Testicular Germ Cell Tumors in Patients with Human Immunodeficiency Virus Infection Marcus U. Hentrich, M.D.’ Norbert G. Brack, M.D.’ Peter Schmid, M.D.’ Tobias Schuster, M.D.~ Christoph Clemm, M . D . ~ Reiner C. Hartenstein, M.D. ’ Department of Medicine IV, Division of Hematology-Oncology, Munich Harlaching City Hospital, Academic Teaching Hospital of the University of Munich, Munich, Germany. Department of Urology Munich Harlaching City Hospital, Academic Teaching Hospital of the University of Munich, Munich, Germany. Oncological Clinic Bad Trissl of the Tumor Center, Munich, Germany. Address for reprints: Marcus Hentrich, M.D., Department of Medicirie IV, Munich Harlaching City Hospital, Academic Teaching Hospital of the University of Munich, Sanatoriumsplatz 2, 81545 Munich, Germany. Received November 2’1, 1995; revision received January 29, 1996; accepted January 30, 1996. 0 1996 American Cartcer Society BACKGROUND. There has been evidence of a higher incidence of testicular germ cell tumors (GCT) in human immunodeficiency virus (HlV)-seropositive men than in the non HIV-infected male population. Most authors recommend standard therapy for HIV-positive patients with GCT but the immunosuppressive effects of Chemotherapy and/or radiotherapy must be considered. METHODS. The records of all patients in whom testicular cancer was diagnosed andlor treated at a single institution between January 1986 and July 1995 were reviewed with regard to HIV seropositivity. Tumor histology, initial staging, treatment, and the patients’ outcomes were analyzed in connection with a review of the literature. RESULTS. Six patients with GCT and documented HIV seropositivity at the time of tumor diagnosis (four homosexuals, one bisexual, and one heterosexual former intravenous drug abuser) of 192 documented cases of testicular cancer are reported. In addition, 1 patient proved to be HIV seropositive 34 months after completing chemotherapy (vinblastine, ifosfamide, and cisplatin) for Stage IIB (minimal disease) seminoma. Intensified platinum-based chemotherapy was administered to two patients with clinical Stage IIIC (advanced disease) nonseminomal.ous germ cell tumors (NSGCT).Both patients achieved a transient partial response but suffered from progressive HIV disease and died 24 and 7 months, respectively, after orchiectomy. One patient with Stage IIIA (moderate disease) seminoma received four courses of chemotherapy (etoposide, ifosfamide, and cisplatin) and has remained in complete remission for 40 months. One patient with bilateral Stage I seminoma underwent adjuvant radiotherapy but was lost to follow-up. One patient with clinical Stage IIA (minimal disease) NSGCT refused any further treatment after hemiorchiectomy, but four courses of chemotherapy (cisplatin, etoposide and bleomycin) had to be given 32 months later because of symptomatic abdominal disease. A partial remission was obtained and there was no evidence of active tumor 16 months after the completion of chemotherapy. A retroperitoneal lymph node dissection was performed in 1 patient with Stage I NSGCT who was free of disease 111 months after diagnosis. The Centers for Disease Control classification for HIV infection and acquired immune deficiency syndrome (AIDS) did not change after therapy in two patients, whereas three patients suffered from progressive HIV disease. CONCLUSIONS. HIV infection should be considered in patients with testicular cancer who belong to an urban population. Oncologic therapy based on a patient’s individual situation is recommended. Cancer 1996; 772109-16. 0 1996 American Cancer Society. KEYWORDS medical oncology, testicular cancer, testicular germ cell tumor, HIV infection, AIDS, cisplatin, radiotherapy. N on-Hodgkin’s lymphoma, Kaposi’s sarcoma, and invasive cervical cancer are considered AIDS-defining malignancies.’m2 Whether other 2110 CANCER May 15,1996 / Volume 77 / Number 10 malignant diseases occur in higher frequency in HIV-infection is a matter of discussion. The prevalence of human papillomavirus-related anal carcinoma seems to be greater in HIV infected homosexuals and there is evidence of an increased risk of basal cell carcinoma in HIVpositive hemophiliac^.