Feminizing adreno-cortical carcinomas in male adults. A dire prognosis
Three cases in a series of 801 adrenalectomies and review of the literature
S. Moreno(1), M. Guillermo(1), M. Decoulx(2), D. Dewailly(2), R. Bresson(2), Ch. Proye(1)
(1) Clinique chirurgicale. Service de chirurgie générale et endocrinienne. Université de Lille. Hôpital Claude Huriez. Rue Michel Polonovski. 59037 Lille Cedex, France.
(2) Clinique endocrinologique Marc Linquette. Université de Lille. Rue du Professeur Laguesse. 59037 Lille Cedex, France.
Reprint request: S. Moreno, Blvd. Algeciras 1508-303, Col. Arbide, León, Guanajuato, México. e-mail : sebastianmg@yahoo.com
Cancers cortico-surrenaliens féminisants chez l’homme adulte. Un sombre pronostic. Trois cas dans une série de 801 surrénalectomies et revue de la littérature
S. Moreno, M. Guillermo, M. Decoulx, D. Dewailly, R. Bresson, Ch. Proye Ann. Endocrinol., 2006 ; 67, 1 : 32-38
Revue de 3 cas de carcinomes cortico-surrénaliens féminisants (CCSF) chez l’homme adulte, visant à définir leur tableau clinique, leurs caractéristiques biologi- ques, les critères de diagnostic, le diagnostic différentiel et l’évolution clinique du syndrome.
Patients : De 1970 à Décembre 2003, parmi 801 surrénalectomies, 3 ont été ef- fectuées pour CCSF.
Résultats : L’âge au moment du diagnostic était respectivement de 74, 63 et 23 ans. Une hypersécrétion d’oestradiol a été observée chez les trois patients, la 17-OH Progestérone était élevée chez 2 d’entre eux avec diminution parallèle de la testostérone. La delta4 Androstenedione était élevée chez un seul. L’imagerie sug- gérait la malignité dans les trois cas au vu d’aspect de nécrose, de l’hétérogénéité, de calcifications, de la taille de la tumeur et de la compression des organes adja- cents. Les trois patients étaient au stade III lors du diagnostic avec un score de Weiss ≥ 6. La taille et le poids des tumeurs étaient respectivement de 30, 20, 15 cm et 3 750, 480 et 275 g respectivement. Tous trois ont reçu en post-opératoire du Mitotane associé à la corticothérapie et tous trois sont morts du néoplasme à 7, 3 et 2 ans respectivement.
Conclusion : Les CCSF de l’homme adulte sont excessivement rares (1 à 2 % de tous les carcinomes cortico-surrenaliens). Les tumeurs sont très volumineuses et même après chirurgie à visée curative, leur pronostic est pire que celui des autres variétés de cancers cortico-surrénaliens sécrétants ou non-sécrétants. Le seul espoir d’amélio- ration du pronostic réside dans un diagnostic et un traitement plus précoce.
Mots-clés : Carcinome cortico-surrnéalien, tumeur fémnisante, surrénalectomie, gynécomastie.
Feminizing adreno-cortical carcinomas in male adults. A dire prognosis
We describe the clinical presentation, biochemical features, diagnostic criteria, clini- cal course and differential diagnosis in three cases of feminizing adreno-cortical car- cinoma (FACC) with a review of the literature.
Patients: From 1970 throughout December 2003 among a series of 801 adrena- lectomies, three had been performed for FACC.
Results: Age at presentation was 74, 63 and 23 years. Estradiol hypersecretion was observed in 3/3 patients, 17 OH progesterone was elevated in 2/3 patients and both of them had a diminution of testosterone, delta 4 androstenedione was elevated in
INTRODUCTION
Feminizing Adrenal Tumors (FAT) in adults are exceedingly rare and almost always malignant (1-2% of Adreno- Cortical Carcinomas [ACC]) [5, 8, 15, 17]. By the end of the seventies less than 100 cases were reported since Bittdorf (1919), including the 60-65 cases gathered by Vague [39] and De- court [7] in 1970 and 1971. By 1984, 120 cases were reported, 15 of these patients were women and more than 90% of all these tumors were malignant, much more frequently in male patients [6, 24].
