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THE ADRENOCORTICALCARCINOMA
G. FaviaUniversity of Padova
Department of Science Surgery and Gastroenterology
Conference presented at 27-th National Congress of Italian Society of Endocrine Surgery, Cagliary, Italy, October 2008
THE ADRENOCORTICAL CARCINOMAG. Favia
University of PadovaDepartment of Surgical Science and Gastroenterology
Abstract:Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Overall incidence is about 0.5-2 / milion inhabitants. ACC could be secreting (about 60% from all the cases) or non-secreting (diagnosed espacially as an incidentaloma during an ultrasound or CT-scan exam). The paper discuss the difficulties of positive diagnosis for ACC, from point of view of histological exam (Weiss criteria), biological markers (e.g. Ki67, p53), imagery techniques (CT-scan, IRM, scintigraphy). Treatment of the ACC is also challenging; radical surgery is possible in early stages. Large „en bloc” resections it is also recommended in locally advance stages. The place of adjuvant therapy and reoperations for recurrence is also discussed. The experience in ACC surgery of the Department of Surgery from Padova University is also presented. Conclusions: ACC carries a poor prognosis for patients commonly presenting with large, locally invasive tumors, and metastaticdisease. A precocious diagnosis using imagery and histologic criteria, aggressive surgery and novel therapies may help to increase survival, which has remained unchanged over the last 20 years.
KEY WORDS: ADRENOCORTICAL CARCINOMA, DIAGNOSIS, PRONOSTIC FACTORS, ADRENALECTOMY[*]
[*]Conference presented at 27-th National Congress of Italian Society of Endocrine Surgery, Cagliary, Italy, October 2008
ADRENOCORTICAL CARCINOMAADRENOCORTICAL CARCINOMA
Incidence: 0.5-2 / milion inhabitants /year
Preoperative Diagnosis - “Difficult”
Histological Diagnosis - “Difficult”: FOLLOW UP
Surgery is “Radical”(?): RECCURENCES
REINTERVENTIONS
ADRENOCORTICAL CARCINOMAADRENOCORTICAL CARCINOMA
SECRETING(60%)
NON-SECRETING(40%)
30% 30% HHYYPERCORTISOLISMPERCORTISOLISM22% 22% VIRILITYVIRILITY10% 10% FEMININITYFEMININITY3%H3%HYYPERALDOSTERONISMPERALDOSTERONISM
35% 35% MIXTED SECRETIONSMIXTED SECRETIONS
INCIDENTALOMINCIDENTALOMAA
What had been changed ?
THE SURGERY OF ADRENOCORTICALCARCINOMA
IMPROVEMENTIMPROVEMENT of HISTOLOGICAL of HISTOLOGICAL DIAGNOSISDIAGNOSIS
IMPROVEMENTIMPROVEMENT of RADIOLOGICAL of RADIOLOGICAL DIAGNOSISDIAGNOSIS
AGGRESSIVEAGGRESSIVE SURGERYSURGERY
ADADJJUVANT TERAPY(?)UVANT TERAPY(?)
NEW ISSUES
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WEISS CRITERWEISS CRITERIIAA1. HIGH DEGREE OF NUCLEATION2. >5 MITOSIS PER 50 HPF3. ATIPICAL MITOSIS4. CITOPLASMATIC EOSINAFILY (>75% cellule tumorali)
5. FIBROSIS AND TRABECOLARY STRIPS6. NECROSIS7. VENOUS INVASION8. SINUSOIDAL INVASION9. CAPSULAR INFILTRATION
WEISS > 4
ADRENOCORTICAL CARCINOMA
HISTOLOGICAL DIAGNOSISHISTOLOGICAL DIAGNOSIS
Adenoma Carcinoma
0 21 3 4 5 6 7
WEISS < 3
Weiss, 95
HIGH DEGREE OF NUCLEATION>5 MITOSIS PER 50 HPF
ATYPICAL MITOSISCYTOPLASMATIC EOSINOFILIA FIBROSISNECROSIS
VENOUS INVASIONCAPSULAR INFILTRATION
WEISS CRITERWEISS CRITERIIAA
ADRENOCORTICAL CARCINOMA
HISTOLOGICAL DIAGNOSISHISTOLOGICAL DIAGNOSIS
???PROBLEMATIC CASES:
Just the present or the appearance of recurrence or the systemic metastasis could confirm the diagnosis of MALIGNITY
We need other MARKERS !!!
