Non-Hodgkin lymphoma (NHL) is the second most common malignancy associated with HIV infection.1 A positive impact of highly active antiretroviral therapy (HAART) on the incidence of HIV-associated lymphoma has been observed, although of a lower magnitude than that observed for other AIDS-related complications.2-5 Thus, an increase in the frequency of lymphoma as an AIDS-indicating diagnosis has been reported in recent years.4
In developed countries, the relative risk of developing NHL in HIV patients is 100 to 300 times greater than in the general population. In some highly prevalent HIV regions in Southern and Central Africa, however, the relative risk of developing NHL is only 5 to 13 times greater. This finding is probably related to the higher incidence of opportunistic infections, limited diagnostic and therapeutic resources, and lack of access to antiretroviral (ARV) therapy, without enough survivors to develop this disease.1,6,7 We have not found estimates or studies based on data from Latin America. Our perception is that this risk is probably higher than in Africa and lower than in developed countries.
Clinical classification of NHL includes systemic NHL (sNHL), primary lymphoma of the central nervous system (PLCNS), and primary lymphoma of cavities (PLC), which represent approximately 80%, 17%, and 3% of cases, respectively.8 Clinical and histologic manifestations and outcomes of HIV-associated sNHL in North America and Europe have been extensively described.8-14 There are few reports from developing countries, however.
We performed a retrospective and prospective study to describe the clinical and pathologic characteristics as well as the outcomes of sNHL patients from a reference center for HIV/AIDS patients in Peru. We also evaluated factors associated with patient survival.
PATIENTS AND METHODS
We reviewed HIV/AIDS-associated sNHL cases diagnosed at the HIV/AIDS Unit of the Guillermo Almenara Irigoyen General Hospital (HNGAI) in Lima, Peru between January 1993 and April 2004. Our HIV/AIDS Unit is a reference center for Peruvian Social Security System patients from central and northern Lima. The unit has around 700 outpatients being administered HAART.
We obtained patient clinical information around the time of sNHL diagnosis from the HIV/AIDS Unit database and clinical records. We considered the following variables: age, gender, risk behavior, previous AIDS diagnosis,15 previous ARV therapy for at least 3 months (HAART was defined as a combination of 2 nucleoside reverse transcriptase inhibitors [NRTIs] plus 1 protease inhibitor [PI] or 1 nonnucleoside reverse transcriptase inhibitor [NNRTI]), Karnofsky score, opportunistic infections, B-cell symptoms (eg, fever, night sweats, weight loss), sNHL localization (nodal or extranodal),16 clinical stage according to the Ann Arbor classification16 (necropsy information was also used in some cases to define the clinical stage), lowest CD4+ cell count measured by flow cytometry or immunofluorescence between 6 months before and 3 months after the diagnosis of sNHL, and serum enzyme-linked immunosorbent assay (ELISA) results for human T-lymphotropic virus type 1 (HTLV-1).
Two senior pathologists (JS, VD) performed the histopathologic investigation of the biopsies and classified the NHL according to the classification system of the World Health Organization (WHO).17 They used paraffin-embedded specimens, conventional hematoxylin-eosin staining for the morphologic study, and immunohistochemical markers for B-cell and T-cell lymphoma antigens (immunophenotyping). The antibodies used for B-cell antigens were anti-CD20 monoclonal antibodies (L26 and M0775). To identify B-cell lymphoma subtypes, we used anti-CD23 antibodies (MHM6 and M6763), anti-CD5 antibodies (CD5/54/F6 and M7194), Bcl2 oncoprotein (124 and M0887), and cyclin D1 (DCS-6 and M7155) (all from Dako, Carpinteria, CA). The antibodies for T-cell antigens were anti-CD3 monoclonal antibodies (F7.2.38 and M7254; Dako). For T-cell lymphomas, we alternatively used anti-CD4 Ab-2 antibodies (IF6 and 392S312B; Neomarkers, CA) and anti-CD8 antibodies (C8/144B and M7103; Dako).