Since 1984 only around 18 more cases have been reported in english literature including 10 carcinomas in male adults [4, 9, 18, 19, 22, 23, 35, 40, 46, 47], 1 adenoma in a female adult [34], 4 adenomas in children [9, 13, 31, 34], and 3 adenomas in male adults [20, 30, 34], two of these lat- ter patients with less than 10 years follow-up, so appearance of long term recurrence or distant metastases can not be excluded as for other pre- vious cases of Feminizing Adrenal Ade- noma (FAA) who turned out to be misdiagnosed carcinomas [4, 9, 10, 12, 21, 37]. To the best of our know- ledge only two cases of FAA in male adults with a follow-up of 10 years or greater have been reported in litera-
1/3 patients. Imaging studies suggested malignancy in 3/3 patients by the presence of necrosis, heterogeneity, calcifications, size of the tumor and compression of adjacent organs. All patients were stage III at presentation and had a Weiss score 6. Size and weight of the tumors were 30, 20, 15cm and 3750, 480 and 275g respectively. All 3 patients received mitotane and cortisone post-operatively and at follow up (7, 3 and 2 years) all 3 died of the disease.
Conclusions: Feminizing adreno-cortical carcinomas in adults are exceedingly rare (1-2% of adreno-cortical carcinomas). Tumors are huge and even after surgery for cure their prognosis is worse than for other varieties of adreno-cortical carcinomas either secreting or non secreting. Early diagnosis and treatment may improve overall prognosis.
Key words: Adreno-cortical carcinoma, feminizing tumor, adrenal surgery.
ture, the first case of Mortensen et al. [29] in 1951 (59 year old male with a 4cm resected tumor and a 14 year follow-up) and the second reported by Kuhn et al. [20] in 2002 (39 year old male with a 2.8 cm/12 g resected tu- mor and a 10 year follow up) both were stage I of Mac- Farlane classification.
OBJECTIVE
The aim of this study is to review 3 patients with Femi- nizing Adreno-Cortical Carcinoma (FACC) (1 previously reported in literature [6] and 2 new observations) to de- fine their clinical presentation, secretory pattern, imaging studies findings, weight and size, histological findings according to Weiss Score [1, 42, 43] (fig. 1) and staging according to MacFarlane [25] classification (fig. 2). Post operative therapy [45] and prognosis are also studied for comparison with a review of the literature.
METHODS
From 1970 throughout December 2003, among 801 adrenal operations performed in the same institution (table I), we culled 3 adult males operated for FACC that were all three resected for cure.
| Score | ||
|---|---|---|
| - High nuclear grade 1 | ||
| - Mitotic rate >5/50 high-power fields | 1 | |
| - Atypical mitotic figures | 1 | |
| - Eosinophilic tumor cell cytoplasm (>75% of tumor cells) | 1 | |
| - Diffuse architecture (>33% of tumor) | 1 | |
| - Necrosis | 1 | |
| - Venous invasion 1 | ||
| - Sinusoidal invasion (no smooth muscle in wall) | 1 | |
| - Capsular invasion | 1 | |
| -TOTAL | /9 |
| TOTAL: | 0-2: | Benign tumor |
| 3: | Undetermined tumor | |
| 4-9: | Malignant tumor |
Figure 1: Weiss score for adreno-cortical tumors. Histologic criteria for definition of adrenocortical neoplasms [42, 43].
Figure 1 : Score de Weiss pour tumeurs cortico-surrenaliennes. Critères histologiques de définition des tumeurs cortico-surrénaliennes [42, 43].
No patient was lost for follow-up and all died of the disease at 7, 3 and 2 years respectively after the surgical resection.
RESULTS
Pre-operative data
Concerning localization, 2 tumors were on the left side and 1 on the right side. Ages at presentation were 74, 63 and 23 years. Feminization signs were present in all 3 cases: 3 gynecomastia, 3 impotence 1 testicular atro- phy. The duration of the symptoms was 9 months, 4 years and 11 years respectively. None of the patients had fever, abdominal pain or inferior vena cava (IVC) syndrome; 2 tu- mors were palpable. Diagnosis was therefore easy and straightforward with the help of biochemical findings, estradiol hypersecretion being 5-20 fold over the upper normal range (table II).
