sign in sign up
<<
Home , Lipochrome, Mediastinum testis, Paradidymis, Sex cords, Spermiogenesis, Tunica vaginalis

TESTICULAR TUMORS: 1 GENERAL CONSIDERATIONS

Since the last quarter of the 20th century, , ANATOMY, great advances have been made in the feld of HISTOLOGY, AND PHYSIOLOGY testicular oncology. There is now effective treat- Several thorough reviews of the embryology ment for almost all testicular tumors (22–31), anatomy (22,25,32,33), and histology (which constitute the great majority of testicular (34–36) of the testis may be consulted for more ); prior to this era, seminoma was the detailed information about these topics. only histologic type of testicular tumor that Embryology could be effectively treated after metastases had developed. The studies of Skakkebaek and his The primordial and undifferentiated gonad is associates (1–9) established that most germ cell frst detectable at about 4 weeks of gestational tumors arise from morphologically distinctive, age when paired thickenings are identifed at intratubular malignant germ cells. These works either side of the midline, between the mes- support a common pathway for the different enteric root and the (fg. 1-1, types of germ cell tumors and reaffrms the ap- left). Genes that promote cellular proliferation proach to nomenclature of the World Health or impede play a role in the initial Organization (WHO) (10). We advocate the use development of these gonadal ridges, includ- of a modifed version of the WHO classifcation ing NR5A1 (SF-1), WT1, LHX1, IGFLR1, LHX9, of testicular germ cell tumors so that meaningful CBX2, and EMX2 (31). At the maximum point comparisons of clinical investigations can be of their development, the gonadal, or genital, made between different institutions. ridges extend from the sixth thoracic to the Cytogenetic and molecular studies have second sacral segments of the embryo. They provided new insights into possible relation- are covered by layers of proliferated coelomic ships between different morphologic types of epithelium (fg. 1-1, right). germ cell tumors (11–21) but, from a practical By 6 weeks of development, germ cells have viewpoint, careful gross evaluation and, even migrated into the developing gonad, following more so, sound light microscopic evaluation a pathway from their initial site of formation remain the bedrocks for the assessment of these in the caudal portion of the wall of the yolk tumors, although plays sac, close to the allantois, along the wall of the a signifcant role in specifc situations. Advances hindgut and the dorsal root of the mesentery, in the feld of sex cord-stromal tumors have and from there to the adjacent gonads (fg. 1- allowed recognition of several new variants 2). Such cells are distinctive and recognizable within that group of tumors (see chapter 6), by their high content of placental-like alkaline and a number of large clinicopathologic studies phosphatase (PLAP), expression of nuclear tran- have signifcantly increased the knowledge of scription factor OCT3/4 (POU5F1) and stage- a variety of miscellaneous primary neoplasms specifc antigen 1, and abundant cytoplasmic (see chapter 7), as well as of metastatic tumors glycogen. This migration is accomplished by and hematopoietic neoplasms. There is also a amoeboid movement of the germ cells, and de- better understanding of the diverse spectrum of pends, at least in part, on transforming growth neoplasms and tumor-like lesions that affect the factor-beta and the FOXC1 gene (37,38). It is paratestis, including morphologic variants that hypothesized that the occurrence of extrago- may lead to misinterpretations. nadal germ cell tumors is explained by the

1 Tumors of the Testis and Adjacent Structures

Figure 1-1 EMBRYOLOGY OF TESTIS Left: At 4 weeks of gestation, the genital ridges are apparent as mesenchymal condensations covered by coelomic epithelium that has proliferated. Right: At 6 weeks, there is ingrowth of the coelomic epithelium with extension into the to form the primitive . (Fig. 11-13 from Langman J. Medical embryology and human development—normal and abnormal, 2nd ed., Baltimore: Williams & Wilkins, 1969:164.)