We used descriptive statistics to characterize the clinical and histologic information on the sNHL cases. The Fisher exact test and Mann-Whitney U test were used to evaluate differences between categoric and continuous clinical characteristics across phenotypes. Survival time was defined as time between data of sNHL diagnosis and date of death or censoring (ie, lost to follow-up or end of study [August 31, 2004]). Survival was estimated using the Kaplan-Meier method. The difference between survival distributions was tested with the log-rank test. The Cox proportional hazards model was used to determine the effect of the following factors on survival: ARV and AIDS diagnosis before lymphoma; CD4+ cell count; Karnofsky score; lymphoma phenotype; concomitant opportunistic infections; clinical stage, origin, and chemotherapy of lymphoma; and HAART after sNHL diagnosis for at least 3 months.
Variables that were associated with death (P < 0.2) in the univariate analysis were chosen for the multivariate analysis. A backward-stepwise method was then applied to obtain the variables independently associated with mortality (P < 0.05). We used SPSS software, version 10.0 (SPSS, Chicago, IL).
We treated approximately 2000 HIV/AIDS patients at our unit between January 1993 and April 2004. Most of them had symptomatic disease and severe immunosuppression. We diagnosed 42 cases (2%) of NHL. Among them, 33 (79%) were sNHL and 9 (21%) were PLCNS. There were no cases of PLC. The diagnosis of HIV infection was confirmed by Western blot (WB) analysis in 29 sNHL cases and by 2 ELISA HIV-positive test results in 4 sNHL cases. We made the sNHL diagnosis by biopsy (n = 30) and necropsy (n = 3). Patient characteristics are displayed in Table 1.
Eight patients had opportunistic diseases concomitant to the sNHL diagnosis: Pneumocystis jiroveci pneumonia (n = 2), meningeal cryptococcosis (n = 2), pulmonary tuberculosis (TB; n = 1), gastrointestinal TB (n = 1), cerebral toxoplasmosis and cytomegalovirus (CMV) retinitis (n = 1), and Kaposi sarcoma (n = 1). Nine patients were receiving ARV therapy at the time of presentation or sNHL diagnosis: 7 received HAART between 7 and 28 months (median = 9 months), and 2 received non-HAART regimens. Moreover, at the time of diagnosis, 4 of the 7 patients on HAART therapy had effective control of HIV replication, with HIV RNA test results less than 2.7 log copies/mL. Further, the 7 patients on HAART had CD4+ cell counts between 62 and 542 cells/μL (median = 325 cells/μL). One of these 7 patients died before the diagnosis of sNHL and was excluded from the survival analysis.
Only 25 patients had CD4+ cell counts available: 12 (48%) had <100 cells/μL, and 9 (36%) had >200 cells/μL. In this group, 2 patients had CD4+ cell counts performed 2 months after diagnosis of sNHL. One of them did not receive chemotherapy at the time of the sample collection but was on HAART for 1 month. The other patient had a CD4+ count 7 months before diagnosis (371 cells/μL) similar to that taken 2 months after diagnosis and after receiving 2 courses of chemotherapy (328 cells/μL). The HIV load was <400 copies/mL in both controls.
The histopathologic investigation yielded 24 (73%) cases of B-cell sNHL and 9 (27%) cases of T-cell sNHL. All T-cell lymphomas were peripheral T-cell lymphoma, subtype unspecified. T-cell lymphomas were CD3+, CD4+, CD8−, and CD20−. The subtypes of sNHL according to the WHO criteria are shown in Table 2. Nineteen cases of sNHL were extranodal. Seventy-nine percent (15 of 19 cases) of extranodal sNHL cases were of B-cell origin. These lymphomas were from the intestinal tract (n = 3), Waldeyer ring (n = 2), stomach (n = 3), rectum (n = 1), lung (n = 1), right thoracic wall (n = 1), pelvis (n = 2), Fallopian tube (n = 1), and multiple visceral locations (n = 1). Four extranodal (21%) sNHL cases were of T-cell origin, including the duodenum (n = 1), colon (n = 2), and eyelid (n = 1). Although we did not find significantly different clinical characteristics between phenotypes, patients with T-cell sNHL tended to have a better Karnofsky score and a lower proportion of prior AIDS diagnosis than patients with B-cell sNHL (see Table 1).
