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Androgen-producing tumors in children and adolescents
Adolesc Pediatr Gynecol (l989) 2:135-142
Adolescent and Pediatric Gynecology © 1989 Springer-Verlag New York Inc.
Mini Reviews
Androgen-Producing Tumors in Children and Adolescents Santiago L. Padilla, M.D. Department of Gynecology, Greater Baltimore Medical Center, Baltimore, Maryland
Abstract. Androgen-producing tumors of the adrenal and the ovary are extremely rare, however, their potential malignancy and the androgen effects can be detrimental to children and adolescents. Adrenal adenomas are usually small, whereas adrenal carcinomas are generally large and very aggressive, requiring prompt intervention. Adrenal tumors mostly secrete !l5 androgens, although at least 12 cases of testosterone-producing adrenal tumors have been reported. One-third of functioning adrenal tumors also have increased secretion of corticosteroids. Primary androgenproducing ovarian tumors are classified under several different histological groups. Incidence of malignancy in these tumors is approximately 5%. Tumors metastatic to the ovary may stimulate the adjacent ovarian stroma and cause virilization. These must be differentiated from primary ovarian tumors because the prognosis is completely different. Ovarian tumors prefer !l4 androgens, although cases mainly producing !l5 androgens have been reported. The dehydroepiandrosterone sulfate and testosterone in serum are the best screening parameters for these tumors, although accurate diagnosis requires computed tomography for adrenal tumors and pelvic exam combined with ultrasonography for ovarian tumors. Venous catheterization studies are rarely indicated. Adrenal carcinoma requires aggressive surgical treatment, whereas adrenal adenomas and primary ovarian tumors can be treated with conservative unilateral procedures.
lignant androgen-producing tumors of the adrenal are extremely rare, occurring with an incidence of approximately two per million per year in the general population, and accounting for only 0.023% of all malignant tumors. 1.2 However, the presence of these tumors along with the effects of the androgens are especially detrimental to children and adolescents. Malignant adrenal tumors are often rapidly fatal and therefore early detection and treatment is extremely important. Malignant androgen-producing tumors of the ovary are also rare. Of the 3,500 cases submitted to the Emil Novak Ovarian Tumor Registry, 3 there are less than 200 ovarian tumors classified as "masculinizing. " There were 55 (28%) tumors in patients younger than age 20. Norris and Jensen4 reviewed the experience of the Armed Forces Institute of Pathology and found 353 patients under the age of 20 with a primary ovarian tumor; this represented only 6% of their total number of ovarian neoplasms. They noted 14 cases of virilizing ovarian tumors in girls under age 20 and only two prior to puberty. The ovarian virilizing tumors are in general less aggressive than the adrenal tumors, but early detection and treatment is also important. Modem biochemical and radiological techniques greatly facilitate diagnosis of these tumors, and early detection with aggressive therapy should result in a better prognosis.
Key Words. Androgen-secreting tumors- VirilizationOvarian tumors-Adrenal tumors
Androgen-Producing Adrenal Tumors Introduction The most important responsibility of the physician caring for a patient with hirsutism and/or virilization is to determine whether there is an androgen-producing malignant tumor of the adrenal or the ovary. MaAddress reprint requests to: Santiago L. Padilla, M.D., Greater Baltimore Medical Center, 6565 N. Charles Street, Suite 207, Baltimore, MD 21204, USA.
Adrenal cortical adenomas are usually poorly encapsulated tumors (Table 1). The surface is reddish to brown, they are usually small, and they weigh 100200 g, although much greater weights of up to 4,200 g have been reported. 1.2.6.7 Large adenomas may have areas of hemorrhage, cystic degeneration, and focal calcification. Although multiple and bilateral adrenal nodules can sometimes occur, only single adrenal nodules are the ones usually considered to be adenomas. In the case of functioning adenomas, the con-
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Table 1. Histopathology of Androgen-Producing Tumors Adrenal Tumors Adenomas are usually small; carcinomas are characteristically large and have a poor prognosis May show areas of hemorrhage, cystic degeneration, and calcification Ovarian Tumors Thecomas/ Uniformly benign fibrothecomas Usually feminizing, occasionally Granulosa cell virilizing. 95% 5-year survival tumors Stromal and epithelial components. Arrhenoblastoma Epithelial elements determine prognosis Recurrences are rare and occur Sertoli-Leydig within 5 years Cells similar to zona fasciculata and Adrenal rest zona reticularis. Uniformly benign Cause masculinization by stimulation Epithelial/metastatic of adjacent stroma
tralateral adrenal gland is usually atrophic. Benign adenomas are arranged in a fasciculate pattern and are clusters of large cells that uniformly contain lipid material. Cellular pleomorphisms and nuclear anaplasia may also be seen. Conversely, adrenal carcinomas are usually large, measuring up to 20 cm in diameter and weighing up to 2,500 g or more. Lanes et al. 5 reported a 1,120 g adrenal cortical carcinoma in a 4-year-old female. Adrenal carcinomas are usually yellowish-brown and contain areas of hemorrhage, necrosis, and calcification. Histological appearance varies from mild to severe degrees of atypia and may sometimes be highly anaplastic. Diagnosis of adrenal carcinoma is facilitated by invasion into the capsule or blood vessels, tumor metastasis, or both.5 Clinical characteristics of androgen-producing adrenal neoplasms are similar whether benign or malignant. Biochemically, there is no reliable way short of surgical excision and histological examination to differentiate between benign and malignant neoplasms. Adrenal neoplasms may occur at any age and have been reported in utero and after menopause. Functioning adrenal tumors in prepubertal children are usually malignant and most series report their propensity to occur in girlS. 8- 1O Endocrine symptoms in children include virilization, heterosexual precocious puberty, Cushing's syndrome, or hyperaldosteronism with hypertension. These symptoms usually start abruptly and develop quickly. Approximately twothirds of the cases have virilization and one-third have Cushingoid signs. 10 Cushing's syndrome in a child under age 10 is almost always due to neoplasia. 9 •10 In addition, virilizing adrenal tumors have been associated with hemihypertrophy, Beckwith-Wiedemann syndrome, congenital malformations of the genitour-
inary tract, an array of hamartomatous disorders, and astrocytoma. 8
Androgen-Producing Ovarian Tumors Ovarian tumors associated with virilization comprise a varied group of neoplasms. Woodruff and Parmleyll suggest that the term "associated with" may be more appropriate than the term "caused by" when referring to ovarian androgen-producing tumors, because the androgens may not be produced by the tumor itself, but by activation of adjacent ovarian stromal cells. All primary functioning tumors of the female gonad are either teratoid or gonadal stromal, with or without luteinization, and with or without epithelial components. The stroma identifies the function of the tumor; the epithelium defines the predominant histopathological features and is of primary prognostic significance. Although it is generally true that a lesion with tubules and interstitial cells is masculinizing, whereas that composed of granulosa cells is generally feminizing, there are exceptions. Similar to adrenal tumors, the individual microscopic features of the tumor cannot describe its hormonal function, and we have to rely on clinical and laboratory findings. Tumors metastatic to the ovary may stimulate the adjacent ovarian stroma and cause virilization. These must be differentiated from primary ovarian tumors because the prognosis is completely different.