Figure 1-2 EMBRYOLOGY OF TESTIS Left: At 3 weeks of gestation, the primordial germ cells form in the wall of the yolk sac. Right: At 6 weeks, the primordial germ cells migrate to the wall of the hindgut, along the dorsal mesenteric root, and into the genital ridges. (Fig. 11-14 from Langman J. Medical embryology and human development—normal and abnormal, 2nd ed., Baltimore: Williams & Wilkins, 1969:165.) aberrant midline migration of some germ cells At 6 to 7 weeks of gestation, the prolifer- to involve such sites as the pineal region, the ated coelomic epithelium on the surface of anterior mediastinum, the sacrococcygeal area, the migrates into the underlying and possibly, the retroperitoneum. mesenchyme to develop into the primitive sex

2 Testicular Tumors: General Considerations

Figure 1-3 EMBRYOLOGY OF TESTIS At 8 weeks of gestation, the albuginea surrounds the developing testis and the cords intermingle with at the hilum. (Fig. 11-15A from Langman J. Medical embryology and human development— normal and abnormal, 2nd ed. Baltimore: Williams & Wilkins, 1969:165.)

cords (fg. 1-1, right). The molecular signals for the medulla of the testis, forming the testis, or this process appear to involve several genes, in- medullary, cords. The testis cords are, therefore, cluding GATA4, ZFPM2, and WT1+KTS, which, composed of a dual population of cells: one de- in turn, activate the SRY gene on the Y chromo- rived from the primitive sex cords and destined some, a key event for the formation of Sertoli to form the Sertoli cells of the seminiferous tu- cells and the initial molecular difference in the bules, and the second representing the migrated development of a testis as opposed to an ovary. germ cells that become the spermatogonia of Subsequently, a longitudinal groove forms be- the testis. At this stage (day 42), the anlage of tween the gonadal ridge and the more lateral the is apparent at the periphery mesonephric body, resulting in a separation of of the embryonic testis as a layer of fattened these structures. At this point (approximately cells. With further development, the testis cords day 42), the developing testis becomes morpho- lose their original connection with the surface logically distinct from a developing ovary. epithelium and the tunica albuginea becomes SRY, also known as TDF (testis-determining better defned (fg. 1-3). factor), gene activation causes downstream acti- With the formation of distinct testis cords, a vation of SOX9, FGF9, and DAX1, which appear third cellular element of the developing testis to play roles in the differentiation of Sertoli cells becomes apparent as the interstitial component and their migration. This gene is also important occupying the area between the cords. The origin in the induction of the AMH (anti-müllerian of these interstitial (Leydig) cells is not entirely hormone, also known as müllerian-inhibiting clear, although a steroidogenic population of substance) gene in Sertoli cells, which produces cells appears to form along the anterior aspect of the hormone that causes regression of the mül- the mesonephros to supply both the gonad and lerian ductal system. The Sertoli cells aggregate adrenal gland, with segregation between the two around the primitive germ cells, incorporating organs perhaps mediated in part by the WNT4 them into solid tubular structures. Activation gene (31). Leydig cells become morphologically of several genes, including PDGFRA, DHH, distinct at about 8 weeks of development. They and ARX, contribute to this process and to are particularly prominent between the 4th and the formation of Leydig cells. With continued 6th months of gestation, only to regress follow- proliferation, the sex cords penetrate deep into ing birth and to reappear at puberty.

3 Tumors of the Testis and Adjacent Structures

Figure 1-4 EMBRYOLOGY OF TESTIS Left: By 4 months of gestation, the rete testis cords have merged with the epigenital tubules of the mesonephros. Right: Diagram of the mature testis after descent showing the relationship of various structures. (Fig. 11-18 from Langman J. Medical embryology and human development - normal and abnormal, 2nd ed. Baltimore: Williams & Wilkins, 1969:169.)

