Clinical, Hormonal and Pathological Findings in a Comparative Study of Adrenocortical Neoplasms in Childhood and Adulthood

Vol. 154,2004-2009, December 1995 Printed in U.S.A.

CLINICAL, HORMONAL AND PATHOLOGICAL FINDINGS IN A COMPARATIVE STUDY OF ADRENOCORTICAL NEOPLASMS IN CHILDHOOD AND ADULTHOOD BERENICE B. MENDONCA,* ANTONIO MARMO LUCON, CLAUDIA A. V. MENEZES, LUIS B. SALDANHA, ANA C. LATRONICO, CLAUDIA ZERBINI, GUIOMAR MADUREIRA, SORAHIA DOMENICE, MARIA ADELAIDE P. ALBERGARIA, MARCIA H.A. CAMARGO, ALFRED0 HALPERN, BERNARDO LIBERMAN, N O J. P. ARNHOLD, WALTER BLOISE, ADAGMAR ANDRIOLO, WILIAN NICOLAU, FREDERICO A. Q. SILVA, ERIC WROCLASKI, SAM1 ARAP AND BERNARDO L. WAJCHENBERG From the Sections of Endocrinology, Urology and Pathology, Hospital das Clinicas, University of Scio Paulo, School of Medicine, Scio Paulo, Brazil

ABSTRACT

Purpose: We reviewed clinical and laboratory findings in 6 male and 32 female patients with functional adrenocortical neoplasms, and compared pediatric and adult data. Materials and Methods: Hormonal measurements were performed by radioimmunoassay, histological analysis was based on Weiss criteria and staging was done according to previously established guidelines. Results: Children had a higher incidence of virilization (72%), whereas in adults the predominant feature was Cushing's syndrome (60%). A high testosterone level was the most common finding in adults and children with virilization followed by high dehydroepiandrosterone sulfate, androstenedione and dehydroepiandrosterone levels. High 11-deoxycortisol levels were frequently associated with tumor recurrence. Cortisol suppression after dexamethasone was altered in 93% of patients with virilization and no clinical features, suggesting autonomous cortisol secretion. Conclusions: No statistically significant relation was noted between tumor weight and prognosis but there was a negative correlation between patient age and prognosis since children had a more favorable followup than adults. Mixed features in both groups resulted in the worst prognosis. A Weiss criteria grade N or greater correlated well with a poor prognosis in adults but not children, while staging was more reliable in children. KEYWORDS:adrenal glands, adrenal gland neoplasms, Cushing's syndrome, virilism

There have been signiticant advances in the diagnosis and management of adrenal neoplasms during the last 20 years. The prevalence of clinically silent, incidentally detected adrenal tumors is much higher than previously assumed due to the wider application of ultrasound, computerized tomography and more recently magnetic resonance imaging. Adrenocortical neoplasms are rare, and can develop at any age and in both genders. The incidence of adrenal tumors in the United States is estimated a t 0.5 per million population per year.' There is a high incidence of adrenal neoplasms in Brazil, particularly the southern part of the country, for reasons yet unknown.2 Most of these tumors are functionally active with a predominance of glucocorticoid and androgen secretion. Functioning neoplasms cause virilization and/or Cushing's syndrome in adults and children as well as pseudoprecocious puberty in children. In rare cases feminization, hypoglycemia and hyperaldosteronism may be present. Nonfunctioning neoplasms present as an abdominal mass or abdominal pain, or by secondary symptoms of their metastases. The incidence of adrenocortical neoplasms remains low in childhood and comparative studies of these neoplasms that affect children and adults are rare.3 Our objective was to evaluate and compare the clinical, hormonal and pathological findings in children and adults referred to our institution with functional adrenocortical neoplasms and identify the

potential prognostic factors of these neoplasms in both age groups. PATIENTS AND METHODS

