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1 14 - NATURAL HISTORY OF UNDESCENDED TESTES Formatted: Numbering: Continuous

2 1. INTRODUCTION
3 2. ETIOLOGY OF UNDESCENDED TESTES
4 3. UNDESCENDED TESTES LESIONS IN CHILDHOOD. A PROPOSAL FOR
5 MORPHOLOGIC CLASSIFICATION
6 4. UNDESCENDED TESTES LESIONS AT PUBERTAL AGE
7 5. UNDESCENDED TESTES LESIONS IN POST-PUBERTAL AGES
8 6. VALIDATION OF THE MORPHOLOGIC CLASSIFICATION OF PREPUBERTAL
9 UNDESCENDED TESTES LESIONS
10 7. EFFECTIVENESS OF TREATMENTS IN UNDESCENDED TESTES
11 8. CONGENITAL ANOMALIES ASSOCIATED WITH UNDESCENDED TESTES
12 8 a. Caudal regression syndrome
13 8 b. Prune-belly syndrome or Eagle-Barrett syndrome
14 8 c. CHARGE syndrome
15 9. CRYPTORCHIDISM ASSOCIATED WITH MALFORMATIVE OR
16 ENDOCRINOLOGICAL SYNDROMES
17 10. COMPLICATIONS OF CRYPTORCHIDISM
18 10 a. Testicular cancer
19 10 b. Infertility
20 11 RETRACTILE TESTES
21 12 TESTICULAR DYSGENESIS SYNDROME
22

23 Cryptorchidism is one of the most frequent problems encountered in pediatric


24 urology. Its etiology, associated lesions and prognosis in terms of fertility have
25 been a source of interest and discrepancies for pediatric pathologists and
26 urological surgeons.
27

28 Keywords: Cryptorchidism, Retractile testes, Testicular dysgenesis, Mixed


29 Atrophy of Testes (MAT).
30

31 1. INTRODUCTION
32 Failure in testicular descent is among the most frequent congenital
33 disorders in newborns. Testicular descent is not always complete at birth.
34 Between four and five percent of newborns have incompletely-descended testes.
35 This percentage is higher in premature newborns, reaching 100% in those
36 weighing less than 900 g at birth (1, 2). Testes usually descend in the first three
37 months of postnatal life, and by the age of one only 0.96 to 1.58% of testes
38 remain undescended. After the first year of life, spontaneous descent is
39 exceptional. The incidence of cryptorchidism seems to have risen in recent
40 years, with the last reported figures around 1.8% of all boys (3, 4).
41 The first item to address when an infant presents with an empty scrotum is
42 whether or not a testis exists, and if it does, where it is located. About five
43 percent of patients presenting with no palpable testis indeed have no testis. The
44 remaining cases can be classified in one of the following categories: true
45 cryptorchidism, testicular ectopia, and retractile testes (5).
46 “True cryptorchidism” defines testes that cannot be moved into the
47 scrotum during physical exploration. They may be located in the abdomen,
48 inguinal duct, or high in the scrotum (6).
49 Ectopic testes are located outside the normal pathway of testicular
50 descent. This group includes the classic ectopies: interstitial (superficial
51 inguinal), femoral (crural), perineal, transverse (crossed testicular ectopia), pubo-
52 penile, pelvic, and other more rare ectopies such as testes in the abdominal wall.
53 (See Chapter 9 Alterations in Number and Location)
54 Retractile testes represent between one-fourth and one-third of testes
55 clinically diagnosed as undescended testes. Retractile testes can be mobilized to
56 the bottom of the scrotum with adequate gentle manipulation.
57 True cryptorchidism represents about 25% of the patients consulting for an
58 empty scrotum. Canalicular (inguinal canal) and high scrotal cryptorchid testes
59 are more common than those with intra-abdominal locations. The latter are found
60 in only five to ten percent of cases. The right side is slightly more frequently
61 involved than the left. In about 18% of cases, cryptorchidism is bilateral.
62 Approximately 14% of cryptorchid patients have a family history of cryptorchidism
63 (7, 8).

64 From an epidemiological viewpoint, the risk of cryptorchidism increases in


65 seemingly disparate situations. These include increased maternal age, maternal
66 obesity, toxemia of pregnancy, alcohol consumption, late pregnancy bleeding,
67 exposure to endocrine-disrupting chemicals during fetal development (9, 10),
68 smoking during pregnancy, high maternal stature, history of subfertility, birth by
69 cesarean section, low weight at birth, prematurity, twinning, intrauterine growth
70 restriction (11), hypospadias (12), other congenital malformations, and births
71 occurring between September and November or during May and June (13, 14).
72 The highest risk is associated with low weight at birth (15). In children, the most
73 common methods for the diagnosis of cryptorchidism are physical examination
74 and surgical evaluation. The value of ultrasonography is controversial (16, 17).
75

76 2. ETIOLOGY OF UNDESCENDED TESTES


77 The causes of testicular maldescent are probably multiple and have not
78 been completely elucidated (see Chapter 2 Factors Involved in Testicular
79 Descent). There are two types of cryptorchidism: congenital and acquired.
80 Congenital cryptorchidism may be due to hormonal dysfunction involving
81 testosterone, anti-müllerian hormone (AMH), epidermal growth factor (EGF) and
82 estrogens. Mechanical causes include anatomical anomalies of the
83 gubernaculum, insufficient abdominal pressure, short spermatic cord,
84 underdeveloped vaginal process, and maldeveloped epididymis. Neuromuscular
85 causes include abnormalities in the calcitonin gene-related peptide (CGRP) and
86 the cremaster nucleus. Genetic causes are mutations in the insulin-like factor 3
87 or its receptor (18). Other hereditary (19, 20) or acquired conditions may produce
88 cryptorchidism.
89 In most cases, cryptorchidism is due to a deficit of fetal androgens or an
90 excess of maternal estrogens. Fetal androgen deficit seems to occur during the
91 second and third trimesters of gestation and is caused by either deficient pituitary
92 gonadotropic stimulation or low placental gonadotropins. Androgen insufficiency
93 seems to be slight and transient, because genital anomalies other than abnormal
94 epididymis growth (21) have been observed. In addition, no alterations on the
95 androgen-regulating gene have been found (22). Elevated levels of maternal
96 estrogens might induce feedback inhibition of follicle stimulating hormone (FSH)
97 by the fetal pituitary. This results in low Sertoli cell proliferation (23), and possibly
98 decreased testosterone production due to inhibitory effects of estrogens on
99 Leydig cells (24).
100 Unilateral cryptorchidism would be explained on the basis of androgenic
101 failure, causing either an ipsilateral anomaly in the development of genito-femoral
102 nerve neurons, or a defect in calcitonin gene-related peptide (CGRP) release
103 which would interfere with the normal migration of the gubernaculum (25).
104 The term “acquired cryptorchidism” refers to descended scrotal testes that,
105 during postnatal life, can ascend and be lodged even in the abdominal cavity (26).
106 This is seen in 1.5% of prepubertal boys (27). Two types of acquired
107 undescended testes have been considered: a) the so-called postoperative
108 “trapped testis” (28) is a normally-descended testis that “escapes” from the
109 scrotum after surgery for inguinal hernia or hydrocele (29-31). This iatrogenic
110 complication may occur in 1.2% of children who undergo hernia repair. An
111 adherence of the testis or the cremaster muscle to the surgically-incised zone
112 causes upward displacement of the testis by myofibroblastic contraction during
113 wound healing. b) The spontaneously-ascended testis. This is considered a late
114 manifestation of congenital cryptorchidism, and has been explained by the “yo-
115 yo” model (32).
116 At birth, a 4-5 cm long spermatic cord allows the testis to become scrotal
117 (descended). As the boy grows, if the spermatic cord does not elongate up to 8-
118 10 cm, the testis ascends again, attaining a high or completely inguinal location
119 around three to six years of age. At puberty, the testosterone effect will cause
120 elongation of the spermatic cord and spontaneous descent of the testis in 77.5%
121 of the cases (33).
122 The etiology of spontaneously-ascended testis is not known but several
123 hypotheses have been proposed. Failure in postnatal spermatic cord elongation
124 is one cause (34-36). This elongation cannot take place if the peritoneo-vaginal
125 duct has become a fibrous remnant (37). Another defect is in the postnatal
126 release of CGRP by the genito-femoral nerve (38). Still other causes include
127 inadequate growth of spermatic vessels (39), failure in reabsorption of the vaginal
128 process (40), permanent spasm of the cremaster muscle (41), abnormal insertion
129 of the gubernaculum (42), and deficient or decreased androgen activity (43).
130

