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Testicular tumors in prepubertal children
TESTICULARTUMORS IN PREPUBERTALCHILDREN
STANLEY
A. BROSMAN,
M.D.
From the Department of Surgery/Urology, University Los Angeles, and the Harbor Medical Center-UCLA, Torrance, California
Testicular tumors in children and adults differ not only in incidence and prognosis but also in clinical manifestations. Because of these differences and the relative rarity of the childhood tumors, considerable confusion exists regarding the classification and management of testicular tumors in infants and children. The confusion is
I. Classi.cation and incidence of556 testis tumors in prepubertal children
TABLE
Classification GERM CELL
TUMORS
Yolk sac carcinoma (endodermal sinus tumor, vitelline tumor, adenocarcinoma of infant testis, testicular adenocarcinoma with clear cells, orchioblastoma, embryonal adenocarcinoma, embryonal cell carcinoma, infantile variant) Teratoma NONGERMINAL
/
JUNE 1979 / VOLUME
424
76
132
24
366
58
TUMORS
Sertoli cell tumors (Sertolic cell adenoma, androblastoma, gonadal stromal tumor, tubular adenoma) Leydig cell tumor Connective tissue tumors Rhabdomyosarcoma Fibroma Leiomyoma Fibrosarcoma Leiomyosarcoma Other Gonadoblastoma Lymphoma Leukemia Hemangioma Metastatic tumors
UROLOGY
Incidence No. Per Cent
22
of California,
reflected in the variety of terms used in describing these tumors and the differing approaches to treatment. Many reports deal with pubertal and postpubertal males in whom the types of tumors resemble those of the adult. The structure of the prepubertal testis differs from that of the adult; consequently, the neoplastic potentialities are different. A group of 556 prepubertal children with tumors of the testis, including 15 patients treated in our hospitals, were selected from the world literature to form the basis of this report. More than 1,000 case reports were reviewed to select patients on the basis of adequate data describing therapy and follow-up. Germinal tumors were found in 76 per cent of these children. The more common germinal tumors of adults (seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma) are either extremely rare or absent in children. On the other hand, teratoma and yolk sac carcinoma have a much higher incidence in children than in adults. The nongerminal tumors, which are generally benign, constitute a larger proportion of testicular tumors in children (24 per cent) than in adults (3 to 5 per cent). The principal nongerminal tumors are rhabdomyosarcoma, Leydig cell tumors, and Sertoli cell tumors. Classification
52 58
XIII,
and Description
The major categories of childhood testicular tumors (Table I) are the same as those occurring in adults. The occurrence of tumors in the prepubertal testis is related to changes in the morphologic development of the testis. The testis includes four principal cellular components: germ cells, Sertoli cells, Leydig cells, and the tunica albuginea. The composition of the developing testis varies with age; the different cell types appearing at specific stages of development (Table II).
NUMBER
6
581
TABLE II.
Cellular composition
Stage Cell Types Germ cells Prespermatogenic (primitive germ cells, gonocytes, prespermatogonia, spermatogonia) Spermatogenic (spermatocytes, spermatids, spermatozoa) Sertoli cells Leydig cells
Tunica albuginea
of
Origin
Development
Location
Extragonadal
Tubules
Surface epithelium Gonadal mesenchyme
Tubules
Gonadal mesenchyme
Subcapsular stroma
Fetus
Puberty
Fetus Differentiate in fetus at 8 wk.; regress; redifferentiate at time of puberty Fetus
Tumors of germ cell origin represent the largest and most controversial group of testicular neoplasms. Because of the multipotentiality of germ cells, a variety of neoplastic possibilities exists. Experimental evidence suggests that the teratoma and the yolk sac carcinoma each represents a selective form of germ cell differentiation. The pattern of tumor development is, in fact, a caricature of normal embryogenesis. The yolk sac carcinoma represents differentiation of extraembryonic tissues, and the teratoma represents differentiation of embryonic tissues. The confusion in terminology arises from the attempts to include tumors in boys in the classification of Dixon and Moore.’ Teilum2 was one of the first investigators to point out that certain tumors in boys have a distinct morphologic appearance which resembled the endodermal sinuses of the yolk sac in rodents. He added the sinus tumor” to the diagnosis “endodermal Dixon-Moore classification and stated that if embryonal carcinoma could differentiate into choriocarcinoma, it should be able to differentiate into other tumors of extraembryonic fetal membranes including yolk sac tumors. Experimentally, Pierce, Bullock, and Huntington3 were able to show that the yolk sac carcinoma of the mouse testis was derived by differentiation from embryonal carcinoma. He reasoned that it is also likely that the germinal tumors of boys are derived by differentiation from embryonal carcinoma and believed that the term “yolk sac carcinoma” was more general and useful than any of the others.
582
of testis
Intertubular stroma
In spite of the experimental data, most pathologists and urologists use the term embryonal carcinoma when referring to the various histologic patterns of this tumor. However, there are distinct clinical an~dhistologic differences between the childhood and adult tumors which should be reflected in the terminology. The term yolk sac carcinoma is preferable since this has an experimental basis and distinguishes the adult form of embryonal carcinoma from childhood disease. Seminoma, teratocarcinoma, and choriocarcinema are additional tumors of germ cell origin, but these do not occur prior to puberty. The seminoma is a tumor of spermatogenic cells (spermatogonia, spermatocytes) and is found only in persons in whom spermatogenesis is present. Seminomas occurring in boys have been found to be associated with early development of puberty and spermatogenesis. Tumors of nongerminal origin comprise a higher proportion of tumors in children as compared to adults. The rarest of these tumors is the Sertoli cell tumor. Sertoli cell tumors have had several alternate designations based on differences in histologic appearance. In children all of the tumors described behave in a similar manner, regardless of histologic appearance, and all appear to be derived from Sertoli cells. Therefore, androblastoma, gonadal stromal tumor, and tubular adenoma are all considered Sertoli cell tumors. Some Sertoli cell tumors are associated with proliferating Leydig cells, possibly a result of hormonal stimulation by the
UROLOGY
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tumor cells. Sertoli cell tumors and Leydig cell tumors are easily distinguished by their differing age incidence, clinical presentation, and microscopic appearance. There is a histologic resemblance to fetal testis.“* The immature testis is characterized by a preponderance of Sertoli cells. The ultrastructure of Sertoli cells in the fetal and neonatal testis indicates their high level of metabolic activity during the early developmental period. 5 The Leydig cell tumor is a well-recognized entity because of its striking endocrine manifestations resulting in precocious puberty in young boyse6 Evidence for a hormonal origin of human Leydig cell tumors is lacking. Tumors of Leydig cells have been produced in male mice by prolonged administration of estrogens and in castrates of either sex by intrasplenic grafts of immature testicular tissue. ‘a* These observations indicate a clear relationship between hormonal imbalance and formation of Leydig cell tumors in animals. The factors responsible for the occurrence of Leydig cell tumors in childhood are unknown. The stroma of the prepubertal testis does not contain fully developed Leydig cells, making it difficult to explain how these tumors arise. Some have suggested that the lesions are derived from ectopic adrenal tissue, a suggestion which is not easy to dispute on the basis of histologic appearance. g Adrenal cortical cells and Leydig cells are remarkably similar in appearance. Lack of response to corticosteroids and the presence of Reinke crystals would indicate testicular rather than adrenal origin, but Reinke crystals generally are not found in childhood tumors. lo Tumors of connective tissue may be benign or malignant. The former include fibroma and leiomyoma. The latter include rhabdomyosarcoma, fibrosarcoma, and leiomyosarcoma. Rhabdomyosarcoma constitutes the majority of tumors in this group. In the case of sarcomas, it is usually impossible to determine whether the tumor originates in the tunica albuginea or in paratesticular structures, because of the early invasion of contiguous structures. Paratesticular origin is probably more frequent. Pure testicular rhabdomyosarcoma has been thought to arise by malignant overgrowth of a teratoma. Morphologic evidence does not support this concept and actually indicates that teratoma does not differentiate into any type of malignant tissue unless associated with embryonal carcinoma. Gonadoblastoma is an unusual testis tumor occurring in phenotypic females with dysgenetic