^,^ Various miscellaneous cancers have been described in patients with HIV infection, but epidemiologic studies have failed to demonstrate a statistically significant a s s o ~ i a t i o n . ~ ~ ” Since the first description of testicular cancer in two homosexual men with cellular immune deficiency in 1985, several cases of HIV-seropositive patients suffering testicular cancer have been reported.” Treatment recommendations are conflicting. The Italian Cooperative Group on AIDS and Tumors (GICAT) reported on 23 patients with testicular germ cell tumors (GCT) associated with HIV infection, 7 of whom received chemotherapy that seemed to be well to1erated.l3The authors concluded that patients with GCT should be offered standard oncologic therapy. However, exact data concerning dose, toxicity, Centers for Disease Control (CDC) classification, and course of CD4+ cells are missing. Timmermann et al. found 9 HIV-seropositive patients with GCT out of 272 patients treated for GCT at their in~titution.’~ Because standard therapy for GCT was well tolerated and in no case was a patient’s HIV disease classification changed by antitumor therapy, the authors suggest standard therapy for all HIV-infected patients with GCT. In contrast, Wilson et al. described two patients with GCT and advanced HIV infection who tolerated chemotherapy poorly, suggesting the need for a therapeutic procedure based on a patient’s individual situation.” We report on six HIV-seropositive patients with testicular GCT treated at a single institution. Another patient was found to be HIV positive after completion of chemotherapy for GCT. METHODS The records of all patients in whom testicular cancer was diagnosed and/or treated at the Munich Harlaching City Hospital between 1986 and July 1995 were reviewed with regard to HIV seropositivity. Tumor histology, initial staging, treatment, and the patients’ outcome were analyzed. Tumors were classified by stage according to the Lugano and Indiana classification system. As far as possible the impact of treatment on the HIV infection was evaluated comparing CD4-positive cell counts measured before, during, and after cytostatic chemotherapy or radiotherapy, respectively. HIV disease was classified according to the revised classification sytem for HIV infection and AIDS (CDC criteria). I In addition, the available literature on patients with testicular cancer and HIV infection was reviewed. RESULTS One hundred ninety-two patients with testicular GCT were diagnosed and/or treated at our institution between January 1986 and July 1995. Six of these patients (3.1%) were known to be seropositive for HIV at the time of tumor diagnosis. One patient proved to be HIV positive 34 months after completing chemotherapy for Stage IIB testicular seminoma. Patient characteristics are listed in Table 1. The vast majority of patients were not tested for HIV antibodies because this procedure is not routinely performed at our departments. Eighteen patients were found to be HIV seronegative. Patient 1 A 35-year-old homosexual businessman, seropositive for HIV since August 1990 when his CD4 lymphocyte count was 320/pL (CDC category A2) noticed an enlarged left testicle in November 1990. Left inguinal orchiectomy was performed and revealed malignant teratoma. On retroperitoneal lymphadenectomy, 7 of 34 abdominal lymph nodes were found to be invaded by tumor (Stage IIA, minimal disease). Alpha-fetoprotein (AFP) and 0-human chorionic gonadotropin (0-HCG) were within the normal range. The patient refused adjuvant chemotherapy. In March 1991, he presented with oral candidiasis (CD4 cell count of 11O/pL, CDC category B3), pulmonary and hepatic metastases, and bulky abdominal lyrnphadenopathy (advanced disease). Tumor markers AFP and 0-HCG were elevated at 273 UlmL and 211 IU/L, respectively. Five courses of intensified chemotherapy were applied with etoposide, 120 mg/m2,on Days 1-4; cyclophosphamide, 300 mg/m2, on Days 1-4; bleomycin, 12 mg/m2, given by continuous infusion on Days 1-4; bleomycin, 15 mg bolus injection, on Day 1, and cisplatin, 30 mg/ m2, on Days 1-4 (ECBC).” Apart from severe nausea/ vomiting (World Health Organization toxicity Grade 3) and peripheral neuropathy (Grade 2), therapy was well tolerated, and hematologic toxicity was moderate (Grade 1-2). A marker-negative partial response was achieved but the patient refused surgical removal of residual masses. During chemotherapy, CD4+ lymphocytes declined from 110 to 20//1L. Regular inhalation of pentamidine as Pneumocystis carinii pneumonia (PCP) prophylaxis was performed starting in March 1991. In September 1991, the