131 2. LESIONS OF UNDESCENDED TESTES IN CHILDHOOD.


132 A PROPOSAL FOR MORPHOLOGIC CLASSIFICATION
133 No functional studies exist to assess the presence and severity of
134 congenital lesions in cryptorchid testes. Histological study is necessary to
135 evaluate damage of the testicular parenchyma in cryptorchidism. We must keep
136 in mind that the testis is a dynamic structure with waves of proliferation and
137 differentiation from birth to puberty (see Chapter 3). Testicular volume increases
138 40-fold by the end of puberty. Measuring approximately 0.5 ml at birth, the testis
139 grows slowly to about 0.6 ml by three years of age and about 1-2 ml in
140 prepubertal boys. Growth then accelerates, reaching 20 ml at puberty.
141 Undescended testes have slower growth and reduced volume, noticeable from
142 six months of age (44) (Fig 1).
143 The parameters usually applied to study adult testicular parenchyma
144 should not be used for prepubertal testes (45). In order to maximize the value of
145 histological assessment of undescended testes, we need to apply both
146 semiquantitative and qualitative parameters. Semiquantitative morphometric
147 parameters include: mean tubular diameter (MTD); tubular fertility index (TFI);
148 number of germ cells per cross-sectioned tubule; Sertoli cell index (SCI); and
149 number of interstitial cells of Leydig. Qualitative findings include: the pattern
150 (regular or irregular) of germ cell distribution within testicular parenchyma;
151 presence of abnormal spermatogonia (multinucleated, hypertrophic and/or
152 atypical) and gonocytes; focal granular changes in Sertoli cells; abnormal tubules
153 (megatubules, ring-shaped tubules); microliths; and androgen receptors in
154 children older than four years of age.
155 Most cryptorchid testes develop lesions in the first year of life, supporting
156 the notion of a primary origin rather than being acquired due to long-standing
157 cryptorchidism. These patients fail to undergo the so-called “minipuberty” which
158 is characterized by increased pituitary gonadotropins and a testosterone peak
159 between three and six months of age (46). This lack of hormonal stimulation has
160 four important consequences: 1) an incomplete migration of gonocytes and fetal
161 spermatogonia from the center of the seminiferous tubules to the periphery
162 where they are to lay over the basal membrane; 2) defective transformation of
163 gonocytes into A dark spermatogonia (Ad); 3) persistence of gonocytes after the
164 first year of life; and, 4) failure of primary spermatocytes to appear by three to
165 four years of age (47).
166 The most frequent histological findings during infancy, in both congenital
167 and acquired cryptorchidism, are decreased germ cell number and reduction in
168 tubular diameter (48). Based on four parameters (TFI, MTD, SCI and the
169 spermatogonial distribution pattern), most testicular biopsies from cryptorchid
170 testes in children less than four years of age can be classified in three types.
171 Type I: testes with slight alterations (31% of undescended testes) (Fig 2).
172 Type II: testes with marked germinal hypoplasia (29%) (Fig 3).
173 Type III: testes with severe germinal hypoplasia (40%) (49) (Figs 4 and 5)
174 (Table 1).
175 About eight percent of testes with type I lesions show many multinucleated
176 spermatogonia (with three or more nuclei) (50) (Figs 6 and 7) and persistent
177 expression of CD117 (c-Kit) and placental alkaline phosphatase (PLAP) in about
178 five percent of immature germ cells. Seminiferous tubules of testes with type II or
179 III lesions show thickened lamina propria during childhood and Sertoli cell
180 hyperplasia at puberty. More than 30% of these testes have microliths (Fig 8),
181 ring-shaped tubules (Fig 9), and granular change in Sertoli cells (Figs 10 and 11).
182 Type I lesions are comparable to those in experimental cryptorchidism, and also
183 in normal testes with lesions induced by increased temperature (51).
184 Patients with bilateral cryptorchidism have a higher incidence of type II
185 and III lesions compared to those with unilateral cryptorchidism. Bilateral
186 cryptorchid testes feature variable abnormalities that, in addition to germ cells,
187 involve Sertoli cells, peritubular myofibroblasts, and Leydig cells. These lesions
188 become evident only after puberty (52), and are more severe in intra-abdominal
189 testes (53).
190 In unilateral cryptorchidism, the contralateral scrotal testis also displays
191 histologic lesions of variable severity, with an incidence ranging from 23 to 60%.
192 These lesions are usually less severe in the scrotal than in the contralateral
193 cryptorchid testis, but may also be similar or even more severe. These findings
194 support the hypothesis of a bilateral defect in many cases of unilateral
195 cryptorchidism.
196 Microdeletions in the long arm of the Y chromosome, including the DAZ,
197 RBM, and AZF a, b, and c genes, are not increased in cryptorchidism (54).
198 In cryptorchid testes that undergo spontaneous ascent, lesions develop
199 later and are similar to those found in congenital cryptorchidism (55). Patients
200 with cryptorchidism following herniotomy show less decrease of germ cell
201 number (56). This is only evident after the age of five years (57).
202

203 4. LESIONS OF UNDESCENDED TESTES AT PUBERTY.


