B-cell lymphoma became an AIDS-defining condition early in the epidemic 1 and remains the second most common malignancy in patients with HIV disease. 2 With the recent advent of highly active antiretroviral therapy (HAART), the incidence of AIDS-related opportunistic infections and Kaposi sarcoma has fallen dramatically. 3,4 Although the incidence of AIDS-related lymphoma has also fallen, this decrease has not been as profound as that seen in the other AIDS-defining conditions, and lymphoma has now become one of the most common of the initial AIDS-defining illnesses. 5 AIDS-related lymphoma is unique from lymphomas occurring de novo in HIV-seronegative individuals. Thus, the majority of patients present with systemic “B” symptoms and have one or more sites of extranodal disease. 6–8 Pathologically, AIDS lymphomas are B-cell tumors, including diffuse large B-cell tumors, Burkitt or Burkitt-like tumors, and/or B-immunoblastic lymphomas. 6,9,10
Over the past 2 decades, several case reports have documented the occurrence of T-cell lymphomas among HIV-infected individuals. 11–19 These lymphomas have consisted of a diverse group of disorders, including peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma, anaplastic large T-cell lymphoma, and angiocentric T-cell lymphoma. 11–19 Although T-cell lymphoma remains relatively rare among HIV-infected individuals, linkage of AIDS and cancer registries in the United States has indicated a 15-fold increase in these lymphomas among AIDS patients when compared with the expected incidence in the general population. 20 The clinical, prognostic, immunologic, and virologic characteristics of T-cell lymphoma occurring in HIV-infected individuals have not yet been reported. Therefore, we studied 11 cases of T-cell lymphoma identified from the AIDS Lymphoma Registry at the University of Southern California. Characteristics of these cases were compared with those of 418 consecutive HIV-infected patients with B-cell lymphoma diagnosed and treated within the same time frame at the same institution.
This study is a retrospective analysis of 429 consecutive HIV-infected patients diagnosed with lymphoma and treated at the Los Angeles County–University of Southern California Medical Center and the University of Southern California/Norris Comprehensive Cancer Center between November 1982 and December 2001. All patients tested positive for HIV using the enzyme-linked immunosorbent assay (ELISA), the results of which were confirmed by Western blot analysis. All patients had pathologically or cytologically proven non-Hodgkin lymphoma and were staged using the Ann-Arbor staging system. The 429 patients included those with primary central nervous system lymphoma as well as systemic AIDS-related lymphoma.
All patients had a complete history and physical examination and underwent routine laboratory tests, which included a complete blood cell count, chemistry panel, lactate dehydrogenase level, and T-cell subset analysis of peripheral blood at the time of diagnosis. Computerized tomography (CT) scans of the chest, abdomen, and pelvis; bone marrow aspirate and biopsy; and lumbar puncture with examination of the cerebrospinal fluid were performed on all patients as part of the routine staging workup. Medical records, pathology reports, laboratory results, treatment regimens, and responses to therapy were analyzed on all patients.
Biopsy samples were collected during standard diagnostic procedures under sterile conditions. Representative portions of each tissue specimen were routinely fixed in buffered formalin and B5 or Bouin solution and embedded in paraffin from which hematoxylin and eosin (H&E) sections were prepared. Morphologically, the diagnosis of lymphoma was made on the H&E specimens by 2 expert hematopathologists (B.N.N. and X.B.). Histologic classification of the T-cell lymphomas was performed according to the revised World Health Organization (WHO) classification system. 21 The immunophenotypic profiles of the tissues were determined by immunohistochemical staining of paraffin tissue sections using a 3-step avidin-biotin immunoperoxidase technique. The monoclonal antibodies used were anti-CD20 (L26, 1:100; Biogenex, San Ramon, CA); anti-CD30 (Ber-H2, 1:25; Dako, Carpinteria, CA); and anti-CD4, anti-CD5, anti-CD8, anti-CD43, anti-CD56, and polyclonal anti-CD3 (1:250; Dako). Control sections were immunostained under identical conditions with buffer solution substituted for the primary antibody. Tissue sections were mounted onto charged slides (Surgipath, Richmond, IL), baked at 56°C for 60 minutes, deparaffinized with xylene, and rehydrated with graded ethanol to distilled water. Sections underwent antigen retrieval consisting of submersion of the sections in buffer, followed by 1 hour of steaming and 10 minutes of cooling. For CD3 and CD20, citrate buffer at pH 6.0 (Citra Solution, Biogenex) was used; for CD30, the buffer was EDTA at pH 8.0 (Zymed, South San Francisco, CA). Reactivity was demonstrated by a streptavidinbiotin immunoperoxidase detection system (Super Sensitive Immunodetection System; Biogenex) employing 3′,3′ diaminobenzidine–tetrahydrochloride dihydrate as the chromogen. When necessary, molecular testing for immunoglobulin heavy chain gene rearrangement or the T-cell receptor gene rearrangement was carried out as well using standard techniques.