Thecoma and Fibrothecoma These lesions are probably the most common of the gonadal stromal tumors and are most frequently asymptomatic and nonfunctioning. Usually they are discovered in the late 4th and 6th decades of life and the site varies tremendously. Virilization is due mainly to foci of "luteinization" in which the cells are large and contain abundant cytoplasm, suggestive of hormonal activity. In young patients, these tumors may be associated with calcification. Malignancy is uncommon and two to three mitoses per high power field may be seen. Lesions with more than four mitoses in any high power field may recur intraabdominally. The majority of these tumors are associated with estrogen production, although hormone profiles have demonstrated that androgens may come from these lesions. 12 The prognosis for this tumor is excellent and unilateral lesions should be treated with unilateral oophorectomy. Granulosa and Granulosa-Theca Cell Tumors These tumors classically cause feminization and are associated with endometrial hyperplasia and occa-
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sionally endometrial cancer. Interestingly, in a small percentage of cases, masculinization has been found. Novak et al. I3 reported 370 such lesions, 14 (4.5%) of which presented with virilization. In contrast to the thecoma, granulosa cell tumors have a definite epithelial component, which makes them potentially malignant. The cell is round and ovoid with the often classic "coffee bean" appearance of the nucleus. Mitoses are common and potentially malignant mainly by rupture of the capsule. Bilateral tumors occur in 5% of cases. Five-year survival, whether feminizing or masculinizing, is 97%. Approximately 5% of these tumors occur before puberty and may cause isosexual precocious puberty. In Novak's series,13 there were no deaths in patients under 15 years of age. Based on this, conservative surgery is indicated in the young patient.
Arrhenoblastoma and Androblastoma The three types of these tumors include 1) the welldifferentiated or Pick's adenoma, 2) the intermediate variety in which "tubules" can be recognized, and 3) the sarcomatoid in which only stroma is present. The latter undoubtedly is a variant of the thecoma with or without focal luteinization. The intermediate type is the gonadal stromal tumor with attempted tubule formation. This tumor is well defined in certain areas, but in others, only columns of stromal or epithelial cells can be poorly differentiated. The androblastoma is a separate category with well-defined tubules and a minimal stromal component. This may be difficult to differentiate· from the classic Sertoli cell tumor. Nevertheless, the Sertoli cell should be much taller and simulate that seen in the male gonad. The epithelial component identifies the prognosis. Meldrum and Abraham l4 observed that both A4 and A5 pathways contribute precursors for the production of testosterone but the A5 pathway predominated. Sertoli, Leydig, and Sertoli-Leydig Tumors Pure Sertoli cell tumors are composed of intertwining tubules lined by tall pale cells with a basal nucleus. These tumors were originally proposed to be a variant of the granulosa cell tumor because of their associated feminization. Consequently, the pure Sertoli cell tumor in the female is not virilizing. Sertoli-Leydig cell tumors and Leydig cell tumors contain annular tubules and have been described histologically.15,16 Recurrences almost invariably occur during the first 5 years after treatment. Several hundred cases have now been published. 16 Microscopically, these tumors may contain Reinke crystalloids and 50% present clinically with virilization. IS An association with mucinous cystadenoma and the Peutz-Jeghers syndrome has been
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described. 15 These tumors are usually unilateral, and conservative surgery in the young patient is indicated.
Adrenal, Adrenal Rest, and Lipoid Tumors Adrenal rests can be found in the broad ligament adjacent to the tube or ovary. The so-called adrenal rest tumor is probably of ovarian stroma in origin. Most of them are not paraovarian, but intraovarian. Ovarian stromal cells, when luteinized, may resemble cells of the adrenal cortex. Hormonal production patterns of at least some of these tumors is more consistent with ovarian stroma than with adrenal cortex. 17 Typically, two types of cells are present in these tumors-a large cell with clear cytoplasm and a smaller round cell with abundant acidophilic cytoplasm. These types are similar to the zona fasciculata and zona reticularis of the normal adrenal. Adrenal rest tumors are usually benign. Among 22 of these tumors reviewed by Ireland and Woodruff,3 only one recurred. They are usually small, however, a 25-cm lesion has been reported. ll The lipoid cell tumor is classified as an adrenal rest tumor. The large cell with nonstaining cytoplasm and nucleus could be adrenal or Leydig in origin and also uniformly benign. Epithelial and Metastatic Ovarian Tumors Rarely, epithelial tumors of the ovary can result in masculinization of the host. The mucinous tumor of the ovary may induce masculinization during pregnancy; histopathology reveals that the stroma adjacent to the tumor is luteinized. 3 Metastatic tumors, through a similar mechanism of induction of stromal luteinization, can cause masculinization; The Krukenberg tumor, carcinoid tumor, and other metastatic tumors, characterized by diffuse infiltration of the stroma with a seemingly innocuous adenomatous pattern, are examples. 3 Certainly these tumors carry a much worse prognosis. The presence of virilization with diffuse infiltration may incorrectly lead to the diagnosis of a primary gonadal stromal tumor. Correct diagnosis is important because metastatic tumors cannot be treated conservatively like primary gonadal stromal tumors.
Differential Diagnosis Several non-neoplastic conditions can cause hirsutism and virilization. Polycystic ovarian disease (PCO), hyperthecosis, Cushing's disease, exogenous androgens, and congenital adrenal hyperplasia (CAH) are examples of these non-neoplastic conditions (Table 2).18.19 The signs and symptoms usually develop slowly in contrast to the androgen-producing tumors which customarily induce symptoms very fast. Prior to puberty, the tumors and CAH may cause a premature
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growth spurt, virilization, and heterosexual precocious puberty. After puberty, all non-neoplastic and neoplastic conditions are commonly related to menstrual disturbances. PCO is the most common cause of amenorrhea and hirsutism after puberty. The amenorrhea is usually secondary, although cases of primary amenorrhea have been reported. PCO will rarely cause virilization. Ovarian hyperthecosis, on the other hand, is very commonly associated with virilization and menstrual abnormalities. 17 In hyperthecosis, androgen levels, especially testosterone, may be in the male range. Many hyperthecosis patients have had ovarian wedge resections to rule out presence of a tumor. IS Cushing's disease is part of the differential diagnosis and a 24-hour urine collection for free cortisol levels is the best screening method to detect this condition. The most common adrenal enzyme deficiency in CAH is 21-hydroxylase deficiency followed by 11hydroxylase deficiency, both of which can cause virilization. 21-hydroxylase deficiency can be salt-losing in 50% of patients, and ll-hydroxylase deficiency can also cause hypertension in 50% of patients. These girls usually present with pubic hair growth, clitoral hypertrophy, facial hair growth, temporal hair recession, acne, deepening of the voice, muscular development, and acceleration of growth rate and skeletal maturation. Careful family history may reveal similar affected siblings. Heterozygote carriers of the affected gene may give a history of menstrual disturbances, early puberty, hirsutism, anovulation, and infertility. 19 Serum electrolytes, urinary sodium excretion, and renin activity will reveal a sodium loss in the saltlosing patients. The electrolyte imbalance requires immediate attention. Serum levels of 17-hydroxyprogesterone and urinary pregnanetriol values will be elevated. Exogenous sources of androgens can very rarely result in heterosexual precocious puberty. Premature pubic hair growth may occur in patients with isosexual precocious puberty and in cases of premature adrenarche but will not be associated with clitoromegaly, deepening of the voice, or any other virilization signs. When enlargement of the clitoris alone is present, a tumor of the clitoris also must be considered.