UROLOGY
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NUMBER
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gonads and a male karyotype (mixed gonadal dysgenesis). Scully” classifies gonadoblastoma separately, as an intimate mixture of germ cells and elements resembling immature granulosa or Sertoli cells in which Leydig cells may or may not be present. He states that gonadoblastoma is a neoplasm because it is composed of two and sometimes three types of cells that proliferate abnormally and commonly form clinically detectable masses. The pattern of gonadoblastoma has not been reported in a metastasis, but mitotic activity is usually present in the germ cells of the tumor, which invades the surrounding tissues in half the patients. Because gonadoblastoma exhibits features which suggest that it may progress into an invasive germinal or other form of malignant tumor, this neoplasm should be surgically removed. Lymphomas of the testis, including lymphosarcoma, Hodgkin disease, and Burkitt lymphoma have been described in children. Incidence The relative incidence of germinal tumors was 76 per cent in the children reviewed in this report, compared with more than 95 per cent in adults. This is higher than that reported in other series. 12-24 Yolk sac carcinoma constitutes the majority of germ cell tumors in children and is the most frequent testicular tumor in infants. This tumor constituted 366 or 86 per cent of the germinal tumors in this series. The mean age at the time of orchiectomy was eighteen months, with 74 per cent of the patients less than twenty-four months old. There were 58 patients with teratoma who were diagnosed at a mean age of twenty months; 57 per cent were age twenty-four months or less. Sertoli cell tumors represented 17 per cent of the nongerminal tumors. The peak incidence Sertoli cell was at age 18.5 months. Incidental adenomas are noted in patients with an undescended testis, or, at autopsy, but they appear to be of no clinical significance. Leydig cell tumors represented 39 per cent of nongerminal tumors. They differ from other childhood testis tumors in that their peak incidence is in midchildhood (age 4.7 years). This is the only testis tumor which is not rare in black children. Sarcomas represented 44 per cent of nongerminal tumors, and rhabdomyosarcoma was the most frequent type. We have included 58 patients in whom enough data were available to evaluate their management and clinical course.
583
TABLE III.
Diagnostic features of tumors of testis in children
Origin
Type
Usual Age at Diagnosis
Symptoms
Yolk sac carcinoma
Germ cell
18 months
Painless
mass
Teratoma
Germ
Painless
mass
Sertoli
cell tumor
Sertoli
cell
Painless
mass
Leydig
cell tumor
Leydig
cell
Any age; most under 4 years Any age; most under 6 months 4 to 9 years
Rhabdomyosarcoma Gonadoblastoma
cell
Tunica albuginea or paratesticular Germ cells, sex cords, mesenchyme
Any age; most under 7 years . .
The mean age at the time of diagnosis was five years. Lymphoma or leukemia was found in less than 2 per cent of patients, but may be the most common bilateral testicular tumor. 12,15 Usually testicular involvement is a manifestation of disseminated disease, but occurrence as a primary testicular tumor is recognized. Diagnosis The most common presenting symptom of testicular tumors in children is painless, unilateral, testicular enlargement (Table III). The testicular mass is generally firm, nontender, and does not transilluminate. The presence of transillumination is not conclusive since hydrocele is frequently associated with tumor and is the most common misdiagnosis made in these children. Hernia, hematocele, and infarction from torsion are other entities commonly confused with tumor. Because an incorrect diagnosis leads to delay in the proper treatment, all scrotal masses should be considered malignant unless proved otherwise. The diagnosis in all cases depends on excision and microscopic examination. An inguinal incision should be used and the spermatic cord secured before delivering the testicle into the wound. The gross appearance of the testicle is usually adequate to make the diagnosis. If there is doubt, an orchiectomy is preferable to an open biopsy. Percutaneous needle biopsy of a testicular mass is unnecessary since all of these lesions require surgical correction. If a hydrocele is aspirated, the fluid should be sent for cytologic examination. The duration of the tumor prior to surgical removal was nearly six months in patients with
584
Laboratory Data Elevated alpha-fetoprotein . . . . . .
Precocious puberty Painless mass
Increase in urinary I7-ketosteroids . . .
Virilism in phenotypic female
Abnormal karyotype
germinal tumors, while the time was protracted to eighteen to twenty-four months for the nongerminal lesions. Endocrine disturbances are generally present with Leydig cell tumors in children, symptoms of sexual precocity being the usual presenting complaint. Gynecomastia occasionally occurs and is related to increased levels of estrogen and progesterone. Bone age is also advanced in patients with Leydig cell tumors. Gittes et al. I6 pointed out that a small intratesticular tumor may lead to isometric enlargement of both the testis and epididymis of the involved side which may mask the expanding lesion. Exploration of the interior of the enlarged testis is required to demonstrate the presence of a tumor. Differentiation can usually be made between Leydig cell tumors and the testis tumor associated with the adrenogenital syndrome (Table IV). A family history of congenital adrenal hyperplasia will be present in some patients. Nocturnal emissions and precocious sexual behavior are more commonly associated with Leydig cell tumors. Bilateral testis tumors are found more often in patients with congenital adrenal hyperplasia. Hormone studies are useful in distinguishing these two entities.” While some elevation in urinary 17-ketosteroid levels may occur in both conditions, a significantly elevated level favors the diagnosis of adrenogenital syndrome particularly in patients with a 21-hydroxylase deficiency. Slight elevations occur in patients having a 17-hydroxylase or 11-hydroxylase deficiency. In congenital adrenal hyperplasia, the urinary 17-ketosteroid excretion is reduced by corticosteroid administration. Urinary pregnanetriol is usually absent in patients with but significant elevations Leydig cell tumors,
UROLOGY / JUNE 1979 / VOLUME XIII, NUMBER 6
TABLE IV. Diffmentiation between Leydig cell tumors and testis tumors associated with congenital adrenal hyperplasia
Clinical Data History
None
Nocturnal emissions Precocious sexual behavior Laterality Serum testosterone
Frequent Frequent
Pregnanetriol
Usually absent
Urine sodium excretion
Normal
Urinary excretion of I7-kerosteroids following cortisone administration Effect of ACTH on urinary 17-OH corticosteroids Effect of cortisone on tumor size Urinary ketosteroids
No change
May be bilateral May be slightly elevated Increased in 21-OH deficiency Usually increased in 21-OH deficiency; low in 11-OH deficiency Reduced
Increased
No change
None
May be reduced
Normal to slight increase
Usually marked increase in 21-OH deficiency; slight elevation in 17hydroxylase or 11-OH deficiency
Therapy Yolk sac carcinoma There has been a great deal of confusion concerning the therapy for this tumor because too few patients have been treated in any one center or in any organized fashion (Tables V and VI). The 366 patients in this study were gathered from over 800 patients reported in the world literature and include 12 patients of our
/ JUNE 1979 / VOLUMEXIII,
May have positive family history Rare Rare
Unilateral Usually elevated
occur in patients with congenital 21-hydroxylase deficiency. Patients having the other varieties of congenital adrenal hyperplasia demonstrate no increase in urinary pregnanetriol excretion. Significantly increased blood and urinary testosterone determinations are found in patients with Leydig cell tumors, but present techniques for measuring testosterone indicate that there is a slight increase in patients with congenital adrenal hyperplasia. The exogenous administration of cortisone will usually reduce urinary l7ketosteroids as well as diminish the size of the associated testis tumor in congenital adrenal hyperplasia.
