ACTA FAC. MED. NAISS. 2003; 20 (3): 169-173

Original article

CLINICAL PROGNOSTIC FACTORS IN PATIENTS WITH UNSPECIFIED PERIPHERAL T-CELL LYMPHOMA
 

Goran Marjanović¹, Vesna Marjanović², Lana Mačukanović-Golubović¹, Mladen Milenović¹, Bojan Marjanović^3
1 Clinic of Hematology and Clinical Immunology, Clinical Center, Niš,
² Clinic of Child Surgery and Orthopedia, Clinical Center, Niš,
³ Clinic of Surgery, Clinical Center, Niš
 

INTRODUCTION
Peripheral T-cell non-Hodgkin's lymphomas (PTCL) account for 15-20% of the aggressive lymphomas and for 7-10% of all the non-Hodgkin's lymphomas (NHL) (1). They usually occur in middle-aged to elderly patients, and the presented features are characterized by a disseminated disease in 68% of the patients, with systemic symptoms in nearly half of them (45%), bone marrow involvement in quarter (25.8%) and extra nodal disease in 1/3 of them (37%). Despite the aggressive therapy, the prognosis is dismal, with more than a half of the patients dying of their disease (1).
The influence of the immunophenotype on the outcome of the aggressive NHL has been questioned for a long time; however, in more recent literature, most authors agree on the adverse prognostic meaning of the T-cell phenotype per se, (2, 3), irrespectively of other well defined clinical prognostic indexes such as the International prognostic Index (IPI) (4).
In the past, a number of definite entities corresponding to recognizable subtypes of T-cell neoplasm, such as Lennerth lymphoma, T-zone lymphoma, pleomorphic T-cell lymphoma, small and medium sized, and large cell T-cell lymphoma and T-immunoblastic lymphoma have been described (5)even if the evidence that these correspond to the distinctive clinicopathological entities is still lacking (6, 1). This is the reason why the recent WHO classification of the hematopoetic and lymphoid neoplasm has collected these under the single broad category of peripheral T-cell lymphoma, unspecified - PTCL-U (10). The natural history of PTCL seems to be unchanged by the use of the second and the third generation chemotherapy regimens 5 year overall survival still remains between 25% and 47%. (2, 8, 9). Although high dose sequential chemotherapy (HDS) followed by the autologous hematopoetic stem cell transplant (ASCT) has been successfully performed, among the small series of patients (7-8), others in a large chort of high risk NHL with HDS followed by ASCT, have definitely demonstrated no benefit of autologous bone marrow transplantation in the subset of T-cell lymphomas (9).
In order to give a better definition of the clinical outcome of T-cell lymphomas grouped within the broad category of PTCL-U as a single entity, various clinically devised prognostic models were introduced (11). In order to assess their clinical relevance in patients from our center, we promoted a retrospective study performed on a 36 newly diagnosed patients at our institution between January 1991 and December 2003.
 

PATIENTS AND METHODS
Among 232 cases of lymphoma recorded through January 1991 and December 2003, we selected all cases of PTCL diagnosed at our clinic. A preliminary working file containing information on 56 cases fulfilling all the characteristics of T-cell lymphoma was created.
Thereafter, we considered eligible for the study all the patients with:
1. Histologically confirmed diagnosis of PTCL according to Updated Kiel and WHO classification (15). Distinctive entities, formerly classified as PTCL and characterized by a definite clinical picture (such as angioimmunoblastic T-cell lymphoma, Anaplastic Large cell lymphoma (ALCL), enteropathy associated T-cell lymphoma, nasal type T-cell lymphoma, or primary cutaneus T-cell lymphoma), were excluded from the analysis. No cases of T-prolymphocytic leukemia, adult T-cell leukemia/lymphoma, or primary hepatosplenic T-cell lymphoma were recorded.
2. Proven T-cell phenotype by immunohistochemistry.
Additional criteria for inclusion were:
1. Availability of complete set of clinical data for an accurate clinical staging, including diagnostic biopsy with immunohistochemistry, complete blood count, biochemistry, bone marrow trephine biopsy or aspirate, and CT scans.
2. A minimum follow up of one year with the last observation recorded no more than six months before data collection.
Out of 56 cases included at the working file, we excluded 10 patients due to the following reasons: 4 of them exhibited clinical characteristics and histological description of "nasal type" T-cell lymphoma, 7 for incomplete clinical data or inadequate follow up and 12 for unproven T-cell phenotype. The following set of clinical data were analyzed: age, sex, complete blood count, ESR, LDH, Ann Arbor stage, IPI, the number of sites of extranodal disease, BM involvement, systemic symptoms, bulky disease, PS, the date of diagnosis, type of treatment, the response to therapy, the date of assessment of the response, the date of relapse, the date of last follow up, status (alive or deceased), and, if deceased, the date and the cause of death. A bulky disease was defined as a mass with the largest diameter, greater or equal to 10 cm, or, for the mediastinum only, a mass larger than one third of the chest diameter. Systemic symptoms were defined, according to Ann Arbor criteria, as a recurrent fever (more than 38°C), or night sweats, or loss of more than 10% of body weight.
The response to the treatment was assessed one month after the end of the induction therapy by performing all the examinations with pathologic values as a baseline, which, concurred to define the stage. A complete remission (CR) was defined as a disappearance of all clinical evidences of the disease and the normalization of all laboratory values and radiological findings that had been considered abnormal before starting with the therapy. Partial remission (PR) was defined to be greater than 50% reduction, for at least one month, of the largest dimension of each measurable anatomical site of disease location. Non-response (NR) was defined as less than 50% regression of the tumor size, or stable/progressive disease. All the deaths occurring because of progression of the disease are related to treatment toxicity were considered as treatment failures, and the patients were included in the NR group.
 

