Primary cutaneous non-Hodgkin’s lymphoma with aggressive histology: inferior outcome is associated with peripheral T-cell type and elevated lactate dehydrogenase, but not extent of cutaneous involvement

C. Visco1, L. J. Medeiros2, D. Jones2, T. Smith3, M. A. Rodriguez1, P. McLaughlin1, J. Romaguera1, F. Cabanillas1 and A. H. Sarris1,+

1 Department of Lymphoma and Myeloma, 2 Department of Hematopathology and 3 Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Received 25 July 2001; revised 21 January 2002; accepted 11 February 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The aim of this study was to explore the association between extent of cutaneous involvement, presenting features and progression-free survival (PFS) in patients with primary cutaneous non-Hodgkin’s lymphoma (PCNHL) of aggressive histology.

Methods:

Previously untreated patients with localized or extensive PCNHL of aggressive histology, treated with combination chemotherapy, but excluding lymphoblastic lymphoma and mycosis fungoides and its variants, were reviewed retrospectively.

Results:

We identified 53 patients, of whom 52 (35 males, 17 females) were treated with doxorubicin-based regimens. Median age was 52 years (range 25–81 years), and disease was localized and extensive in 37 and 16 patients, respectively. Twenty-four patients had diffuse large B-cell lymphoma, nine had grade 3 follicular lymphoma, 13 had peripheral T-cell lymphoma (PTCL; not otherwise specified) and seven had anaplastic large cell lymphoma (WHO classification). With a median follow-up of 101 months (range 2–237 months) for survivors, the 10-year PFS was 65 ± 7% and overall survival was 72 ± 8%. The first failure involved the skin in 33% of B-cell and 91% of relapsing T-cell lymphomas. Univariate analysis revealed that PTCL (P = 0.005), lymphopenia (P = 0.01) and high serum levels of ß2-microglobulin (P = 0.0006) and LDH (P = 0.002), but not extent of skin involvement, were associated with inferior PFS. Multivariate analysis revealed that only PTCL and high serum lactate dehydrogenase (LDH) were independently associated with inferior PFS.

Conclusions:

PTCL and elevated serum LDH level, but not extent of cutaneous involvement are associated with inferior PFS in aggressive PCNHL treated with combination chemotherapy.

Key words: histology, lymphoma, prognosis, skin, stage


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Primary cutaneous non-Hodgkin’s lymphoma (PCNHL) is defined as lymphoma limited to skin without extracutaneous involvement at presentation, and accounts for ~5% of all non-Hodgkin’s lymphomas (NHLs) [1, 2]. When mycosis fungoides and lymphoblastic lymphoma are excluded, PCNHL encompasses peripheral T-cell lymphoma (PTCL; not otherwise specified), anaplastic large cell lymphoma (ALCL), follicular lymphoma, diffuse large B-cell lymphoma (B-DLCL) and marginal zone lymphoma [3]. For some investigators, the definition of PCNHL requires that there be no progression to extracutaneous sites for at least 6 months after diagnosis and without treatment, based on adequate staging procedures [47]. This criterion introduces a strong selection bias: patients with aggressive disease might thus be excluded and only those with clinically indolent disease, irrespective of histology, would retrospectively be included in these studies. Clearly, this definition of PCNHL is difficult to use in clinical practice because it does not allow for treatment decisions at the time of initial patient presentation.

The treatment of PCNHL has varied over the years and has included radiotherapy, combination chemotherapy or combined modality regimens [5, 813]. Only one prospective study [14] has been performed on PCNHL, excluding mycosis fungoides and its variants. However, the optimal treatment of PCNHL with aggressive histology, of either B-cell or T-cell immunophenotype, has not yet been defined. Radiotherapy alone has been used for patients with localized B-cell PCNHL [4, 7, 8, 15], but relapse rates ranging from 32% to 100% have been reported [8, 1618]. However, when the absence of extracutaneous disease for 6 months was not required as a diagnostic criterion, PCNHLs with aggressive histology were not curable with radiotherapy alone [11, 18]. In contrast, after doxorubicin-based regimens and variable adjuvant radiotherapy, the 12-year progression-free survival (PFS) for Ann Arbor Stage (AAS) I PCNHL was 71% [18]. A multicenter prospective clinical trial of 49 patients with aggressive PCNHL reported event-free survival (EFS) of only 50% at 5 years after combination chemotherapy [14].

