Adrenocortical carcinoma (ACC) is a relatively rare malignancy with an estimated incidence of 0.7-2.0 per 1 million population per year showing two distinct age peaks in early childhood and in the 4th-5th decade of life. Most cases of ACCs are sporadic but can also occur in association with several hereditary syndromes, including Li-Fraumeni, Beckwith-Wiedemann, multiple endocrine neoplasia (MEN) 1, congenital adrenal hyperplasia, familial polyposis coli, and germline β-catenin or p53 mutations. Patients with ACC present with either symptoms due to hormone hypersecretion or manifestations of tumor mass effect, although an increasing percentage is discovered as incidentalomas during abdominal imaging.

1. RESULTS
CONCLUSION
REFERENCES
SUBJECTS AND METHODS
Prognostic parameters in Adrenocortical Carcinoma.
George Zografos1, Eleftherios Chatzellis2, George Boutzios2, Efi Kyrodimou3, Dimitris Thomas2, Gregory Kaltsas2
1Third Department of Surgery, “G. Gennimatas” Athens General Hospital. 2Department of Pathophysiology,
Medical School, National University of Athens. 3Pathology Department, “G. Gennimatas” Athens General Hospital.
BACKGROUND
Table 3: Patient characteristics (n=17)
Sex Female
Male
7 (41%)
10 (59%)
Age at
diagnosis
Median
Range
50.5 yrs
27-74 years
Location Right adrenal
Left adrenal
Bilateral
8 (47%)
7 (41%)
2 (12%)
Tumor Size Median
Range
9.9 cm
6-18 cm
ENSAT
STAGE at
diagnosis
I
II
III
IV
0 (0%)
11 (65%)
3 (17.5%)
3 (17.5%)
Secretion Cortisol only
Androgens only
Aldosterone
Cortisol and androgens
Non-secreting
Unknown
4 (23.5%)
1 (6%)
1 (6%)
3 (17.5%)
6 (35%)
2 (12%)
Sporadic 16 (94%)
Syndromic MEN1 1 (6%)
Symptoms Endocrine-related
Local tumor growth
Non-specific
Incidental finding
7 (41%)
2 (12%)
5 (29.5%)
3 (17.5%)
1st line
Treatment
Adjuvant mitotane
Not adjuvant mitotane
EDP + mitotane
11
4 (before 2008)
2
(1) Kaltsas G, Zografos G, Chroussos G, Kassi E. 2009. Current Issues in the Diagnosis and Management of Adrenocortical Carcinomas. http://www.endotext.org
(2) van't Sant HP, Bouvy ND, Kazemier G, Bonjer HJ, Hop WC, Feelders RA, de Herder WW, de Krijger RR. 2007. The prognostic value of two different histopathological scoring systems for adrenocortical carcinomas. Histopathology;51(2):239-45
(3) Aubert S et al 2002. Weiss System Revisited: A Clinicopathologic and Immunohistochemical Study of 49 Adrenocortical Tumors. Am J Surg Pathol; 26:1612-9
(4) Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willenberg HS, Beuschlein F, Terzolo M, Mueller HH, Hahner S, Allolio B 2009. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal
for a revised TNM classification. Cancer 115: 243–250
(5) Terzolo et al 2007. Adjuvant mitotane in Adrenocortical Carcinoma. NEJM 2007; 356;23
(6) A. Berruti, E. Baudin, H. Gelderblom, H. R. Haak, F. Porpiglia, M. Fassnacht & G. Pentheroudakis on behalf of the ESMO Guidelines Working Group 2012. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
This small series showed that higher mitotic rate (>5 per 50 HPF), ki67 >7% and secreting tumors are negatively affecting progression-free survival in patients with localized ACC after debulking
surgery and adjuvant mitotane treatment. The Weiss score and Van Slooten criteria system, used primarily for diagnosis of ACC, may also serve as useful prognostic factors affecting progression-free
survival of these patients. Overall survival also seems to be negatively affected by the presence of higher proliferative markers (mitoses and ki67) suggesting further their validity.
