ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 9, No. 2 Copyright (£) 1979, Institute for Clinical Science, Inc.

Ley dig Cell Tumors of the Testis

IVAN DAMJANOV, M.D., Ph .D.,* SHEILA MORIBER KATZ, M.D.,* and M ICHAEL A. S. JEW ETT, M.D., F.R.C.S. (c)f

*Department o f Pathology and Laboratory Medicine, Hahnemann Medical College and Hospital,

Philadelphia, PA 19102 and

f Division o f Urology, D epartm ent o f Surgery , University o f Toronto, Ontario, M4Y 1J3, Canada

ABSTRACT

Leydig cell tumors represent approximately one to three percent of all testicular tumors. W hereas in experimental animals predisposing condi­tions include administration of chemical carcinogens, hormones and heavy metals, environm ental or endogenous factors in man are presently unrec­ognized. Leydig cell tumors do not show preferential lateralization or tendency for bilaterality. The symptoms are related to the local effects or to hormones released into the systemic circulation. Laboratory findings are variable, depending on endocrinological activity. Typical tumors rarely ex­ceed five cm in diameter, are brown on cross section and are composed of polyhedral cells with acidophilic, granular cytoplasm. Ultrastructurally, neoplastic Leydig cells resem ble normal Leydig cells. Surgical ablation is curative for benign Leydig cell tumors.

T esticu la r in te rs titia l (Leydig) ce ll tumors are relatively rare and account for a sm all p o rtion o f a ll te s tic u la r n e o p la sm s.10,16 A lthough th e tum ors originate from cells that synthesize and sec re te an d ro g en ic ho rm ones u n d er physiological conditions, the neoplasm may present with virilization, fem iniza­tion or no obv ious e n d o c rin e sym p­toms.3,10,15 Owing to the unpredictable hormonal activity of neoplastic Leydig cells, there are no genera lly app lica ­ble diagnostic tests, and in practice, each case has to be evaluated individually. O w ing to the scarcity o f L egdig cell

tumors, even large institutions have lim­ite d ex p e rien c e w ith th is ty p e of neoplasm . The p resen t authors have, therefore, review ed cases of Leydig cell tumors from the literature and have criti­cally evaluated and sum m arized those clinical, laboratory and morphologic find­ings of practical value. Our experience with five cases, two of which were previ­ously reported,2 is also summarized.

Incidence

Leydig cell tumors represent approxi­mately one to three percent of all testicu­

0091-7370/79/0300-0157 $01.20 © Institute for Clinical Science, Inc.

158 DAMJANOV, KATZ AND JE W E T T

lar tum ors.8,14 T his incidence was re­ported from various parts of the world, suggesting no geographic difference in the occurrence of this tumor. In a review of 612 te s tic u la r tum ors in ch ild ren , Giebink and Ruymann4 found 51 Leydig cell tumors.

Age

Leydig cell tumors occur more often in adults than in children. Approximately two-thirds of all Leydig cell tumors re­corded in the literature were discovered in postpubertal patients, whereas the re­maining third was found in children.1,7 Although most tumors in adults occur be­tween 25 and 35 years, peak incidence of prepubertal cases is be tw een one and five years of age.

Predisposing Conditions

Leydig cell tumors develop in experi­mental animals subsequent to adm inis­tra tion o f chem ical carcinogens, hor­mones or heavy m etals such as cadmium. A lthough th e o ld er l i te ra tu re 8 lis ts X-irradiation as a reliable procedure for induction of Leydig cell tumors in rats, recent experiments have failed to confirm these claim s.6 Leydig cell tum ors de­velop spontaneously in aging rats of cer­tain strains.8

No environm ental or endogenous fac­tors are known to predispose to the de­velopm ent of Leydig cell tumors in man. Although it is known that plutonium is preferentially deposited in or near the in­terstitial cells of the testis, no cases of Leydig cell tumors have been related to exposure to any radioactive substance or to prolonged irradiation.6 On the basis of a Leydig cell tumor described in a patient w ith clinical evidence of chronic lead in­toxication, Medras e t al9 have speculated abou t the re la tio n sh ip b e tw e e n the neoplastic proliferation of Leydig cells and lead or lead induced porphyria. No additional cases of testicular neoplasms

w ere rep o rted in p a tien ts ex h ib itin g signs of heavy m etal intoxication tha t would corroborate these speculations.

Gryptorchid testes often contain foci of Leydig cell hyperplasia, bu t the tumors do not appear to be more common in un­descended than in scrotal testes.1

H orm onally active testicu lar tum ors are relatively common in patients with congenital adrenal hyperplasia.13 These lesions have been considered to rep re­sent e ither Leydig cell tumors or tumors of adrenal rests. Although hormonally ac­tive tumors appear morphologically in­d is tin g u ish a b le from L eyd ig ce ll neoplasm s, functionally they resem ble adrenal cortical cells and, therefore, most likely represent adrenal rests located in the scrotum.