Differences in demographic, HIV, and lymphoma-related characteristics between T- and B-cell cases were examined using the Fisher exact test. 22 Survival time was defined as the date from first pathologic diagnosis of lymphoma to the time of death or last follow-up, with median survival defined as the 50% point on the Kaplan-Meier curve. 23 Data on patients who were alive or lost to follow-up were censored as of the date these patients were last seen, using a cutoff follow-up date of December 1, 2001 Differences in survival were calculated using the log-rank test. 24
Of the 429 patients with AIDS-related lymphoma, 11 had T-cell and 418 had B-cell lymphomas. As shown (Table 1), more than 90% of patients were male, and the median age was similar at 33 years for T-cell disease and 38 years for B-cell disease (P = 0.28). There were no significant differences in terms of race or ethnicity among T-cell versus B-cell lymphoma cases, and the risk group for acquisition of HIV infection was similar as well, with 73% of patients from both groups consisting of men who have sex with men.
The median CD4 cell count at diagnosis of lymphoma was 101 cells/mm3 (range: 13–935 mm3) in T-cell cases and 73 cells/mm3 (range: 0–1927 mm3) in patients with B-cell lymphoma (P = 0.54). Likewise, the groups were similar in terms of history of an opportunistic infection before the diagnosis of lymphoma, occurring in 36% of T-cell cases and 45% of B-cell cases (P = 0.76; see Table 1). There was no difference in the number of patients receiving HAART before the diagnosis of lymphoma when comparing the T-cell versus B-cell lymphomas (P = 0.64).
Clinical Characteristics of Lymphoma
All patients with T-cell lymphoma presented with systemic disease, whereas 51 (12%) of the B-cell lymphomas were isolated to the central nervous system. Systemic “B” symptoms consisting of fever, drenching night sweats, and/or unexplained weight loss were common, occurring in 82% of T-cell cases and 67% of B-cell cases (P = 0.35). Likewise, both groups presented with advanced lymphomatous disease, with stage IV confirmed in 91% of T-cell lymphoma patients and 59% of B-cell lymphoma patients. Sites of extranodal disease are detailed in Table 2. Of note, bone marrow was more often involved in T-cell versus B-cell lymphoma (45% vs. 15%, P = 0.019). Similarly, skin involvement was more common among patients with T-cell lymphoma, occurring in 36% versus 2% with B-cell lymphoma (P < 0.001). Lymphomatous involvement of the leptomeninges occurred in 9% of T-cell cases and 10% of B-cell cases (P = 1.00). Likewise, other sites of extranodal disease were similar in the 2 groups.
Pathologic and Immunophenotypic Features of T-Cell Lymphomas
The T-cell lymphomas diagnosed in these patients were pathologically diverse. Anaplastic large cell lymphoma (ALCL) of T-cell type was diagnosed in 3 patients, whereas 5 had peripheral T-cell lymphomas. Angioimmunoblastic T-cell lymphoma was diagnosed in 1 case, as was human T-cell lymphotropic virus-I (HTLV-I)–associated adult T-cell lymphoma/leukemia and enteropathy-type T-cell lymphoma.
The immunophenotypic characterization of the T-cell lymphomas is detailed in Table 3. The designation of T-cell lymphoma was based on the expression of at least 1 pan-T antigen and/or 1 subset T antigen, with a lack of pan-B antigen expression. The most commonly expressed T-cell antigen was CD43, observed in all 11 cases. In addition, CD3 expression was common, detected in 82% of cases, whereas CD4 staining was demonstrated in 63% of cases. Staining for Ki-67 was accomplished in 8 cases and was found to be positive in >80% (range: 10%–90%) of cells in 5 of these (63%). Epstein-Barr virus (EBV) genome was detectable in 3 patients (cases 7–9), all of whom had peripheral T-cell lymphomas. T-cell receptor gene rearrangement was performed in 3 patients in whom morphologic and/or immunophenotypic characterization was difficult; all 3 demonstrated T-cell receptor gene rearrangement.
Treatment and Survival
The specific treatments used in the 11 patients with T-cell lymphoma and results of therapy are provided in Table 4. Patient 2, with angioimmunoblastic T-cell lymphoma, had Pneumocystis jiroveci (formerly carinii) pneumonia, cerebral toxoplasmosis, and Mycobacterium tuberculosis at the time that lymphoma was diagnosed; he died before receiving therapy. Eight patients received combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) 25 or CHOP-based regimens, and 1 received methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD). 26 All 3 patients with anaplastic large T-cell lymphoma achieved complete remission with CHOP or similar regimens, whereas none of the 5 patients with peripheral T-cell lymphoma had a complete remission with the CHOP regimen. Combination chemotherapy with etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) 27 was used as salvage therapy in 4 patients and was associated with complete remission and long-term disease-free survival in 1 patient (case 7) with peripheral T-cell lymphoma; this patient remains in complete remission without evidence of lymphoma more than 81.3 months from initial diagnosis.
Patients with systemic B-cell lymphoma were treated as follows: CHOP-based regimens were given to 136 (37%), whereas m-BACOD–based regimens were used in 158 patients (43%). Various miscellaneous regimens were given to 38 patients, whereas 35 patients received no therapy for their AIDS-related lymphoma.
