26 Small Tumors, Lymphomas, and and Tumors of the Bladder, , 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 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 in men over 60 years Lymphoid 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 . 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)

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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- 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- bulin gene 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 [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 , [18] and Rosenwald et al. [19] performed large- or . 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, , 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 of a t(14;18)(q32;q21) translocation, sent a mechanism by which testicular DLBCLs with resultant dysregulation of its expression can evade a host antitumor immune response. It [25–27]. The t(14;18) is seen almost exclusively is interesting that primary DLBCLs of the CNS, in DLBCLs with a germinal center cell phenotype a site to which testicular DLBCL characteristi- [27,28]. However, the Bcl-2 protein is expressed cally disseminates, show similar defects in HLA in approximately 50% to 60% of DLBCLs, and is molecule expression [36]. The characteristic not restricted to those with a germinal center cell pattern of extranodal spread displayed by testic- phenotype [22–24,28]. In many t(14;18)-negative ular DLBCL may also reflect differences in adhe- cases this may result from amplification of the sion molecule expression compared to DLBCL at BCL2 gene locus [29]. Although most studies other sites [38]. have failed to show that the presence of a t(14;18) has any prognostic impact [25–27], many have Treatment and Outcome demonstrated that the expression of Bcl-2 protein is associated with an adverse clinical Although the treatment and outcome of testicu- outcome [22–26]. Lambrechts et al. [30] showed lar DLBCL has varied over the years, most recent that the Bcl-2 protein is consistently expressed studies show 5-year overall survival rates of 37% by testicular DLBCLs, suggesting that the to 48%, and median survival times of 32 to 58 antiapoptotic functions of Bcl-2 may play an months [6,12,39]. Stage I/II testicular DLBCL important role in the of these lym- has a considerably worse outcome than stage I/II phomas. However, t(14;18) was not detected in nodal DLBCL (5-year overall survival approxi- any of the 29 cases studied [15,30]. The BCL6 mately 45% to 58% vs. 75% to 80%) [6,40]. The gene at 3q27 is dysregulated by translocation most consistent prognostic factor for testicular (often to the immunoglobulin heavy chain gene DLBCL is Ann Arbor stage [4,7,12,39]. In the locus) in 25% to 40% of DLBCLs [25,31], and by large series of Zucca et al. [6], the 5-year overall mutation of its 5¢ regulatory region in a further survival and median survival respectively were 15% of cases [32]. Because the Bcl-6 protein is a as follows: stage I, 58%, 6.1 years; stage II, 46%, transcriptional repressor that controls the 3.9 years; stage III/IV, 22%, 1.1 years. Other terminal stages of B-cell differentiation, these prognostic factors identified include age, Inter- may promote lymphomagenesis by national Prognostic Index, presence or absence altering B-cell terminal differentiation. Muta- of B symptoms, and presence or absence of tions in the P53 gene are found in approximately microscopic sclerosis within the lymphoma 20% of DLBCLs and are associated in most [4,6,10]. Despite exceptional cures (which studies with an adverse clinical outcome [33]. provide evidence for true primary testicular The MYC gene is translocated in up to 10% of lymphoma), the vast majority of patients, even cases [25]. Amplification of 2p12–16, which with stage I disease, relapse and die of disease includes the REL proto-oncogene, a nuclear after treatment by orchidectomy alone [4,6]. factor (NF)-kB family member, is observed in Likewise, although locoregional radiotherapy approximately 20% of DLBCLs (including one of provides good local control, more than 70% of two testicular DLBCLs studied) [34]. Activation patients with stage I/II disease treated by of NF-kB appears important in the pathogenesis orchidectomy and locoregional radiotherapy of DLBCLs, particularly those with an activated alone relapse distally and succumb to lym- B-cell–like gene expression profile [35]. phoma [4]. More recent treatment protocols Differences in host–tumor interactions have have employed adjuvant anthracycline-based been identified between testicular and nodal combined chemotherapy regimens, and several DLBCL. Although a small subset of nodal studies have found such chemotherapy to be DLBCLs is associated with defective expression associated with improved progression-free and of human leukocyte antigen (HLA) class I and II overall survival at all stages of disease molecules, this appears particularly prevalent in [4,6–8,41]. testicular DLBCL, in which loss of HLA class I/II Although 70% to 90% of patients achieve an molecules was detected in 61% of cases as a initial complete response, 30% to 80% subse- result of homozygous and hemizygous deletions quently relapse [6–9,12,13,39]. It is characteris- in the HLA locus and genetic aberrations in the tic of testicular DLBCLs that the majority b2-microglobulin gene [36,37]. This may repre- (approximately 80%) of relapses involve extran- 313

Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis odal sites, including the CNS, contralateral testis, However, 5% to 10% of patients experience overt bone and bone marrow, skin, lung, and adrenal testicular involvement at relapse, either alone or glands [4,6–8]. Although most relapses occur in with simultaneous bone marrow disease [45]. the first 2 years after treatment,testicular DLBCL Again, with modern treatment protocols, these is also unusual in a significant incidence of late patients fare no worse than those without testic- relapses—up to 14 years after treatment in some ular disease at relapse. Rarely, primary follicular studies [6,8,13].A CNS relapse occurs in approx- lymphomas of the testis arise in children. To imately 15% to 30% of patients with testicular date, these have all been stage I tumors, with DLBCL, including many with stage I/II disease WHO grade 3 morphology with or without areas [6,7,12,13,39]. This high rate has led many of DLBCL, and have shown indolent clinical centers to give intrathecal chemotherapy as CNS behavior. Inasmuch as they have been uniformly prophylaxis to all patients, but the efficacy of negative for Bcl-2 protein expression and such an approach remains unproven [6,8,39]. t(14;18), they may represent a clinicopathologi- This may be in part due to the propensity for cal entity distinct from usual adult follicular parenchymal, rather than meningeal, relapse lymphoma [46]. seen in most studies [6,8,13,39]. Another char- acteristic site of relapse, seen in 5% to 15% of Plasma Cell Neoplasia patients, is the contralateral testis [6–8,12,13]. Extraosseous plasmacytomas represent only This may be effectively prevented by prophylac- approximately 0.1% of all testis tumors, and tes- tic irradiation of the contralateral testis at first ticular involvement is seen in only approxi- treatment [4,6,8]. Thus, current treatment proto- mately 2% of myeloma patients [47,48]. They cols at many centers now include orchidectomy, present as a painless mass at a median age of combination anthracycline-based chemother- approximately 55 years. Microscopically, the apy, prophylactic radiotherapy to the contralat- testis is infiltrated by nodules of atypical mono- eral testis, and CNS prophylaxis, with the clonal plasma cells with a predominantly inter- possible addition of regional radiotherapy in stitial pattern of infiltration [47]. More than half patients with disease in regional lymph nodes of these patients have preceding or concurrent [2]. Addition of the therapeutic anti-CD20 anti- plasma cell myeloma, and the vast majority of body Rituximab, as used successfully against the remainder develop myeloma in the follow- DLBCLs at other sites [42], may also be ing 2 to 3 years [48]. Cases of solitary testicular considered. plasmacytoma not followed by myeloma are exceptional, but appear to have a favorable prognosis. Other Lymphoproliferative Disorders Involving the Testis Mature T/NK Cell Lymphomas Testicular Lymphoproliferative Disorders Mature T/NK cell lymphomas of the testis are in Childhood very rare, and have been documented primarily as case reports. The majority are extranodal The testis is involved in approximately 5% of NK/ lymphoma, nasal type, an aggressive childhood lymphomas, most commonly in dis- angiocentric and angiodestructive Epstein-Barr seminated Burkitt lymphoma, an aggressive virus–associated lymphoma of NK-cell or mature B-cell lymphoma associated in all cases cytotoxic T-cell origin. All have had a rapidly with translocation of the MYC gene. [43]. With fatal outcome [49]. There have also been occa- modern combination chemotherapy protocols, sional reports of peripheral T-cell lymphoma, testicular involvement at diagnosis does not unspecified, and other subtypes presenting in appear to confer a worse prognosis [43]. The the testis. testis is also not infrequently involved during the course of precursor B- or T-cell ALL (more com- Lymphoma of Paratesticular Tissues monly precursor T-cell ALL). It is rarely clini- cally involved at presentation, although up to Lymphomas of the and spermatic 25% of boys have occult testicular disease at cord most often occur as a result of spread from diagnosis without adverse prognostic effect [44]. the testis, or sometimes as a site of dissemina- 314

