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Profile and outcome of pureandrogen-secreting adrenal tumorsin women: Experience of 21 casesSebastian Moreno, MD, Guillermo Montoya, MD, John Armstrong, MD, Emmanuelle Leteurtre, PhD,Sebastien Aubert, MD, Marie-Christine Vantyghem, MD, Didier Dewailly, MD,Jean-Louis Wemeau, MD, and Charles Proye, FRCS (Eng), FRCS Ed (Hon), Lille, France

Background. The aim of the study was to determine the outcome and possible prognostic factors of pureandrogen-secreting adrenal tumors (PASATs).Methods. In a review of 801 adrenal operations from 1970 through 2003, 21 women with PASATs weredivided into 2 groups, benign and undetermined tumors (Weiss score # 3) (BT = 11) and malignanttumors (Weiss $4 or nonresectable) (MT = 10).Results. In both groups, age at presentation was similar. There were no differences concerning type ofsecretion, but increase in testosterone level was 2.6-fold greater in malignant tumors (MT) than benigntumors (BT). Imaging studies allowed diagnosis of malignancy in 4 of 10 MT. Size and weight weregreater for MT than for BT (average, 13.7 vs 9.2 cm and 1462 vs 206 g). At follow-up (median, 17 y;range, 1 to 33 y) 2 of 11 patients with BT died of unrelated causes, and 9 of 11 are alive withoutrecurrence; 5 of 10 patients with MT died of disease, and 3 are alive with disease; 7 of those 8 patientshad stage III or IV disease and/or had a Weiss score of 6 or greater. Two patients with MT are alivewithout disease; both were Weiss 7, stage II and received mitotane postoperatively.Conclusions. PASATs of undetermined benign condition share the good prognosis of BT. Weiss score isdiagnostic of malignancy. MacFarlane classification determines the prognosis, and long-term disease-freesurvivors at stages III/IV are never observed after operation only. Postoperative mitotane therapy mightbe beneficial at stage II. (Surgery 2004;136:1192-98.)

From Clinique Chirurgicale, Service de Chirurgie Generale et Endocrinienne, and Clinique EndocrinologiqueMarc Linquette, Universite de Lille; and Service d’ Anatomie et Cytologie Pathologique, Pole Biologie,Pathologie, Parc Eurasante, Lille, France

THE RECENT OPTIMISTIC REPORT of the Mayo Clinicexperience on 11 patients with pure androgen-secreting adrenal tumors1 (PASATs) prompted usto review our own series of 21 patients. The aims ofthe study were to determine the outcome and todefine preoperative features suggestive of malig-nancy and prognostic factors of PASAT in relation-ship with their clinical presentation, secretorypattern, imaging studies findings, weight and size,histologic findings (Weiss score),2-4 staging accord-

Presented at the 25th Annual Meeting of the AmericanAssociation of Endocrine Surgeons, Charlottesville, Virginia,April 4-6, 2004.

Reprint requests: Charles A. G. Proye, MD, Clinique Chirurgi-cale, Service de Chirurgie generale et endocrinienne, Universitede Lille, Hopital Claude Huriez, Rue Michel Polonovski, 59037Lille Cedex, France.

0039-6060/$ - see front matter

� 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.surg.2004.06.046

SURGERY

ing to the MacFarlane5 classification, and post-operative therapy.6

METHODS

From 1970 through December 2003, fromamong 801 adrenal operations performed in thesame institution (Table I), we culled 19 womenoperated for PASATs that were resected. During thesame period, 2 such tumors were seen but deemedto be nonresectable, obtaining an overall group of21 patients. The latter 2 patients were not operatedon and belonged to a group of 220 patients withadrenocortical tumors observed only. During thatperiod, only 1 PASAT was successfully resected inthe pediatric surgical unit (Pr Besson, Universityof Lille) in an 8-year-old girl. We also resected 1virilizing tumor with mixed aldosterone secretionin a 14-year-old girl. Concurrently, among 65female patients operated for Cushing’s syndromeand adrenal tumor, 22 (34%) had virilizing syn-drome much more often in malignant tumors thanin benign tumors, 65% versus 17%.