Twenty-five patients had ELISA HTLV-1 results available. These corresponded to 17 B-cell and 8 T-cell sNHL cases. One patient with B-cell sNHL had a positive result for this test. All T-cell sNHL cases had negative results for HTLV-1.
Twenty-eight of 33 patients were alive at the time of sNHL diagnosis. Three of the other 5 patients with sNHL were diagnosed at necropsy, and the remaining 2 patients underwent biopsy but died before the diagnosis of sNHL. These 28 patients were analyzed regarding treatment and survival. Thirteen of these 28 patients received chemotherapy with curative intent, including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; Table 3). Eleven of these 13 patients died after the first (n = 5) or second (n = 6) chemotherapy course, however. The combination of etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) was used as salvage therapy in 2 patients without a response to CHOP. In both cases, the sNHL progressed, however. One patient had Kaposi sarcoma (KS) and sNHL but died 13 months after receiving chemotherapy. Four of 28 patients received palliative corticoids, and 3 died in a short time. The fourth patient had cerebral toxoplasmosis and retinal CMV. This patient received HAART simultaneously and had complete remission of the lymphoma. Seven of 28 patients did not receive any treatment for lymphoma. The clinical condition of these patients was poor, and they died of infectious complications.
Six of 28 patients who were alive at the time of sNHL diagnosis and were receiving HAART continued with the treatment. Another 5 patients began HAART after the diagnosis of sNHL. The remaining 17 patients did not receive HAART afterward because the treatment was not available or their clinical condition was poor. At the end of the study, 3 of the 5 patients who began HAART after sNHL diagnosis were alive in comparison to only 1 of the 6 patients who were receiving HAART at the time of sNHL diagnosis. No patients without HAART were alive at the end of the study.
At the end of the study, there were 23 deaths, 1 patient lost to follow-up, and 4 patients alive. The overall median survival was 2 months (95% confidence interval [CI]: 0 to 6). The median survival times for patients with T-cell (n = 8) and B-cell (n = 20) sNHL were 10 months (95% CI: 0 to 24) and 2 months (95% CI: 0.4 to 3.7), respectively. These survival times were not statistically different (P = 0.08).
Karnofsky score, lymphoma clinical stage, and HAART after sNHL diagnosis were associated with death in univariate analysis (Table 4). CD4+ count and phenotype were less strongly associated. Patients with lymphoma clinical stage IV and without HAART after sNHL diagnosis had the highest risk of death in multivariate analysis (Table 5).
The sNHL patients died mainly because of disease complications (eg, central nervous system [CNS] compromise, digestive hemorrhage) or infectious complications (eg, sepsis, pneumonia). Other patients died as a result of direct complications (eg, cardiac arrest caused by doxorubicin) or complications indirectly related to chemotherapy (eg, renal failure after tumor lysis, sepsis after pancytopenia) (see Table 3).
We found a high proportion of T-cell lymphomas at an HIV/AIDS reference center in Lima, Peru. This proportion was higher than previously reported in developed and developing countries. We did not find differences in clinical presentation between the lymphomas according to phenotype. These surprising results may be explained by chance, the small number of sNHL patients, or the reference center status of our study population. Alternatively, the results may be true and may represent a notable difference in the histopathologic presentation in comparison with other settings.
