Tumors of Dog Testis

Bethany Sabatino, DVM and Jagannatha Mysore, MVSc, PhD, DACVP

Class of 2007 (Sabatino), College of Veterinary Medicine, Mississippi State University and Department of Pathology (Mysore), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Primary testicular neoplasms are common in dogs greater than 6 years old, with a mean age at diagnosis of 10 years.⁷ The most common primary testicular neoplasms – seminoma, sustentacular (Sertoli) cell tumor, and interstitial (Leydig) cell tumor – occur with approximately equal frequency.³ Metastases is uncommon, particularly in Leydig cell tumors.¹ Approximately one third of all cases of Sertoli cell tumor are hormonally productive, and may be associated with signs of hyperestrogenism such as feminization, gynecomastia, symmetrical alopecia, bone marrow atrophy, squamous metaplasia of the prostate, and atrophy of the contralateral testicle.² Other testicular neoplasms are rarely hormonally productive. Testicular neoplasms may be unilateral or bilateral, and are often mixed-origin, especially in cryptorchid testicles.²

Signalment and Risk Factors

As with most neoplastic diseases, testicular tumors are most common in older animals. The mean age at diagnosis is reportedly 10 years old, with increased risk in dogs greater than 6 years old. Among dog breeds, increased risk reported in the boxer, German shepherd, Afghan hound, Weimaraner, and Shetland sheepdog.⁹ The most consistent risk factor for the development of testicular tumors appears to be cryptorchidism.

Classification

Primary testicular tumors can be grossly and histologically classified into four main groups according to their origin: (1) Sex-Cord Stromal Tumors, (2) Germ Cell Tumors, (3) Mixed Tumors, and (4) Miscellaneous Tumors.

(1) Sex-Cord Stromal Tumors are derived from sustentacular (Sertoli) or interstitial (Leydig) cells. The normal function of these cells is to provide structural and physiological support to nearby gametocytes.

Sex-Cord Stromal Testicular Tumors - Sustentacular (Sertoli) Cell tumors

Normal Sertoli Cell Physiology

Structurally, Sertoli cells with contractile myoid cells form a series of tight junctions which aid in the formation of the blood-testis barrier, an important immunoregulating layer.³ In addition to providing structural support, Sertoli cells produce several hormones involved in the regulation of normal reproductive physiology. The most notable hormones produced by Sertoli cells are estrogen, inhibin, and Mullerian inhibiting hormone (MIH).³

Clinical Syndromes Associated with Sertoli Cell Tumors

Approximately one third of dogs with Sertoli cell tumor will manifest signs of apparent hyperestrogenism, characterized by any combination of feminization, gynecomastia, atrophy of the contralateral testicle, squamous metaplasia within the prostate gland (often with accompanying suppurative prostatitis), symmetrical alopecia, and bone marrow atrophy.¹ The mechanisms for these clinical syndromes have not been completely described. The incidence of feminization increase from approximately 15% with scrotally located Sertoli cell tumors to 70% in abdominally located Sertoli cell tumors.^{6, 8}

The first manifestations of a functional Sertoli cell tumor are usually changes in the skin and hair coat. Bilaterally symmetrical alopecia typically starts at the genital area and extends craniodorsally with time. The skin is usually hyperpigmented and the hair is often easily epilated.⁶ Microscopically, the epidermis varies from normal thickness to moderately acanthotic, with follicular atrophy and a thin dermis.⁶ Approximately one fourth of dogs with feminizing syndrome are attractive to other male dogs similar to a bitch in heat.⁶ Redistribution of body fat, gynecomastia with or without mammary secretions, and squamous metaplasia of the prostate are also frequently apparent. Marked squamous metaplasia of the epithelial lining of the ducts and glands of the prostate can lead to glandular obstruction with secondary cyst formation. Secondary infection frequently develops in these cystic glands, and prostatic abscessation may result.⁶ In non-metastasized tumors, most of the signs of hyperestrogenism disappear after castration, however, the effects of severe bone marrow suppression may be irrevocable due to the acquisition of secondary disease. Bone marrow effects are initially characterized by transient increased granulocytopoiesis and neutrophilic leukocytosis, followed by decreased hematopoiesis leading to progressive leukopenia, thrombocytopenia, and nonregenerative anemia.⁸ The resulting thrombocytopenia may precipitate a hemorrhagic diathesis, and overwhelming bacterial infection may occur subsequent to granulocytopenia. These stages of the syndrome are often refractive to treatment and progress to death.⁸

Figure 1.A.1. Typical gross appearance of a Sertoli cell tumor. The tumor is large, firm, diffuse, and white, with extensive distortion of surrounding testicular tissue. (Picture used with permission from Noah’s Arkive, UGA)	Figure 1.A.2.  Histological appearance of an intratubular Sertoli cell tumor.  Note elongate cells with indistinct borders, and the presence of fibrous tissue.  (Picture used with permission from Noah’s Arkive, UGA)