204 During puberty, undescended testes have a severe maturation delay in
205 both tubular and interstitial components (58). Seminiferous tubules display an
206 apparent Sertoli cell hyperplasia per cross-sectioned tubule. This results from a
207 failure in lengthening and coiling of seminiferous tubules during pubertal
208 development (Fig 12). They also show decreased diameters, and when germ
209 cells are present, they have delayed proliferation. Frequently, as puberty
210 progresses, testicular development is irregular, varying from one testicular lobule
211 to another (Fig 13). Seminiferous tubules that have initiated spermatogenesis are
212 adjacent to others showing a prepubertal maturation pattern. Careful study
213 reveals delay in Sertoli cell maturation as estimated by nuclear morphology.
214 Irregular expression of androgen receptors in these Sertoli cells has been
215 detected by immunohistochemical methods (59) (Fig 14). Tubules with
216 prepubertal pattern also show delayed maturation of myofibroblasts which are
217 unable to express muscle specific actin (Fig 15). The interstitium appears
218 progressively more fibrotic (Figs 16 and 17).
219

220 5. LESIONS OF UNDESCENDED TESTES IN POST-PUBERTAL AGES


221 Histological analyses of most cryptorchid testes from adults reveal lesions
222 in all their structural components, including rete testis and epididymis.
223 Seminiferous tubules have reduced diameters and deficient spermatogenesis.
224 The most frequent germ cell pattern is spermatogonial maturation arrest (Fig 18).
225 This is followed by Sertoli-cell-only tubules with dysgenetic Sertoli cells (Fig 19),
226 mixed atrophy (Fig 20) and diffuse tubular sclerosis (Fig 21).
227 Nuclei of Sertoli cells are normal only in tubules with advanced
228 spermatogenesis (60). Dysgenetic Sertoli cells within Sertoli-cell-only tubules
229 show positive immunostaining for vimentin (similar to normal adult Sertoli cells).
230 They may also express cytokeratins and desmin in the basal cytoplasm. This
231 staining pattern is also seen in intraluminal aggregates of sloughed Sertoli cells
232 (61).

233 The tubular wall has decreased elastic fibers (62) (Fig 22). Increased
234 collagenization, irregular deposits of collagen IV (Fig 23) and laminin are found
235 in the basal lamina (52). In experimental cryptorchidism, peritubular myoid cells
236 have disorganized actin filaments (63).
237 Undescended testes removed from adults often present straight or slightly
238 coiled tubules with frequent branching (Fig 24). These testes also have
239 hypoplastic tubules with a small lumen and thick wall, lined by a tall columnar
240 epithelium formed only by Sertoli cells of eosinophilic cytoplasm (Fig 25). Other
241 abnormalities in cryptorchid adult testes include Sertoli cells nodules (Fig 26)
242 (see Chapter 11), seminiferous tubules with granular changes in Sertoli cells (Fig
243 27), and Leydig cell hyperplasia (Fig 28). Interstitial Leydig cells often contain
244 cytoplasmic vacuoles; their number is truly increased in some cases, and only
245 apparently increased in others. Testicular parenchyma adjacent to the rete testis
246 often has foci of adipose metaplasia.
247 Most cryptorchid testes, especially those with Sertoli-cell-only tubules,
248 show an underdeveloped rete testis. The epithelium has not differentiated into
249 squamous and columnar cells (as is normal in puberty). The epithelium retains
250 an infantile pattern (64). This has been called “dysgenetic rete testis”. Other rete
251 testis anomalies are frequent, including hypoplasia, cystic hypoplasia and
252 adenomatous hyperplasia (65) (Fig 29).
253 Biopsies and fine-needle aspiration studies of the normally-descended
254 contralateral testis (66) show a variety of histological patterns from normal to
255 alterations similar to those of cryptorchid testes (Figs 30 and 31). This variability
256 is probably related to the cause of cryptorchidism. Bilateral lesions suggest a
257 congenital or genetic cause, whereas normal contralateral testes suggest local
258 anatomical abnormalities (67).
259

260 6. VALIDATION OF MORPHOLOGIC CLASSIFICATION OF PREPUBERTAL


261 LESIONS IN UNDESCENDED TESTES
262 In institutions with a large number of pediatric and adult testicular biopsies,
263 it is possible to compare histologic findings in bilateral testicular biopsies taken at
264 orchidopexy from cryptorchid children, with those obtained from the same
265 patients at adulthood performed for evaluation of infertility. In a series of 21 such
266 patients (68), more than two-thirds of testes with higher tubular fertility index
267 (normal testes and those with type I lesions) revealed diffuse and complete
268 spermatogenesis, although they showed quantitatively abnormal germ cell
269 numbers (Fig 32). The remaining cases developed mixed atrophy of the testis
270 (MAT) (69). MAT is defined as the synchronous occurrence of tubules containing
271 germ cells (with variable degrees of spermatogenesis) and Sertoli-cell-only
272 tubules (Fig 33). All testes with type II lesions and 85% of those with type III
273 lesions developed MAT, leading us to conclude that MAT is the most frequent
274 lesion (68.29%) in adult excryptorchid patients presenting with infertility (Table 2).
275 In most patients with unilateral cryptorchidism, MAT was observed in both
276 undescended testis and contralateral descended testis, even if the surgical
277 correction occurred at an early age. An inverse correlation was found between
278 the severity of the testicular lesions in childhood and the amount of
279 spermatogenesis in adulthood. About 85% of adult testes with type III lesions in
280 infancy developed MAT with spermatogenesis in less than 50% of tubules.
281 Another five percent of these testes showed hypospermatogenesis plus
282 spermatocyte I sloughing (Fig 34); around ten percent presented Sertoli-cell-only
283 tubules throughout the testis (Fig 35). Prepubertal testes with clustering of germ
284 cell-containing tubules usually have incomplete spermatogenesis in adulthood
285 and, if this was complete, it occurred in less than 50% of tubules (68).
286 Anomalies of the sperm excretory ducts occur in 9 to 36% of cryptorchid
287 patients (70, 71) (Fig 36). Since these anomalies can cause obstruction of the
288 excretory ducts, testicular biopsies can also reveal an obstructive pattern
289 superimposed on the seminiferous tubule lesions (Fig 32).
290 In summary, the classification of childhood testicular lesions into types I, II
291 and III correlates with the amount of spermatogenesis in post-pubertal biopsies.
292 The most important parameter is TFI. Spermatogenesis can also be impaired by
293 a complete or incomplete, functional or organic, obstructive process. Testicular
294 biopsy not only allows an adequate evaluation of congenital or obstructive
295 lesions, but also identifies testes with focal spermatogenesis. This opens the
296 possibility of assisted reproduction.
297

