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© 2003 American Society for Clinical Oncology Multicenter Study of Human Immunodeficiency Virus–Related Germ Cell TumorsFrom the Chelsea and Westminster Hospital, St Bartholomew’s & Royal London Hospital, Guys and St Thomas Hospital, and Royal Free Hospital, London; Royal Sussex County Hospital, Brighton, United Kingdom; and Rigshospitalet, Copenhagen, Denmark. Address reprint requests to Mark Bower, PhD, Department of Oncology, Chelsea & Westminster Hospital, 369 Fulham Rd, London SW10 9NH, United Kingdom; email: m.bower{at}ic.ac.uk.
Purpose: Testicular germ cell tumors (GCT) occur at increased frequency in men with human immunodeficiency virus (HIV). This multicenter study addresses the characteristics of these tumors. Patients and Methods: Patients with HIV-related GCT were identified from six HIV treatment centers. The incidence was calculated from the center with the most complete linked oncology and HIV databases. Results: Thirty-five patients with HIV-related GCT were identified. The median age at GCT diagnosis was 34 years (range, 27 to 64 years). The median CD4 cell count was 315/mm3 (range, 90 to 960/mm3) at this time. The histologic classification was seminoma in 26 patients (74%) and nonseminomatous GCT in nine patients (26%). Twenty-one patients (60%) had stage I disease and 14 patients had metastatic disease. Overall six patients relapsed, three died from GCT, and seven died from HIV disease, resulting in a 2-year overall survival rate of 81%. HIV-related seminoma occurred more frequently than in the age- and sex-matched HIV-negative population, with a relative risk of 5.4 (95% confidence interval, 3.35 to 8.10); however, nonseminomatous GCT did not occur more frequently, and there was no change in the incidence of GCT since the introduction of highly active antiretroviral therapy. Conclusion: Testicular seminoma occurs significantly more frequently in HIV-positive men than in the matched control population. Patients with HIV-related GCTs present and should be treated in a similar manner to those in the HIV-negative population. After a median follow-up of 4.6 years, 9% of the patients died from GCT. Most of the mortality relates to HIV infection.
HUMAN IMMUNODEFICIENCY virus (HIV) is associated with the development of a number of malignancies, including Kaposi’s sarcoma and non-Hodgkin’s lymphoma, which together account for most of these tumors.1 More recently, it has become apparent that other non–AIDS-defining tumors, including testicular germ cell tumors (GCT), also occur with increased frequency in people with HIV.2–6 Histologically, GCTs are divided into seminomas and nonseminomatous GCTs (NSGCT), and the incidence of both is increasing in the general population.7 Seminomas are considered less aggressive and tend to occur later in life.8 The incidence of GCT in HIV-positive compared with HIV-negative individuals remains controversial, as does the ratio of seminoma to nonseminomatous tumors.4,6,9–14 Although most HIV-negative patients with GCTs are cured, initial studies indicated that this was not the case for patients with HIV-related GCT, who had a poor outcome compared with HIV-negative people,15,16 as has been the case with other HIV-related malignancies.17,18 However, more recent publications have reported that the disease can be cured if treated in an identical manner to treatment in the HIV-negative population.10,11,13 Little is known about the long-term outcome of patients with HIV-related GCT because previous studies were performed before the highly active antiretroviral therapy (HAART) era, with short follow-up periods and markedly reduced life expectancies caused by the HIV infection. This large multi-institutional study, with the longest published follow-up period, examines the clinical history of GCT in patients with HIV and the effect of HAART on the epidemiology of HIV-related GCT.
Six European HIV treatment centers were involved in the study (Chelsea and Westminster Hospital, n = 14; St Bartholomew’s & Royal London Hospital, n = 6; Royal Free Hospital, n = 2; Guys and St Thomas’ Hospital, n = 1 [London[; Royal Sussex County Hospital, n = 2 [Brighton, United Kingdom]; and Rigshospitalet, n = 10 [Copenhagen Denmark]). Patients were identified from hospital databases and were included in the study if they were diagnosed with histologically confirmed GCT after their HIV diagnosis. The study included individuals diagnosed with GCT between 1985 and 2001. Staging was evaluated using the American Joint Committee on Cancer and the International Union Against Cancer staging systems.19 Patients with metastatic disease were also classified using the International Germ Cell Cancer Collaboration Group prognostic scoring scheme, which divides metastatic GCT into good-, intermediate-, and poor-prognosis groups.20 Response to treatment and toxicity were evaluated by using the World Health Organization guidelines and the National Cancer Institute common toxicity criteria, respectively.21 The incidence of HIV-related GCT was calculated from the Chelsea and Westminster Hospital prospective cohort of 8,640 HIV-1–seropositive patients, which represents 42,188 patient years of follow-up. The incidence was compared with that of the age- and sex-matched HIV-negative male population in Southeast England; these data were made available by the Thames Cancer Registry (Thames Cancer Registry, personal communication).