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Those 21 patients with PASATs were divided into2 subsets according to Weiss score2-4 (Table II)and/or resectability: (1) benign (6 patients) andundetermined tumors (5 patients), BT = 11 pa-tients; and (2) malignant (8 patients) and non-resectable tumors (2 patients), MT = 10 patients.Those latter were stratified according to MacFar-lane staging (Table II).5

No patient was lost to follow-up (median, 17years; range, 1-33 years). Pathologic specimenshave been reviewed for this study.

Results are presented as mean value ± standarddeviation unless otherwise stated. Statistical analy-sis was performed with SPSS software (SPSS Inc,Chicago, Ill). Comparisons between groups weremade by using the Student t test and chi-squaretest. P value was considered statistically significantwhen less than .1, considering heterogeneity andsmall number of patients for each group.

RESULTS

Preoperative data. Demographics and maincomparative data between BT and MT are summa-rized in Table III. Concerning localization, 15tumors were on the left side (8 BT and 7 MT)and 6 on the right side (3 BTand 3 MT). Range andmedian ages at presentation were similar, but meanage was greater for MT than for BT (45 ± 17 vs 35 ±17 years), a difference of 10.8 years (P < 0.19).

In the BT group, 8 of 11 and 3 of 11 patientswere premenopausal and postmenopausal, respec-tively, versus 6 of 10 and 4 of 10, respectively, in theMT group. Only 2 of 11 patients with BT had had 1

Table I. Adrenal surgery in Lille (France)1970-2003

Type of lesion Number (%)

Primary adrenocortical tumors 430 (54)Pheochromocytomas 263 (33)Secreting adrenocortical hyperplasia 45 (6)Adrenal metastasis 39 (5)Adrenal cysts 14 (2)Adrenalectomies for hypertension 8 (1)Hyperplasic ‘‘enzymatic block’’ 2 (0.2)Total 801 (100)

Characteristics Benign Malignant Total

Primary adrenocortical tumorsCushing’s syndrome 52 27 79Hyperaldosteronism 154 2 156PASAT 11 8 19*Feminizing tumor 0 3 3Others (secreting, nonsecreting) 173

Total 430

*Plus 2 nonresectable tumors = 21 PASATs.

or more pregnancies before presentation, whereas6 of 10 patients with MT did. Infertility was thepresenting symptom in 2 of 11 BT patient; 5 of 8premenopausal BT patients presented menstrua-tion alterations including only 2 cases of amenor-rhea versus 5 cases in 6 premenopausal MTpatients. One patient with MT had postmeno-pausal metrorrhagia. Hirsutism was found in allpatients with BT and 7 of 10 patients with MT.Virilization signs (clitoral enlargement, deepeningof the voice, hair loss, acne, and masculine somaticcharacteristics of android obesity, aggressiveness,and baldness) were present in 5 patients only, 3 BTand 2 MT.

In the MT group, 1 patient had fever, 6 hadabdominal pain, 2 had inferior vena cava (IVC)syndrome, and 4 tumors were palpable. In the BTgroup, 3 patients had abdominal pain, and 1 tumoronly was palpable. The duration of the symptomswas much greater in BT than in MT: less than 1 yearin 8 of 10 MT patients, and greater than 1 year in 10of 11 BT patients, including 5 patients with greaterthan 5 years.

By definition, all patients had normal cortisoland adrenocorticotrophic hormone (ACTH) lev-els. There were no significant differences betweenthe groups regarding frequency of increased con-centrations of testosterone, dehydroepiandroster-one (DHEA) and its sulfate (DHEAS), delta 4androstenedione, 17 OH progesterone, sex binding

Table II. Pathologic staging and scoring ofadrenal tumors

Stage

MacFarlane staging for adrenocorticalcarcinoma

T < 5 cm without regional extension (N0) IT > 5 cm without regional extension (N0) IIEvery T with regional extension and/or N+ IIIDistant metastases IV

Score

Weiss score for adrenocortical tumorsHigh nuclear grade 1Mitotic rate > 5/50 high-power fields 1Atypical mitotic figures 1Eosinophilic tumor cell cytoplasm (>75% of

tumor cells)1

Diffuse architecture (>33% of tumor) 1Necrosis 1Venous invasion 1Sinusoidal invasion (no smooth muscle in wall) 1Capsular invasion 1

Total 9

Histologic criteria for definition of adrenocortical neoplasms:0-2, benign tumor; 3, undetermined tumor; 4-9, malignant tumor.