UROLOGY
Congenital Adrenal Hyperplasia
Leydig Cell Tumor
NUMBER6
own. Only those patients whose follow-up was at least two years were evaluated. Most patients with recurrent disease presented within two years of the original therapy. Unfortunately, the data may not accurately reflect the true clinical situation since the group is selected and diverse in surgical, radiotherapeutic, and chemotherapeutic techniques.
TABLE
V.
Therapy of testis tumors in children
Type Yolk sac carcinoma
Teratoma Sertoli cell tumor Leydig cell tumor Rhabdomyosarcoma
Gonadoblastoma
Therapy Orchiectomy with chemotherapy and or lymphadenectomy depending on tumor markers Simple orchiectomy Simple orchiectomy Simple orchiectomy Radical orchiectomy with extensive local dissection, retroperitoneal lymph node dissection; chemotherapy and radiation therapy Orchiectomy with local lymph node dissection
585
TABLE VI. Yolk sac carcinoma; survival compared with therapy
Therapy Orchiectomy Orchiectomy + Chemotherapy Orchiectomy + X-ray Orchiectomy + Lymphadenectomy Negative nodes Positive nodes TOTALS
Alive 2 Yr. Without Per Cent Tumor Dead Total Survival 117
77
194
60
10
0
10
loo
55
9
64
86
78 3
16 1
94 4
83 75
263
-103
366
-
72
Age has been considered an important prognostic factor in this disease. There were 270 patients who were less than two years of age and 29 (11 per cent) died. There were 96 patients who were older than two years and 74 (77 per cent) died of cancer. This supports the concept that the disease is more serious in the “older” child and should be treated more aggressively. Orchiectomy was the only form of treatment in 169 children. One hundred seventeen (60 per cent) were alive without tumor beyond two years. Pulmonary metastases were usually the initial finding of recurrent tumor. Chemotherapy has been a recent addition to the therapeutic regimen-l8 An adequate course of multiple drug chemotherapy after orchiectomy could be determined in only 10 cases. These patients did not have clinical evidence of metastatic disease when they were initially treated but later metastases developed. All were alive two years after initiation of therapy. This group is too small to ascertain the effectiveness of this therapeutic strategy. Other patients were unsuccessfully treated with single drugs, short courses of therapy, or after the disease was far advanced. Many patients were treated prior to the advent of aggressive chemotherapy in young children. Radiation therapy was utilized in 64 patients and is considered by some to be valuable therapy.igmzl Fifty-five (86 per cent) survived beyond two years. The role of radiation therapy is not defined since the fear of delayed growth, bone marrow arrest, sterilization of the remaining testis, radiation nephritis, and enterocolitis has made surgeons wary of its use.22,23 The favorable experience with retroperitoneal lymph node dissection in nonseminomatous
586
germinal tumors of the adult has led to the application of this surgical technique in children.24-27 There were 98 patients who were treated with orchiectomy and retroperitoneal lymph node dissection. No evidence of lymph node metastases were found in 94 patients, but 16 eventually died of cancer. Only 4 patients had lymph node metastases, and 3 were alive after two years. The two-year survival in patients having a negative lymphadenectomy was 83 per cent. The outcome cannot be explained on the basis of the lymph node dissection. Young et ~1.‘~ reported that lymphadenectomy did not increase survival rates in their group of 18 patients, causing them to question its need. They presented evidence which suggests that yolk sac carcinoma has a greater propensity for hematogenous spread than embryonal carcinoma of the adult testis. Bracken et ~1.‘~ reported similar data attesting to the rarity of lymphatic spread in this disease. However, they believed that lymphangiography should be performed, and if normal, a lymphadenectomy done until biologic markers are available for this disease. Our data strongly support this view. The disease has a different clinical behavior than embryonal carcinoma in the adult. The propensity for hematogenous spread is greater in children emphasizing the need for systemic therapy and a lesser need for lymphadenectomy. In the 12 patients treated in our hospitals, 8 had lymphadenectomies and all were normal. Only 1 patient died of cancer, and this child had undergone a negative lymphadenectomy. The tumor markers, HCG-B and alphafetoprotein (AFP), have been shown to be valuable in adults but have not been well studied in children.28-30 We have been able to obtain data on 7 boys with yolk sac carcinoma. These boys are not included in the over-all series because they have not all been followed for longer than two years and will be the subject of a separate study. The AFP was significantly elevated in all of the patients prior to orchiectomy. The normal AFP is less than 40 ng./dl., but these patients had extremely high levels exceeding 200 ng./dl. The high AFP levels are consistent with the extraembryonic origins of this tumor and add support to the term “yolk sac carcinoma.” HCG-B was minimally elevated in 2 boys and reverted to normal following orchiectomy. Two boys continued to have significantly elevated AFP levels, and one a slight increase in AFP after orchiectomy, even though there was
UROLOGY / JUNE 1979 / VOLUMEXIII, NUMBER6
TABLE VII. Rhabdomyosarcoma: compared with therapy Therapy Orchiectomy Orchiectomy + Chemotherapy + X-ray + Lymphadenectomy Postive nodes Negative nodes Orchiectomy + X-ray TOTALS
Alive 2 Yrs.
Dead
survival Per Cent Total Survival
21
7
28
75
12 6
1 1
13 7
92 86
6
10 -
40 -
15
58
74
_
4
43
-
no clinical evidence of metastatic disease. Lymphadenectomy was negative in 2 of these children, but they were treated with chemotherapy positive. The AFP because the AFP remained returned to normal within two months after initiating chemotherapy, and they have remained tumor free. The third patient with a positive AFP following orchiectomy did not have lymphadenectomy but was started on chemotherapy. The AFP reverted to normal, and the child remains free of disease fourteen months after beginning therapy. The remaining 4 patients had normal tumor markers after orchiectomy. Two of these patients had negative lymphadenectomies. The remaining 2 patients were treated with orchiectomy alone, and their tumor markers have remained normal. No additional therapy has been given. In these 7 patients the AFP has been a sensitive, reliable, and accurate indicator of the disease stage. HCG-B does not appear to be as valuable a marker for this tumor as the AFP. If the effectiveness of chemotherapy and the accuracy of tumor markers in children are substantiated, the role of retroperitoneal lymphadenectomy could be redefined and its use limited to specific indications. Teratoma The teratoma of childhood follows a benign course.4,12*14*27,31 Most of the children are diagnosed within the first few years of life and require no other treatment than an orchiectomy. Sertoli cell tumor Twenty-two patients with clear evidence of this tumor have been reported. As a rule these tumors are diagnosed in infancy when they are
UROLOGY / JUNE 1979 / VOLUME XIII, NUMBER 6
small and asymptomatic.r2,13 Gynecomastia may be associated with Sertoli cell tumors in adults but not in children.32 Although several malignant cases have been reported in adults, only one has been described in a child. Metastases to lymph nodes and liver were reported by Rosvoll and Woodard33 in an eight-year-old child. Their patient was treated with lymph node dissection, radiation, and chemotherapy. There was no tumor recurrence after two years. While orchiectomy has been successful in 21 of 22 patients, careful clinical staging and follow-up are necessary. Leydig
cell tumor
Leydig cell tumors in childhood are benign. Malignant Leydig cell tumors have been rein children and ported in adults. 34 Tumors adults differ in that endocrine manifestations are usually absent in adults while most children have associated endocrine disturbances.35 The treatment is orchiectomy, but this may not produce regression of the physical manifestations of precocity or bone age. However, urinary 17ketosteroid levels fall to normal after surgical intervention. If they do not, or if they later return to high levels, bilateral testis tumors associated with the adrenogenital syndrome should be suspected. Rhabdomyosarcoma An aggressive therapeutic approach is indicated for this neoplasm.26,27,36,37 Orchiectomy with extensive local excision is the first stage. If the scrotal skin has been invaded, ipsilateral inguinal lymph node excision should be included with removal of the involved scrotum. Because metastases may occur by lymphatic and vascular channels, retroperitoneal lymph node dissection and chemotherapy are necessary. Metastatic disease should be treated with a combination of radiation, surgical resection, and chemotherapy. In the group of 58 patients there was an over-all survival of 74 per cent (Table VII). The best survival was in the patients who received systemic chemotherapy in addition to lymphadenectomy. The behavior of this tumor necessitates this type of approach. It is interesting to note that even in the children who had orchiectomy alone, survival was 75 per cent. The better prognosis in this type of sarcoma can be explained by the location and easier detection of these testis tumors compared with sarcomas in other parts of the body.