Statistical Analysis
Patient Characteristics Thirty-five men with HIV infection and a histologically confirmed diagnosis of GCT were identified. A median time of 4.2 years (range, 0 to 14 years) elapsed between the time patients tested HIV-positive and developed GCT. Thirty-two patients were homosexuals, two patients were intravenous drug users, and one patient contracted HIV from an unknown source. Twenty-two in the pre-HAART era and 13 patients developed the malignancy in the post-HAART era (after January 1, 1996). The immunologic features of the patients are listed in Table 1  .
Twenty-six (74%) patients were diagnosed with seminoma and nine (26%) were diagnosed with NSGCT. The patients with seminoma were of a similar age to those with NSGCT (mean, 34 v 33 years, respectively; t test; P = .81) and had a similar median CD4 cell count at time of diagnosis of 294/mm3 (range, 90 to 960/mm3) compared with 377/mm3, respectively (range, 150 to 602/mm3; Mann-Whitney U test; P = .46). The stage and International Germ Cell Cancer Collaboration Group classification at presentation of GCT are listed in Tables 2 and 3. Serum tumor markers (alpha-fetoprotein, human chorionic gonadotrophin, and lactate dehydrogenase) at presentation were abnormal in only 33% of the patients (19% with seminoma and 89% with NSGCT). These figures are similar to those in the HIV-negative population.22,23
Treatment and Outcome Seminoma. Two of 17 patients with stage I seminoma on surveillance relapsed; both were treated successfully to complete remission and are currently disease-free. Two other patients with stage I seminoma on surveillance developed clinical signs consistent with relapsed disease, which subsequently were found to be due to HIV disease. One patient developed lymphadenopathy caused by HIV-related Mycobacterium tuberculosis, which was treated successfully, whereas the other patient developed increasing serum tumor markers caused by HAART-related hepatitis. His antiretroviral therapy was altered, and the marker normalized. Both patients are currently alive and free from tumor. These two examples emphasize the need for oncologists and HIV physicians to collaborate in the treatment of these patients (Tables 4 and 5).
Only one of nine patients with metastatic seminoma died from GCT. This patient had advanced HIV disease and refused active treatment for GCT. NSGCTs. One of four stage I NSGCT patients on surveillance died. He developed primary chemotherapy resistance, despite complying fully with the surveillance protocol. One of five patients with metastatic NSGCT died; this individual did not comply with chemotherapy regimens.
Follow-Up and Survival
Toxicity Data No toxicity was reported for the patients receiving radiotherapy. In all, 17 chemotherapy regimens were given for metastatic or relapsed disease. National Cancer Institute common toxicity criteria grade 3 or 4 toxicity was reported in 10 of 17 patients. This included hematologic toxicity in six patients, peripheral neuropathy in three patients, and nephrotoxicity in one patient. None of the patients has developed a secondary malignancy subsequent to the chemotherapy.
Effects of Treatment on HIV and Immune Parameters
Incidence Data Fourteen patients with HIV-related GCT were identified from the prospective Chelsea and Westminster Hospital cohort of 8,640 HIV-1–seropositive patients. The incidence of HIV-related GCT was 3.32/105 male patient years of follow-up (95% CI, 1.82 to 5.57). This is significantly higher than in the HIV-negative age- and sex-matched population in southeast England (0.76/105 patient years; 95% CI, 0.67 to 0.85; P < .01; Table 8 ). The relative risk for the development of HIV-related GCT is 4.36 (95% CI, 2.71 to 6.55).
Seminoma occurred at a significantly higher frequency in HIV-positive patients compared with the age- and sex-matched general population (relative risk, 5.45; 95% CI, 3.35 to 8.10). This was not the case for nonseminoma, which occurred at a similar frequency (Table 8  ). There was no significant difference in the incidence of GCT in the pre- and post-HAART era: 4.0/105 patient years of follow-up (95% CI, 1.8 to 7.5) compared with 3.7/105 patient years of follow-up (95% CI, 1.2 to 8.7), respectively.