Urological Cancers: Science and Treatment tion of systemic lymphoma. Primary paratestic- that of a single or sometimes multiple, submu- ular lymphoma is very rare [50,51]. Patients with cosal, sessile, or polypoid mass protruding into primary lymphoma of the have a the lumen, typically without ulceration [53]. mean age of approximately 55 years, and present Diffuse thickening of the bladder wall may also with hard masses in the groin resembling be seen. Approximately 20% of patients with inguinal hernias. The lymphomas are mostly primary bladder lymphoma have a clinical DLBCLs, and show clinical features and a poor history of prior chronic cystitis [53,54,56]. prognosis similar to testicular DLBCLs [50,51]. Primary epididymal lymphoma has been reported in patients with a wide age range (20 to Pathology 73 years). Although the older patients mostly Studies have shown that almost all low-grade developed DLBCL, follicular lymphomas and primary lymphomas of the bladder, although an extranodal marginal zone lymphoma of rare, are MALT lymphomas [53,55,56]. These mucosa-associated lymphoid tissue (MALT lym- tend to remain localized to the bladder (stage 1) phoma), with a more indolent course, were seen [53,56]. A smaller subset of primary bladder in the younger patients [50,51]. Extraosseous lymphomas are DLBCLs, perhaps arising by plasmacytoma may also occasionally be seen in transformation of MALT lymphoma in some paratesticular tissues [50]. cases [53,55].Very occasional cases of T-cell lym- phoma, plasmacytoma, and Burkitt lymphoma Lymphoma of the Bladder in an HIV-positive person have been reported. Secondary involvement of the bladder is usually The majority of lymphomas affecting the lower by DLBCL, followed by follicular lymphoma, urinary tract involve the bladder. Lymphoma MALT lymphoma, Burkitt lymphoma, mantle arising within, and localized to, the bladder cell lymphoma, and classical Hodgkin lym- (primary bladder lymphoma, stage I) is very phoma [53,55]. In a postmortem series, 16% of rare, representing only approximately 0.1% to patients who died of CLL and 26% of those who 0.2% of all extranodal lymphomas [1]. More died of ALL had infiltration of the bladder by common is secondary involvement of the leukemia [52]; this is usually subclinical. bladder by previously diagnosed lymphoma Microscopically, MALT lymphoma consists of arising elsewhere. In a postmortem series, the a proliferation of neoplastic small to medium- bladder was involved in 13% of patients who sized marginal zone cells between and around died of advanced lymphoma [52]. A third, rare reactive lymphoid follicles, frequently infiltrat- group of patients presents with urinary ing into the muscularis [3,53,55–57] (Fig. 26.2). tract–related symptoms, but has lymphoma These cells show variable cytology, often includ- beyond the bladder at diagnosis [53]. A propor- ing plasma cell differentiation. In many cases the tion of these patients, in whom the bladder con- neoplastic cells infiltrate the epithelium of cysti- tains the bulk of the disease, may also represent tis glandularis, or sometimes surface transi- primary bladder lymphoma, stages II to IV. tional epithelium, in small clusters forming characteristic lymphoepithelial lesions. Often a Clinical Features reactive lymphoid infiltrate suggestive of chronic cystitis is seen in the background. The Primary lymphoma of the bladder affects pre- neoplastic cells have an immunophenotype dominantly adult women (male/female ratio similar to that of normal marginal zone cells approximately 1:5), at a median age of app- (positive for CD20, immunoglobulins [Igs] M roximately 65 years (20 to 85 years) [53–55]. and A; negative for CD10, Bcl-6, IgD). The histo- Secondary involvement of the bladder occurs logical features of DLBCLs in the bladder are equally in men and women, at a similar age similar to those in other organs [3]. [53,55]. The most common presenting symp- toms are painless hematuria, dysuria, urgency, frequency, and nocturia [53,54]. Systemic (“B”) Biology and Genetics symptoms, regional pain, and obstructive fea- tures are more frequent in those with advanced MALT lymphoma is thought to arise from the disease. The cystoscopic appearance is usually marginal zone B cells of MALT, acquired as a 315

Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis

Fig. 26.2. A mucosa-associated lymphoid tissue (MALT) lymphoma of the bladder (A, H&E) showing characteristic plasma cell differ- entiation (top right of each panel). Tumor cells express CD20 (B) and immunoglobulin M (IgM) (C), but not IgD (D). Original magnification: each 100¥. result of chronic inflammation of a mucosa A number of recurrent genetic abnormalities normally devoid of lymphoid tissue [3,58]. have been identified in MALT lymphomas. Examples include Helicobacter pylori–associated Thirty to 60% of cases, including one reported gastritis and Hashimoto thyroiditis. There is evi- case in the bladder, show trisomy 3 [58,59]. Many dence to suggest that, at least early in its course, others contain one of three known recurrent MALT lymphoma may be partially dependent on translocations [58,60]: t(11;18)(q21;q21) results antigen and T-cell–mediated stimulation occur- in the formation of a chimeric fusion protein ring in such a microenvironment [58]. Although between the apoptosis inhibitor API2 and the no studies have specifically investigated the paracaspase MALT1; t(14;18)(q32;q21) translo- biology of MALT lymphoma arising in the cates the MALT1 gene to the immunoglobulin bladder, the lack of convincing native lymphoid heavy chain gene locus; and t(1;14)(p22;q32) tissue in the bladder, the clinical or histological translocates the BCL10 gene to the immuno- evidence of antecedent chronic cystitis in many globulin heavy chain gene locus. MALT1 and patients, and the higher incidence in women Bcl10 both function in a biochemical signaling than in men of both MALT lymphoma of the pathway connecting lymphocyte antigen recep- bladder and chronic cystitis suggests a similar tor signaling to activation of the transcription pathogenesis at this site, in which chronic cysti- factor NF-kB, and dysregulation of this pathway tis is a nonobligate precursor for MALT lym- is thought to be important in MALT lympho- phoma [53,55–57]. magenesis [58]. However, to date, these trans- 316

Urological Cancers: Science and Treatment locations have not been reported in MALT lym- ary to known systemic lymphoma/leukemia, phoma of the bladder. and 17% to be unclassifiable as primary or secondary. Treatment and Outcome Clinical Features Due to its rarity, there is little information regarding the optimal treatment of primary Almost all patients diagnosed with prostatic bladder lymphoma. Cases of primary MALT lymphoma, whether primary or secondary, lymphoma of the bladder reported in the present with symptoms of lower urinary tract literature have been variably treated with obstruction [64,65,67]. Occasional patients transurethral or radical surgery, radiotherapy, or present with pain or hematuria, and some with chemotherapy, alone or in combination. In systemic disease have “B” symptoms. Serum keeping with MALT lymphomas at other sites, prostate-specific antigen is raised in approxi- the outcome has been favorable in almost all mately 20% of patients. On digital rectal cases, with very few lymphoma-related deaths examination the prostate appears diffusely reported [53–57]. Some have recommended enlarged or nodular, and firm. A tissue diagno- radiotherapy as the treatment of choice for local- sis is usually obtained by examination of needle ized cases [2,61]. Interestingly, similar to the biopsies or tissue obtained by transurethral ability of antibiotic-mediated H. pylori eradica- resection. Occasionally lymphoma/leukemia is tion to cure many gastric MALT lymphomas diagnosed as an incidental finding in a radical [58], two primary MALT lymphomas of the prostatectomy specimen removed for known bladder have resolved after Helicobacter eradi- prostatic . Of note, the urologist cation therapy or antibiotics for chronic cystitis and pathologist may also encounter lym- [62,63]. Several case reports and small series phoma/leukemia as an incidental finding in have also reported good outcomes for localized approximately 0.2% to 1.2% of the pelvic lymph DLBCL treated with radiotherapy or chem- node resections performed at radical prostatec- otherapy with or without surgical intervention tomy [68,69]. [54,55]. In contrast, in the largest retrospective series published, nonlocalized lymphoma Pathology and Biology involving the bladder at first diagnosis and lym- The majority of primary lymphomas of the phoma involving the bladder secondarily in the prostate are DLBCLs, but primary prostatic course of widespread lymphoma had a much small lymphocytic lymphomas (SLLs), follicular worse prognosis (9-year and 0.6-year median lymphomas, Burkitt lymphomas, MALT lym- survival, respectively) [53]. phomas, and mantle cell lymphomas have also been reported [64,65,67,70]. A similar spectrum of lymphomas affects the prostate secondarily Lymphoma of the Prostate during the course of disseminated disease, and rare cases of secondary prostatic peripheral Primary lymphoma of the prostate is very rare, T-cell lymphoma, myeloma, and classical representing only approximately 0.2% to 0.8% of “Hodgkin” lymphoma have also been docu- extranodal lymphomas and 0.1% of all prostate mented [67]. Histologically, lymphomas within neoplasms [1,64,65]. Secondary involvement of the prostate gland show patchy or diffuse the prostate by lymphoma or leukemia is more stromal infiltration, with compression, but frequent,being found at postmortem in up to 8% preservation, of ducts and acini. Intraepithelial of “non-Hodgkin” lymphomas and up to 20% of infiltration of neoplastic cells is seen in some cases of CLL [66]. However, in most cases this cases. The morphologic and immunophenotypic involvement is not clinically apparent. In a series features of prostatic lymphomas are similar to of 62 prostatic lymphomas, Bostwick et al. [67] those of extraprostatic disease [3]. No studies found 35% to be primary (defined by presenting have specifically addressed the genetics of pro- symptoms of prostatic enlargement, predomi- static lymphomas. nant involvement of the prostate,and no involve- As mentioned above, leukemic cells not infre- ment of lymph nodes, , liver, or spleen quently infiltrate the prostate, sometimes as the within 1 month of diagnosis), 48% to be second- only site of solid tissue involvement [66]. One 317

Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis recent study showed that CLL cells from patients information provided, and in particular on the with prostatic infiltration (but not from those age of the patient. In children and adolescents, without) bound to prostatic epithelial cells via the most common small round blue-cell tumor clonally expressed surface IgM [71]. This sug- of the bladder and prostate, other than leukemia gests a mechanism for accumulation of CLL cells and lymphoma, is embryonal rhabdomyosar- in the of some patients. coma. Although there are reports of other rare primary or metastatic tumors occurring in the Treatment and Outcome bladder and prostate, including primitive neu- roectodermal tumor (PNET), neuroblastoma, Because of the rarity with which lymphoma Wilms’ tumor, and desmoplastic small round cell presents in the prostate, little is known of its tumor [73–78], these should be considered only prognosis and optimal treatment. In the series of after exclusion of the more common entities out- Bostwick et al. [67], 47% of patients with follow- lined above. In adults, the main differential diag- up died of lymphoma, with a lymphoma-specific nosis of nonlymphoid small round blue-cell 5-year survival of only 33%; 73% of patients tumors includes poorly differentiated carcin- with primary prostatic lymphoma developed oma and neuroendocrine tumors such as car- extraprostatic disease 1 to 59 months from cinoid and small cell carcinoma. More rarely, diagnosis. There were no significant differences neoplasms such as paraganglioma, synovial in survival between patients receiving dif- sarcoma, metastatic lymphoepithelioma-like ferent therapies (chemotherapy, radiotherapy, carcinoma, and small cell have been chemotherapy and radiotherapy, surgery only), reported at these sites [79–84]. between patients with primary or secondary The following section outlines a few of the prostatic lymphoma, or between patients with more common and clinically relevant entities in different types of lymphoma. However, patients more detail. in this retrospective study were treated over a 58- year period, and it is unlikely that these data reflect the results that would be achieved using Small Cell Carcinoma of the Bladder current stage and subtype-specific therapeutic regimens. Indeed, a number of more recent Primary small cell carcinoma of the bladder was case studies have reported good outcomes for first reported by Cramer et al. [85] in 1981 as a patients with high-grade prostatic lymphoma rare aggressive vesical tumor sharing morpho- treated with anthracycline-based combination logical and ultrastructural features with oat cell chemotherapy [65,72], and it remains uncertain (small cell) carcinoma of the lung [85]. Since whether the prognosis of lymphoma presenting then, only about 150 cases have been described in the prostate is significantly worse than that of worldwide [86]. Although they account for less equivalent lymphomas presenting at most other than 1% of bladder tumors, their importance lies extranodal sites. in the fact that the tumors have a characteristic histological appearance and are usually associ- ated with a rapidly progressive course, requiring Small Cell Tumors of the adjuvant treatment with a tailored chemother- apy regimen that often differs from that used to Bladder and Prostate treat high-grade urothelial carcinoma. The vast majority of small round blue-cell Clinical and Radiological Features tumors of the bladder and prostate prove to be either lymphomas or systemic infiltrates in The majority of patients present with urinary patients with a known history of leukemia.These symptoms, including dysuria and hematuria entities have been covered in detail in the pre- [87], and over 50% have metastatic deposits at ceding section. the time of diagnosis in the lymph nodes, bone After exclusion of lymphoma, the pathologist liver, or lung [88]. In rare cases, the secretion must consider a variety of other tumors that may of neuropeptides by the tumor cells may rarely arise at these sites, including tumors of also lead to paraneoplastic symptoms such as both epithelial and mesenchymal origin.The dif- peripheral neuropathy and electrolyte abnorm- ferential diagnosis greatly relies on the clinical alities including hypercalcemia and hypophos- 318

Urological Cancers: Science and Treatment phatemia [89,90]. Radiological studies using differentiated urothelial carcinoma, respectively computed tomography (CT) and magnetic reso- [98]. However, separation of a primary bladder nance imaging (MRI) have shown that these small cell carcinoma from a metastatic small cell tumors often are large, broad-based polypoid carcinoma of pulmonary origin relies more intramural masses, and are most frequently heavily on clinical and radiological findings, located on the posterior bladder wall or in the as their immunohistochemical profile may be region of the trigone [91,92]. Rare cases are identical. also reported as arising within a bladder diverticulum. Biology and Genetics Pathology The exact origin of small cell carcinoma of the bladder is unknown, but it has been postulated Small cell carcinomas are malignant epithelial that these tumors may arise either from a small tumors showing neuroendocrine differentiation, population of resident (“Kulchitsky-type”) neu- and are composed of small, hyperchromatic roendocrine cells in the vesical mucosa, from cells with a coarse “salt-and-pepper” chromatin neuroendocrine of urothelial cells, or pattern, scant , and inconspicuous from a mucosal with a capacity for mul- nucleoli. The tumor cells show characteristic fea- tipotential differentiation [94,99]. tures including the presence of nuclear mold- Although relatively little is known about the ing and encrustation of tumor cell DNA within genetic alterations in these tumors, on account blood vessel walls (Azzopardi phenomenon). of their rarity, studies using comparative Mitoses are frequent and necrosis may be focally genomic hybridization (CGH) have shown that present. Specific criteria for diagnosing these vesical small cell carcinomas contain a high tumor cells in cytological preparations have also number of genomic alterations (a mean of 11.3 been described [93]. In a cytological study, from per tumor), including amplification, gains and 23 patients with subsequent biopsy and histo- deletions at specific loci coding for known onco- logical confirmation, a combination of cellular genes, and tumor-suppressor genes [100]. Ele- and nuclear features were used to correctly diag- vated telomerase levels have also been identified nose all the tumors as small cell carcinomas on in exfoliated tumor cells from urine and bladder the basis of urine cytology alone [94].About 50% washings in patients with small cell carcinoma, of vesical small cell carcinomas show focal areas and may be involved in tumor cell immortaliza- with the morphology of classical urothelial tion, although the significance of this finding is carcinoma, and some may contain small foci unclear [101]. of squamous cell or adenocarcinoma [95]. The presence of these elements is still considered Treatment and Outcome compatible with a diagnosis of small cell carci- noma, if the remainder of the tumor shows the As mentioned above, these tumors pursue an characteristic histological features mentioned aggressive clinical course, with early lymphovas- above. cular and muscle invasion and are frequently metastatic at the time of presentation. The Ultrastructure and Immunohistochemical overall 5-year survival of patients with localized Profile small cell carcinoma may be as low as 8% [88,102]. Predictors of poor survival include age Tumor cells have been shown to contain neu- greater than 65 years, tumor stage, and presence rosecretory granules on electron microscopy of lymphovascular invasion [103]. Treatment (1). often shows options consist of cystectomy and adjuvant positive staining for neuroendocrine markers, chemotherapy or radiotherapy, and a large including CD56 (92%), neuron-specific enolase number of different regimens are in use, (87%), and chromogranin A (up to 65%), and showing varying success rates [104,105]. shows dot-like positivity with antibodies against cytokeratins such as CAM5.2 (60%) [96,97]. A Small Cell Carcinoma of the Prostate negative staining pattern for CD45 (leukocyte common antigen) and CD44v6 enables distinc- Small cell carcinoma is a rare variant of prosta- tion from tumors with a similar morphological tic carcinoma, accounting for less than 1% of all appearance, including lymphoma and poorly tumors arising in the gland [106]. It behaves in 319

Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis an aggressive manner, metastasizes early, and is have been conflicting results with this marker, unresponsive to some types of chemotherapeu- and further characterization with this antibody tic regimens [107]. Although pure small cell car- is required [111,112]. cinoma is rare, the presence of neuroendocrine differentiation is not uncommonly seen to some Biology extent in prostatic carcinoma and may take one The histogenesis of these tumors is unclear. One of three forms: hypothesis is that they originate from a multi- • Focal neuroendocrine differentiation in a con- potential stem cell in the prostatic epithelium, ventional prostatic adenocarcinoma whereas others favor either malignant transfor- • Carcinoid tumor (well-differentiated neuroen- mation of normal prostatic neuroendocrine cells docrine tumor) or metaplastic change in a conventional acinar • Small cell carcinoma (poorly differentiated adenocarcinoma [107]. There is also evidence to neuroendocrine carcinoma) suggest that prostatic tumors with a significant neuroendocrine component may be largely Thus, although virtually all prostatic carcinomas -independent and are thus resistant to show focal neuroendocrine differentiation in conventional forms of treatment, particularly terms of scattered neurosecretory cells within hormonal deprivation, used to treat classical the tumor, only about 5% to 10% contain acinar prostatic adenocarcinoma [113]. significant groups of cells demonstrating neu- roendocrine markers by immunostaining [108]. Treatment and Outcome The average survival for patients with prostatic Clinical Features small cell carcinoma is less than 1 year. There A significant proportion of small cell carcinomas appears to be no difference in survival between of the prostate arise in patients with a previous patients with a pure small cell carcinoma and history of hormonally treated acinar adenocar- those with a mixed small cell–acinar tumor. cinoma [109]. These patients subsequently Unlike its counterpart in the lung and bladder, present with worsening urinary symptoms and studies have reported that small cell carcinoma increasing tumor load, in the setting of a per- of the prostate does not appear to respond to sistently low serum prostate-specific antigen treatment with cisplatin-based chemotherapy (PSA) level. As the neuroendocrine component regimens [103]. However, conflicting studies predominates, patients may present with para- have suggested that other chemotherapeutic reg- neoplastic symptoms associated with elevated imens may confer a small survival advantage levels of adrenocorticotropic (ACTH) [114]. or antidiuretic hormone (ADH). Rhabdomyosarcoma of the Bladder Pathology and Immunohistochemical Profile Rhabdomyosarcoma of the bladder is a rare malignant mesenchymal neoplasm composed of The morphology of small cell carcinoma of the tumor cells that recapitulate the morphological prostate is identical to that seen in the bladder features of skeletal muscle. Most commonly seen (see above) and lung. In about 50% of cases, the in childhood and adolescence, the majority of tumors are composed of a mixture of small cell these tumors are of the embryonal subtype in carcinoma and acinar adenocarcinoma [110]. the bladder (and are also known as “sarcoma The small cell component is positive for CD56, botryoides”). In contrast, the alveolar subtype, neuron-specific enolase (NSE), and chromo- carrying a distinct chromosomal translocation granin A, and shows dot-like positivity using (t2:13), is most commonly seen in the deep soft CAM5.2, but is negative for PSA and prostatic tissues and rarely arises in the bladder. acid phosphatase (PSAP). The acinar component shows the reverse immunoprofile. It has been Clinical Features suggested that primary small cell carcinoma of the prostate may be distinguished from a metas- Patients typically present under the age of 10 tasis from the lung by the absence of staining for years, although cases have been reported in ado- transcription factor-1 (TTF-1), but there lescents, young adults, and rarely into middle age 320

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[115,116]. In hollow organs such as the bladder Treatment and Outcome or vagina, the tumor grows in a polypoid fashion into the lumen of the viscus, producing a Rhabdomyosarcomas are aggressive neoplasms, characteristic appearance resembling a bunch usually treated with a combination of surgery, of grapes on endoscopic and ultrasonic exam- radiotherapy, and chemotherapy [121–123]. The ination [117]. Vesical rhabdomyosarcoma exophytic botryoid subtype, commonly seen in commonly presents with urinary symptoms, the bladder, has the best prognosis, with an including hematuria, dysuria, and obstruction to overall 5-year survival of 65% [124]. urinary flow.