Gross and Histological Appearance of Sertoli Cell Tumors

The Sertoli cell tumor is generally the firmest of the canine testicular tumors.¹ These tumors can become quite large and are typically nodular or multinodular to discrete with a diffuse white or gray appearance (Figure 1.A.1.).^1,4 Tan or yellow areas of hemorrhage or fluid-filled cysts are occasionally observed.^1,2 Tumors are histologically sub-classified as intratubular or diffuse, with the diffuse subtype representing a continued progression of the intratubular type to a more infiltrative pattern.² The tumor cells are elongate with indistinct borders and oval or spindle shaped nuclei (Figure 1.A.2.). Their cytoplasm is typically eosinophilic, vacuolated or dense, with lipochrome pigment granules.^1,2 Both patterns of neoplastic Sertoli cells elicit a sizable fibrous stromal response which often undergoes hyalinization.^1,2

Metastatic Potential of Sertoli Cell Tumors

Sertoli cell tumors are almost always benign, with the rate of metastasis reportedly less than 10%.⁵ Metastasis is more likely to occur in large tumors of the diffuse subtype.¹ The most common site of metastasis is regional lymph nodes, but metastasis to a wide variety of internal organs has also been reported.⁷ Metastatic nodules may be hormonally active, and they typically have a histological appearance similar to the primary tumor.¹

Sex-Cord Stromal Testicular Tumors - Interstitial (Leydig) Cell tumors

Normal Leydig Cell Physiology

Normal interstitial (Leydig) cells lie in the interstices between the seminiferous tubules and constitute about 20% of the mass of the adult testes.¹⁰ Under the stimulus of luteinizing hormone (LH), these cells secrete several androgenic hormones, including testosterone, dihydrotestosterone, and androstenedione.¹⁰

Figure 1.B.1. Typical gross appearance of an Interstitial (Leydig) cell tumor. The tumor is small, soft, focal, and yellow, with minimal distortion of surrounding testicular tissue. These tumors are often associated with hemorrhagic nodules. (Picture used with permission from Noah’s Arkive, UGA)	Figure 1.B.2. Histological appearance of a solid/diffuse Interstitial (Leydig) cell tumor. Note the variably shaped cells with dull, eosinophilic cytoplasm arranged in sheets separated by thin strands of connective tissue. (Picture used with permission from Noah’s Arkive, UGA)

Gross and Histological Appearance of Leydig Cell Tumors

Leydig cell tumors are grossly distinct as small, yellow to brown, soft, well circumscribed, sharply delineated masses that typically produce little or only subtle distortion of the affected testicle (Figure 1.B.1).^1,2 The tumor is predisposed to hemorrhage, which causes dark discoloration, and to cyst formation in areas.³ Tumors are histologically sub-classified as solid/diffuse, cystic/vascular, or pseudoadenomatous, but such classification appears to have little relationship to the biological behavior of the tumor.^1,3 Regardless of the subtype, tumor cells are often variable in appearance. They may be polyhedral, cuboidal, or columnar, with small, round, dark nuclei and an eosinophilic, dull cytoplasm (Figure 1.B.2) that is often vacuolated.² Mitotic figures are extremely unusual. In the dog, the cytoplasm typically contains lipid, and some cells may contain lipochrome pigments.²

Metastatic Potential and Behavior of Leydig Cell Tumors

Even though interstitial (Leydig) cells normally secrete androgens, Leydig cell tumors rarely produce clinically evident manifestations of excessive androgen secretion.¹ Metastasis is extremely rare, and interstitial (Leydig) cell tumors are thought to be the least likely of the testicular tumors to metastasize.³

(2) Germ cell tumors of the testis are derived from precursors of meitotically-active sex cells. Seminoma, teratoma, embryonal carcinoma, and yolk sac carcinoma are all derived from germ cells, but seminoma is the only one that occurs frequently in domestic animals.¹

Germ Cell Testicular Tumors - Testicular Seminomas

Origin of Testicular Seminomas

The seminoma of the testis develops from germ cells before somatic differentiation.² They arise from cells of the spermatogenic series, presumably from basal spermatogonia.³ The etiology is not well understood, but cryptorchidism and increased age are well-known risk factors.¹ These tumors do not secrete hormones, and they rarely metastasize.³

Figure 2.A.1. Typical gross appearance of a testicular seminoma (right) is pictured next to a normal testicle (left). The seminoma is large, semi-firm, diffuse, and white, with extensive distortion of surrounding testicular tissue. (Picture used with permission from Noah’s Arkive, UGA)	Figure 2.A.2. Histological appearance of diffuse testicular seminoma. Note the presence of large polyhedral tumor cells with sharp borders and basophilic cytoplasm. A mitotic figure is present in the center of the image. (Picture used with permission from Noah’s Arkive, UGA)