All imaging studies identified the tumor. Ultrasono- graphy was performed in 2/3, Computed Tomography (CT) in 3/3 and Magnetic Nuclear Imaging (MRI) in 1/3 FACC respectively. According to well recognized criteria (necrosis, heterogeneity, calcifications, size of the tumor and compression to adjacent organs) malignancy was suspected by ultrasonography in 1/2, by CT in 3/3 and by MRI in 1/1 FACC respectively. Overall imaging studies suggested preoperative diagnosis of malignancy in 3/3 FACC, all patients were stage III at presentation.
Operative data
All 3 operations were open (1 midline incision, 1 right thoraco-phreno-laparotomy and 1 bilateral sub costal incision), tumor size and weight are given in (table III).
| Stage I | T <5 cm without regional extension (N0) |
| Stage II | T>5 cm without regional extension (NO) |
| Stage III | Every T with regional extension and/or N+ |
| Stage IV | Distant metastases |
Figure 2: Mac Farlane staging for adreno-cortical carcinoma [25]. Figure 2 : Stadification des cancers cortico-surrenaliens selon Mac Farlane.
| Type of lesion | Number (%) |
|---|---|
| Primary adrenocortical tumors | 430 (53.7) |
| Pheochromocytomas | 263 (32.8) |
| Secreting adrenocortical hyperplasia | 45 (5.6) |
| Adrenal Metastasis | 39 (4.9) |
| Adrenal cysts | 14 (1.7) |
| Adrenalectomies for hypertension | 8 (1.0) |
| Hyperplasic "Enzymatic Bloc" | 2 (0.2) |
| Total | 801 (100) |
| Characteristics | Benign | Malignant | Total |
|---|---|---|---|
| Cushing syndrom | 79 | ||
| Hyperaldosteronism | 154 | 2 | 156 |
| PASAT* | 11 | 8 | 19 |
| FACC | 0 | 3 | 3 |
| Others (secreting, non secreting) | 173 | ||
| Total 430 | |||
* Pure Androgen Secreting Adrenal Tumors (PASAT).
| Hormone | Patient 1 | Patient 2 | Patient 3 | Normal Values |
|---|---|---|---|---|
| Estrone (E1) (pg/ml) | 215 | 408 | NA | 15-45 |
| Estradiol (E2) (pg/ml) | 314 | 310 | 1065 | 19-45 |
| 17 OH Progesterone ng/ml) | 12.3 | 1.0 | 3.8 | 0.54-2.5 |
| Testosterone (ng/ml) | 1.58 | 3.72 | 3.0 | 3.5-9.5 |
| DHEA-S (umol/L) | 15.6 | 15.7 | NA | 2-15 |
| Delta 4- Androstenedione (ng/ml) | 3.30 | 2.27 | NA | 0.5-2.8 |
| 17- urinary ketogenic steroids | 74.1 | 15.2 | 21 | 3-10.4 |
| FSH (UI/L) | 0.5 | 0.7 | undectable | 1.4-10 |
| LH (UI/L) | 0.7 | 4.5 | undectable | 2-12 |
* NA = Not available.
| Patient | 1 | 2 | 3 |
|---|---|---|---|
| Age at presentation | 74 | 23 | 63 |
| Estradiol | 314 (5 fold N) | 310 (5 fold N) | 1065 (20 fold N) |
| Tumor size | 30 | 15 | 20 |
| Tumor weight (g) | 3750* | 275 | 480 |
| Survival (years, months) | 7y5m | 3y | 1y10m |
| Type of recurrence | distant metastases | local recurrence | local recurrence |
* Combined nephrectomy and splenectomy.
Surgery was extended to the spleen, and left kidney in both left tumors and to the right kidney in the right tumor. Adrenalectomy was always accompanied by complete clearance of the surrounding fat of the adrenal fossa. Pa- tient 2 suffered intraoperative capsular rupture.
Post-operative data
There was no intra or post-operative mortality and mor- bidity was limited to 1 case of lymphatic discharge (left adrenalectomy), lasting few days with a spontaneous resolution.