Localization

Leydig cell tumors do not show signifi­cant predilection for either the right or the left testis, although somewhat more tumors were reported on the right side. Of the 151 tumors reviewed by Hugues and Caron,7 73 (48.3 percent) were in the right and 61 (40.4 percent) in the left tes­ticle. Seven tumors (4.6 percent) were bilateral and three (2 percent) were para- testicu lar. Sym ington and C am eron16 rev ie w e d 43 cases from th e B ritish T esticu la r Tum or Panel and Registry m aterial and repo rted that 20 tum ors were right-sided and 16 left-sided. One tumor was bilateral and, in six cases, the side involved was not recorded. Thus, Leydig cell tumors do not appear to show preferential lateralization or a tendency for bilaterality.

The existence of paratesticular Leydig cell tumors has been questioned, prima­rily because of conflicting views as to w hether or not the extratesticular endo­crine cells in the scrotum represent ec­topic adrenal tissue or Leydig cells. Ul- trastructural findings of Peters11 indicate that cells w ith eosinophilic cytoplasm found in the funiculus spermaticus repre­

LEY D IG C E L L TUM ORS O F T H E TESTIS 159

sent w ell d ifferen tia ted Leydig cells. Hence, tumors may conceivably develop from ectopic Leydig cells.

Symptoms

Sym ptom s caused by L ey d ig ce ll tumors are related either to the local ef­fects of the growing neoplasm or to the hormones released into the systemic cir­culation. O f the 85 patients with benign Leydig cell tumors review ed by Hugues and Caron,7 42.6 percent presented with gynecom astia, 41.2 p e rcen t had com ­plaints related to the enlargem ent of the testis, 9 percent com plained of loss of libido and 8.8 percent had experienced scro ta l pa in . C h ild h o o d L ey d ig cell tumors often cause precocious puberty and virilization.17 Patients with malignant Leydig cell tumors frequently develop systemic m etastases.12 Average survival of patients w ith malignant tumors is 42 ± 5.7 months from the tim e of diagnosis.7 Range of longevity is from 42 days after diagnosis of Leydig cell carcinoma to 17 years after removal of the primary tumor.

Laboratory F indings

Laboratory findings vary from one case to another.3,5,7 Virilizing tumors usually secrete predom inantly androgenic hor­mones and fem inizing tumors predom i­nantly estrogens. The endocrinologically inactive tumors cause few, if any, altera­tions in the hormonal status of the tumor bearing host. In patients w ith gyneco­mastia and loss of libido, plasma and urin­alysis w ill u su a lly show in c re ase d amounts of total estrogens, estrone E x, e s tra d io l E 2, e s tr io l E 3, p reg n an e - diol and pregnanetrio l. 17-Ketosteroid excretion in urine was normal in 15 pa­tien ts w ith fem inization rev iew ed by Gabrilove et al.3 Excretion of 17-OH ste­ro id s in u rin e is u su a lly norm al in fem inized patients. Plasma levels of tes­tosterone may be significantly decreased. G abrilove e t al,3 have suggested that

gynecomastia develops in these patients prim arily because of an imbalance be­tw een circulating androgens and estro­gens.

In precociously v irilized boys w ith Leydig cell tumors, urinary 17-ketoste- ro ids are ex c re te d in u rin e in large amounts.17 Plasma levels of testosterone, androstened ione and 17-OH progeste­rone may be elevated to normal adult values or higher. Large amounts of 17- ketosteroids excreted in the urine or high levels o f estrogens in the plasm a and urine without concomitant gynecomastia are considered by Gabrilove et al.3 to be suggestive of Leydig cell carcinoma.

Analysis of testicu lar effluent blood may aid in localization of hormonally ac­tive tumors not palpable owing to central location or small size.3 Stimulation by in ­fusion of HCG is occasionally performed to distinguish autonom ously secreting, H CG independent, Leydig cell tumors from Leydig cell hyperplasia. Adrenal cortical hyperp lasia and adrenal rests localized in the scrotum may be d istin ­guished from Leydig cell tumors with a dexamethasone inhibition test.13

Pathology

Leydig cell tumors vary in size and shape.1,10 In general, malignant tumors are larger than benign tumors. The size of the tumor does not appear to be related to its endocrine activity. Most tumors are well dem arcated from the testicular tis­sue. Only a few of the tumors review ed by Dalgaard and H esselberg1 exceeded five cm in diam eter and none of the ac­ceptable cases showed areas of necrosis, hem orrhage or cyst formation. Typical tumors are brown, brown-yellow or dark brown on cross section. They are composed o f p o ly h ed ra l ce lls w ith a b u n d a n t acidophilic, granular cytoplasm and lipid granules. Reinke’s crystals are found in less than ha lf of all tumors.7 Approxi­m ately 10 p e rc e n t o f a ll L eyd ig cell tumors are m alignant.7 Distinction of be­

160 DAMJANOV, KATZ AND JE W E T T

nign from m alignant tumors cannot be made on histologic examination, and m e­tastasis is the only definite indicator of malignancy.