We studied 38 patients with adrenocortical neoplasms who were referred to our facility from 1980 to 1992. Since all previous studies show that there are no definite means to differentiate adrenocortical carcinomas from benign adenomas, we used the term neoplasms throughout this study. Patients were considered to have Cushing's syndrome if they presented with moon face, weight gain, centripetal fat distribution, striae andor hypertension as well as growth retardation in children. Children were considered to have virilization if they presented with clitorimegaly or macrogenitosomia, hirsutism, deep voice, precocious pubarche, acne and/or increased muscle mass. Tumor was revealed by ultrasonography, computerized tomography and more recently magnetic resonance imaging. The clinical data of the pediatric group are shown in table 1. Patients were clinically evaluated and bone age was determined according to Greulich and Pyle.4 The 5 boys and 13 girls were white and age ranged from 7.9 months to 14.58 years (median 2.5 years) at diagnosis. Bone age ranged from 0.5 to 15 years. The interval between the probable onset of symptoms and diagnosis ranged from 0.05 to 7 years (mean 1.45).A total of 13 children had clinical signs and symptoms Accepted for publication A~ril21. 1995. * Requests fo; reprints: Endocrinology, Hospital das Clinicas, P.O. of virilization, 1 had the clinical presentation of Cushing's Box 8091-01065-970, Siio Paulo, SP, Brazil. syndrome and 4 had signs of virilization associated with 2004

