Gr.T.

Popa University of Medicine and Pharmacy of Iasi Endocrinology

Consideration on adrenocortical carcinoma

-case series-

* Sahdev et al.2011

Background

Incidence 1,7-2 cases per million

Clical diagnostic difficult, delayed

o adrenocortical carcinoma(ACC) agresive developemet clinical manifestation: atypical/ absent
? Differential diagnostic : Subclinical Cushing syndrome (adenoma)/ pseudo Cushing syndrome

Histological scores and imunostainings (ki-67, p53)differential diagnostic /follow-up/prognostic

Genetic determination (TP53, IGF2, WNT-catenin, SF1 ) biological markers/ differenial diagnostic/
treatment response/ prognostic/ biological therapy

5 years survival rate in advanced stages16-44%

Therapeutical management:
oSurgery intervention curative / palliative
recurrence reintervention
oMitotane adjuvant /+EDP down-staging
Fig. 1-Survival rate correlated with stage at
oDrugs for the treatment of hormonal excess
diagnostic *Fassnacht et al, 2009
o Radiotherapy/ Local therapy adjuvant/ palliative / metastasis
oMetronomic therapy
oBiological therapy

Aim/objectives

Case series of ACC diagnosed patients,

in the Department of Endocrinology, Iasi between 2004-2013.

Objectives
Clinical and paraclinical features on dignostic

Survival parameters in study group

Evolutive and therapeutical particularities

Management issues correlated with time of
diagnostic
Disease stage, analysing diagnostic and treatment
protocols

Materials and methods

Clinical data of all patients with ACC diagnosed and treated in the
Department of Endocrinology of Iasi, Romania between 2004 and
2013 were retrospectively reviewed.
Risk factors
Evaluated parameters:
Clinical presentation

Hormonal profile
Particularities in manifestation
Morphopathological features
Staging
Survival time
Therapeutical aproach
Recurrences and metastasis

Results/Discussions
Fig.7.Age distribution

years
years

40,6 years

51 years

years

Fig.8.Gender distribution

male
female

Female predominance(58,2%)

Results/Discussions
Fig.9.Tumour dimension in study group vs literature data
Tumour size

<=5 cm
6-10 cm
10-20 cm
>20 cm

4/8
4/8

Variation of
tumour dimension
unrelated with
patients evolution

29%
55%

Malignant
tumours are
usually >6 cm

Fig.10.Anatomopathological features
Metastasis
Invasion of veins
Invasion of capsule
Invazia of nearby organs

1/9
2/8
3/8
3/8
8/8

Necroses

Imunostaining (2 cases) possitive for many

ACC associated markers
KI-67 index : 20 %, 38%
KI-67 index> 5%= malignancy

Results/Discussions
incidentaloma
Cushing syndrome
virilisation

1/3- asymptomatic, incidentaloma

Inflamatory syndrome
Cushing syndrome+
virilisation
Hypertension+virilisation

Increased polimorphism
13 -

16,7%

20% of incidentalomas, without clinical

expression or poor manifestation hormonal

Mass
efect

secretion malignant (feocromocitoma, ACC,

Fig.11.Clinical presentation in current group

vs literature data

metastasis)
Systematic, complete evaluation of functional

Cushing syndrome

incidentalomas

virilisation
feminising
Mass efect
Palpable mass
Inflamatory syndrome

40 % of ACC do not have signs of hormonal

hypersecretion at diagnositic, although it has
been demonstrated that 95% of this malignant
tumours are functional.

incidentaloma

Increase in number of imaging evaluations

incidentalomas

Results/Discussions
Non functional
Cortisol
Androgens

Non functional
Estrogens

Altered glucocorticoid
secretion

Androgens

Cortisol+androgens
Estrogens

Aldosteron

Multiple secretion

Altered
glucocorticoid
secretion

Hormonal profile
Fig.12.Hormonal profile in study group

Fig.13.Hormonal profile in each patient

Altered glucocorticoid secretion: lack or insufficient supression at DXM 1mg (23.00) /
inverted cortisol cycle ( 3of 5 cases)
Incidentaloma: 74% adenomas aprox 10% show altered cortisol secretion
5-10% malignancies also have this pattern
Complete adrenal hormonal profile even in asymptomatic patients