587
Summary A clinical analysis was made of 556 prepubertal children with testis tumors. Germinal tumors comprised 76 per cent of this group, and the most common of these tumors was the yolk sac carcinoma. Although many appellations have been used to describe this tumor, experimental and clinical evidence support the use of this term. The over-all two-year survival was 72 per cent and was better in children less than two years of age. The tumor is distinctly different from the embryonal carcinoma of the adult. The role of lymphadenectomy needs to be reassessed in view of the low incidence of lymph node metastases and the propensity for pulmonary metastases. Chemotherapy appears to be of benefit. Tumor markers, particularly alphafetoprotein, may be of assistance in planning therapy. The other germinal tumor is the teratoma. This is a benign, nonmetastasizing disease in children and requires only orchiectomy. Nongerminal tumors comprised 24 per cent of tumors and require only orchiectomy. Sertoli cell tumors are rare, and there has been only one report of metastatic disease. Leydig cell tumors present with endocrine manifestations and are benign in children. They may be difficult to distinguish from tumors associated with congenital adrenal hyperplasia. Rhabdomyosarcomas should be treated with a combination of surgery, chemotherapy, and radiation. The over-all survival of 74 per cent for these patients indicates the benefits of aggressive therapy. Harbor General Hospital 1000 West Carson Street Torrance, California 90509
References 1. Dixon FJ, and Moore RA: Tumors of the male sex organs, in Atlas of Tumor Pathology, Armed Forces Institute of Pathology, Washington, D.C., 1952, vol. 8, p. 316. 2. Teilum G: Special Tumors of Ovary and Testis and Related Extragonadal Lesions; Comparative Pathology and Histological Identification, Philadelphia, J, B. Lippincott Press, 1971. 3. Pierce GB, Bullock WK, and Huntington RW: Yolk sac tumors of the testis, Cancer 25: 644 (1970). 4. Holtz F, and Abel1 MR: Testicular neoplasms in infants and children. II. Tumors of non-germ cell origin, ibid. 16: 982 (1963). 5. Flickinger CJ: The postnatal development of the Sertoli cells of the mouse, Z. Zellforsch. 78: 92 (1967). 6. Turner JH, and Bloodworth JMB: In: Endocrine Pathology, Baltimore, Williams and Wilkins Press, 1968. 7. Bonser GM, and Robson JM: Effect of prolonged oestrogen administration upon male mice of various strains: development of
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testicular tumors in strong A strain, J, Pathol. Bacterial. 51: 9 11940). 8. Twombly GH, Meisel D, and Stout AP: Leydig-cell tumors induced experimentally in the rat, Cancer 2: 884 (1949). 9. Glenn J, and Boyce W: Adrenogenitalism with testicular adrenal rests simulating interstitial cell tumor, Trans. Am. Assoc. Genitourin. Surg. 54: 59 (1962). 10. Savard K, et al: Clinical, morphological and biochemical studies of a virilizing tumor in the testis, J. Clin. Invest. 39: 534 (1960). 11. Scully RE: Gonadoblastoma. A review of 74 cases, Cancer 25: 1340 (1970). 12. Houser R, Izant RJ, and Persky L: Testicular tumors in children, Am. J. Surg. 110: 876 (1965). 13. Phelan JT, Wollner LB, and Hayles AB: Testicular tumors in infants and children, Surg. Gynecol. Obstet. 105: 569 (1957). 14. Bachmann KD, and Von Grawert H: Tumoren des Hodeus im Kindesalter: Bericht iiber 545 Falle, Monatsschr. Kinderheilkd. 120: 40 (1972). 15. Shivde AU, and Junnarkar RV: Primary lymphosarcoma of the testis: report of a case, J. Ural. 103: 762 (1970). 16. Gittes RF, Smith G, Conn CA, and Smith F: Local androgenic effect of interstitial cell tumor of the testis, ibid. 104: 774 (1970). 17. Brosman S, and Gondos B: Testicular tumors in children, in Johnston JH, and Goodwin WE, Eds: Reviews in Paediatric Urology, Excerpta Medica, 1974. 18. Karamehmedovic 0, Woodtli W, and Pluss HJ: Testicular tumors in childhood, J. Pediatr. Surg. 10: 109 (1975). 19. Ise T, Ohtsuki H, Matsumoto K, and Sane R: Management of malignant testicular tumors in children, Cancer 37: 1539 (1976). 20. Matsumoto K, Nakauchi K, and Fujita K: Radiation therapy for the embryonal carcinoma of testis in childhood, J. Ural. 104: 778 (1970). 21. Tetft M, Vawter GF, and Mitus A: Radiotherapeutic management of testicular neoplasms in children, Radiotherapy 88: 457 (1967). 22. Young PG, Mount BM, Foote W, and Whitmore WF: Embryonal adenocarcinoma in the prepubertal testis. A clinicopathologic study of 18 cases, Cancer 26: 1065 (1970). 23. Johnson DE, Kuhn CR, and Guinn GA: Testicular tumors in children, J. Ural. 104: 940 (1970). 24. Bracken RB, Johnson DE, Cangir A, and Ayala A: Regional lymph nodes in infants with embryonal carcinoma of testis, Urology II: 376 (1978). 25. Smith JP: Testicular tumors in infants and children, ibid. 2: 353 (1973). 26. Colodny AH, and Hopkins TB: Testicular tumors in infants and children, Ural. Clin. North Am. 4: 347 (1977). 27. Giebink GS, and Ruymann FB: Testicular tumors in childhood, Am. J. Dis. Child. 127: 433 (1974). 28. Bourgeaux C, Martel N, Sizaret P, and Guerrin J: Prognostic value of alpha-fetoprotein radioimmunoassay in surgically treated patients with embryonal cell carcinoma of the testis, Cancer 38: 1658 (1976). sinus tumor) 29. Tsuchida Y, et al: Yolk sac tumor (endodermal and alpha-fetoprotein. A report of three cases, ibid. 32: 917 (1973). 30. Javadpour N, and Bergman S: Recent advances in testicular cancer, Curr. Prob. Surg. vol. 15, no. 2 (1978). 31. Abell MR, and Holtz F: Testicular neoplasms in infants and children. Tumors of germ cell origin, Cancer 16: 965 (1963). 32. McArthur JW: Gonadotrophins in relation to sexual maturity, in Savena BB, Beling CG, and Gandy HM, Eds: Gonadotropics, New York, Wiley-Interscience Press, 1972. 33. Rosvoll RV, and Woodard JR: Malignant Sertoli cell tumor of the testis, Cancer 22: 8 (1968). 34. Tamoney JJ, and Noriega A: Malignant interstitial cell tumor of the testis, ibid. 24: 547 (1969). 35. Johnstone G: Prepubertal gynecomastia in association with an interstitial cell tumor of the testis, Br. J. Urol. 39: 211 (1967). 36. Brosman S, Cohen A, and Fay R: Rhabdomyosarcoma of testis and spermatic cord in children, Urology 3: 568 (1974). 37. Tank ES, et al: Treatment of urogenital tract rhabdomyosarcoma in infants and children, J. Urol. 107: 324 (1972).
UROLOGY
/
JUNE
1979
/
VOLUME
XIII,
NUMBER
6
STANLEY
A. BROSMAN,
M.D.
