Öregedő mellékvese diagnosztikus és klinikai dilemmák Dr Valkusz Zsuzsanna

Age Related Changes Adrenals - 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 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).

Disorders of the Adrenal Gland 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 Gland 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 Gland 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

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 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

Definition 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? 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.

Anatomy 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

Anatomy

Anatomy

Anatomy

Physiology 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 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

Histological 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.

Physiological 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

Physiological 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) 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 Studies 24h urinary studies: Serum Studies: cortisol: 588 (nl 9- 53) Serum ACTH: undetectable VMA: 2.6 Metanephrines: <40 Serum Studies: Testosterone 291 (nl 14-76) Cortisol 41.8 DHEA elevated

Imaging 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

Epidemiology 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 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.

Hypercortisolism 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 Steroids Other 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 Assays Serum Testosterone Serum DHEA and DHEA-S 24 hour urinary ketosteroids Plasma estradiol and/ or estrone Plasma aldosterone/ renin Urinary catecholamines/ metanephrines in all patients

Imaging CT detects 98% of adrenal carcinomas MRI 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.

Staging Hormonal studies directed at symptoms 24h urine studies to r/o pheochromocytoma CT scanning to determine extent and resectability of lesion MRI if vascular invasion unclear; R sided lesions have a propensity to form venous tumor emboli

Staging 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 Specimen Adrenal cortical carcinoma. Bulky, soft, encapsulated tumor with hemorrhage and necrosis sitting above and medially to the kidney. (Note size of tumor, > 10 cm).

Microscopic Specimen Note the mitotic figure This patient presented with Cushing’s syndrome and hypertension. CT scan revealed a 12.5 cm left adrenal mass. It turned out to be adrenocortical carcinoma. Adrenal tumors this large (12.5 cm) are rarely benign. Adrenal adenomas rarely exceed 5 cm or 50 grams. Note the mitotic figure – another feature that is usually missing in adenomas. Note the mitotic figure

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

Chemotherapeutic 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

Mitotane 1,1- dichloro-2-(o-chlorophenyl) ethane (o,p-DDD). Chemical relative to DDT Found 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 Studies van Slooten H, Moolenaar AJ, van Seters AP, Smeenk D. The treatment of adrenocortical carcinoma with o,p'-DDD: prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol. 1984 Jan;20(1):47-53. Thirty-four patients with adrenocortical carcinoma were treated with o,p'-DDD. Twenty-eight patients presented with metastases at entry, and spillage of tumour cells occurred at surgery in 6 other patients. Eight patients had objective tumour regression, of whom 7 had serum levels over 14 micrograms/ml. The 3 patients with a lasting remission had levels of greater than 15, greater than 25, greater than 25 micrograms/ml respectively during prolonged periods. Increased survival times were found in the group of 14 patients with o,p'-DDD serum levels higher than 14 micrograms/ml when compared with patients not treated after discovery of metastases. In the patients with levels less than or equal to 10 micrograms/ml no therapeutic effect was seen. Levels of over 20 micrograms/ml are associated with symptoms of reversible neuromuscular toxicity. Monitoring of serum levels during treatment is mandatory. It is suggested that serum levels of about 25 micrograms/ml during longer periods may be curative.

Other symptom- palliative Options Metyrapone (11B hydroxylase inhibitor) Ketoconazole Aminoglutehamide

Cytotoxics 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

Summary Adrenocortical carcinoma is a rare disease that often presents late Primary curative therapy is surgical No role for adjuvant chemotherapy has been demonstrated to date Palliative 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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