As shown in Figure 1, the overall median survival of patients with T-cell lymphoma was 10.6 months versus 6.6 months for the patients with B-cell AIDS lymphoma (P = 0.13). If considering only those patients with systemic AIDS lymphoma, the median survival of T-cell patients was unchanged at 10.6 months, whereas that of the B-cell patients was 6.8 months (P = 0.21).
Although the clinical and pathologic spectrum of HIV-related B-cell lymphomas is well known, current understanding of the T-cell lymphomas that occur in HIV-infected individuals is rudimentary. Nonetheless, recent evidence suggests that HIV-infected individuals are at increased risk for developing a broad spectrum of T-cell lymphomas. 20 We have therefore identified a group of 11 HIV-infected patients with T-cell lymphoma defined on the basis of morphologic, immunologic, and molecular criteria and compared the characteristics of these individuals with those of 418 HIV-infected patients with B-cell lymphoma, all pathologically evaluated, staged, and treated by the same group of pathologists and clinicians. The prevalence of T-cell lymphomas in our population was approximately 3%, consistent with what has been reported by Biggar et al. 20
The pathologic spectrum of T-cell lymphomas among our cohort was quite diverse, consisting of enteropathy type T-cell lymphoma, angioimmunoblastic T-cell lymphoma, ALCL, peripheral T-cell lymphoma, and HTLV-I–associated adult T-cell lymphoma/leukemia. This diversity in our cohort would suggest the absence of a common pathogenic mechanism of T-cell malignancy that may occur among HIV-infected persons. The wide spectrum of T-cell malignancies in HIV-infected patients is supported by case reports published in the literature (Table 5).
In terms of clinical characteristics of disease, we found a statistically increased likelihood of cutaneous (36% vs. 2%) and bone marrow (45% vs. 15%) involvement among HIV-infected patients with T-cell lymphoma when compared with patients with B-cell malignancy. Cutaneous and bone marrow involvement has also been documented among HIV-negative patients with T-cell lymphoma, with these sites more commonly involved than in patients with de novo B-cell lymphomas. 28–32 We found no other clinical differences between T-cell and B-cell lymphomas in our cohort of HIV-infected persons. Also, when limiting the data analysis to patients with only systemic lymphoma, there were no differences in any demographic or clinical characteristics.
The median survival of our HIV-infected patients with T-cell lymphoma was also similar to that of patients with characteristic B-cell AIDS-related lymphoma, with a median survival of 10.6 months in T-cell lymphoma patients versus 6.6 months in all B-cell lymphoma patients and 6.8 months in those B-cell patients with systemic AIDS-related lymphoma. The absence of a survival difference between our 2 patient groups was remarkable, because with the exception of anaplastic lymphoma kinase (ALK)-positive ALCL, T-cell lymphoma is usually associated with a poorer response to therapy and shorter survival than described in patients with B-cell lymphoma. 28,32,33 Lower CD4 cells (<100 cells/mm3) are associated with poorer prognosis in patients with B-cell AIDS lymphoma. 34,35 Of interest, the median CD4+ count was extremely low in both the T-cell and B-cell cohorts, reflecting the significant levels of immune suppression usually seen in patients with advanced HIV infection. It is possible that the similar median survival times in the 2 groups reflected the uniformly poor prognosis associated with such profound degrees of immune suppression, thus obviating the importance of other potential indicators of poor prognosis, such as T-cell phenotype. In addition, our cohort of T-cell lymphomas included 3 cases (27%) of ALCL, which may have a better prognosis than other types of T-cell lymphoma, thus serving to improve the overall prognosis of the T-cell group. Nonetheless, Tirelli and colleagues 36 and Nosari and colleagues 37 have shown that HIV-infected patients with ALCL are similar prognostically to HIV-infected patients with high-grade B-cell lymphoma, whereas Chadburn and colleagues have shown that ALCL behaves similarly among HIV-infected or -uninfected patients. 38 These data again suggest that severe immunosuppression caused by HIV may override the expected favorable prognosis of the ALK-positive ALCL type of T-cell lymphoma. Of interest, of the 4 T-cell lymphoma patients who remain alive, 3 were on HAART at the time of lymphoma diagnosis. The remaining T-cell lymphoma patients were diagnosed and treated before the availability of HAART.
The results of this retrospective study suggest that among HIV-infected individuals, T-cell lymphomas behave differently from B-cell HIV-related lymphomas in terms of specific extranodal sites of disease. Our findings also suggest that HIV-related T-cell neoplasms carry the same poor prognosis as their B-cell counterparts. The current study was retrospective in nature and included only small numbers of patients with AIDS-related T-cell lymphoma. These retrospective observations must thus be confirmed in larger prospective series. Nonetheless, whereas the numbers of HIV-infected patients with T-cell lymphoma remain small (approximately 3% of AIDS-related lymphoma), the prevalence of these T-cell lymphomas is statistically increased among HIV-infected individuals when evaluated in population-based studies. 20 Further data are awaited that may clarify the pathogenesis, etiology, and optimal therapy for T-cell lymphoma in the setting of underlying infection by HIV.
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