According to MacFarlane’s classification all patients fell in stage III at presentation. Down grading of stage III cases can’t be excluded if they had occult metastases. Weiss scoring was performed in all 3 surgical samples being 6, 8, 7 respectively, i.e. assessing high grade of malignancy.
All patients had laboratory controls at follow-up at 5, 15 and 60 days respectively, showing normalization of estradiol hypersecretion in one patient only. However when Mitotane therapy was administrated all patients returned to normal estradiol levels as verified by bio- chemical controls at 3, 10, 15 and 24 months post- operatively.
Follow-up imaging was performed in the 3 patients 6, 14 and 7 months after surgery respectively, showing local recurrence with positive lymph nodes in 2 cases (1 with intraoperative capsule rupture) and distant me- tastases in all 3 patients.
Post-operatively Mitotane was given to all 3 patients, duration of the treatment was 17, 22 and 60 months. All patients received additional radio and chemotherapy
(1st patient by Adriablastine, 2nd patient by Paraplatine and the 3rd patient by association of Cisplatine and Ve- peside) with temporary involution of local recurrence or metastases. Finally, at follow up (7, 3 and 2 years) all patients died of the disease.
DISCUSSION
Syndromes of adrenocortical hyperfunction include pri- mary aldosteronism, Cushing’s syndrome and the adre- nogenital syndrome. Feminizing tumors account for the lesser part of ACC, however they have the most severe prognosis. FACC is more frequent in the male adult, conversely to all other adrenal tumors [24, 38].
Pre-operative data
FACC usually affects men between 20-50 years, but has also been observed in children and menopausal woman [12, 27]. Presenting symptoms are characterized by iso- sexual or heterosexual pseudo-puberty in childhood; meno-metrorragia in post-menopausal women (diffe- rential diagnosis of endometrial carcinoma), whereas in the female adult of reproductive age their diagnosis is difficult until symptoms and signs of malignancy develop. In the male adult gynecomastia is the most frequent sign (98% of cases) with or without demasculinisation symp- toms: diminished libido and sexual potency, feminizing hair change and atrophy of the testes (50% cases) with azoospermia [2, 6, 7, 12, 18, 27].
Gynecomastia (commonly referred to plastic surgeons) is the major clinical expression, it is a “true” gyneco- mastia that resembles a normal female gland, tender with sensible mammary lobules and enlarged areola not necessarily hyper-pigmented, with no secretion. Other causes of gynecomastia must always be considered (anti- hypertensive and anti-dopaminergic drugs, digoxine, cir- rhosis, bronchial cancer and other syndromes of ectopic secretion, and testicular causes including testicular femi- nizing syndrome). Four different causes of abnormal breast development have been identified: excess in es- trogen production, androgen deficiency, drugs and he- patic failure. Clinically we can and must think of an eventual adrenal tumor in the presence of a frank, iso- lated gynecomastia without testicular abnormalities [7, 12, 22, 37, 38].
Other clinical manifestations had been described: ab- dominal pain, obesity, elevation of the blood pressure, increased skin pigmentation, varicocele and acne [12].
Duration of symptoms in our patients was long, from 9 months up to 11 years. The detection of symptoms and the early diagnosis of FACC may improve outcome. FACC are large tumors and usually palpable (62% of cases) in
advanced stages. In the great majority of cases when the tumor is discovered its diameter is already greater than 10 cm [12, 18, 27, 38].
The characteristic secretory profile encompasses plasma estrogens elevation, elevated urinary androgens, normal or decreased testosterone and sometimes a slight increase in glucococorticoids [6, 24]. Adrenal an- drogens are substrates for estrogen production by pe- ripheral tissues. However, it has not been demonstrated that estrogens could be synthesized by the normal adre- nal in males [46]. In contrast, the main characteristic of these adrenal tumors is their ability to produce estro- gens, by the increase in substrate (Androstenedione) availability and the presence of aromatase activity within the tumor resulting in a capacity of the tumor to synthe- size estrone efficiently [46]. FACC produce estriol and estrone in a higher proportion than the biologically ac- tive estradiol [2, 7, 12, 14, 37, 40]. Depression of serum testosterone by such endocrinologically active tumors is due mainly to gonadotrophic inhibition by high levels of circulating estradiol, as well as the direct effect of these levels on the Leydig cells [22, 40]. This estrogen secre- tion does not respond to dexamethasone inhibition test, however these tumors are slightly sensible to the action of corticotrophin (ACTH) [6, 7, 12, 24, 31, 33, 37].