Near the hilum of the developing testis, the duce seminiferous tubules. These structures are, testis cords break up into a network of very in turn, invested by peritubular myoid cells. At small strands of cells that intermingle with this time, continuity is established between the mesonephric cells. The rete testis forms out of tubuli recti and the tubules of the rete testis. these components, although the contribution of The initially elongated confguration of the the sex cords and mesonephros to its structure developing testis becomes contracted to a more remains controversial (39). During subsequent adult-like ovoid form by about 8 weeks of ges- development, the rete testis cords merge with tation; at this time, the testis extends from the portions of the regressing mesonephric tubules, diaphragm to the site of the abdominal inguinal establishing the basis for the subsequent con- ring. During subsequent development, the testis tinuity between the seminiferous tubules and attains a position in the iliac fossa near the inter- the excretory duct of the mesonephros (wolffan nal inguinal ring until descent, which normally duct) (fg. 1-4). Continued growth of the testis begins at the 7th month. The excretory ducts of cords, now designated seminiferous cords, re- the testis develop as some of the mesonephric sults in a looped confguration, with the ends tubules (epigenital tubules) establish continuity of the loops developing into the narrow tubuli with the cords of the rete testis to become the recti. The seminiferous cords remain solid until efferent ductules (fg. 1-4). Just caudal to the ef- begins at puberty at which ferent ductules, the mesonephric, or wolffan, time lumens develop within the cords to pro- duct, under the trophic infuence of testosterone

4 Testicular Tumors: General Considerations

Figure 1-5 ANATOMY OF TESTIS Diagram of testicular anat- omy, with vestigial embryonic remnants. The appendix testis, the appendix , the aberrant ductules, and the para- didymis are seen. The efferent ductules of the epididymis bridge to the testis at the hilum. (Fig. 12- 1 from Bostwick DG. and testicular adnexa. In: Bostwick DG, Eble JN, eds. Urologic surgical . St. Louis: Mosby, 1997:648.)

produced by the fetal Leydig cells of the ipsi- factor, INSL3, without which there is impaired lateral testis, becomes briefy elongated and development of the (40). En- convoluted, forming thereby the body and tail largement of the caudal end of the gubernacu- of the epididymis, with the efferent ductules lum through mitotic activity and the generation forming the head (fg. 1-4, right). The remain- of hyaluronic acid (the “swelling reaction”) is ing portion of the forms the critical to testicular descent (41). As the testes vas (ductus) deferens. Vestigial remnants of the move caudally toward the embryonic scrotal cranial portion of the mesonephric duct may swellings, two outpouchings of the peritoneal persist as the appendix epididymis (fgs. 1-4, 1- cavity, the vaginal processes, protrude through 5). AMH, a glycoprotein produced by the fetal the into the twin scrotal sacs. Sertoli cells and a member of the transforming Both testes follow this pathway but remain growth factor-b superfamily of growth factors, retroperitoneal and localize within the . causes the müllerian (paramesonephric) duct Obliterative changes subsequently occur in the to regress by apoptosis as early as day 51. The upper portions of the vaginal processes, whereas action of AMH is unilateral on the side of its pro- the caudal-most portions of these processes con- duction. A small remnant of the müllerian duct tinue to invest the testes as the tunicae vaginalis. often persists on the anterior-superior surface of Incomplete obliteration of the processus vagi- the testis, near the head of the epididymis, as nalis permits intrascrotal leakage of peritoneal the appendix testis (fgs. 1-4, right; 1-5). fuid and the formation of a . The descent of the testis begins at about the Anatomy 7th month of gestation, at which time the go- nad occupies a retroperitoneal position in the The adult testis is normally located in one iliac fossa. In animal models, normal descent of two testicular compartments within the requires both an intact receptor as scrotum. It is ovoid, has an average weight of well as expression of an insulin-like growth 19 to 20 g (42), measures approximately 4.0