patient suffered focal seizures and transient hemiplegia and cerebral irradiation had to be performed because of newly diagnosed cerebral metastases. During irradiation, a cytomegalovirus-retinitis developed that was consistent with the diagnosis of frank acquired immune deficiency syndrome (AIDS) (CD4, count of 10ipL; CDC category C3), and could successfully be treated with ganciclovir. In February 1992, a peripheral pancytopenia was diagnosed requiring transfusions of platelets and erythrocytes. The patient refused an examination of the Testicular Germ Cell Tumors and HlVlHentrich et al. 2111 TABLE 1 Patients Characterislics,Treatment, and Outcome Patient No. lnitital CD(: category' Histologylclinical stage ~~~ 1 A2 TeraromalllA 2 3 4 .A2 SemiiioniailllA R3 Al EinbryonalllllC Bilateral Serninoma!l J A1 G - , Seminoma and Embryoiiallllh Seminoma and leratomall SeniinomaiIlH Last CDC Category Primary therapy Further therapy Left orchiectoniy KIA Right orchiectomy PEl i4r) I.efr orchiertomp Bilateral orchiectoniy Paraaortic irradiation left orchiecioniy Right orchiectomy R I A Left orchiectomy ECRC (5x1: cerebral irradiation None I-:CBC Qx), PEl ( I r ) None (3 A2 c3 PEB (4x1 Sone VIP 14x1 I32 A2 A3 survival ~~ A2 Died :AIi)S) Stld 14 - b Ilird !AII)S) SEI) lost 10 folio's-up SFO 527'' SEI) 11 I T i.os1 to follo\v-up (bni~ol:1X:BC: rroposide!cispla~in/blrnm~cin/c~tlopl~r~spl~am~d~~: I'FI: cisplaiin!rloposid~~!iiosia~iiide:PFH: c i s ~ ~ l a r i n ! e f o p n s i ~ l ~ i I ~UP: l ~ ~ ~vinblajliiir!iiuriaiiiidricisplatin; ~n~ri~i: KID o l diswr: FHA. r?\roperiroirralIymphadrireriomy: -. no1 repimed. "lime IJIluiiior diagnusis. ' \lunrhs froin lieniirirrhiectoniy. 110 widenc? bone marrow bul chemo- and radiotherapy as well as treatment with ganciclovir might have contributed to myelosuppression. There was no secondary infection and granulocyte-coloiiy stimulating factor (G-CSF) was not used. Acute gastrointestinal bleeding (hemoglobin, 3 g/ dl,) occurred in September 1992. Two months later, the patient died because of recurrent acute, severe gastrointestinal and cerebral bleeding. Patient 2 A 46-year-old honiosexual male nurse was admitted in March 1992 with a 2-year history of swelling of the right testis. His serum was reactive to HIV antibodies in 1986. Right orchiectomy and clinical staging led to the diagnosis of clinical Stage IlIA (moderate disease) pure seminoma. p-HCG was slightly elevated at 6.2 I U / L (normal, < 5 I U / l J . At this time, the CD4+ lymphocyte count was 497/pI. without evidence of symptomatic HIV disease (CIIC category A2).tie received 4 courses of chemotherapy with etoposide 75 mg/m'; ifosfamide, 1.2 g / m 2 ,and cisplatin, 20 ing/m.!, on Days 1-4 (PEI)" which was well tolerated. The patient attained a complete remission and was free of disease 44 months after diagnosis. During chemotherapy, his t3D4 + lymphocytes declined from 497 to 297/p1,, but subsequently increased to 441 /PI,. The patient is doing well and does not receive antiretroviral treatment. His latest (XI4 t lymphocyte count was 3651 pI. (CDC category A2). Patient 3 A 45-year-old heterosexual unemployed varnisher was transferred to our department in June 1993. Three months before admission, left orchiectomy had been performed because of an enlarged left testicle that had been noticed by the patient for approximately 2 years. Histo- logic examination had revealed embryonal carcinoma. AFP and P-HCC were within the normal range, and lactic dehydrogenase (LDH) was elevated at 1020 L J / L Abdominal lymphadenopathy and pulmonary metastases were found o n further examination (Stage IIIB, moderate disease). There was a history of hepatitis 13 and C and he had been addicted to drugs for many years until 1982. The patient was known to be positive for HIV since 1990 when he suffered oral candidiasis ( 0 4 lymphocyte count, 159IpI.: CDC category B3). Since then, he had received azidothymidine, 500 mg per day, and inhaled pentamidine as PCP prophylaxis at %week intervals. Three months after diagnosis of testicular cancer, the patient had agreed to be treated with chemotherapy when computed tomography documented progressive disease with pulmonary and hepatic metastases that were increasing in size (Stage IIIC, advanced disease). In June 1993, the patient was given a four-drug chemotherapy ( E C K ) supported by (;-CSF.'" Because of severe side effects (hematologic toxicity WHO