The estrogen/androgen ratio is obviously more important than the absolute levels of each hormone in determining the clinical picture [12, 27]. It has been demonstrated for these, as for other adrenal tumors, that the presence of mixed steroids secretion is a predictor factor of worse prognosis [28].
Sky-high estradiol levels are assumed to indicate a ma- lignant tumor, therefore a worse prognosis [27, 44]; in our series the patient with the greatest increase in estra- diol level (20 fold normal) had the worst prognosis with a survival of 1 year and 10 months, the other two pa- tients had estradiol levels 5 fold normal with a survival of 7 years 5 months and 3 years respectively.
In general, patients with FACC tend to have a higher urinary excretion of 17-urinary ketogenic steroids (ob- served in all our three patients), some investigators have even suggested that if the urinary excretion ex- ceeds 100 mg/24 hours the diagnosis is certainly carci- noma [12].
Combined imaging studies (Ultrasonography, CT and MRI) are diagnostic in all cases. CT criteria for separating benign and malignant adrenal masses have been pro- posed. Size, contrast enhancement and heterogeneity are significant discriminators of malignant from benign adrenal masses. Malignant adrenal lesions tend to be larger than benign lesions, with a 6 cm diameter being considered significant. Malignant masses show signifi- cant (20 Hounsfield units) CT enhancement after adminis- tration of intravenous contrast material, benign masses
do not enhance to this extent. Malignant adrenal masses usually present areas of necrosis, heterogeneity (hypo- dense and soft tissue areas mixed haphazardly) and compression to adjacent organs. Calcification, especially if stippled, in an adrenal mass favors malignancy. When these criteria are considered it is usually possible to dif- ferentiate malignant from benign adrenal masses [9].
The presence of distant metastases must be excluded: in decreasing frequency liver, lung and regional lymph nodes are affected; less frequently metastases are en- countered in the bones, the mediastinum or the brain. Metastatic deposits can also affect the contralateral ad- renal gland but concurrently the presence of incidental adenomas in the opposite gland has also been reported [7, 12, 38].
Operative data
Surgery is always indicated in any case of resectable FACC in the absence of metastases as pathological ex- amination is the final mean of diagnosis for malignancy of those tumors and surgery the only chance for cure.
General rules of adrenal surgery apply to these tumors and surgical extension to the ipsilateral kidney, the spleen and clearance of the surrounding fat of the adre- nal fossa is recommended. FACC are usually voluminous tumors, round shaped and well encapsulated, yellow or orange colored, and the cut surface of the mass exhibits necrotic and hemorrhagic zones. Tumor capsule is fra- gile and the risk of capsular rupture is threatening.
FACC are large tumors and their size and the certainty of malignancy preclude laparoscopic or other endo- scopic approaches.
Post-operative data
All 3 patients had regression of symptoms, characteri- zed principally by a diminution of gynecomastia and al- legedly increase of libido after surgery. Lack of fall or recurrence of elevated titers of seric and urinary estro- gens were due to local recurrence or distant metastases [12].
MacFarlane classification determines that stages III (and IV) are beyond the scope of cure [5, 17, 26, 32], not unlike as for other ACC. Several other prognostic factors have been identified and are described in figure 3 [3, 9, 24, 27, 28, 38, 44].
Weiss scoring proves to be extremely accurate for dia- gnosis of malignancy in keeping with the late outcome of the patients [1, 42, 43]. Cytoplasmic organelles show some parallels when feminizing and androgen-secreting adrenal tumors are compared [27]. Mitoses or atypical cells may be very rare or even absent in FAT and for that
reason some investigators insist in avoiding the term “adenoma” for these tumors and suggest that as a rule, adrenal feminization is caused by a malignant tumor [12, 27, 37, 41]. The majority of the rare reported cases of FAA occurred in children [3, 7, 9, 11, 12, 16, 39], in contrast with the generally malignant nature of adrenal tumors causing Cushing’s syndrome [37]. The other FAA were tumors initially diagnosed as benign who pre- sented recurrence or metastasis few months or years later [12, 24]; even one case classified as adenoma lived free of disease for 19 years and died afterwards of tu- mor metastases [7].