T e s tic u la r t is su e su rro u n d in g the tumor may show compression atrophy in non-functional tumors, and either arrest of sperm atogenesis, hyposperm atogen- esis or aspermatogenesis in estrogen pro­ducing tumors.14 Prem ature maturation of seminiferous tubules occurs in prepuber­tal boys with virilizing tumors.17

Ultrastructural FindingsNeoplastic Legdig cells resem ble nor­

mal Leydig cells. Like the normal Leydig cells, th e tum or ce lls have abundan t smooth endoplasm ic reticulum, well de­veloped rough endoplasm ic reticulum , large numbers of mitochondria with ve­sicular cristae, m icrobodies and lip id droplets.2,15 In contrast to normal cells, n eo p lastic ce lls have p ro m in en t and often m ultiple nucleoli with a complex nucleolonem a and irregularly undulating nuclear m em branes. The cytoplasm of tum or c e lls u su a lly con ta in s few er lipofuscin granules, paracrystalline in ­clusions and Reinke crystals than normal Leydig cells. In addition, neoplastic cells often show prom inent whorls of rough and smooth endoplasm ic reticulum. Vi­

rilizing tumors do not differ ultrastructu- rally from fem inizing neoplasm s, and hormonally active tumors are ultrastruc- turally better differentiated than the inac­tive tumors.2,15

Treatm ent

Whereas surgical ablation o f the tumor or semicastration is curative for benign Leydig cell tumors, there is no effective therapy for malignant lesions. Removal of tumors usually leads to regression of en­docrine symptoms, although gynecomas­tia and hormonal imbalance may occa­sionally persist for prolonged periods, even without evidence of rem aining or recurrent neoplastic disease.5

Illustrative Clinical Material

Our clinical experience with Leydig cell tumors is based on the study of five cases. Two cases w ere p rev iously re ­ported.2 Pertinent clinical and pathologic findings are tabulated in table I.

All patients were adults. Four patients had benign tumors, whereas one tumor was malignant. Three tumors originated from the right testis and one from the left testis. The site of origin in the fifth case could not be definitely established, al­though it is p resum ed that the tum or

TABLE I

C lin ic o -p a th o lo g ic F in d in gs

P a t - Y e a r s T um or S i z e B e n ig n (B ) S y m p to m si e n t O ld ( i n cm ) M a l i g n a n t (M) L o c a t i o n D u r a t i o n L o c a l E n d o c r i n e N o t e s

1 21 5 x 5 x 4.5 B Right testis 18 months + - Electron microscopy2 45 2.5 x 5 x 3 B Right testis 5 years + + Electron microscopy

(gynecomastia)3 34 3 B Left testis 3 months +4 81 - B Right testis5 64 6 M Left inguinal 2% months Died 1 yea*- after

canal removal of primarytumor. Metastases in lung, liver, kidneys, right adrenal gland, abdominal lymph nodes and bones

LEYDIG C E LL TUM ORS O F T H E T ESTIS 161

FIGURE 1. Hormonally active tumor from patient No. 1. Tumor is composed of well differentiated cells. Note the well developed rough endoplasmic reticulum, mitochondria, lipid droplets (x 6,300).

F ig u r e 2. Hormonally active tumor from patient No. 1. Cells contain whorls of smooth endoplasmic reticulum apposed to mitochondria with vesicular cristae. Smooth endoplasmic reticulum (SER) is well developed (x 9,800).

1 6 2 DAMJANOV, KATZ AND JE W E T T

F ig u r e 3. Hormonally inactive tumor from patient No. 2. Cells vary in size and shape. Some cells are dark, whereas others are light and have a clear cytoplasm. The cytoplasm of the light cells contains free ribosomes (r) or smooth endoplasmic reticulum (SER). The dark cell cytoplasm contains lipid droplets, mitochondria, and myelin-like figures (asterisk) (x 6,300).

arose from a cryptorchid testis located in the inguinal canal. O ne tum or p resented with gynecomastia, w hereas the rem ain­ing four were hormonally inactive. Histo­logically, all five tumors d isplayed the a p p e a ra n c e ty p ic a l o f L e y d ig ce l l neoplasms, and the malignant tumor did not differ h is torically from b en ig n le ­sions. Tw o tum ors w e re ex am in ed by electron microscopy.