Grade 4 , oral mucositis Grade 3 ) , the dose of the second course had to be reduced by 25%. A partial response was obtained with complete disappearance of hepatic metastases. However, toxicity remained considerable (hematologic toxicity WHO Grade 4, oral mucositis Grade 3, diarrhea Grade 3 , and pain Grade 3). During chemotherapy, his CD4+ lymphocyte count declined from 108 to 18/pI,. After the second chemotherapy course, the patient developed respiratory failure due to severe pneumonia, which improved with some delay after broad-spectrum antibiotic therapy (CDC category C3, AIDS). He received another course of chemotherapy with cisplatin, 20 mg/ni'; etoposide, 100 mg/m', and ifosfamide, 1 g/mLfollowed by G-CSF. Once more, hema.. tologic toxicity was severe (Grade 4) and the patient suffered neutropenic sepsis that subsequently improved by 2112 CANCER May 15,1996 / Volume 77 / Number 10 adequate therapy. However, abdominal lymphadenopathy again increased in size. In view of his poor tolerance of chemotherapy and tumor progression, further cytostatic treatment was withdrawn. After recovery, the patient was discharged, and he died at home a few weeks later. Patient 4 In May 1993, a 33-year-old homosexual businessman presented with a 5-month history of an enlarged and tender left testicle. He was known to be HIV seropositive since 1989. His CD4 lymphocytes were lowered to 540/pL at the time of admission (CDC category All. Left orchiectomy led to the diagnosis of pure seminoma (Stage IA, minimal disease). AFP and P-HCG were within the normal range and metastases could not be found on further examination. However, ultrasound revealed a suspect area within the right testicle. Right orchiectomy was subsequently performed and another Stage IA (pT1) pure seminoma was documented. Both testes showed intratubular germ cell neoplasia. The patient was treated with adjuvant infradiaphragmatic paraaortic irradiation and tolerated therapy without complication. His CD4 lymphocyte count declined from 540 to 3461pL during radiotherapy but there was no evidence of HIV-associated disease (CDC category A2).Unfortunately, the patient was lost to follow-up after discharge. Patient 5 A 40-year-old bisexual programmer was admitted in July 1991 with a 3-day complaint of left inguinal pain and an enlarged left testicle. Six weeks before admission, his serum was reactive to HIV antibodies. There was a positive history of syphilis, gonorrhea, and hepatitis B. Left orchiectomy was performed and revealed Stage pT2 seminoma with focal areas of embryonal carcinoma. P-HCG and AFP were within normal limits. An abdominal computed tomography scan showed some paraaortic lymph nodes to be questionably enlarged (clinical Stage IIA, minimal .disease). However, the patient refused a retroperitoneal lymphadenectomy. CD418 ratio (0.54) and the CD4 lymphocyte count (500/pL) were significantly lowered at the time of diagnosis (CDC categoryA1). In October 1993, he developed oral candidiasis. At this time, the CD4 count had declined to 380/pL and the CD4/8 ratio was markedly depressed at 0.2 (CDC category B2). In February 1994, the patient complained of severe abdominal pain and a subsequent computed tomography scan demonstrated enlarged abdominal lymph nodes (Stage IIB). Levels of AFP and P-HCG were normal. A tumor biopsy showed embryonal carcinoma. Between April and July 1994,the patient received 4 courses of chemotherapy with cisplatin, 20 mg/m’, on Days 1-4; etoposide, 100 mglm’, on Days 1-4, and bleomycin, 30 mg/m2, on Days 1, 8, and 15 (PEB). Because of advanced HIV infection (CDC category B2), doses of cisplatin and etoposide were reduced to 80% of the original PEB protocol.’” Hematologic toxicity was moderate (WHO Grade 3). A partial remission could be achieved and secondary surgery was not performed to avoid further immunosuppression. However, a positron-emission tomography-scan showed no evidence of vital tumor within the abdominal residual mass. The patient did not want to have his CD4 and CD8 lymphocyte values checked but his clinical CDC category B did not change during chemotherapy. In February 1995, he suffered severe herpes zoster that improved with treatment with acyclovir. He has remained well without evidence of progressive HIV disease nor of recurrent testicular cancer 16 months after the completion of chemotherapy. Patient 6 A 26-year-old homosexual man, who had been known to