Most studies report survival, which is affected by both initial and post-relapse therapy. The latter is always variable and has changed greatly over time. Survival is also limited by the immutable natural limit of life expectancy, which is obviously shorter for older patients. Therefore, we consider PFS a more suitable end point for retrospective analysis.

The outcome of aggressive histology PCNHL with extensive cutaneous disease remains undefined. Our objective was to define the frequency, clinical and laboratory features, response to combination chemotherapy, patterns of relapse, PFS and survival of adults with histologically aggressive PCNHL. We also wished to determine any association between extent of skin involvement, presenting features and clinical outcome.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient population
We searched the Institutional Lymphoma Planning Clinic Database and the Lymphoma Investigational Protocol Database for the time interval from 1971 to 2000 for patients with NHL that was limited to skin. These databases contain previously untreated lymphoma patients initially presenting to the M.D. Anderson Cancer Center. Patient inclusion criteria were as follows: (i) presented only with clinically detectable skin lesions; (ii) had no extracutaneous disease detected by comprehensive staging at diagnosis; (iii) had available tissue allowing diagnosis of an aggressive histological type according to World Health Organization (WHO) classification [19]; (iv) were treated with combination regimens that were preferably anthracycline-based; (v) had received no prior therapy for the lymphoma; (vi) had no prior or concurrent history of mycosis fungoides, Sézary Syndrome or any prior lymphoma at any site; (vii) were >16 years of age; (viii) did not have lymphomatoid papulosis [20]; and (ix) patients with lymphoblastic lymphoma were also excluded, because based on our prior experience [18] they should be treated with acute lymphoblastic leukemia regimens.

Pathology review
After review of all available slides, diagnoses were rendered according to the WHO classification [19]. Tumor types considered as having an aggressive histology included B-DLCL, ALCL, follicular lymphoma (FL) grade 3 (large cell) and all subtypes of PTCL.

Staging
All available records were reviewed to verify presentation, staging, treatment and outcome. Staging evaluation included physical examination, bone marrow aspirates and biopsies, and chest radiographs. Computerized axial tomography of chest, abdomen and pelvis was performed in 49 patients. In four patients presenting before the introduction of computerized axial tomography, the radiographic exclusion of thoracic and abdominal involvement was based on tomograms and lymphangiograms, and was confirmed by negative exploratory laparotomy in three of them. Radioimmunoassay was used to determine serum levels of ß2-microglobulin, whose upper normal limit was 2.0 mg/dl. However, for analysis of PFS, ß2-microglobulin levels were considered high if >3.0 mg/dl, as previously defined in the tumor score model [21].

The AAS [22] was determined after review of all clinical, laboratory, pathological and radiographic data in a multidisciplinary planning conference attended by hematologists, medical oncologists, radiation oncologists, hematopathologists and diagnostic radiologists. We determined the AAS to be I in 37 patients with one or more lesions, which were localized to a restricted single anatomic area. These included a single upper extremity in six patients, a single lower extremity in five patients, the head in 11 patients, and either anterior or posterior trunk in 15 patients. By contrast, the AAS was determined to be IV in 16 patients who had multiple skin lesions involving more than one anatomic area. The assignment of AAS IV was based on the involvement of anterior and posterior trunk in six patients, of upper and lower extremities in two patients, of trunk and either upper or lower extremities in four patients, of trunk and scalp in one patient, of scalp and lower extremities in one patient, and of both lower extremities in two patients.