12th ENS@T Scientific Meeting - 22-23 Nov 2013
Table 1: Histopathological scoring systems for separating benign from malignant adrenocortical tumors
Weiss score system Modified Weiss score system by Aubert et al
Criteria Criteria Value
1. High nuclear grade (grade 3 or 4 according to criteria of Fuhrman)
2. Mitotic rate greater than 5 per 50 HPF
3. Atypical mitoses
4. Clear cells comprising 25% or less of the tumor
5. Diffuse architecture (greater than one third of the tumor)
6. Necrosis
7. Invasion of venous structures
8. Invasion of sinusoidal structures
9. Invasion of capsule of tumor
1. Mitotic rate (>5 per 50 HPF)*
2. Cytoplasm (clear cells comprising 25% or less of the tumor)*
3. Abnormal mitoses
4. Necrosis
5. Capsular invasion
2
2
1
1
1
Van Slooten System
Criteria Value
1. Regressive changes (necrosis, hemorrhage, fibrosis, or calcification)
2. Loss of normal structure
3. Nuclear atypia (moderate/marked)
4. Nuclear hyperchromasia (moderate/marked)
5. Abnormal nucleoli
6. Mitotic activity (>2 mitotic figures per 10 HPF)
7. Capsular and/or vascular invasion
5.7
1.6
2.1
2.6
4.1
9.0
3.3
A score of 3 or greater correlates with subsequent malignant behavior.
The presence of 3 or more
criteria correlates with
malignant behavior
Summating the discriminating values of each parameter present
generates a histologic index. An index greater than 8 is associated with
malignancy
Seventeen patients (10 males) diagnosed with ACC since 2002 [mean age of diagnosis 50,5 years (range 27-74)] were retrospectively reviewed
regarding tumor characteristics, histological features (Weiss and Van Slooten criteria), secretory status and clinical course, to identify factors that affect
progression-free and overall survival (Table 3).
Most of the patients (14/17) had stage II or III disease at diagnosis. Six patients (35%) had non-secreting tumors and 9 (53%) had secreting tumors.
Cortisol was the most frequently secreted hormone alone (23,5%) or in combination with androgens (17,5%). All patients studied had sporadic tumors
17 after
adrenalectomy
11
mitotane
(10 adjuvant)
4
no adjuvant
mitotane
3
progressive disease
and died (OS<5 years)
4
Relapsed (distant metastases)
PFS < 12 months
7
No relapse
4 Free of disease
Stopped mitotane (3years)
(follow up 42, 53, 59, 60 months)
3 w/o progression
Still under mitotane
(8, 16, 53 months)
1 EDP  Died (w/o progression)
ΟS = 19 months
2 EDP  Progression
(alive 28 and 23 mo after surgery)
1 TIP  Progression
(alive 30 mo after surgery)
2
EDP + mitotane
1 Sunitinib
10 months after surgery
2
Progressive Disease
1 Free of disease
60 months after surgery (MEN1
patient)
1 Died
ΟS = 13 months
4: stage II
1: stage II
1: stage III
1: stage IV
1: stage III
3: stage II
2: stage IV
1: stage II
8: stage II
2: stage III
1: stage IV
3: stage II
1: stage III
Figure 1: Flow chart representing treatment and clinical course of patients with ACC
in the present series. Distribution of patients according to ENSAT stage is also shown.
EDP: etoposide-doxorubicin-cisplatin, TIP: paclitaxel-ifosfamide-cisplatin
except one patient with bilateral tumors in the context
of MEN1 syndrome. One other patient developed ACC
during the course of ectopic ACTH secretion later
attributed to an atypical lung carcinoid.
Patients were treated according to best practice
guidelines before ESMO guidelines (6). Adjuvant
mitotane treatment was not administered in 3 patients
(5), while 11 with localized disease, were treated with
mitotane, after resection of the primary tumor. Patients
with stage IV disease were treated with the combination
of mitotane and EDP (etoposide - doxorubicin - cisplatin)
except one patient who received mitotane treatment
alone, due to advanced age and poor health status.
Figure 1 depicts patients’ clinical course according to
stage and received treatment.
Data were analyzed with SPSS statistical software
in order to identify factors with prognostic value.
Survival analysis showed ki67>7% to be associated with shorter overall survival (p=0,028) regardless of stage, treatment and
other factors such as secretory status, size, age and sex (Fig.2). Number of mitoses >5 per 50 HPF also showed a similar tendency,
although this difference was not statistically significant (Fig. 3).
In order to better evaluate the effect of secretion status, ki67 and number of mitoses on prognosis by eliminating the effect
of disease stage and type of treatment, the same analysis was conducted in a subgroup of patients with localized disease on
diagnosis (Stage II and III) who received adjuvant mitotane therapy after complete tumor resection (n=10). In this subgroup
secreting tumors, ki67>7% and mitoses >5 per 50 HPF were significantly associated with worse progression-free survival (Fig.