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protein, and urinary 17-ketosteroids as demon-strated in Table IV. However, there was a differencein level of increase for testosterone; the highestconcentration of testosterone was 7.40 ng/mL (11-fold normal) for BT versus 19.40 ng/mL (28-foldnormal) for MT, with a mean level of 3.25 ± 2.77ng/mL (5-fold normal) for BT versus 8.52 ± 6.35ng/mL (12-fold normal) for MT (P < .08). Estra-diol levels were elevated in 2 of 6 patients with BT(1 premenopausal and 1 postmenopausal woman)and in 1 of 6 patients with MT (postmenopausal).

All imaging studies identified the tumor. Ultra-sonography was performed in 4 of 11 BT patientsand 5 of 10 MT patients, computed tomography(CT) in 7 of 11 BT patients and 8 of 10 MT patients,and magnetic resonance imaging (MRI) in 4 of11 BT patients and 3 of 10 MT patients. Otherimaging studies were historical or anecdotal. Ac-cording to well-recognized criteria (calcification,venous thrombus, enlarged nodes, or liver metas-tasis), malignancy was suspected by ultrasonogra-phy in 2 of 5 MT patients, by CT in 6 of 8 MTpatients, and by MRI in 2 of 3 MT patients.However, overall imaging studies allowed preoper-ative diagnosis of malignancy only in 4 of 10 MTpatients (all at stage III or IV) and stronglysuspected malignancy by the presence of micro-calcifications in 3 other patients (7 of 10 MTpatients); they did not suggest malignancy in anyBT patient. Of note in this latter group, heteroge-neity in one or several imaging studies was observedin 3 of 5 BT patients with a Weiss score of 3 versus0 of 6 BT patients with a Weiss score of less than 3.

Operative data. Two of 21 patients with PASATsdid not undergo surgery; both had local invasionto the kidney and IVC combined with distantmetastasis, and one of them also had portalthrombosis. All 19 operations were open; nonewere laparoscopic. Except for 1 BT patient whounderwent surgery via a posterior approach, allthe surgeries were performed either by an anterior

Table III. Comparative chart of BT vs MT

BT (11) MT (10)

Age atpresentation (y)P < .19

Range, 17-66 Range, 15-71Mean, 34.5 ± 17 Mean, 45 ± 17Median, 42 Median, 43

Tumor size (cm)P < .05

Range, 4-22 Range, 6.5-21Mean, 9 ± 5 Mean, 14 ± 5Median, 13 Median, 14

Tumor weight (g)P < .03

Range, 18-1100 Range, 48-4700*Mean, 206 ± 306 Mean, 1462 ± 1676Median, 559 Median, 2400

*Combined nephrectomy and splenectomy.

or lateral approach, 9 each respectively, including7 thoracophrenolaparotomies.

Tumor size and weight are given in Table III.Mean size and weight were greater for MT than forBT, 13.7 ± 4.5 versus 9.2 ± 4.8 cm (P < .05) and 1462± 1676 versus 206 ± 306 g (P < .03), respectively. Itshould be noted that there is great overlap inranges; the largest of all tumors was a BT of 22 cmand weighing 1100 g, whereas the smallest MT was6.5 cm in size and 48 g in weight.

In MT, surgery was extended to the spleen in 6patients, to the left kidney in 3 patients, andcombined to lateroaortic node clearance in 2patients, and extraction of a huge thrombus inthe IVC in 1 patient. Adrenalectomy for MT wasalways accompanied by complete clearance of thesurrounding fat of the adrenal fossa.

Postoperative data. There were no intraopera-tive or postoperative deaths. Morbidity was minimaland unrelated to surgery except for 1 patient withpelvic thrombosis. Mean hospital stay was 10.2 days(range, 6-16 days) for BTand 12.1 days (range, 8-19days) for the MT group. Androgen secretion wasmeasured before discharge in 14 of 19 surgicalpatients (8 of 11 BT and 6 of 8 MT) with nopersistence of hypersecretion in any group afteroperation. Type of surgical incision had no impacton the outcome.