Usefulness of post-operative mitotane therapy is well demonstrated in our and other [2, 7, 18] series, as nor- malization of estradiol levels was obtained only after the initiation of this treatment. Radio and chemotherapy as- sociation seems to be beneficial with regard to local re- currence and distant metastasis.
Follow-up imaging must be performed to recognize the appearance of possible metastases. As always for malignant endocrine tumors, biochemical recurrence i.e. in those cases elevation of urinary estrogens is a much earlier harbinger predictor of recurrence rather than positive imaging studies [28]. Post-operative biochemical hormone monitoring is therefore mandatory [31, 44].
Even if mortality among adult males with FACC is high, with a less than 20% survival rate 3 years after re- section, surgery is beneficial as MacFarlane [25] quoted an average survival in the untreated cases of 2.9 months
| Good prognosis | Bad prognosis |
|---|---|
| - Young age at presentation | - Old age at presentation |
| - Small tumor size: < 3cm (smallest | - Big tumor size: >6cm |
| identified ACC associated with | |
| metastases reported was 3 cm in diameter) | |
| - Stage I-II (MacFarlane) | - Stage III-IV (MacFarlane) |
| - Low levels of estrogen excretion | - Elevated levels of estrogen excretion |
| - Pure excretion | - Mixed excretion (other steroids or precursors) |
| - Absence of metastasis or capsular | - Histological alterations (nuclear atypias, |
| rupture | capsular and vascular invasion). |
| - Absence of venous invasion | - Lack of fall or recurrence of elevated |
| - Absence of androgen elevation 2 years | titers of seric and urinary estrogens. |
| after surgery. | |
| Abbreviations | |
| ACC | Adreno-Cortical Carcinomas |
| ACTH | Corticotrophin |
| CT | Computed Tomography |
| DHEA | Dehydroepiandrosterone |
| DHEA-S | Dehydroepiandrosterone-sulfate |
| E1 | Estrone |
| E2 | Estradiol |
| FAA | Feminizing Adrenal Adenoma |
| FACC | Feminizing Adreno-Cortical Carcinoma |
| FAT | Feminizing Adrenal Tumors |
| IVC | Inferior Vena Cava |
| MRI | Magnetic Nuclear Imaging |
| PASAT | Pure Androgen-Secreting Adrenal Tumors. |
only from the time of diagnosis. The outcome seems to be more favorable in children since long-term survival has been documented [3, 7, 12, 15, 27, 36].
CONCLUSION
FACC in adults are exceedingly rare and almost all or maybe all of these tumors are malignant. Every gyneco- mastia without obvious iatrogenic cause must be screened for estrogen hypersecretion. Duration of symp- toms is quite long and diagnosis in early stages (Mac- Farlane I and II) should improve their dire prognosis. Aggressive surgical treatment is recommended. Mitotane can normalize secretory profile and palliative chemo and radio therapy are indicated in treatment of recurrence and metastasis.
REFERENCES
1. Aubert S, Wacrenier A, Leroy X et al. Weiss system revisited. A clinicopathological and immunohistochemical study of 50 adrenocortical tumors. Am J Surg Pathology 2002 ; 26 : 1612- 9.
2. Barcelo B, Abascal J, Ardaiz J et al. Feminizing adrenocortical carcinoma in a postmenopausal woman. Postgrad Med J 1979 ; 55 : 406-8.
3. Bhettay E, Bonnici F. Pure oestrogen-secreting feminizing adrenocortical adenoma. Arch Dis Child 1977 ; 52 : 241-3.
4. Bouraima H, Lireux B, Mittre H et al. Major hyperestrogenism in a feminizing adrenocortical adenoma despite a moderate overexpression of the aromatase enzyme. Eur J Endocrinol 2003 ; 148 : 457-1.
5. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P. The Italian registry for adrenal cortical carcinoma: analysis of a multiinstitutional series of 129 patients. Surgery 1996 ; 119 : 161-70.