Pathology and Immunohistochemical Profile Sex Cord–Stromal Rhabdomyosarcomas are usually composed of a mixture of small round cells with hyperchro- (Mesenchymal) Tumors matic nuclei and scant cytoplasm, and variable of the Testis numbers of larger elongated cells with abundant eosinophilic cytoplasm (rhabdomyoblasts). The Sex cord–stromal tumors (SCSTs) are a related tumor cells contain intracytoplasmic cross- group of testicular tumors that are composed of striations that may be visible on routine hema- neoplastic cells that recapitulate the primitive toxylin and eosin (H&E)-stained sections, but sex cord elements and surrounding immature are more clearly identified using special stain- mesenchyme of the fetal testis. They are thus dis- ing techniques. Although classically exophytic, tinct from germ cell tumors of the testis, and forming papillary structures with a central only very rare mixed forms occur [125]. The fibrovascular core, these tumors may show focal SCSTs account for approximately 3% to 5% of all accumulation of rhabdomyoblasts under adja- adult testicular neoplasms and are predomi- cent residual vesical mucosa, resulting in a dis- nantly either Leydig or Sertoli cell tumors, tinctive subepithelial zone of hypercellularity although a smaller proportion of (cambium layer). This architectural feature tumors and rare mixed or indeterminate types may be useful in the distinction of rhabdomy- may also be seen. They may present at any age osarcoma from other tumors with a similar from infancy to old age, but are most commonly morphology such as lymphoma and small seen in young children (under the age of 10 cell carcinoma. Tumor cells stain positive for years), and account for up to 25% of testicular muscle-specific actin, desmin, and nuclear myo- tumors in this pediatric age group. genin and myoD1, the latter two being specific Although no specific etiological factors have markers for skeletal muscle differentiation been established in the majority of patients, [118]. case reports note the association of Leydig tumors with tubular atrophy and Leydig Biology and Genetics cell , for example in Nelson’s, Klinefelter’s, and adrenogenital and androgen Several studies have been performed to elucidate insensitivity syndromes. the cytogenetic profile of embryonal rhabdomy- In the latter, multiple Leydig-Sertoli hamar- osarcomas, using a variety of techniques includ- tomas are found. These underlying conditions, ing CGH and fluorescent in situ hybridization therefore, should be considered as possible pre- (FISH). These have identified a number of disposing factors, particularly in cases with an chromosomal abnormalities in these tumors, unusual clinical presentation or in patients with including gains of regions on chromosomes 2, 7, multiple, bilateral tumors. 8, 11, 12, 13, and 20, and losses of regions on As the majority of SCSTs are either of Leydig chromosomes 1, 6, 14, and 17 [119,120]. Further or Sertoli type, these are discussed in further work is currently aimed at establishing the exact detail below, with particular reference to their identity of the oncogenes and tumor-suppressor clinical presentation, pathological features, and genes involved at these sites. treatment options. 321

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Leydig Cell Tumors cularized stroma is present between the tumor cells, but occasionally this may be hyalinized Leydig cell tumors (LCTs) are a group of sex (fibrotic) or edematous (myxoid) in appearance. cord–stromal tumors of the testis composed of Rare examples of LCT may show foci of neoplastic cells that recapitulate the appearance adipocytic differentiation, calcification, ossi- of Leydig cells. fication, and areas with a spindle cell mor- phology [134]. Clinical Features Malignant Leydig Cell Tumors Leydig cell tumors account for 2% to 3% of all testicular neoplasms [126], with 20% arising in About 10% of LCTs behave in a malignant young children (ages 5 to 10 years), and the fashion [132,135]. The following clinical and remaining 80% seen in young or middle-aged morphological features have been reported as adults (ages 30 to 60 years). These tumors may correlating with an increased risk of malig- present with signs of increased androgen and/or nant behavior: age >60 years, tumor size >5cm, production (most commonly as isosex- marked nuclear pleomorphism, increased ual pseudoprecocity in children [127] or gyneco- mitotic activity (>3/10 high power fields) or pro- mastia in adults [128,129]) or as a painless liferation rate (>10% with MIB-1), the presence testicular swelling. Around 3% to 5% of tumors of lymphovascular invasion or coagulative occur bilaterally, either synchronously or necrosis, infiltrative margins, extension into rete metachronously [130], and up to 10% display or tunica, and aneuploidy [127,135–138]. aggressive behavior (malignant LCT) with evidence of subsequent local recurrence or Immunophenotype metastatic spread [131,132]. In most instances, ultrasound examination of the testis reveals a The tumor cells are positive for vimentin, well-circumscribed hypoechoic mass, but the inhibin [139], calretinin [140], and melan-A radiological appearances are indistinguishable [141,142], but negative for placental alkaline from . Furthermore, there are no phosphatase (PLAP). Focal cytokeratin and S- firm radiological criteria to determine whether 100 positivity has been reported in some cases a particular lesion will behave in a benign or [143]. In addition, Leydig cells in the testis malignant manner. are noted to be positive for neuroendocrine markers, such as PGP9.5 [144]. Pathology Biology and Genetics Most LCTs are small (3 to 5cm), well- circumscribed solid masses,with a yellow/brown The majority of LCTs are sporadic, and the eti- cut surface. Commonly, a thin capsule surrounds ology of these tumors remains largely unknown. the tumor, and focal areas of microcalcification In the minority of cases associated with and hemorrhage may be seen. Up to 10% cases underlying predisposing conditions (mentioned show extratunical spread, with infiltration of above), there is an increased risk of Leydig or paratesticular soft tissues by tumor. mixed Sertoli-Leydig tumors, and these usually The tumor may show a variety of patterns, present as multiple lesions bilaterally. It has including areas with a solid, pseudoglandular, previously been reported that inactivation trabecular, or insular growth pattern. Tumor of the receptor (LHR) cells are large and polygonal, with indistinct cell gene on chromosome 2p may result in Leydig borders. Nuclei are round and vesicular and cell hypoplasia and male hypogonadism [145]. contain prominent central nucleoli (Fig. 26.3). Studies examining a small number of LCTs The cytoplasm is abundant and eosinophilic, have reported the presence of activating muta- and focally may be foamy or vacuolated, and up tions of the LHR gene in these tumors [146,147]. to 50% of cases contain intracytoplasmic Reinke However, their results have not been confirmed crystalloids or pigment [133]. Mitoses by other studies [148], and thus further valida- are scarce, and usually amount to no more than tion of these findings in large-scale studies of one or two per 10 high power fields. A fine vas- LCTs is required. 322

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Fig.26.3. A Leydig cell tumor showing strong cytoplasmic immunohistochemical staining for inhibin (inset) in the majority of tumour cells. Original magnification: H&E, 400¥; inhibin, 600¥.

Treatment and Outcome A role for laparoscopic retroperitoneal lymph node dissection in addition to standard radical The mainstay of treatment for LCT is surgery. orchidectomy has been advocated for selected This usually involves radical orchidectomy, but patient groups (especially those with clinical or there has been, in recent years, an increasing histopathological features of malignancy or trend for testis-sparing surgery, particularly in known small-volume metastatic disease), but its children and younger adults, or those with bilat- potential utility remains to be proven in clinical eral tumors. In such instances the diagnosis is terms [153,154]. The vast majority (90%) of LCTs made on intraoperative frozen section, allowing are benign, and potentially cured by local planning of conservative surgery rather than excision of the primary mass. In the remaining orchidectomy. Reports of small series of LCT 10% cases, there is an increased risk of treated with conservative surgery show a good local recurrence or distant metastasis, and response to organ-sparing surgery and success- these may require further surgery as well as ful preservation of fertility in the majority of adjuvant chemotherapy and/or radiotherapy. cases, provided that there are no clinical (preop- Although metastatic LCTs are often resistant to erative) or histopathological (postoperative) fea- chemotherapy [155], there are some cases that tures to suggest malignancy and that local appear to respond to cisplatin-based regimens resection is complete [149–152]. [156]. 323