Histological findings
Table 1 lists the different histological subtypes conforming to PTCL-U diagnosis.
The most frequent subtype (18/36: 18%) was characterized by a simple cytological description of the tumor, and it included a number of sub-entities (large cell, large and medium sized cell, pleomorphic cell, small cell) differing both in size and in the relative proportion of large or small cells. Other categories were PTCL-U not otherwise specified (PTCL-U NOS), T-zone lymphoma, lymphoepitheloid lymphoma (or Lennerth lymphoma).
 

Treatment strategies
Patients were grouped in three main categories according to the adopted treatment strategy: a) only supportive care 1/36 (2.7%), b) non anthracycline chemotherapy 2/36 (5.55%), anthracycline-based chemotherapy 33/36 (91.66 %).
 

Statistical analysis
All data were analyzed with statistical package NCSS 97. The overall survival (OS) curve was calculated according to the Kaplan and Meier method. OS was calculated starting from the date of the diagnosis until the death, no matter the cause, or the date of the last contact, for living patients. For patients in CR, a relapse free survival was calculated from the date of diagnosis to the first evidence of the relapsing disease. The association between the clinical factors and the probability of attaining CR was evaluated by likelihood ratio c2 test. In cases where the date of the therapy onset was not available, the survival was calculated from the date of the diagnosis until the date of the last follow up or death. The univariate association between the individual clinical features and the overall survival were determined with the log-rank test. Factors independently associated with OS were identified in multivariate analysis by the Cox proportional hazards regression model . The limit of significance for all analyses was defined as p=0.05. Two sided tests were used in all calculations.
 

RESULTS
The characteristics of 36 patients that fulfilled the inclusion criteria and entered the study are summarized in Table 2.
The median age was 58 years (range 24-82), there was no preponderance between males and females 1:1. The extension of the disease and the frequency of extranodal sites were suggestive of an aggressive onset: 89% were in stage III or IV, and more than one third of patients (27.77%) had extensive extranodal organ involvement. Table 4 shows the extranodal spread of the disease, with spleen being the most frequent site (14/36; 38.88%), followed by the bone marrow (10/36; 27.77%), liver (8/36; 22.22%) and skin (5/36; 13.88%).
Bulky disease was present in a minority of the patients (2/36; 5.55%): mean hemoglobin value was 12.35 gr/dl; men absolute neutrophil count was 5.3 /µl and the mean platelet count was 152.792 µ/l (range 14 -300). Almost 90 % (32/36; 88%) patients presented with systemic symptoms while less than a half showed an ambulatory performance status (16/36; 44.44%). LDH was elevated in almost two thirds of the cases (22/36; 61.11%).
IPI scoring was available in all selected patients; accordingly 2 (5.55%) patients were classified as low risk (0-1 r), 8 (22.22%) as intermediate low (2); 15 (41.66%) as intermediate high (3) and 11 (30.55%) as high risk ones. (4-5).
ILI scoring was available in 34/36 (94.44%) of the patients; accordingly 2 (5.55%) as low risk; 3 (8.33%) as intermediate risk and 31 (86.11%) as high risk ones.
PIT scoring was available in 35 (97.22% of the patients) with only 2 (5.55%) patients in group 1(0 risk-factors); 11 (30.55%) patients in group 2 (1 risk-factor); 14 (38.88%) in group 3 (2 risk- -factors)and 8 (22.22%) in the group 4 (over 3 risk factors present).
 

Analysis of response
In 7 out of 36 patients the response to the therapy was not properly recorded and in the case of one patient no therapy was given. With the induction therapy, 12/28 (42.8%) of the patients achieved a CR and 9/28 (32.1%) achieved a PR, with an overall response rate of 65%.
 