WEISS > 4
Adenoma Carcinoma
0 21 3 4 5 6 7
WEISS < 3
ADRENOCORTICAL CARCINOMA
HISTOLOGICAL DIAGNOSISHISTOLOGICAL DIAGNOSIS
KiKi--67 67 ■■p53p53
Martins 2005Stojadinovic 2003
Higher in Carcinoma (36%) lower in Adenoma (0%)Correlation with Survival
Diagnosis criteria Prognosis factor
ADRENOCORTICAL CARCINOMA
HISTOLOGICAL DIAGNOSISHISTOLOGICAL DIAGNOSIS
InsulinInsulin likelike GrowthGrowth FactorFactor II II (IGF 2)(IGF 2)
Sidhu 2003
Growth factor(cromosome 11 p15)
Diagnosis criteria Prognosis factor
Higher in Carcinoma (90%) lower in Adenoma (0%)Correlation with survival
ADRENOCORTICAL CARCINOMA
HISTOLOGICAL DIAGNOSISHISTOLOGICAL DIAGNOSIS ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSIS
General speaking, it is easy to establish the diagnosisof “adrenal tumor”and in some cases to establish the
diagnosis of adrenal carcinoma (e.g. invasion, metastasis).
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It is difficult to differentiate a carcinoma from a benign tumor (incidentaloma).
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSIS
Malignant Tumor98% > 6 cm
2% < 6 cm Diameter > 6 cm
85% BENIGNANT
15%MALIGNANT
Mantero, 2000
VOLUMETRIC Criteria
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSIS
LIMITS of the CUT-OFF POINT
Mantero, 2000
SURGERY
85%: Benignant tumor
FOLLOW UP
2-4%: Carcinoma
< 6cm > 6cm
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSIS• Size
• Regular form• Clear-cut
• Homogeneous lession
ADENOMA:High lipidic content
without contrastcorrelation with lipidic content
CARCINOMA:Low lipidic content
DENSITY - HU*
* Hounsfield units
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the CT-SCAN
25 HU: SMALL MALIGN TUMOR
2 HU: LARGE BENIGN MASS
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the CT-SCAN
• DENSITY without contrast < 10 HU
Benign vs Malign
SENSIBILITY - 71%SPECIFICITY - 98%
Boland 1998
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the CT-SCAN
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DENSITY (HU) with contrast < 30 HU
75 HU: MALIGN TUMOR
21 HU: BENIGN MASS
Al-Hawary 1998
Benign vs Malign
SENSIBILITY – 69%SPECIFICITY - 97%
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the CT-SCAN
Al-Hawary 2005
• Size• Vascular Invasion
•Hyperintensity in T2
The intensity in T2 is correlatedwith fluid content
ADENOMALow Fluid Content
CARCINOMAHigh Fluid Content
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the IRM
Elsayes 2004
Hyperintensity in T2+
Chemical Shift
Diagnosis accuracyof
98%ADRENOCORTICALCARCINOMA
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the IRM
Surgery, 2000
Low level of radionuclidinto the tumor.
