Öregedő mellékvese Öregedő mellékvese diagnosztikus és klinikai diagnosztikus és klinikai

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Dr Valkusz Zsuzsanna

Age Related ChangesAge Related ChangesAdrenals -

connective tissue replaces degenerating tissue

age-related decline in cortical secretions

glucocorticoids

decline in aldosterone over 50

no apparent effect on salt and water balance

medullary hormones actually increase

epinephrine

Disorders of the Adrenal GlandDisorders of the Adrenal Gland

Adrenocortical Insufficiency

A) Primiary Adrenal Insufficiency (Addison’s disease)

-most common cause is autoimmune-mediated destruction of the adrenal glands (>80%)

-secondary to tuberculosis (20%)

-chronic fungal infections, infection by cytomegalovirus (CMV), metastasis to the glands by cancer cells (rare).

B) Secondary Adrenal Insufficiency:

-Addison’s Disease caused by inadequate secretion of ACTH by the pituitary gland

-may arise due to the prolonged or improper use of glucocorticoid

Example: Glucocorticoid hormones such as prednisone are used to treat chronic diseases such as rheumatoid arthritis, asthma, and other inflammatory illnesses by suppressing the secretion of ACTH and thus the secretion of cortisol.

-tumors may produce ACTH on their own

-less common causes of secondary adrenal insufficiency include pituitary tumors, or damage to the pituitary gland during

surgery or radiation.

Disorders of the Adrenal Disorders of the Adrenal GlandGland

Adrenocortical Hyperfunction

A) Congenital adrenal hyperplasia:

-is a common inherited form of adrenal insufficiency

-due to mutations in genes for several enzymes needed for the production of adrenal cortex hormones.

-about 95% of cases of are caused by 21-hydroxylase deficiency

-this enzyme is necessary for production of cortisol and aldosterone –-sensing low levels of cortisol, the adrenal, via the hypothalamus and pituitary glands, the adrenal cortex synthesizes androgens.

-thus, while one part of the adrenal functions poorly, making inadequate amounts of cortisol and aldosterone, another portion of the gland

over-produces androgens

Disorders of the Adrenal Disorders of the Adrenal GlandGland

B) Cushing’s Syndrome

Therapeutic ("iatrogenic": caused by the treatment)

-Cushing's Syndrome is a disease caused by an excess of cortisol production or by excessive use of cortisol or other similar steroid (glucocorticoid) hormones

-unfortunate necessary side effect when high doses of these steroid hormones must be used to treat certain life-threatening illnesses, such as asthma, rheumatoid arthritis, systemic lupus, inflammatory bowel

disease, some allergies, and others

Disorders of the Adrenal GlandDisorders of the Adrenal Gland

Spontaneous overproduction of cortisol: Two groups

-those due to an excess of ACTH: A pituitary tumor producing

too much ACTH, stimulating the adrenals to grow

(hyperplasia) and to produce to much cortisol (>70%);

"ectopic" ACTH production (30%)

-those not due to excess ACTH: Adrenal cortex tumors that make

cortisol can be benign (an adenoma), or malignant (a carcinoma) and are

usually found on only one side.

Adrenal Incidentalomas Adrenal Incidentalomas

Increased use of cross sectional imaging has lead to improved detection

Since prevalence of these masses increases with age, and improved detection, appropriate management of adrenal tumours will be a growing challenge in an aging society

DefinitionDefinition

Non-functioning adrenal tumours discovered on imaging study performed for indications exclusive of adrenal related pathology.

Based on autopsy studies, adrenal masses are among the most common tumours in human

Adrenal mass occurs in at least 3 percent of persons over age 50

Why are these lesions important?. . When detected, clinically inapparent adrenal masses

raise challenging questions for physicians and their patients Most adrenal masses cause no health problems

Approximately 1 out of every 4,000 adrenal tumours is malignant.

Diagnostic evaluation is performed to determine: 1.) Is the lesion hormonally active or non-functioning 2.)Is it malignant or benign?

Radiologists Role?Radiologists Role?