ADRENOCORTICAL NEOPLASMS IN CHILDHOOD AND ADULTHOOD

2005

All 38 patients underwent complete surgical resection of the neoplasm. Nephrectomy was performed en bloc with tuClinical Features Duration mor resection in 2 children (patients 1 and 9) and 5 adults No. (yrs.) (YrS.) Age (YSJ (patients 21, 31, 34, 36 and 38) to achieve complete tumor 1 - M - 1.83 1.5 Virilization 0.5 resection. Histological analysis was reviewed by 1 patholo2 - F - 0.66 0.5 Virilization and Cushiog's 0.75 gist (L. B.S.) using Weiss histological criteria.6 Histological syndrome material from patient 33 was poorly represented and could 3 - F -3.16 8.83 Virilization 4 - F -0.83 1.5 Virilization ::$ not be completely analyzed. Each tumor was graded from 0 to 5 - F - 1.66 2 Virilization 0.5 M according to the presence of the following features: l-nu6 - F - 1.75 4.16 Virilization 1.41 clear size I11 or N,%mitotic rate greater than 5/50cells per 3 Virilization '.08 1 - M -1.41 high power field, &atypical mitoses, 4-clear cells compris7 Virilization 1.33 8 - F -2.5 9 - F - 14.58 11 Cushing's syndrome 5.58 ing 25% or less of the tumor, &diffuse architecture, 6-mi10 - F - 5.58 6.83 Vilization 0.25 croscopic necrosis, 7-invasion of venous structures, 8-in11 - F -2.83 Virilization 0.05 vasion of sinusoidal structures and 9-invasion of tumor 12 - F -2.41 3 Vilization 0.75 capsule. For mitotic rate 10 high power fields were analyzed 13 - F - 1.08 3.5 Virilization and Cushing's 1.08 in each case on hematoxylin and eosin stained histological syndrome 14 - F -7 15 Virilization 7 sections. Tumors that met 4 or more of the 9 criteria were 15 - M -1.16 Virilization 0.41 defined as malignant.6 Disease was staged at presentation to 16 - M -1 1 Virilization 1 our hospital according to Nader et aL7 17 - M -2.5 2.7 Vilization and Cuahing's o,41 We studied the clinical aspects, hormonal findings, chrosyndrome 18 - F -4.75 5 Virilization and Cushing'a 1 nological age, tumor weight and size, Weiss histological feasyndrome tures and total Weiss score, and compared them in both groups for cases with more than 3 years of followup using the nonparametric Mann-Whitney U test. We also compared surcusbngssyndrome. abdominal mass was palpable in vival rates with clinical features in the adult and pediatric patient 17, who also had lung metastases at the time of groups. clinical evaluation. The clinical data of the adult group are shown in table 2. RESULTS The 18 white women, 1black woman (patient 31) and 1white man ranged in age from 18 to 57 years (median 33) at diagCzinicQz and honnonnz findings- There was a Predomimerewas an interval of 3 months to 5 years (mean 2 nance of adrenal tumors in female patients: the femde-to,,ears) from the probable onset of symptoms to diagnosis. male ratio was 2.6:l in children and 19:l in adults. The Eight patients had clinical signs of virilization, 10 had probable duration Of disease before the diagnosis W a s S h h r Cushing's syndrome, and 2 had signs of virilization and in both groups. A total of 20 neoplasms (12 in adults and 8 in children) was in the right adrenal gland (53%) and 18 (10 Cushing's syndrome. gland Hormonal evaluation in the 38 cases was done under basal in children and in adults) were in the left fasting conditions. ~ ~ u c o c o ~ iand c o iandrogen ~ semetion (47%).None of the patients had bilateral tumors. We noted a were assessed by measuring s e m cortisol, 1l-deoxycortisol, higher incidence of virilization in comparison to Cushing's 17-hydroxyprogesterone, androstenedione, testosterone, de- syndrome in the pediatric group (72461, whereas in adults the hydroepiandrosterone and dehydroepiandrosterone sulfate. predominant feature was cusug's syndrome (60%and 2). Cortisol levels were also evaluated after the administration children with virilization *One age was advanced in of dexamethasone (1or 2 mg. at 12 p.m.1 with blood collection at 8 a.m. on the following day. Levels of greater than the except Patients 2 and l6, who were 0.66 Years and parOld, mean +2 standard deviations of the control group were con- respectively. Ofthe 4 children with virilization and Gushing's sidered elevated. All hormonal measurements were per- Syndrome advanced bone age was present in 1(patient 13). formed by r a d i o h u n o a s s a y according to Abraham6 except The hormonal data of the Pediatric group are shown in table cortisol, which was measured using a commercial kit. Inter- 3. All children had a high basal testosterone level except Only had Of cushg's assay variation coefficient was less than 18%for all steroids. pubertal femalepatient syndrome. Dehydroepiandrosterone sulfate was elevated in 17 children but only slightly in 3 (163 to 368 ngJml.), which was within the normal range for isolated Cushing's synTABLE2. Clinical data ofadults with adrenocortical neoplasms. drome. Dehydroepiandrosteroneone, which was measured in 15 Disease children, was increased in 13 and normal in 2, of whom 1 Pt. -Sex - Age Duration Clinical Features (patient 12) had clinical signs of virilization and the other No. (ma.) fyra,) had isolated Cushing's syndrome. Androetenedione was 19- F -38 Virilization 2 elevated in 17 children of whom 12 had clinical signs of 20 - F - 29 Cushing's syndrome 1 21- F -57 Vilization 3 virilization, 1 had signs of Cushing's syndrome and 4 had 22 - F -46 Gushing's syndrome 2 virilization with Cushing's syndrome. In 12 children 111.4 23 - F - 41 Cushing's syndrome deoxycortisol evaluation revealed increased levels in 7 of 24- F -27 Virilization 1.5 whom 3 had virilization and 4 had virilization with Cushing's 25 - F -29 Cushing'a syndrome 1 Cushing's syndrome 2 syndrome. In 12 children 17-hydroxyprogesterone measure26 - F - 30 1.25 ment showed elevated levels in 6 of whom 4 had virilization 27 - F - 35 Cushing's syndrome 28- F -30 Virilization 2 and 2 had virilization with Cushing's syndrome. Basal corti29- F - 33 Cushing's syndrome 1 sol was determined in all children but was increased in only 30 - M - 38 Cushing's syndrome and virilization 1 31 - F - 45 Cushing's syndrome and virilization 1 the 3 who had Cushing's syndrome and virilization. 32 - F -35 Cushing's syndmme 2 Hormonal data of the adult group are shown in table 4. 33 - F - 33 Cushing's syndrome 5 Testosterone evaluation in 18 women demonstrated in34 - F - 48 Cushing's syndrome 3 creased levels in 10, of whom 7 had virilization, 1 had 3 35- F -30 Virilization Cushing's syndrome and 2 had virilization with Cushing's 36- F -26 Virilization 5 37 - F - 18 Virilization 1.5 syndrome. Dehydroepiandrosterone sulfate measurement in 0.25 38- F -34 Virilization 17 patients showed elevated levels in 9, of whom 5 had TABLE1. Clinical data ofchildren with adrenocortical neoplasms

pt. - Sex - Age

Bone

msease

ADRENOCORTICAL NEOPLASMS IN CHILDHOOD AND ADULTHOOD

2006

TABLE 3. Hormonal data of children with adrenocortical neoplasms

~

Virilization Virilization and Cushing's syndrome Virilization Virilization Virilization Virilization

1 2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Virilization Virilization Cushing'ssyndrome Virilization Virilization Virilization Virilization and Cushing's syndrome Virilization Virilization Virilization V i a t i o n and Cushing's syndrome Virilization and Cushing's syndrome

