Testis
THE UNREMARKABLE TESTIS
ANATOMY AND HISTOLOGY
The testicles are paired organs that normally descend into the scrotum, attached to the spermatic cord. Their embryologic development begins high in the abdomen and follows the path of the gubernaculum through the inguinal canal and into the scrotum as their final destination. The vascular and lymphatic supply of the testis are linked to the embryologic development. The scrotal skin is the outermost layer, below which is the dartos muscle, Colles fascia, and then the parietal layer of tunica vaginalis surrounds the testis. The testicles are invested within three layers of thin tissue: the tunica vaginalis that is in direct continuity with the peritoneum, the tunica albuginea, which provides a protective fibrous covering, and the tunica vasculosa which interdigitates within the parenchyma. Within the testicular parenchyma, seminiferous tubules convolute into around 250 tightly packed lobules, separated by fibrous septa1 (Figure 4.1).
The interstitial component between tubules is loose and contains blood vessels, lymphatic vessels, nerves, and Leydig cells (Figure 4.2). Leydig cells are granular eosinophilic cells that produce testicular androgens in response to luteinizing hormone (LH) (Figure 4.3). The tunica vasculosa is in close approximation with Leydig cells to facilitate delivery of hormones between the tubules and interstitium.
The seminiferous tubules converge into the rete testis in the testicular hilum, then enter the epididymis and ultimately into the ductus deferentia. The rete testis functions as an intermediate between the seminiferous tubules and the epididymis and allows various substances to mix with seminal fluid or resorb back into the epithelium (Figure 4.4).
The epididymis is a paratesticular structure attached to the posterosuperior aspect of the testis (Figure 4.5). The tubules exiting the rete testis enter the head of the epididymis at the superior aspect of the testis, continue through the body and tail, and then exit the epididymis at the inferior aspect into the vas deferens.
The types of germ cells and their supporting cellular elements are listed in Table 4.1.1 The testicular tubular architecture, relative amounts, and types of these cells change over time based on the influence of the sex hormones. A general overview of testicular maturation is described in Table 4.2 and demonstrated in Figures 4.6,4.7,4.8,4.9,4.10,4.11,4.12,4.13,4.14,4.15.
THE NEAR NORMAL TESTIS
Cryptorchidism
Cryptorchidism refers to the absence of one or both testes, usually due to failure of the testis to descend completely into the scrotum. The testis is usually identified along the path of testicular descent in the upper scrotum, inguinal region, or abdomen. Testicular
descent normally begins around 8 to 15 weeks of gestation and is normally completed by the 35th week of gestation. This is a common condition affecting approximately 2% to 8% of male children. Risk factors for cryptorchidism include low birth weight, being small for gestational age, and prematurity.2
descent normally begins around 8 to 15 weeks of gestation and is normally completed by the 35th week of gestation. This is a common condition affecting approximately 2% to 8% of male children. Risk factors for cryptorchidism include low birth weight, being small for gestational age, and prematurity.2
 Figure 4.1. Low power image of multiple normal spermatic tubules demonstrating intact spermatogenesis. Leydig cell clusters are present in the interstitium along with small blood vessels. |
 Figure 4.2. The interstitium of the testis contains blood vessels, lymphatic vessels, nerves, and Leydig cells within loose fibrous stroma. |
 Figure 4.3. Leydig cells are found within the interstitium of the testis and produce androgens to support germ cell development. |
 Figure 4.4. The rete testis is located in the hilum or mediastinum of the testis and comprises slitlike, complex glands that act as a conduit between the spermatic tubules and the epididymis. |
 Figure 4.5. The epididymis is located within the scrotum on the posterior aspect of the testis. The tubules in the epididymis show a distinct straight luminal border lined with pseudostratified, ciliated epithelial cells. In this image, the lumens are filled with sperm. |
The cryptorchid testis is at increased risk of developing germ cell tumors (GCTs), with approximately 5% of GCTs arising in the setting of cryptorchidism. The risk of germ cell neoplasia is even higher in patients with bilateral cryptorchidism. As a result, prompt surgical correction is recommended in the form of orchidopexy. This procedure involves the identification of the undescended testis within the inguinal canal or abdomen, placement of the testis into the scrotum, and tacking it into place. In addition to the risk of neoplasia, infertility is more common in patients with cryptorchidism. Torsion is also more common in cryptorchid testes when compared to normally descended testes.