According to the MacFarlane classification, noMT fell in stage I, 3 fell in stage II, 4 in stage III, and3 in stage IV at presentation. Downgrading of stageIII patients cannot be excluded if they had occultmetastases. Weiss scoring was performed in all 19surgical samples; 6 patients were scored less than 3and 5 patients at 3, constituting the group of 11 BTpatients; 8 were scored 4 or greater, and the 2

Table IV. Increase of hormonal levels

Hormone

BT (n = 11)Number increased/Number performed*

MT (n = 10)Number increased/Number performed*

Testosterone 7/7 6/6DHEA 3/4 2/3DHEAS 6/8 4/6Delta 4androstenedione

6/7 6/6

17 OHProgesterone

3/6 2/2

Estradiol 2/6 1/617-Urinaryketogenicsteroids

6/7 2/2

*Number of patients with increased serum or urinary hormonelevels/Number of patients in whom test was performed for eachgroup.

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nonresectable patients were assumed to be 4 orgreater, making a total of 10 MT patients.

All patients had laboratory tests during follow-up. None of the BT group exhibited recurrence orandrogen elevation. In the MT group, 5 of 6surgical patients with recurrence had androgenelevation, and the 2 patients alive without diseasehave normal serum and urinary androgen concen-trations. Follow-up imaging was performed in 6 of 8MT patients after surgery, showing no recurrencein 2 patients and local recurrence with livermetastases in 4 others.

Postoperatively, mitotane was given to 12 pa-tients, 8 with MT and 4 with BT (3 undetermined);in the only patient with true BT, mitotane wasprescribed because of equivocal gross findings ata time when the Weiss score was still unpublished.Duration of the treatment was 2 to 6 years for BTand 2 months to 18 years for MT. One patient withMT, the longest survivor, also received decarbazine(Deticene; Aventis Pharma, France) chemotherapyand radiotherapy.

Finally, at follow-up (median, 17 years; range, 1-33 years) 2 of 11 patients with BT died of unrelatedcauses (stroke and chronic myeloid leukemia),whereas 9 are alive without recurrence. Also in thisgroup, 2 pregnancies have been successfully com-pleted. Five of 10 patients with MT died of thedisease, and 3 of 10 are alive with disease; 7 of thoselatter 8 patients were stage III or IV at presentationand/or had a Weiss score of 6 or greater. Twopatients with MT are alive without disease. Bothwere stage II at presentation, had a Weiss score of 7,and received mitotane postoperatively; their follow-up is 7 years and 1 year, respectively. Outcomeaccording to Weiss score for both groups andaccording to MacFarlane classification for MT isgiven in Tables V and VI.

DISCUSSION

Series of PASATs are scarce in the surgicalliterature.1,7-9 Adenomas account for approxi-mately 39% of testosterone-producing tumors ofthe adrenal cortex,1,7-9 and 9 of the largest series ofadrenocortical carcinomas report more than 1180patients, including 62 with PASAT, which corre-sponds to 0% to 11% of their individual series andan overall rate of 5.3%.1,8,10-17 In our own experi-ence, PASATs barely account for 2.4% of the bulk ofadrenalectomies, but they make up 4.4% of adre-nocortical tumors for which surgery is performed,and 49% of virilizing syndromes in women. Mixedcortisol and androgen secretion is highly suggestiveof malignancy.

Preoperative data. PASATs almost always havea large size, and that is no surprise becauseadrenal glands excrete only weak androgens bycontrast to ovarian virilizing tumors, which aremost often small and sometimes even occult. Thishas 3 important practical consequences: (1) Largesize is not necessarily a harbinger of malignancy;even a benign tumor can be palpable, weigh morethan 1 kg, and be cured with a 30-year follow-up;(2) In the setting of a virilizing syndrome, diagnosisof PASAT and of its possible malignancy is mostlygrounded on imaging studies rather than on subtlediscussions of the secretory profile; and (3) Iftheoretically, by definition, PASAT should neverbe discovered as adrenal incidentalomas, the con-trary might also be true. In our own series, eitherbecause of small size or by lack of obvious virilizingsymptoms, 2 patients were discovered by chance,either in the course of a gynecologic checkup (1patient) or in retrospect at the time of recurrenceof a large adrenocortical carcinoma supposed to benonsecreting (1 patient).