Results/Discussions
Treatment:
Suprarenalectomy:

the only curative approach

laparotomy/ laparoscopy incomplete resection or tumour contamination
nefrectomy erenal excision do not increase survival rate; contrary, it may reduce chimiotherapics clearance nd
increase their toxicity

R0-favorable prognostic factor

Curative/ palliativeintervention in stage IV, although unresectable tumour .evolution
Multiple recurrencesreintervention

Chemotherapy:
Doxorubicin, Cisplatin, Etoposid, Carboplatin, Farmorubicin
in association , adjuvant or for local or distant recurrences
1 patient exhibit a good response on chemotherapy , probably due to early diagnostic, stage II;
4 cases: temporary stabilization
FIRM-ACT trial:M-EDP :temporary stabilization in one IV stage case

Mitotane
Drugs for hormonal hypersecretion -1 caz-necomplianhypersecretioncomplicationsdeath
Radioterapy/local therapy- 2 cases-temporary control of liver metastasis

Results/Discussions
Fig.14.Secondary effects of Mitotane administration
*adrenal

Gastrointestinal

insuficiency possible secondary to

controlateral adrenal atrophy

Adrenocortical insufficiency
Elevated liver enzymes
Dyslipidemia
Enzyme induction
Leucopenia

^possible association between mitotane

efect and presence of multiple liver
metastasis

Trombocitopenia
Anemia

possible association with adverse efect of

Zolendronat concomitantly administration

Frequent secondary efects reported by literature

adrenal insuficiency, elevated liver enzymes,
dyslipidemia
Medular suppression less frequent in other studies
( <10%).
Adrenal insufficiency was controled with
progressive high doses of HHC (40-50-60 mg/day)
and fludrocortisone (0,1mg/day)
enzyme
induction efect of mitotane

for bone metastasis

2 of 3 patients with long time

Mitotane treatment have a
stationary evolution

Results/Discussions
Fig.15.Postsurgical evolution: recurrences

Number of
recurrences
Local

case 1

case2

case3

case4

case5

case6

case7

case8

2(I, II)

3 (I, II, III)

3(I, II, III)

1(I)

I, II, III

I, II, III

I, II

Controlateral
Sites of

adrenal
Liver

metastasis/

Bone

recurrences

I
I, II

Lung
Peritoneal
Pleural

I, II

Out

Dis

of

eas

reco

rd

free

Dise

I, II, III

ase

I, II, III

III

free

9
-

Di
se
as
e
fr

II
I

50 % local recurrence
50 % postsurgical metastasis

Fig.16.Metastasis sites

case

Fig.17.Patients disease status in 2013

ee

Results/Discussions
Fig.15.Postsurgical evolution: recurrences

Number of
recurrences
Local

case 1

case2

case3

case4

case5

case6

case7

case8

2(I, II)

3 (I, II, III)

3(I, II, III)

1(I)

I, II, III

I, II, III

I, II

Controlateral
Sites of

adrenal
Liver

metastasis/

Bone

recurrences

I
I, II

Lung
Peritoneal
Pleural

I, II

Out

Dis

of

eas

reco

rd

free

Dise

I, II, III

I, II, III

III

ase
free

9
-

Di
se
as
e
fr

II
I

50 % local recurrence
50 % postsurgical metastasis

Fig.16.Metastasis sites

case

Fig.17.Patients disease status in 2013

ee

Results/Discussions
Fig.15.Postsurgical evolution: recurrences

Number of
recurrences
Local

case 1

case2

case3

case4

case5

case6

case7

case8

2(I, II)

3 (I, II, III)

3(I, II, III)

1(I)