Treatment
Treatment according to standard or investigational regimens was based on risk assessment according to histological diagnosis and previously published prognostic criteria [21], and was decided in a multidisciplinary planning clinical conference attended by hematologists, medical oncologists, radiation oncologists, hematopathologists, and diagnostic radiologists. Therapy was administered either at the University of Texas M.D. Anderson Cancer Center, or by collaborating community physicians. However, all response determinations were performed at the M.D. Anderson Cancer Center. Signed informed consent was obtained before all procedures and investigational therapy, as required by the Investigational Review Board. Treatment of localized aggressive lymphomas changed after 1980 from radiation therapy alone to combination chemotherapy, almost always including doxorubicin and often followed by adjuvant radiotherapy. Combination chemotherapy regimens were assigned partly according to the pathological diagnosis, which was in turn rendered according to the Working Formulation [23] before 1994, and thereafter according to the Revised European American Lymphoma (REAL) classification [24], and is currently determined according to the WHO classification [19]. Treatment regimens included: cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) [25] in 13 patients; CHOP with bleomycin (CHOP-B) [26] in 21 patients; CHOP alternating with etoposide, mitoxantrone, vincristine and prednisone (OPEN) [27] in 10 patients; cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) [28] in one patient; CHOP-B alternating with cisplatin, high-dose cytarabine and dexamethasone (DHAP) [29] in one patient; CHOP alternating with cyclophosphamide, methotrexate, etoposide and dexamethazone (C-MED) [30] in three patients; hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethazone and high-dose cytarabine and methotrexate (Hyper-CVAD) [31] in one patient; and alternating triple therapy consisting of doxorubicin, cisplatin, cytarabine and methylprednisolone (ASHAP), alternating with methotrexate, leucovorin, doxorubicin, vincristine, bleomycin, cyclophosphamide and methylprednisolone (M-BACOS), and with ifosfamide, mesna, mitoxantrone and etoposide (MINE) in two patients [32]. One patient with subcutaneous panniculitis-like PTCL was originally thought to have mycosis fungoides and was initially treated with C-MED and interferon, however, the diagnosis was subsequently revised following pathology review. For the purpose of this analysis, CNOP was considered a doxorubicin-equivalent regimen. Radiotherapy was administered at the end of chemotherapy to 31 patients according to specific investigational protocols or at the discretion of the treating physicians. Median dose was 40 Gy (range 30–50 Gy).

Response definitions, outcome end points and statistical analysis
Complete remission (CR) was defined as absence of disease for at least 1 month, as determined by physical examination, appropriate laboratory and imaging studies, and skin biopsy, if indicated. Partial response (PR) was defined as >50% reduction of tumor area measurable in two dimensions. Progressive disease (PD) was defined as enlargement (>25%) of an existing site of disease, or the development of disease in a previously uninvolved site. All other responses were considered as stable disease (SD). Primary treatment failure was defined as failure to achieve either CR or PR during initial therapy. Relapse was defined as disease progression occuring at least 1 month after the achievement of CR or PR. PFS was measured from the beginning of treatment to the time of primary treatment failure, relapse or last follow-up. All other events, including toxic deaths, deaths from unrelated causes or the development of non-lymphoid neoplasms, were censored. Survival was measured from start of treatment to last follow-up or to death from any cause. The actuarial probability of PFS and overall survival was determined by the method of Kaplan–Meier [33]. The statistical significance of differences between groups was determined with the log-rank test, and the statistical relationship between variables with Cox’s proportional hazards model [34].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Frequency and presenting features
Between 1971 and 2000, a total of 2670 previously untreated patients with NHL presented to the M.D. Anderson Cancer Center. Seventy-seven patients presented with PCNHL of aggressive histology, representing 3% of all untreated NHLs. Twenty-four of these 77 patients were excluded from this analysis. Twelve of them presented before January 1980, were treated only with radiotherapy, and were excluded because, in our experience, radiotherapy alone was an inadequate treatment for PCNHL with aggressive histology [18]. Eleven patients did not have material available for immunophenotypic studies to allow diagnosis according to the WHO classification. One patient did not receive any treatment because of coexisting serious medical problems. The remaining 53 patients are the subject of this analysis. Their presenting clinical and laboratory features are shown in Table 1. The classification of disease as extensive (or AAS IV) or limited (AAS I) was assigned during the multidisciplinary planning conference, as described in the section above entitled ‘Staging’.


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Table 1.  Presenting clinical and laboratory features of the 53 patients with aggressive PCNHL
 
Histology and immunophenotype
According to the WHO classification, 33 patients had B-cell lymphomas, 18 patients had T-cell lymphomas and two patients had null-cell lymphomas. The most common subtype was diffuse large B-cell lymphoma (B-DLCL), which was seen in 24 (45%) patients, followed by PTCL, not otherwise specified, in 13 (25%) patients (Table 1). In the latter group, these tumors did not have anaplastic morphological features and they were not angiocentric. Seven patients fulfilled the WHO classification criteria for the diagnosis of cutaneous ALCL, of whom five had T-cell, and two had null-cell phenotypes. Since spontaneous regressions were not observed, the diagnosis of lymphomatoid papulosis was excluded in these seven patients with ALCL [20].