In our series, median age is similar for BT andMT, mean age is 10.8 years younger for BT, andduration of symptoms is longer for this group,whereas abrupt onset of the disease is highly sug-gestive of malignancy. The longer course of thedisease of BT is consistent in premenopausalwomen, with primary infertility observed in 2

Table V. Weiss score and outcome

Weiss score Number

Outcome

Dead (n = 7) Alive (n = 14)

Of diseaseUnrelatedcauses

Withdisease

Withoutdisease

<3 6 0 1 0 53 5 0 1 0 4>3 10* 5 0 3 2

*2 nonresected metastatic cases assumed to be >3.

Table VI. MacFarlane staging for 10 malignanttumors and outcome

Stage Number

Outcome

Dead (n = 5) Alive (n = 5)

Of diseaseUnrelatedcauses

Withdisease

Withoutdisease

I 0 0 0 0 0II 3 1 0 0 2III 4 2 0 2 0IV 3 2 0 1 0Total 10 5 0 3 2

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patients and occurrence of postoperative pregnan-cies in 2 patients. Amenorrhea is more frequentlyobserved in MT than in BT. We noticed that allpatients with BT had hirsutism, whereas 2 patientswith MT did not. This can be explained by theabrupt onset of the tumor, leaving no time forandrogens to act on the receptors and manifest thissymptom.

Actually, imaging studies are diagnostic of ma-lignancy only at stages III and IV, where there is nohope for cure. At stage II they can suspect but notexclude malignancy. Confirmation of promisingresults of positron emission tomography scan iseagerly awaited to usher in a new era of pre-operative diagnosis.

Wehave been very disappointed also to be unableto define a qualitative secretory profile that isdiagnostic or even suggestive of malignancy; how-ever, highly elevated testosterone levels (>7.40 ng/mL, 11-fold normal) should suggest a malignantpathology.

Testosterone in women comes from directovarian secretion (25%) and from direct adrenalsecretion (25%). Almost half of testosterone pro-duction is obtained by a peripheral conversion bythe liver, fat, and skin tissue of their precursors(delta 4, DHEAS, DHEA). General mechanisms ofandrogen synthesis are identical in ovaries andadrenal glands. Testosterone is the most potentcirculating androgen in women. DHEAS is the bestmarker for PASAT.

Derksen9 has demonstrated in a convincing waythat the differential diagnosis between an adrenaltumor and other causes of hyperandrogenism canbe clarified by the dexamethasone suppression test,because androgens were not suppressed in anyadrenal tumor. Neither ACTH administration nordexamethasone suppression has any effect onplasma and urine androgen concentration. Viriliz-ing adrenal tumors secrete androgens autono-mously without ACTH regulation, and peripheralconversion continues.14,18 A long time ago Gui-net18 described the anarchic characteristic of an-drogen excretion of malignant adrenal virilizingtumors, in which pathologic release of steroids isnot fundamentally different from a normal process,but the principal abnormalities are quantitative.Estradiol, the final product of estrogen synthesisthrough the androgen pathway, is uncommonlyelevated in BT and MT.

Etiologically, there is an intriguing subset ofgonadotropin-driven testosterone secreting adre-nal adenomas; only 14 cases have been reportedworldwide.19-21 None of our patients apparently fellin this group, but specific dynamic tests were not

performed. Laszlo et al21 demonstrated in suchtumors the presence of illicit human chorionicgonadotropin receptors as described initially byLacroix22 for gastrointestinal peptide receptors incases of food-dependent Cushing’s syndrome.Ovarian thecal metaplasia in adrenal glands ofpostmenopausal women can be suggested as analternative explanation.

Operative data. Surgery is always indicated inany case of resectable PASAT, because pathologicexamination is the only means of diagnosis of thenature of those tumors in the absence of localinvasion or distant metastases. The secretory pro-file of PASAT itself has no influence on surgicalstrategy; general rules of adrenal surgery apply tothose tumors. Liberal use of thoracophrenolapar-otomy (7 patients) even for BTwas elicited by theirsize and hence fear of possible malignancy.

No patient in this series spanning over 33 yearshas been operated laparoscopically.23 The issue israised whether this approach can be recommendedfor such large tumors. Lack of certainty of pre-operative diagnosis of malignancy either by radio-logic or biochemical findings mitigates against this.In our series practically all MTs were greater than6.5 cm in diameter; therefore we think thatlaparoscopic approach can be safely recommendedfor PASATof 6 cm or less, and this is in keeping withindications currently accepted for other adrenaltumors.