From the Department of Surgery/Urology, University Los Angeles, and the Harbor Medical Center-UCLA, Torrance, California
Testicular tumors in children and adults differ not only in incidence and prognosis but also in clinical manifestations. Because of these differences and the relative rarity of the childhood tumors, considerable confusion exists regarding the classification and management of testicular tumors in infants and children. The confusion is
I. Classi.cation and incidence of556 testis tumors in prepubertal children
TABLE
Classification GERM CELL
TUMORS
Yolk sac carcinoma (endodermal sinus tumor, vitelline tumor, adenocarcinoma of infant testis, testicular adenocarcinoma with clear cells, orchioblastoma, embryonal adenocarcinoma, embryonal cell carcinoma, infantile variant) Teratoma NONGERMINAL
/
JUNE 1979 / VOLUME
424
76
132
24
366
58
TUMORS
Sertoli cell tumors (Sertolic cell adenoma, androblastoma, gonadal stromal tumor, tubular adenoma) Leydig cell tumor Connective tissue tumors Rhabdomyosarcoma Fibroma Leiomyoma Fibrosarcoma Leiomyosarcoma Other Gonadoblastoma Lymphoma Leukemia Hemangioma Metastatic tumors
UROLOGY
Incidence No. Per Cent
22
of California,
reflected in the variety of terms used in describing these tumors and the differing approaches to treatment. Many reports deal with pubertal and postpubertal males in whom the types of tumors resemble those of the adult. The structure of the prepubertal testis differs from that of the adult; consequently, the neoplastic potentialities are different. A group of 556 prepubertal children with tumors of the testis, including 15 patients treated in our hospitals, were selected from the world literature to form the basis of this report. More than 1,000 case reports were reviewed to select patients on the basis of adequate data describing therapy and follow-up. Germinal tumors were found in 76 per cent of these children. The more common germinal tumors of adults (seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma) are either extremely rare or absent in children. On the other hand, teratoma and yolk sac carcinoma have a much higher incidence in children than in adults. The nongerminal tumors, which are generally benign, constitute a larger proportion of testicular tumors in children (24 per cent) than in adults (3 to 5 per cent). The principal nongerminal tumors are rhabdomyosarcoma, Leydig cell tumors, and Sertoli cell tumors. Classification
52 58
XIII,
and Description
The major categories of childhood testicular tumors (Table I) are the same as those occurring in adults. The occurrence of tumors in the prepubertal testis is related to changes in the morphologic development of the testis. The testis includes four principal cellular components: germ cells, Sertoli cells, Leydig cells, and the tunica albuginea. The composition of the developing testis varies with age; the different cell types appearing at specific stages of development (Table II).
NUMBER
6
581
TABLE II.
Cellular composition
Stage Cell Types Germ cells Prespermatogenic (primitive germ cells, gonocytes, prespermatogonia, spermatogonia) Spermatogenic (spermatocytes, spermatids, spermatozoa) Sertoli cells Leydig cells
Tunica albuginea
of
Origin
Development
Location
Extragonadal
Tubules
Surface epithelium Gonadal mesenchyme
Tubules
Gonadal mesenchyme
Subcapsular stroma
Fetus
Puberty
Fetus Differentiate in fetus at 8 wk.; regress; redifferentiate at time of puberty Fetus
Tumors of germ cell origin represent the largest and most controversial group of testicular neoplasms. Because of the multipotentiality of germ cells, a variety of neoplastic possibilities exists. Experimental evidence suggests that the teratoma and the yolk sac carcinoma each represents a selective form of germ cell differentiation. The pattern of tumor development is, in fact, a caricature of normal embryogenesis. The yolk sac carcinoma represents differentiation of extraembryonic tissues, and the teratoma represents differentiation of embryonic tissues. The confusion in terminology arises from the attempts to include tumors in boys in the classification of Dixon and Moore.’ Teilum2 was one of the first investigators to point out that certain tumors in boys have a distinct morphologic appearance which resembled the endodermal sinuses of the yolk sac in rodents. He added the sinus tumor” to the diagnosis “endodermal Dixon-Moore classification and stated that if embryonal carcinoma could differentiate into choriocarcinoma, it should be able to differentiate into other tumors of extraembryonic fetal membranes including yolk sac tumors. Experimentally, Pierce, Bullock, and Huntington3 were able to show that the yolk sac carcinoma of the mouse testis was derived by differentiation from embryonal carcinoma. He reasoned that it is also likely that the germinal tumors of boys are derived by differentiation from embryonal carcinoma and believed that the term “yolk sac carcinoma” was more general and useful than any of the others.
582
of testis
Intertubular stroma
In spite of the experimental data, most pathologists and urologists use the term embryonal carcinoma when referring to the various histologic patterns of this tumor. However, there are distinct clinical an~dhistologic differences between the childhood and adult tumors which should be reflected in the terminology. The term yolk sac carcinoma is preferable since this has an experimental basis and distinguishes the adult form of embryonal carcinoma from childhood disease. Seminoma, teratocarcinoma, and choriocarcinema are additional tumors of germ cell origin, but these do not occur prior to puberty. The seminoma is a tumor of spermatogenic cells (spermatogonia, spermatocytes) and is found only in persons in whom spermatogenesis is present. Seminomas occurring in boys have been found to be associated with early development of puberty and spermatogenesis. Tumors of nongerminal origin comprise a higher proportion of tumors in children as compared to adults. The rarest of these tumors is the Sertoli cell tumor. Sertoli cell tumors have had several alternate designations based on differences in histologic appearance. In children all of the tumors described behave in a similar manner, regardless of histologic appearance, and all appear to be derived from Sertoli cells. Therefore, androblastoma, gonadal stromal tumor, and tubular adenoma are all considered Sertoli cell tumors. Some Sertoli cell tumors are associated with proliferating Leydig cells, possibly a result of hormonal stimulation by the
UROLOGY
/ JUNE 1979 / VOLUME
XIII,
NUMBER
6
tumor cells. Sertoli cell tumors and Leydig cell tumors are easily distinguished by their differing age incidence, clinical presentation, and microscopic appearance. There is a histologic resemblance to fetal testis.“* The immature testis is characterized by a preponderance of Sertoli cells. The ultrastructure of Sertoli cells in the fetal and neonatal testis indicates their high level of metabolic activity during the early developmental period. 5 The Leydig cell tumor is a well-recognized entity because of its striking endocrine manifestations resulting in precocious puberty in young boyse6 Evidence for a hormonal origin of human Leydig cell tumors is lacking. Tumors of Leydig cells have been produced in male mice by prolonged administration of estrogens and in castrates of either sex by intrasplenic grafts of immature testicular tissue. ‘a* These observations indicate a clear relationship between hormonal imbalance and formation of Leydig cell tumors in animals. The factors responsible for the occurrence of Leydig cell tumors in childhood are unknown. The stroma of the prepubertal testis does not contain fully developed Leydig cells, making it difficult to explain how these tumors arise. Some have suggested that the lesions are derived from ectopic adrenal tissue, a suggestion which is not easy to dispute on the basis of histologic appearance. g Adrenal cortical cells and Leydig cells are remarkably similar in appearance. Lack of response to corticosteroids and the presence of Reinke crystals would indicate testicular rather than adrenal origin, but Reinke crystals generally are not found in childhood tumors. lo Tumors of connective tissue may be benign or malignant. The former include fibroma and leiomyoma. The latter include rhabdomyosarcoma, fibrosarcoma, and leiomyosarcoma. Rhabdomyosarcoma constitutes the majority of tumors in this group. In the case of sarcomas, it is usually impossible to determine whether the tumor originates in the tunica albuginea or in paratesticular structures, because of the early invasion of contiguous structures. Paratesticular origin is probably more frequent. Pure testicular rhabdomyosarcoma has been thought to arise by malignant overgrowth of a teratoma. Morphologic evidence does not support this concept and actually indicates that teratoma does not differentiate into any type of malignant tissue unless associated with embryonal carcinoma. Gonadoblastoma is an unusual testis tumor occurring in phenotypic females with dysgenetic