6. Decoulx M, Mazzuca M, Racadot A et al. Une nouvelle obser- vation de corticosurrénalome féminisant. Intérét particulier de l’Op’DDD. Rev Franç Endocrinol Clin 1983 ; 24 : 209-17.
7. Decourt J, De Gennes J, Fattoum S. Les tumeurs féminisantes de la cortico-surrénale. In “Actualités endocrinologiques”. Expansion scientifique (Paris) 1971 ; 79-94.
8. Derksen J. Androgen-secreting adrenal neoplasms. In: Azziz R, Nestler JE, Dewailly D, editors. Androgen excess disorders in women. 1st ed. Philadelphia: Lippincott- Raven Publishers ; 1997. 545-53.
9. Desai MB, Kapadia SN. Feminizing adrenocortical tumors in male patients : adenoma versus carcinoma. J Urol 1988 ; 139 : 101-3.
10. Dohan FC, Rose E, Eiman JW, Richardson EM, Zintel H. Increased urinary estrogen excretion associated with adrenal tumors: report of four cases. J Clin Endocrin 1953 ; 13 : 415.
11. Fontaine R, Sacrez R, Klein M et al. Puberté précoce avec déve- loppement des seins chez un garçon porteur d’une tumeur de la surrénale. Arch franç pédiat 1954 ; 11 : 417.
12. Gabrilove J, Sharma D, Wotiz H, Dorfman R. Feminizing adre- nocortical tumors in the male: a review of 52 cases including a case report. Medicine 1965 ; 44 : 37-79.
13. Galifer RB, Couture A, Dyon JF et al. Solid tumors of the adrenal gland in children (excluding neuroblastomas). A study of a series of 18 cases. Chir Pediatr 1989 ; 30 : 209-14.
14. Greenwood R. Selective feminization due to an adrenal carci- noma. Proceedings of the Royal Society of Medicine 1974 ; 67 : 671.
15. Henley DJ, van Heerden JA, Grant CS, Carney JA, Carpenter PC. Adrenal cortical carcinoma - a continuing challenge. Surgery 1983 ; 94 : 926-31.
16. Howard C, Takahashi H, Hayles A. Feminizing adrenal ade- noma in a boy. Mayo Clinic Proc 1977 ; 52 : 354-7.
17. Icard P, Goudet P, Charpenay C et al. Adrenocortical carcino- mas Surgical trends and results of a 253- patient series from the French Association of Endocrine Surgeons Study Group. World J Surg 2001 ; 25 : 891-7.
18. Kadiri A, Chraibi A. Bilateral gynecomastia revealing malignant feminizing adrenocortical carcinoma. Ann Endocrinol (Paris) 1994 ; 55 : 43-4.
19. Klein F, Miller N, Hackler R. Flow cytometry in feminizing adre- nocortical carcinoma. J Urol 1985 ; 134 : 933-5.
20. Kuhn J, Lefebvre H, Duparc C, Pellerin A, Luton J, Strauch G. Cosecretion of estrogen and inhibin B by a feminizing adreno- cortical adenoma: impact on gonadotropin secretion. J Clin Endocrinol Metab 2002 ; 87 : 2367-75.
21. Landau RL, Stimmel BF, Humphreys E, Clark DE. Gynecomastia and retarded sexual development resulting from a long-stan- ding estrogen-secreting adrenal tumor. J Clin Endocrin 1954 ; 14 :1097.
22. Lanigan D, Choa R, Evans J. A feminizing adrenocortical car- cinoma presenting with gynecomastia. Postgrad Med J 1993 ; 69 : 481-3.
23. Limone P, Molinatti P, Merlini C, Molinatti G. Gynaecomastia and azoospermia as sole presenting symptoms of feminizing adrenal tumor. Panminerva Med 1989 ; 31 : 83-7.
24. Luton J, Kuhn J, De Gennes J et al. Adénome surrenalien sécré- teur exclusif d’estrogènes chez un femme en période d’activité génitale. La Presse Médicale 1984 ; 13 : 23-6.
25. MacFarlane D. Cancer of the adrenal cortex: the natural his- tory, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl 1958 ; 23 : 155-86.