According to estimates of the United Nations/WHO Joint Program on HIV/AIDS (UNAIDS), the HIV-infected population in Peru was approximately 82,000 at the end of 2003.18 The number of reported AIDS cases reached 16,832 by April 2005, although significant underreporting is highly likely.19 Access to ARV therapy in the country is limited to a small number of patients, mainly within the Social Security System. During the 11-year study period, we identified NHL in 2% of our HIV patients, which is between the reported figures in Barcelona, Spain (5%)12 and South Korea (1%).20 The proportional distribution of sNHL and PLCNS was similar to the findings of other reports.8,10 No cases of PLC have been reported in Peru or in other developing countries.6
The average age of our patients was similar to that in some series21 but higher than that in other series.10,22,23 The male/female ratio was also similar to that of other reports.10 The association between NHL and sexual risk behavior or HIV exposition is generally weak.24 Our cases were similarly distributed between homosexual and heterosexual persons. No sNHL patient in our series used intravenous drugs, which is an unusual modality of drug abuse in Peru.19 The presentation of sNHL as the first AIDS-defining disease was the case in most of our patients. The proportion of sNHL patients with a previous AIDS diagnosis was slightly lower than in other series (range: 35%-43%)10,21,25 but higher than in others (17%).23 Seven patients developed lymphoma while on HAART, and 4 of them had effective control of HIV replication. This observation was also seen in a large series from a French study.26 In this study, 39% (27 of 70) of patients receiving HAART at the time of sNHL diagnosis had a suppressed HIV viral load. This finding may be related to the observed slight decrease in sNHL incidence during the HAART era.2,3
Most sNHL cases were extranodal and at an advanced clinical stage, in concordance with previous reports.8-10 Moreover, most of the cases of extranodal sNHL originated from the digestive tract, as was reported previously.27 A lower proportion of systemic B symptoms (39%) was observed in our patients than in other reports (range: 69%-71%).10,23
Many of our patients had opportunistic infections associated with the diagnosis of sNHL. Few reports have addressed this point; however, a single report described 23% of sNHL patients with opportunistic infections, most of them viral (herpes zoster and simplex).21 Further, there was no close relation between the presence of sNHL and the degree of immunosuppression in our sNHL patients, although most published data support this relation in PLCNS and PLC. For instance, 36% of the 25 patients with available CD4+ cell counts developed sNHL with levels >200 cells/μL. The median value of CD4+ T cells in our patients was similar (113 cells/μL)10 or lower (249 cells/μL)23 than in other reports.
In developed countries, HIV-associated sNHL is mainly composed of B cells. T-cell lymphoma cases have been reported occasionally.28-31 Thus, this phenotype is not considered to be an AIDS-defining disease.32 The frequency of T-cell sNHL has increased in the past few years, however.33 The lifetime risk of developing this type of lymphoma in AIDS patients is moderate (relative risk = 15, 95% CI: 10 to 22). Moreover, the risk is increased in all types of T-cell sNHL.34
In particular, only a few publications about phenotype from Peruvian NHL patients are available, although without major clinical information. Three main hospitals take care of cancer patients in Lima: the Peruvian National Cancer Institute (INEN), the Edgardo Rebagliati Martins General Hospital (HNERM), and our hospital (HNGAI). In the year 2000, the INEN reported 25% (89 of 356) of cases of T-cell lymphoma (Carlos Barrionuevo, Department of Pathology, INEN, personal communication, 2004). Similarly, the HNERM reported 26% (71 of 273) of cases of T-cell lymphoma between 1997 and 2000,35 and the HNGAI reported 29% (27 of 93) of cases of T-cell lymphoma between 1999 and 2000.36,37 This last study excluded HIV patients and a few patients without immunophenotyping tests. In contrast, another study38 reported a prevalence of 5% (5 of 107) of cases of T-cell NHL in northern Peru. This study was performed primarily in patients with nodal lymphomas, however, and the immunophenotype was not determined in 10% of cases (n = 11), mainly because of the lack of the CD3 marker. Together, these data suggest that the high proportion of T-cell sNHL we found in HIV patients may also be related to the high prevalence of the T phenotype in the Peruvian general population. A high prevalence of T-cell NHL has also been reported in Korea (35%)39 and nonendemic HTLV areas of Japan (19%).40 Areas of low prevalence of T-cell sNHL include Western industrial countries (7%),41 Uganda (7%),42 and other regions of sub-Saharan Africa.7
Studies conducted in HTLV-1 endemic regions, such as the Caribbean region and Japan, have established an etiopathogenic role for HTLV-1 as the cause of adult T-cell leukemia lymphoma (TCLLA).43 This virus does not explain the diversity of T-cell NHL, however. A large American series of T-cell NHL cases only found a 4% prevalence of HTLV-1 infection.43 In our series, all patients with T-cell sNHL had negative results for HTLV-1 by ELISA. Likewise, it has been argued that HIV and Epstein-Barr virus (EBV), closely related to B-cell sNHL, may play a role in the pathogenesis of T-cell sNHL.44,45 More studies are needed to resolve this issue.