Hormonal Evaluation Biochemical testing helps the clinician identify the source of androgen secretion (Table 3). Adrenal glands tend to produce larger amounts of weaker androgens such as androstenedione (A), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). These compounds are partially converted to 17 ketosteroids (17-KS) in peripheral tissues. Pa-
Table 2. Differential Diagnosis of Androgen-Producing Tumors Polycystic ovarian disease Congenital adrenal hyperplasia Ovarian hyperthecosis Cushing's disease Exogenous androgens Pseudo virilization by tumor of the clitoris
tients with hirsutism and/or virilization resulting from adrenal androgens will usually have elevated DHEAS concentration and elevated urinary 17-KS. DHEAS can substitute the urinary 17-KS in the evaluation of hirsutism. 20 Over 96% of the serum DHEAS is of adrenal origin and, therefore, it is a more direct measurement of adrenal androgen output than the urinary 17-KS. In addition, urinary 17-KS measures not only adrenal androgens but also metabolites of ovarian androgens, corticosteroids, and some nonspecific pigments. Accurate measurement of urinary 17-KS requires a 24-hour collection to avoid circadian variation in steroid secretion. Refrigeration is essential to avoid degradation of metabolites. The urinary creatinine level should be checked to assure the validity of the 24hour collection. Many clinics have eliminated the determination of 17-KS and rely almost entirely on serum DHEAS as an index of adrenal androgen production. A random DHEAS sample is sufficient and there is no need to correct for body weight, circadian variation, or creatinine excretion. A high circulating serum concentration of DHEAS, along with a slow turnover rate and a long half-life, results in a large and stable pool with insignificant variation. As with urinary 17-KS, aging is associated with a decrease in the blood concentration of DHEAS and careful attention should be taken to establish n~rmal values for all age groups. Virilizing adrenal tumors primarily secrete DHEA and DHEAS, over testoster-
Table 3. Diagnostic Modalities Circulating Androgen Levels Total testosterone (T) and DHEAS are the best screening parameters In virilized patients, DHEA and urinary 17KS should be obtained if T and DHEAS are normal Hormonal stimulation and suppression studies are not helpful Radiology Adrenal glands: CT scan is most useful. Magnetic resonance imaging (MRI) and ultrasound can aid in diagnosis Ovary: Ultrasound is most useful. CT scan and MRI have limited value Venous Catheterization Technically difficult with potential complications in children and adolescents Helpful in selected cases where other radiological studies are non diagnostic
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one (T). 21 Lipsett et a1. 20 suggested that urinary 17KS measuring over 50 mg for 24 hours, which corresponds to about 800 J..Lg/dl of DHEAS, is almost pathognomonic of an adrenal tumor in virilized women; however, if the DHEAS is normal, adrenal disease is most unlikely. There have been several reports of adrenal tumors that secrete testosterone primarily. 22-32 Some of these adrenal tumors may actually respond to gonadotropin stimulation.23.24.26 At least 10 of the reported testosterone-producing adrenal tumors underwent ovarian wedge resection, ovarian biopsy, or oophorectomy before the correct diagnosis was determined.33.34-37 Androgen-producing tumors of the ovary are associated with testosterone levels in the male range. 14 .20 Some investigators have suggested that testosterone levels > 200 ng/ dl indicate the presence of an ovarian or adrenal androgen-producing tumor. 8.14 This arbitrary point has been challenged because variations of hormonal secretions and laboratory variability can yield misleading values. 38- 4o It is recommended that at least three daily samples reach a level 2.5 times greater than the upper limit of normal for the given laboratory .40 DHEAS is not unique to adrenal tumors. Surrey et a1. 39 reported an ovarian tumor with a peripheral DHEAS level of 973.8 J..Lg/dl which is above the suggested cut-off value of 800 fLg/dl for adrenal tumors. Circulating serum T levels are elevated in many women with anovulation and hirsutism. Individual variation is great due to changes in T -binding capacity of the sex hormone-binding globulin in the blood. Androgens lower testosterone binding; the total T (free and bound T measured by radioimmunoassay) can be normal in hirsute women. Some clinicians measure unbound or free T in women with hirsutism. For practical purposes, it is not necessary to measure free T because the main purpose of the T level, in evaluating the hirsute women, is to rule out the presence of a testosterone-secreting tumor. The fine discrimination of the free T is not necessary. Hormone stimulation tests can give false-positive and false-negative results. 23 •24 ,26 In addition, suppression studies do not specifically isolate ovarian or adrenal function in neoplastic and non-neoplastic conditions. 38 ,41
Venous Catheterization and Radiological Evaluation Radiological studies are indispensable in evaluating the adrenal glands, and in detecting ovarian neoplasia (Table 3). Plain abdominal x-ray films, excreting urography, venography with effluent venous sam-
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pIing, computed tomography (CT), ultrasonography, and scintigraphy are among the techniques used. Calcifications may be seen on a plain abdominal x-ray film in cases of adrenal carcinoma, neuroblastoma, pheochromocytomas, and in some ovarian tumors. Rarely, adrenal adenomas may form calcifications; adrenal hyperplasia never causes calcifications. 42 High-dose excretory urography in conjunction with conventional serial tomography can detect adrenal masses measuring > 20 mm in diameter. Large adrenal masses may cause downward displacement of the ipsilateral kidney. Conventional radiographic techniques are reportedly 70% accurate in diagnosing adrenal tumors; high false-negative and false-positive results have been reported. 43 Angiography may be useful for diagnosing adrenal masses, but technical difficulties and complications have reduced the use of angiography as a primary means of evaluating these patients. 44 ,45 Venography combined with steroid analysis of effluent blood can help determine the site of abnormal hormonal production in some patients. 39,4649 One group reported a 77% successful bilateral catheterization of both adrenal and ovarian veins in 13 patients. 47 Successful catheterization of the right adrenal vein was reported in 36 of 50 patients, but the left adrenal vein was entered in all 50 patients. 50 Left adrenal and ovarian veins are more anatomically consistent and the venous blood from the left side is relatively easier to obtain. 51 The right adrenal vein enters the vena cava at an acute angle, whereas the right gonadal vein enters the vena cava either by way of the right renal vein, or directly at the site of entry of the right renal vein. 52 Adrenography performed in 50 virilized women yielded an anatomic explanation for virilization in only 13 (26%) of the patients. 50 Although adrenography and steroid analysis of ovarian and adrenal venous effluents can be useful diagnostic tools, potential complications and technical difficulties in children and adolescents limit their value. CT is by far the primary procedure for diagnosis of adrenal tumors. Its usefulness, accuracy, and success rate compared with other techniques is very good. When the adrenal gland is scanned using 10-mm slices at lO-mm intervals, both the adrenals are seen in 90% of normal patients. Using 7-mm slices at lO-mm intervals, the figure rises to 99%.53-55 CT of the adrenals correctly identified 11 of 13 steroid-producing adenomas without any false-positives, the smallest tumor measuring 1 cm in diameter. 56 Of the two false-negatives, one 0.5-cm adenoma was confirmed at surgery and the other was diagnosed by venous sampling. 56 Another series of 24 patients yielded 23 tumors in scanning, the smallest measuring 0.5 cm in diameter. 57 Small masses are usually easily detected in adrenals because the borders of both glands
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are either concave or straight. 55 Present technology limits the resolution of the adrenal tumors to between 0.5 and 1.0 cm. In adrenal hyperplasia, the glands may be symmetrically enlarged or normal in size. 58 Ultrasonography is useful in evaluating the adrenals. 59- 62 An 85% detection rate has been reported and a mass as small as 13 mm has been detected. Ultrasonography is probably most useful in very thin patients and children where little retroperitoneal fat is present. 59-62 Ovarian ultrasonography is useful, with some limitations, in localizing ovarian tumors. 39 Most virilizing ovarian tumors are solid, making the ultrasound visualization difficult. Availability of high-resolution, real-time sector scanners has improved the visualization of the ovaries. 63 •64 Pelvic ultrasound requires a full bladder which poses another limitation in children who may have little bladder control. 63,64 Adrenal and ovarian scintigraphic studies are helpful although not used frequently for demonstrating hyperplasia, adenoma, or carcinoma. 65 - 67 Scintigraphy is limited by the necessity of pretreating patients with Lugol's solution and steroids prior to receiving iodocholesterol, and by the high dose of radioactive material that must be used. 65 - 67 The experience with magnetic resonance imaging (MRI) in the evaluation of adrenal pathology is accumulating68 and reports show that adrenal masses can be identified by MRI. 68-71 Once enough data are collected, this procedure may replace the CT scan as the primary diagnostic tool to evaluate the adrenal glands.