UROLOGY
/ JUNE 1979 / VOLUME
XIII,
NUMBER
6
gonads and a male karyotype (mixed gonadal dysgenesis). Scully” classifies gonadoblastoma separately, as an intimate mixture of germ cells and elements resembling immature granulosa or Sertoli cells in which Leydig cells may or may not be present. He states that gonadoblastoma is a neoplasm because it is composed of two and sometimes three types of cells that proliferate abnormally and commonly form clinically detectable masses. The pattern of gonadoblastoma has not been reported in a metastasis, but mitotic activity is usually present in the germ cells of the tumor, which invades the surrounding tissues in half the patients. Because gonadoblastoma exhibits features which suggest that it may progress into an invasive germinal or other form of malignant tumor, this neoplasm should be surgically removed. Lymphomas of the testis, including lymphosarcoma, Hodgkin disease, and Burkitt lymphoma have been described in children. Incidence The relative incidence of germinal tumors was 76 per cent in the children reviewed in this report, compared with more than 95 per cent in adults. This is higher than that reported in other series. 12-24 Yolk sac carcinoma constitutes the majority of germ cell tumors in children and is the most frequent testicular tumor in infants. This tumor constituted 366 or 86 per cent of the germinal tumors in this series. The mean age at the time of orchiectomy was eighteen months, with 74 per cent of the patients less than twenty-four months old. There were 58 patients with teratoma who were diagnosed at a mean age of twenty months; 57 per cent were age twenty-four months or less. Sertoli cell tumors represented 17 per cent of the nongerminal tumors. The peak incidence Sertoli cell was at age 18.5 months. Incidental adenomas are noted in patients with an undescended testis, or, at autopsy, but they appear to be of no clinical significance. Leydig cell tumors represented 39 per cent of nongerminal tumors. They differ from other childhood testis tumors in that their peak incidence is in midchildhood (age 4.7 years). This is the only testis tumor which is not rare in black children. Sarcomas represented 44 per cent of nongerminal tumors, and rhabdomyosarcoma was the most frequent type. We have included 58 patients in whom enough data were available to evaluate their management and clinical course.
583
TABLE III.
Diagnostic features of tumors of testis in children
Origin
Type
Usual Age at Diagnosis
Symptoms
Yolk sac carcinoma
Germ cell
18 months
Painless
mass
Teratoma
Germ
Painless
mass
Sertoli
cell tumor
Sertoli
cell
Painless
mass
Leydig
cell tumor
Leydig
cell
Any age; most under 4 years Any age; most under 6 months 4 to 9 years
Rhabdomyosarcoma Gonadoblastoma
cell
Tunica albuginea or paratesticular Germ cells, sex cords, mesenchyme
Any age; most under 7 years . .
The mean age at the time of diagnosis was five years. Lymphoma or leukemia was found in less than 2 per cent of patients, but may be the most common bilateral testicular tumor. 12,15 Usually testicular involvement is a manifestation of disseminated disease, but occurrence as a primary testicular tumor is recognized. Diagnosis The most common presenting symptom of testicular tumors in children is painless, unilateral, testicular enlargement (Table III). The testicular mass is generally firm, nontender, and does not transilluminate. The presence of transillumination is not conclusive since hydrocele is frequently associated with tumor and is the most common misdiagnosis made in these children. Hernia, hematocele, and infarction from torsion are other entities commonly confused with tumor. Because an incorrect diagnosis leads to delay in the proper treatment, all scrotal masses should be considered malignant unless proved otherwise. The diagnosis in all cases depends on excision and microscopic examination. An inguinal incision should be used and the spermatic cord secured before delivering the testicle into the wound. The gross appearance of the testicle is usually adequate to make the diagnosis. If there is doubt, an orchiectomy is preferable to an open biopsy. Percutaneous needle biopsy of a testicular mass is unnecessary since all of these lesions require surgical correction. If a hydrocele is aspirated, the fluid should be sent for cytologic examination. The duration of the tumor prior to surgical removal was nearly six months in patients with
584
Laboratory Data Elevated alpha-fetoprotein . . . . . .
Precocious puberty Painless mass
Increase in urinary I7-ketosteroids . . .
Virilism in phenotypic female
Abnormal karyotype
germinal tumors, while the time was protracted to eighteen to twenty-four months for the nongerminal lesions. Endocrine disturbances are generally present with Leydig cell tumors in children, symptoms of sexual precocity being the usual presenting complaint. Gynecomastia occasionally occurs and is related to increased levels of estrogen and progesterone. Bone age is also advanced in patients with Leydig cell tumors. Gittes et al. I6 pointed out that a small intratesticular tumor may lead to isometric enlargement of both the testis and epididymis of the involved side which may mask the expanding lesion. Exploration of the interior of the enlarged testis is required to demonstrate the presence of a tumor. Differentiation can usually be made between Leydig cell tumors and the testis tumor associated with the adrenogenital syndrome (Table IV). A family history of congenital adrenal hyperplasia will be present in some patients. Nocturnal emissions and precocious sexual behavior are more commonly associated with Leydig cell tumors. Bilateral testis tumors are found more often in patients with congenital adrenal hyperplasia. Hormone studies are useful in distinguishing these two entities.” While some elevation in urinary 17-ketosteroid levels may occur in both conditions, a significantly elevated level favors the diagnosis of adrenogenital syndrome particularly in patients with a 21-hydroxylase deficiency. Slight elevations occur in patients having a 17-hydroxylase or 11-hydroxylase deficiency. In congenital adrenal hyperplasia, the urinary 17-ketosteroid excretion is reduced by corticosteroid administration. Urinary pregnanetriol is usually absent in patients with but significant elevations Leydig cell tumors,
UROLOGY / JUNE 1979 / VOLUME XIII, NUMBER 6
TABLE IV. Diffmentiation between Leydig cell tumors and testis tumors associated with congenital adrenal hyperplasia
Clinical Data History
None
Nocturnal emissions Precocious sexual behavior Laterality Serum testosterone
Frequent Frequent
Pregnanetriol
Usually absent
Urine sodium excretion
Normal
Urinary excretion of I7-kerosteroids following cortisone administration Effect of ACTH on urinary 17-OH corticosteroids Effect of cortisone on tumor size Urinary ketosteroids
No change
May be bilateral May be slightly elevated Increased in 21-OH deficiency Usually increased in 21-OH deficiency; low in 11-OH deficiency Reduced
Increased
No change
None
May be reduced
Normal to slight increase
Usually marked increase in 21-OH deficiency; slight elevation in 17hydroxylase or 11-OH deficiency
Therapy Yolk sac carcinoma There has been a great deal of confusion concerning the therapy for this tumor because too few patients have been treated in any one center or in any organized fashion (Tables V and VI). The 366 patients in this study were gathered from over 800 patients reported in the world literature and include 12 patients of our
/ JUNE 1979 / VOLUMEXIII,
May have positive family history Rare Rare
Unilateral Usually elevated
occur in patients with congenital 21-hydroxylase deficiency. Patients having the other varieties of congenital adrenal hyperplasia demonstrate no increase in urinary pregnanetriol excretion. Significantly increased blood and urinary testosterone determinations are found in patients with Leydig cell tumors, but present techniques for measuring testosterone indicate that there is a slight increase in patients with congenital adrenal hyperplasia. The exogenous administration of cortisone will usually reduce urinary l7ketosteroids as well as diminish the size of the associated testis tumor in congenital adrenal hyperplasia.
