adrenal medullary tumors

CURRENT DIAGNOSIS AND MANAGEMENT OF

ADRENAL TUMORS

Special endocrinological lecture for students

20. 04. 2016.

Dr. G. Békési

INTRODUCTION

ADRENAL MEDULLARY TUMORS

ADRENOCORTICAL TUMORS

METASTATIC TUMORS

INCIDENTALOMAS

INTRODUCTION

Adrenal tumors evoke considerable interest and diagnostic challenges.

This rare group of tumors includes functional tumors with a gamut of clinical presentations, as well as adrenocortical carcinoma, with its advanced disease at presentation and dismal prognosis posing additional challenge.

Increasing detection of incidentalomas adds further interest with the concomitant diagnostic and management dilemmas.

INTRODUCTION

Adrenal masses are among the most common tumors, found in at least 3% of people (≥50 years) in autopsy studies.

Most are nonfunctional and only 1 in 4000 is malignant.

Adrenal tumors can be stratified into adrenal medullary and adrenocortical tumors.

The aim of this lecture is to summarize recent advances in biochemical, genetic and radiological diagnosis while emphasizing current management options.

INTRODUCTION INTRODUCTION

INTRODUCTION



METASTATIC TUMORS

INCIDENTALOMAS


They include pheochromocytomas, rare ganglioneuromas, ganglioneuroblastomas and neuroblastomas.

Pheochromocytomas: catecholamine-producing, neuroendocrin tumors arising from chromaffin cells in the adrenal medulla (WHO classif. 2004)

Estimated incidences in general population: 0.005-0.1 %; in the adult hypertensive population: 0.1-0.2%

Annually 3-4 diagnoses/million in the US; incidence of hereditary predisposition: 20-30 %; higher prevalence of bilateral tumors in this group

Prevalence of extra-adrenal tumors: 23%; malignancy in this group: 33%


PHEOCHROMOCYTOMA

PHEOCHROMOCYTOMA

Similar signs and symptoms in many other clinical conditions: 3-year mean diagnostic delay until definitive diagnosis

25% of pheochromocytomas are diagnosed incidentally (with increasing utilization of imaging studies).

Advances in genetics have identified germline mutations for familial pheochromocytomas in five genes (VHL, RET, NF1, SDHB, SDHD).

Mutation testing is available for four of these.

Genetic examinations are necessary: family history or younger than 50 years old, multiple tumors, malignant and bilateral tumors


PHEOCHROMOCYTOMA - laboratory

Diagnostic confirmation requires biochemical evidence.

Traditionally has been used: VMA (vanillylmandelic acid) with urinary and plasma catecholamines

Pheochromocytomas secrete catecholamines episodically but metabolize them continuously: measurement of plasma and urinary metanephrine and normetanephrine (break down-products) provides superior diagnostic capability.

False positive results can arise from dietary or drug interferences and inappropriate sampling conditions.


PHEOCHROMOCYTOMA – imaging studies

Similar sensitivity and specificity between CT and MRI: both of them are appropriate

CT image of pheochromocytoma MRI image of pheochromocytoma

(hypersignal in T2)


Pregnant women, children and patients with

contrast allergy: MRI is preferred

On MRI pheochromocytomas are hypointense on T1-weighted images and markedly hyperintense on T2-weighted images.

Adrenal venous sampling for elevated catecholamines or metanephrines: when conventional imaging studies fail to localize the tumor




(a) A 2.5-cm mass (white arrow) has slightly increased T1 signal on MRI.

(b)The same mass (black arrow) has increased T2 signal on MRI, which is classic for pheochromocytoma.


Functional imaging with 123I-meta-iodobenzylguanide (MIBG) scintigraphy can be used to distinquish pheochromocytomas or paragangliomas (95 % specificity, low sensitivity).

MIBG scintigraphy: useful for determining the extent of disease for patients with increased risk of malignancy (extra-adrenal or ≥5 cm tumors) and in whom CT/MRI failed to identify the tumor(s)



Anterior and posterior whole body 123I MIBG images.