Vanishing testis or testicular regression occurs when testicular development halts around the seventh month of gestation, so the testicular remnant is often present along with an epididymis and vas deferens. In testicular regression, both testes fail to form or completely disappear. The testicular remnant may be identified with fibrosis, hemosiderin deposition, and calcifications3 (Figures 4.16 and 4.17).
KEY FEATURES: Histologic Findings in Cryptorchid Testis
Tubular atrophy with decreased tubular diameter
Sertoli-only pattern or Sertoli cell nodules “Pick adenoma” (Figure 4.18)
Microlithiasis within tubules (Figure 4.19)
Peritubular fibrosis, fibrotic interstitium with prominent Leydig cells
Hemosiderin deposition (Figure 4.20)
In adults with cryptorchid testis that has undergone orchidopexy, may see a mixed pattern of maturation arrest, Sertoli-only pattern, and hypospermatogenesis, along with Leydig cell hyperplasia
TABLE 4.1: Normal Testicular Cellular Components | ||||||||||||||||||||||||||||||||||||
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 Figure 4.6. In Table 4.1: Spermatogonium. Arrows point to the basally oriented spermatogonia. These are the most primitive germ cell within the spermatic tubule. |
 Figure 4.7. In Table 4.1: Primary spermatocyte. Arrows point to primary spermatocytes, which are present just above the basal aspect of the tubule, but not yet to the luminal surface. |
 Figure 4.8. In Table 4.1: Secondary spermatocyte. Arrows point to secondary spermatocytes. These cells are located more towards the luminal aspect when compared to primary spermatocytes. In reality, they are incredibly difficult to differentiate from primary spermatocytes on H&E alone. |
 Figure 4.9. In Table 4.1: Spermatid. Arrows point to spermatids, which still show attachment to the Sertoli cells within the tubule. |
 Figure 4.10. In Table 4.1: Spermatozoa. Arrows point to spermatozoa, which have been released into the lumen and will be carried out of the testis via the vas deferens. |
 Figure 4.11. In Table 4.1: Sertoli cell. Arrows point to Sertoli cells, which are pyramidal shaped cells with prominent nucleoli. They have indistinct cell borders as they interdigitate between the germ cells of the tubule. |
 Figure 4.12. In Table 4.1: Leydig cell. Arrows point to Leydig cells present in the interstitium surrounding the tubule. |
 Figure 4.13. The fetal testis comprises immature seminiferous tubules without lumens. The tubules are lined by immature, cuboidal Sertoli cells. Immature Leydig cells are present in the interstitium. |
 Figure 4.14. Prepubertal seminiferous tubules showing incomplete maturation lacking spermatozoa. Sertoli cells are prominent. |
 Figure 4.15. Complete spermatogenesis in the adult male. All stages of germ cell maturation are present, with spermatozoa identified in the tubular lumen. Sertoli cells, with prominent nucleoli, are admixed between germ cells to provide necessary factors for germ cell development. |
Disorders of Sexual Development
“Disorders of sexual development” is a broad category of conditions that include gonadal dysgenesis, agonadism, and ovotesticular disorder. This term was chosen by a consensus group in 2006 to encompass “congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical.”4 The underlying physiology of these conditions varies and may be related to chromosomal abnormalities (Turner syndrome and Klinefelter syndrome), disorders of testicular or ovarian development (ovotesticular syndrome), or alterations in androgen signaling (5-alpha reductase deficiency and congenital adrenal hyperplasia [CAH]).
Ovotesticular Disorder
Ovotestis is the most common anatomical finding in the setting of disordered sexual differentiation. The most common chromosomal karyotype in these patients is 46,XX, although mosaic phenotypes with combinations of XY and XXY are also seen. Patients usually present with ambiguous genitalia. Grossly, the mixed ovotestis will show an end-to-end arrangement of ovarian tissue and testicular tissue (Figure 4.21). Histologically, a combination
of the ovarian parenchyma with the fallopian tube is present in close association with immature spermatic tubules (Figure 4.22). The seminiferous tubules are lined by immature Sertoli cells, lack open lumens, and germ cells are absent (Figure 4.23). Ovarian fibrous stroma is indicative of the ovarian component, along with the serous-epithelium-lined fallopian tube (Figure 4.24).
of the ovarian parenchyma with the fallopian tube is present in close association with immature spermatic tubules (Figure 4.22). The seminiferous tubules are lined by immature Sertoli cells, lack open lumens, and germ cells are absent (Figure 4.23). Ovarian fibrous stroma is indicative of the ovarian component, along with the serous-epithelium-lined fallopian tube (Figure 4.24).
