EBV) is found in approximately 30% of all cases of PTCL-NOS and may be associated with a more aggressive course (
Dupuis 2006). Cytotoxic granule expression is seen more frequently in EBV positive PTCL-NOS and in one analysis was associated with a more aggressive course, adjusting for the IPI (Asano 2005). A high proliferative index (Ki-67 > 80%) is found in approximately 11% of cases of PTCL-NOS and emerged as stronger predictor of survival compared to clinical factor variables ( Went 2006) although this marker suffers from poor reproducibility (de Jong 2007).
Gene expression profiling has been utilized to define prognostic signatures within PTCL-NOS. However, in comparison to B-cell lymphomas, large scale studies are lacking. A recent study evaluating 35 cases of nodal PTCL-NOS found that high expression genes associated with cellular proliferation correlated with a more aggressive course (Cuadros 2007). Another study found that expression of NF-κB pathway genes was associated with a more favorable prognosis in PTCL-NOS (
Martinez-Delgado 2005).
Clinically, the IPI remains the most effective prognostic model to define risk groups within PTCL-NOS diagnosed according to the WHO classification (Savage 2004; Gallamini 2004). A new prognostic model for PTCL-NOS has also been proposed which incorporates many of the current IPI factors (age, PS, LDH) but also recognizes the importance of bone marrow involvement ( Gallamini 2004). In this model, the so-called PIT (prognostic index for T-cell lymphoma) identified patients with a highly variable 5 y OS ranging from 18% (4 factors) to 62% (1 factor).
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6. TREATMENT
6.1 Treatment of limited disease (Stage I-II)
Approximately 20-30% of patients with PTCL-NOS have a stage I-II disease at presentation (Vose 2008; Gallamini 2004). Since this clinical presentation is so rare, a standard treatment has not been established. As for limited stage non-bulky aggressive B-cell lymphomas combined treatment with primary systemic conventional-dose polychemotherapy followed by radiation therapy is suitable for individual clinical use on a type R basis ( Lopez-Guillermo 1998).
6.2 Treatment of advanced disease (Stage III-IV)
The standard therapeutic option for patients with stage III-IV disease is conventional-dose systemic anthracycline-containing chemotherapy. With this treatment, an overall response rate of more than 60% has been reported, however relapses are frequent and the 5 year OS is approximately 20-30% (
Vose 2008). Despite these suboptimal results, few studies have compared CHOP to other regimens in the initial treatment of PTCL and it remains the standard treatment in this disease, on a type 2 level of evidence . However, there is limited evidence that suggest that anthracylines may not improve outcome in PTCLs, in particular in PTCLNOS. In the ITLP, the outcome of PTCLNOS patients was similar in patients who received anthracycline-based combination chemotherapy compared to those that did not (Vose 2008), suggesting that CHOP-like chemotherapy may not be the optimal combination in PTCL and new combinations or dose-intensified approaches should be explored. The German Non-Hodgkin’s Lymphoma Group (DSHNHL) evaluated the outcome of all T-cell lymphomas based on treatment regimens received in 7 German High grade studies (n=331). In the NHL-B1 trial (
Pfreundschuh 2004) young good risk patients with T-cell lymphoma had an improved 3 y event-free survival (EFS) (71 vs. 50%) when etoposide was added to CHOP-14 or CHOP21 (p=.01) (Schmitz 2008); however, many of these patients had ALCL. The GOELAMS group tested alternating VIP (etoposide, ifosfamide, cisplatin)/ABVD(adriamycin, bleomycin, vinblastine, dacarbazine) for a total of 6 cycles against CHOP for 8 cycles in treatment naïve patients with PTCLs and found there was no difference in EFS and OS between these regimens ( Gressin 2006).
The role of high-dose chemotherapy supported by autologous or allogeneic bone marrow transplantation in the primary therapy of PTCL-NOS is still investigational (Shustov 2010). Due to disease rarity, the majority of studies combine PTCL subtypes, obscuring potential benefit in individual histologic groups. There have been five prospective non-randomized clinical trials evaluated autologous stem cell transplant (ASCT) in the primary treatment of PTCL (
Reimer 2004a; Reimer 2004b; Rodriguez 2007; Corradini 2006; Mercadal 2008). The first phase II study published evaluated 30 newly diagnosed PTCL patients, excluding ALK-pos ALCL (Reimer 2004). The transplant rate was 70% and 76% of these individuals were in CR 15 months after ASCT. An updated analysis of 65 patients with longer follow-up demonstrated that only 42% remained in CR post transplant ( Reimer 2004). The GEL-TAMO group reviewed 26 patients with PTCL of whom 19 underwent ASCT (Rodriguez 2007) and the 3 year OS and PFS were 73% and 53% respectively. For transplanted patients (>PR) the 2-year OS and PFS were 84% and 56% respectively. Corradini et al. reported the combined results of two phase II studies of planned primary ASCT in 62 patients including ALK-pos ALCL (n=19) and other histologies of PTCL. Following induction chemotherapy, 46 of these patients received ASCT. For the entire study population (intent-to-treat (ITT) analysis) the 12-year OS and DFS were 62% and 54% in ALK+ALCL patients and 21% and 18% for other histologies. The Spanish GELCAB group evaluated intensive chemotherapy (high-dose CHOP and ESHAP) followed by ASCT in responding PTCL patients (
Mercadal 2008). Although 24 patients were candidates for ASCT after the chemotherapy, only 17 were transplanted. In the ITT analysis, the 4-year OS and PFS were 39% and 30% respectively and in the eligible transplant patients there was no difference in survival whether they ultimately underwent ASCT or not.