In th e p a t i e n t w i th g y n e c o m a s t ia , tumor cells w ere well differentiated and contained ab u n d an t smooth endoplasm ic reticulum and stacks of rough endoplas­m ic r e t i c u lu m (f ig u re 1). W h o r ls of smooth and rough endoplasm ic reticulum were also seen (figure 2). Smooth endo­plasmic reticulum was often dilated. Mito­chondria w ere large and num erous and

had vesicular cristae. Lipid was present in some cells in the form of m em brane b ound and nonm em brane b o u n d drop­lets. In the pa tien t with hormonally inac­tive tum or, the cells w ere less d iffer­entiated and con ta ined less endoplasmic reticulum, few er m itochondria and more free ribosomes than the functionally ac­tive tumor (figure 3).

Acknowledgm ent

Thanks are extended to Mrs. Myrna Bolt for the secretarial help and to Mr. Jerry Calvin for technical assistance.

References1. D a l g a a r d , J. B. and H e s s e l b e r g , F.: Inters­

titial cell tumors of the testis. Two cases and survey. Acta Path. Microbiol. Scand. 41 :219- 234, 1957.

LEY D IG C E L L TUM ORS O F T H E TESTIS 163

2. D amjanov, I., Vuckovtc, I., Apic, R., and Ka- TIC, V.: Tumori intersticijalnih stanica testisa. Lijec. Vjes. 96:296-299, 1974.

3. G abrilove , J. L., N ico lis, G. L., M itty , H. A., and So h va l , A. R.: Feminizing interstitial cell tumor of the testis: personal observations and a review o f the literature. Cancer 35:1184-1202, 1975.

4. G œ bink , G. S. and Ru ym an , F. B.: Testicular tumors in childhood. Amer. J. D is. Child. 227:433-438, 1974.

5. H ew ig , K. R. and Vin so n , R. K.: Interstitial ce ll tumor. Profile o f hormone-producing tumor. Urology 11 :283-284, 1978.

6. H u l s e , E. V.: Can radiation induce interstitial-cell (Leydig-cell) tumours of the testis? Int. J. Radiat. Biol. 32:185-190, 1970.

7. H u g u es , F. C. and Ca ro n , M.: Les tumeurs leydigiennes. Etude generale a propos d’une observation. Sem. Hop. Paris 52:1157-1162,1976.

8. LACASSAGNE, A.: Revue critique des tumeurs expérim entales des ce llu les de L eydig plus p articu lièrem en t ch ez le rat. B ull. Cancer 58:235-276, 1971.

9. M ed ra s , K., An dr ea sik , Z., Zaw irska , B.,KORNOBIS, J., and CHMIEL-NOCEN, A.: In- terstioma testis feminisans. Zbl. Allg. Path. 222:501-504, 1968.

10. MOSTOFI, F. K. and PRICE, E. B., Jr.: Tumors of the male genital system. Atlas of Tumor Pathology, Series II, Fascicle 8. Washington,

D. C., Armed Forces Institute of Pathology,1973, pp. 86-99.

11. P eter s , K. H.: D ie Ultrastruktur heterotoper L eydigzellen beim M enschen. Andrologia 9:337-348, 1977.

12. O ber , W. B., Kabak ow , B., and Heckt , H.: Malignant interstitial cell tumor of the testis: a problem in endocrine oncology. Bull. N.Y. Acad. Med. 52:561-583, 1976.

13. Ra d fa r , N., Ba r tter , F. C., Ea sley , R., Ko- l in s , J., Ja va d po u r , N., and Sh e r in s , R. J.: Evidence for endogenous LH suppression in a man with bilateral testicular tumors and con­genital adrenal hyperplasia. J. Clin. Endocr. Metab. 45:11941204, 1977.

14. Sohval, A. R., Churg , J., Suzuki, Y., Katz , N., and Gabrilove , J. L.: Effects of a feminizing testicular Leydig cell tumour on nontumorous testicular tissue: an ultrastructural study. Clin. Endocrin. 6:127-137, 1977.

15. Soh val , A. R., Ch u r g , J., Su zuk i, Y., Ka t z , N., and Gabrilove , J. L.: Electron microscopy of a feminizing Leydig cell tumor of the testis. Human Path. 8:621-634, 1977.

16. Sym ington , T. and Cam eron , K. M.: Endo­crine and genetic lesions. Pathology of the Tes­tis. Pugh, R. C. B., ed. Oxford, Blackwell Scien­tific Publications, 1976, pp. 259-303.

17. U rban , M. D., Le e , P. A., Plotnick , L. P., and M ig eo n , C. J.: The diagnosis o f Leydig cell tumors in childhood. Amer. J. Dis. Child. 232:494-497, 1978.