5 Tumors of the Testis and Adjacent Structures

Figure 1-6 ANATOMY OF TESTIS Cross sectional diagram of testicular anatomy at the level of the . The space between the parietal and visceral layers of the is accentuated. (Fig.8.38 from Romanes GJ, ed. Cunningham’s textbook of anatomy, 12th ed. Oxford: Oxford University Press, 1981:555.) to 5.0 x 2.5 x 3.0 cm, and is surrounded, over lobules separated by thin fbrous septa (fg. 1-7). most of its area, by a peritoneal sac, the tunica The terminal portions of the seminiferous tubules vaginalis. A small amount of serous fuid may empty into the tubuli recti (or straight tubules), be present in the space of the tunica vaginalis. which then connect with the tubules of the rete The tunica albuginea is a tough, fbrous coat- testis at the testicular hilum. Although a portion of ing that invests the testis; its external surface is the rete testis tubules intermingles with the struc- lined by the peritoneal-derived tures of the testicular parenchyma near the hilum, that constitutes the visceral layer of the tunica the majority of the rete testis is surrounded by an vaginalis (fg. 1-6). The epididymis is closely intratesticular extension of dense fbrous tissue applied to the testicular surface, with the epi- of the tunica albuginea at the testicular hilum; didymal head present superomedially and the this combination of rete testis and fbrous tissue tail posterolaterally (fg. 1-5). constitutes the mediastinum testis (fg. 1-6). The testicular parenchyma is homogeneous The rete testis tubules anastomose with 15 to and light tan, consisting of densely packed 20 efferent ductules (or ductuli efferentes), which seminiferous tubules arranged in poorly defned penetrate the tunica albuginea and coil to form

6 Testicular Tumors: General Considerations

Figure 1-8 VASCULAR SUPPLY OF TESTIS Schematic diagram of the arterial supply and venous drainage of the testis. See the text for details. (AE = anterior Figure 1-7 epididymal artery, AVD = artery of the , CB = centripetal artery branch, MV = mediastinal venous plexus, NORMAL GROSS APPEARANCE OF TESTIS PE = posterior epididymal artery, PP = pampiniform venous This normal testis from a prepubertal boy who had plexus, PV = peripheral veins, TA = testicular artery.) (Fig. 22- paratesticular rhabdomyosarcoma shows the usual light 2 from Wheeler JE. Anatomy, embryology and physiology tan appearance with poorly defned lobules. of the testis and its ducts. In: Hill GS, ed. Uropathology, New York: Churchill-Livingstone, 1989:937.) the head of the epididymis (fgs. 1-4, 1-5). These tubules are in continuity with the epididymal as the internal spermatic artery), which most duct of the body and tail, which in turn drains commonly originates from the aorta, slightly into the vas (ductus) deferens. The vas deferens inferior to the renal artery. It passes through exits the scrotum through the inguinal canal the inguinal ring with the other structures of as one of the structures of the spermatic cord. the spermatic cord. As the testicular artery ap- Vestigial tubular structures include the appendix proaches the testis, it gives off two branches to testis (fgs. 1-4, 1-5), derived from the regressed supply the head (the anterior epididymal artery) müllerian duct; the appendix epididymis (fgs. and the body and tail (the posterior epididymal 1-4, 1-5), derived from the cranial portion of the artery) of the epididymis, and often further sub- mesonephric duct; the ductuli aberrantes (vas divides into two or three branches to penetrate aberrans of Haller) (fg. 1-5), derived from me- the tunica albuginea of the posterior testis (fg. sonephric remnants; and the (fgs. 1-8). These branches then run along the surface 1-4, 1-5), derived from the caudal portion of the of the testis, giving off penetrating branches mesonephric tubules (the paragenital tubules). at intervals (centripetal arterial branches) to The major arterial supply to the testis is supply the testicular parenchyma (fg. 1-8). derived from the testicular artery (also known They cannot be visualized through the tunica