Treatment Surgery is the treatment of choice for adrenal and ovarian tumors. Because the vast majority are benign and unilateral, a conservative surgical approach is indicated. Adrenal carcinoma and tumors metastatic to the ovary are certainly aggressive and require an individualized approach based on staging and prognosis. Because wedge resection of the ovary has a high risk of adhesion formation that may compromise future fertility, 72 it should be reserved for patients in whom an ovarian tumor is strongly suspected, or in the contralateral ovary if one ovary has a potentially malignant tumor (i.e., granulosa cell, Sertoli-Leydig, or arrhenoblastoma).
Summary Although the overall incidence of androgen-producing tumors of the adrenal and ovary is low, it is not uncommon to encounter them when evaluating a child
or adolescent with virilization. Adrenal tumors are more commonly malignant than ovarian tumors. Virilization is very rare in non-neoplastic androgen-producing conditions (with the exception of CAR) in adolescents and especially in children. Neoplasia must be ruled out when virilization is present. Serum T and DREAS levels are very good screening tests when combined with a good clinical evaluation. In contrast, hormonal suppression and stimulation tests are not useful in detecting the presence of a tumor. CT scan is currently the best way of evaluating the adrenals, and thorough pelvic exam and detailed ultrasonography are the hallmarks in evaluating the ovaries. Venous catheterization has potential complications and technical difficulties in children and adolescents and should only be used in selected cases. The treatment of choice for androgen-producing tumors is surgery. Adrenal carcinomas and tumors metastatic to the ovary should be treated according to stage and prognosis; primary ovarian virilizing tumors have a 95% 5-year survival rate and can be treated conservati vel y.
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31. Spaulding SW, Masuda R, Osawa Y: Increased 17Bhydroxy steroid dehydrogenase activity in a masculinizing adrenal adenoma in a patient with isolated testosterone overproduction. J Clin Endocrinol Metab 1980; 50:537 32. Kamilaris TC, DeBold CR, Manolos KJ, et al: Testosterone-secreting adrenal adenoma in a peripubertal girl. JAMA 1987; 258:2558 33. Abraham GE, Maroulis GB, Buster JE, et al: Effect of dexamethasone on serum cortisol and androgen levels in hirsute patients. Obstet Gynecol 1976; 47:395 34. Kelly TR, Mayors DJ, Boutsicaris PS: Adrenal adenoma-isolated testosterone secretion. Am Surg 1982; 48:604 35. Kogan BA, Sonda LP, Diakno AL: Virilizing adrenal adenoma secreting testosterone. J Urol 1981; 126:787 36. Trost BN, Koenig MP, Zimmerman A, et al: Virilization of a postmenopausal woman by a testosteronesecreting Leydig cell type adrenal adenoma. Acta Endocrinol 1981; 98:274 37. Yuen BH, Moon YS, Mincey EK, et al. Adrenal and sex steroid hormone production by a virilizing adrenal adenoma and its diagnosis with computerized tomography. Am J Obstet Gynecol 1983; 145:164 38. Brumsted JR, Chapitis J, Riddick D, Gibson M: Norethindrone inhibition of testosterone secretion by an ovarian Sertoli-Leydig cell tumor. J Clin Endocrinol Metab 1987; 65:194 39. Surrey ES, deZiegler D, Gambone JC, et al: Preoperative localization of androgen-secreting tumors: clinical, endocrinologic and radiologic evaluation of ten patients. Am J Obstet Gynecol 1988; 158:1315 40. Friedman CI, Schmidt GE, Kim MH, et al: Serum testosterone concentrations in the evaluation of androgenproducing tumors. Am J Obstet Gynecol 1985; 153:44 41. Moltz L, Schwartz U: Gonadal and adrenal androgen secretion in hirsute females. Clin Endocrinol Metab 1986; 15:229 42. Kahn PC: The radiologic identification of functioning adrenal tumors. Radiol Clin North Am 1967; 5:221 43. Pickering RS, Hartman GW, Weeks RE, et al: Excreting urographic localization of adrenal cortical tumors and pheochromocytomas. Radiology 1975; 114:345 44. Colapinto RF, Steed BL: Arteriography of adrenal tumors. Radiology 1971; 100:343 45. Reynes W, Churchill R, Moncada R, et al: Computed tomography of adrenal glands. Radio Clin North Am 1979; 17:91 46. Kirschner MA, Jacobs JB: Combined ovarian and adrenal vein catheterization to determine the site(s) of androgen overproduction in hirsute women. J Clin Endocrinol Metab 1971; 33:199 47. Farber M, Millan VG, Turksoy RN, et al: Diagnostic evaluation of hirsutism in women by selective bilateral adrenal and ovarian venous catheterization. Fertil Steril 1978; 30:283 48. Melby JC, Spark RF, Dale SL, et al: Diagnosis and localization of aldosterone-producing adenomas by adrenal-vein catheterization. N Engl J Med 1967; 277:1050
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49. Wentz AC, White RI, Migeon CJ, et al: Differential ovarian and adrenal vein catheterization. Am J Obstet Gynecol 1976; 125:1000 50. Blair AJ, Reuter SR: Adrenal venography in virilized women. JAMA 1970; 213:1623 51. Reuter SR, Blair AJ, Schteingart DE, et al: Adrenal venography. Radiology 1967; 89:805 52. Jacobs JB: Selective gonadal venography. Radiology 1969; 92:885 53. Brownlie K, Kreel L: Computer-assisted tomography of normal suprarenal glands. J Comput Assist Tomogr 1978; 2: 1 54. Schaner EG, Head GL, Kalman MA, et al: Whole body computed tomography in the diagnosis of abdominal and thoracic malignancy: review of 600 cases. Cancer Treat Rep 1977; 61:1537 55. Karstaedt MB, Sagel SS, Stanley RJ, et al: Computed tomography of the adrenal gland. Radiology 1978; 129:723 56. Dunnick NR, Schaner EG, Doppman JL, et al: Computed tomography in adrenal tumors. Am J Roentgenol 1979; 132:43 57. Eghrari M, McLoughlin MJ, Rosen IE, et al: The role of computed tomography in assessment of tumoral pathology of the adrenal glands. J Comput Assist Tomogr 1980; 4:71 58. Korobkin M, White EA, Dressel HY, et al: Computed tomography in the diagnosis of adrenal disease. Am J Roentgenol 1979; 132:231 59. Sample WF: Adrenal ultrasonography. Radiology 1978; 127:461 60. Yeh HC, Mitty HA, Rose J, et al: Ultrasonography of adrenal masses: usual features. Radiology 1978; 127:467 61. Hamper VM, Fishman EK, Hartman DS, et al: Primary adrenocortical carcinoma: sonographic evaluation with clinical and pathologic correlation in 26 pa-
