26 Small Cell Tumors, Lymphomas, and Sertoli Cell and Leydig Cell Tumors of the Bladder, Prostate, and Testis Chris M. Bacon and Alex Freeman Lymphomas of the Testis, pathological features, therapeutic needs, and prognoses, and all require specialist manage- Bladder, and Prostate ment. Another major determinant of treatment choice and outcome is the stage of lymphoma at Approximately one third of lymphomas arise presentation. In this regard, lymphomas of the at an extranodal site (primary extranodal lym- genitourinary tract are, like lymphomas arising phomas), and both primary nodal lymphomas elsewhere, staged according to the Ann Arbor and leukemias not infrequently infiltrate extran- staging system. odal tissues secondarily during their course. The genitourinary tract is the site of less than 5% Lymphoma of the Testis of primary extranodal lymphomas [1]. Among these the testis is the most frequent site. Post- Clinically apparent lymphoma of the testis is mortem studies indicate that the genitourinary rare, representing only approximately 1% of all tract is secondarily involved by lymphoid neo- lymphomas and 5% of all testicular tumors [4,5]. plasms in up to 50% of patients, and such invol- Unlike germ cell tumors, testicular lymphoma vement may be clinically apparent in up to 10% typically occurs in older patients, being the com- of patients [2]. monest testicular neoplasm in men over 60 years Lymphoid neoplasms are currently classified of age [4]. Lymphoma may arise primarily in the according to the World Health Organization testis, or may manifest in the testis secondarily (WHO) Classification of Tumors of the (albeit often early) during the course of systemic Hematopoietic and Lymphoid tissues [3]. In disease. It may sometimes be impossible to dis- this globally accepted classification, devised tinguish these scenarios, even in patients with by an international panel of pathologists, hema- limited (stage I/II) disease, but in most studies tologists, and oncologists, lymphomas and primary testicular lymphoma is defined prag- leukemias are categorized into discrete entities matically as that in which a testicular mass was according to morphological, immunohistologi- the predominant site of clinical disease at pres- cal, genetic, and clinical features. Although some entation [6–9]. There are no established predis- lymphomas are defined by their sites of origin, posing factors for the development of testicular there are no lymphoid neoplasms that arise only lymphoma, although there is an increased inci- in the genitourinary tract. In the clinical setting, dence among men infected with HIV [4]. the correct identification and then subclassi- The majority (approximately 80% to 90%) of fication of lymphoid neoplasms by urologists primary testicular lymphomas are diffuse large and urological pathologists is crucial, as many B cell lymphomas (DLBCLs) [10–13]. Other sub- of the entities defined have distinctive clinico- types, including mature T/natural killer (NK) 309 310 Urological Cancers: Science and Treatment cell lymphomas, follicular lymphomas, Burkitt large,with vesicular nuclei and prominent nucle- lymphomas, and plasma cell neoplasms, are rare oli, although there is variation in morphology primary testicular tumors. Most non-Hodgkin between cases [3]. They express pan–B-cell anti- lymphomas may secondarily involve the testis, gens such as CD20, and many express detectable as may chronic lymphocytic leukemia (CLL) immunoglobulin. In most cases, lymphoma cells and precursor B- or T-cell acute lymphoblastic express the antiapoptotic protein Bcl-2, and a leukemia (ALL), the latter especially in children. high proportion of cells (>40%) express the cell Involvement of the testis by classical Hodgkin cycle protein Ki67, indicating that they are in cell lymphoma is exceptional. These different types cycle. Similar to nodal DLBCL [14], the germinal of lymphoproliferative disorder are biologically center–associated proteins Bcl-6 and CD10 are and clinically distinct, and are thus considered expressed by approximately 80% and 50% of separately below. testicular DLBCL, respectively (unpublished observations). Testicular Diffuse Large B Cell Lymphoma Biology and Genetics Clinical Features Although relatively few studies have specifically Testicular DLBCL typically presents with unilat- examined the biomolecular features of testi- eral painless scrotal swelling in men whose cular DLBCL, available evidence suggests that median age is 60 to 70 years [6–9,12]. Both testes the pathobiology of testicular DLBCL is similar are involved at presentation in up to 15% of in many ways to DLBCL arising elsewhere. patients [6–8], and 5% to 15% present with sys- Both primary testicular DLBCL and DLBCL temic (“B”) symptoms [6–9,13]. Approximately