Response to treatment
Overall, 50 of the 53 patients (94%) who received combination chemotherapy achieved a complete remission. Progressive disease during the initial therapy was observed only in three patients, all of whom had PTCL; two with AAS I and one with AAS IV. One patient died from progressive lymphoma, while the other two underwent salvage therapy followed by autologous bone marrow transplantation, and are alive and free of disease after 38 and 70 months, respectively. All seven patients with primary cutaneous ALCL received doxorubicin-based therapy, which was followed by adjuvant radiotherapy in four. Four of them are still in complete remission, and one died free of disease 18 years after treatment. Two patients relapsed, and one was salvaged with MINE [32] and is now in remission 6 years later. The other patient presented with a single lesion on his lower extremity, but died of progressive lymphoma in spite of all salvage therapy. The two patients with ALCL of null-cell phenotype achieved complete remission and did not relapse.

PFS, survival and prognostic features
After a median follow-up of 101 months (range 2–237 months) for survivors, 20 patients remain in complete remission, 20 have progressed and 13 have died. Ten of these deaths were due to progressive lymphoma, but none were due to treatment-related toxicity. The estimated 10-year PFS (actuarial ± standard error) was 65% ± 7% (Figure 1A), and survival was 72% ± 8% (Figure 1B).



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Figure 1. (A) PFS and (B) overall survival for all 53 patients in the study.

 
When analyzed according to immunophenotype, the 10-year PFS was 77% ± 7% for B-cell lymphoma and 38% ± 12% (P = 0.01) for T-cell lymphoma (Figure 2A). However, analysis according to lymphoma type (Table 2; Figure 2B) revealed that there was no statistically significant difference between the 10-year PFS of patients with B-DLCL, follicular large cell lymphoma and ALCL (73% ± 9%, 86% ± 13% and 86% ± 13%, respectively; P = 0.88 by log-rank). By contrast, patients with PTCL, not otherwise specified, had a significantly lower PFS than the others (31% ± 13%, P = 0.004 by log-rank). Therefore, in subsequent multivariate analyses we included lymphoma type and not immunophenotype.



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Figure 2. PFS according to (A) immunophenotype and (B) lymphoma type.

 

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Table 2.  Univariate analysis for progression-free survival (PFS)
 
The PFS of patients with AAS I versus IV disease was 72% ± 8% versus 49% ± 13%, respectively (Figure 3), but this difference was not statistically significant (P = 0.11). However, in most (71%) patients with AAS I the tumors were of B-cell lineage, whereas among patients with AAS IV disease both B-cell and T-cell lineages were equally represented. When we analyzed the association of AAS with PFS separately for B-cell versus T-cell immunophenotype, the extent of the disease (AAS) was not associated with different PFS in B-cell histology (Figure 3B). In contrast, among patients with the T-cell immunophenotype, those with AAS IV disease had inferior PFS than those with AAS I disease. However, the number of patients was small and this difference was not statistically significant (Figure 3C). Univariate analysis also identified high serum ß2-microglobulin levels (P = 0.0006), high serum LDH levels (P = 0.002) and lymphopenia (P = 0.01) as adverse prognostic variables for PFS (Table 2; Figures 4, 5 and 6).



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Figure 3. PFS according to extent of skin involvement and immunophenotype. (A) Either B- or T-cell; (B) B-cell; (C) T-cell.

 


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Figure 4. PFS according to serum LDH level.

 


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Figure 5. PFS according to absolute lymphocyte count (ALC).

 


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Figure 6. PFS according to ß2-microglobulin (ß-2M) level.

 
With only 20 failures to date, our sample was small for a conclusive multivariate analysis. We therefore used Cox’s proportional hazards model to generate hypotheses by asking which factor might contribute to a model containing PTCL type. Serum LDH level was the only variable retaining statistical significance when added to PTCL (Table 3). Since serum levels of ß2-microglobulin were available in only 39 of the 53 patients, and were elevated in only four, this variable could not be adequately evaluated with the proportional hazards model. The combination of PTCL and high serum LDH levels demonstrated that the 5-year PFS for patients with no, one or two adverse features was 76% ± 8%, 58% ± 14% and 0%, respectively (P <0.0001; Figure 7).


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Table 3.  Multivariate analysis for progression-free survival
 


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Figure 7. PFS according to the number of adverse prognostic features: PTCL type and elevated serum LDH levels.