UROLOGY
Congenital Adrenal Hyperplasia
Leydig Cell Tumor
NUMBER6
own. Only those patients whose follow-up was at least two years were evaluated. Most patients with recurrent disease presented within two years of the original therapy. Unfortunately, the data may not accurately reflect the true clinical situation since the group is selected and diverse in surgical, radiotherapeutic, and chemotherapeutic techniques.
TABLE
V.
Therapy of testis tumors in children
Type Yolk sac carcinoma
Teratoma Sertoli cell tumor Leydig cell tumor Rhabdomyosarcoma
Gonadoblastoma
Therapy Orchiectomy with chemotherapy and or lymphadenectomy depending on tumor markers Simple orchiectomy Simple orchiectomy Simple orchiectomy Radical orchiectomy with extensive local dissection, retroperitoneal lymph node dissection; chemotherapy and radiation therapy Orchiectomy with local lymph node dissection
585
TABLE VI. Yolk sac carcinoma; survival compared with therapy
Therapy Orchiectomy Orchiectomy + Chemotherapy Orchiectomy + X-ray Orchiectomy + Lymphadenectomy Negative nodes Positive nodes TOTALS
Alive 2 Yr. Without Per Cent Tumor Dead Total Survival 117
77
194
60
10
0
10
loo
55
9
64
86
78 3
16 1
94 4
83 75
263
-103
366
-
72
Age has been considered an important prognostic factor in this disease. There were 270 patients who were less than two years of age and 29 (11 per cent) died. There were 96 patients who were older than two years and 74 (77 per cent) died of cancer. This supports the concept that the disease is more serious in the “older” child and should be treated more aggressively. Orchiectomy was the only form of treatment in 169 children. One hundred seventeen (60 per cent) were alive without tumor beyond two years. Pulmonary metastases were usually the initial finding of recurrent tumor. Chemotherapy has been a recent addition to the therapeutic regimen-l8 An adequate course of multiple drug chemotherapy after orchiectomy could be determined in only 10 cases. These patients did not have clinical evidence of metastatic disease when they were initially treated but later metastases developed. All were alive two years after initiation of therapy. This group is too small to ascertain the effectiveness of this therapeutic strategy. Other patients were unsuccessfully treated with single drugs, short courses of therapy, or after the disease was far advanced. Many patients were treated prior to the advent of aggressive chemotherapy in young children. Radiation therapy was utilized in 64 patients and is considered by some to be valuable therapy.igmzl Fifty-five (86 per cent) survived beyond two years. The role of radiation therapy is not defined since the fear of delayed growth, bone marrow arrest, sterilization of the remaining testis, radiation nephritis, and enterocolitis has made surgeons wary of its use.22,23 The favorable experience with retroperitoneal lymph node dissection in nonseminomatous
586
germinal tumors of the adult has led to the application of this surgical technique in children.24-27 There were 98 patients who were treated with orchiectomy and retroperitoneal lymph node dissection. No evidence of lymph node metastases were found in 94 patients, but 16 eventually died of cancer. Only 4 patients had lymph node metastases, and 3 were alive after two years. The two-year survival in patients having a negative lymphadenectomy was 83 per cent. The outcome cannot be explained on the basis of the lymph node dissection. Young et ~1.‘~ reported that lymphadenectomy did not increase survival rates in their group of 18 patients, causing them to question its need. They presented evidence which suggests that yolk sac carcinoma has a greater propensity for hematogenous spread than embryonal carcinoma of the adult testis. Bracken et ~1.‘~ reported similar data attesting to the rarity of lymphatic spread in this disease. However, they believed that lymphangiography should be performed, and if normal, a lymphadenectomy done until biologic markers are available for this disease. Our data strongly support this view. The disease has a different clinical behavior than embryonal carcinoma in the adult. The propensity for hematogenous spread is greater in children emphasizing the need for systemic therapy and a lesser need for lymphadenectomy. In the 12 patients treated in our hospitals, 8 had lymphadenectomies and all were normal. Only 1 patient died of cancer, and this child had undergone a negative lymphadenectomy. The tumor markers, HCG-B and alphafetoprotein (AFP), have been shown to be valuable in adults but have not been well studied in children.28-30 We have been able to obtain data on 7 boys with yolk sac carcinoma. These boys are not included in the over-all series because they have not all been followed for longer than two years and will be the subject of a separate study. The AFP was significantly elevated in all of the patients prior to orchiectomy. The normal AFP is less than 40 ng./dl., but these patients had extremely high levels exceeding 200 ng./dl. The high AFP levels are consistent with the extraembryonic origins of this tumor and add support to the term “yolk sac carcinoma.” HCG-B was minimally elevated in 2 boys and reverted to normal following orchiectomy. Two boys continued to have significantly elevated AFP levels, and one a slight increase in AFP after orchiectomy, even though there was
UROLOGY / JUNE 1979 / VOLUMEXIII, NUMBER6
TABLE VII. Rhabdomyosarcoma: compared with therapy Therapy Orchiectomy Orchiectomy + Chemotherapy + X-ray + Lymphadenectomy Postive nodes Negative nodes Orchiectomy + X-ray TOTALS
Alive 2 Yrs.
Dead
survival Per Cent Total Survival
21
7
28
75
12 6
1 1
13 7
92 86
6
10 -
40 -
15
58
74
_
4
43
-
no clinical evidence of metastatic disease. Lymphadenectomy was negative in 2 of these children, but they were treated with chemotherapy positive. The AFP because the AFP remained returned to normal within two months after initiating chemotherapy, and they have remained tumor free. The third patient with a positive AFP following orchiectomy did not have lymphadenectomy but was started on chemotherapy. The AFP reverted to normal, and the child remains free of disease fourteen months after beginning therapy. The remaining 4 patients had normal tumor markers after orchiectomy. Two of these patients had negative lymphadenectomies. The remaining 2 patients were treated with orchiectomy alone, and their tumor markers have remained normal. No additional therapy has been given. In these 7 patients the AFP has been a sensitive, reliable, and accurate indicator of the disease stage. HCG-B does not appear to be as valuable a marker for this tumor as the AFP. If the effectiveness of chemotherapy and the accuracy of tumor markers in children are substantiated, the role of retroperitoneal lymphadenectomy could be redefined and its use limited to specific indications. Teratoma The teratoma of childhood follows a benign course.4,12*14*27,31 Most of the children are diagnosed within the first few years of life and require no other treatment than an orchiectomy. Sertoli cell tumor Twenty-two patients with clear evidence of this tumor have been reported. As a rule these tumors are diagnosed in infancy when they are
UROLOGY / JUNE 1979 / VOLUME XIII, NUMBER 6
small and asymptomatic.r2,13 Gynecomastia may be associated with Sertoli cell tumors in adults but not in children.32 Although several malignant cases have been reported in adults, only one has been described in a child. Metastases to lymph nodes and liver were reported by Rosvoll and Woodard33 in an eight-year-old child. Their patient was treated with lymph node dissection, radiation, and chemotherapy. There was no tumor recurrence after two years. While orchiectomy has been successful in 21 of 22 patients, careful clinical staging and follow-up are necessary. Leydig
cell tumor
Leydig cell tumors in childhood are benign. Malignant Leydig cell tumors have been rein children and ported in adults. 34 Tumors adults differ in that endocrine manifestations are usually absent in adults while most children have associated endocrine disturbances.35 The treatment is orchiectomy, but this may not produce regression of the physical manifestations of precocity or bone age. However, urinary 17ketosteroid levels fall to normal after surgical intervention. If they do not, or if they later return to high levels, bilateral testis tumors associated with the adrenogenital syndrome should be suspected. Rhabdomyosarcoma An aggressive therapeutic approach is indicated for this neoplasm.26,27,36,37 Orchiectomy with extensive local excision is the first stage. If the scrotal skin has been invaded, ipsilateral inguinal lymph node excision should be included with removal of the involved scrotum. Because metastases may occur by lymphatic and vascular channels, retroperitoneal lymph node dissection and chemotherapy are necessary. Metastatic disease should be treated with a combination of radiation, surgical resection, and chemotherapy. In the group of 58 patients there was an over-all survival of 74 per cent (Table VII). The best survival was in the patients who received systemic chemotherapy in addition to lymphadenectomy. The behavior of this tumor necessitates this type of approach. It is interesting to note that even in the children who had orchiectomy alone, survival was 75 per cent. The better prognosis in this type of sarcoma can be explained by the location and easier detection of these testis tumors compared with sarcomas in other parts of the body.