7 Tumors of the Testis and Adjacent Structures

albuginea, and, since there is a risk of vascular damage to the testis in performing testicular biopsies, these procedures are usually directed at the anterosuperior aspect of the testis, an area least likely to contain a surface arterial branch. The artery of the vas deferens provides a second source of blood to the testis. It is derived as a branch of the superior vesical artery, supplies the vas deferens, and may anastomose with the main testicular artery or the posterior epididy- mal branch of the testicular artery. The venous drainage of the testis occurs through a series of small veins that interconnect and exit the testis as four to eight branches at the mediastinum. Other small veins may run be- neath the tunica albuginea and connect with the venous branches at the mediastinum testis. These venous structures then form a convoluted mass of veins, the pampiniform plexus, which invests the testicular artery in the spermatic cord (fg. 1-8). Eventually, anastomoses occur and reduce the number of veins to one on the right side and one or two on the left side. The right testicular vein usually empties into the inferior vena cava slightly below the ostium of the right renal vein. The left testicular vein(s) most commonly drains into the left renal vein. The difference in the ve- Figure 1-9 nous drainage between the right and left testis, NORMAL HISTOLOGY OF ADULT TESTIS with increased hydrostatic pressure on the left Clusters of Leydig cells (lower, mid-right), small side due to its perpendicular anastomosis with vessels, and spindle-shaped stromal cells are present in the the renal vein, is a frequently cited explanation interstitium between seminiferous tubules, which show for the predominance of left-sided varicoceles active spermatogenesis with germ cells and Sertoli cells. when that disorder is unilateral. septa converge at the mediastinum. An average Histology testis is subdivided into 200 to 300 such lobules, The visceral layer of the tunica vaginalis with a total testicular content of 400 to 600 consists of a layer of fattened mesothelium seminiferous tubules, each 30- to 80-cm long. on a supporting basement membrane that is The estimated total combined length of the applied to the external aspect of the compact, seminiferous tubules in both testes is 300 to 980 sparsely cellular fbrous tissue of the tunica meters (43). Small blood vessels, lymphatics, albuginea. The densely collagenous portion of scattered macrophages, testosterone-producing the tunica albuginea is typically about 0.5-mm interstitial (Leydig) cells, and spindle-shaped thick in adults. Ducts, nerves, and vessels enter stromal cells are present between the seminifer- and exit the testis at its posterior aspect where ous tubules (fg. 1-9). the tunica albuginea is thickened and forms the Each is surrounded by mediastinum testis. The innermost aspect of the a thin layer of connective tissue and a well-de- tunica albuginea, the tunica vasculosa, consists fned basement membrane, which separate the of loose connective tissue containing vessels; seminiferous epithelium from the underlying this is continuous with the fbrous septa that connective tissue, the lamina propria of the tes- divide the testis into lobules containing one tis. Three to fve layers of fattened myoid cells to four convoluted seminiferous tubules. The in the lamina propria surround the tubules and

8 Testicular Tumors: General Considerations

Figure 1-10 NORMAL HISTOLOGY OF ADULT TESTIS At high magnifcation, a normal seminiferous tubule shows basally arranged spermatogonia and a patchy dis- Figure 1-11 tribution of Sertoli cells. The Sertoli cells have prominent SPERMATOGENESIS nucleoli (mid to lower left). There are primary with the characteristic meiotic ; and Different cell types in the seminiferous tubules during spermatozoa are seen near the lumen. different stages of spermatogenesis. Sertoli cells (Ser); type A spermatogonia (Ap and Ad); type B spermatogonia (B); primary spermatocytes in stages of meiosis (R = resting, L = promote movement of spermatozoa into the leptotene, Z = zygotene, P = pachytene, Di = diplotene, Sptc ductal system of the testis by contractile activ- Im = division); secondary spermatocytes (Sptc II); spermatids ity. The seminiferous epithelium is composed (Sa, Sb, Sc, and Sd), and residual bodies (RB). (Fig. 3 from Clermont Y. The cycle of the seminiferous epithelium in of two basic cell types: the Sertoli cells and the man. Am J Anat 1963;112:39.) various spermatogenic cells (fg. 1-10). Sertoli cells have an elongated, triangular contour and extend the entire thickness of the spermatogenic cells. A distinctive ultrastructural seminiferous epithelium, from the basement feature in human Sertoli cells of postpubertal membrane to the luminal surface (fg. 1-11). In subjects is the presence of long, spindle-shaped hematoxylin and eosin (H&E)-stained prepara- inclusions in the basal and perinuclear aspects tions, Sertoli cells have ill-defned, lightly eosin- of the , known as Charcot-Böttcher ophilic cytoplasm; nuclei with fne chromatin; flaments or inclusion bodies (fg. 1-13). Adja- and moderate-sized, round nucleoli. Notches cent Sertoli cells are joined by long tight junc- in the nuclear membrane are common (fg. tions where the membranes undergo fusion; 1-11) (44). Ultrastructurally, Sertoli cells have this resultant structure is considered to be re- extremely intricate cytoplasmic processes (fg. sponsible for the maintenance of a blood-testis 1-12) that completely surround the adjacent barrier (34). Lipid droplets and a well-developed