A number of studies have found an increased incidence of GCT in patients with HIV and report relative risks ranging from 2 to 61.3–5,14,16 Moreover, epidemiologic studies have demonstrated a relationship between HIV and seminoma, but not between HIV and NSGCT; however, this has not been confirmed in any cohort studies. The data presented here include the largest cohort study to date and confirm the epidemiologic findings, with a relative risk for GCT and seminoma of 4.36 (95% CI, 2.71 to 6.55) and 5.45 (95% CI, 3.35 to 8.10), respectively. It had been suggested that because both HIV and GCT occur in young men, it should not be surprising that the disease is common.10,11 However, this series and other series have been age matched and still demonstrate a significant increase in GCT.6 There has been speculation about the cause of HIV-related GCT. Most HIV-related malignancies have been linked to viral oncogenes.24–26 As yet, no viral oncogene has been implicated in the development of HIV-related GCT, although mumps orchitis, human papillomavirus, Epstein-Barr virus, and human endogenous retrovirus K10 have been implicated in the HIV-negative population.27–30 Attempts to isolate human endogenous retrovirus K10 in HIV-related GCT have been unsuccessful.31 The development of seminoma is thought to have both genetic and immune components.32,33 The latter can be demonstrated histologically by the presence of tumor-infiltrating lymphocytes, which are not present in NSGCT.34 Moreover, lack of these tumor-infiltrating lymphocytes predicts relapse in patients with stage I seminoma who are treated by orchidectomy and surveillance.35 HIV infection impairs immune surveillance, and this may predispose patients to the development of seminoma. This hypothesis is supported by epidemiologic data showing that only seminoma occurs more frequently with HIV infection. In addition, the age of diagnosis in this series of seminomas and NSGCT was similar, whereas in the general population, the average age at diagnosis of seminoma is 7 years older than that for NSGCT.8 This acceleration in the development of seminoma in men with HIV could be due to reduced immune surveillance. Despite these arguments, this study and others have found that the development of HIV-related GCT is associated with relatively well-preserved immunity, with a median CD4 cell count at GCT diagnosis of 315/mm3 in our series.14 As the incidence of opportunistic infections decreases and patients with HIV live longer, one might expect the incidence of tumors associated with moderate immune suppression to increase.36 This study found no difference when the incidence of HIV-related GCT was compared in the pre- and post-HAART eras. However, if a number of years of chronic immune suppression are required for HIV-related GCT to develop, an increase in incidence may become apparent only with more prolonged follow-up.
HIV-negative patients with stage I GCT can be treated safely with orchidectomy and surveillance alone,37 and most stage I patients in this cohort were treated in this manner, without chemotherapy and radiotherapy, which are known to affect immune parameters adversely.38–40 The four patients treated with adjuvant radiotherapy experienced a decrease in the median CD4 cell count of more than 100/mm3. Only one patient with stage I disease has died from NSGCT, which is consistent with survival data for the HIV-negative population.37,41 Table 9
Early in the HIV epidemic, there was concern about the detrimental effect of chemotherapy on HIV disease, resulting in frequent chemotherapy dose reductions.15,16 It is well known that dose reductions in HIV-negative GCT patients have a detrimental effect on tumor response and outcome,42 and this may account for the poor outcomes reported in early series. This study emphasizes the need to treat HIV-related GCT patients aggressively because the tumor is potentially curable. It is noteworthy that two of the three patients who died from GCT in this study declined or did not comply with chemotherapy. Chemotherapy or radiotherapy resulted in a 32% decrease in the median CD4 cell count, even though many of the patients received HAART. This has implications for the use of prophylactic antibiotics against opportunistic infections. The patient’s immune function may decrease to levels where prophylaxis is recommended during therapy. It has been suggested that HAART should be stopped during chemotherapy for GCT to reduce the possibility of drug interactions and side effects.10 However, recent data in the HIV-related lymphoma setting indicate not only that it is safe to continue HAART, but that this may prevent long-term detrimental effects of chemotherapy on the immune parameters.39 This is especially important in HIV-related GCT patients because the cancer is associated with an excellent overall survival. In conclusion, this study, along with others,4–6 has demonstrated an increased incidence of seminoma in HIV-positive men, and the authors speculate that this may be due to chronic immune suppression caused by HIV infection. HAART has resulted in an increase in the number of people living with chronic immune suppression, which may lead to an increase in the incidence of HIV-related GCT over the next few years. HIV-related GCT presents similarly and may be treated in a similar manner to GCT in the HIV-negative population, resulting in an excellent overall survival with respect to the GCT. In this series, 70% of the mortality is attributed to HIV rather than GCT. Orchidectomy and surveillance for stage I disease in this population prevents the need for adjuvant therapies that have a detrimental effect on immune parameters. Moreover, chemotherapy and radiotherapy can be given safely in combination with HAART.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test for nominal variables, Mann-Whitney U test for nonparametric variables, and t test for parametric variables. A log-linear regression analysis was used to determine the incidence of GCT from the Chelsea and Westminster cohort. A log-transformed person time at risk was used as a multiplier in the log-linear model. A person time at risk was defined from entry into the cohort as an HIV-positive patient until either the date of death or the most recent follow-up date. All P values were two sided. Log-linear regression models were used to derive incidence rated per patient year and the corresponding rate ratios. These were derived using the GENMOD procedure (SAS Institute, Cary, NC), with the assumption that GCT events occurred randomly and followed a Poisson distribution. 