163

90 47 1 78 307 1,120

3,870 1,820

5 14

5.1 4

4.8 6.7

0.59 0.6

10 25

968

4 12

6.7 6.3 2.2 6

8.2 4.2

-

1.5 2.3 0.77 1.3

10 11 8 23

4.2 1.7 3.9 3.5 1.7 2.6 11.6

8.9 2.96

5.16 0.38

16 19 21 25 16 14 31

747 238 40 74 160 90 235

3,613 1,493 Greater than 10,Ooo 46,850 8,724 467 9,438 986 368 14,395

202 281 313 189

3,278 6,286 163 5,610

6 12 2.8 29

465

279

20-150 50-500

-

40 6.5 6.8 2.1 23

-

1.3

-

-

0.66

-

9.4 13.8

4.9

7

1.4

-

15.8 12.6 49 0.4

-

25 20

0.49 23

21 6 13 44

3.8 20

2.8

49

22

0.14.8 0.1-0.8

5-25 5-25

6.8 1.98 0.65 5.2

4.6

-

-

4.4 9.2

4.6

2.7

17.1

0.2-1 0.2-3

0.14.6 0.1-0.6

5.8

-

Normal rangdage: 0-25 0-25

1-5 yrs. 5-11 m.

0.85 0.84

Leas than 2 Leas than 2

TAFJLE4. Hormonal data of adults with adrenocortical neoplasms. Pt.No. 19 20 21 22 23 24 25 26 27 ~. 28 29 30 31

32 33

34 35 36 37 38

Clinical Features Virilization Cushing's syndrome Virilization Cushing's syndrome Cushing's syndrome ViriIization Cushing's syndrome Cushing's syndrome Cushing's syndrome Virilization C u s h i d s syndrome Cushing's syndrome and virilization Virilization and Cushing's syndrome Cushing's syndrome Cushing's syndrome Cushing's syndrome Virilization Vization Viation Virilization

Normal rangeJsex: F M

E:ze

epiandmsterone

(ngJdl.)

(ng,/ml,)

172 11 252 6.7 113 184

6,592 Less than 100 2,122 124 3,541 3,732

-

Less than 8 24.6 168 28 384 251

9.3 3 1.7 0.1 5.2 3.8 1

-

-

49 338 8,429 389 9,058

0.8 7.5

12.4 0.4 33 0.5 3.3 31.6 0.6 Less than 0.2

-

-

5.2 1 19

10,788

3.1

19

402

-

62.4 36 23 254 116 209 39.2

Less than 50 293 7,549

30-60 250-1,030

4074,300 45M.450

-

-

17-Hydroxy-

DehydroAndroepiandrosterone stenedione (ngJml.) (ngJm1.)

0.6 0.1

37

-

5,625

1.1

-

1.1 6 7.5

-

4.9 1.8-5.9 3.b5.7

virilization, 2 had Cushing's syndrome and 2 had virilization with Cushing's syndrome. Dehydroepiandrosterone was determined in 13 patients and was elevated in 3 who had isolated signs of virilization. Androstenedione evaluation in 17 patients revealed increased levels in 10, of whom 7 had virilization, 1had Cushing's syndrome and 2 had virilization with Cushing's syndrome. In 14 patients 11-deoxycortisol measurement demonstrated increased levels in 6, of whom 2 had Cushing's syndrome, 2 had virilization and 1 had virilization with Cushing's syndrome. In 9 patients 17hydroxyprogesterone determination showed elevated levels in 3, of whom 2 had virilization and 1 had Cushing's syndrome. Basal cortisol, which was determined in 19 patients, was greater than normal in 4, of whom 3 had Cushing's

0.6-1.9 1.1-2

progesterone (ngJm1.b

3.1 4.3 24 6.7

-

3.8 3

-

4.7 a.1 4.6

-

0.95

-

2.67 0.25 4.72 1.3 0.18

-

0.64 3.2

-

-

15 6.2

-

4.6 3.3 -

13 1&5 1.6-5

0.23-1.1 0.75- 1.54

Cortisol (pgJdl.) Basal

ZiFG-

8 27 24 16 45 20 22 18 20

6 23 19 25 55

33 36

24 36

51

49

18 23 29 7 21 14 21

32

5-27 5-27

Less than 2 Less than 2

-

-

17 20

-

-

-

8 12 12 4

syndrome and 1 had Cushing's syndrome with virilization. Cortisol levels analyzed after low dose dexamethasone administration in 15 adults and 13 children were higher than in normal controls (less than 2 pg./dl.) except in 1 child with virilization (patient lo), although 8 children and 5 adults with an abnormal response had only signs of virilization (tables 3 and 4). Anatomo-pathological findings. In the children tumor weight and diameter ranged from 4 to 250 gm.(mean 65.4) and 1.5 to 21 cm. (mean 61, respectively. Five neoplasms were Weiss criteria grade I11 or less and the others were grade TV or more, including 1 grade VIII (table 5). Of the 18 children 16 (88%)had localized disease (stage I) and 2 (11%) had distant disease (stage 111).