Analysis of survival
After a mean follow up of 50 months 29/36 (80.55 %) out of of the patients had died, and the cumulative probability of survival at the age of 5 years (Fig. 1) was 28.5%. Forty-one percent of deaths occurred in the first 12 months and the additional 29% occurred in the following year.
Factors significantly associated with the reduced survival in multivariate analysis (Cox-Mantel) are listed in table 5: performance status ECOG, equal or greater than 2 (p=0.014), LDH ł than normal values (p=0.0383), elevated sedimentation rate (ESR) (p=0.045) and complete response vs. no response vs. partial response to therapy (p=0.00395). Univariate analysis showed that age greater than 60 years (p=0.042) adversely influenced on survival while multivariate analysis showed no difference. No significance was recorded for gender (p= 0.585); the presence of B symptoms (p=0.852), advanced disease (stage III or IV) (p=0.388); bone marrow infiltration (p=0.443) and serum albumin level (p=0.259).
Figure 2 shows borderline significance of the international prognostic index in stratifying prognostic groups of patients (p=0,047). A simplified two class IPI with merging of low and low-intermediate risk group into one as well as high-intermediate and high risk groups in other category, stratified patients more accurately (p=0,014437). Figure 3.
A similar prognostic model designed especially for peripheral T-cell Lymphoma Unspecified (11) called PIT, was able to identify 4 groups of patients with different outcome (Figure 4). PIT was based on combining prognostic factors more specific for PTCL-U: age, LDH, performance status, and bone marrow attainment in a scoring system in the following way: Group 1 no adverse factor, Group 2: one factor, Group 3: 2 factors, Group 4:3 or 4 adverse factors. This novel prognostic model was able to stratify the risk groups (Log Rank p= 0.041350). As in IPI, this prognostic model was simplified in two classes PIT stratifying four risk groups into two risk categories. The first category containing group 1 and 2 and the second groups 3 and 4 as it can be seen in figure 7. Simplified two-class PIT fared better than simplified two-class IP (Log Rank p=0.010973 versus p=0.041350).
The last prognostic model called ILI (Integrupo Italiano Lymphoma)(12) originally designed for indolent lymphomas was also able to stratify three groups of patients but without any prognostic significance (Log Rank p=0.4.). (12) Our attempt to use simplified two-class ILI rendered similar results (p=0.2).
 

DISCUSSION
Peripheral T-cell lymphomas are an heterogeneous group of neoplasm presenting as advanced disease, and characterized by widespread dissemination, aggressive behavior and a very poor outcome. In literature published so far, the 5-year overall survival ranges between 25 % and 45% (2, 3, 4, 13). However, the meta-analysis of the prognosis of these neoplasms from the retrospective clinical reviews is somewhat cumbersome, due to the differences of the histological subtypes accured and of different follow up times. Moreover, in 1994 the REAL classification and in 1997 the WHO classification introduced a substantial modification in the classification of these disorders. A number of different T-cell peripheral lymphomas, once considered as distinctive entities due to the lack of reproducibility are now, in the WHO classification, collectively referred to as PTCL-U. The cytology of the neoplastic cell has long been debated as a prognostic factor. Applying the updated Kiel Classification (15), Ascani et all (1) and Noordyn et al. (14) were unable to find any survival difference between low and high-grade histological forms, while Rudiger et al (13) found that the number of transformed blasts in ten random high power fields was prognostically relevant.
The 5-year overall survival 28.5 % in this study is slightly below lower limit reported in the literature. This may be because median age was 58 with the predominance of older population with the a pronounced poorer performance status and comorbid conditions.
The risk of death is the highest in the first two years since diagnosis decreases over time; although a true plateau was never reached, 41% and 70% (29%) of the deaths were recorded within the first 12 and 24 months respectively. This pattern of survival curve (Fig.1) seems also to demonstrate that the therapy was unable to change the course of the disease whatever the strategy chosen; however, the survival of patients attaining CR was significantly longer. Nevertheless, we are fully aware that no definite conclusions regarding the role of the therapy can be drawn from a retrospective trial with an accrual time spanning more than a decade.
As in other aggressive lymphomas, IPI proved to be able to identify subsets of patients with different prognosis. The PIT model was able to identify risk group patients, and in our study simplified two-class PIT proved to be superior over the simplified two-class IPI. ILI prognostic model designed for indolent lymphoma is not useful in aggressive lymphomas like PTCL-U.
In conclusion, instead of improving risk classification in respect to ILI and IPI, the PIT model clearly showed that groups 3 and 4 had very dismal prognosis and very low 5 year survival probability. For these patients a new therapeutic strategy should be explored.
 

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