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Sertoli Cell Tumors Immunophenotype and Electron Microscopy Sertoli cell tumors (SCTs) are a group of sex cord–stromal tumors of the testis that are com- The tumor cells are usually positive for posed of neoplastic cells recapitulating fetal or vimentin, cytokeratin, and inhibin [139,143], adult-type Sertoli cells. and may focally stain for S-100 [165] and calre- tinin. A few cases have been reported as show- ing positivity for epithelial membrane antigen Clinical Features (EMA) and NSE. There is no staining with anti- Although rare, accounting for less than 1% of all bodies to placental alkaline phosphatase (PLAP), testicular neoplasms, SCTs may arise at any age excluding , which may be a diagnostic (most commonly middle age). They may present problem in some cases [166]. Antibodies against with a painless testicular swelling or with symp- human chorionic gonadotrophin (HCG) and a- toms of or impotence. Most are fetoprotein are also negative. Ultrastructurally, sporadic tumors, but there is an increased risk of features of -secreting cells are usually seen SCT in patients with Peutz-Jeghers polyposis, in SCT including abundant cisternae of smooth and Carney’s and androgen insensitivity . Charcot-Bottcher fila- syndromes [157,158]. Ultrasound examination ments (perinuclear bundles of fine filaments) shows a well-circumscribed, hypoechoic mass, are considered to be pathognomonic of Sertoli with a variable amount of cystic change [159]. cells [167]. Most cases show no features enabling distinction from other testicular neoplasms, including germ cell tumors. A rare variant, the large cell calcify- Variants of Sertoli Cell Tumor ing SCT, however, commonly presents in young Large Cell Calcifying SCT children and adolescents with bilateral tumors containing large calcified areas, and has a char- This is a rare variant of SCT, characterized by acteristic ultrasound pattern of bright echo- large cells with abundant eosinophilic cytoplasm genicity and posterior acoustic shadowing [160]. and calcification [162,163,168]. These tumors are commonly seen in the context of Peutz-Jeghers or Carney’s syndromes and affect mostly young Pathology children and adolescents, with a mean age 17 Sertoli cell tumors are well-circumscribed lobu- years [169]. Most are solitary and benign, but lated lesions with a variable size (ranging from up to 40% may be bilateral [170]. Tumor cells 2 to 20cm) and a pale white/yellow solid cut are large and polygonal, with vesicular nuclei surface. Focal cystic change or hemorrhage may and prominent nucleoli. Mitoses are scarce. be seen, but necrosis is usually absent [161]. The stroma is hyalinized, with a prominent Most cases are unilateral, except for cases in neutrophilic infiltrate and characteristic large patients with Peutz-Jeghers syndrome or those areas of microcalcification and/or ossification with a large cell calcifying variant [162,163]. (Fig. 26.4). Although few cases behave in a The tumor forms a variety of patterns, com- malignant manner, possible morphological in- monly including areas with a tubular or glandu- dicators of aggressive behavior include large lar pattern of growth. The tubules may show a size, necrosis, marked nuclear atypia, lympho- central lumen or form solid islands. Tumor cells vascular permeation, and mitotic rate greater have oval, elongated nuclei with small micronu- than three mitoses per 10 high power fields cleoli and pale eosinophilic or vacuolated cyto- [171–173]. plasm [161]. The nucleus may show features of indentation or nuclear grooving, especially on Sclerosing SCT cytological preparations [164]. There is minimal nuclear pleomorphism, and mitotic activity is This is a rare variant seen in young adults (com- not prominent (usually <5 per 10 high power monly 25 to 35 years age) with tubules composed fields). The surrounding stroma may be focally of neoplastic Sertoli cells entrapped in a dense cellular and fibrotic or show areas of sclerotic stroma. Usually these tumors have a hyalinization. benign outcome [174,175]. 324

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Fig. 26.4. A large cell calcifying Sertoli cell tumor (A,H&E) showing strong cytoplasmic immunohistochemical staining for inhibin (B) and weaker staining for calretinin (C). Original magnification: A, 400¥; B and C, 200¥.

Malignant SCT behave in a malignant fashion are usually very aggressive, resulting in a poor prognosis with Although rare (<10% of cases), a malignant median survival of around 1 year. In these, a form of SCT does occur. The following are clin- combination of retroperitoneal lymph node ical and morphological features that correlate dissection, chemotherapy, and radiotherapy with an increased risk of malignant behavior: appears to offer the best palliative treatment large tumor size (>5cm), marked nuclear pleo- [178]. In the large cell calcifying variant of morphism, increased mitotic activity (>5 per 10 Sertoli cell tumor (LCCSCT), the prognosis is high power fields), necrosis, infiltrative margins, good in the majority of cases, particularly in and the presence of lymphovascular invasion younger children, and some authors advocate [161]. Malignant cases may arise at any age, conservative treatment with testis-sparing including childhood (unlike LCT), and more surgery for cases identified as LCCSCT by ultra- commonly present with gynecomastia than sonographic criteria [179]. benign tumors. Biology and Genetics The majority of SCTs are sporadic, and their eti- References ology remains unknown. In patients at increased risk of SCT, including those with androgen 1. Freeman C, Berg JW, Cutler SJ. Occurrence and insensitivity syndrome, there are individual case prognosis of extranodal lymphomas. Cancer reports of patients whose tumors show activat- 1972;29:252–260. ing point mutations of the androgen receptor 2. Colevas AD, Kantoff PW, DeWolf WC, et al. Malignant lymphoma of the genitourinary tract. (AR) gene [176,177]. However, whether these In: Vogelzanf NJ, Shipley WU, Scardino PT, et al., findings can be extrapolated to a larger group of eds. Comprehensive Textbook of Genitourinary sporadic SCTs, in patients without androgen , 2nd ed. Philadelphia: Lippincott insensitivity syndrome, remains to be Williams & Wilkins, 2000:1120–1132. elucidated. 3. Jaffe ES, Harris NL, Stein H, et al., eds. World Health Organization Classification of Tumours. Treatment and Outcome Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: The majority of SCTs are benign and thus poten- IARC Press, 2001. tially curable by complete local excision of the 4. Shahab N, Doll DC. Testicular lymphoma. Semin primary tumor mass. The minority of SCTs that Oncol 1999;26:259–269. 325

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5. Moller MB, d’Amore F, Christensen BE. 18. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct Testicular lymphoma: a population-based study types of diffuse large B-cell lymphoma identified of incidence, clinicopathological correlations by gene expression profiling. Nature 2000;403: and prognosis. Eur J Cancer 1994;30A:1760– 503–511. 1764. 19. Rosenwald A, Wright G, Chan WC, et al. The 6. Zucca E, Conconi A, Mughal TI, et al. Patterns of use of molecular profiling to predict survival outcome and prognostic factors in primary after chemotherapy for diffuse large-B-cell lym- large-cell lymphoma of the testis in a survey by phoma. N Engl J Med 2002;346:1937–1947. the international extranodal lymphoma study 20. Shipp MA, Ross KN, Tamayo P, et al. Diffuse group. J Clin Oncol 2003;21:20–27. large B-cell lymphoma outcome prediction by 7. Visco C, Medeiros LJ, Mesina OM, et al. Non- gene-expression profiling and supervised machine Hodgkin’s lymphoma affecting the testis: Is it learning. Nat Med 2002;8:68–74. curable with doxorubicin-based therapy? Clin 21. de Leval L, Harris NL.Variability in immunophe- Lymphoma 2001;2:40–46. notype in diffuse large B-cell lymphoma and its 8. Seymour JF, Solomon B, Wolf MM, et al. Primary clinical relevance. 2003;43:509– large-cell non-Hodgkin’s lymphoma of the testis: 528. a retrospective analysis of patterns of failure and 22. Colomo L, Lopez-Guillermo A, Perales M, et al. prognostic factors. Clin Lymphoma 2001;2:109– Clinical impact of the differentiation profile 115. assessed by immunophenotyping in patients 9. Linassier C, Desablens B, Lefrancq T, et al. with diffuse large B-cell lymphoma. Blood 2003; Stage I-IIe primary non-Hodgkin’s lymphoma of 101:78–84. the testis: results of a prospective trial by the 23. Barrans SL, Carter I, Owen RG, et al. Germinal GOELAMS study group. Clin Lymphoma 2002;3: center phenotype and bcl-2 expression com- 167–172. bined with the international prognostic index 10. Ferry JA, Harris NL, Young RH, et al. Malignant improves patient risk stratification in diffuse lymphoma of the testis, epididymis, and sper- large b-cell lymphoma. Blood 2002;99:1136– matic cord. A clinicopathologic study of 69 cases 1143. with immunophenotypic analysis. Am J Surg 24. Hans CP, Weisenburger DD, Greiner TC, et al. Pathol 1994;18:376–390. Confirmation of the molecular classification of 11. Wilkins BS, Williamson JM, O’Brien CJ. Morpho- diffuse large B-cell lymphoma by immunohisto- logical and immunohistological study of testicu- chemistry using a tissue microarray. Blood 2004; lar lymphomas. Histopathology 1989;15:147– 103:275–282. 156. 25. Kramer MH, Hermans J, Wijburg E, et al. Clini- 12. Lagrange JL, Ramaioli A, Theodore CH, et al. cal relevance of bcl-2, bcl-6, and myc rearrange- Non-Hodgkin’s lymphoma of the testis: a retro- ments in diffuse large B-cell lymphoma. Blood spective study of 84 patients treated in the 1998;92:3152–3162. French anticancer centres. Ann Oncol 2001;12: 26. Gascoyne RD, Adomat SA, Krajewski S, et al. 1313–1319. Prognostic significance of bcl-2 protein expres- 13. Fonseca R, Habermann TM, Colgan JP,et al. Tes- sion and bcl-2 gene rearrangement in diffuse ticular lymphoma is associated with a high inci- aggressive non-Hodgkin’s lymphoma.Blood 1997; dence of extranodal recurrence. Cancer 2000;88: 90:244–251. 154–161. 27. Barrans SL, Evans PA, O’Connor SJ, et al. The 14. Dogan A, Bagdi E, Munson P, et al. CD10 and t(14;18) is associated with germinal center- bcl-6 expression in paraffin sections of normal derived diffuse large B-cell lymphoma and is a lymphoid tissue and B-cell lymphomas. Am J strong predictor of outcome. Clin Cancer Res Surg Pathol 2000;24:846–852. 2003;9:2133–2139. 15. Hyland J, Lasota J, Jasinski M, et al. Molecular 28. Huang JZ, Sanger WG, Greiner TC, et al. The pathological analysis of testicular diffuse large t(14;18) defines a unique subset of diffuse large cell lymphomas. Hum Pathol 1998;29:1231– B-cell lymphoma with a germinal center B-cell 1239. gene expression profile. Blood 2002;99:2285– 16. Lossos IS, Okada CY, Tibshirani R, et al. Molecu- 2290. lar analysis of immunoglobulin genes in diffuse 29. Monni O, Joensuu H, Franssila K, et al. Bcl-2 large B-cell lymphomas. Blood 2000;95:1797– overexpression associated with chromosomal 1803. amplification in diffuse large B-cell lymphoma. 17. Pasqualucci L, Neumeister P, Goossens T, et al. Blood 1997;90:1168–1174. Hypermutation of multiple proto-oncogenes in 30. Lambrechts AC, Looijenga LH, van’t Veer MB, et B-cell diffuse large-cell lymphomas. Nature 2001; al. Lymphomas with testicular localisation show 412:341–346. a consistent bcl-2 expression without a translo- 326