9 Tumors of the Testis and Adjacent Structures

Figure 1-12 Figure 1-13 SERTOLI CELLS SERTOLI CELLS Electron micrograph of Sertoli cells shows intricate, with prominent, juxtanuclear Charcot- interdigitating cytoplasmic processes. The cell at the bottom Böttcher flaments, cytoplasmic lipid droplets, and cisternae left has numerous lipid droplets and annulate lamellae. of smooth and rough endoplasmic reticulum. Inset: The characteristic parallel arrangement of Charcot-Böttcher flaments is shown. smooth endoplasmic reticulum are consistent with the steroid hormone synthesizing capac- ity of Sertoli cells (fg. 1-13). Sertoli cells, in nuclear membrane, fnely granular chromatin, addition to providing a “nurturing” function and generally pale cytoplasm (fg. 1-11). Type B for the maturing germ cell population, are also spermatogonia have a more rounded nucleus, phagocytic and may contain fragments of de- clumps of peripheral nuclear chromatin, and a generated germ cells. single central nucleolus (fg. 1-11) (44). The spermatogonia are the frst cells of sper- The primary spermatocytes are tetraploid matogenesis and occupy a basal position in the cells that occupy the cell layers just luminal to seminiferous tubules, adjacent to the basement the basal layer of spermatogonia and participate membrane. Two types of spermatogonia are in meiotic division to give rise to the distinctive, described: type A cells, which serve as self- flamentous chromatin patterns of a prolonged renewing stem cells, and type B cells, which prophase (fg. 1-11). The product of the frst are derived from the mitotic division of type meiotic division of a primary is A spermatogonia but which later differentiate, the secondary spermatocyte, which contains a after additional mitotic divisions, to more ma- diploid amount of DNA but a haploid number of ture spermatogenic cells, primary spermatocytes chromosomes. These cells are rarely observed in (44). Type A spermatogonia have an ovoid sections because they rapidly undergo a second nucleus, one or two nucleoli adjacent to the meiotic division to form the haploid spermatids,