The GELA group performed a matched control analysis within two randomized trials (LNH-87 and LNH-93) to evaluate the benefit of upfront ASCT in the subgroup of patients with PTCL who attain a complete remission after initial intensive chemotherapy. Cases (ASCT) and controls (consolidative sequential chemotherapy) were matched 1:1 by treatment protocol, histology (anaplastic or non-anaplastic PTCL), aaIPI, bone marrow involvement, number of extranodal sites. Among the 29 patients with non-anaplastic PTCL (including 2 LBL), there was no difference in DFS or OS between the two groups (Gisselbrecht 2002; Mounier 2004
). Prospective randomized clinical trials will be required to confirm whether primary ASCT improves outcome in PTCL-NOS and it remains experimental at this time (grade 2C).
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6.3 Treatment of relapsed or refractory disease
The standard therapeutic option for patients with relapsed or refractory disease has not been established. Patients with relapsed PTCL with chemosensitive disease respond favorably to high dose chemotherapy and ASCT with long term survival rates of approximately 35-45% (Jagasia 2004; Rodriguez 2003; Song 2003). The results in patients with refractory PTCL are variable with some studies reporting no long term survivors (Rodriguez 2003) whereas others report success rates comparable to the relapsed setting
(Rodriguez 2003). Salvage rates are lower with PTCL-NOS compared to ALCL ( Song 2003; Blystad 2001; Jagasia 2004). Patients with relapsed or refractory PTCL and documented chemosensitive disease, should be offered HDC and SCT, similar to the practice in DLBCL given the lack of valid therapeutic alternatives, on a type 2 level of evidence. However, since the worldwide experience is limited, it remains an investigational option. There is very little experience with allogeneic SCT in PTCL however, limited suggests that a graft vs lymphoma effect in PTCL does exists. Reduced intensity conditioning has recently emerged as an attractive strategy for patients at increased risk of treatment-related toxicity, although it has not been extensively evaluated in aggressive lymphomas. A small pilot study (n=17) was recently performed evaluating RIC in patients with PTCL (
Corradini 2004). The majority of cases were PTCL US (9) and many had relapsed after autologous HDC SCT. Although this was a highly selected population including many with a history of late relapse and all demonstrating chemosensitive disease, the 3-year overall and progression-free survival were encouraging at 81% and 64%, respectively, and responses were observed following donor lymphocyte infusion suggesting that a graft-versus-T-cell lymphoma effect may exist ( Corradini 2004). This remains an investigational approach, on a type 3 level of evidence. 6.4 New active drugs and therapeutic optionsThe lack of anthracycline sensitivity seen in PTCL may in part be due to P-glycoprotein expression ( Gianni 1997). Thus, chemotherapy agents that bypass this mechanism of resistance are being explored. Gemcitabine has been evaluated (1200 mg/m2, days 1, 8 and 15 of a 28-day schedule) has been in 13 relapsed patients with a variety of T-cell lymphomas, achieving one complete remission and 8 partial remissions with a median duration of 11 months (
Zinzani 1998). The use of gemcitabine is suitable for individual clinical use in the palliative setting, on a type 3 level of evidence. Other gemcitabine combination regimens are currently being explored. GEM-P (gemcitabine, cisplatin, methylprednisolone) showed promise in 16 mostly pre-treated patients with PTCL in whom 11 (69%) responded ( Arkenau 2007). The Southwestern Oncology Group is studying a novel front line regimen, PEGS (cisplatin, etoposide, gemcitabine, and solumedrol) in a phase II study in patients with PTCL. Alemtuzumab is monoclonal anti-CD52 antibdody that has shown activity in PTCL. However, given widespread expression, it is extremely immunosuppressive and associated with a high frequency of Grade 3-4 infections. Two phase II studies have been published evaluating CHOP in combination with alemtuzumab, in addition to anti-infective prophylactic therapy, as primary treatment in patients with PTCL (
Gallamini 2007; Kim 2007). In the first report, the ORR was 80% (65% CR) and the 1-year EFS was 43% although patients with high or high-intermediate risk disease by the IPI were eligible for consolidation with high dose chemotherapy and stem cell transplant. Unfortunately, toxicity was substantial and this study was also closed early due to significant infectious and hematologic adverse events (90% grade 4 neutropenia; 55% febrile neutropenia), including two treatment-related deaths (Kim 2007). In the second study, the CR rate of CHOP + alemtuzumab was 71% and the 1 year failure-free survival was projected to be 54%; however, follow-up is still short (mean 495 days). Toxicity was also modest, in particular neutropenia and life-threatening infections, but no treatment-related deaths were reported. Given that only 30-40% of PTCL-NOS are CD52 +, the antigen status needs confirmation all patients receiving this therapy ( Rodig 2006; Piccaluga 2007
). Alemtuzumab either alone or in combination in the treatment of PTCLs is still considered experimental and should not be used outside of a clinical trial. Pralatrexate is emerging as a promising new agent in the treatment of PTCLs. Pralatrexate belongs to a class of folate analogues called the 10-deazaaminopterins. Compared to methotrexate, it has enhanced activity through more efficient internalization and intracellular accumulation. A phase II study of pralatrexate demonstrated at response rate of 27% and duration of response of over 9 months ( O'Connor 2008). As a result, FDA approval is underway and this agent may soon be available for use in the United States, on a type 2 level of evidence.
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Contributors
Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute - Milan, Italy
mail: ferreri.andres@hsr.it
Prof. Stefano A. Pileri (Reviewer)
University School of Medicine - Bologna, Italy
e-mail: stefano.pileri@unibo.it
Dr. Kerry Savage (Author)
British Columbia Cancer Agency - Vancouver, Canada
e-mail: KSavage@bccancer.bc.ca
Prof. Pier Luigi Zinzani (Author)
Institute of Hematology and Oncology Seragnoli, University of Bologna, Italy
mail: plzinzo@med.unibo.it
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