be HIV positive since April 1986, presented in August 1986 with a 3-week history of a hard swelling of his right testis. P-HCG was slightly elevated at 10 mU/L (normal: up to 5 mU1L) and AFP was within the normal range. The CD41 8 ratio was moderately depressed at 0.68. Right orchiectomy revealed a Stage I testicular germ cell tumor of mixed histology (seminoma and intermediate type malignant teratoma). The level of P-HCG normalized postoperatively and no metastases were found on retroperitoneal lymph node dissection. There has been no evidence of recurrent disease on regular follow-up examinations for more than 9 years. The patient is doing well and does not suffer HIV-associated diseases. His latest CD4+ lymphocyte count was 350/pL (CDC categoryA2) with a CD4/ 8 ratio markedly lowered at 0.3. Patient 7 A 35-year-old homosexual mechanical engineer was transferred to our department in October 1987 with a 4month history of abdominal pain and recurrent vomiting. A retroperitoneal space-occupying lesion of 4 cm x 4.5 cm, which had been revealed on abdominal ultrasound, was characterized as seminomatous in origin on explorative laparatomy. Levels of AFP and P-HCG were normal. Left orchiectomy was performed and histologic examination confirmed the diagnosis of a burned-out seminoma. At this time, the patient was found to be HIV seronegative. He received four courses of chemotherapy with vinblastine, ifosfamide, and cisplatin (VIP) and attained a durable complete remis~ion.’~ In July 1990, another HIV antibody test was positive. There were no HIV-associated symptoms, and the CD4+ lymphocyte count was 300/pL (CDC category A2).In March 1993, the patient showed no evidence of recurrent GCT or symptomatic HIV disease, but the CD4+ cell count had declined to 1271pL (CDC categoryA3). Antiretroviral treatment and PCP pro- Testicular Germ Cell Tumors and HIWHentrich et al. 2113 TABLE 2 Reported Cases of Testicular Germ Cell Tumors (GCT) in HIV Seropositive Patients No. of Year Patients 2 1 Histology (SINSIMx) Chemotherapyapplied (no. of patients) 2( P W 1 (PVBIPVC) 3 (PEB) 1 (PVBD) None None VB for KS 4 (3PEB 1 PE) - 1985 1985 1987 1988 1989 1989 1989 1989 1990 1991 1991 1991 1992 1993 1993 1993 1994 1994 1994 1994 2 15 3 23 -- (-111 1) (- 11 1 -) (l/-/-) (5111-) (11-/-) (21-1-1 (2121-1 (21-/-) (1/11-) (bilateral) (1/-1-) (4/-1-) (1 bilateral) (1 1-14) (1 bilateral) (21-1-) (1 bilateral) (10151-) (131101-) Total 79 (4512115) 1 6 1 2 4 2 1 1 3 1 4 3 3 1 ~~~~~~~ None 2 None 1 None 1 - 26 Reference no. - 12" 23" 24 25 26 27,28,29 30 31 33 34 22 35 15 9 36 37 38 14,39,3:! 40 13 - 1 (Carbo) 7 (3PEB,2PVB lPVB1PEB 1 rn-BACODIPEB) 7 (6 PEB 1 PVB) ~~ Radiotherapy applied (no. of patients) 1 None 1 6 - 10 22 ~~~~~ ~~ ~ S: seminoma; NS: nonsemincmatous GCT Mx: mixed histology HIV: human immunodeficiency V~IUS; PW cisplatin, vinblastine, bleomycin; PEB cisplatin, etoposide, bleomycin; PVC: cisplatin, vinblastine, cyclophosphamide; PE: cisplatin, etoposide; PVBD cisplatin, vinblastine, bleomycin, dactinomycin: Carbo: carboplatin; m-BACOD: methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexarnethasone; VB vinblastine, bleomyin; KS: Kaposi sarcoma: -: not reported. a Clinical and pathologic diagnosis because HlV antibody tests were not available in 1985. phylaxis were recommended. However, the patient was unfortunately lost to follow-up. DISCUSSION It has been suggested that testicular cancer, which is the most common malignancy in men aged 20-34 years with a low age-adjusted incidence rate of 4 per 100,OOO,'o occurs with a higher frequency in HIV-positive men than in the healthy male p o p u l a t i ~ n . ' ~ Moyle ~~'~'~ et al., on the basis of 3 seminomas in 2205 HIV-positive patients, and Wilson et al., reporting on 5 GCTs in 3015 HIV positive men, calculated a considerably higher GCT incidence in HIV-positive individ~als.''~'~ However, this assumption could not be confirmed by large epidemiologic studies.5,8-11 Seventy-nine cases of patients with testicular GCT and HIV infection have been documented in the available literature (Table 2).23-40 Data of 25 patients with testicular cancer reported by Tessler and Catanese are difficult to interpret because the authors did not differentiate patients who were found to have AIDS or AIDS-related complex from those who were considered to run a risk of developing AIDS.21 Furthermore, two cases of extrago- nadal GCT in HIV-positive patients have been reIt is difficult to establish the prevalance of HIV seropositivity on the basis of an urban testicular cancer population because HIV-infected individuals are mainly concentrated in metropolitan areas, whereas the prevalence of testicular cancer is the same in rural and urban environments. There are no data on the expected incidence of HIV-1 in young men in Munich, Germany. However, since the onset of the HIV epidemic in Germany, the city of Munich has produced one of the highest rates of HIV infection. As of June 1995, 55% of all HIV-infected people and 57% of all AIDS patients registered in Germany lwed in 6 major For this reason, one should be careful about epidemiologic conclusions drawn on the basis of our Munich experience. In addition, the number of six HIV-seropositive patients with GCT may be too low because testing for HIV antibodies was only performed in patients with at-risk behavior or at a patient's special request, with the vast majority of patients remaining untested. Therefore, all patients with GCT should be routinely tested for HIV-1 prospectively so that the true incidence of the association can be determined. 2114 CANCER May 15, 1996 / Volume 77 I Number 10 Some authors presume that special histologic patterns predominate but more cases of seminomas than nonseminomas have been reported in the available literature (48 vs. 30; Tables l and 2). However, the number of cases is still too small for unequivocal conclusions, especially because seminomas account for approximately 40-55% of all testicular GCT, depending on the series The available literature described the cases of four HIV infected patients with bilateral GCT (three patients with synchronous GCT and one with consecutive bilateral GCT) and we added another case of Stage I synchronous bilateral pure ~eminoma.’~“‘”~”~ It is worth noting that this incidence of 5.9% (5 of 85 HIV-seropositive patients with GCT) is higher than the bilateral frequency of 1.54.3% reported in the literature.45246 The prognosis of bilateral testicular cancer is generally Our patient (Patient 4) underwent bilateral hemiorchiectomy and received adjuvant infradiaphragmatic irradiation. During radiotherapy, a slight increase in the CD4/8 ratio could be observed despite declining CD4 and CD8 cells. The CDC category changed from A1 to A2 at the end of radiotherapy. Unfortunately, the patient was lost to follow-up. Tolerance of radiotherapy in HIV-infected patients may depend on the CDC category they correspond with and severe side effects of irradiation should be considered, particularly in patients in advanced stages of HIV disease. Patient 1 (CDC category B3) developed cytomegalovirus-retinits (primaryAIDS-definingillness) during radiation therapy for symptomatic cerebral metastases with a further decline in the CD4 and CD8 lymphocyte counts as well as the CD4/8 ratio. It cannot be ruled out that the low level of CD4+ lymphocytes at the beginning of cerebral irradiation may be responsible for this opportunistic infection. However, the available literature describes several cases of opportunistic infections developing during radiotherapy. Beuzedoc et al., for example, reported on a HIV-positive patient with Stage IIB seminoma (CDC category B3) who underwent radiotherapy, resulting in a marked decline in the CD4 counts from 163 to 5/mL3 followed by life-threatening opportunistic infections.’’ Three cases of PCP after radiotherapy for Stage I seminoma in HIV-infected men have also been ~ b s e r v e d . “ , ~At~ ~least ~ ‘ one of these patients was in an advanced stage of HIV disease with a CD4/8 ratio markedly depressed at 0.13.31 By contrast, there are also reports of HIV-seropositive patients with testicular GCT who underwent radiotherapy without major complications, although data on the CD4+ lymphocyte count before and after therapy are not available in most of these case^.'^"^^^' Radiation sensitivity of CD4 lymphocytes has been described in patients with breast cancer not infected by HIV and further studies on the influence of radiotherapy on CD4+ lymphocytes are necessa~y.~’ There is also evidence of a suppressive effect of the combination of local radiation and chemotherapy on CD4+ lymphocyte counts in HIV-negative patients with breast and ovarian ~ a n c e r . ~Because ~ ’ ~ ’ declining numbers and percentages of CD4+ lymphocytes have been established as an important predictor of progression from asymptomatic HIV infection to AIDS, the course of CD4+ lymphocytes should be monitored regularly during radi~therapy.