Is the Testis a Chemo-Privileged Site? Is There a Blood–Testis Barrier?

Point-Counterpoint

RIU0310_02-13.qxd 2/14/07 6:04 PM Page 28 POINT-COUNTERPOINT Is the Testis a Chemo-Privileged Site? Is There a Blood–Testis Barrier? Dhiren S. Dave, MD, John T. Leppert, MD, Jacob Rajfer, MD Division of Urology, Harbor-UCLA Medical Center, Torrance, CA The incidence of testicular cancer, primarily seminoma, has been increasing in many countries, including the United States. The testis is often the site of residual cancer after adequate treatment with systemic chemotherapy. The blood-testis barrier is commonly cited as the explanation for residual tumor within the gonad after chemotherapy and as the indication for delayed orchiectomy. Conversely, complete eradication of viable tumor from the primary site is common and argues against the testis as a “tumor sanctuary.” Residual tumor is also demonstrated within metastatic foci, and the disparity between the histopathologic response of the primary tumor and metastatic sites may be best explained by tumor heterogeneity and multiple tumor clones. Regardless of the scientific and academic arguments, delayed radical orchiectomy remains an important part of treatment for patients undergoing primary chemotherapy. [Rev Urol. 2007;9(1):28-32] © 2007 MedReviews, LLC Key words: Testicular cancer • Blood–testis barrier • Orchiectomy • Chemotherapy ew cases of testicular cancer and deaths from the disease were estimated at 8250 and 370, respectively, for 2006 in the United States.1 Although the reason is unknown, the incidence of testicular cancer, primarily seminoma, has been increasing in many countries, including the United States. Advances in surgical technique, radiation therapy, and chemotherapy for testicular cancer have resulted in a steady rise in the expected 5-year survival rate, which now exceeds 95%.1 Despite this encouraging trend, the surgical treatment of patients with N 28 VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY RIU0310_02-13.qxd 2/14/07 6:04 PM Page 29 Is There a Blood–Testis Barrier? testicular masses continues to be examined and refined. Radical orchiectomy, performed through an inguinal incision with high ligation of the spermatic cord, is traditionally accepted as the first step in diagnosis and treatment of patients with testicular neoplasms. Extirpation of the affected testicle is curative for the vast majority of patients with localized disease. In addition, the specimen provides histologic diagnosis and pathologic information useful for determining the risk of lymphatic spread of the cancer, with minimal morbidity. In the setting of presumed extragonadal germ cell tumors and advanced germ cell cancers with life-threatening metastatic disease, chemotherapy may be initiated before orchiectomy. In these select patients, a diagnosis of germ cell neoplasm is made on the basis of biopsy of an extragonadal mass, 10-lb unintentional weight loss, fatigue, malaise, and anorexia. Physical examination confirmed the presence of a large, firm, nontender left scrotal mass, left flank mass, and a left supraclavicular mass. Laboratory studies revealed an elevated serum creatinine level of 2.0 mg/dL and anemia, with a hematocrit of 31.5%. Tumor marker analysis demonstrated normal alpha-fetoprotein levels but elevated levels of human chorionic gonadotropin (HCG) and lactate dehydrogenase, 324 and 1029 U/L, respectively. Ultrasonography of the scrotum identified a 9
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5-cm heterogeneous intratesticular mass. Abdominal computed tomography (CT) demonstrated significant bilateral retroperitoneal lymphadenopathy, a large mass adjacent to the left renal hilum, and bilateral hydronephrosis. CT evaluation of the chest and neck confirmed The necessity of such a delayed orchiectomy procedure calls into question whether the testicle is truly a sanctuary site, protected from exposure to systemic chemotherapy. site or on the basis of elevated tumor markers. Delayed orchiectomy is recommended to confirm complete response of the primary tumor to systemic chemotherapy.2 The necessity of such a delayed orchiectomy procedure calls into question whether the testicle is truly a sanctuary site, protected from exposure to systemic chemotherapy. In this article, we present the case of a patient with metastatic testicular cancer, which initiated our debate regarding whether there is a blood–testis barrier (BTB) and its clinical relevance to the treatment of testicular carcinoma. Case Report A 36-year-old African American man presented with a 2-month history of a rapidly enlarging, painless scrotal the presence of a solid, 7-cm left supraclavicular mass. The patient underwent retrograde