4a,b,c). All relapses in these patients (4/10) occurred in less than 12 months. In addition, ki67, Weiss and Van Slooten scores were
higher in the group of patients who showed disease relapse (Fig. 5a,b,c). Secretion status and mitoses >5 per 50 HPF were also
significantly associated with higher relapse rates with a p value of 0,009 for both factors (Fig. 6a,b).
Figure 3
Figure 2: Overall survival of all patients based on ki67: >7% (green line), <7% (blue line)
Figure 3: Overall survival of all patients based on number of mitoses per 50 HPF: >5 (green line), <5 (blue line)
Figure 2
p=0,028
ki67
Figure 4: Progression-free survival of patients with localised disease after adjuvant mitotane therapy, based on:
a. number of mitoses per 50 HPF: >5 (green line), <5 (blue line)
b. secretory status: secreting tumors (green line), non-secreting tumors (blue line)
c. ki67: >7% (green line), <7% (blue line)
Mitoses
p=0,11
Figure 4a Figure 4cFigure 4b
ki67SecretionMitoses
p=0,013 p=0,013 p=0,013 Figure 5 (up): Comparison of mean values of ki67 (a),
van Slooten score (b) and Weiss score (c), between
patients with localized disease who had recurrent
disease and patients who did not relapse, after adjuvant
mitotane treatment.
Figure 6 (left): In the subgroup of patients with Stage II-
III disease after adjuvant mitotane treatment, higher
relapse rates were noticed in secreting tumors (6a) and
in tumors with >5 mitoses per 50 HPF (6b).
Figure 5a
ki67
Figure 5b
Van Slooten
Figure 5c
Weiss
p=0,009
SecretionFigure 6a
p=0,009
MitosesFigure 6b
Adrenocortical carcinoma (ACC) is a relatively rare malignancy with an estimated incidence of
0.7-2.0 per 1 million population per year showing two distinct age peaks in early childhood and
in the 4th-5th decade of life. Most cases of ACCs are sporadic but can also occur in association
with several hereditary syndromes, including Li-Fraumeni, Beckwith-Wiedemann, multiple
endocrine neoplasia (MEN) 1, congenital adrenal hyperplasia, familial polyposis coli, and
germline β-catenin or p53 mutations. Patients with ACC present with either symptoms due to
hormone hypersecretion or manifestations of tumor mass effect, although an increasing
percentage is discovered as incidentalomas during abdominal imaging (1).
The pathological diagnosis of ACC, is based on gross and microscopic criteria. Different
diagnostic scores have been introduced for diagnosis of malignancy with the Van Slooten and Weiss
scoring systems being the most accurate (2), however the latter, and its modified version (3), is less
complex and most widely used (Table 1).
ACCs are characterized by a relative dismal outcome, as only 16-38% of patients exhibit a more
than 5-year survival after diagnosis, and approximately 75-85% will have a relapse after radical
resection (1). Among the various parameters that have been shown to provide a powerful
prognostic tool for predicting both disease-free and disease-specific survival, TNM tumor staging has
been demonstrated as one of the most important. In 2008, the ENSAT proposed a revision of TNM
staging classification in an attempt to improve the prognostic accuracy for disease-specific survival in
patients with ACC (4) as shown in Table 2.
AIM: The purpose of this study was to evaluate the prognostic value of tumor and patient
characteristics in predicting progression-free and overall survival in a small series of patients with
ACC, followed up by our department.
Table 2: Staging systems for ACC proposed by the UICC in 2004 and the ENSAT in 2008 (4)
UICC/WHO 2004 ENSAT 2008 T1: tumor <5 cm
STAGE TNM 5-yr disease free survival TNM 5-yr disease free survival T2: tumor > 5 cm
I T1N0M0 82% T1N0M0 82% T3: infiltration in surrounding tissues
II T2N0M0 58% T2N0M0 61% T4: invasion in adjacent organs (in ENSAT, also venous tumor
thrombus in vena cava/renal vein)
III T1-2N1M0
T3N0M0
55% T1-2N1M0
T3-4N0-1M0
50% N0: no positive lymph nodes
N1: positive lymph node(s)
IV T1-4N0-1M1
T3N1M0
T4N0-1M0
18% T1-4N0-1M1 13%
M0: no distant metastases
M1: presence of distant metastases
Relapse
Deaths