Gross and Histological Appearance of Testicular Seminomas

Testicular seminomas are typically focal to diffuse and flaccid to semi-firm with a homogenous glistening gray/white appearance on cut surface.¹ Similar to Sertoli cell tumors, they are often lobulated and compress the surrounding testicular tissue (Figure 2.A.1).² Occasional foci of necrosis and hemorrhage may be present.² The texture of seminomas helps differentiate them from Sertoli cell tumors, which are usually more firm.¹ Seminomas have a unique histological appearance, and are sub-classified as intratubular and diffuse/solid. The diffuse subtype is a continued progression of the intratubular type to a more infiltrative pattern, and no proven correlation exists between subtype and metastatic behavior.² Tumor cells are highly characteristic and appear as very large, polyhedral cells with sharp borders, vesicular nuclei, prominent nucleoli, and scant basophilic to amphophilic cytoplasm.¹ In many seminomas, multinucleate cells are common, and mitotic figures are typically numerous and bizarre (Figure 2.A.2.).^1,2 Tumors may be subdivided by loose stroma infiltrated by focal aggregates of lymphocytes.^1,2 Individual cell necrosis with scattered histiocytes may produce a classic "starry-sky" appearance, which is characteristic for but not diagnostic of diffuse testicular seminomas.

Germ Cell Testicular Tumors - Testicular Teratomas

A teratoma is defined as a tumor consisting of tissues from more than one germinal layer (ectoderm, mesoderm, and endoderm).^1,4 Presumably, teratomas arise from multipotential germ cells that have undergone partial differentiation without organization.² Testicular teratomas are rare in all domestic species. They can be large, cystic, or polycystic and can contain hair, mucus, bone, and other structures. Most teratomas are benign.⁴

(3) Mixed testicular tumors are tumors that contain a mixture of both neoplastic sex-cord stromal cells as well as neoplastic germ cells within the same tumor focus (not to be confused with multiple tumors, in which different populations of neoplastic cells are present independently in focal areas of the testicle). It is thought that a substantial percentage of tumors in cryptorchid testicles are mixed testicular tumors.² Mixed testicular tumors are typically large, firm, multilobulated to diffuse grey/white to tan masses that may obliterate the majority of the testicular parenchyma. Areas of hemorrhage or necrosis may be present, particularly in larger tumors.^1,2 These tumors are histologically unique and appear as neoplastic Sertoli cells admixed with neoplastic germ cells in tubular structures. The metastatic potential of these tumors compared to traditional testicular tumors in not well described.

(4) Miscellaneous Testicular Tumors - Other primary testicular tumors are extremely uncommon, and include mesothelioma, fibroma/fibrosarcoma, hemangioma/hemangiosarcoma, leiomyoma/leiomyosarcoma, which are similar in appearance and behavior to similar tumors at other sites in the body.² Secondary testicular tumor are rare, but some cases of metastatic lymphosarcoma and hemangiosarcoma have been reported.²

Summary

The three most common canine testicular neoplasms are Sertoli cell tumors, interstitial (Leydig) cell tumors, and seminomas. Metastasis in all three tumor types is extremely rare. The Sertoli cell tumor is the only known testicular tumor that commonly produces hormones with clinical effects. The hyperestrogenism syndrome that characterizes many Sertoli cell tumors can be associated with severe bone marrow atrophy, pancytopenia, and progression to death. Because the risk of harmful consequences of testicular tumors increases as the tumor ages, early and aggressive removal of all testicular neoplasms is always warranted.

References

1. Meuten DJ: Tumors in Domestic Animals, 4^th ed. Ames, Iowa State Press, 2002, pp. 561-567.

2. Kennedy PC, Cullen JM, Edwards JF, Goldschmidt MH, Larsen S, Munson L, and Nielson S: Histological Classification of Tumors of the Genital System of Domestic Animals. Washington DC, Armed Forces Institute of Pathology, 1998, pp. 15-20.

3. Ladd PW: The male genital system. In Jubb KVF, Kennedy PC, and Palmer N (eds) Pathology of Domestic Animals, 4^th ed. San Diego, Academic Press, 1993, pp. 504-511.

4. Acland HM: Reproductive System – Male. In McGavin, Calton, Zachary (eds) Thomson’s Special Veterinary Pathology, 3^rd ed. Philadelphia, Mosby Inc, 2001, pp. 635-644.

5. MacEwen EG, and Withrow SJ: Small Animal Clinical Oncology, 3^rd ed. Philadelphia, W.B. Saunders Company, 2001, pp. 478-483.

6. Pulley LT: Sertoli Cell Tumor. Veterinary clinics of North America 1979; 29:1, pp.145-150.

7. Reif JS, Magruire TG, Kennedy RM, Brodey RS: A cohort study of canine testicular neoplasia. J Am Vet Med Association 1979; 175, pp. 719-723.

8. Sherding RG, Wilson GP, Kociba GJ: Bone Marrow Hypoplasia in Eight Dogs with Sertoli Cell Tumor. J Am Vet Med Association 1981; 178:5, pp. 497-501.

9. Priester WA, McKay FW: The occurrence of tumors in domestic animals. National Cancer Institutes 1980; 54, pp. 1-210.

10. Guyton AC, Hall JE: Textbook of Medical Physiology, 9^th ed. Philadelphia, W.B. Saunders Co, 1996, pp. 1003-1016.

Acknowledgement

"Rescued Dog" by Marie Mason is from the Dog & Cat Art Prints section of the Bella and Company website and is used with permission.

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