tients. Am J Roentgenol 1987; 148:915 62. Davies RP, Lam AH: Adrenocortical neoplasm in children-ultrasound appearance. J Ultrasound Med 1987; 6:325 63. Haller JO: Pediatric pelvic ultrasound, Diagnostic Ultrasound-Text and Cases, 2nd ed. Edited by DA Sarti. Chicago, Year Book Medical Publishers, 1987, pp 1139-1148 64. Neiman HC, Mendelson EB: Ultrasound evaluation of the ovary. In: Ultrasonography in Obstetrics and Gynecology, 2nd ed. Edited by PW Callen. Philadelphia, WB Saunders, 1988, pp 423-446 65. Schteingart DE, Seabold JE, Gross MD, et al: lodocholesterol adrenal tissue uptake and imaging in adrenal neoplasms. J Clin Endocrinol Metab 1981; 52:1156 66. Seabold JE, Cohen EL, Beierwaltes WH, et al: Adrenal imaging with 131 1_19 iodocholesterol in the diagnostic evaluation of patients with aldosteronism. J Clin Endocrinol Metal 1976; 42:41 67. Taylor L, Ayers JWT, Gross MD: Diagnostic considerations in virilization, iodomethyl-norcholesterol scanning in the localization of androgen-secreting tumors. Fertil Steril 1986; 46: 1005 68. Demas BE, Hricak H: Adrenal glands, Magnetic Resonance Imaging. Edited by DD Starkk and WG Bradley. Washington DC, CV Mosby, 1988, pp 1164-1186 69. Moon KL, Hricak H, Crooks LE, et al: Nuclear magnetic resonance imaging of the adrenal gland: a preliminary report. Radiology 1983; 147:155 70. Reinig JW, Doppman JL, Dwyer AJ, et al: Adrenal masses differentiated by MR. Radiology 1986; 158:81 71. Reinig JW, Doppman JL, Dwyer AJ et al: MRI of indeterminate adrenal masses. Am J Roentgenol 1986; 147:493 72. Buttram VC, Vaguero C: Post-ovarian wedge resection adhesive disease. Fertil Steril 1975; 26:874
Adolescent and Pediatric Gynecology © 1989 Springer-Verlag New York Inc.
Mini Reviews
Androgen-Producing Tumors in Children and Adolescents Santiago L. Padilla, M.D. Department of Gynecology, Greater Baltimore Medical Center, Baltimore, Maryland
Abstract. Androgen-producing tumors of the adrenal and the ovary are extremely rare, however, their potential malignancy and the androgen effects can be detrimental to children and adolescents. Adrenal adenomas are usually small, whereas adrenal carcinomas are generally large and very aggressive, requiring prompt intervention. Adrenal tumors mostly secrete !l5 androgens, although at least 12 cases of testosterone-producing adrenal tumors have been reported. One-third of functioning adrenal tumors also have increased secretion of corticosteroids. Primary androgenproducing ovarian tumors are classified under several different histological groups. Incidence of malignancy in these tumors is approximately 5%. Tumors metastatic to the ovary may stimulate the adjacent ovarian stroma and cause virilization. These must be differentiated from primary ovarian tumors because the prognosis is completely different. Ovarian tumors prefer !l4 androgens, although cases mainly producing !l5 androgens have been reported. The dehydroepiandrosterone sulfate and testosterone in serum are the best screening parameters for these tumors, although accurate diagnosis requires computed tomography for adrenal tumors and pelvic exam combined with ultrasonography for ovarian tumors. Venous catheterization studies are rarely indicated. Adrenal carcinoma requires aggressive surgical treatment, whereas adrenal adenomas and primary ovarian tumors can be treated with conservative unilateral procedures.
lignant androgen-producing tumors of the adrenal are extremely rare, occurring with an incidence of approximately two per million per year in the general population, and accounting for only 0.023% of all malignant tumors. 1.2 However, the presence of these tumors along with the effects of the androgens are especially detrimental to children and adolescents. Malignant adrenal tumors are often rapidly fatal and therefore early detection and treatment is extremely important. Malignant androgen-producing tumors of the ovary are also rare. Of the 3,500 cases submitted to the Emil Novak Ovarian Tumor Registry, 3 there are less than 200 ovarian tumors classified as "masculinizing. " There were 55 (28%) tumors in patients younger than age 20. Norris and Jensen4 reviewed the experience of the Armed Forces Institute of Pathology and found 353 patients under the age of 20 with a primary ovarian tumor; this represented only 6% of their total number of ovarian neoplasms. They noted 14 cases of virilizing ovarian tumors in girls under age 20 and only two prior to puberty. The ovarian virilizing tumors are in general less aggressive than the adrenal tumors, but early detection and treatment is also important. Modem biochemical and radiological techniques greatly facilitate diagnosis of these tumors, and early detection with aggressive therapy should result in a better prognosis.
Key Words. Androgen-secreting tumors- VirilizationOvarian tumors-Adrenal tumors
Androgen-Producing Adrenal Tumors Introduction The most important responsibility of the physician caring for a patient with hirsutism and/or virilization is to determine whether there is an androgen-producing malignant tumor of the adrenal or the ovary. MaAddress reprint requests to: Santiago L. Padilla, M.D., Greater Baltimore Medical Center, 6565 N. Charles Street, Suite 207, Baltimore, MD 21204, USA.