Postoperative data. Weiss scoring proves to beextremely accurate for diagnosis of benign condi-tion or malignancy in keeping with the late out-come of the patients. We believe that the tumors inthe ‘‘gray area’’ of Weiss score of 3 share the goodprognosis of BT with a score less than 3, but it is ofnote that 3 of 5 received mitotane postoperatively.Refinements of Weiss scoring3,4 in the future mightclarify this gray area and prevent unnecessarypostoperative therapy. With regard to the MacFar-lane classification, our series confirmed the direprognosis of stages III and IV that are beyond thescope of cure.10-12,24,25 For MT only surgery per-formed at stages I or II might be curative.

Usefulness of postoperative mitotane therapyhas been discussed in depth in the literature.9,26

We can only report that all 3 long-time survivorswith MT received mitotane postoperatively. Thepatient with the longest survival (21 years), whohad stage III disease at presentation and a Weissscore of 7, received mitotane for 18 years. We areunable to conclude whether the good prognosis ofundetermined tumors in our series is related topostoperative use of mitotane given in 3 of 5patients; lack of late recurrence after stopping

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the treatment, 11, 8, and 1 year(s), respectively,rather argues against this treatment.

Finally, combination of the Weiss score and theMacFarlane staging provides us with an excellentdiagnostic and prognostic tool for PASAT, as forother adrenocortical tumors.

CONCLUSION

PASATs are rare and most often large adrenaltumors secreting weak androgens. They are malig-nant in 50% of patients. No qualitative biochemicalprofile is suggestive of malignancy, but testosteronelevels greater than 12-fold normal do suggestmalignancy. Imaging studies allow a diagnosis ofmalignancy in 40% of patients. Weiss score of 4 orgreater is diagnostic of malignancy. PASAT ofundetermined benign condition with a Weiss scoreof 3 shares the good prognosis of BT. For MT, theMacFarlane classification rules out the prognosis,and long-term disease-free survivors at stages IIIand IV are never observed after operation only.Mitotane therapy might be beneficial at stage II.

We gratefully acknowledge medical endocrinologistswho referred their patients to our surgical unit: DrsBourdelle-Hego, Buvat, Coliche, Dubreuil, Fossati, Ham-zalag, Mesmacque, Mycinski-Decaudeveine, and Verier-Mine.

REFERENCES

1. Cordera F, Grant CS, van Heerden JA, Thompson GB,Young W. Androgen-secreting adrenal tumors. Surgery2003;134:874-80.

2. Weiss LM. Comparative histologic study of 43 metastasizingand nonmetastasizing adrenocortical tumors. Am J SurgPathol 1984;8:163-9.

3. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features ofprognostic significance in adrenocortical carcinoma. Am JSurg Pathol 1989;13:202-6.

4. Aubert S, Wacrenier A, Leroy X, Devos P, Carnaille B, ProyeC, et al. Weiss system revisited. Am J Surg Pathol 2002;26:1612-9.

5. MacFarlane D. Cancer of the adrenal cortex: the naturalhistory, prognosis and treatment in a study of fifty-five cases.Ann R Coll Surg Engl 1958;23:155-86.

6. Wooten MD, King DK. Adrenal cortical carcinoma: epide-miology and treatment with mitotane and review of theliterature. Cancer 1993;72:3145-55.

7. Mattox JH, Phelan S. The evaluation of adult females withtestosterone producing neoplasms of the adrenal cortex.Surg Gynecol Obstet 1987;164:98-101.

8. Del Gaudio A, Del Gaudio GA. Virilizing adrenocorticaltumors in adult women: report of 10 patients, 2 of whomeach had a tumor secreting only testosterone. Cancer 1993;72:1997-2003.

9. Derksen J. Androgen-secreting adrenal neoplasms. In: AzzizR, Nestler JE, Dewailly D, editors. Androgen excess disor-ders in women. 1st ed. Philadelphia: Lippincott-RavenPublishers; 1997. p. 545-53.

10. Icard P, Chapuis Y, Andreassian B, Bernard A, Proye C.Adrenocortical carcinoma in surgically treated patients:a retrospective study on 156 cases by the French Associationof Endocrine Surgery. Surgery 1992;112:972-80.