2007

ADRENOCORTICAL NEOPLASMS IN CHILDHOOD AND ADULTHOOD

TABLE5 . Pathological findings according to Weiss criteria, pathological stage and followup of children with adrenocortical neoplasms pt. Nuclear Mitotic

No. Grade I1 1

Rate I

Atypical Mitoses Absent

Z Cytoplasm Necrosis Character Less than 25 Absent

Venous Sinusoidal Invasion Invasion Absent Present

Capsule Weis Size W t Invasion Criteria (an.) (gm.) 'tage7 AbsentC 1.5 4 I 111

FoUlowup

cvrs.)

No evidence of

4

disease 2

I1

I

1

I1

I

Absent

Less than 25

Present

Resent

Present

Absent

VI

3.5

40

I

Noevidence of

Absent

Less than 25

Absent

Present

Absent

Absent

In

1.5

4

I

Noevidenceof

4

disease 4

disease I1

I

Present

4

I1

I1

Present

Less than 25

Absent

Absent

Absent

Absent

V

4.5

20

I

Noevidenceof

5

I1

Absent

Absent

Less than 25

Absent

Present

Absent

Present

V

3

10

I

Noevidenceof

3

Less than 25

Absent

Absent

Absent

Absent

N

5

4

0

I

Noevidenceof

5

disease 4

disease 5.5

disease Present

Less than 25

Present

Resent

Present

Absent

Absent

Less than 25

Absent

Absent

Absent

Absent

I1

Absent

Present

75

Absent

Absent

Absent

Present

I11

Absent

Absent

50

Present

Present

Absent

Absent

Absent

Less than 25

Present

Present

Absent

I

Absent

Less than 25

Absent

Present

N

I

Present

Less than 25

Absent

I1

I

Present

Less than 25

Absent

111

-

Present

Lessthan25

Present

Absent

6

I1

7

I1

8

I1

9

I

10

N

I

11

N

12 13 14

I

190

I

5.5

55

I

4

20

I

V

7.5

36

I

Absent

V

7.5

35

I

Present

Resent

VI

3

20

I

Present

Present

Present

vn

-

30

I

Absent

Absent

Present

N

9

140

I

Present

Resent

Present

VIn

19

I

VII

21

Noevidenceof disease Noevidenceof

3.5 6.5

base

Noevidenceof disease Noevidenceof

4 7

disease

Noevidenceof diseaee Noevidenceof disease Noevidenceof

6

9.5 9.5

disease 3.5

15

I1

1

Absent

Less than 25

Absent

Absent

Absent

Absent

I1

5

9

I

16

N

111

Present

Less than 25

Absent

Absent

Present

Absent

VI

2

20

I

Present Present

Present Resent

Present Present

Absent Absent

V

20

250 70

III

2

Noevidenceof disease Noevidenceof diEease Noevidenceof disea8e Noevidenceof

6.5 7 3.5

4

diseaee Absent I Less than25 I Absent Less than25 Architecture of all neoplasms was diffuse.

