Transcript Adrenal Incidentalomas Diagnostic and Clinical Dilemma

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 lifethreatening 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 nonfunctioning
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 noncontrast 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:
– cortisol:
–Serum
ACTH:
–VMA:
–Metanephrines:
•Serum Studies:
–Testosterone
–Cortisol
–DHEA
588 (nl 9- 53)
undetectable
2.6
<40
291 (nl 14-76)
41.8
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
Microscopic Specimen
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
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
Thanks