Interstitial Cell Hyperplasia Or Adenoma

THE JOURNAL OF UROLOGY

Vol. 70, No. 5, November 1953 Printed in U.S.A.

INTERSTITIAL CELL HYPERPLASIA OR ADENOMA K. E. BLUNDON, SIMON RUSSI

AND

R. CARL BUNTS

From Departments of Urology and Pathology, McGuire Veterans Administration Hospital, Richmond, Va.

Interstitial cell tumor of the testis is by general agreement a rare entity, Friedman and Moore reporting a 1 per cent and Lewis an 0.8 per cent incidence in their respective large series of testicular tumors. Pathologic classification has therefore been based on the observation in a very limited number of cases and on occasion on single case findings. To date, less than 50 cases have been reported in the literature and about 40 per cent of these have been added since 1945. Many cases have been controversial. For example, Pana's case which was reported as adenoma was substantiated by some investigators but ·was also called Leydig cell hyperplasia and an adrenal cortical rest by others. Shupe's case was called an adrenal cortical tumor by Karsner and also by Stewart but was accepted by the Armed Forces Institute of Pathology as interstitial cell adenoma. In tabulating the cases reported as interstitial cell tumors, almost one-third were found to have occurred in patients with atrophic testis or with cryptorchidism, although not necessarily in the same testis. However, it would seem to indicate that interstitial cell tumor is often found in conjunction with decreased spermatogenesis. The normal histologic and physiologic pattern of Leydig cells has been described in some detail. The vacuolated polyhedral Leydig cells, which are believed to be derived from primordial mesenchymal cells, are usually found interspersed in groups of ten to twelve cells in the loose connective tissue between the seminiferous tubules and are said to comprise some 12 per cent of the bulk of the adult testis. Cytologically these cells are distinguishable by their large eccentric vesicular nuclei, a heavy brown intracellular pigment, and heavy deposits of lipid. This lipid is believed to be the androgenic hormone or a precursor thereof and, according to Lynch and Scott, assumes maximum concentration in the years of greatest sexual activity. Androgenic hormone is excreted in the urine as 17 -ketosteroids. In the male about three-eighths of the 17ketosteroid output is derived from the testis with five-eighths coming from adrenal cortical hormone metabolites. Theoretically at least, one is inclined to believe that 17-ketosteroid output should be increased in either Leydig cell hyperplasia or in true tumor. This determination has been listed in only six cases, in four of which it was elevated. Leydig cell hyperplasia of varied degree is of fairly common occurrence and occurs as sheets of cells resembling liver cells or adrenal cells interspersed between seminiferous tubules. Interstitial cell hyperplasia is an apparently normal finding in the testis of senility. It is known to occur in cryptorchidism with debated frequency and is Published with the permission of the Chief Medical Director, Department of Medicine and Surgery, Veterans Administration, who assumes no responsibility for the opinions expressed or the conclusions drawn by the authors. Accepted for publication May 27, 1952. 759

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BLUNDON, RUSSI AND BUNTS

often described as an autopsy finding in such debilitating diseases as tuberculosis, syphilis, pernicious anemia and carcinoma. Hyperplasia has also been induced by a number of other conditions such as x-ray radiation, estrogens, vitamin E deficiency and vasectomy. The generally accepted criteria for differentiation of a Leydig cell adenoma from hyperplasia are: 1) Encapsulation: Adenomas are usually encapsulated or at least distinctly demarcated from the host tissue. 2) Displacement of the host tissue and absence of seminiferous tubules scattered throughout the lesion. Tabulation of pathologic characteristics in cases reported to date indicates that almost 50 per cent of cases reported as tumor can not be differentiated from hyperplasia by present morphologic criteria. One might categorically TABLE

Children*. .... . Adults ... ....... Total . .

1. Tabulation of clinical findings in interstitial cell tumors TOTAL CASES

GYNECOMASTIA

13 32

1 3

. . . . . . .....

. . . . . . . . . . . ....

45

4

!

ATROPHY OR CRYPTORCHIDISM

INCREASED 17-KETOSTEROID

3

1 3

10 i

13

I

4

* All children showed precocious puberty, macrogenitalism and skeletal maturation. TABLE

2 PRESENCE

Capsule. . . . . . . . . . . . . . . . . . . . Interspersed sem. tubules. ....

.... ......

. ..