17

I1

V

6.5

111

Dead Dead

0.5 1

The 6 patients with Cushing's syndrome associated with In the adults tumor weight and diameter ranged from 7.5 to 1,500gm.(mean 285)and 3 to 21 cm. (mean 9.531,respec- excessive androgen secretion (2adults and 4 children) pretively. Five neoplasms were grade IV or more, including 1 sented with metastases, which resulted in death in 5. The grade M (table 6).A tumor in patient 33 could not be histo- patients who presented with metastases in whom ll-deoxylogically analyzed because the material was insufficient for cortisol was measured had increased levels (2adults and 2 study. Of the 20 adult patients 19 (95%)had localized disease children). Thus, the lowest survival rate occurred in those (stage I) and 1 (5%) had regional disease extending to pen- with mixed clinical features (Cushing's syndrome and viriladrenal fat (stage 11).We noted a high incidence of neoplasms ization). The highest survival rate occurred in patients who of Weiss criteria grade IV or greater (75%) that were not asso- presented with isolated Cushing's syndrome. Nephrectomy ciated with malignant behavior in the perhatric group (table 7). did not prevent tumor recurrence since 3 of the 7 patients Followup. Of the 18 children 16 had no evidence of disease who underwent nephreetomy had local recurrence. Tumor 24 to 114 months &r surgery. Patient 17 had lung metas- weight and size, Weiss histological features and total Weiss tases at surgery and liver metastases 4 months postopera- score did not have any statistically significant relation to tively. Patient 18 had liver and lymph node metastases 12 prognosis in either group (p >0.05).Chronological age seems months aRer surgery followed by 4 monthly cycles of cispla- to be related to survival since only 2 of the 18 children died tin and etoposide for 1 year. In patient 17 tumor weight was compared to 4 of the 20 adults. 250 gm. and in patient 18 it was 70 gm. Patient 18 had undergone adrenal tumor resection elsewhere 1 year previDISCUSSION ously. Patient 17 died 2 months and patient 18 died 2 years We studied 38 patients with functional adrenocortical neoafter recurrence. Of the 20 adults 16 had no evidence of disease 18 to 132 plasms from a single center and reviewed the clinical, labomonths after surgery (table 6). Patient 28 died of ovarian ratory and histological findings. There was a striking precarcinoma 3 years after adrenal surgery without any evi- dominance of female patients in our series.2-8.9 As in the dence of recurrence of adrenal disease. Patients 21,30,31,34 United States national incidence data, the majority of our and 37 presented with metastatic disease 0.8 to 5 years after patients were white.'" Considering that there is a high incisurgery, and patients 21,30and 31 presented with lung and dence of miscegenation between black and white individuals liver metastases between 10 and 20 months after surgery. in Brazil we suppose that black people have a lower incidence Patients 21 and 30 died 2 and 4 years &r recmence, of adrenal neoplasms. It is noteworthy that the only patient respectively. Patient 31 is without evidence of disease aRer 1 who responded to mitotane treatment resulting in the cure of year of treatment with mitotane for lung metastases. She has pulmonary metastases was a black woman (patient 31). In been without medication and well for the last 5 years. Patient the pediatric group the early onset of symptoms (5 patients 34 had liver and bone metastases, and patient 37 had meta- younger than 2 years) could suggest a possible genetic role. static disease to the lung, bone and liver. They died 2 and 5 Our study confirmed previous reports that in most pediatric years after recurrence, respectively. Tumor weight ranged patients there is a predominance of virilization (72%) over from 60 to 1,500gm.in the patients who died. In the surviv- Cushing's syndrome in comparison to adults of whom 60% presented with Cushing's syndrome and 35% with virilizaing patients tumor weight ranged from 10 to 1,300gm.

32 33 34 35 36 37

19 20 21 22 23 24 25 26 27 28 29 30 31

Pt. No.

Absent

Absent

I1 -

I I1 I1

Iv

I I Absent I I

Absent

N

I

I

-

Absent Absent I11 Absent Absent Absent Absent Absent Absent Absent Absent Absent I

Absent I I Absent I 1 Absent

I1

Rate

Grade

Absent Absent Absent Present Absent

-

Absent

Absent Absent Absent Absent Present Absent Absent Absent Absent Absent Absent Absent Absent

Mitoses

Less than 25 Less than 25 Less than 25 Less than 25 Less than 25

-

Greater than 50

Greater than 50 Less than 25

50

75 Less than 25 Greater than 75 Less than 25 Greater than 75 Greater than 75 50 Less than 25 25

Less than 25

: : : ?&%

Diffiae Nodular Diffuse Diffiae Diffuse Diffuse Diffuse

Diffuse Diffuse Diffuse Nodular Diffuse Nodular Diffise Diffuse Diffise Diffuse Dfise Diffuse Diffise

&.c,jte&ure

Present Absent Present Present Present

-

Absent

Absent Absent Absent Present Present Absent Absent Absent Present Present Absent Present Present

Necrosis

Present Absent Absent Present Present

-

Absent

Absent Absent Absent Absent Present Absent Absent Absent Absent Absent Absent Present Absent

Invasion Venous

Absent Absent Absent Present Absent

-

Absent

Absent Absent Absent Absent Present Absent Absent Absent Absent Absent Absent Present Absent