Adrenal cortical adenomas are usually poorly encapsulated tumors (Table 1). The surface is reddish to brown, they are usually small, and they weigh 100200 g, although much greater weights of up to 4,200 g have been reported. 1.2.6.7 Large adenomas may have areas of hemorrhage, cystic degeneration, and focal calcification. Although multiple and bilateral adrenal nodules can sometimes occur, only single adrenal nodules are the ones usually considered to be adenomas. In the case of functioning adenomas, the con-
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Table 1. Histopathology of Androgen-Producing Tumors Adrenal Tumors Adenomas are usually small; carcinomas are characteristically large and have a poor prognosis May show areas of hemorrhage, cystic degeneration, and calcification Ovarian Tumors Thecomas/ Uniformly benign fibrothecomas Usually feminizing, occasionally Granulosa cell virilizing. 95% 5-year survival tumors Stromal and epithelial components. Arrhenoblastoma Epithelial elements determine prognosis Recurrences are rare and occur Sertoli-Leydig within 5 years Cells similar to zona fasciculata and Adrenal rest zona reticularis. Uniformly benign Cause masculinization by stimulation Epithelial/metastatic of adjacent stroma
tralateral adrenal gland is usually atrophic. Benign adenomas are arranged in a fasciculate pattern and are clusters of large cells that uniformly contain lipid material. Cellular pleomorphisms and nuclear anaplasia may also be seen. Conversely, adrenal carcinomas are usually large, measuring up to 20 cm in diameter and weighing up to 2,500 g or more. Lanes et al. 5 reported a 1,120 g adrenal cortical carcinoma in a 4-year-old female. Adrenal carcinomas are usually yellowish-brown and contain areas of hemorrhage, necrosis, and calcification. Histological appearance varies from mild to severe degrees of atypia and may sometimes be highly anaplastic. Diagnosis of adrenal carcinoma is facilitated by invasion into the capsule or blood vessels, tumor metastasis, or both.5 Clinical characteristics of androgen-producing adrenal neoplasms are similar whether benign or malignant. Biochemically, there is no reliable way short of surgical excision and histological examination to differentiate between benign and malignant neoplasms. Adrenal neoplasms may occur at any age and have been reported in utero and after menopause. Functioning adrenal tumors in prepubertal children are usually malignant and most series report their propensity to occur in girlS. 8- 1O Endocrine symptoms in children include virilization, heterosexual precocious puberty, Cushing's syndrome, or hyperaldosteronism with hypertension. These symptoms usually start abruptly and develop quickly. Approximately twothirds of the cases have virilization and one-third have Cushingoid signs. 10 Cushing's syndrome in a child under age 10 is almost always due to neoplasia. 9 •10 In addition, virilizing adrenal tumors have been associated with hemihypertrophy, Beckwith-Wiedemann syndrome, congenital malformations of the genitour-
inary tract, an array of hamartomatous disorders, and astrocytoma. 8
Androgen-Producing Ovarian Tumors Ovarian tumors associated with virilization comprise a varied group of neoplasms. Woodruff and Parmleyll suggest that the term "associated with" may be more appropriate than the term "caused by" when referring to ovarian androgen-producing tumors, because the androgens may not be produced by the tumor itself, but by activation of adjacent ovarian stromal cells. All primary functioning tumors of the female gonad are either teratoid or gonadal stromal, with or without luteinization, and with or without epithelial components. The stroma identifies the function of the tumor; the epithelium defines the predominant histopathological features and is of primary prognostic significance. Although it is generally true that a lesion with tubules and interstitial cells is masculinizing, whereas that composed of granulosa cells is generally feminizing, there are exceptions. Similar to adrenal tumors, the individual microscopic features of the tumor cannot describe its hormonal function, and we have to rely on clinical and laboratory findings. Tumors metastatic to the ovary may stimulate the adjacent ovarian stroma and cause virilization. These must be differentiated from primary ovarian tumors because the prognosis is completely different.
Thecoma and Fibrothecoma These lesions are probably the most common of the gonadal stromal tumors and are most frequently asymptomatic and nonfunctioning. Usually they are discovered in the late 4th and 6th decades of life and the site varies tremendously. Virilization is due mainly to foci of "luteinization" in which the cells are large and contain abundant cytoplasm, suggestive of hormonal activity. In young patients, these tumors may be associated with calcification. Malignancy is uncommon and two to three mitoses per high power field may be seen. Lesions with more than four mitoses in any high power field may recur intraabdominally. The majority of these tumors are associated with estrogen production, although hormone profiles have demonstrated that androgens may come from these lesions. 12 The prognosis for this tumor is excellent and unilateral lesions should be treated with unilateral oophorectomy. Granulosa and Granulosa-Theca Cell Tumors These tumors classically cause feminization and are associated with endometrial hyperplasia and occa-
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sionally endometrial cancer. Interestingly, in a small percentage of cases, masculinization has been found. Novak et al. I3 reported 370 such lesions, 14 (4.5%) of which presented with virilization. In contrast to the thecoma, granulosa cell tumors have a definite epithelial component, which makes them potentially malignant. The cell is round and ovoid with the often classic "coffee bean" appearance of the nucleus. Mitoses are common and potentially malignant mainly by rupture of the capsule. Bilateral tumors occur in 5% of cases. Five-year survival, whether feminizing or masculinizing, is 97%. Approximately 5% of these tumors occur before puberty and may cause isosexual precocious puberty. In Novak's series,13 there were no deaths in patients under 15 years of age. Based on this, conservative surgery is indicated in the young patient.
Arrhenoblastoma and Androblastoma The three types of these tumors include 1) the welldifferentiated or Pick's adenoma, 2) the intermediate variety in which "tubules" can be recognized, and 3) the sarcomatoid in which only stroma is present. The latter undoubtedly is a variant of the thecoma with or without focal luteinization. The intermediate type is the gonadal stromal tumor with attempted tubule formation. This tumor is well defined in certain areas, but in others, only columns of stromal or epithelial cells can be poorly differentiated. The androblastoma is a separate category with well-defined tubules and a minimal stromal component. This may be difficult to differentiate· from the classic Sertoli cell tumor. Nevertheless, the Sertoli cell should be much taller and simulate that seen in the male gonad. The epithelial component identifies the prognosis. Meldrum and Abraham l4 observed that both A4 and A5 pathways contribute precursors for the production of testosterone but the A5 pathway predominated. Sertoli, Leydig, and Sertoli-Leydig Tumors Pure Sertoli cell tumors are composed of intertwining tubules lined by tall pale cells with a basal nucleus. These tumors were originally proposed to be a variant of the granulosa cell tumor because of their associated feminization. Consequently, the pure Sertoli cell tumor in the female is not virilizing. Sertoli-Leydig cell tumors and Leydig cell tumors contain annular tubules and have been described histologically.15,16 Recurrences almost invariably occur during the first 5 years after treatment. Several hundred cases have now been published. 16 Microscopically, these tumors may contain Reinke crystalloids and 50% present clinically with virilization. IS An association with mucinous cystadenoma and the Peutz-Jeghers syndrome has been
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described. 15 These tumors are usually unilateral, and conservative surgery in the young patient is indicated.