TABLE 4.2: Testicular Development and Histology by Developmental Age Group | ||||||||||||||
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 Figure 4.16. In cryptorchid testes, the testicle is often identified in the inguinal canal or even in the abdomen. The testicle is small and fibrotic. |
 Figure 4.17. At medium power, numerous vessels, hemosiderin deposition, and calcifications are present and well-formed spermatic tubules are absent. |
FAQ: Features of Gonadoblastoma
Gonadoblastoma usually arises in the setting of disordered sexual development
Most commonly identified in gonadal dysgenesis involving the Y chromosome
Tumors comprise of a mixture of GCT and sex cord stromal tumor
Areas that resemble seminoma/dysgerminoma with annular tubules surrounded by ovarian stroma (Figure 4.25)
Calcifications are common (Figure 4.26)
 Figure 4.18. The finding of Sertoli cell-only pattern, discussed below, is common in cryptorchid testis. A discrete nodule of Sertoli cells, the so-called Pick adenoma, is also associated with cryptorchidism. |
 Figure 4.19. Microlithiasis within the remnant of spermatic tubules is another feature of cryptorchid testis. |
 Figure 4.20. Hemosiderin deposition is a common feature of cryptorchid testis, along with prominent vessels. |
 Figure 4.21. Gross photograph of an ovotestis demonstrates the intact fallopian tube on the left, leading to a combined ovary and testis. The fimbriated end of the fallopian tube is present at the right side of the image. |
 Figure 4.22. Low-power image of an ovotestis with the fallopian tube coursing along the right and top of the image and immature spermatic tubules on the left. |
 Figure 4.23. At higher power, the spermatic tubules in the ovotestis show fetal-type immature Sertoli cells, without any germ cells present. |
 Figure 4.24. Ovarian fibrous stroma is present in ovotestis, surrounding the fallopian tube with serous-type epithelium. |
 Figure 4.25. Gonadoblastomas are mixed germ cell and sex cord stromal tumors that occur in the setting of gonadal dysgenesis. Microscopically, they resemble seminoma/dysgerminoma in the germ cell component but also show foci of eosinophilic material similar to sex cord tumor with annular tubules. |
 Figure 4.26. In gonadoblastoma, tubules are surrounded by ovarian-type stroma. Calcifications and hyalinization are common in these tumors. |
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia is an autosomal recessive syndrome in which specific enzyme deficiencies cause lack of production of sex hormones. Depending on which enzyme is deficient, the clinical presentation can vary. Because sex hormones are impacted, these syndromes often present with virilization and hirsutism associated with androgen excess.
The most common type of CAH is 21-Hydroxylase deficiency, which is responsible for over 95% of cases. 21-hydroxylase deficiency is the syndrome most closely associated with testicular “tumor” of the adrenogenital syndrome (TTAGS). These proliferations of steroid cells are usually located in the testicular hilum and are thought to arise from excess hormonal stimulation of preexisting cells. These tumors have also been referred to as “testicular adrenal rest tumors (TARTs)” though this term is less favored given the hypothesis that the steroid cells are a normal component of the testicular hilum, rather than an ectopic location of the adrenal tissue.
TTAGS is often nodular and comprises of round cells with abundant eosinophilic cytoplasm, morphologically similar to Leydig cells (Figure 4.27). Bilaterality is common in this entity, a finding that should immediately raise the possibility of CAH, rather than Leydig cell tumor. Consistent with their endocrine origin, random nuclear atypia is commonly identified, and rare mitotic figures are acceptable (Figure 4.28). Given the histologic overlap with Leydig cells, Leydig cell tumor is leading differential diagnosis for TTAGS. Clues to the correct diagnosis include the clinical presentation of other signs of CAH, bilaterality and the presence of fibrous bands, adipose metaplasia, and nuclear pleomorphism. Immunohistochemically, TTAGS strongly expresses CD56 and is negative for androgen receptor (AR), whereas Leydig cell tumors are positive for androgen receptor.5 Of note, Leydig cell tumor may have some expression of both CD56 and synaptophysin, so AR positivity strongly supports Leydig cell tumor.
Androgen Insensitivity Syndrome
Androgen insensitivity syndrome (AIS) is a type of disordered sexual development where the presence of a Y chromosome leads to formation of testicles, which may occur in otherwise phenotypically female patients. The testicles produce androgens and luteinizing hormone; however, patients lack functional androgen receptors and therefore virilization does not occur. Clinically, the most common presentation is a 46X,Y chromosomal compliment in a patient who appears phenotypically female, often with tall stature, and lack of development of gynecologic organs. These patients have an increased risk of developing GCTs, and gonadectomy is generally recommended. Gonads are often located in the abdomen, inguinal canal, or may be within labia. Histologically, AIS gonads show small tubules lacking lumina lined by immature Sertoli cells (Figure 4.29). Leydig cell hyperplasia is common because of persistent LH elevation.