 
Patterns of relapse
Of the 20 patients who progressed during initial therapy or later relapsed, 15 underwent biopsy, including the two patients with late relapses occurring 12 and 14 years after initial presentation. Histological findings at relapse were unchanged from the initial presentation in 12 patients, but were different in three. The first patient with a change in histology at the time of second biopsy initially presented with AAS I PTCL, and was treated with CHOP followed by radiotherapy to the involved field. Subsequently, he developed both PTCL and mycosis fungoides at the edge of the radiotherapy field. He did not respond to several salvage regimens and died of progressive lymphoma. This patient had no signs or symptoms suggestive of mycosis fungoides at any time before initial presentation. Retrospectively, he is considered a de novo transformation of mycosis fungoides, presenting as PTCL type. The second patient developed Hodgkin’s disease 145 months after the initial diagnosis of B-DLCL. The third patient presented with grade 3 follicular lymphoma and relapsed with B-DLCL 166 months after the initial presentation.

Time to relapse was shorter for the T-cell immunophenotype: 75% of their relapses occurred within the first year (range 1–44 months; Figure 2). In contrast, only 30% of the recurrences of B-cell tumors occurred within the first year (range 6–197 months) and a more protracted pattern of relapse was evident (Figure 2).

The site of the first failure was exclusively cutaneous, without evidence of dissemination to lymph nodes or viscera, in eight of 20 (40%) relapsing patients. Relapses were exclusively extracutaneous in seven patients (35%), and three involved the central nervous system. Five patients had simultaneous cutaneous and extracutaneous relapse (25%). Thus, among all 20 relapsing patients, the skin was involved during the first relapse in 13 (65%). No significant difference was found in terms of patterns of relapse between patients who presented with either AAS I or IV disease (data not shown). Failures involving the skin occurred sooner after the beginning of treatment (10 out of 13 within 1 year, range 1–34 months) than exclusively extracutaneous failures (range 8–166 months). This difference probably reflects the fact that 91% of relapsing lymphomas with a T-cell immunophenotype did so with cutaneous involvement compared with 33% for relapsing lymphomas with a B-cell immunophenotype. Therefore, T-cell immunophenotype is not only characterized by a more frequent and earlier relapse than its B-cell counterpart, but also by a strikingly more frequent cutaneous tropism. The location of the cutaneous relapse in relation to the radiotherapy ports could be determined in nine patients; it was within the radiotherapy port in four patients, at its margin in one and at distant cutaneous sites in four.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We report that PTCL type and serum LDH elevation, but not extent of cutaneous involvement are independently associated with inferior PFS in PCNHL. These features can be used to identify patients groups who have progressively inferior PFS and who might thus be candidates for investigational therapy.

This conclusion is based on a retrospective analysis of patients with localized or disseminated PCNHL of aggressive histology, excluding lymphoblastic lymphoma and mycosis fungoides and its variants. These patients were identified from a database including all untreated patients with lymphoma presenting to our institution, without requiring that disease remained localized to skin for 6 months after the initial diagnosis. This criterion eliminates possible selection bias by excluding from the study patients with an aggressive clinical course, and allows for treatment decisions at the time of the initial patient presentation. According to departmental policy, all these patients were treated with combination chemotherapy regimens suitable for aggressive lymphomas. These regimens almost always contained doxorubicin, and were followed by adjuvant radiotherapy in 58% of them. Thus, there is little chance of selection bias by only treating with chemotherapy patients with perceived adverse presentations.

Our results for PFS are comparable to those of Brice et al. [14], whose prospective treatment of 49 patients with aggressive PCNHL with combination chemotherapy resulted in a 5-year event-free survival of 50%. However, they also included 22 patients with lymph node involvement at presentation, and who thus did not fulfill the criteria of PCNHL. Like us, they found T-cell PCNHL to have significantly worse 5-year PFS (35%) than diffuse large B-cell lymphoma (80%). There were only seven patients with primary cutaneous ALCL in our series, and even though this small number does not allow firm conclusions, their outcome appears favorable and is comparable with previous reports of nodal ALCL [14, 35]. The inferior outcome of PTCL compared with B-DLCL has also been observed in systemic NHLs by both the GELA group [36] and by us [37]. The similarity of outcomes between nodal and primary cutaneous NHL suggests that a separate classification scheme for PCNHL [6] is probably not needed. However, prospective investigations of the molecular and cytogenetic characteristics should determine whether the molecular pathogenesis of PCNHL is different from that of nodal NHLs.