10 Testicular Tumors: General Considerations

the early forms of which they closely resemble. The early is recognized on the lumi- nal aspect of the primary spermatocyte layer as a round cell with fnely granular, pale chromatin and a nuclear diameter of about 6 µm (fg. 1-11). Spermatids gradually transform, in the process of , into spermatozoa as the nuclear chromatin condenses and the nucleus becomes oval to pear-shaped (fg. 1-11). A given cross section of a seminiferous tubule may not show complete spermatogenesis because of a wave-like pattern of maturation that occurs within the seminiferous tubules. Examination of many cross sections is therefore necessary before a conclusion concerning pathologic maturation arrest is indicated, and, indeed, some investigators conclude that “maturation arrest” is actually an artifact of this pattern in patients with hypospermatogenesis (45). The interstitium of the testis comprises the space between the seminiferous tubules, and is occupied by blood vessels, lymphatics, loose connective tissue with fbrocytes, mast cells, peritubular myoid cells, and Leydig cells. Leydig cells are normally few in number from just after the neonatal period to puberty, at which time they proliferate and become numerous. Leydig Figure 1-14 cells characteristically occur in clusters and vary LEYDIG CELLS from round or polygonal to ovoid. They have Leydig cells are clustered in the testicular interstitium. a round nucleus with a central nucleolus and Round, eccentrically placed nuclei; round nucleoli; and eosinophilic, sometimes vacuolated, cytoplasm abundant eosinophilic cytoplasm are seen. There are rod- that, in postpubertal patients, often contains shaped, intracytoplasmic Reinke crystals with surrounding retraction artifact (center). lipochrome pigment or Reinke crystals. The latter are intracytoplasmic rod-shaped crystals measuring up to 20 µm (fg. 1-14). They have the interstitium between seminiferous tubules, characteristic geometric confgurations on ultra- Leydig cells may also be seen in the testicular structural examination (fg. 1-15) and contain mediastinum, within the tunica albuginea, and proteins and glycosylated proteins, but their in the paratesticular soft tissues, including those precise functional signifcance, if any, remains associated with the epididymis and vas deferens. unclear. Immunohistochemical study has local- Such “ectopic” Leydig cells are often associated ized nestin, an intermediate flament protein with small nerves (fg. 1-16) (47). expressed in non-neoplastic stem cells and The straight tubules (tubuli recti) are lined by embryonic cells of mesenchymal and neuroec- cuboidal epithelium and lack the Sertoli cells todermal lineage, to Reinke crystals (46). Large characteristic of the seminiferous tubules. They numbers of vesicles of smooth endoplasmic run a short distance to empty into the branching reticulum, mitochondria with tubular cristae, channels of the rete testis, which, for the most and lipid droplets, all of which are character- part, are invested by the dense connective tissue istics of steroid hormone-producing cells, oc- of the mediastinum testis (fg. 1-17), although cupy the cytoplasm of Leydig cells (fg. 1-15). occasional tubules of the rete testis are present Leydig cells synthesize testosterone and other among the seminiferous tubules adjacent to steroid hormones. In addition to occurring in the testicular mediastinum. The tubules of the

11 Tumors of the Testis and Adjacent Structures

Figure 1-15 Figure 1-16 LEYDIG CELLS LEYDIG CELLS A cluster of Leydig cells shows prominent vesicles of Clusters of Leydig cells are present in the paratesticular smooth endoplasmic reticulum, lipid droplets, lysosomes, soft tissues associated with small nerves. This is a normal and characteristic geometric patterns of Reinke crystals. fnding. Inset: Striking periodicity of the Reinke crystals.

Figure 1-17 RETE TESTIS Branching tubules of the rete testis are set in the dense, hypocellular, fbrous stroma of the mediastinum testis.

12 Testicular Tumors: General Considerations

Figure 1-18 EPIDIDYMIS The efferent ductules (left) have an undulating luminal surface unlike the straight luminal border of the epididymal tubules (right).

rete testis are lined by epithelium varying from cells (the principal cells) with elongated nuclei. cuboidal to columnar, with frequently grooved Unlike the efferent ductules, the epididymal nuclei. Occasional tufts of the underlying con- tubules have a smooth luminal surface that is nective tissue of the mediastinum testis project punctuated by long stereocilia (fg. 1-19, left), as epithelial-lined papillae into the lumens of long branching microvilli that are artifactually the rete testis and are known as the chordae aggregated in routine histologic preparations. retis. The tubules of the rete testis empty into A few concentrically arranged smooth muscle the efferent ductules, groups of 8 to12 tubular cells invest this highly convoluted epididymal channels that are interposed between the rete duct. Cribriform arrangements of the epithe- testis and the epididymal tubules (fg. 1-18). lium may sometimes occur (fg. 1-20). Periodic These structures comprise part of the head of the acid–Schiff (PAS)-positive intranuclear inclu- epididymis and are lined by pseudostratifed, sions are present in the principal cells as well columnar epithelium with foci of interspersed as the epithelium of the vasa deferentia and cuboidal epithelium, a pattern that produces a . Other fndings in the normal characteristic undulating luminal surface. Intra- epididymis include cytoplasmic cytoplasmic lipofuscin occurs in the epithelium granules, foci of Paneth cell-like (fg. of the efferent ductules. A small amount of 1-21), intranuclear cytoplasmic inclusions, and circular smooth muscle is closely applied to the focal moderate to severe nuclear atypia (fg 1-19, basal aspect of the epithelium of the efferent right) (48–50). ductules, separated from it only by a basement The epididymal duct in turn joins the vas membrane and scant connective tissue. deferens at the tail of the epididymis. The epithe- The efferent ductules empty into a highly lium of the vas deferens is similar to that of the convoluted tubule, the ductus epididymis, epididymal duct, and stereocilia are visible along which forms the body and tail of the epi- its luminal surface. Three thick layers of smooth didymis. Cross sections of the convoluted muscle comprise the wall of the vas deferens: an epididymal duct produce multiple profiles innermost longitudinally oriented layer, a middle often referred to as epididymal tubules. These circular layer, and an outermost longitudinal epididymal tubules are lined by two layers of layer. These are applied closely to the epithelium cells: a basal layer of smaller cells with spheri- of the vas deferens, with only a thin layer of cal nuclei and a luminal layer of tall columnar connective tissue separating them.