 Figure 4.27. Testicular tumors of the adrenogenital syndrome (TTAGSs) are associated with adrenogenital syndrome and result from hyperplasia of existing steroid cells in the testis. They arise within the testis and comprise eosinophilic nests of cells that are morphologically similar to Leydig cells. |
 Figure 4.28. A higher power image of testicular tumor of the adrenogenital syndrome (TTAGS) shows their granular eosinophilic cytoplasm, round nuclei with random atypia—consistent with their endocrine origin. |
PEARLS AND PITFALLS: Adrenocortical Rests
Nodules of benign adrenal cortical tissue found in the paratesticular soft tissue, as well as along the spermatic cord and epididymis
Exceedingly rare instances of adrenal tissue within testicular tissue reported
May be more common in cryptorchid males
Occurs when adrenal tissue follows testis from abdomen into the inguinal region during development
Rests are well circumscribed, contain only adrenal cortical tissue, and lack a medullary component (Figure 4.30)
FAQ: What Ectopic Tissues May Be Identified in Testis and Paratestis?
Spleen: Splenogonadal fusion occurs when the embryonic gonad fuses with ectopic spleen and migrates to the scrotum. The left testicle is exclusively involved, consistent with the usual anatomic location of the spleen.6
Liver: Hepatotesticular fusion has been reported in hernia specimens and in undescended testis.7
Kidney: Ectopic renal tissue associated with undescended testis.8
Various metaplastic tissues may be seen in testes including fat, cartilage, and bone.9
NONNEOPLASTIC TESTIS AND EPIDIDYMIS
TESTIS BIOPSY FOR INFERTILITY
Organic azoospermia is the clinical term for the absence of sperm within semen. In the workup of azoospermia, testis biopsy may be employed for histologic confirmation of the cause of azoospermia (Figure 4.31). Azoospermia can be caused by obstruction within the vas deferens (as seen in cystic fibrosis) or nonobstructive causes stemming from abnormal spermatogenesis. The five main categories of findings for testicular biopsy for fertility include normal, hypospermatogenesis, maturation arrest, Sertoli cell-only pattern, and atrophy.10 A description of the common patterns identified on testicular biopsies for infertility is provided in Table 4.3. When the patterns co-occur, it is useful to give percentages of each pattern seen in the sampled tubules.
 Figure 4.29. Histologic examination of androgen insensitivity syndrome showing small, packed seminiferous tubules lined by immature Sertoli cells. Germ cells are largely absent. |
 Figure 4.30. Adrenocortical rests are benign nodules of adrenal cortical cells most commonly identified in the paratesticular soft tissue. |
 Figure 4.31. Testicular biopsies performed for fertility workup are challenging specimens due to frequent architectural and cytologic distortion. At low power, it is helpful to scan the specimen to get a sense for the degree of crush artifact and number of intact and evaluable tubules. Providing an estimated number of evaluable tubules may provide an idea of adequacy of the specimen. |
TABLE 4.3: Common Patterns for Testicular Biopsy for Infertility | ||||||||||||||||||||||||||||||
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A recent study highlighted the use of select immunomarkers for detection of germ cells and spermatogonia. DOG1 was expressed in spermatocytes and spermatids, and MAGE-A4 was expressed preferentially in spermatogonia, helping to distinguish maturation arrest from Sertoli-only syndrome (Figures 4.32,4.33,4.34,4.35,4.36,4.37,4.38,4.39,4.40,4.41).11
PEARLS AND PITFALLS: Klinefelter Syndrome
Klinefelter syndrome occurs in males with an extra X chromosome (47,XXY)
Findings include infertility and small testicular volume with decreased testosterone production
Testicular biopsy demonstrates numerous sclerotic tubules and Leydig cell hyperplasia, with overall reduction in the number of germ cells
When sperms are present, microtesticular sperm extraction (TESE) may be successful for assisted reproduction
CHECKLIST: Approach to Testicular Biopsy for Fertility10