There are few descriptions of clinical characteristics in HIV patients according to their histologic pattern and phenotype of sNHL. A large series of HIV-related aggressive lymphomas in France found that the Burkitt-like type infiltrated the bone marrow, extracerebral nervous system, and liver.46 Other series in non-HIV patients found a higher proportion of lymphoproliferative and autoimmune disorders associated with T-cell NHL than with B-cell NHL.47 Likewise, most cases of NHL were mainly nodal, with occasional compromise of the gastrointestinal tract.47,48 In contrast, our patients did not have other lymphoproliferative or immunoproliferative disorders, and many cases originated from the gastrointestinal tract. Likewise, many of our sNHL cases were of B-cell origin, and they compromised unusual organs, such as the rectum, lung, and pelvic organs.8,13 A recent study49 compared the clinical characteristics and outcomes of 429 HIV-positive patients with sNHL (11 T-cell and 418 B-cell lymphomas). There were no major differences between these phenotypes. Moreover, in contrast to our study, this study showed a diversity of histopathologic types of T-cell sNHL.
We did not find differences in clinical characteristics between B-cell and T-cell lymphomas. Patients with T-cell sNHL had a better Karnofsky score and a lower proportion of prior AIDS diagnosis than patients with B-cell sNHL, however. Moreover, the survival of patients with T-cell sNHL was nonsignificantly longer than the survival of patients with B-cell sNHL. These findings may reflect a less aggressive nature of the T-cell lymphomas in our population.
Survival of HIV patients with sNHL is poor and ranges from 4 to 6 months.50,51 Our results are even worse. Several reasons explain this finding: more advanced sNHL, a smaller proportion of patients with HAART, and chemotherapy complications. Other potential reasons may be the delay in sNHL diagnosis and the aggressive non-HIV chemotherapy applied to HIV patients.
Patients who began HAART after the diagnosis of sNHL had a somewhat better prognosis than those who did not. This benefit has been reported previously.51-53 A recent study54 demonstrated that patients on HAART reached complete remission of sNHL with chemotherapy and that their survival is similar to those without HIV. We did not find a beneficial effect of chemotherapy, probably because of severe complications.
Although not significant, patients with the T-cell phenotype had a lower risk of death in comparison to patients with the B-cell phenotype, similar to the report by Arzoo et al.49 This is an interesting finding, and it is contrary to what has been reported in non-HIV patients.55,56 All T-cell lymphomas were peripheral and unspecified in comparison to the B-cell lymphomas, which were mainly diffuse with large cells. Other unknown reasons may also explain this difference.
Several limitations should be acknowledged. First, our study population was too small to have the power to detect significant differences or to be certain about some actual differences. Second, few patients had CD4+ cell counts available. Third, a relatively small number of patients were administered HAART and chemotherapy in our study. These issues made the interpretation of our comparisons difficult.
In conclusion, HIV-associated sNHL patients from the HNGAI in Peru had similar clinical characteristics to patients in developed countries. We found a notably high proportion of T-cell lymphomas, however. Although we did not find statistically significant differences according to phenotype, patients with T-cell lymphomas had less severe disease and better survival than patients with B-cell lymphomas. Further studies with larger sample sizes and with a national level scope are necessary to confirm our findings.
The authors express their sincere gratitude to Alexandra M. Levine and 2 anonymous reviewers for their useful comments and suggestions on the manuscript.
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