META-IODOBENZYLGUANIDE SCAN



Radio-labeled octreotide (Octreoscan): better efficacy in imaging extra-adrenal and metastatic pheochromocytoma (reserved for patients with negative MIBG scintigraphy)

Other options: PET imaging with nonspecific ligand 18F-fluorodeoxyglucose (18F-FDG PET) and specific ligands like (18F)-dihydroxyphenylalanine


Scans were performed after the intravenous administration of 6 mCi of 111indium octreotide. Shown below are anterior planar

images obtained at 4 and 24 hours.


PHEOCHROMOCYTOMA – therapy Surgical resection is definitive treatment for

pheochromocytoma.

Preoperative treatment with α-adrenoceptor preceding β-adrenoceptor antagonists; increased salt and fluid intake for volume expansion, use of preoperative calcium channel blockers against intraoperative blood-pressure fluctuations: perioperative mortality: less than 3%

Laparoscopic adrenalectomy: decreased pain, shorter hospitalization, less recovery time, improved patient satisfaction: it is preferred approach for benign functioning and nonfunctioning tumors≤12cm


Any evidence of malignancy (local invasion): open adrenalectomy due to increased risk of tumor fragmentation and difficulty in removing these tumors laparoscopically

Recurrent pheochromocytoma occurs more commonly in patients with extra-adrenal disease or familial pheochromocytoma.

PHEOCHROMOCYTOMA – therapy


High incidence of bilaterality in familial disease: adrenocortical-sparing partial adrenalectomy has beeen advocated to minimize adrenal insufficiency; This must be weighed against the risk of tumor recurrence following partial adrenalectomy.

Annual follow-up, continued indefinitely with extra-adrenal or familial pheochromocytoma for early detection of recurrences


PHEOCHROMOCYTOMA – therapy

MALIGNANT PHEOCHROMOCYTOMA

No histological features, including cytologic atypia can predict or provide evidence of malignant potential.

Only metastasis establishes malignancy definitively.

Most common metastatic sites: bones, lungs, liver, lymph nodes

Incidence of metastatic pheochromocytoma: 3-36%; 5 year survival rate: 34-60% (depending on tumor site and genetic predisposition)

Increased rate of malignancy: tumors ≥ 5 cm, extra-adrenal localisation, SDHB mutations, increased plasma or urinary concentrations of dopamine (more premature catecholamine secretion) and norepinephrine


MALIGNANT PHEOCHROMOCYTOMA - therapy

There is no effective treatment for malignant pheochromocytoma: radical debulking is the mainstay for symptomatic improvement without proven survival advantage.

Palliation: external irradiation for skeletal metastasis and radiofrequency ablation

Combination chemotherapy /cyclophosphamid, vincristin, dacarbazine/: short term remission (50%)

131I-MIBG therapy: symptomatic effect (80%); complete remission: 5%; partial: 30%

Cytotoxic chemotherapeutic agents may increase uptake of MIBG (which is not always sufficient).


INTRODUCTION



METASTATIC TUMORS

INCIDENTALOMAS

They include benign adenomas, myelolipomas and adrenocortical carcinoma /ACC/.

Benign and malignant tumors may be functional (cortisol, aldosterone, sex steroids; Cushing’s syndrome, Conn’s syndrome, virilization /these are more likely to be ACC/)

Benign tumors increase in prevalence with age (in 3-7% of adults≥50 years)

ACC accounts for 0.02% of all reported cancers and 0.2% of cancer-related deaths annually; incidence between Brazilian children: 4,2/million (10x higher than the worldwide incidence); bimodal age distribution (<5 and >40-50 years)


Advances in understanding the molecular mechanisms responsible for rare genetic, familial and sporadic adrenocortical tumors:

TP53 gene mutation (Li-Fraumeni syndr., sporadic tumors); Menin gene mutation (MEN 1 syndr., sporadic tumors); PRKARIA gene mutation (Carney complex); CYP 21 gene mutation (sporadic tumors); IGF-II overexpression (Beckwith-Wiedemann syndr.)