298 7. EFFECTIVENESS OF TREATMENTS IN UNDESCENDED TESTES


299 Identifying the best treatment for congenital undescended testes has been
300 a matter of debate for decades. The consensus is that surgical treatment is
301 mandatory in cryptorchid infants. In patients with palpable inguinal cryptorchid
302 testes, orchidopexy should be performed within the first year of life, and no later
303 than 18 months of age. This recommendation, issued by the European
304 Association of Urology (72), is supported by several studies (73-76). The Nordic
305 Consensus recommends anticipating orchidopexy as early as the first 6-12
306 months of life (77). Surgical treatment benefits all cases of primary cryptorchidism
307 and also retractile testis, even in children whose testes were surgically
308 descended at a more advanced age (78).
309 The efficacy of hormonal treatments following orchidopexy is still
310 controversial. Results are contradictory and great variations have been reported.
311 While human chorionic gonadotropin (hCG) and gonadotropin-releasing hormone
312 (GnRH) treatments have been effective in some cases of cryptorchidism (77, 79),
313 they have been useless in others (46, 80). A recent meta-analysis has shown that
314 about 15 to 20% of cryptorchid testes descend during hormonal treatment,
315 although one-fifth of these re-ascend later. Furthermore, treatment with hCG
316 increases germ cell apoptosis, with subsequent damage to future
317 spermatogenesis (77). Histology seems to be the safer guide to clarify this
318 controversy. Biopsy is the only method to identify cryptorchid boys who need
319 treatment with luteinizing hormone-releasing hormone (LH-RH) following
320 successful surgery. Consequently, some authors propose that biopsy should be
321 performed routinely during orchidopexy (81). Neonatal gonocytes transform into
322 type A spermatogonia at 3–12 months. This process is disrupted in
323 undescended testes, but orchidopexy at an early age may prevent this disruption.
324 The presence of Ad spermatogonia at the time of surgery is an excellent
325 prognostic indicator of future fertility. Cryptorchid boys lacking these cells will be
326 infertile despite successful orchidopexy at an early age (46). In all testes with low
327 numbers of Ad spermatogonia and suboptimal response to hCG stimulation,
328 hormonal treatments should be advised in an attempt to increase the number of
329 germ cells. The question of whether different modalities and periods of hormonal
330 therapy in patients with impaired Leydig cell response could lead to improved
331 testicular histology (and better fertility) remains to be answered (82, 83).
332 In childhood, the probability of detecting an occult cancer or a
333 precancerous lesion in a biopsy is low because intratubular germ cell neoplasia
334 is not diffusely distributed through the testis, and because of the frequent
335 persistence of gonocytes beyond the first year. However, a testicular biopsy
336 should be performed in all patients with intra-abdominal testes, abnormal
337 external genitalia, or abnormal karyotype (84).
338 Testicular autotransplantation (85) has been used in some patients with
339 high intra-abdominal testes as an alternative to the Fowler-Stephens technique
340 (86, 87). The latter involves transecting the vessels to the testis while bringing it

341 down to the scrotum with the hope that collateral vessels provide adequate
342 circulation. Autotransplanted testes represent approximately five percent of all
343 undescended testes (88). Histological studies performed after autotransplantation
344 have shown Leydig cell development, tubular diameter increase, and some
345 spermatogenesis (89, 90), although no paternity has yet been reported.
346 No consensus has been reached on the treatment of acquired
347 undescended testis. Recommendations vary from surgery at diagnosis to a
348 conservative approach, delaying orchidopexy until puberty. Early surgery
349 prevents injury from elevated temperature, while the conservative stance relies
350 on the effect of testosterone leading to spontaneous descent at puberty (three of
351 four cases) (91). An orchidopexy performed at puberty does not guarantee that
352 the excryptorchid testis will reach a normal volume (92).
353

354 8. CONGENITAL ANOMALIES ASSOCIATED WITH UNDESCENDED TESTES


355 Most cryptorchid patients (62-90%) have an ipsilateral patent vaginal
356 process (93, 94). This probably enabled the few descents achieved after hormonal
357 treatment (95). Some 34% of patients with unilateral palpable undescended testis
358 have a contralateral patent processus vaginalis (96). Between 65 and 75% of
359 cryptorchid males have a hernia sac, although most are not apparent.
360 Urological anomalies are present in 10.5% of patients. The most frequent
361 are hypospadias (5.7 to 9.3%) (4), complete duplication of the urinary tract, non-
362 obstructive urethral dilation, kidney malrotation, and posterior urethral valves.
363 Cryptorchidism is frequent in patients with nervous system anomalies,
364 including microcephaly, myelomeningocele, and spina bifida (25%) (97). It is also
365 frequent with other malformations such as omphalocele (33%), gastroschisis (30
366 to 38.7%) (98, 99), micropenis, imperforate anus (100, 101), and cloacal exstrophy
367 (102).

368 The incidence of anomalies of the sperm excretory duct is high in patients
369 with undescended testes. They involve both intra- and extratesticular ducts.
370 Dysgenesis of the rete testis is observed in more than 80% of adults with
371 undescended testes (103). The incidence of extratesticular spermatic duct
372 anomalies varies from 36 (104) to 79% (6, 70, 105-108) (see Chapter 12 Congenital
373 Epididymal Anomalies).
374 In addition to macroscopic anomalies, the epididymis features abnormal
375 development of the ductuli efferentes and ductus epididymis from infancy
376 onward. The epithelium of both types of ducts is low and the muscular wall is
377 poorly developed. In cryptorchid adults, cross-sections of the ductuli efferentes
378 have an inner circular outline instead of the wavy outline imparted by the different
379 epithelial heights of the normal epididymis (109). The poor development of muscle
380 in the wall suggests that propulsion of testicular fluid is compromised, resulting in
381 stasis within ductuli efferentes, rete testis, and even seminiferous tubules.
382 A close relationship exists between patent vaginal processes and
383 epididymal anomalies, regardless of the location of the cryptorchid testis. In
384 cryptorchid patients with an open vaginal process, the incidence of these
385 anomalies rises to 80%, whereas it is only 5% in descended testes with closed
386 vaginal processes (110).
387 Anomalies of the gubernaculum are also frequent in cryptorchidism. The
388 gubernaculum is attached to the testis and epididymis in 72.2% of cryptorchid
389 testes, but in 98.8% of normal fetuses. The gubernaculum is attached only to the
390 testis (the cauda epididymis is free) in 22.2% of cryptorchid testes and 1.19% of
391 normal fetal testes. The gubernaculum is attached only to the cauda epididymis
392 in 5.6% of cryptorchid testes, whereas this condition is not observed in normal
393 fetuses (111).
394 Another anomaly is the presence of short spermatic vessels that hinder
395 testicular descent. This is frequent in cryptorchid testes with type III lesions and
396 less frequent in those with type II lesions. This observation further supports the
397 dysgenetic nature of these testes (112).
398 Ultrasonography can produce images that explain many of the anomalies
399 and the poor outcomes after surgical descent of these testes (113).
400

401 9. CRYPTORCHIDISM ASSOCIATED WITH MALFORMATIVE OR


402 ENDOCRINOLOGICAL SYNDROMES
403 Although cryptorchidism usually appears as an isolated anomaly, it is often
404 associated with congenital endocrine or chromosomal disorders, and disorders of
405 sexual development (114, 115). Cryptorchidism has been reported in patients with
406 GnRH deficit and Maestre de San Juan syndrome (commonly referred to as
407 Kallman syndrome). Cryptorchidism is also found in Prader-Willi, Klinefelter, and
408 Noonan syndromes. Still other conditions with cryptorchidism include testicular
409 feminization caused by androgen-receptor anomalies, 5-α-reductase deficiency,
410 and several types of undermasculinization caused by absent anti-müllerian
411 hormone. The association of impalpable testes with hypospadias suggests a
412 disorder of sexual development. This is confirmed in 27 to 30% of cases (116, 117).
413 Cryptorchidism also occurs in patients with the following syndromes: caudal
414 regression, prune-belly, Smith-Lemli-Opitz, Cornelia De Lange, DiGeorge,
415 Beckwith-Wiedemann (118), Aarkog-Scott (also called Rubinstein-Taybi syndrome
416 or CHARGE association), and trisomies 13, 18, and 21.
417