13 Tumors of the Testis and Adjacent Structures

Figure 1-19 EPIDIDYMIS Left: Epididymal tubules are lined by an innermost layer of tall columnar cells with luminal stereocilia and a much less conspicuous layer of basal cells. Right: There is focal nuclear atypia, a normal variant.

Figure 1-20 EPIDIDYMIS The epithelium is arranged in a cribriform pattern, a normal variant.

14 Testicular Tumors: General Considerations

Testosterone is the principal androgenic hor- mone produced by the Leydig cells, although it often undergoes conversion to a more tran- scriptionally active form, dihydrotestosterone, in certain target cells. LH stimulates testosterone production and release from Leydig cells, and circulating testosterone and other provide negative feedback for LH secretion from the pituitary gland. In addition to AMH and ABP, Sertoli cells also secrete inhibins (inhibin A and inhibin B) which inhibit FSH secretion from the pituitary gland. Activins are related proteins formed by hetero and homo dimerization of the beta subunits found in inhibin A and inhibin B, and have a stimulatory effect on FSH secretion. Sertoli cells also contain aromatase, an enzyme that converts androgens to estrogens and is respon- sible for the estrogenic manifestations of some Sertoli cell neoplasms. It is common for testicular germ cell tumors with a component of syncytiotrophoblast cells to produce human chorionic gonadotropin (hCG). hCG has LH-like and thyroid-stimulat- ing hormone (TSH)-like activity. It therefore stimulates Leydig cells to proliferate and secrete testosterone, which is converted to estrogen in adipose tissue, resulting in gynecomastia in Figure 1-21 some cases. TSH-like activity may result in thy- EPIDIDYMIS roid gland and thyrotoxicosis. The epithelial cells show Paneth-cell-like change, a CLASSIFICATION normal variant. Table 1-1 provides a classifcation of testicu- lar neoplasms and non-neoplastic lesions that Physiology may, either clinically or pathologically, mimic Testicular function is under the control of a neoplasms. The classifcation of testicular germ number of hormones. Gonadotropin-releasing cell tumors used in this text is a modifcation hormone (GnRH), secreted by the hypothala- of the WHO classifcation, which, in turn, is mus, stimulates the secretion of follicle-stimu- derived largely from the work of Friedman and lating hormone (FSH) and luteinizing hormone Moore (51), Dixon and Moore (52,53), Melicow (LH) from the anterior pituitary gland. FSH, (54), and Mostof and Price (55). The funda- in turn, causes the Sertoli cells to release an- mental tenet of this classifcation is that all of drogen-binding protein (ABP), leading to high the different morphologic types of germ cell levels of androgen in the fuid of the seminif- tumors are derived from neoplastic germ cells erous tubules. Local androgen then acts upon that differentiate along various pathways. The the Sertoli cells, permitting the maturation of close association of virtually all of the morpho- spermatids embedded within their cytoplasm logic types of germ cell tumors (except for sper- to spermatozoa. FSH also acts directly on Sertoli matocytic seminoma and specialized forms of cells to aid in this maturation. It appears that teratoma [dermoid , carcinoid tumor]) with the progression of spermatogonia to spermatids the lesion designated “intratubular germ cell is androgen independent. neoplasia, unclassifed” (see chapter 2), provides

15