Proportion of functional tumors increased from 50% to 79% due to improved hormonal assay sensitivities

Nonfunctional ACC (60%): weight loss, abdominal pain, palpable mass


ACC with Cushing’s syndrome (before and after diagnosis)

By courtesy of Prof. Dr. Gláz Edit - SU II. Dept. of Medicine


Virilization

By courtesy of Prof. Dr. Gláz Edit and Dr. Tóth Miklós- SU II. Dept. of Medicine


ACC in childhood with Cushing’s syndrome

By courtesy of Dr. Halász Zita- SU I. Dept of Pediatry


IMAGING MODALITIES

Adrenal scintigraphy, CT, MRI, PET: these modalities can localize the tumors and predict malignancy

Criteria suggesting benign adenoma: attenuation values fewer than 10 HU (unenhanced CT) and fewer than 30 HU (on enhanced scan); washout in 10-min delayed CT greater than 50%; signal drop out on out-of-phase chemical shift MRI

Tumors with more than 10 HU /hyperattenuating lesions/: lipid poor adenomas, pheochromocytomas, metastases, ACC


IMAGING MODALITIES

Delayed enhanced CT or chemical shift MRI ? - no significant difference in diagnostic accuracy

Adrenal scintigraphy: unproven diagnostic utility, limited availability: seldom used

FDG-PET: useful in distinquishing adenomas from malignant tumors

PET using 11C-labeled metomidate: it binds to adrenal 11β-hydroxilase – tissue specific imaging procedure: excellent tool to distinquis adrenocortical origin-adrenal adenomas and ACC from other lesions


HISTOLOGY

Fine-needle aspiration/biopsy: risk of needle tract seeding, limited diagnostic value in differentiating benign from malignat tumors: not recommended

It is indicated (only after excluding pheochromocytoma) for inoperable lesions prior to starting radiation or chemotherapy.

Weiss revisited index (WRI) and Van Slooten index (VSI): assessment of malignancy risk; equal validity, correlation with survival

/nuclear atypia, atypical and frequent mitoses, vascular and capsular invasion, necrosis are suggestive of malignancy/


HISTOPATHOLOGY

Molecular markers: IGF-II overexpression, allelic losses at 17p13, immunohistochemistry of Cyclin E or Ki-67: tools to assess malignancy

Tumor staging: important prognostic factor in ACC; 2004 TNM staging categories: I <5 cm; II >5 cm; III locally

invasive or regional lymph nodes metastasis; IV metastatic tumor or invading adjacent organs

Stage II tumors are more common in recent studies (due to improved imaging techniques

Better prognosis in young patients and for stage I and II; cortisol secreting tumors are associated with worse prognosis


Macroscopic image of ACC

By courtesy of Semmelweis University II. Dept. of Pathology


Adrenocortical adenoma

By courtesy of Dr. Zalatnai Attila- SU I. Pathology


ACC

By courtesy of Dr. Zalatnai Attila SU I. Pathology


TREATMENT

Laparoscopic adrenalectomy is indicated for functional and nonfunctional adenomas less than 12 cm.

Almost all functional, benign adrenocortical tumors should be removed regardless of size.

Laparoscopy is relatively contraindicated in benign tumors larger than 12 cm, locally invasive tumors and ACC.


TREATMENT

Stage I-III ACC: open adrenalectomy and complete tumor extirpation – only chance to obtain long-term remission

En-bloc resection of locally invaded organs (kidney, liver, spleen pancreas and stomach), regional lymphadenectomy, extraction of tumor thrombus from the inferior vena cava or renal vein, if present

Stage IV functional tumors : tumor debulking with removal of the primary tumor: palliation of symptoms


ADJUVANT TREATMENT OF ADRENOCORTICAL CARCINOMA

I.

Radiation is generally ineffective, it is reserved for skeletal metastasis palliation to reduce pain or the risk of fractures;

Tumor bed irradiation: decreased 5 year recurrence

Mitotane: adrenolytic agent (insecticide derivate)– modest response in ACC (14-36%), 2 times longer recurrence-free survival;

Narrow therapeutic index, marked toxicity with a daily dose of more than 6 mg – monitoring of serum levels is required;

Mitotane can induce adrenal insufficiency – glucocorticoid and mineralocorticoid supplementation


ADJUVANT TREATMENT OF ADRENOCORTICAL CARCINOMA

II. Chemotherapy regimens: EDP/M (etoposide, doxorubicin, and

platinium in combination with mitotane); Streptozotocin+mitotane – partial response rates up to 50%

ACC is resistant to chemotherapy as tumor cells express high levels of the multidrug-resistance protein (MDR1) – MDR1 caused efflux pump inhibitor (Tariquidar) /phase-III trial/, epidermal growth factor inhibitors (Gefitinib), anti-vascular-endothelial growth factor (Bevacizumab) and tyrosine kinase inhibitor (Sunitimib) are currently beeing conducted in patients with ACC.