□ Look for intact spermatogenesis in all tubules; if absent in any tubules, consider diagnostic entities in Table 4.3
□ Determine if the process involves all tubules versus heterogeneous, mixed pattern
□ If heterogeneous, give approximate percentage of tubules involved by each pattern
□ Comment on presence or absence of germ cell neoplasia in situ (GCNIS)
□ Assess interstitium for presence of Leydig cells and other findings such as fibrosis, inflammation, or granulomas
□ Report the number of tubular cross sections present as a biopsy-quality indicator
 Figure 4.32. A reference image of complete spermatogenesis in a well-oriented seminiferous tubule showing all stages of germ cell maturation from spermatogonia to spermatozoa. Sertoli cells are admixed within the adluminal space providing nutrients to the developing germ cells. A few Leydig cells are present in the interstitium surrounding the tubule. |
 Figure 4.33. Testis biopsy showing typical distortion of seminiferous tubules due to handling of small specimens. Despite the artifactual changes, mature spermatozoa are present in the lumen of this tubule, consistent with intact spermatogenesis. Sloughed maturing germ cells are commonly identified in the lumen and are also likely due to rough handling of the specimen. |
 Figure 4.34. Higher power image of tubular lumen showing mature spermatozoa with tapered nuclei and no appreciable cytoplasm. The presence of spermatozoa is consistent with intact spermatogenesis. |
 Figure 4.35. When spermatozoa are only identified in some tubules with other tubules showing maturation arrest or Sertoli cell-only pattern, the recommended diagnosis is hypospermatogenesis and including the other patterns and the approximate percentage of those patterns. |
 Figure 4.36. In maturation arrest, germ cells are present and show maturation to the secondary spermatocyte stage in this tubule. The tubular lumen is obscured and no spermatids or spermatozoa are identified. |
 Figure 4.37. At higher power, the cytologic features of secondary spermatocytes are evident by the filamentous chromatin pattern and presence of the cells away from the adluminal compartment. Again, no spermatids or spermatozoa are present in the tubule. |
INFECTIOUS/INFLAMMATORY
Orchitis and Epididymitis
Inflammation of the testis or epididymis is referred to as orchitis and epididymitis, respectively; however, they often occur together. These are usually clinical rather than histologic diagnoses, made when a patient presents with testicular pain and swelling. If a mass persists after appropriate antibiotic treatment, or the pain does not resolve, an orchiectomy may be performed for symptom relief. Categories that are more specific include acute, chronic, and granulomatous orchitis. Histologically, the inflammatory component may be either acute (neutrophilic) or chronic (lymphoplasmacytic or granulomatous), which can provide information about possible etiologies.
Acute infectious orchitis often occurs along with epididymitis, and common infectious agents include the usual urinary tract bacteria Escherichia coli, Pseudomonas, Klebsiella, Staphylococcus, Streptococcus, and Actinomyces species. Neisseria gonorrhea and Chlamydia trachomatis may be causative organisms in sexually active men. In acute epididymo-orchitis,
a prominent neutrophilic infiltrate is expected, with a dominant abscess or microabscesses commonly identified. Chronic epididymo-orchitis may result from a long-standing bacterial infection, with a transition to more lymphoplasmacytic inflammatory cells and associated fibrosis and tubular destruction. This fibrotic stage is more likely to be confused for a possible malignancy as the tissues become fixed to surrounding soft tissue.
a prominent neutrophilic infiltrate is expected, with a dominant abscess or microabscesses commonly identified. Chronic epididymo-orchitis may result from a long-standing bacterial infection, with a transition to more lymphoplasmacytic inflammatory cells and associated fibrosis and tubular destruction. This fibrotic stage is more likely to be confused for a possible malignancy as the tissues become fixed to surrounding soft tissue.