Adrenal, Adrenal Rest, and Lipoid Tumors Adrenal rests can be found in the broad ligament adjacent to the tube or ovary. The so-called adrenal rest tumor is probably of ovarian stroma in origin. Most of them are not paraovarian, but intraovarian. Ovarian stromal cells, when luteinized, may resemble cells of the adrenal cortex. Hormonal production patterns of at least some of these tumors is more consistent with ovarian stroma than with adrenal cortex. 17 Typically, two types of cells are present in these tumors-a large cell with clear cytoplasm and a smaller round cell with abundant acidophilic cytoplasm. These types are similar to the zona fasciculata and zona reticularis of the normal adrenal. Adrenal rest tumors are usually benign. Among 22 of these tumors reviewed by Ireland and Woodruff,3 only one recurred. They are usually small, however, a 25-cm lesion has been reported. ll The lipoid cell tumor is classified as an adrenal rest tumor. The large cell with nonstaining cytoplasm and nucleus could be adrenal or Leydig in origin and also uniformly benign. Epithelial and Metastatic Ovarian Tumors Rarely, epithelial tumors of the ovary can result in masculinization of the host. The mucinous tumor of the ovary may induce masculinization during pregnancy; histopathology reveals that the stroma adjacent to the tumor is luteinized. 3 Metastatic tumors, through a similar mechanism of induction of stromal luteinization, can cause masculinization; The Krukenberg tumor, carcinoid tumor, and other metastatic tumors, characterized by diffuse infiltration of the stroma with a seemingly innocuous adenomatous pattern, are examples. 3 Certainly these tumors carry a much worse prognosis. The presence of virilization with diffuse infiltration may incorrectly lead to the diagnosis of a primary gonadal stromal tumor. Correct diagnosis is important because metastatic tumors cannot be treated conservatively like primary gonadal stromal tumors.
Differential Diagnosis Several non-neoplastic conditions can cause hirsutism and virilization. Polycystic ovarian disease (PCO), hyperthecosis, Cushing's disease, exogenous androgens, and congenital adrenal hyperplasia (CAH) are examples of these non-neoplastic conditions (Table 2).18.19 The signs and symptoms usually develop slowly in contrast to the androgen-producing tumors which customarily induce symptoms very fast. Prior to puberty, the tumors and CAH may cause a premature
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growth spurt, virilization, and heterosexual precocious puberty. After puberty, all non-neoplastic and neoplastic conditions are commonly related to menstrual disturbances. PCO is the most common cause of amenorrhea and hirsutism after puberty. The amenorrhea is usually secondary, although cases of primary amenorrhea have been reported. PCO will rarely cause virilization. Ovarian hyperthecosis, on the other hand, is very commonly associated with virilization and menstrual abnormalities. 17 In hyperthecosis, androgen levels, especially testosterone, may be in the male range. Many hyperthecosis patients have had ovarian wedge resections to rule out presence of a tumor. IS Cushing's disease is part of the differential diagnosis and a 24-hour urine collection for free cortisol levels is the best screening method to detect this condition. The most common adrenal enzyme deficiency in CAH is 21-hydroxylase deficiency followed by 11hydroxylase deficiency, both of which can cause virilization. 21-hydroxylase deficiency can be salt-losing in 50% of patients, and ll-hydroxylase deficiency can also cause hypertension in 50% of patients. These girls usually present with pubic hair growth, clitoral hypertrophy, facial hair growth, temporal hair recession, acne, deepening of the voice, muscular development, and acceleration of growth rate and skeletal maturation. Careful family history may reveal similar affected siblings. Heterozygote carriers of the affected gene may give a history of menstrual disturbances, early puberty, hirsutism, anovulation, and infertility. 19 Serum electrolytes, urinary sodium excretion, and renin activity will reveal a sodium loss in the saltlosing patients. The electrolyte imbalance requires immediate attention. Serum levels of 17-hydroxyprogesterone and urinary pregnanetriol values will be elevated. Exogenous sources of androgens can very rarely result in heterosexual precocious puberty. Premature pubic hair growth may occur in patients with isosexual precocious puberty and in cases of premature adrenarche but will not be associated with clitoromegaly, deepening of the voice, or any other virilization signs. When enlargement of the clitoris alone is present, a tumor of the clitoris also must be considered.
Hormonal Evaluation Biochemical testing helps the clinician identify the source of androgen secretion (Table 3). Adrenal glands tend to produce larger amounts of weaker androgens such as androstenedione (A), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). These compounds are partially converted to 17 ketosteroids (17-KS) in peripheral tissues. Pa-
Table 2. Differential Diagnosis of Androgen-Producing Tumors Polycystic ovarian disease Congenital adrenal hyperplasia Ovarian hyperthecosis Cushing's disease Exogenous androgens Pseudo virilization by tumor of the clitoris
tients with hirsutism and/or virilization resulting from adrenal androgens will usually have elevated DHEAS concentration and elevated urinary 17-KS. DHEAS can substitute the urinary 17-KS in the evaluation of hirsutism. 20 Over 96% of the serum DHEAS is of adrenal origin and, therefore, it is a more direct measurement of adrenal androgen output than the urinary 17-KS. In addition, urinary 17-KS measures not only adrenal androgens but also metabolites of ovarian androgens, corticosteroids, and some nonspecific pigments. Accurate measurement of urinary 17-KS requires a 24-hour collection to avoid circadian variation in steroid secretion. Refrigeration is essential to avoid degradation of metabolites. The urinary creatinine level should be checked to assure the validity of the 24hour collection. Many clinics have eliminated the determination of 17-KS and rely almost entirely on serum DHEAS as an index of adrenal androgen production. A random DHEAS sample is sufficient and there is no need to correct for body weight, circadian variation, or creatinine excretion. A high circulating serum concentration of DHEAS, along with a slow turnover rate and a long half-life, results in a large and stable pool with insignificant variation. As with urinary 17-KS, aging is associated with a decrease in the blood concentration of DHEAS and careful attention should be taken to establish n~rmal values for all age groups. Virilizing adrenal tumors primarily secrete DHEA and DHEAS, over testoster-
Table 3. Diagnostic Modalities Circulating Androgen Levels Total testosterone (T) and DHEAS are the best screening parameters In virilized patients, DHEA and urinary 17KS should be obtained if T and DHEAS are normal Hormonal stimulation and suppression studies are not helpful Radiology Adrenal glands: CT scan is most useful. Magnetic resonance imaging (MRI) and ultrasound can aid in diagnosis Ovary: Ultrasound is most useful. CT scan and MRI have limited value Venous Catheterization Technically difficult with potential complications in children and adolescents Helpful in selected cases where other radiological studies are non diagnostic
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one (T). 21 Lipsett et a1. 20 suggested that urinary 17KS measuring over 50 mg for 24 hours, which corresponds to about 800 J..Lg/dl of DHEAS, is almost pathognomonic of an adrenal tumor in virilized women; however, if the DHEAS is normal, adrenal disease is most unlikely. There have been several reports of adrenal tumors that secrete testosterone primarily. 22-32 Some of these adrenal tumors may actually respond to gonadotropin stimulation.23.24.26 At least 10 of the reported testosterone-producing adrenal tumors underwent ovarian wedge resection, ovarian biopsy, or oophorectomy before the correct diagnosis was determined.33.34-37 Androgen-producing tumors of the ovary are associated with testosterone levels in the male range. 14 .20 Some investigators have suggested that testosterone levels > 200 ng/ dl indicate the presence of an ovarian or adrenal androgen-producing tumor. 8.14 This arbitrary point has been challenged because variations of hormonal secretions and laboratory variability can yield misleading values. 38- 4o It is recommended that at least three daily samples reach a level 2.5 times greater than the upper limit of normal for the given laboratory .40 DHEAS is not unique to adrenal tumors. Surrey et a1. 39 reported an ovarian tumor with a peripheral DHEAS level of 973.8 J..Lg/dl which is above the suggested cut-off value of 800 fLg/dl for adrenal tumors. Circulating serum T levels are elevated in many women with anovulation and hirsutism. Individual variation is great due to changes in T -binding capacity of the sex hormone-binding globulin in the blood. Androgens lower testosterone binding; the total T (free and bound T measured by radioimmunoassay) can be normal in hirsute women. Some clinicians measure unbound or free T in women with hirsutism. For practical purposes, it is not necessary to measure free T because the main purpose of the T level, in evaluating the hirsute women, is to rule out the presence of a testosterone-secreting tumor. The fine discrimination of the free T is not necessary. Hormone stimulation tests can give false-positive and false-negative results. 23 •24 ,26 In addition, suppression studies do not specifically isolate ovarian or adrenal function in neoplastic and non-neoplastic conditions. 38 ,41
Venous Catheterization and Radiological Evaluation Radiological studies are indispensable in evaluating the adrenal glands, and in detecting ovarian neoplasia (Table 3). Plain abdominal x-ray films, excreting urography, venography with effluent venous sam-
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pIing, computed tomography (CT), ultrasonography, and scintigraphy are among the techniques used. Calcifications may be seen on a plain abdominal x-ray film in cases of adrenal carcinoma, neuroblastoma, pheochromocytomas, and in some ovarian tumors. Rarely, adrenal adenomas may form calcifications; adrenal hyperplasia never causes calcifications. 42 High-dose excretory urography in conjunction with conventional serial tomography can detect adrenal masses measuring > 20 mm in diameter. Large adrenal masses may cause downward displacement of the ipsilateral kidney. Conventional radiographic techniques are reportedly 70% accurate in diagnosing adrenal tumors; high false-negative and false-positive results have been reported. 43 Angiography may be useful for diagnosing adrenal masses, but technical difficulties and complications have reduced the use of angiography as a primary means of evaluating these patients. 44 ,45 Venography combined with steroid analysis of effluent blood can help determine the site of abnormal hormonal production in some patients. 39,4649 One group reported a 77% successful bilateral catheterization of both adrenal and ovarian veins in 13 patients. 47 Successful catheterization of the right adrenal vein was reported in 36 of 50 patients, but the left adrenal vein was entered in all 50 patients. 50 Left adrenal and ovarian veins are more anatomically consistent and the venous blood from the left side is relatively easier to obtain. 51 The right adrenal vein enters the vena cava at an acute angle, whereas the right gonadal vein enters the vena cava either by way of the right renal vein, or directly at the site of entry of the right renal vein. 52 Adrenography performed in 50 virilized women yielded an anatomic explanation for virilization in only 13 (26%) of the patients. 50 Although adrenography and steroid analysis of ovarian and adrenal venous effluents can be useful diagnostic tools, potential complications and technical difficulties in children and adolescents limit their value. CT is by far the primary procedure for diagnosis of adrenal tumors. Its usefulness, accuracy, and success rate compared with other techniques is very good. When the adrenal gland is scanned using 10-mm slices at lO-mm intervals, both the adrenals are seen in 90% of normal patients. Using 7-mm slices at lO-mm intervals, the figure rises to 99%.53-55 CT of the adrenals correctly identified 11 of 13 steroid-producing adenomas without any false-positives, the smallest tumor measuring 1 cm in diameter. 56 Of the two false-negatives, one 0.5-cm adenoma was confirmed at surgery and the other was diagnosed by venous sampling. 56 Another series of 24 patients yielded 23 tumors in scanning, the smallest measuring 0.5 cm in diameter. 57 Small masses are usually easily detected in adrenals because the borders of both glands
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are either concave or straight. 55 Present technology limits the resolution of the adrenal tumors to between 0.5 and 1.0 cm. In adrenal hyperplasia, the glands may be symmetrically enlarged or normal in size. 58 Ultrasonography is useful in evaluating the adrenals. 59- 62 An 85% detection rate has been reported and a mass as small as 13 mm has been detected. Ultrasonography is probably most useful in very thin patients and children where little retroperitoneal fat is present. 59-62 Ovarian ultrasonography is useful, with some limitations, in localizing ovarian tumors. 39 Most virilizing ovarian tumors are solid, making the ultrasound visualization difficult. Availability of high-resolution, real-time sector scanners has improved the visualization of the ovaries. 63 •64 Pelvic ultrasound requires a full bladder which poses another limitation in children who may have little bladder control. 63,64 Adrenal and ovarian scintigraphic studies are helpful although not used frequently for demonstrating hyperplasia, adenoma, or carcinoma. 65 - 67 Scintigraphy is limited by the necessity of pretreating patients with Lugol's solution and steroids prior to receiving iodocholesterol, and by the high dose of radioactive material that must be used. 65 - 67 The experience with magnetic resonance imaging (MRI) in the evaluation of adrenal pathology is accumulating68 and reports show that adrenal masses can be identified by MRI. 68-71 Once enough data are collected, this procedure may replace the CT scan as the primary diagnostic tool to evaluate the adrenal glands.
Treatment Surgery is the treatment of choice for adrenal and ovarian tumors. Because the vast majority are benign and unilateral, a conservative surgical approach is indicated. Adrenal carcinoma and tumors metastatic to the ovary are certainly aggressive and require an individualized approach based on staging and prognosis. Because wedge resection of the ovary has a high risk of adhesion formation that may compromise future fertility, 72 it should be reserved for patients in whom an ovarian tumor is strongly suspected, or in the contralateral ovary if one ovary has a potentially malignant tumor (i.e., granulosa cell, Sertoli-Leydig, or arrhenoblastoma).
Summary Although the overall incidence of androgen-producing tumors of the adrenal and ovary is low, it is not uncommon to encounter them when evaluating a child
or adolescent with virilization. Adrenal tumors are more commonly malignant than ovarian tumors. Virilization is very rare in non-neoplastic androgen-producing conditions (with the exception of CAR) in adolescents and especially in children. Neoplasia must be ruled out when virilization is present. Serum T and DREAS levels are very good screening tests when combined with a good clinical evaluation. In contrast, hormonal suppression and stimulation tests are not useful in detecting the presence of a tumor. CT scan is currently the best way of evaluating the adrenals, and thorough pelvic exam and detailed ultrasonography are the hallmarks in evaluating the ovaries. Venous catheterization has potential complications and technical difficulties in children and adolescents and should only be used in selected cases. The treatment of choice for androgen-producing tumors is surgery. Adrenal carcinomas and tumors metastatic to the ovary should be treated according to stage and prognosis; primary ovarian virilizing tumors have a 95% 5-year survival rate and can be treated conservati vel y.
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Padilla:
Androgen-Producing Tumors
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