Limits:HighPrice
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the SCINTIGRAPHY
PET (18FDG) marker of cell metabolism
TC morphological correlation
Advantage:Accuracy in diagnosis
(86-96%)
Limits:High priceLow disponibility
Bergstrom 2000Jana 2005
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the PET-CT
Endocrinosurgery PD (2003-2007)
n=20 casesSensibility : 75%; Specificity: 75%
RMN (suspicion of renal
infiltration)
PET (negative) ADENOMA
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the PET-CT
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PET-TC positive ADRENOCORTICALCarcinoma
ADRENOCORTICAL CARCINOMA
IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the PET-CT
“RADICAL”
SURGERY“En bloc” large resection
Adrenal carcinoma - Left Adrenal GlandAdrenalectomy + Nephrectomy
ADRENOCORTICAL CARCINOMA
SURGICAL TREATMENTSURGICAL TREATMENT
Adrenal carcinoma - Right Adrenal GlandOpen Adrenalectomy
+ resection and thrombectomy
Dackiw 2001
ADRENOCORTICAL CARCINOMA
SURGICAL TREATMENTSURGICAL TREATMENT
“RADICALE”
SURGERY
Survival: 9 months
Survival: 40% at 5 years
PALLIATIVE
SURGERY
Unsuccessful !!!BACKSLIDING
(>60%)
“FOLLOW “The Backslides!!!
ADRENOCORTICAL CARCINOMA
SURGICAL TREATMENTSURGICAL TREATMENTROLE of the OPERATION
ADRENOCORTICAL Carcinoma2-nd Reoperation - Hepatic Resection for liver MTS
ADRENAL CARCINOMA
SURGICAL TREATMENTSURGICAL TREATMENTROLE of the OPERATION
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Icard 2001
p=0.7
NO effects in survival (p=0.7)…but…
ADRENCORTICAL CARCINOMA
ADJUVANT THERAPYADJUVANT THERAPYROLE of the MITOTANE
Berruti at al Endocr Relat Cancer. 2005; 12(3): 657
Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a largeprospective phase II trial.
“Down-staging”Increase up the median survival (p<0.002)
ADRENCORTICAL CARCINOMA
ADJUVANT THERAPYADJUVANT THERAPYROLE of the MITOTANE
Disease Free-Survival(p<0.01)
SurvivalVs German Group (p<0.01)
Vs Italian Group (p=NS)
NEJM 2007
ADRENCORTICAL CARCINOMA
ADJUVANT THERAPYADJUVANT THERAPYROLE of the MITOTANE
489 489 ADRENALECTOMIESADRENALECTOMIES
ENDOCRINOSURGERYENDOCRINOSURGERYUniversityUniversity ofof PadovaPadova
11985 985 -- 20082008
167
108
88
67
59
0 100 200Cushing
Conn
Feo
TNS
ACC
The cases of ENDOCRINOThe cases of ENDOCRINOSURGERYSURGERYPDPD ((19851985–– 2008)2008) Patients withPatients with ACC = 45ACC = 45
34
9
205
10152025303540
1 Inte
rvento
2 Inte
rventi
>2 Inte
rventi
TOTAL NUMBER59 OPERATIONS
Median Age:50 years
(range 25-75)
Sex Ratio W/M: 2
Median Size:11 cm
(range 4-19)
48%
36%
16%
0%
10%
20%
30%
40%
50%
60%
Stadio 1
e 2
Stadio 3
Stadio 4
Mortalityperioperatory:
1 case (4-th Stage)
p36months
24months
12month
<0,0<0,0116%6%
32%32%
71%71%
90%90%
29%29%GradGrad 3 e 43 e 4
74%74%GradGrad 1 e 21 e 2
SurvivalSurvival
StatisticsStatistics of Firstof First InterventionIntervention
SurvivalSurvival afterafter 11°° InterventionIntervention
The cases of ENDOCRINOThe cases of ENDOCRINOSURGERYSURGERYPDPD ((19851985–– 2008)2008)
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Histological diagnosisCriteria of Weiss
Biological Markers(Ki67, P53, IGF2)
CONCLUSIONSPREOPERATIVE DIAGNOSIS
Insufficience of Volumetric Criteria
TC(Density)
RMN(T2 e Chemical Shift)
PET - TC
Precocious Diagnosis
Improvement of Prognosis
CONCLUSIONS
SURGERY still remain today the only treatment even if we
could not obtain the RADICALITY
BACKSLIDES
REOPERATIONS could improve the survival
ADJUVANT THERAPY ???
CONCLUSIONS
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