 Figure 4.38. Sertoli cell-only pattern at low power, the tubules show a single cell type and lack mature spermatozoa in the lumens. |
 Figure 4.39. At high power, the classic cytologic features of Sertoli cells are present—pyramidal cells with wispy eosinophilic cytoplasm and ill-defined cell borders. Nuclei are round with prominent nucleoli. |
 Figure 4.40. Atrophic testis showing hyalinized tubules with small diameters. The interstitium appears fibrotic with loss of Leydig cells. |
 Figure 4.41. At high power, atrophic testis showing obliteration of tubular lumens and loose collagen occupying the majority of the surface area. No germ cells or Sertoli cells are present within the tubule. |
PEARLS AND PITFALLS: Mumps
Orchitis and epididymitis usually co-occur, and isolated epididymitis is rare
In a patient with isolated epididymitis, mumps should be the primary clinical consideration as epididymitis often occurs prior to orchitis
Mumps epididymo-orchitis is an important diagnosis to make as it can often lead to infertility
Specific etiologies of granulomatous orchitis include fungal infection, tuberculosis, and sarcoidosis. Rarely, brucellosis can cause orchitis in men who handle livestock. A fungal organism known to cause epididymo-orchitis is Histoplasma, characterized by granulomas and small yeast forms with narrow-based budding. The yeast forms are highlighted on silver staining. Tuberculous epididymo-orchitis demonstrates findings similar to tubercular infections elsewhere, with caseating granulomas surrounded by multinucleated Langhans-type giant cells and histiocytes (Figure 4.42). Acid-fast bacilli can be demonstrated by Ziehl-Neelsen staining. In contrast to the caseating granulomas seen in tuberculosis, sarcoidosis involving the testis and epididymis demonstrates well-defined noncaseating granulomas.12
CHECKLIST: Differential Diagnosis of Granulomatous Processes in the Testis and Paratestis13
□ Fungal infection
□ Tuberculosis
□ Sarcoidosis
□ Vasculitis
□ Malakoplakia
□ Sperm granuloma
□ Sclerosing lipogranuloma
□ Seminoma with brisk granulomatous response
Malakoplakia
Malakoplakia can involve the testis and epididymis similar to other anatomic regions in continuity with the urinary tract. It involves the testis alone in more than two-thirds of cases and the testis and epididymis in a smaller percentage. Similar to other genitourinary cases, it is associated with chronic E. coli infections. It has a similar appearance of sheets of histiocytes, some of which contain targetoid inclusions (Michaelis-Gutmann bodies) (Figures 4.43 and 4.44). The process can be mass forming and lead to a concern for malignancy. Leydig cell tumor shares similar morphologic features of numerous cells with abundant eosinophilic cytoplasm; however, this differential is easily resolved with immunohistochemistry (Figure 4.45). Malakoplakia will show diffuse positivity for CD68 with an iron stain highlighting Michaelis-Gutmann bodies, and Leydig cell tumor will not express CD68 and show diffuse staining for inhibin and calretinin.12
 Figure 4.42. Granulomatous inflammation within the testis presents a broad differential diagnosis. In this image, the giant cells are of Langhans type, raising the possibility of tuberculous epididymo-orchitis. |
 Figure 4.43. At low power, malakoplakia appears as sheets of eosinophilic histiocytes with scattered chronic inflammation. |
 Figure 4.44. Close inspection of the histiocytes reveals basophilic rounded inclusions within the cytoplasm, some of which have a targetoid appearance. These inclusions are Michaelis-Gutmann bodies, which result from incomplete phagocytosis of bacterial organisms. |
 Figure 4.45. The epithelioid nature of the histiocytes with their abundant eosinophilic cytoplasm leads to some morphologic overlap with Leydig cell tumors. |
Sperm Granuloma
Sperm granulomas form in reaction to extravasated sperm, which may occur after trauma or vasectomy. The resultant mass is painful and may mimic malignancy. These lesions are centered in the epididymis, with an initial neutrophilic response to sperm which evolves to granulomatous inflammation and fibrosis.12
TORSION AND VASCULITIS
Altered blood supply to the testis results in areas of infarction. The blood supply may be disrupted as a result of torsion, where the spermatic cord twists and cuts off the afferent blood supply, or vasculitis, where damaged blood vessels deliver insufficient blood to the testis. The clinical presentation of either type of the infarct is severe pain, which usually prompts a clinical examination and testicular ultrasound.
If torsion is suspected clinically, the urologist may first attempt a gentle twist of the testicle to see if blood flow can be quickly restored. Complete occlusion of blood supply to the testis can result in loss of a testicle, so this is treated as a urologic emergency. If the scrotal ultrasound shows no blood flow after the attempt to untwist the testis and the testicle is considered nonviable, an orchiectomy is performed. Depending on the time interval between initial torsion and orchiectomy, different histologic appearances are seen. Because the blood supply to the entire testis is affected in torsion, all of the parenchyma is infarcted. In the acute phase, there is hemorrhagic infarct with dilated vessels and extravasated red blood cells surrounding relatively normal tubules (Figure 4.46). As the time interval increases, the tubules begin to show necrosis, and fibrinoid vascular necrosis may predominate.