With a little clinical and endocrinological information

the radiologist can make the diagnosis and effect

management

The results from these tests will influence whether the

mass is removed surgically or treated nonsurgically in

most cases.

AnatomyAnatomy

Named For location : AD_renal = above kidneys

Weights 5g

Has a characteristic Y, V or T shape.

Embryology: Cortex derived from mesoderm

: Medulla derived from neural crest

cells

AnatomyAnatomy

AnatomyAnatomy

AnatomyAnatomy

PhysiologyPhysiology

Influence or regulate the body's metabolism, salt and water balance, and response to stress by secreting a variety of hormones.

Cortex has 3 layers that secrete cortisol, aldosterone and androgens.

Medulla secretes adrenaline and noradrenaline

Imaging ModalitiesImaging Modalities

Widespread use of CT scanning has lead to incidentalomas detected in approximately 0.5% of the population scanned CT Scanning CT scanning is used to characterise a large

number of adrenal incidentalomas Several different Strategies used in CT scanning 3 criteria used: Histologic, Physiologic and

Morphologic

HistologicalHistological

 Non Contrast CT

Principle

Both macroscopic fat (myelolipoma or lipoma) of the adrenal gland

as well as intracytoplasmic fat in sufficient concentrations maybe

detectable.

Adrenal cortex and many benign adrenocortical tumours contain

intracytoplasmic fat (mainly cholesterol, fatty acids and neutral fat)

Malignant as well as metastasis lesions do not generally contain fat.

PhysiologicalPhysiological

Contrast Enhanced CT Scanning (Perfusion CT) Utility Most adrenal incidentalomas are seen on contrast

CT scanning. To permit rapid diagnosis ,prevent repeat

scanning (cost and time inefficient) with a non-contrast CT scan and prevent excess radiation exposure certain strategies can be used with contrast enhanced CT

PhysiologicalPhysiological

Principle: Adrenal glands (both metastatic and adenomas)

enhance rapidly post contrast to the same degree, which complicates the use of adrenal density values

30 % of adrenal adenomas do not have sufficient fat to be characterised with non-contrast CT. Contrast CT is valuable for these lesions.

Case Study- PJ (early 2003)Case Study- PJ (early 2003)

56 year old white female presented to medical attention due to a blood pressure of 210/125 discovered at work

Over several months, she had been dealing with worsening diabetes, persistent worsening hypertension, deepening voice and progressive hirsutism. Also noted vaginal bleeding despite being postmenopausal (LMP several years prior)

Lab StudiesLab Studies

24h urinary studies:– cortisol: 588 (nl 9- 53)

•Serum Studies:–Testosterone 291 (nl 14-76)–Cortisol 41.8–DHEA elevated

–VMA: 2.6–Metanephrines: <40

–Serum ACTH: undetectable

ImagingImaging

•CT scan revealed a mass involving the adrenal gland, apparently completely contained within. The lesion demonstrated scattered calcification and signal heterogeneity

Its appearance, coupled with the patient history, physical exam, and laboratory data strongly suggested an adrenocortical carcinoma

EpidemiologyEpidemiology

Estimated incidence of 0.5-2 per 106 patients per year

Peaks of age distribution at age <5 and in the 4th and 5th decades

Scattered reports of gene associations, but rarity of lesion precludes clear associations

Functioning LesionsFunctioning Lesions

60-65% of adrenocortical carcinomas are functioning lesions– Cushings– Virilization– Feminization– Hyperaldosteronism

Hormonal studies can be a first diagnostic test which confirms ectopic steroid hormone secretion, leading to an imaging and tissue diagnosis.

They also can be a “tumor marker” which can be useful for monitoring response to therapy and suspicion of recurrence.

HypercortisolismHypercortisolism

24 hour urinary cortisol exrection– More than 90% of Cushinoid patients have free

cortisol levels greater than 200mcg/ 24 hours. 97% of normals have levels less than 100mcg/ 24 hours

ACTH measured with serum cortisol will demonstrate ACTH independent nature of hypercortisolism.

Other SteroidsOther SteroidsOther steroids are elevated:

– androstenediol and adrosetenedione– DHEA and DHEA-S– 11- deoxycortisol– urinary 17- ketosteroids– aldosterone

Many intermediate enzymes are defective or dysregulated, leading to inefficient steroid production and precursor buildup

Potential Functional AssaysPotential Functional Assays

Serum TestosteroneSerum DHEA and DHEA-S24 hour urinary ketosteroidsPlasma estradiol and/ or estronePlasma aldosterone/ reninUrinary catecholamines/ metanephrines

in all patients

ImagingImaging

CT detects 98% of adrenal carcinomasMRI scanning can also provide vascular

invasion/ tumor thrombosis information.Also provides many incidentalomas

– Malignant lesions tend to be > 5cm, have irregular shapes/ blurred margins, and be heterogeneously enhancing.

StagingStaging

Hormonal studies directed at symptoms24h urine studies to r/o pheochromocytomaCT scanning to determine extent and

resectability of lesionMRI if vascular invasion unclear; R sided

lesions have a propensity to form venous tumor emboli

StagingStaging

Stage I — Disease confined to the adrenal gland and <5 cm in diameter (approx 20%)

Stage II — Disease confined to the adrenal gland and >5 cm in diameter (approx 20%)

Stage III — Local invasion that does not involve adjacent organs or regional lymph nodes (approx 20%)

Stage IV — Distant metastases or invasion into adjacent organs plus regional lymph nodes (approx 40%)

Gross SpecimenGross Specimen

Microscopic SpecimenMicroscopic Specimen

Note the mitotic figure

Prognostic factorsPrognostic factors

In a case review of 46 patients at MSKCC, 3 histologic factors correlated with survival:– tumor> 12cm– 6 or more mitotic figures/ 10hpf– presence of histologic evidence of intratumoral

hemorrhage– 5 year survivals:

0 factors: 83% 1 factor: 42% 2 factors: 33%

Radiation ApproachRadiation Approach

There are scattered case reports demonstrating improved pain when palliative XRT used for localized lesions

Chemotherapeutic ApproachChemotherapeutic Approach

Review of the literature reveals case reports, retrospective treatment data, and reviews.

A few phase II trials do exist from some cooperative or national groups

No true modern- design controlled phase III trials exist

MitotaneMitotane

1,1- dichloro-2-(o-chlorophenyl) ethane (o,p-DDD).

Chemical relative to DDTFound to have adrenolytic activity in dogs

in vivo (selectively destroyed the zonae reticularis and fasciculata)

inhibits the intramitochondrial conversion of cholesterol to pregnenolone and the conversion of 11-deoxycortisol to cortisol (11B- hydroxylation). It produces selective adrenocortical necrosis in both the adrenal tumor and metastases

Side effects are major and frequent, including:– CNS disturbance (vertigo, somnolence, ataxia)– Liver Toxicity– Renal Toxicity– Nausea, Vomiting– Diarrhea– Rash

Selected Mitotane StudiesSelected Mitotane Studies

Other symptom- palliative Other symptom- palliative OptionsOptions

Metyrapone (11B hydroxylase inhibitor)KetoconazoleAminoglutehamide

CytotoxicsCytotoxics

Various systemic cytotoxics have been used for advanced disease, usually for those failing mitotane.

Most studied have been Etoposide, cisplatin, and adriamycin.

Paclitaxel and Temozolamide have recently demonstrated antitumor activity in vitro

SummarySummary

Adrenocortical carcinoma is a rare disease that often presents late

Primary curative therapy is surgicalNo role for adjuvant chemotherapy has

been demonstrated to datePalliative therapy with mitotane may be

useful; its palliative effect may be entirely due to adrenolytic effect

Reoperation appears to be the only long term curative option in recurrent cases

Cytotoxic chemotherapy in the advanced/ metastatic setting has not been definitively demonstrated to be useful in controlled trials

EDP-M may be useful in metastatic settings; more evaluation is needed

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