I, II, III

I, II, III

I, II

Controlateral
Sites of

adrenal
Liver

metastasis/

Bone

recurrences

I
I, II

Lung
Peritoneal
Pleural

I, II

Out

Dis

of

eas

reco

rd

free

Dise

I, II, III

ase

I, II, III

III

free

9
-

Di
se
as
e
fr

II
I

50 % local recurrence
50 % postsurgical metastasis

Fig.16.Metastasis sites

case

Fig.17.Patients disease status in 2013

ee

Results/Discussions
Fig.18.Survival parameters
PFS

DFS

(months) (months) (months)

15

>18

>18

>11

>11

11

36

18

40

11

11

15 years

15years

15 years

Particular aspects:
Long term use of oral contraception in two patients history (over
10 years)

Higher risk developing ACC (OR=1,8 Hsing et all)

Paraneoplastic thrombocytosis (without correlation with disease

evolution: 3 cases)
Association between incidentaloma and thrombocytosis
shoud be investigated for ACC

Survival time
PFS-Progression free survival
DFS-Disease free survival

2 years survival rate: 7 of 9 patients

3 years survival rate 4 of 9 patients ( literature data: 2 years mortality rate: 50%),
15 years free disease in a child with a tumour developed on congenital adrenal
hyperplasia

Results/Discussions
Imaging evaluation:
o
o
o

CT and IRM staging, follow-up

PET metastasis and recurrences evaluation
Ultrasonography follow-up

Issues:
o Agressive and rapid evolution in 2 patients presenting recurrences within two months
after surgery
Would imagistic evaluation under 2 months in patients with high relapse risk
(advanced stage, capsular invasion, venous invasion, size >8 cm, Rx,1,2
postresectional status, Ki-67 index>10%) improve the overall survival?
o 1.2cm incidentaloma6 months imagistic reevaluation: 6 cm
o differential dianostic between pulmonary inflammatory lesions and metastasis:
2 patients responded to antibiotics treatment/ 1 patient had lung metastasis

Case presentation
D.P. 55 years
02. 2012
Incidentaloma-US

Asymptomatic
Estradiol+ DHEAs
CT- right adrenal masscentral necroses, invasion
of capsule, posible
infiltration of right kidney,
liver and bone metastasis
Diagnostic laparotomy
Weiss 6, positive
imunohistochemistry
staining
07.T4N1M1
2012 stage

Adrenalectomy+liver
metastasis resection,
lymph node resection
Renal or inferior vena
cava invasion have not
been identified
T4N0M1 stage

03. 2012
Wurzburg

Similar clinical
and paraclinical
features

EDP-M:first

04. 2012

05.2012

06.2012

2nd cure
Anemia
Neutropeni
a

CTstabilization
3rd cure

CT-stabilization
posible inferiour
vena cava and renal
invasion
Four th cure

cure

Hormonal substitution- 30mg60 mg HHC

Zolendronate
Mitotane-4,5mg6 mg/daynausea, hypercholesterolemia, GT
10. 2012

12. 2012

04. 2014

07. 2014

Adrenal insufficiencyHHC substitution 40mg -60 mg/day + fludrocortisone

Mitotane-6g - 2 g/day (therapeutic concentration range reached in 7 months : 14-20
mg/l)

CT-no signs of recurrence

Bone metastatis lesionscondensing features
Gastric ulcer

Conclusions
1) ACC is characterized by clinical, paraclinical and evolutive polymorphism
2) Imagistic evaluation:
1) Systematic evalation of adrenals
2) Adrenal imagistic reevaluation interval for under 5 cm incidentalomas shoud be reconsidered.
3) Frequent imagistic monitorization of pacients with elevated risc of recurrence might be usefull.

3) Complete hormonal evaluation of incidentalomas for asyptomatic patients is necessary

4) Association between incidentaloma and thrombocytosis shoud be investigated for ACC
5) Radical surgery is the only curative approach and is recomended for all patients with resectable
tumour including those with recurrent disease or metastases.
6) The frequent secondary efects of mitotane like adrenal insufficiency, induction of hepatic enzyme
activity, medulary supression, support the monthy cell blood count, mitotane serum level and
hormonal substitution monitoring.
7) Mitotane as adjuvant might facilitated disease regression or stabilization in this study group
.

Thank you!

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