Isolated acute torsion is the primary cause of testicular torsion and has been associated with the bell-clapper deformity, which permits the testis to rotate within the tunica vaginalis. Given this association and the possibility of a bilateral deformity, orchidopexy is performed on the contralateral testis to ensure it does not torse in the future. There is also some evidence that torsion may be intermittent; histologic findings in these cases show vasculitis manifested by chronic vasculitis and fibrinoid necrosis of vessels, without any history or future development of systemic vasculitis.14
The differential diagnosis of an ischemic testis includes vasculitis. Testicular vasculitis is often a manifestation of a systemic process. Obtaining the patient’s clinical history may reveal signs and symptoms of vasculitis affecting other organs. Polyarteritis nodosa (PAN)-like vasculitis is the most common type of vasculitis to affect the testis. Less commonly,
granulomatosis with polyangiitis is responsible for testicular vasculitis.15 The full differential diagnosis of the specific type of vasculitis depends on the size of vessels involved and is beyond the scope of this chapter. Regardless, recognition of a vasculitic process in the testis should prompt additional clinical workup.
granulomatosis with polyangiitis is responsible for testicular vasculitis.15 The full differential diagnosis of the specific type of vasculitis depends on the size of vessels involved and is beyond the scope of this chapter. Regardless, recognition of a vasculitic process in the testis should prompt additional clinical workup.
The most important clue to the diagnosis of vasculitis is the presence of a segmental, rather than global, infarct (Figures 4.47 and 4.48). In the area of infarct, tubules may be completely necrotic, and only the outlines of “ghost tubules” remain (Figure 4.49). This often will involve only one lobule of the testis, with the remainder staying perfused and viable. In cases of segmental infarct, close inspection of the vessels is necessary to identify features of vasculitis: leukocytoclasis, red cell extravasation, fibrinoid necrosis, and granulomatous or nongranulomatous inflammation (Figures 4.50 and 4.51).
 Figure 4.46. Acute testicular torsion in a pediatric patient showing diffuse hemorrhage within the interstitium. A subset of the tubules appears necrotic in the upper right corner, while others remain viable. If vascular occlusion persists, all of the tubules will become necrotic. |
 Figure 4.47. A segmental infarct of the testis resulting in focal necrosis of tubules, surrounded by viable tubules. This finding should prompt close examination of the vessels both adjacent and remote from the infarct. |
 Figure 4.48. Another low-power image demonstrating the focal necrosis of a segmental infarct, with necrotic tubules immediately adjacent to viable tubules. |
 Figure 4.49. Area of remote infarction showing outlines of necrotic tubules with surrounding inflammation. |
 Figure 4.50. Close examination of the vessels of the testis should be undertaken for signs of vasculitis. At high power, leukocytoclasis—neutrophils transgressing the vessel wall—is identified in this specimen. |
 Figure 4.51. This vessel has been obliterated with fibrinoid necrosis evident in the vessel wall. Extravasated red blood cells are present surrounding the vessel, consistent with damaged, leaky vessels. |
TESTICULAR TUMORS
Testicular tumors include all of the benign and malignant neoplasms arising in the testicular parenchyma, located within the tunica albuginea. The most common category of tumors within the testis is GCTs, those tumors that originate from the primordial germ cell.16 These tumors can have a vast array of differing morphologies and will be discussed based on their general patterns below. It is important to know that while GCTs can arise in pure forms, especially in children, they are most commonly encountered as mixed GCTs comprised of multiple tumor types. The second most common category of testicular tumors is sex cord stromal tumors, which arise from the supporting cells within the testicular interstitium. The last category of testicular tumors is those that involve the testis secondarily in the form of metastatic disease or direct extension. The classic categorization of testicular tumors by cell of origin as designated in the 2016 WHO monograph is included in Table 4.4.17
When evaluating a testicular tumor, it is useful to start with a pattern-based approach. Specifically, recognizing whether you are dealing with a pure or mixed pattern can help direct you to a category—sex cord stromal tumors are generally a pure population of cells, whereas GCTs are often mixtures of different tumor types. Pure GCTs do occur, more commonly in children than in young adults. Once a general category of tumor is favored, or a focused differential diagnosis is formed, immunohistochemistry can be employed to confirm your impression.
The discussion on testicular tumors will be organized based on overall pattern recognition, with monomorphic or “pure” cell populations discussed first, followed by pleomorphic and organoid (forming organized cellular structures.)
MONOMORPHIC
Tumors in this category show a generally monomorphic pattern of growth. At scanning magnification, this group of neoplasms typically demonstrates solid or diffuse architecture. The cells are largely monotonous, with each individual cell looking quite similar to its neighboring cells in most cases. By pattern, the tumors included in monomorphic category include seminoma, lymphoma, Leydig cell tumor, granulosa cell tumor, and carcinoid/neuroendocrine tumor.
Seminoma
Seminoma is the most common GCT of the testis, comprising almost 50% of testicular GCTs. Seminoma is also the most common pure GCT, though it is also commonly identified in mixed GCTs. In clinical terms, a mixed GCT that contains any component other than
seminoma would be considered “nonseminomatous,” despite the presence of a seminoma component. This can be confusing as “nonseminomatous” does not exclude the presence of some amount of seminoma in a mixed GCT.
seminoma would be considered “nonseminomatous,” despite the presence of a seminoma component. This can be confusing as “nonseminomatous” does not exclude the presence of some amount of seminoma in a mixed GCT.
The gross appearance of seminoma is a well-circumscribed, white-tan fleshy lobulated mass (Figure 4.52). The gross lobular growth pattern is derived from the fibrous septa found within the tumor (Figure 4.53). Along the septa and scattered with the sheets of tumor are lymphocytes (Figure 4.54). At low power, the pattern of a white or cleared out area interrupted by pink (fibrosis) and blue (lymphocytes) is a useful pattern to recognize for seminoma.
Microscopically, the tumors show monotonous sheets of large cells with clear cytoplasm, polygonal nuclei (often with rounded square corners), and prominent central nucleoli. The classic description of these cells is the “fried egg” appearance, of a yolk in the middle of the cooked white (Figures 4.55 and 4.56). However, seminoma may exhibit more eosinophilic cytoplasm or even very scant cytoplasm. It is also common to see a granulomatous reaction within the tumor with numerous plump histiocytes, which may be located within tubules (Figure 4.57). The presence of a granulomatous reaction within the testis should prompt a careful search for possible seminoma or GCNIS (Figures 4.58 and 4.59). Likewise, clusters of lymphocytes are a helpful clue for possible intertubular seminoma, small tumors which may be grossly undetectable.12
TABLE 4.4: Malignant Testicular Tumors, Organized by Cell of Origin | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 Figure 4.52. Gross photograph of a testis with seminoma. The gross appearance shows a white-tan, lobulated mass that bulges on cut section. |
 Figure 4.53. At low power, fibrous septa are evident as pink bands intersecting lobules of tumor. These bands correspond to the gross lobulated appearance. |
 Figure 4.54. Lymphocytes are often closely associated with seminoma and often congregate along the fibrous septa. |
 Figure 4.55. Cytologically, seminomas are often described as “fried egg” cells with abundant clear cytoplasm, polygonal nuclei, and prominent nucleoli. The clear cytoplasm and relatively low nuclear-to-cytoplasmic ratio give the tumor an overall white appearance. |
 Figure 4.56. Nuclear features of seminoma are demonstrated in this image with the polygonal, squared-off nuclei and prominent macronucleoli. |
 Figure 4.57. A granulomatous reaction is frequently present in seminomas. Plump eosinophilic histiocytes are present along with lymphocytes and seminoma cells. The finding of histiocytic reaction in a testis should prompt a close examination for possible seminoma cells. |
 Figure 4.58. A brisk histiocytic response and numerous admixed lymphocytes in this image should raise suspicion for a possible seminoma. |
 Figure 4.59. The presence of germ cell neoplasia in situ (GCNIS) (arrow) within the tubules also suggests a germ cell tumor is present. |
Syncytiotrophoblastic cells may also be present in classic seminoma and do not represent a component of choriocarcinoma. These cells are large and multinucleated with abundant cytoplasm, morphologically identical to their counterparts in choriocarcinoma (Figures 4.60 and 4.61). Syncytiotrophoblastic cells can produce beta-human chorionic gonadotropin (bHCG) in measurable quantities—usually in the hundreds, rather than the thousands, which is more commonly seen when a choriocarcinoma is present. Presence of syncytiotrophoblastic cells and mild elevations in bHCG in an otherwise pure seminoma are not sufficient evidence of a choriocarcinoma.
Seminoma classically expresses OCT3/4, placental alkaline phosphatase (PLAP), and KIT, with OCT3/4 being the most specific stain for this entity. OCT3/4 also stains embryonal carcinoma, however. In seminomas with syncytiotrophoblastic cells, these multinucleated cells will stain for bHCG and should not be confused with a choriocarcinoma component.
PEARLS AND PITFALLS: Uncommon Architectural Patterns of Seminoma
While classically solid, less common patterns of seminoma have been described and may cause confusion with other GCTs
Unusual morphologic variants and their nonseminomatous mimickers include:
Microcystic → yolk sac tumor (YST)18
Pseudoglandular → embryonal carcinoma (Figures 4.62 and 4.63)
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