26. Miccoli P, Bernini GP. Adrenocortical Carcinoma. In: Doherty GM, Skögseid B, editors. Surgical Endocrinology. 1 st ed. Philadelphia (PA-USA) : Lippincott Williams & Wilk- ins; 2001. p 263-71.
27. Mitschke H, Saeger W, Breustedt H. Feminizing adrenocortical tumor. Histological and ultrastructural study. Virchows Arch A Pathol Anat Histol 1978 ; 377 : 301-9.
28. Moreno S, Montoya G, Armstrong J et al. Profile and outcome of pure androgen-secreting adrenal tumors in female adults. Surgery 2004 ; 136 : 1192-8.
29. Mortensen J, Murphy L. Feminizing adrenal tumor in an adult male. J Urol 1951 ; 65 : 709.
30. Paja M, Diez S, Lucas T, Ojeda A, Salto L, Estrada J. Dexa- methasone-suppressible feminizing adrenal adenoma. Pos- tgrad Med J 1994 ; 70 : 584-8.
31. Phornphutkul C, Okubo T, Wu K et al. Aromatase P450 expres- sion in a feminizing adrenal adenoma presenting as isosexual precocious puberty. J Clin Endocrinol Metab 2001 ; 86 : 649-52.
32. Proye C, Armstrong J, Pattou P. Adrenocortical carcinoma: non functioning and functioning. In: Clark, Duh, Kebebew. Text- book of endocrine surgery. 2nd Ed. Philadelphia (PA-USA) : ELSEVIER SAUNDERS; 2005-604-1.
33. Pugeat M, Saez J, Riou J, Merchak A, Tourniaire J. A feminizing adrenal carcinoma in man: in vivo and in vitro study. Ann Endocrinol (Paris) 1979 ; 40 : 567-9.
34. Qin WB. Feminizing adrenocortical tumor. Zhonghua Wai Ke Za Zhi (China) 1991 ; 29 : 635-6, 654.
35. Saadi H, Bravo E, Aron D. Feminizing adrenocortical tumor: steroid hormone response to ketoconazole. J Clin Endocrinol Metab 1990 ; 70 : 540-3.
36. Solomon S, Swersie S, Paulsen C, Biglieri E. Feminizing adre- nocortical carcinoma with hypertension. J Clin Endocr 1968 ; 28 : 608-12.
37. Stewart W, Fleming L, Woitz H. The feminizing syndrome in male subjects with adrenocortical neoplasms. Am J Med 1964 ; 37 : 455-72.
38. Tourneur R. Les tumeurs cortico-surrénales. La revue du prac- ticien (Paris) 1966 ; 31 : 4195-8.
39. Vague J, Boyer J, Nicolino S et al. Les corticosurrénalomes féminisants de l’homme. Ann Endocrinol (Paris) 1970 ; 31 : 19.
40. Veldhuis J, Sowers J, Rogol A, Klein F, Miller N, Dufau M. Pathophysiology of male hypogonadism associated with endo- genous hyperestrogenism. N Engl J Med 1985 ; 312 : 1371-5.
41. Wallach S, Brown H, Englert E, Eiknes K. Adrenocortical carci- noma with gynecomastia: a case report and review of the lite- rature. J Clin Endocrinol 1957 ; 17 : 945.
42. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984 ; 8 : 163-9.
43. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989 ; 13 : 202-6.
44. Woitz H, Chattoraj S, Gabrilove J. Urinary estrogen titers in a patient with feminizing adrenocortical carcinoma. J Clin Endocr 1968 ; 28 : 192-7.
45. Wooten MD, King DK. Adrenal cortical carcinoma: epidemio- logy and treatment with mitotane and review of the literature. Cancer 1993 ; 72 : 3145-55.
46. Young J, Bulun S, Agarwal V et al. Aromatase -expression in a feminizing adrenocortical tumor. J Clin Endocrinol Metab 1996 ; 81 : 3173-6.
47. Zayed A, Stock JL, Liepman MK, Wollin M, Longcope C. Femi- nization as a result of both peripheral conversion of androgens and direct estrogen production from an adrenocortical carci- noma. J Endocrinol Invest 1994 ; 17 : 275-8.