Urological Cancers: Science and Treatment

cation (14;18): a molecular and immunohisto- 44. Kim TH, Hargreaves HK, Chan WC, et al. Sequen- chemical study. Br J Cancer 1995;71:73–77. tial testicular biopsies in childhood acute lym- 31. Ye BH, Chaganti S, Chang CC, et al. Chromoso- phocytic leukemia. Cancer 1986;57:1038–1041. mal translocations cause deregulated bcl-6 45. Grundy RG,Leiper AD,Stanhope R,et al.Survival expression by promoter substitution in B cell and endocrine outcome after testicular relapse in lymphoma. EMBO J 1995;14:6209–6217. acute lymphoblastic leukaemia. Arch Dis Child 32. Pasqualucci L, Migliazza A, Basso K, et al. Muta- 1997;76:190–196. tions of the bcl-6 proto-oncogene disrupt its 46. Pileri SA, Sabattini E, Rosito P,et al. Primary fol- negative autoregulation in diffuse large B-cell licular lymphoma of the testis in childhood: an lymphoma. Blood 2003;101:2914–2923. entity with peculiar clinical and molecular char- 33. Ichikawa A, Kinoshita T,Watanabe T, et al. Muta- acteristics. J Clin Pathol 2002;55:684–688. tions of the p53 gene as a prognostic factor in 47. Ferry JA, Young RH, Scully RE. Testicular and aggressive B-cell lymphoma. N Engl J Med 1997; epididymal plasmacytoma: a report of 7 cases, 337:529–534. including three that were the initial manifesta- 34. Houldsworth J, Mathew S, Rao PH, et al. Rel tion of plasma cell myeloma. Am J Surg Pathol proto-oncogene is frequently amplified in extra- 1997;21:590–598. nodal diffuse large cell lymphoma. Blood 1996; 48. Anghel G, Petti N, Remotti D, et al. Testicular 87:25–29. plasmacytoma: report of a case and review of the 35. Davis RE, Brown KD, Siebenlist U, et al. Consti- literature. Am J Hematol 2002;71:98–104. tutive nuclear factor kappaB activity is required 49. Kim YB, Chang SK,Yang WI, et al. Primary NK/T for survival of activated B cell-like diffuse large cell lymphoma of the testis. A case report and B cell lymphoma cells. J Exp Med 2001;194:1861– review of the literature. Acta Haematol 2003;109: 1874. 95–100. 36. Riemersma SA, Jordanova ES, Schop RF, et al. 50. Henley JD, Ferry J, Ulbright TM. Miscellaneous Extensive genetic alterations of the HLA region, rare paratesticular tumors. Semin Diagn Pathol including homozygous deletions of HLA class II 2000;17:319–339. genes in B-cell lymphomas arising in immune- 51. Vega F, Medeiros LJ, Abruzzo LV. Primary parat- privileged sites. Blood 2000;96:3569–3577. esticular lymphoma: a report of 2 cases and 37. Jordanova ES, Riemersma SA, Philippo K, et al. review of literature. Arch Pathol Lab Med 2001; Beta 2–microglobulin aberrations in diffuse 125:428–432. large B-cell lymphoma of the testis and the 52. Givler RL. Involvement of the bladder in central nervous system. Int J Cancer 2003;103: leukemia and lymphoma. J Urol 1971;105:667– 393–398. 670. 38. Horstmann WG, Timens W. Lack of adhesion 53. Kempton CL, Kurtin PJ, Inwards DJ, et al. Malig- molecules in testicular diffuse centroblastic and nant lymphoma of the bladder: evidence from 36 immunoblastic B cell lymphomas as a contribu- cases that low-grade lymphoma of the MALT- tory factor in malignant behaviour. Virchows type is the most common primary bladder lym- Arch 1996;429:83–90. phoma. Am J Surg Pathol 1997;21:1324–1333. 39. Zouhair A, Weber D, Belkacemi Y, et al. Outcome 54. Ohsawa M,Aozasa K,Horiuchi K,et al.Malignant and patterns of failure in testicular lymphoma: lymphoma of bladder. Report of three cases and a multicenter rare cancer network study. Int J review of the literature. Cancer 1993;72:1969– Radiat Oncol Biol Phys 2002;52:652–656. 1974. 40. Moller MB, Pedersen NT,Christensen BE. Diffuse 55. Bates AW, Norton AJ, Baithun SI. Malignant lym- large B-cell lymphoma: clinical implications of phoma of the urinary bladder: a clinicopatho- extranodal versus nodal presentation—a popu- logical study of 11 cases. J Clin Pathol 2000;53: lation-based study of 1575 cases. Br J Haematol 458–461. 2004;124:151–159. 56. Al-Maghrabi J, Kamel-Reid S, Jewett M, et al. 41. Connors JM, Klimo P, Voss N, et al. Testicular Primary low-grade B-cell lymphoma of mucosa- lymphoma: improved outcome with early brief associated lymphoid tissue type arising in the chemotherapy. J Clin Oncol 1988;6:776–781. urinary bladder: report of 4 cases with molecu- 42. Coiffier B, Lepage E, Briere J, et al. CHOP lar genetic analysis. Arch Pathol Lab Med 2001; chemotherapy plus Rituximab compared with 125:332–336. CHOP alone in elderly patients with diffuse 57. Pawade J, Banerjee SS, Harris M, et al. Lym- large-B-cell lymphoma. N Engl J Med 2002;346: phomas of mucosa-associated lymphoid tissue 235–242. arising in the urinary bladder. Histopathology 43. Dalle JH, Mechinaud F, Michon J, et al. Testicular 1993;23:147–151. disease in childhood B-cell non-Hodgkin’s lym- 58. Du MQ, Isaccson PG. Gastric MALT lymphoma: phoma: the French society of pediatric oncology From aetiology to treatment. Lancet Oncol 2002; experience. J Clin Oncol 2001;19:2397–2403. 3:97–104. 327

Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis

59. Krober SM, Aepinus C, Ruck P, et al. Extranodal 74. Yokoyama S, Hirakawa H, Ueno S, et al. Neurob- marginal zone B cell lymphoma of MALT type lastoma of the urinary bladder, preclinically involving the mucosa of both the urinary bladder detected by mass screening. Pediatrics 1999;103: and stomach. J Clin Pathol 2002;55:554–557. e67. 60. Streubel B, Lamprecht A, Dierlamm J, et al. 75. Kruger S, Schmidt H, Kausch I, et al. Primitive T(14;18)(q32;q21) involving IgH and MALT1 is a neuroectodermal tumor (PNET) of the urinary frequent chromosomal aberration in MALT lym- bladder. Pathol Res Pract 2003;199:751–754. phoma. Blood 2003;101:2335–2339. 76. Ijiri R, Tanaka Y,Kou K, et al. Bladder origin neu- 61. Tsang RW, Gospodarowicz MK, Pintilie M, et al. roblastoma detected by mass screening. Urology Stage I and II MALT lymphoma: results of treat- 1998;52:1139–1141. ment with radiotherapy. Int J Radiat Oncol Biol 77. Gupta A, Menon P, Rao KL, et al. Wilms’ tumor: Phys 2001;50:1258–1264. Transureteral intravesical extension and presen- 62. van den Bosch J, Kropman RF, Blok P, et al. Dis- tation as urinary retention. J Pediatr Surg 2003; appearance of a mucosa-associated lymphoid 38:E4–5. tissue (MALT) lymphoma of the urinary bladder 78. Mitchell CS,Yeo TA. Noninvasive botryoid exten- after treatment for Helicobacter pylori. Eur J sion of Wilms’ tumor into the bladder. Pediatr Haematol 2002;68:187–188. Radiol 1997;27:818–820. 63. Oscier D, Bramble J, Hodges E, et al. Regression 79. Williams DH, Hua VN, Chowdhry AA, et al. Syn- of mucosa-associated lymphoid tissue lym- ovial sarcoma of the prostate. J Urol 2004;171: phoma of the bladder after antibiotic therapy. 2376. J Clin Oncol 2002;20:882. 80. Iwasaki H, Ishiguro M, Ohjimi Y, et al. Synovial 64. Patel DR, Gomez GA, Henderson ES, et al. sarcoma of the prostate with t(x;18)(p11.2; Primary prostatic involvement in non-Hodgkin q11.2). Am J Surg Pathol 1999;23:220–226. lymphoma. Urology 1988;32:96–98. 81. Cunningham JA, Fendler JP, Nichols PJ, et al. 65. Sarris A, Dimopoulos M, Pugh W, et al. Primary Metastatic malignant melanoma: an unusual lymphoma of the prostate: good outcome with case presentation. Urology 1994;44:924–926. doxorubicin-based combination chemotherapy. 82. Demirkesen O,Yaycioglu O, Uygun N, et al.A case J Urol 1995;153:1852–1854. of metastatic malignant melanoma presenting 66. Zein TA, Huben R, Lane W, et al. Secondary with hematuria. Urol Int 2000;64:118–120. tumors of the prostate. J Urol 1985;133:615– 83. Lee CS, Komenaka IK, Hurst-Wicker KS, et al. 616. Management of metastatic malignant melanoma 67. Bostwick DG, Iczkowski KA, Amin MB, et al. of the bladder. Urology 2003;62:351. Malignant lymphoma involving the prostate: 84. Nesi G, Vezzosi V, Amorosi A, et al. Paragan- report of 62 cases. Cancer 1998;83:732–738. glioma of the urinary bladder. Urol Int 1996;56: 68. Winstanley AM, Sandison A, Bott SR, et al. Inci- 250–253. dental findings in pelvic lymph nodes at radical 85. Cramer SF,Aikawa M,Cebelin M.Neurosecretory prostatectomy. J Clin Pathol 2002;55:623–626. granules in small cell invasive carcinoma of the 69. Weir EG, Epstein JI. Incidental small lympho- urinary bladder. Cancer 1981;47:724–730. cytic lymphoma/chronic lymphocytic leukemia 86. Fujita K, Nishimura K, Nonomura N, et al. Early in pelvic lymph nodes excised at radical prosta- stage small cell carcinoma of the urinary tectomy. Arch Pathol Lab Med 2003;127:567– bladder. Int J Urol 2001;8:643–644. 572. 87. Grignon DJ, Ro JY,Ayala AG, et al. Small cell car- 70. Tomaru U, Ishikura H, Kon S, et al. Primary lym- cinoma of the urinary bladder. A clinicopatho- phoma of the prostate with features of low grade logic analysis of 22 cases. Cancer 1992;69:527– B-cell lymphoma of mucosa associated lym- 536. phoid tissue: a rare cause of urinary obstruction. 88. Trias I, Algaba F, Condom E, et al. Small cell car- J Urol 1999;162:496–497. cinoma of the urinary bladder.Presentation of 23 71. Bogdan CA, Alexander AA, Gorny MK, et al. cases and review of 134 published cases. Eur Urol Chronic lymphocytic leukemia with prostate 2001;39:85–90. infiltration mediated by specific clonal mem- 89. Partanen S, Asikainen U. Oat cell carcinoma of brane-bound IgM. Cancer Res 2003;63:2067– the urinary bladder with ectopic adrenocorti- 2071. cotropic hormone production. Hum Pathol 1985; 72. Leung TW, Tung SY, Sze WK, et al. Primary non- 16:313–315. Hodgkin’s lymphoma of the prostate. Clin Oncol 90. Reyes CV, Soneru I. Small cell carcinoma of the (R Coll Radiol) 1997;9:264–266. urinary bladder with hypercalcemia.Cancer 1985; 73. Entz-Werle N, Marcellin L, Becmeur F, et al. The 56:2530–2533. urinary bladder: an extremely rare location of 91. Kim JC, Kim KH, Jung S. Small cell carcinoma pediatric neuroblastoma. J Pediatr Surg 2003;38: of the urinary bladder: CT and MR imaging E10–12. findings. Korean J Radiol 2003;4:130–135. 328