placement of bilateral ureteral stents and had a subsequent modest lowering of the serum creatinine value, to 1.7 mg/dL. A renal scan then demonstrated persistent obstruction of the left kidney. A percutaneous nephrostomy tube was placed, with subsequent normalization of the patient’s creatinine level. A percutaneous needle biopsy of the left supraclavicular mass was insufficient for diagnosis but was “suspicious for a neoplastic process.” Unfortunately, the patient then refused further percutaneous or surgical procedures. With a presumptive diagnosis of advanced stage 3 testicular cancer of unknown histology, the patient was started on chemotherapy with bleomycin, etoposide, and cisplatin. After chemotherapy, the patient’s tumor marker levels normalized. A persistent testicular mass was noted on physical examination, unchanged from initial presentation. The patient reluctantly agreed to a left radical orchiectomy. Final pathology revealed necrotic tumor with features suggestive of germ cell tumor, but no viable tumor was identified in the orchiectomy specimen. Point (Dhiren S. Dave, MD): Evidence Supporting the Existence of the BTB Several clinical observations suggest the existence of the BTB. Principally, spermatogenesis, beginning at puberty, involves the expression of novel cell-surface antigens after the immune system has refined the ability to distinguish self from non-self. Sperm located within the testis, however, do not elicit an immune response. Additionally, whereas macrophages and lymphocytes are commonly found within the interstitial spaces of the testis, these antigen-presenting cells are rarely seen within the seminiferous tubules. These observations have led to the concept of the testicle as an immune-privileged site. Further evidence of the existence of the BTB evolves from the treatment of childhood leukemias, in which the highest rates of relapse occur within the central nervous system (CNS) and testes, both believed to be protected from exposure to systemic chemotherapy, presumably as a result of the blood–brain barrier and BTB, respectively. Consequently, gender remains an important prognostic factor in treatment of acute lymphoblastic leukemia, with testicular relapses reported in up to 17% of patients after complete remission.3-5 These rates are comparable to the rate of relapse within the CNS in this same group of patients.6,7 Additional clinical VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY 29 RIU0310_02-13.qxd 2/14/07 6:04 PM Page 30 Is There a Blood–Testis Barrier? continued evidence comes from retrospective studies of men with primary testicular lymphomas treated with chemotherapy. Essentially all treatment failures involve either the CNS or the contralateral testis, with a 40% to 45% rate of testicular relapse in some series.8 Furthermore, chemotherapeutic agents achieve reduced concentrations within the interstitium of the testis when compared with plasma levels, suggesting that a certain thought to contribute another layer of protection for developing sperm.11 In addition to the mechanical barrier provided by tight junctions, an active system of transmembrane transporters is postulated to remove small lipophilic molecules from the intertubular space. P-glycoprotein and multidrug resistance–associated protein 1 (MRP1) are 2 examples of transmembrane adenosine triphosphate–dependent efflux pumps thought to decrease the concentration In retrospective studies of men with primary testicular lymphomas treated with chemotherapy, essentially all treatment failures involve either the CNS or the contralateral testis, with a 40% to 45% rate of testicular relapse in some series. “barrier” property exists between capillaries and the interstitial space.9,10 Multiple studies have demonstrated the inability of specific large and small molecules to cross between the testicular interstitial space and germinal tubules.11-13 The Anatomy of the BTB The testis consists of approximately 250 lobules, each composed of 1 to 4 seminiferous tubules. The space between these tubules, known as the interstitial space, harbors testosteroneproducing Leydig cells and numerous capillaries. Within the lobules, ultrastructural studies in rats have shown that the Sertoli cells are connected to one another along the basolateral aspect by tight junctions, which form a physical barrier against the migration of large molecules into the tubular environment.11,14-16 Tight junctions have also been demonstrated between capillary endothelial cells, suggesting that endothelial tight junctions also contribute to the mechanical BTB.11,17 Tight junctions have also been identified between myoid cells and are 30 VOL. 9 NO. 1 2007 of cytotoxic compounds within the