~’,~’ In conclusion, radiotherapy should be the treatment of choice in HIV-infected patients with low stage seminoma unless an AIDS-defining disease is present or CD4+ lymphocyte counts are severely depressed. Surgical procedures such as orchiectomy and retroperitoneal lymphadenectomy obviously did not alter CD4+ lymphocyte counts in our patients and similar observations have been made by other a ~ t h o r s . ’ ~ , Nev~’~~~~~’ ertheless, primary chemotherapy with two courses of PEB in Stage I and three courses of PEB in Stage IIA/B nonseminomatous germ cell tumors (NSGCT) might be an alternative to retroperitoneal lymphadenectomy. Our first patient with resected Stage 2A NSGCT and negative tumor markers refused adjuvant chemotherapy for fear of deterioration of his immunologic status (CDC category A2 at the time). Early tumor relapse occurred (advanced disease) and forced the initiation of chemotherapy when HIV infection had already progressed to CDC category B3 (oral candidiasis). He achieved a marker-negative partial response lasting for 6 months, at which time cerebral metastases became symptomatic. Three other cases of HIV seropositive males with Stage IIA NSGCT who were observed after complete retroperitoneal lymph node dissection have been reported in the available literat~re.’~”‘ Two presented with pulmonary metastases and supraclavicular adenopathy 1 and 9 months later, respectively. At this time, their immunologic status had deteriorated to AIDS and chemotherapy was poorly t01erated.l~The other patient did not suffer recurrent testicular cancer and died of AIDS 3 years after his HIV infection diagn~sis.~’ Thus, to avoid early tumor relapse, adjuvant chemotherapy might be recommended for patients with Stage IIA NSGCT who do not demonstrate AIDS-indicatingconditions. In Patient 1, the intensified chemotherapy (ECBC) led to a decline of CD4+ cell counts from 110 to 201pL. Patient 3, with advanced embryonal carcinoma and CDC category B3 indicating severe immunosuppression, tolerated the same protocol (ECBC) poorly. His number of CD4+ lymphocytes decreased from 108 to 18/pL and overt AIDS developed during cytostatic treatment. This corresponds with another report on a patient suffering both advanced GCT and advanced HIV infe~tion.’~ Testicular Germ Cell Tumors and HlVlHentrich et al. Lymphocyte depletion during treatment with intensive chemotherapy for cancer in HIV-seronegative patients has been described recently. In addition, thymic capacity for regeneration of CD4+ lymphocytes appears to diminish with age.52,53 Interestingly, the results of very dose-intensive regimens for patients with AIDS-related lymphomas were also associated with high rates of complicating opportunistic infections leading to death in 2878% of patient^.^^ There is a strong evidence of an increased susceptibility of opportunistic infections in patients with CD4+ cell counts of less than 200lyL and this phenomenon could be one reason for the poor outcome of patients with advanced HIV infection treated by intensive chemotherapeutic regimens.55 By contrast, our second patient, who had moderate disease and was CDC category A l , as well as Patient 5 , who had minimal disease and was CDC category B2, tolerated standard chemotherapy well (PEB and PEI, respectively). There are some reports on standard chemotherapy for treatment of GCT in HIV-seropositive men and PEB does not seem to be associated with more complications in these patient^.'^,^"*^' Vaccher et al., for example, reported five patients with advanced disease treated with PEB, which was overall well tolerated without further development of opportunistic infection^.'^ In another series of seven men receiving PEB or PVB, the patients' HIV disease classification (CDC category) did not change in any case.39Because vinblastine is less immunosuppressive and less injurious to platelet production than bleomycin, PVB mighr be substituted for PEB for patients with Stage II/III NSGCT, minimal or moderate disease, but vinblastine neurotoxicity must be considered. In summary, testicular cancer does not appear to be an AIDS-defining malignancy. Oncologic treatment should be tailored to the individual HIV-positive patient with testicular GCT. 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