Urological Cancers: Science and Treatment

92. Kim JC. CT features of bladder small cell carci- 106. Lopez Cubillana P,Martinez Barba E, Prieto A, et noma. Clin Imaging 2004;28:201–205. al. Oat-cell carcinoma of the prostate. Diagnosis, 93. Yamaguchi T, Imamura Y, Shimamoto T, et al. prognosis and therapeutic implications. Urol Int Small cell carcinoma of the bladder. Two cases 2001;67:209–212. diagnosed by urinary cytology. Acta Cytol 2000; 107. Helpap B, Kollermann J. Undifferentiated carci- 44:403–409. noma of the prostate with small cell features: 94. Ali SZ, Reuter VE, Zakowski MF. Small cell neu- immunohistochemical subtyping and reflections roendocrine carcinoma of the urinary bladder.A on histogenesis. Virchows Arch 1999;434:385– clinicopathologic study with emphasis on cyto- 391. logic features. Cancer 1997;79:356–361. 108. Abrahamsson PA. Neuroendocrine differentia- 95. Algaba F, Sauter G, Schoenberg MP. Small cell tion in prostatic carcinoma. Prostate 1999;39: carcinoma. In: Eble JN, Sauter G, Epstein JI, et al., 135–148. eds. Pathology and Genetics of Tumours of the 109. diSant’Agnese PA,Egevad L,Epstein JI,et al.Neu- and Male Genital Organs. Lyon: roendocrine tumours. In: Eble JN, Sauter G, IARC Press, 2004:135–136. Epstein JI, et al., eds. Pathology and Genetics of 96. Chuang CK, Liao SK. A retrospective immuno- Tumours of the Urinary System and Male Genital histochemical and clinicopathological study of Organs. Lyon: IARC Press, 2004:207–208. small cell carcinomas of the urinary tract. Chang 110. Spieth ME, Lin YG, Nguyen TT. Diagnosing and Gung Med J 2003;26:26–33. treating small-cell carcinomas of prostatic 97. Kaufmann O, Georgi T,Dietel M. Utility of 123C3 origin. Clin Nucl Med 2002;27:11–17. monoclonal antibody against CD56 (NCAM) 111. Agoff SN, Lamps LW, Philip AT, et al. Thyroid. for the diagnosis of small cell carcinomas on transcription factor-1 is expressed in extrapul- paraffin sections. Hum Pathol 1997;28:1373– monary small cell carcinomas but not in other 1378. extrapulmonary neuroendocrine tumors. Mod 98. Iczkowski KA, Shanks JH, Allsbrook WC, et al. Pathol 2000;13:238–242. Small cell carcinoma of urinary bladder is 112. Ordonez NG. Value of thyroid transcription differentiated from urothelial carcinoma by factor-1 immunostaining in distinguishing small chromogranin expression, absence of CD44 cell lung carcinomas from other small cell carci- variant 6 expression, a unique pattern of cytok- nomas. Am J Surg Pathol 2000;24:1217–1223. eratin expression, and more intense gamma- 113. Ito T, Yamamoto S, Ohno Y, et al. Up-regulation enolase expression. Histopathology 1999;35: of neuroendocrine differentiation in prostate 150–156. cancer after androgen deprivation therapy, 99. Blomjous CE,Vos W,De Voogt HJ, et al. Small cell degree and androgen independence. Oncol Rep carcinoma of the urinary bladder. A clinico- 2001;8:1221–1224. pathologic, morphometric, immunohistochemi- 114. Amato RJ, Logothetis CJ, Hallinan R, et al. cal, and ultrastructural study of 18 cases. Cancer Chemotherapy for small cell carcinoma of pro- 1989;64:1347–1357. static origin. J Urol 1992;147:935–937. 100. Terracciano L, Richter J, Tornillo L, et al. Chro- 115. El-Sherbiny MT, El-Mekresh MH, El-Baz MA, et mosomal imbalances in small cell carcinomas of al. Paediatric lower urinary tract rhabdomyosar- the urinary bladder. J Pathol 1999;189:230–235. coma: a single-centre experience of 30 patients. 101. Selli C, Gelmini S, Scott CA, et al. Evidence for BJU Int 2000;86:260–267. elevated telomerase activity in small cell carci- 116. Konety BR, Schneck FX. Botryoid rhab- noma of the bladder. Urology 2000;56:331. domyosarcoma of the bladder. Urology 1997;50: 102. Abbas F, Civantos F, Benedetto P, et al. Small cell 604–605. carcinoma of the bladder and prostate. Urology 117. Poggiani C, Teani M, Auriemma A, et al. Sono- 1995;46:617–630. graphic detection of rhabdomyosarcoma of the 103. Mackey JR, Au HJ, Hugh J, et al. Genitourinary urinary bladder. Eur J Ultrasound 2001;13:35–39. small cell carcinoma: determination of clinical 118. Kumar S, Perlman E, Harris CA, et al. Myogenin and therapeutic factors associated with survival. is a specific marker for rhabdomyosarcoma: J Urol 1998;159:1624–1629. an immunohistochemical study in paraffin- 104. Lohrisch C, Murray N, Pickles T, et al. Small cell embedded tissues. Mod Pathol 2000;13:988–993. carcinoma of the bladder: long term outcome 119. Lee W, Han K, Harris CP, et al. Detection of with integrated chemoradiation. Cancer 1999;86: aneuploidy and possible deletion in paraffin- 2346–2352. embedded rhabdomyosarcoma cells with FISH. 105. Nejat RJ, Purohit R, Goluboff ET, et al. Cure of Cancer Genet Cytogenet 1993;68:99–103. undifferentiated small cell carcinoma of the 120. Bridge JA, Liu J, Weibolt V, et al. Novel genomic urinary bladder with M-VAC chemotherapy.2001; imbalances in embryonal rhabdomyosarcoma 6:53–55. revealed by comparative genomic hybridization 329

Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis

and fluorescence in situ hybridization: an inter- with ossification, and spindle-shaped tumor group rhabdomyosarcoma study. Genes Chro- cells. Am J Surg Pathol 2002;26:1424–1433. mosomes Cancer 2000;27:337–344. 135. McCluggage WG, Shanks JH, Arthur K, et al. Cel- 121. Raney B Jr, Heyn R, Hays DM, et al. Sequelae of lular proliferation and nuclear ploidy assess- treatment in 109 patients followed for 5 to 15 ments augment established prognostic factors in years after diagnosis of sarcoma of the bladder predicting malignancy in testicular Leydig cell and prostate. A report from the Intergroup tumours. Histopathology 1998;33:361–368. Rhabdomyosarcoma Study Committee. Cancer 136. Palazzo JP,Petersen RO,Young RH,et al.Deoxyri- 1993;71:2387–2394. bonucleic acid flow cytometry of testicular 122. Kaefer M, Rink RC. Genitourinary rhab- Leydig cell tumors. J Urol 1994;152:415–417. domyosarcoma. Treatment options. Urol Clin 137. Cheville JC, Sebo TJ, Lager DJ, et al. Leydig cell North Am 2000;27:471–487. tumor of the testis: a clinicopathologic, DNA 123. Ashlock R, Johnstone PA. Treatment modalities content, and MIB-1 comparison of nonmetasta- of bladder/prostate rhabdomyosarcoma: a sizing and metastasizing tumors. Am J Surg review. Prostatic Dis 2003;6:112– Pathol 1998;22:1361–1367. 120. 138. Hekimgil M, Altay B, Yakut BD, et al. Leydig cell 124. Leuschner I, Harms D, Mattke A, et al. Rhab- tumor of the testis: comparison of histopatho- domyosarcoma of the urinary bladder and logical and immunohistochemical features of vagina: a clinicopathologic study with emphasis three azoospermic cases and one malignant case. on recurrent disease: a report from the Kiel Pedi- Pathol Int 2001;51:792–796. atric Tumor Registry and the German CWS 139. Iczkowski KA, Bostwick DG, Roche PC, et al. Study. Am J Surg Pathol 2001;25:856–864. Inhibin A is a sensitive and specific marker for 125. Ulbright TM, Srigley JR, Reuter VE, et al. Sex testicular sex cord-stromal tumors. Mod Pathol cord-stromal tumors of the testis with entrapped 1998;11:774–779. germ cells: a lesion mimicking unclassified 140. Augusto D, Leteurtre E, De La Taille A, et al. mixed germ cell sex cord-stromal tumors. Am J Calretinin: a valuable marker of normal and Surg Pathol 2000;24:535–542. neoplastic Leydig cells of the testis. Appl 126. Mikuz G, Schwarz S, Hopfel-Kreiner I, et al. Immunohistochem Mol Morphol 2002;10:159– Leydig cell tumor of the testis. Morphological 162. and endocrinological investigations in two cases. 141. Stewart CJ, Nandini CL, Richmond JA. Value of Eur Urol 1980;6:293–300. A103 (Melan-A) immunostaining in the differ- 127. Kim I, Young RH, Scully RE. Leydig cell tumors ential diagnosis of ovarian sex cord stromal of the testis. A clinicopathological analysis of 40 tumours. J Clin Pathol 2000;53:206–211. cases and review of the literature. Am J Surg 142. Yao DX, Soslow RA, Hedvat CV, et al. Melan-A Pathol 1985;9:177–192. (A103) and inhibin expression in ovarian neo- 128. Shimp WS, Schultz AL, Hastings JR, et al. Leydig- plasms. Appl Immunohistochem Mol Morphol cell tumor of the testis with gynecomastia and 2003;11:244–249. elevated estrogen levels. Am J Clin Pathol 1977; 143. McCluggage WG, Shanks JH, Whiteside C, et al. 67:562–566. Immunohistochemical study of testicular sex 129. Caldamone AA,Altebarmakian V,Frank IN, et al. cord-stromal tumors, including staining with Leydig cell tumor of testis. Urology 1979;14:39– anti-inhibin antibody. Am J Surg Pathol 1998;22: 43. 615–619. 130. Akman H, Ege G, Yildiz S, et al. Incidental bilat- 144. Wilson PO, Barber PC, Hamid QA, et al. The eral Leydig cell tumor of the testes. Urol Int immunolocalization of protein gene product 9.5 2003;71:316–318. using polyclonal and mouse monoclonal 131. Mahon FB, Jr., Gosset F, Trinity RG, et al. Malig- antibodies. Br J Exp Pathol 1988;69:91–104. nant interstitial cell testicular tumor. Cancer 145. Wu SM, Leschek EW,Rennert OM, et al. Luteiniz- 1973;31:1208–1212. ing hormone receptor mutations in disorders of 132. Grem JL, Robins HI, Wilson KS, et al. Metastatic sexual development and cancer.Front Biosci 2000; Leydig cell tumor of the testis. Report of three 5:D343–352. cases and review of the literature. Cancer 1986; 146. Liu G, Duranteau L, Carel JC, et al. Leydig-cell 58:2116–2119. tumors caused by an activating mutation of the 133. De Kretser DM. Crystals of Reinke in the nuclei gene encoding the luteinizing hormone receptor. of human testicular interstitial cells. Experientia N Engl J Med 1999;341:1731–1736. 1968;24:587–588. 147. Canto P,Soderlund D, Ramon G, et al. Mutational 134. Ulbright TM, Srigley JR, Hatzianastassiou DK, et analysis of the luteinizing hormone receptor al. Leydig cell tumors of the testis with unusual gene in two individuals with Leydig cell tumors. features: Adipose differentiation, calcification Am J Med Genet 2002;108:148–152. 330

Urological Cancers: Science and Treatment

148. Vieira TC, Cerutti JM, Dias da Silva MR, et al. Analysis of clinical and prognostic features. Urol Absence of activating mutations in the hot spots Int 2003;70:205–210. of the LH receptor and Gs-alpha genes in Leydig 164. Terayama K, Hirokawa M, Shimizu M, et al. cell tumors. J Endocrinol Invest 2002;25:598– Sertoli cell tumor of the testis. Report of a case 602. with imprint cytology findings. Acta Cytol 1998; 149. Wegner HE, Herbst H, Andresen R, et al. Leydig 42:1458–1460. cell tumor recurrence after enucleation. J Urol 165. McLaren K, Thomson D. Localization of S-100 1996;156:1443–1444. protein in a Leydig and of 150. Wegner HE, Dieckmann KP, Herbst H, et al. testis. Histopathology 1989;15:649–652. Leydig cell tumor—comparison of results of 166. Henley JD, Young RH, Ulbright TM. Malignant radical and testis-sparing surgery in a single Sertoli cell tumors of the testis: a study of 13 center. Urol Int 1997;59:170–173. examples of a neoplasm frequently misinter- 151. Masoudi JF, Van Arsdalen K, Rovner ES. Organ- preted as seminoma. Am J Surg Pathol 2002;26: sparing surgery for bilateral Leydig cell tumor of 541–550. the testis. Urology 1999;54:744. 167. Tetu B, Ro JY, Ayala AG. Large cell calcifying 152. Merlini E, Seymandi PL, Betta PG, et al. Testis Sertoli cell tumor of the testis. A clinicopatho- sparing enucleation of a Leydig-cell tumour in a logic, immunohistochemical, and ultrastructural boy. Pediatr Med Chir 2003;25:63–65. study of two cases.Am J Clin Pathol 1991;96:717– 153. Farkas LM, Szekely JG, Pusztai C, et al. High 722. frequency of metastatic Leydig cell testicular 168. Proppe KH, Scully RE. Large-cell calcifying tumours. Oncology 2000;59:118–121. Sertoli cell tumor of the testis. Am J Clin Pathol 154. Mosharafa AA, Foster RS, Bihrle R, et al. 1980;74:607–619. Does retroperitoneal lymph node dissection 169. Kratzer SS, Ulbright TM, Talerman A, et al. Large have a curative role for patients with sex cord- cell calcifying Sertoli cell tumor of the testis: stromal testicular tumors? Cancer 2003;98:753– contrasting features of six malignant and six 757. benign tumors and a review of the literature. Am 155. Bertram KA, Bratloff B, Hodges GF, et al. Treat- J Surg Pathol 1997;21:1271–1280. ment of malignant Leydig cell tumor. Cancer 170. Cano-Valdez AM, Chanona-Vilchis J, 1991;68:2324–2329. Dominguez-Malagon H. Large cell calcifying 156. Dieckmann KP, Loy V.Response of metastasized Sertoli cell tumor of the testis: a clinicopatho- sex cord gonadal stromal tumor of the testis to logical, immunohistochemical, and ultrastruc- cisplatin-based chemotherapy. J Urol 1994;151: tural study of two cases. Ultrastruct Pathol 1024–1026. 1999;23:259–265. 157. Wysocka B, Serkies K, Debniak J, et al. 171. Nogales FF, Andujar M, Zuluaga A, et al. Malig- Sertoli cell tumor in androgen insensitivity nant large cell calcifying Sertoli cell tumor of the syndrome—a case report. Gynecol Oncol 1999; testis. J Urol 1995;153:1935–1937. 75:480–483. 172. Bufo P,Pennella A, Serio G, et al. Malignant large 158. Rodewald A, Kittner T, Hahn G. The Carney cell calcifying Sertoli cell tumor of the testis complex: a rare differential diagnosis in cases (LCCSCTT). Report of a case in an elderly man with pituitary adenoma and testicular Sertoli cell and review of the literature. Pathologica 1999;91: tumour. Clin Radiol 2001;56:993–996. 107–114. 159. Liu P, Thorner P. Sonographic appearance of 173. De Raeve H, Schoonooghe P, Wibowo R, et al. Sertoli cell tumour: with pathologic correlation. Malignant large cell calcifying Sertoli cell tumor Pediatr Radiol 1993;23:127–128. of the testis. Pathol Res Pract 2003;199:113–117. 160. Gierke CL, King BF,Bostwick DG, et al. Large-cell 174. Anderson GA. Sclerosing Sertoli cell tumor of calcifying Sertoli cell tumor of the testis: appear- the testis: a distinct histological subtype. J Urol ance at sonography. AJR Am J Roentgenol 1994; 1995;154:1756–1758. 163:373–375. 175. Gravas S, Papadimitriou K, Kyriakidis A. Scle- 161. Young RH, Koelliker DD, Scully RE. Sertoli cell rosing Sertoli cell tumor of the testis—a case tumors of the testis, not otherwise specified: a report and review of the literature. Scand J Urol clinicopathologic analysis of 60 cases. Am J Surg Nephrol 1999;33:197–199. Pathol 1998;22:709–721. 176. Knoke I, Jakubiczka S, Ottersen T, et al. A(870)E 162. Chang B, Borer JG, Tan PE, et al. Large-cell calci- mutation of the androgen receptor gene in a fying Sertoli cell tumor of the testis: case report patient with complete androgen insensitivity and review of the literature. Urology 1998;52: syndrome and Sertoli cell tumor. Cancer Genet 520–522; discussion 522–523. Cytogenet 1997;98:139–141. 163. Giglio M, Medica M, De Rose AF, et al. Testicular 177. Ko HM, Chung JH, Lee JH, et al. Androgen re- Sertoli cell tumours and relative sub-types. ceptor gene mutation associated with complete 331

Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis

androgen insensitivity syndrome and Sertoli cell 179. Nonomura K, Koyama T, Kakizaki H, et al. adenoma. Int J Gynecol Pathol 2001;20:196–199. Testicular-sparing surgery for the prepubertal 178. Mene MP, Finkelstein LH, Manfrey SJ, et al. testicular tumor. Experience of two cases with Metastatic Sertoli cell carcinoma of the testis. large cell calcifying Sertoli cell tumors. Eur Urol J Am Osteopath Assoc 1996;96:612–614. 2001;40:699–704.