testis. Interestingly, these proteins were first identified as part of a group of proteins conferring resistance to chemotherapy by various tumors.18,19 P-glycoprotein is heavily expressed at the basolateral side of capillary endothelial cells, as well as at the myoid cell layer,20 and is known to excrete a number of different compounds, including carcinogens, hormones, and bilirubin, from the intratubular compartment.21,22 Animal models have confirmed that animals lacking Pglycoprotein show increased tubular cytotoxic compounds by pumping them into the interstitial space.24 The BTB in Germ Cell Cancers Although the presence of a BTB can be inferred from the previously mentioned clinical experience and from laboratory studies, the need to perform a radical orchiectomy after treatment with chemotherapy, especially when no evidence of residual disease exists, has been questioned for many years. Multiple retrospective series have examined delayed orchiectomy after treatment with systemic chemotherapy for advanced germ cell tumors.25-31 Table 1 summarizes the rates of residual viable tumor within the testis after systemic chemotherapy. Persistent viable primary tumor was found in 8.3% to 37.5% of patients, and several of these studies have demonstrated the presence of residual viable tumor in the testis despite successful eradication of metastatic disease.25,27,31 This argues that a BTB interferes with the ability of systemic chemotherapy to successfully treat germ cell cancers within the testis. Counterpoint (John T. Leppert, MD): The BTB Is Not Clinically Significant At first review, the data presented above by Dr. Dave strongly argue in favor of a clinically significant BTB. Careful examination of published reports of delayed orchiectomy after systemic chemotherapy calls into question whether the BTB is relevant to the treatment of germ cell cancers. concentrations of cytotoxic agents, such as vincristine, supporting the concept of the efflux pump barrier.23 Studies in rats have shown that MRP1 is expressed on the basal surface of Sertoli cells, as well as on Leydig cells, protecting these cells from REVIEWS IN UROLOGY However, careful examination of published reports of delayed orchiectomy after systemic chemotherapy calls into question whether the BTB is relevant to the treatment of germ cell cancers. In the largest published series, Leibovitch and colleagues29 reviewed RIU0310_02-13.qxd 2/14/07 6:04 PM Page 31 Is There a Blood–Testis Barrier? Table 1 Pathology of Orchiectomy Specimen After Treatment With Systemic Chemotherapy for Metastatic Testicular Cancer N Leibovitch I et al29 Fibrosis/Scar (%) 160 Ondrus D et al30 36 2 Teratoma (%) 43.7 50 50 41.7 Viable Tumor (%) 25 8.3 Simmonds PD et al 24 62.5 Chong C et al26 16 N/A N/A 25 8 N/A N/A 37.5 20 55 30 Snow BW et al31 Greist A et al28 25 12.5 15 NA, not applicable. 160 patients with nonseminomatous germ cell carcinoma who underwent delayed orchiectomy after chemotherapy. Pathologic evaluation of the testicle identified necrotic tumor and scar in 70 patients (43%) and pure teratoma in 50 (31.2%), whereas 40 patients (25%) demonstrated persistent viable tumor. The systemic response to chemotherapy in these 40 patients was also evaluated by concurrent retroperitoneal lymph node dissection. Seventeen (42%) of these 40 patients demonstrated sterilization of the retroperitoneum by systemic chemotherapy, whereas 16 patients (40%) harbored teratoma and 7 (18%) were found to have residual viable tumor. The histopathologic findings in the postchemotherapy testis and retroperitoneal lymph node specimens correlated in only half of the cases. Indeed, of the 70 patients with complete eradication of the testicular tumor burden, 35 harbored residual retroperitoneal disease. Furthermore, the pathologic findings within the testicle specimen did not correlate with the clinical relapse rate or the cancer-specific survival. Other investigators have published similar results. Snow and coworkers31 found residual germ cell cancer in the delayed orchiectomy specimens of 3 of 7 patients after treatment with chemotherapy. The remaining 4 specimens showed either testicular atrophy or pathologic evidence of tumor necrosis. Of note, 2 of the 3 patients with residual testicular tumor burden progressed to have distant disease relapse and required further systemic treatment. Chong and colleagues26 also reported similar results. The investigators studied 16 patients with metastatic disease who underwent initial chemotherapy followed by delayed orchiectomy for unrecognized primary tumor (3 patients) and for life-threatening distant metastatic disease (13 patients). They found that 3 of 13 patients (23%) with apparent complete response after