418 9 a. Caudal regression syndrome


419 Cryptorchidism has a high incidence in caudal regression syndrome (also
420 called caudal dysplasia syndrome) (119). Cryptorchidism appears in all patients
421 with tritonmelia, the male variant of sirenomelia, and is associated with
422 malformations and dysplasias of the kidney, ureter and spine (T10-S5 levels).
423 This association has been observed in 18% of cryptorchid boys younger than
424 three years of age, 34% of cryptorchid fetuses who died in the third trimester of
425 gestation, and 65% of cryptorchid patients with imperforate anus (120).
426

427 9 b. Prune-belly syndrome (PBS) or Eagle-Barrett syndrome


428 This syndrome involves musculoskeletal, gastrointestinal, respiratory,
429 cardiovascular, central nervous and genitourinary systems (121, 122). The classic
430 triad described by Osler is comprised of bilateral cryptorchidism, defective or
431 absent abdominal wall musculature (prune belly), and malformation of the
432 urogenital tract. The incidence of this syndrome is 3.8 in 100,000 live male births
433 (123) affecting males almost exclusively (>95%). PBS is lethal in 50% of the

434 affected individuals and is associated with high morbidity in the survivors.
435 The cause of PBS is still unknown although one genomic HNF1 β mutation
436 has been observed in three percent of patients (124) . It can be associated with
437 Turner and Down syndromes, trisomies 18 and 13, monosomy 16, VACTERL
438 association, or Beckwith-Wiedemann syndrome (125-127). PBS has a primary
439 defect of the embryonal lateral and intermediate mesoderm (128). Patients with a
440 prune belly abdomen, but no urinary tract anomalies or cryptorchidism, are
441 known as having “prune belly phenotype” or “pseudo prune belly syndrome” (129,
442 130). This is similar to the megacystic-megaureter syndrome in regard to the

443 flaccid, stretched abdominal wall (131) (Fig 37). Prenatal diagnosis is possible
444 even at the thirteenth week of gestation. The diagnosis of PBS is based on
445 abnormal distension of the urinary bladder and abdomen, and absence of the
446 "keyhole sign" (132).
447 Testes of prune belly patients are intra-abdominal, located at the level of
448 the iliac vessels. When the muscle thinning is not as severe, testes can be
449 located in a lower abdominal position, even in the inguinal canal (133). The
450 testicular lesions may be detected even in fetal life (134). The most remarkable
451 microscopic lesions are germ cell depletion and Leydig cell hyperplasia. Early in
452 infancy, gonocytes (which can be easily detected by their staining with placental
453 alkaline phosphatase) can be present until seven months of age. This suggests
454 an arrest in the normal evolution of these cells, which should have been
455 transformed into spermatogonia in the first months of life. Whether gonocytes
456 degenerate or may be the origin of an infiltrating tumor later is not known (135).
457 Adult patients are azoospermic, their prostate is hypoplastic, and the
458 prostatic urethra is widened. The most frequent histological testicular pattern is
459 Sertoli-cell-only tubules. Leydig cells are normal or hyperplastic. FSH and LH
460 serum levels are elevated, while testosterone levels are normal. Seminomatous
461 and non-seminomatous germ cell tumors have been reported (136, 137).
462

463 9 c. CHARGE
464 The first descriptions of this syndrome or association appeared
465 independently in the studies of Hall and Hittner, et al in 1979 (138, 139). The
466 acronym CHARGE was coined by Pagon et al in 1981 (140), grouping the most
467 characteristic anomalies: coloboma, congenital heart disease, choanal atresia,
468 retarded growth, mental retardation and/or central nervous system anomalies,
469 genital hypoplasia, ear anomalies and/or deafness. Most cases are sporadic; in
470 familial cases autosomal dominant inheritance has been suggested. The disorder
471 is caused by mutations in CHD7 gene (chromodomain helicase DNA binding
472 protein) in approximately 60 to 70% (141-144) of cases. CDH7 belongs to a protein
473 family involved in chromatin organization in a large number of developmental
474 pathways in fetal life (145). CHARGE incidence is 1 in 10,000 newborns, without
475 gender distinction. This association has several overlapping clinical
476 characteristics with Kallmann syndrome (146), DiGeorge syndrome (147),
477 sensorineural deafness, renal disease (Barakat´s syndrome) and
478 hypoparathyroidism with or without bilateral multicystic renal dysplasia (148).
479 Urinary tract anomalies are present in 10-40% of patients with CHARGE
480 syndrome including renal ectopia, renal agenesis, duplex kidney, horseshoe
481 kidney, urethral anomalies, micropenis, and cryptorchidism. Micropenis and
482 cryptorchidism are expressions of hypogonadotropic hypogonadism which is
483 present even during fetal life (146, 149, 150).
484

485 10. COMPLICATIONS OF CRYPTORCHIDISM


486 The most frequent complications of cryptorchidism are testicular cancer,
487 infertility, testicular torsion, iatrogenic atrophy, and psychological problems
488 derived from an empty scrotum (151).
489

490 10 a. Testicular cancer


491 Both congenital undescended and contralateral scrotal testes show a
492 higher predisposition to develop testicular cancer compared with testes of the
493 general population. The cancer risk of undescended testis is 6.33 times higher
494 than the general population. For the contralateral testis the risk is 1.74 to 2.90
495 times higher in meta-analysis studies by Akre et al (152) and by Lip et al (153). In
496 Northern countries, the risk of testicular cancer arising in cryptorchid patients is
497 an estimated four times higher than that of the general population (154, 155); with
498 abdominal testes, the risk is six times higher than that of cryptorchid testes with a
499 lower location (154-156). The risk of cancer increases if cryptorchidism is bilateral
500 and associated with anomalies of the external genitalia or with chromosomal
501 anomalies, such as 45, X/46, XY (157).
502 Approximately two to three percent of adult cryptorchid testes show
503 intratubular germ cell neoplasia unclassified/carcinoma in situ (ITGCNU/CIS) (158,
504 159). Half of cryptorchid patients with CIS develop testicular cancer within five

505 years and 70% within seven years. In Denmark, one of the countries with the
506 highest incidence of testicular cancer, an estimated 0.5% of males will develop
507 CIS (160), and one out of five testicular cancers will develop in the contralateral
508 scrotal testis.
509 In infancy, ITGCNU/CIS may go undetected. Atypical gonocytes may not
510 be located directly over the tubular basement membrane but in the center of the
511 lumen, and their numbers may be very low (161). In five percent of testicular
512 biopsies in infants, cells similar to those of ITGCNU/CIS have been observed,
513 although progression toward an infiltrating tumor is not agreed upon (162, 163).
514 Cryptorchid testes with numerous multinucleated spermatogonia seem to be
515 associated with increased risk of testicular malignancy later in life (50).
516 The most frequent tumor in cryptorchid testes is seminoma (164).
517 Orchidopexy, independent of age, does not decrease the risk of cancer but
518 allows for earlier detection (165). The prognosis of germ cell tumors in intra-
519 abdominal testes is similar to that of tumors in normally-descended testes (166),
520 although the disease may be more advanced at the time of diagnosis.
521 The incidence of tumors in patients with acquired cryptorchidism should
522 not be different from that of the normal population. In these patients the testicular
523 ascent is a late event, months or years after gonocytes had transformed into
524 spermatogonia during a normal minipuberty (167).
525