ABSENCE

NOT MENTIONED

23

12

10

19

17

9

classify such cases as hyperplasia had they not often clinically presented such marked endocrinologic changes or even metastases. The only valid criterion of malignancy is apparently the presence of metastases. Benign lesions cannot be differentiated from malignant ones morphologically. Eight out of 45 cases develop metastases. The difficulty in differentiating true interstitial cell adenoma from hyperplasia in a case recently under our care stimulated the review of differential criteria for the diagnosis of interstitial cell adenoma, carcinoma or hyperplasia. CASE REPORT

A 27 year old white man was first admitted to McGuire V. A. Hospital on October 31, 1950, free of symptoms. A tumor of the right testis had been discovered 3 months before admission in the course of a physical examination for employment. Immediate orchiectomy had been advised at that time, but the patient had procrastinated. Despite the lapse of 3 months before reporting to the hospital, the patient had remained symptom free and the testis had not

761

INTERSTITIAL CELL HYPERPLASIA TABLE

3. Pathologic characteristic of interstitial cell tumor

NAME

CAPSULE

INTRACELL LIPOID

INTERSPERSED SEM. TUBULES

METASTASES

I Sacchi, 1895 ... ... ........ . . . . . . . . . . Chevassu, 1906 .. .. . .... . . . . .. . ... . ... Kaufman, 1908. ..... . . . . . . . .... . . . . Kaufman, 1908 ........ Masson and Sencert, 1923. ...... De Josselin De Jong, 1926. ...... ..... Rowlands and Nicholson, 1929. . . . . . . . . .. Pitrolffy-Szabo, 1938. .. Pana, 1931 .......... .... . . . . . . ...... .......... ... . . . . Rigoletti, 1936 .... Stewart, Bell, Roehlke, et al., 1936. ..... ...... Hunt and Budd, 1939. J emerin, 1937 .. . . ......... . . . . . . ... Braun, 1939. ........ . . . . .. ......... . ... Huffman, 1941. ..... .. . . . . . . . Somerford, 1941 ..... . . . . . . . . .... . .... Warren, S. and Olshausen, 1932. ...... .. Masson and Venning, 1942. ..... Bonser and Hawksley, 1943. Bonser and Hawksley, 1943 .. .. . . ... Rezek, 1943 ...... . . . . . . . . . . . . . . . . .... . . . . . . ..... Masson, 1943 ...... Demirleau, et al., 1943. . . . . . . . . . . ... Nation, et al., 1944. ..... . . . . . . . . . . . Nation, et al., 1944. ... ... . . . . . . . . . . . . . . ... Nation, et al., 1944. Neeve and Marsh, 1944. ....... . . . . . . . . . . . . .. Werner, 1944. . . . . . Ranstrom, 1945 .... . . . . .. . . . . . . . . . . . . . . . . ... Anderson, 1946 .... Wilbur and Burger, 1948. .......... .. Price, 1948. ... . . . . ....... . ...... Sandblom, 1948. ...... Scully and Parham, 1948 .. . . .... . . .. . ..... Reiners and Horn, 1949. ...... Meli cow, et al., 1949. James and Shupe, 1950 . . . . ...... ... . . . ...... . .. Fraser, 1950. .... . . . . . . . Gharpure, 1950 Garvey and Daniel, 1951.. . . . . . . .... ... . . . . ..... Grabstald, et al., 1951. Flynn and Severance, 1951. . . . . . . .... Tedeschi and Burke, 1951. . ..... .... . . . . Authors. ..... Christeson and Nettleship, 1952. . . ...

+.

X

X

X

0

+

+ + + + + + + + + 0 + +

+ + + 0

+ + + + 0 + +

± ± ± 0 ± X

± 0

+

0

0 0 X 0 0 0

X

X

+ +

0 ±

X X

X X

+ + +

0 ± ± ±

+ + +

X

0 X

0

+ + +

0

+ + X X X

+

+

+

X X X

+ +

X

X

± 0 0 ±

0 0 0 0

X

X

+ + + +

+

±

X

0

0 0 0

X

0 0 0

+

+ + 0 0

0 ± 0 ± 0 ±

X

+

X

+

0 0

X X

0 0

+ X + + + + 0

Present= Absent = 0. Few=±. Not indicated = X. Note: Cases unsubstantiated by majority of reviews are not included.

+ +

762

BLUNDON, RUSSI AND BUNTS

significantly enlarged in the interim. Although bilateral testicular atrophy had been present as long as the patient could remember, there was no history of mumps, orchitis, or injury. Puberty had been delayed to the age of fifteen and body hair and beard had been sparse. Libido had been virtually absent until the age of twenty-four, after which normal sexual drive had apparently been present. Physical examination showed a tall, eunuchoid male, 6 feet 1½ inches tall, weighing 146 pounds. The beard was very sparse. The voice was normal in timbre. The lungs were clear and there was no gynecomastia present. No abdominal masses were present. Both testes were in the scrotum. The right testis was about two-thirds normal size and was hard and somewhat nodular. The left testis was about one-fourth normal size but of normal configuration. The penis and pubic hair were normal in development and prostate was of normal size and consistency.