Sinusoidal Invasion

Absent Absent Absent Present Present

-

Absent

Capsule Invasion Absent Absent Absent Absent Absent Absent Absent Absent Resent Absent Absent Present Absent

V

M

111

I1

N

I

-

I1

vi

I11 I

111

I

I

0

VI

I

111

I

Weiss Criteria I

4 5.4 10.5 9 9 21 15

5.5 10 3.5 15 18

10 12 150 16 190 1500 1350

52 7.5 60 11 445 45 15 14 50 300 16 810 640

4.5 4 7 4.5 11 5 8 3

Wt. (@I.)

Size

(cm.)

I

I I I I I I

I I1 I I I I

I I

I

I I

I

I

stagel

Status No evidence of diseaee No evidence of disease Dead No evidence of disease No evidence of disease No evidence of disease No evidence of disease No evidence of disease No evidence of disease No evidence of disease No evidence of disease Dead No evidence of disease after mitotane No evidence of disease No evidence of disease Dead No evidence of disease No evidence of disease Dead No evidence of disease

TABLE6. Pathological findings according to Weiss criteria, pathological stage and followup of adults with adrenocortical neoplasms

1.5 1.5 2 4 2 5 6.5

4.5 2 5 10 5 3.6 11 7.5 3 4 2 5

4

cvrs.)

Followup

ADRENOCORTICAL NEOPLASMS IN CHILDHOOD AND ADULTHOOD

pediatric patients, as previously described.2.8It is important to mention that histological analysis in the children suggested malignant evolution in 14 (77.7%)but only 2 had signs of recurrence followed by death. In adults Weiss criteria were more precise than in children in determining prognosis. In all adults with poor followup tumors were grade IV or greater except in patient 21, who died of tumor recurrence although the tumor was grade 111. Staging of adrenocortical neoplasms was more reliable in children than adults since all stage I tumors in children had a favorable followup and 26% of stage I tumors in adults had distant metastases. None of the examined histological and staging parameters was useful in distinguishing adrenocortical adenoma from carcinoma. Careful clinical followup may remain the final indicator for the diagnosis of some of these tumors. Therefore, tumor size in both groups and histological features according to Weiss criteria in the pediatric group were not reliable indications of benign or malignant behavior. Regarding hormonal secretion, we observed that mixed features (Cushing and virilization syndromes) were associated with a poorer prognosis. Furthermore, there was a better prognosis for these adrenocortical neoplasms in children than in adults, as reported by others.7~8-18However, the prognosis for our patients in both groups was better than that described in the literature, probably due to earlier diagnosis and the fact that our patients had smaller tumors (stage I in the majority).2.s.s.9-12.*3.17,18 Deoxyribonucleic acid content evaluation may be helpful to classify some of these neoplasms but experience with children is limited.20.21 Cytogenetic analysis of adrenocortical neoplasms has rarely been reported.22 Chromosomal abnormalities have been identified but their significance for or contribution to a better understanding of the prognosis in adrenocortical tumors remains unkn0wn.~3Earlier diagnosis aided by new imaging techniques plus precocious and effective surgical treatment in patients with adrenocortical neoplasms appear to offer the best hope for improving prognosis. Ms. Sonia Strong provided translation assistance. REFERENCES

1. Brennan, M. F. and Macdonald, J. S.: Cancer of the endocrine system. In: Cancer: Principles and Practice of Oncology, 2nd ed. Edited by V.T. DeVita, Jr., S. Hellman and S.A. Rosenbere. Philadelnhia: J. B. Linnincott Co.. vol. 2.chant. 35. pp. 1179-11242,1985. 2. Ribeiro, R. C., Sandrini Neto, R. S.. Schell, M. J., Lacerda, L., Sambaio, G. A. and Cat, I.: Adrenocortical carcinoma in children: a study of 40 cases. J. Clin. Oncol., 8: 67,1990. 3. Cagle, P. T., Hough, A. J.. Pysher, J., Page, D. L., Johnson, E. H., Kirkland, R. T., Holcombe, J. H. and Hawkins, E. P.: Comparison of adrenal cortical tumors in children and adults. Cancer. 57 2235,1986. 4. Greulich, W. W. and file, S. I.: Radiomaphic Atlas of Skeletal Development of the Hand and Wrist, 2nd ed. Stanford, California: Stanford University Press, 1959. 5. Abraham, F.:Radioimmunoassay of steroid in biological materials. Acta Endoer.. SUDD~.183.75: I. 1974. 6. Weiss, L. M.:Compara&e hisklogic’study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Amer. J. Surg.