526 10 b. Infertility
527 Infertility is one of the most frequent problems of cryptorchid men. From
528 2.5% (168) to 9% (169) of infertile men are or were affected by cryptorchidism.
529 Cryptorchidism-related infertility depends on several factors; bilateral or
530 unilateral cryptorchidism, location and size of the cryptorchid testis, tubular
531 fertility index, number of germ cells per cross-section, germ cell distribution,
532 anomalous DNA content in germ cells, congenital anomalies of sperm excretory
533 ducts, and iatrogenic injury to the testes, epididymis, ductus deferens or
534 spermatic cord during orchidopexy (170).
535 Bilaterality of the lesion. Only 16 (171) to 25% (172) of bilateral cryptorchid
536 patients have sperm concentrations above 20 million/ml. Patients with bilateral
537 impalpable testes (172, 173) or with associated elevation of FSH levels (104) have
538 azoospermia or severe oligozoospermia. In contrast, 31 to 55.8% of men with
539 unilateral cryptorchidism have sperm concentrations over 20 million/ml, 38.2 to
540 62% have oligozoospermia, and only 6 to 7.6% show azoospermia (174, 175).
541 Paternity rates are 50 to 63.3% in bilateral cryptorchidism, 89.7% in unilateral
542 cryptorchidism and 93.2% in controls (176). The time elapsed from orchidopexy to
543 fertilization is longer in patients who suffered bilateral cryptorchidism (177). Many
544 patients with repaired bilateral cryptorchidism require assisted fertilization
545 techniques such as intracytoplasmic sperm injection (ICSI), to achieve successful
546 fertilization (178).
547 Both location and size of the cryptorchid testis have been considered
548 important. It is assumed that patients with high scrotal testes, or testes lodged in
549 the superficial inguinal pouch, show the best spermiograms, and that patients
550 with intra-abdominal or canalicular testes are oligozoospermic or azoospermic.
551 The more severe testicular malfunctions can be due to either more severe
552 histological lesions (53), or injury produced during orchidopexy, because these
553 testes require more mobilization than those in lower locations (179). Patients
554 whose testes are nearly normal in size also have better spermiograms (172).
555 Nevertheless, some series have shown that neither preoperative location of the
556 testis in unilateral cryptorchidism nor testicular size at orchidopexy is an
557 important factor concerning fertility (180-182).
558 Germ cell number. The most important prognostic indicator of fertility is the
559 number of spermatogonia per cross-sectioned tubule. Usually, a cryptorchid child
560 with fewer than 0.2 spermatogonia per cross-sectioned tubule will have a
561 deficient adult spermiogram and compromised fertility. In unilateral
562 cryptorchidism, prognosis depends on the number of spermatogonia in the
563 contralateral testis. However, if spermatogonia numbers per cross-sectioned
564 tubule in the cryptorchid testis are lower than one percent of the normal value for
565 age, the risk of infertility is 33%. In bilateral cryptorchidism, the risk of infertility
566 reaches 73% and even 100% when spermatogonia numbers in one or both
567 testes are below one percent of normal values (120, 171, 183-186). The number of
568 spermatogonia per cross-sectioned tubule correlates not only with sperm
569 numbers in spermiograms, but also with the volume of surgically-repaired testes,
570 serum levels of inhibin B, and testicular volume reached in adulthood. Testicular
571 volume at infancy is not a reliable parameter to predict testes that will have low
572 germ cell numbers, and thus bad prognosis requiring hormonal treatment. Biopsy
573 with histology is the only reliable method to assess germ cell conditions (187).
574 Postoperative patients who fail to show rising serum levels of inhibin B have low
575 numbers of spermatogonia per cross-sectioned tubule, and a low tubular fertility
576 index (188). In most cases, the volume of the contralateral testis correlates
577 positively with sperm concentration, total number of spermatozoa, and the
578 presence of live and mobile spermatozoa (184, 185). On the other hand, FSH levels
579 are negatively correlated with testicular volume, sperm concentration, and total
580 number of spermatozoa. The perspective of fertility for excryptorchid patients is
581 changing due to testicular sperm extraction (TESE). In a series of 142
582 azoospermic men with history of cryptorchidism, sperm retrieval was performed
583 in 61.9% of them, and in patients with bilateral cryptorchidism the rate of
584 extraction was 63%. Those patients whose FSH is normal and/or whose
585 testicular volume is higher than 10 cm3 have an even better prognosis because
586 the rate of TESE with positive sperm retrieval is 75% (189).
587 Testicular Torsion. Torsion of an intra-abdominal testis was first reported
588 by Gerster in 1898 (190).The risk of torsion of the spermatic cord is ten times
589 higher in undescended testes than in scrotal testes. The absence of
590 gubernaculum, a closed internal inguinal ring, and laxity of the spermatic vessels
591 could be the anatomical bases to explain this form of torsion (191). The cause of
592 the testicular torsion within the inguinal canal is not well understood, since it is
593 frequently associated with a short spermatic cord or a hernia sac that would
594 make torsion more difficult. Abnormal cremaster contraction (192, 193) or an
595 abnormal suspensory system could play a role (194-197). According to some, the
596 contralateral testis should be fixed by orchidopexy if suspensory anomalies are
597 observed (198). The number of testes that can thus be preserved is low because
598 of delays in diagnosis (199-201). Adult testes that were fixed by orchidopexy show
599 calcifications in the tunica albuginea at the point of fixation. These calcifications
600 appear mainly when chromic suture material is used (202), and are not related to
601 the pathological features present in cryptorchid testes at the time of orchidopexy
602 or later. Intra-abdominal testes can also undergo torsion (203).
603 Iatrogenic atrophy. The large number of children subjected to orchidopexy
604 has led to the recognition of postsurgical atrophy. Its frequency is estimated from
605 one to five percent for inguinal canal testes, and 25% for intra-abdominal testes
606 (204) (Fig 38).

607 Psychological problems. The psychological implication of an integral


608 anatomy, including having two testes, should be considered when performing an
609 orchidopexy. Losing one or both testes may disrupt the development of male
610 identity (205). If an orchidectomy is performed in a child, a testicular prosthesis
611 should be considered to avoid psychological trauma, keeping in mind that
612 testicular prostheses should be replaced in adulthood (206). Studies carried out
613 in adults whose testes were surgically descended before puberty revealed a
614 normal male development and behavior. Although these men seem to be
615 sexually less active than controls, this does not seem to be related to either the
616 orchidopexy or the age at which it was performed (207).