In our series, T-cell PCNHL exhibited a remarkable predilection for cutaneous involvement during the first relapse or progression, with recurrent involvement of the skin in 91% of T-cell PCNHLs, which was exclusively cutaneous in 45% of patients. However, only 33% of B-cell PCNHL recurred in the skin at the time of first relapse. This persistent cutaneous tropism of T-cell lymphomas has previously been reported [7, 8, 14, 38, 39], but its molecular basis remains undefined. A possible explanation is that subpopulations of normal T-lymphocytes, and presumably their neoplastic counterparts, preferentially home to the skin, the site where they presumably encountered antigen for the first time. The cutaneous tropism of T-lymphocytes is most characteristic of mycosis fungoides, where multiple cutaneous relapses usually precede visceral dissemination [40]. However, other cutaneous T-cells and tumors can also express skin-homing receptors [9, 41, 42], including cutaneous lymphocyte-associated antigen, a skin-homing receptor that is expressed on normal memory T-lymphocytes and in cutaneous T-cell lymphomas [43, 44], but not in their B-cell counterparts [45]. The recirculation of lymphocytes between skin and the intravascular compartment is accomplished by complex interactions involving adhesion molecules expressed on lymphocytes, endothelial cells and parenchymal cells, and chemokines secreted by non-lymphoid cells [46, 47]. Interferon-inducible protein-10 (IP-10), which is chemotactic for T-lymphocytes, probably contributes to the epidermotropism of cutaneous T-cell lymphomas [4850]. This is consistent with the preferential detection of its cognate receptor in epidermotropic T-cell lymphomas [51]. Many chemokines, including IP-10, can protect subsets of hemopoietic progenitor cells from cytotoxic chemotherapy in vitro [52]. It is therefore possible that IP-10, or other unidentified chemokines, may contribute both to cutaneous tropism and to the chemoresistance of T-cell PCNHL.

Univariate analysis revealed that PTCL type, high serum LDH, high serum ß2-microglobulin and lymphopenia, but not AAS, were associated with significantly lower PFS. We classified as AAS IV patients with widespread cutaneous lesions at presentation, which were not limited to a single anatomic area as described in the section above entitled ‘Staging’. Even though patients with localized disease seemed to have a higher PFS than those with extensive disease, this was largely due to the preferential presentation of B-cell PCNHL with localized disease. When PFS was analyzed separately for patients with T-cell compared with B-cell immunophenotype, extensive cutaneous involvement was not associated with a statistically inferior PFS. Our data are clear for B-cell histologies, but additional patients should be analyzed to confirm this for T-cell histologies where the number of patients was small. Thus, for staging purposes, it appears that skin involvement, irrespective of its extent, might be considered AAS I. This independence of PFS from extent of cutaneous involvement was also demonstrated by multivariate analysis and is consistent with previously published results [13, 53]. The AAS system, as initially designed [22], was based on the contiguous dissemination in Hodgkin’s disease from one nodal area to the next, and was prognostic for radiotherapy-treated patients with this disease. The weak predictive power of AAS in PCNHL probably reflects the differences in biology between Hodgkin’s disease and PCNHL, some of which have been discussed previously.

Since there were only 20 failures in this study, the maximal number of independent factors that could be optimally included in a Cox’s proportional hazards model was two. We present here a prognostic model including PTCL histology and high serum LDH levels. However, since the number of patients is small, it is probably prudent to consider this model as hypothesis-generating for future investigations in larger retrospective and prospective series.

We conclude that PTCL type and elevated serum LDH levels, but not extent of cutaneous involvement, are independently associated with inferior PFS among patients with PCNHL of aggressive histology treated with combination chemotherapy. A model based on these features identifies groups of patients with unfavorable PFS who may be suitable candidates for investigational therapy.


    Acknowledgements
 
This work was supported in part by Cancer Center Support Grant CA-16672 to the University of Texas M.D. Anderson Cancer Center.


    Footnotes
 
+ Correspondence to: Dr A. H. Sarris, 35 Tsaldari Street, 14561 Kifissia, Athens, Greece. Tel: +30-10-807-7721; Fax: +30-10-6845-089; E-mail: a.sarris@hygeia.gr Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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