Fm. 1. Photograph of resected testicle

The laboratory examinations, including the Friedman test, 17-ketosteroids excretion, radiogram of the chest and excretory urogram, were all within normal range. Radiographic examination of the sella turcica revealed no findings suggestive of pituitary tumor. A simple right orchiectomy was performed in November 1950 through an inguinal incision. The capsule of the testis was smooth, gray, glistening and uniformly tense. A few delicate tortuous vessels radiated from the hilar portion of the testis (fig. 1). The cut surface revealed an eccentrically placed ovoid cyst filled with pale yellow crumbling material. At one pole of the cyst was a hard, small nodule which cut with resistance suggesting calcification. Between the periphery of the cyst and the tunica albuginea was a layer of orange-yellow tissue varying from 1 to 5 mm. in thickness. Microscopic examination of multiple segments of the specimen revealed a

INTERSTITIAL CELL HYPERPLASIA

763

FIG. 2. Photograph of small ossified shell with central cystic area filled with laminated keratin. X 15

FIG. 3. Showing massive proliferation of interstitial cells arranged in cords and lobules. X 100

simple epidermoid cyst filled with keratin and lined by compressed squamous stratified epithelium. The epithelium was supported by a dense layer of hyalinized connective tissue. The hard nodule afore-mentioned was made up of a well localized crescent-shaped focus of ossification (fig. 2). In the central portion of

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BLUNDON, RUSSI AND BUNTS

Fm. 4. Showing gra.nular pigment in cytoplasm of interstitial cells. X 440

:Fm. 5. Showing section of seminiferous tubule surrounded by masses of interstitial cells. X 200

the bone was a minute cystic area which was apparently a recess of the large epidermoid cyst. We interpreted this finding as an adult teratoma made up of a peripheral layer of bone and a central epidermoid cyst. The cyst expanded in

INTERSTITIAL CELL HYPERPLASIA

765

the course of years, due to distention by desquamated keratin and subsequently extruded from its bony cage compressing and displacing the host tissue. The orange-yellow layer between the wall of the cyst and the tunica albuginea was made up of cellular tissue arranged in lobules and cords in a manner resembling the pattern of liver parenchyma (fig. 3). The individual cells had an eosinophilic cytoplasm which in some of the cells was vacuolated containing sudanophilic material and in some others was impregnated with a fine brown pigment (fig. 4). The nuclei were fairly uniform in size and staining intensity. The shapes of the nuclei varied from round to short ovals and some showed a wrinkled nuclear membrane. Some contained prominent punctate nucleoli. There was no evidence of invasive tendencies, pleomorphism or mitotic activity. Occasional seminiferous tubules in various stages of atrophy and hyalinization were scattered through the tissue (fig. 5).

Fm. 6. Biopsy from controlateral testis showing proliferation of interstitial cells identical in appearance with lesion in other testis.

The postoperative course was uncomplicated and follow-up 15 months after orchiectomy has revealed no evidence of local recurrence or metastases. Six months after the first operation a sperm count was performed to determine the degree of spermatogenesis that was present in the remaining atrophic testis. Complete azospermia was found. A biopsy of the remaining testis revealed masses of Leydig cells assuming the same pattern as in the removed testis (fig. 6). DISCUSSION

We should like to limit the discussion of the adult teratoma as it presented little difficulty in diagnosis and due to the mature components offered a favorable prognosis. We are puzzled, however, by the peculiar proliferation of the interstitial cells, which poses the following problems: 1) Is it a true tumor or hyperplasia? 2) If it is a tumor, is it benign, malignant or potentially malignant?; and 3) the

766

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BLUNDON, RUSSI AND BUNTS

practical question, should the controlateral testicle be removed or treated otherwise? To answer the first question, whether the lesion in our case is an adenoma or diffuse hyperplasia, we reviewed the postulates for differentiation. An adenoma should be an encapsulated or at least a discrete lesion displacing. the host tissue. In our case there was a diffuse numerical increase of interstitial cells with almost total replacement of the spermatogenic elements of the gonad. The only barriers were the tunica albuginea and the wall of the cyst. Another criterion is absence of seminiferous tubules within the adenoma. In our case the seminiferous tubules, however scanty and atrophic, were scattered here and there throughout the lesion. One argument in favor of hyperplasia versus tumor is the presence of a bilateral lesion. It seems improbable for one man to develop three tumors in two testicles. We realize that this point is based more on conjecture rather than of fact. To answer the second question whether the lesion is benign or malignant we have to assume that it is a tumor in spite of the fact that it does not exactly fit the postulates stated above. We have no criteria to determine its benign or malignant character. All of the eight previously reported cases which developed metastases had the same morphologic features as benign tumors, and three of the eight could not be differentiated morphologically from hyperplasia. Metastases may occur as late as 10 years after the removal of the primary lesion. To answer the third question as to the treatment of the other testicle we are inclined to withhold x-ray therapy. Warren as well as Best and Taylor found that interstitial cells are radioresistant. Kyrle has actually induced hyperplasia by radiation. The advisability of the surgical removal of the other testis hinges on the debatable pathological classification of the first testis. In addition to our own studies, we sought and obtained the help of several consultants in several medical centers. The opinions of the consultants were divided, however, between the diagnosis of interstitial cell adenoma and hyperplasia. The diagnosis of adenoma for the most part was preferred. SUMMARY AND CONCLUSIONS

A case of bilateral diffuse proliferation of Leydig cells associated with a unilateral teratoma of the testicle is presented. is believed that there is no sharp definite line of demarcation separating neoplasia from hyperplasia in cases of massive interstitial cell proliferation.

llt

r

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