THE ADRENOCORTICAL CARCINOMA

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

325

Articole Multimedia Jurnalul de Chirurgie, Iaşi, 2008, Vol. 4, Nr. 4 [ISSN 1584 – 9341]

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



???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



KiKi--67 67 ■■p53p53

Martins 2005Stojadinovic 2003

Higher in Carcinoma (36%) lower in Adenoma (0%)Correlation with Survival

Diagnosis criteria Prognosis factor



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


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).



Malignant Tumor98% > 6 cm

2% < 6 cm Diameter > 6 cm

85% BENIGNANT

15%MALIGNANT

Mantero, 2000

VOLUMETRIC Criteria



LIMITS of the CUT-OFF POINT

Mantero, 2000

SURGERY

85%: Benignant tumor

FOLLOW UP

2-4%: Carcinoma

< 6cm > 6cm


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


IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the CT-SCAN

25 HU: SMALL MALIGN TUMOR

2 HU: LARGE BENIGN MASS



• DENSITY without contrast < 10 HU

Benign vs Malign

SENSIBILITY - 71%SPECIFICITY - 98%

Boland 1998



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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%



Al-Hawary 2005

• Size• Vascular Invasion

•Hyperintensity in T2

The intensity in T2 is correlatedwith fluid content

ADENOMALow Fluid Content

CARCINOMAHigh Fluid Content


IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the IRM

Elsayes 2004

Hyperintensity in T2+

Chemical Shift

Diagnosis accuracyof

98%ADRENOCORTICALCARCINOMA


IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the IRM

Surgery, 2000

Low level of radionuclidinto the tumor.

Limits:HighPrice


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


IMAGERYIMAGERY DIAGNOSISDIAGNOSISROLE of the PET-CT

Endocrinosurgery PD (2003-2007)

n=20 casesSensibility : 75%; Specificity: 75%

RMN (suspicion of renal

infiltration)

PET (negative) ADENOMA



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PET-TC positive ADRENOCORTICALCarcinoma



“RADICAL”

SURGERY“En bloc” large resection

Adrenal carcinoma - Left Adrenal GlandAdrenalectomy + Nephrectomy


SURGICAL TREATMENTSURGICAL TREATMENT

Adrenal carcinoma - Right Adrenal GlandOpen Adrenalectomy

+ resection and thrombectomy

Dackiw 2001


SURGICAL TREATMENTSURGICAL TREATMENT

“RADICALE”

SURGERY

Survival: 9 months

Survival: 40% at 5 years

PALLIATIVE

SURGERY

Unsuccessful !!!BACKSLIDING

(>60%)

“FOLLOW “The Backslides!!!


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)



Disease Free-Survival(p<0.01)

SurvivalVs German Group (p<0.01)

Vs Italian Group (p=NS)

NEJM 2007



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)

330


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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THE ADRENOCORTICAL CARCINOMA