11. Crucitti F, Bellantone R, Ferrante A, Boscherini M, CrucittiP. The Italian registry for adrenal cortical carcinoma:analysis of a multiinstitutional series of 129 patients.Surgery 1996;119:161-70.

12. Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B,Chapuis Y, et al. Adrenocortical carcinomas: surgical trendsand results of a 253-patient series from the FrenchAssociation of Endocrine Surgeons Study Group. World JSurg 2001;25:891-7.

13. Kendrick ML, Lloyd R, Erickson L, Farley DR, Grant CS,Thompson GB, et al. Adrenocortical carcinoma: surgicalprogress or status quo? Arch Surg 2001;136:543-9.

14. Imai T, Tobinaga J, Morita-Matsuyama T, Kikumori T,Sasano H, Seo H, et al. Virilizing adrenocortical adenoma:in vitro steroidogenesis, immunohistochemical studies ofsteroid enzymes, and gene expression of corticotropinreceptor. Surgery 1999;125:369-402.

15. Henley DJ, van Heerden JA, Grant CS, Carney JA, Carpen-ter PC. Adrenal cortical carcinoma: a continuing challenge.Surgery 1983;94:926-31.

16. Bodie B, Novick A, Pontes J, Straffon RA, Montie JE, BabiakT, et al. The Cleveland Clinic experience with adrenalcortical carcinoma. J Urol 1989;141:257-60.

17. Soreide J, Brabrand K, Thoresen S. Adrenal cortical car-cinoma in Norway, 1970-1984. World J Surg 1992;16:663-8.

18. Guinet P. L’hypercorticisme androgenique. La Revue dupracticien (Paris) 1966;16:4165-80.

19. Kogan BA, Sonda PL, Diokno AC. Virilizing adrenaladenoma secreting testosterone. J Urol 1981;126:787-8.

20. Werk EE, Sholiton LJ, Kalejs L. Testosterone-secretingadrenal adenoma under gonadotropin control. N Engl JMed 1973;289:767-70.

21. Laszlo FA, Toth S, Kocsis J, Pavo I, Szecsi M. Testosterone-secreting gonadotropin-responsive adrenal adenoma and itstreatment with the antiandrogen flutamide. J EndocrinolInvest 2001;24:622-7.

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DISCUSSION

Dr Steven K. Libutti (Bethesda, Md). This is veryelegantly presented work. Obviously, with higher stagelesions, the outcome is fairly dismal for these patients.Although mitotane can sometimes be of benefit, it isclearly not the cure-all or panacea for patients withsystemic disease. Are there any ideas you might have or

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1198 Moreno et al

any thoughts to approaches with adjuvant therapies tosurgery that might improve on the outcome for patientswith higher stage lesions?

Dr Tsuneo Imai (Nagoya, Japan). I am interested inACTH responsiveness of androgen-secreting adrenaltumors. You presented that your patients all had normalcortisol and ACTH levels, but there are considerablevariations of steroid hormone production between thepatients with adrenal tumors even in the normal basalcortisol or ACTH. Do you have the data of endocrino-logic examinations such as dexamethasone suppressiontest, ACTH stimulation test, or diurnal variations ofcortisol or ACTH?

Dr Douglas B. Evans (Houston, Tex). In your generalpopulation of more than 400 patients, have you lookedat the same thing? We all struggle with the proper follow-up of patients who are reported to have benign orindeterminate histologies, yet their tumor size is in the

rage of 5, 6, or 7 cm. Do you typically follow all thosepatients? Have you found any who have been demon-strated to have metastatic disease, despite the absence ofa malignant diagnosis on initial histopathologic review?

Dr Moreno. Dr Libutti, concerning mitotane, weobserved that 3 of our patients with the longest survivalhave received this treatment, and the longest survivor(21 years) received additional chemotherapy (Deticene).

Dr Imai, actually these tumors do not respond toACTH or dexamethasone suppression tests because theyhave an autonomous secretion.

Dr Evans, we have observed that the Weiss score isdiagnostic. Even though a new modified Weiss score hasbeen used and shown to be very accurate for all adrenaltumors in determining benign from malignant tumors,we have seen that the outcome of patients with a Weissscore of less than 3 is good, without any case of latedistant metastasis or local recurrence.