in general are clonal proliferations of mature 50% of patients present with stage I disease B cells whose immunoglobulin genes have (testes only), 20% with stage II disease (regional undergone VDJ (variable-diversity-joining lymph node involvement), 5% with stage III region) rearrangement and, in most cases, disease, and 25% with stage IV disease (dissem- somatic hypermutation [15,16]. Because the inated) [6–8,12]. Characteristic sites of distant latter is a mechanism for diversification of organ involvement include the central nervous immunoglobulin genes that occurs during system (CNS) (especially), Waldeyer’s ring, skin, the germinal center reaction of an immune bone and bone marrow, kidneys, adrenal glands, response, it is believed that DLBCLs arise from and lungs [4,6–8]. Compared to nodal DLBCL, germinal center or postgerminal center B cells. testicular lymphoma is associated with presen- Hyland et al. [15] showed that testicular DLBCLs tation at an earlier stage and a greater propen- display ongoing somatic hypermutation, clonal sity for spread to other extranodal sites. diversification, and a pattern of immunoglo- Pathology bulin gene mutation suggestive of a role for ongoing antigen selection in the evolution of Macroscopically, testicular DLBCL usually forms the lymphoma [15]. Pasqualucci et al. [17] de- an ill-defined, firm or soft, gray, tan, or pink monstrated that more than half of DLBCLs mass, sometimes with areas of hemorrhage or show aberrant somatic hypermutation activity necrosis [4,10]. The lymphoma extends into resulting in mutation of several known proto- paratesticular structures in up to 50% of cases. oncogenes, including MYC [17]. Thus, aberrant Microscopically, a diffuse infiltrate of atypical hypermutation may contribute to genomic lymphoid cells dissects between seminiferous instability in DLBCLs. tubules, or sometimes effaces testicular architec- There is now considerable evidence that ture (Fig 26.1). In many cases lymphoma cells DLBCL is both biologically and clinically het- show at least focal intratubular growth, and erogeneous. In landmark studies, Alizadeh et al. tubules often show suppressed spermatogenesis, [18] and Rosenwald et al. [19] performed large- or atrophy. Interstitial sclerosis is present in scale DNA microarray-based gene expression a third of cases [4,10,11]. Testicular DLBCL analyses of DLBCLs and demonstrated that is cytologically and immunophenotypically DLBCLs showed diverse gene expression pat- similar to DLBCL arising in lymph nodes. The terns, but could be divided into subgroups with neoplastic cells are typically medium-sized to germinal center B-cell–like profiles, in vitro 311 Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis Fig. 26.1. A diffuse large B-cell lymphoma of the testis (A, H&E) showing positive immunohistochemical staining for CD20 (B), Bcl-2 (C) and nuclear BCL-6 (D). Original magnification: A, 100¥; B–D, 200¥. activated B-cell–like profiles, or poorly defined genes were used to successfully formulate prog- heterogeneous type 3 gene expression profiles. nostic algorithms or outcome predictors for Interestingly, these subgroups showed differ- DLBCLs [19,20]. ences in biochemistry and genetics (see below) Several studies have used immunohistochem- and in clinical outcome. Patients whose tumors istry to subclassify DLBCLs into those with a had germinal center B-cell–like gene expression germinal center cell phenotype and those with a profiles had a significantly better 5-year overall postgerminal center cell phenotype according to survival than those whose tumors did not. Two the presence or absence of proteins expressed studies have used DNA microarray technology predominantly by germinal center B cells (Bcl-6 to identify genes whose expression correlates and CD10) or postgerminal center B cells (IRF- with the outcome of DLBCL [19,20]. Many of the 4/MUM-1) [21–24]. Some of these studies have genes implicated are associated with cell prolif- shown germinal center–type protein expression eration, apoptosis, B-cell receptor signaling, to be associated with a favorable overall survival germinal center B-cell phenotype, or lymph [21,23,24], whereas others have failed to demon- node stromal and immune cells, or are major strate any significance [21,22]. histocompatibility complex (MHC) class II Although many DLBCLs exhibit complex genes, highlighting the importance of both cytogenetic abnormalities, several recurrent intrinsic properties of the lymphoma cells genetic alterations have been identified. In 15% and host–tumor interactions in the behavior of to 30% of cases, the BCL2 gene is translocated to DLBCLs. Some of the differentially expressed the immunoglobulin heavy chain gene locus 312 Urological Cancers: Science and Treatment as a result