617

618 11. RETRACTILE TESTES


619 The term “testicular retraction” designates the ascending mobility of one or
620 both testes to the superficial inguinal pouch (Denis Browne pouch) in response to
621 an active cremasteric reflex (208). This has an estimated incidence in children of
622 3.9%. The cremaster muscle controls testicular temperature and protects the
623 testis from trauma. The cremasteric reflex is the result of contraction of two
624 muscles, the cremaster and the inner oblique muscle, producing elevation of the
625 ipsilateral testis in response to stimulation of a sensitive branch of the
626 genitofemoral nerve. This reflex may be spontaneous or induced by cold (209).
627 The cremasteric reflex is present at birth in almost half of newborns (42.7%). Its
628 percentage decreases at four years of age (38.1%), and increases two-fold from
629 that age to puberty (210, 211).
630 Retractile testes have been considered a) a variant of cryptorchidism (212-
631 214); and b) normal testes that should be excluded from the study of

632 undescended testes pathology (the most accepted concept) (156, 215). Authors
633 supporting the first notion believe that retractile testes are cryptorchid as the
634 result of: 1) a defect in spermatic cord development; 2) a patent, although partly
635 obliterated vaginal process; or 3) a spasm of the cremaster, like that observed in
636 children with cerebral palsy or spastic dysplasia (216). Administration of hCG may
637 be useful to distinguish between retractile and cryptorchid testis, because in most
638 cases only the former descend with this treatment (217, 218). Retractile testes are
639 more frequent in infertile patients with history of cryptorchidism (219).
640 Retractile testes cannot always be mobilized to a low scrotal position (70-
641 75 mm from the pubic tubercle). Retractile testes in school-age children (7-12
642 years old) have a lower volume (1.82 ± 1.41 ml) than normal testes (2.38 ± 1.40
643 mm, p<0.05) (220). Differences in volume can be detected early. The mean
644 volume at the age of six months is 0.36 ml vs. 0.53 ml in control cases (74).
645 Retractile testes have a softer consistency and are prone to undergo upward
646 displacement. Between 2 and 45% of them become an ascending or acquired
647 undescended testis (221), a risk higher in boys under seven years of age, and
648 also when the spermatic cord seems tight or inelastic (222, 223). Retractile testes
649 remain high after the age of six, after which the cremasteric reflex steadily
650 declines (224).
651 Histological studies of infantile retractile testes show a decrease in both
652 tubular diameter and TFI (225-229). Fertility is variable. In some series (230, 231),
653 most adults with retractile testes that descended spontaneously were fertile,
654 whereas in other series (232-235), most patients were infertile.
655 Spermiograms were considered normal in 24% of the patients consulting
656 for infertility. The remaining 76% had abnormalities including oligozoospermia in
657 13%, and severe oligoasthenozoospermia in another 13% (236, 237).

658 Ultrastructural study of spermatozoa reveals a high proportion of round and


659 hyperelongated nuclei, lack of chromatin condensation, and hypoplastic
660 acrosomes.
661 In infertile patients with a history of retractile testes, the most frequent
662 histological testicular pattern is germ cell depletion. This varies in intensity from
663 one testicular lobule to another from seminiferous tubules with slight alterations
664 of the adluminal compartment to Sertoli-cell-only tubules (214, 237) (Fig 39).
665 Three mechanisms have been proposed to explain lesions of retractile
666 testes. The first is an increased suprascrotal temperature 2º C higher than the
667 intrascrotal temperature, although this factor only acts for short periods (238). The
668 second possible mechanism is compression of sperm excretory ducts at two
669 levels, either in the rete testis (caused by the testicular centripetal veins) or in the
670 ductuli efferentes (testicular ascent produces shortening of spermatic cord and
671 testicular rotation). The third mechanism is a primary testicular anomaly, since
672 the histological pattern of testicular atrophy observed in retractile testes is similar
673 to that observed in cryptorchid testes (214).
674 Based on these findings, patients with retractile testes should be
675 examined regularly. If the expected testicular descent does not occur,
676 orchidopexy should be considered (239) even though this does not always result
677 in adequate spermatogenesis (214, 224, 240, 241).
678