Radiofrequency ablation is an alternative to surgical resection in patients with prohibitive surgical risk;

Chemoembolization: recurrent ACC and metastasis in the liver


Malignant adrenocortical tumor unenhanced and enhanced CT scan

By courtesy of Dr. Németh Andrea SU Transplantation Clinic

Metastasis in spleen


ACC by Ultrasound



COMPUTED TOMOGRAPHY SCAN SHOWING ADRENOCORTICAL CARCINOMA

The CT scan shows a large, inhomogeneous adrenocortical carcinoma (large arrow) arising from the left adrenal gland; also shown are multiple

hepatic and pulmonary metastases (small arrows).


MANAGEMENT ALGORITHM FOR ADRENOCORTICAL CARCINOMA


INTRODUCTION



METASTATIC TUMORS

INCIDENTALOMAS

Adrenal incidentaloma: discovered incidentally during radiologic examnation for indications other than evaluating adrenal disease

Prevalence: 0.2% in patients <30 years and 7% in patients>70 years

In patients with prior malignancy, most adrenal masses (75%) are metastatic; in patients without a history of malignancy: 66% are benign adenomas.

70% of incidentalomas are nonfunctional; 5-20% of patients have subclinical Cushing’s syndrome, 5% have pheochromocytomas, and 1% have aldosterone producing adenomas.

INCIDENTALOMAS

Risk of malignancy: 2% (<4cm); 6% (4-6 cm); 25% (>6cm)

Surgical resection for nonfunctional incidentalomas larger than 6 cm /according to recent studies larger than 4 cm/, observation for tumors smaller than 4cm (2002 NIH consensus cnference), management of 4-6 cm tumors: controversial

INCIDENTALOMAS

Image-guided needle biopsy (after excluding pheochromocytoma) should be reserved for differentiating adrenal from nonadrenal lesions (metastatic disease).

Patients with hormonally active tumors /regardless of size/, nonfunctional tumors>4 cm and incidentalomas with features for malignancy: laparoscopic adrenalectomy

Any signs of local invasion: open adrenalectomy

INCIDENTALOMAS

Adrenocortical adenoma on CT


INCIDENTALOMAS

MRI OF ABDOMEN SHOWING SMALL MASS

MRI of the abdomen shows a small mass (1 cm) involving the anterior limb of the left adrenal gland (arrow); it is isointense to the remaining adrenal on T2 weighted sequence and demonstrates significant dropout on the out-of-phase sequences. No abnormal enhancement was seen after Gadolinium; final pathology confirmed aldosteronoma.

INCIDENTALOMAS

MANAGEMENT ALGORITHM FOR ADRENAL INCIDENTALOMAS

INCIDENTALOMAS

INTRODUCTION



METASTATIC TUMORS

INCIDENTALOMAS

Most common sites of tumors metastasizing to adrenals: lung, kidney, colon, breast, esophagus, pancreas, liver, stomach;

Metastases are the cause of adrenal masses in 75 % of patients with a history of malignancy and are frequently bilateral.

16 % of benign adenomas have increased uptake during 18F-FDG PET: limitation of the utility

Absence of activity on 11C-metomidate (MTO)-PET: specific for tumors of nonadrenocortical origin

METASTATIC TUMORS

CT-guided and EUS-quided needle biopsy: differentiation between adrenal and nonadrenal tissues

Management of isolated adrenal metastases is controversial . Laparoscopic resection can be undertaken in carefully selected patients without local invasion.

Suspicion of local invason or ACC: open adrenalectomy

There is no evidence supporting resection of adrenal metastasis of unknown origin.

METASTATIC TUMORS

LUNG CARCINOMA AND ITS ADRENAL METASTASIS BY CT


METASTATIC TUMORS

BILATERAL ADRENAL METASTASIS BY CT


METASTATIC TUMORS

Patient 1. Pheochromocytoma by CT

Patient 2. (Bilateral incidentaloma)

Enhanced CT image MRI

MRI

Patient with aldosteronoma – CT image

adrenal medullary tumors

Documents