587
Summary A clinical analysis was made of 556 prepubertal children with testis tumors. Germinal tumors comprised 76 per cent of this group, and the most common of these tumors was the yolk sac carcinoma. Although many appellations have been used to describe this tumor, experimental and clinical evidence support the use of this term. The over-all two-year survival was 72 per cent and was better in children less than two years of age. The tumor is distinctly different from the embryonal carcinoma of the adult. The role of lymphadenectomy needs to be reassessed in view of the low incidence of lymph node metastases and the propensity for pulmonary metastases. Chemotherapy appears to be of benefit. Tumor markers, particularly alphafetoprotein, may be of assistance in planning therapy. The other germinal tumor is the teratoma. This is a benign, nonmetastasizing disease in children and requires only orchiectomy. Nongerminal tumors comprised 24 per cent of tumors and require only orchiectomy. Sertoli cell tumors are rare, and there has been only one report of metastatic disease. Leydig cell tumors present with endocrine manifestations and are benign in children. They may be difficult to distinguish from tumors associated with congenital adrenal hyperplasia. Rhabdomyosarcomas should be treated with a combination of surgery, chemotherapy, and radiation. The over-all survival of 74 per cent for these patients indicates the benefits of aggressive therapy. Harbor General Hospital 1000 West Carson Street Torrance, California 90509
References 1. Dixon FJ, and Moore RA: Tumors of the male sex organs, in Atlas of Tumor Pathology, Armed Forces Institute of Pathology, Washington, D.C., 1952, vol. 8, p. 316. 2. Teilum G: Special Tumors of Ovary and Testis and Related Extragonadal Lesions; Comparative Pathology and Histological Identification, Philadelphia, J, B. Lippincott Press, 1971. 3. Pierce GB, Bullock WK, and Huntington RW: Yolk sac tumors of the testis, Cancer 25: 644 (1970). 4. Holtz F, and Abel1 MR: Testicular neoplasms in infants and children. II. Tumors of non-germ cell origin, ibid. 16: 982 (1963). 5. Flickinger CJ: The postnatal development of the Sertoli cells of the mouse, Z. Zellforsch. 78: 92 (1967). 6. Turner JH, and Bloodworth JMB: In: Endocrine Pathology, Baltimore, Williams and Wilkins Press, 1968. 7. Bonser GM, and Robson JM: Effect of prolonged oestrogen administration upon male mice of various strains: development of
588
testicular tumors in strong A strain, J, Pathol. Bacterial. 51: 9 11940). 8. Twombly GH, Meisel D, and Stout AP: Leydig-cell tumors induced experimentally in the rat, Cancer 2: 884 (1949). 9. Glenn J, and Boyce W: Adrenogenitalism with testicular adrenal rests simulating interstitial cell tumor, Trans. Am. Assoc. Genitourin. Surg. 54: 59 (1962). 10. Savard K, et al: Clinical, morphological and biochemical studies of a virilizing tumor in the testis, J. Clin. Invest. 39: 534 (1960). 11. Scully RE: Gonadoblastoma. A review of 74 cases, Cancer 25: 1340 (1970). 12. Houser R, Izant RJ, and Persky L: Testicular tumors in children, Am. J. Surg. 110: 876 (1965). 13. Phelan JT, Wollner LB, and Hayles AB: Testicular tumors in infants and children, Surg. Gynecol. Obstet. 105: 569 (1957). 14. Bachmann KD, and Von Grawert H: Tumoren des Hodeus im Kindesalter: Bericht iiber 545 Falle, Monatsschr. Kinderheilkd. 120: 40 (1972). 15. Shivde AU, and Junnarkar RV: Primary lymphosarcoma of the testis: report of a case, J. Ural. 103: 762 (1970). 16. Gittes RF, Smith G, Conn CA, and Smith F: Local androgenic effect of interstitial cell tumor of the testis, ibid. 104: 774 (1970). 17. Brosman S, and Gondos B: Testicular tumors in children, in Johnston JH, and Goodwin WE, Eds: Reviews in Paediatric Urology, Excerpta Medica, 1974. 18. Karamehmedovic 0, Woodtli W, and Pluss HJ: Testicular tumors in childhood, J. Pediatr. Surg. 10: 109 (1975). 19. Ise T, Ohtsuki H, Matsumoto K, and Sane R: Management of malignant testicular tumors in children, Cancer 37: 1539 (1976). 20. Matsumoto K, Nakauchi K, and Fujita K: Radiation therapy for the embryonal carcinoma of testis in childhood, J. Ural. 104: 778 (1970). 21. Tetft M, Vawter GF, and Mitus A: Radiotherapeutic management of testicular neoplasms in children, Radiotherapy 88: 457 (1967). 22. Young PG, Mount BM, Foote W, and Whitmore WF: Embryonal adenocarcinoma in the prepubertal testis. A clinicopathologic study of 18 cases, Cancer 26: 1065 (1970). 23. Johnson DE, Kuhn CR, and Guinn GA: Testicular tumors in children, J. Ural. 104: 940 (1970). 24. Bracken RB, Johnson DE, Cangir A, and Ayala A: Regional lymph nodes in infants with embryonal carcinoma of testis, Urology II: 376 (1978). 25. Smith JP: Testicular tumors in infants and children, ibid. 2: 353 (1973). 26. Colodny AH, and Hopkins TB: Testicular tumors in infants and children, Ural. Clin. North Am. 4: 347 (1977). 27. Giebink GS, and Ruymann FB: Testicular tumors in childhood, Am. J. Dis. Child. 127: 433 (1974). 28. Bourgeaux C, Martel N, Sizaret P, and Guerrin J: Prognostic value of alpha-fetoprotein radioimmunoassay in surgically treated patients with embryonal cell carcinoma of the testis, Cancer 38: 1658 (1976). sinus tumor) 29. Tsuchida Y, et al: Yolk sac tumor (endodermal and alpha-fetoprotein. A report of three cases, ibid. 32: 917 (1973). 30. Javadpour N, and Bergman S: Recent advances in testicular cancer, Curr. Prob. Surg. vol. 15, no. 2 (1978). 31. Abell MR, and Holtz F: Testicular neoplasms in infants and children. Tumors of germ cell origin, Cancer 16: 965 (1963). 32. McArthur JW: Gonadotrophins in relation to sexual maturity, in Savena BB, Beling CG, and Gandy HM, Eds: Gonadotropics, New York, Wiley-Interscience Press, 1972. 33. Rosvoll RV, and Woodard JR: Malignant Sertoli cell tumor of the testis, Cancer 22: 8 (1968). 34. Tamoney JJ, and Noriega A: Malignant interstitial cell tumor of the testis, ibid. 24: 547 (1969). 35. Johnstone G: Prepubertal gynecomastia in association with an interstitial cell tumor of the testis, Br. J. Urol. 39: 211 (1967). 36. Brosman S, Cohen A, and Fay R: Rhabdomyosarcoma of testis and spermatic cord in children, Urology 3: 568 (1974). 37. Tank ES, et al: Treatment of urogenital tract rhabdomyosarcoma in infants and children, J. Urol. 107: 324 (1972).
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/
JUNE
1979
/
VOLUME
XIII,
NUMBER
6