679 12. TESTICULAR DYSGENESIS SYNDROME


680 Testicular dysgenesis syndrome (TDS) is a relatively recent clinico-
681 pathologic concept attracting attention (10, 242-245). TDS comprises a spectrum of
682 male reproductive disorders including cryptorchidism, hypospadias, poor sperm
683 quality, and testicular cancer, with variable clinical presentations. TDS may result
684 from both genetic and environmental factors causing poor testicular
685 development. The apparent increase in prevalence of cryptorchidism in some
686 areas and the geographic differences suggest that both genetic and
687 environmental factors play a role. Other male reproductive disorders, such as
688 hypospadias, reduced semen quality, and testicular cancer all show similarities
689 with cryptorchidism in their geographical distribution and temporal trends (243).
690 They also share common risk factors which suggest prenatal impairment of
691 testicular development as a common cause.
692 Based on the observation that contralateral descended testes from men
693 with cryptorchidism and/or testicular cancer display dysgenetic features (such as
694 Sertoli-cell-only tubules, MAT, abnormally-developed tubules, microlithiasis,
695 granular changes in Sertoli cells, nodular Leydig cell hyperplasia and CIS), these
696 disorders may share a common embryonal origin, possibly leading to a disruption
697 of Sertoli and/or Leydig cell function.
698 The initial abnormality may be an imbalance between estrogens and
699 androgens during fetal life, specifically related to increased estrogen exposure in
700 utero (23). This hypothesis would be further supported by exposure to
701 environmental toxins, which are potential endocrine disruptors of fetal sexual
702 differentiation by either an estrogenic or antiandrogenic effect (246). Various
703 environmental chemicals such as certain phthalates and pesticides are able to
704 alter endogenous levels of androgens. Estrogens, polychlorinated biphenyls, and
705 polyhalogenated hydrocarbons may also be harmful (247-251). In the case of
706 estrogens, cryptorchidism and hypospadias may be induced by suppressing
707 androgen production or action. Additionally, estrogens can induce cryptorchidism
708 by suppressing insulin-like factor 3 (252-255), as well as testicular cancer (256).
709 Genetic predisposition seems to be present in some cases (257).
710 Prenatal exposure to phthalates (the most abundantly-produced
711 plasticizers which leach out from polyvinyl chloride plastics) shows a negative
712 correlation with serum levels of testosterone and with anogenital distance (258).
713 Although testicular dysgenesis syndrome still raises many epidemiological
714 and pathogenetic questions, it provides a unifying hypothesis, particularly since
715 so little is known about the etiologies of this spectrum (259-261).
716
717
718 LEGENDS
719
720 Fig 1. Longitudinal section from cryptorchid testis and epididymis of a three-
721 year-old child showing scant seminiferous tubules, abundant interstitial
722 connective tissue and abnormal insertion of the epididymis head.
723
724 Fig 2. Cryptorchidism type I. Testicular parenchyma showing a central relatively
725 straight tubule lacking germ cells, surrounded by tubes with normal numbers of
726 germ cells.
727
728 Fig 3. Cryptorchidism type II. Approximately half of tubules show reduced
729 caliber and lack germ cells.
730
731 Fig 4. Cryptorchidism type III. Cross- and oblique sections of Sertoli-cell-only
732 tubules.
733
734 Fig 5. Cryptorchidism type III in a three-year-old child. Immunohistochemistry is
735 strongly positive for inhibin in Sertoli cells.
736
737 Fig 6. Multinucleate spermatogonia in a child with cryptorchidism type I.
738
739 Fig 7. Persistence of immature germ cells in the center or lying on the basement
740 membrane of the tubule in a three-year-old cryptorchid child.
741
742 Fig 8. Microlith inside ring tubules in a type III cryptorchidism.
743
744 Fig 9. Ring tubule surrounding loose stroma in a type III cryptorchidism.
745
746 Fig 10. Cryptorchidism type III. Three tubules with eosinophilic granules in the
747 cytoplasm of Sertoli cells.
748
749 Fig 11. Cryptorchidism type III. Granular change in Sertoli cells highlighted by
750 immunohistochemistry for CD68.
751
752 Fig 12. Cryptorchid testis in a 15-year-old boy. Tubules show numerous
753 immature Sertoli cells. Occasional interstitial cells of Leydig are present.
754
755 Fig 13. Cryptorchid testis at puberty. Two adjacent lobules, one (upper right)
756 with the beginning of pubertal maturation (luminal development, increased
757 number of germinal cells), and another (lower left) with a prepubertal pattern.
758
759 Fig 14. Pubertal cryptorchid testis. Immunohistochemistry for androgen
760 receptor. Irregular nuclear staining of Sertoli cells reflecting abnormal tubular
761 maturation.
762
763 Fig 15. Cryptorchid pubertal testis. Immunohistochemistry for muscle specific
764 actin. Note strong staining of myoid cells in areas with more advanced
765 maturation.
766
767 Fig 16. Pubertal cryptorchid testis from a 15-year-old boy. White septa join the
768 rete testis with the tunica albuginea, separating testicular lobules.
769
770 Fig 17. Pubertal cryptorchid testis. Testicular lobules appear individualized and
771 separated by expansion of interlobular septa.
772
773 Fig 18. Post-pubertal cryptorchid testis. Abnormal proliferation of
774 spermatogonia, many of which are multinucleated.
775
776 Fig 19. Post-pubertal cryptorchid testis. Nineteen-year-old patient with
777 numerous dysgenetic Sertoli cells (pseudostratified epithelium with spherical
778 nuclei and central nucleoli) in Sertoli-only tubules.
779
780 Fig 20. Post-pubertal cryptorchid testis. Mixed atrophy with seminiferous tubules
781 showing maturation arrest of spermatogonia adjacent to smaller Sertoli-cell-only
782 tubules.
783
784 Fig 21. Post-pubertal cryptorchid testis. Seminiferous tubules with thickened
785 basement membranes and deficient spermatogenesis. Only spermatogonia and
786 type I spermatocytes (dark round nuclei) are found in some tubules.
787
788 Fig 22. Post-pubertal cryptorchid testis. Orcein stain showing tubules with
789 partial lack of elastic fibers. Note the elastic lamina in the small arteriole.
790
791 Fig 23. Post-pubertal cryptorchid testis. Collagen IV staining showing irregular
792 thickening of tubular wall.
793
794 Fig 24. Post-pubertal cryptorchid testis showing anastomosing Sertoli-cell-only
795 tubules with isolated spermatogonia.
796
797 Fig 25. Post-pubertal cryptorchid testis. Tubules show thick walls lined by
798 columnar, eosinophilic Sertoli cells with elongated nuclei without post-pubertal
799 maturation.
800
801 Fig 26. Post-pubertal cryptorchid testis. Sertoli cell nodule underlying the tunica
802 albuginea. It has associated focal Leydig cell hyperplasia.
803
804 Fig 27. Post-pubertal cryptorchid testis. Sertoli only seminiferous tubules with
805 cells showing spheric nuclei and abundant eosinophilic cytoplasmic granulations.
806
807 Fig 28. Focal Leydig cell hyperplasia in a cryptorchid testis with Sertoli-only
808 tubules and isolated spermatogonia.
809 Fig 29. Adenomatous hyperplasia of rete testis associated with Leydig cell
810 hyperplasia in a cryptorchid testis.
811
812 Fig 30. Scrotal testis contralateral to a cryptorchid testis from a patient with
813 infertility. Complete spermatogenesis (although quantitatively abnormal) and
814 Leydig cell hyperplasia are noted.
815
816 Fig 31. Detail from Figure 30 showing Leydig cells with marked vacuolization
817 and signet-ring morphology.
818
819 Fig 32. Testis from patient with infertility. Complete spermatogenesis with
820 marked tubular ectasia is found. The testis descended prepubertally.
821
822 Fig 33. Infertile patient with cryptorchidism treated prepubertally. The testis has
823 mixed atrophy (tubules with spermatogenesis adjacent to Sertoli-only tubules).
824
825 Fig 34. Cross-section of a seminiferous tubule with hypospermatogenesis.
826
827 Fig 35. Several seminiferous tubules with dysgenetic Sertoli cells (elongated
828 nuclei and marked cytoplasmic vacuolation) and prominent Leydig cell
829 hyperplasia and hypertrophy.
830
831 Fig 36. Ductuli efferentes from a cryptorchid testis in an adult with markedly-
832 decreased ductular diameter and intertubular fibrosis.
833
834 Fig 37. Autopsy specimen from a child with prune-belly syndrome, showing renal
835 dysplasia, urinary tract malformation and cryptorchid testes.
836
837 Fig 38. Longitudinal section from a cryptorchid testis descended in two stages,
838 showing marked atrophy with extensive areas of fibrosis, possibly of ischemic
839 origin.
840
841 Fig 39. Two central tubules showing only Sertoli cells in an infertile patient. He
842 had a history of retractile testis.
843
844 Table 1
845
846 Classification of histological lesions in prepubertal cryptorchid testis according to morphometric
847 parameters.
848
Type of Lesion Spermatogonia
MTD TFI SCN
(Incidence) distribution
Slightly decreased
Type I (31%) (90% normal values)
>50% Normal Regular

Markedly decreased
Type II (29%) (90-60% normal values)
30-50% Decreased Irregular

Severely decreased
Type III (40%) (< 60% normal values)
0-30% Very low Irregular

849
850 MTD: mean tubular diameter; SCN: Sertoli cell number (average Sertoli cell number per cross-
851 sectioned tubule); TFI: tubular fertility index (percentage of germ cell containing tubules).
852
853
854
855
856
857
858
859 Table 2
860
861 Post-pubertal evolution of lesions in testes descended in infancy
862
Type of Lesion Post-pubertal testicular pathology
Type I Adluminal compartment lesions (57%)
Mixed atrophy of the testis (29%)
Basal and adluminal compartment lesions (14%)
Type II Mixed atrophy of the testis (100%)

Type III Mixed atrophy of the testis with spermatogenesis in < 50% tubules (85% of
cases)
Sertoli-cell-only tubules (10% of cases)
Hypospermatogenesis + spermatocyte I sloughing (5% of cases)
863
864
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