chemotherapy and 1 of 3 (33%) with partial response harbored residual viable tumor within the testicle. Although the BTB may indeed be a clinically and anatomically significant entity, it may not completely account for the discrepancy in response to chemotherapy between the primary and metastatic sites in the context of therapy for testicular cancer. Nonseminomatous germ cell cancers often present with multiple cell lines within a single tumor. This multiclonal phenomenon may provide additional explanation for the varied clinical response of germ cell tumors within the testicle, as well as in extragonadal locations. This tumor heterogeneity may be a result of spontaneous mutations, selective clonal metastasis, or differentiation of multipotential tumor cells along different lines.26,32,33 As such, an argument can be made to remove the testicle that harbors the primary tumor to ensure successful treatment and eradication of the particular clonal variants, which may not respond to systemic treatment. This line of reasoning is in contrast to the traditional paradigm that orchiectomy should be performed because the BTB prevents adequate delivery of chemotherapy to the primary site. Conclusions The available data show that the testis is often the site of residual cancer after adequate treatment with systemic chemotherapy. The BTB is commonly cited as the explanation for residual tumor within the gonad after chemotherapy and as the indication for delayed orchiectomy. Conversely, complete eradication of viable tumor from the primary site is common, as demonstrated by the included case report, and argues against the testis as a “tumor sanctuary.” Residual tumor is also demonstrated within metastatic foci, and the disparity between the histopathologic response of the primary tumor and metastatic sites may be best explained by tumor heterogeneity and multiple tumor clones. Regardless of the scientific and academic arguments, delayed radical orchiectomy remains an important part of treatment for patients undergoing primary chemotherapy. This procedure, performed alone or at the time of retroperitoneal lymph node dissection, is safe and is associated with minimal morbidity. Additionally, delayed orchiectomy provides important VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY 31 RIU0310_02-13.qxd 2/14/07 6:04 PM Page 32 Is There a Blood–Testis Barrier? continued postchemotherapy staging information, clinical information that may affect adjuvant treatment strategies and the potential for resection of occult residual disease. 11. 12. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106-130. Simmonds PD, Mead GM, Lee AH, et al. Orchiectomy after chemotherapy in patients with metastatic testicular cancer. Is it indicated? Cancer. 1995;75:1018-1024. Chessells JM, Richards SM, Bailey CC, et al. Gender and treatment outcome in childhood lymphoblastic leukaemia: report from the MRC UKALL trials. Br J Haematol. 1995;89:364-372. Lanning M, Garwicz S, Hertz H, et al. Superior treatment results in females with high-risk acute lymphoblastic leukemia in childhood. Acta Paediatr. 1992;81:66-68. Sather H, Miller D, Nesbit M, et al. Differences in prognosis for boys and girls with acute lymphoblastic leukaemia. Lancet. 1981;1:739-743. Kamps WA, Bokkerink JP, Hahlen K, et al. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group Protocol ALL7 (1988-1991). Blood. 1999;94:1226-1236. Miniero R, Saracco P, Pastore G, et al. Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: a 10-year follow-up study. Italian Association of Pediatric Hematology-Oncology (AIEOP). Med Pediatr Oncol. 1995;24:71-76. Touroutoglou N, Dimopoulos MA, Younes A, et al. Testicular lymphoma: late relapses and poor outcome despite doxorubicin-based therapy. J Clin Oncol. 1995;13:1361-1367. Forrest JB, Turner TT, Howards SS. Cyclophosphamide and blood-testis barrier. Surg Forum. 1979;30:552-553. 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Main Points • Several clinical observations suggest the existence of the blood–testis barrier (BTB). • Evidence from retrospective series argues that a BTB interferes with the ability of systemic chemotherapy to successfully treat germ cell cancers within the testis. • Conversely, it can be argued that although the BTB may be a clinically and anatomically significant entity, it may not completely account for the discrepancy in response to chemotherapy between the primary and metastatic sites in the context of therapy for testicular cancer. • Regardless of the scientific and academic arguments, delayed radical orchiectomy remains an important part of treatment for patients undergoing primary chemotherapy. 32 VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY