I. NORMAL ANATOMY. The normal adult testis is an ovoid paired organ, measuring 4.5 × 2.5 × 3 cm3, and weighing approximately 20 g. The testes are suspended within scrotal sacs by spermatic cords. The testis is covered by a capsule composed of an outer tunica vaginalis lined by mesothelium, the collagenous tunica albuginea, and the inner tunica vasculosa. The tunica vaginalis forms a sac filled with serous fluid. The posterior portion of the testis not covered by a capsule is called the mediastinum and contains blood vessels, nerves, lymphatics, and the extratesticular rete testis.
The testicular parenchyma is subdivided into lobules containing seminiferous tubules separated by fibrous septae. The terminal portions of the seminiferous tubules drain into the tubuli recti that connect to the tubules of the rete testis at the mediastinum. The tubules of the rete testis anastomose with the ductuli efferentes, which form the head of the epididymis and empty into the vas deferens, which traverses the inguinal canal as a component of the spermatic cord. The testicular artery arises from the aorta and is the major source of vascular supply to the testes.
The venous drainage occurs through numerous small veins that form a convoluted mass known as the pampiniform plexus that surrounds the testicular artery. These small veins anastomose to form the right testicular vein, which drains into the inferior vena cava, and two left testicular veins, which drain into the left renal vein.
Histologically, prepubertal and postpubertal seminiferous tubules are quite different. Prepubertal tubules are small, with few or no lumina, and contain mostly Sertoli cells with a few primordial germ cells (e-Fig. 28.1).* Postpubertal seminiferous tubules are larger and harbor Sertoli cells and germ cells at varying stages of maturation (e-Fig. 28.2). The Sertoli cells abut the basement membrane and are aligned perpendicular to the membrane; their nuclei are round to oval with prominent nucleoli, and the cytoplasm has Charcot-Böttcher crystals, which can occasionally be seen by light microscopy. Within the seminiferous tubules, the least mature germ cells—spermatogonia—are present along the basement membrane, with the most mature cells—elongate spermatids—found at the luminal border. Primary and secondary spermatocytes are found in an adluminal position.
The interstitial tissue between the seminiferous tubules contains Leydig cells, vessels, and connective tissue. Leydig cells are arranged singly and in clusters
(e-Fig. 28.3), and can be associated with nerves. They are large and irregularly spherical to polyhedral, with small spherical nuclei and abundant acidophilic cytoplasm. The cytoplasm can exhibit lipofuscin and rod-shaped Reinke crystals.
II. GROSS EXAMINATION, TISSUE SAMPLING, AND HISTOLOGIC SLIDE PREPARATION. Tissue samples of the testes received for surgical pathologic examination include testicular biopsies, and unilateral and bilateral orchiectomy specimens. Retroperitoneal lymph node dissection can be performed as part of a staging maneuver for testicular cancer.
A. Fine needle aspiration biopsy of the testis in infertile patients (with sperm aspiration and cytopathologic examination) is occasionally performed. Cytologic touch imprints or wet preparations may be made at the time of open testicular biopsy in infertile patients to rapidly identify the presence of sperm. The role of cytology in the evaluation of testicular tumors is limited to diagnosis of lymph node metastases by fine needle aspiration. Although seminomas can usually be differentiated from nonseminomatous tumors, subtyping of nonseminomatous tumors cannot be reliably performed by cytology.
B. Testicular biopsies, which can be open or percutaneous, are typically performed for evaluation of infertility. They are usually contraindicated in the evaluation of solid testicular masses, with the possible exception of epidermoid cysts, which can be removed by excisional biopsy. Testicular biopsy specimens are usually received in Bouin’s fixative. An accurate documentation of the number and size of the biopsy fragments and exact site(s) of the biopsy for each container should be made during gross dictation. The biopsy fragments should be inked with hematoxylin to facilitate identification during embedding, wrapped in lens paper, placed between sponges, and processed entirely. Three hematoxylin and eosin (H&E)-stained slides, each with three to four serial sections, should be prepared from each block.
C. Unilateral simple orchiectomy is performed in cases of testicular torsion. Gross examination of the testis similar to that for tumor cases should be performed. One section of the testicular parenchyma in relation to the capsule, and a section each of the epididymis and spermatic cord, should be submitted with description and sampling of focal lesions.
D. Radical orchiectomy is performed for testicular tumors. The specimen consists of the testis and paratesticular organs (surrounding tunica vaginalis, epididymis, soft tissue, and a segment of spermatic cord). In cases of tumor resection, the specimen should ideally be sent fresh and intact to the surgical pathology laboratory for immediate gross examination. Alternatively, when delay is anticipated, the specimen is placed in 10% buffered formalin and sent intact. In such cases, tumor morphology is often suboptimal due to poor fixation. The surgeon may occasionally bisect the specimen to aid fixation; this approach is not recommended as it prevents evaluation of involvement of the tunica by the tumor as well as procurement of fresh tissue for ancillary studies.
The specimen is weighed, and measurements are recorded in three dimensions. The length and diameter of the resected segment of spermatic cord are noted separately. The external surfaces of the testis and spermatic cord are examined for involvement by tumor. The proximal shave resection margin of the spermatic cord is submitted in a separate cassette, and then the cord is serially sectioned and inspected for tumor involvement; representative sections are submitted proximal to distal. The tunica vaginalis is opened anteriorly to show the tunica albuginea; presence of fluid, if any, within the sac is noted. The testis is then bisected anteroposteriorly through the epididymis, and serial sections are made parallel to this plane. Each slice is examined, and the tumor is described in relation to the epididymis and the tunica albuginea. The size, color, and consistency of the tumor should be noted. Foci of hemorrhage, necrosis, and variegation, as well as multifocality, if present, should be described.
Photographs or digital images should be taken and tissue procured for tumor bank and ancillary studies such as flow cytometry and karyotyping, if necessary. The specimen should then be fixed overnight in an adequate amount of 10% buffered formalin prior to submission of one section per centimeter of tumor. Representative sections should include heterogenous areas and sections of tumor in relation to uninvolved parenchyma, epididymis, and tunica albuginea. One section of grossly normal-appearing parenchyma should be included. If correlation of identified histologic tumor type with serum markers (alpha-fetoprotein [AFP] and human chorionic gonadotropin [hCG]) is not achieved, additional sections should be submitted (note that such correlation will not always be perfect because metastatic deposits may harbor different elements than the primary tumor).
E. Retroperitoneal lymph node dissection is performed as a separate procedure. The specimen is received in 10% buffered formalin. During gross examination, the tissue fragments should be measured in aggregate and carefully dissected to harvest as many lymph nodes as possible, and the size of the largest and the smallest putative nodes should be noted. Possible foci of tumor encountered during dissection should be measured and sampled. An effort should be made to sample any area(s) suspicious for viable tumor.
F. Bilateral orchiectomy specimens may be submitted as part of treatment of carcinoma of the prostate. Gross examination and sectioning are similar to that for unilateral simple orchiectomy. Prostate cancer is rarely encountered within these specimens.
III. DIAGNOSTIC FEATURES OF BENIGN DISEASES OF THE TESTIS
A. Congenital abnormalities
1. Cryptorchidism is maldescent of the testis in which the testis is found, after 1 year of age, to be located high in the scrotum, within the inguinal canal, or in an intra-abdominal location. Grossly, the prepubertal undescended testis differs little from normal, but after puberty the undescended testis is smaller. Histologically, there is a progressive loss of germ cells with age, along with decreased size of seminiferous tubules and increased thickness of tubular tunica propria. Sertoli cell nodules (e-Fig. 28.4), which are foci of tubules containing immature Sertoli cells and laminated calcific deposits, are often seen in cryptorchid testes. These are likely hyperplastic foci, although they have also been termed tubular adenoma of Pick. Rarely, Sertoli cell nodules can present as a mass (Am J Surg Pathol. 2010;23:1874). The major complications of cryptorchidism are infertility and germ cell neoplasia, ranging from intratubular germ cell neoplasia (IGCN) to invasive germ cell tumors, particularly seminoma, embryonal carcinoma, and embryonal carcinoma/teratoma. For patients >1 year of age, placental-like alkaline phosphatase (PLAP) and CD117 immunostains can be useful in highlighting intratubular germ cell neoplastic cells.
2. Anorchism and polyorchidism are absence of testes and more than two testes, respectively.
3. In testicular-splenic fusion, encapsulated splenic tissue is found adjacent to the left testis, which can show germ cell aplasia in the seminiferous tubules.
4. Adrenal cortical rests are usually incidental, millimeter-sized nodules of adrenal cortical tissue that are detected along the pathway of descent of the testis, including along the spermatic cord and testis.
B. Infertility. The causes of infertility may be pretesticular, which include endocrine disorders involving the pituitary and adrenal glands; testicular, including genetic disorders; or posttesticular, which are mainly obstructive and include varicocele and cystic fibrosis. The evaluation of the patient includes a detailed clinical history, physical examination, semen analysis, tests of endocrine function, analysis of sperm function, and serology for antisperm antibody. Testicular biopsy
(preferably open biopsy) is indicated in cases where an endocrine dysfunction has been ruled out. Biopsies from patients with azoospermia may show germ cell aplasia (Sertoli cell only) (e-Fig. 28.5), maturation arrest (e-Fig. 28.6), and/or normal spermatogenesis that points to an obstructive etiology (Arch Pathol Lab Med. 2010;134:1197). Patients with oligospermia show a combination of one or more of the following: tubular hyalinization, fibrosis, hypospermatogenesis, normal or arrested spermatogenesis, and sloughing or disorganization. Although testicular biopsies are rarely performed in cases of endocrine dysfunction, the findings include small tubules with fibrosis and basement membrane thickening, and Leydig cell aplasia or hyperplasia. Synoptic-style reporting of testicular biopsies for infertility is described in Table 28.1.
TABLE 28.1 Reporting Infertility Biopsies
1. Method of obtaining sample
a. Percutaneous testis sperm aspiration
b. Incisional testis sperm extraction
2. Presence/absence of testicular tissue
3. Seminiferous tubules
b. Tunica propria: Normal/thickened
c. Mean number of spermatozoa/tubule (count 20 tubules)
d. Most advanced stage of spermatogenesis
e. Sertoli cells: Present/absent
a. Leydig cells: Present/absent/hyperplastic
b. Amount of interstitial inflammation
c. Presence of macrophages and mast cells
5. Extratesticular/other comments
a. Epididymis: Present/absent
b. Vas deferens: Present/absent
c. Immunohistochemical/special stains
6. Histologic diagnoses
a. The most advanced histologic pattern is:
b. The predominant histologic pattern is:
C. Inflammation and infection.
1. Epididymitis is typically more common and severe than orchitis, and is commonly related to urinary tract infection (from the urinary bladder, urethra, or prostate) by Chlamydia, Neisseria, Escherichia coli, or Pseudomonas. Tissue sampling is not needed for the diagnosis of orchitis and/or epididymitis.
2. Most cases of orchitis are due to infection that spreads from the vas deferens and epididymis. Infectious agents that can cause orchitis include bacteria, mycobacteria, fungi, viruses, or spirochetes.
a. Tuberculous orchitis always emanates from another site and spreads into the testis from the epididymis or bloodstream. Both testes are usually involved. The testicular inflammatory infiltrate varies from nonspecific to caseating granulomas.
b. Mumps orchitis is caused by a paramyxovirus. Microscopically, there is an initial interstitial lymphocytic inflammatory infiltrate, followed by a mixed infiltrate that can result in tubular atrophy and peritubular fibrosis.
c. Syphilitic orchitis occurs prior to infection of the epididymis. Histologically, peritubular lymphocytes and plasma cells can be seen along with obliterative endarteritis and perivascular plasma cells. Gummas can form an intratesticular mass with central necrosis.
d. Other types of orchitis include nonspecific granulomatous orchitis and malakoplakia. Before diagnosing nonspecific granulomatous orchitis, a specific infectious orchitis, sarcoidosis, lymphoma, and exuberant granulomatous inflammation associated with a germ cell neoplasm should be excluded.
D. Vascular disorders
1. Systemic vasculitis can affect the testis, but isolated vasculitis involving only the testis is rare. Testicular vasculitis can cause infarction that clinically simulates a neoplasm. Most cases of testicular vasculitis are characterized by polyarteritis nodosa-like changes in small- to medium-sized arteries, with transmural necrotizing inflammation (Urology. 2011;77:1043).
2. Varicocele is an abnormal dilatation and tortuosity of veins of the pampiniform plexus of the spermatic cord.
3. Torsion and infarction generally occur in young men and in the setting of abnormal testicular descent. Initially, there is congestion, edema, and hemorrhage, followed by hemorrhagic infarction (e-Fig. 28.7).
E. Atrophy can be caused by many factors, but the morphologic findings are similar. Grossly, the testis is small. Microscopically, the tubules are decreased in size and the tunica propria is thickened and hyalinized. End-stage atrophic tubules are completely hyalinized, without intraluminal cells (e-Fig. 28.8).
IV. TUMORS OF THE TESTIS. These are of germ cell origin in the vast majority of cases, with sex cord/gonadal stromal tumors occurring in 4% to 6% of cases. The highest incidence is found in Europe and parts of New Zealand. Populations in Africa and Asia show a much lower incidence. The 2004 World Health Organization classification of the neoplasms of the testis is given in Table 28.2.
A. Germ cell tumors. Clinical diagnosis is usually made when the patient presents with a painless mass in the testis. Associated symptoms such as a dull ache in the scrotum or lower abdomen may be present. Less commonly, patients present with gynecomastia and thyrotoxicosis. In 10% of cases, metastatic disease may produce presenting signs and symptoms. Patients with cryptorchidism are at an increased risk (about three- to fivefold) of developing germ cell neoplasia both in the cryptorchid and in the normal contralateral testis. Patients with testicular microlithiasis, testicular atrophy, infertility, a family history of germ cell neoplasia, 46,XY or 45,X/46,XY mixed gonadal dysgenesis, testicular dysgenesis syndrome (TDS), or a previous history of IGCN are also at an increased risk. The age of the patient as well as characteristic elevations in the levels of serum tumor markers in different subtypes of germ cell tumors can be very helpful in predicting tumor type. Yolk sac tumor and/or teratoma are seen in infants and children; seminomas and nonseminomatous germ cell neoplasms (including embryonal carcinoma, teratoma, yolk sac tumor, and choriocarcinoma) are found in adolescents and young adults; and spermatocytic seminoma occurs in patients older than 50 years. Serum AFP levels can be elevated in nonseminomatous germ cell tumors, especially those with a yolk sac tumor component, whereas serum beta-hCG levels are increased in choriocarcinoma and tumors with syncytiotrophoblasts, which include about 10% of seminomas. The levels of these tumor markers are monitored posttreatment and are indicators of residual disease.
Imaging studies such as ultrasound are extremely sensitive and inexpensive in evaluating testicular masses. Localization of the mass, including evaluation of extratesticular versus intratesticular sites of involvement, and presence of heterogeneity within the tumor can be accurately determined. Epididymal lesions cannot be characterized with a similar degree of sensitivity. Computed tomography and magnetic resonance imaging are not used as primary diagnostic tools but can be helpful in tumor staging.
TABLE 28.2 WHO Histologic Classification of Tumors of the Testis and Paratestis
Germ cell tumors
Tumors of one histologic type (pure forms)
Seminoma with syncytiotrophoblastic cells
Spermatocytic seminoma with sarcoma
Yolk sac tumor
Trophoblastic neoplasms other than choriocarcinoma
Placental site trophoblastic tumor
Teratoma with somatic type malignancies
Tumors of more than one histologic type (mixed forms)
Mixed embryonal carcinoma and teratoma
Mixed teratoma and seminoma
Choriocarcinoma and teratoma/embryonal carcinoma
Sex cord/gonadal stromal tumors
Leydig cell tumor
Malignant Leydig cell tumor
Sertoli cell tumor
Sertoli cell tumor, lipid-rich variant
Sclerosing Sertoli cell tumor
Large cell-calcifying Sertoli cell tumor
Malignant Sertoli cell tumor
Granulosa cell tumor
Adult-type granulosa cell tumor
Juvenile-type granulosa cell tumor
Tumors of the thecoma/fibroma group
Sex cord/gonadal stromal tumor
Sex cord/gonadal stromal tumors, mixed forms
Malignant sex cord/gonadal stromal tumors
Tumors containing both germ cell and sex cord/gonadal stromal elements
Germ cell sex cord/gonadal stromal tumor, unclassified
Miscellaneous tumors of the testis
Tumors of ovarian epithelial types
Serous tumor of borderline malignancy
Well-differentiated endometrioid carcinoma
Tumors of collecting ducts and rete
Tumors of paratesticular structures
Well-differentiated papillary mesothelioma
Adenocarcinoma of the epididymis
Papillary cystadenoma of the epididymis
Melanotic neuroectodermal tumor
Desmoplastic small round cell tumor
Mesenchymal tumors of the spinal cord and testicular adnexae
Secondary tumors of the testes
From: Eble JN, Sauter G, Epstein JI, et al., eds. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press; 2004. Used with permission.
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