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Path., 8 163, 1984. 7. Nader, S.,Hickey, R. C.. Sellin, R. V. and Samaan, N. A.: Adred cortical carcinoma. A study of 77 cases. Cancer, 6 2 707, 1983. 8. Lack, E. E., Mulvibill, J. J., Travis, W. D. and Kozakewich, H.P.: Adrenal cortical neoplasms in the pediatric and adolescent age group. Clinicopathological study of 30 cams with emphasis on epidemiologicaland prognostic factors. Path. Ann., 27: 1.1992. 9. H 4 a r , R. A., Hickey, R. C. and Samaan, N.A: Adrenal cortical carcinoma. A study of 32 patients. Cancer, 96:549, 1975. 10. Young, J. L.,Jr., Percy, C. L., hire, A J., Berg,J. W.,Cusano, M. M., Gloecker, L. A., Horm, J. W., Lourie, W. I., Jr.. Pollack, E. S. and Shambaugh, E. M.: Cancer incidence and mortality in the Unitad States, 1973-77. Natl. Cancer lost. Monogr., 51: 1, 1981. 11. Hayles, A. B.,Hahn, H. B., Jr. and Sprague, R. G.: Hormonesecreting tumors of the adrenal cortex in children. Pediatrics, 37: 19,1966. 12. Bertagna, C. and Orth, D. N.: Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951to 1978).Amer. J. Med., 71: 855,1981. 13. Doerr, H. G.,Sippell, W. G., h o p , S. L., Bidlingmaier, F.and Knorr, D.: Evidence of 11-beta-hydruxyhe deficiency in childhood adrenocortical tumors. The plasma cortimaterondlldeoxycortimterone ratio as a possible marker for malignancy. Cancer, 60:1625, 1987. 14. Humphrey, G. B.. Physer, T. and Holcombe, J.: Overview on the management of adrenocortical carcinoma (ACC). Cancer Treat. Res., 17: 349,1983. 15. Hough, A.J.,Hollifield,J. W., Page,D. L. and Hartmann, W. H.: Prognostic factors in adrenal cortical tumors. A mathematical analysis of clinical and morphologic data. Amer. J. Clin. Path., 72 390,1979. 16. van Slooten,H., Schaberg, A., Smeenk, D. and Moolenaar, A. J.: Morphologic charactaristica of benign and malignant adrenocortical tumors. Cancer, 55: 766,1985. 17. Karakousis, C. P., Rao, U. and Moore, R.: Adrenal adenoearcinomas: histologic grading and survival. J. Surg. Oncol., 29: 105, 1985. 18. Weiss, L. M., Medeiros, L. J. and Vickery, k L., Jr.: Pathologic features of prognostic significance in adrenocortical carcinoma. Amer. J. Surg. Path., 1 3 202,1989. 19. Bugg, M. F., Ribeiro, R. C., Roberson, P. K, Lloyd, R. V., Sandrini, R., Silva, J. B., Epelman, S., Shapiro, D. N. and Parham, D. M.: Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. A study of a Brazilian population. Brazilian Group for Treatment of Childhood Adrenocortical Tumors. Amer. J. Clin. Path., 101: 625. 1994. 20. Zerbini, C., Kozakewich, H. P., Weinberg, D. S., Mundt, D. J., Edwards, J. A., 111 and Lack, E. E.: Adrenocortical neoplasms in childhood and adolescence: analysis of prognostic factors including DNA content. Endoer. Path., 3 116, 1992. 21. Taylor, S. R.,Roederer, M.and Murphy, R. F.: Flow cytometric DNA analysis of adrenocortical tumors in children. Cancer, 89: 2059, 1987. 22. Limon, J., Dal Cin, P., Kakati, S., Hubin, R. P. and Sandberg, k A: Cytogenetic findings in a primary adrenooortical carcinoma. Cancer Genet. Cytogenet., 28: 271, 1987. 23. Limon,J., Dal Cin, P., Gaeta, J. and Sandberg, A. A: Tramlocation t(4;ll)(q35;p13)in an adrenocortical-carcinoma. Cancer Genet. Cytogenet., 28: 343,1987.