It gives a good summary of adrenal tumors and the approach to diagnose and treat them.

1. By Ruhama Yoseph (MD)
Adrenal Tumors

2. Outline
 Overview of anatomy, embryology, physiology
 Hyperaldosteronism (Conn Syndrome)
 Cushing’s syndrome (Hypercortisolism)
 Adrenal Adenoma/Hyperplasia
 Adrenal Carcinoma
 Sex hormone secreting tumors
 Pheochromocytoma
 Incidentaloma
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3. Objectives
 To know the differentials of mass lesions of the
adrenal
 To know their pathophysiology
 To know their clinical presentation
 To determine their laboratory diagnosis
 To know their imaging features
 To know the principles of management
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4. Overview of Adrenal Anatomy
 The adrenal are paired retroperitoneal organs
situated superior and medial to the kidneys
 They have both cortex and medulla parts
 Each gland has arterial supply from 3
branches and I venous drainage
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5. Anatomy- microscopic
 Histologically, the cortex is divided into three
zones
 zona glomerulosa
 zona fasciculata
 zona reticularis
 The outer area of the zona glomerulosa is the site
of production of the mineralocorticoid hormone,
aldosterone
 The zona fasciculata and zona reticularis cells
are the site of production of glucocorticoids and
adrenal androgens
 The adrenal medulla constitutes up to 10% to
20% of the gland’s volume and produces the
catecholamine hormones epinephrine and
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6. Embryology
 The cortex is derived from mesoderm while the
medulla is derived from ectodermal neural crest
cells
 The adrenal medulla are modified sympathetic
postganglionic neurons
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7. Physiology
 The cortex secrets aldosterone, cortisol, and sex
hormones from the outer, middle and inner layers
respectively which are derived from cholesterol
 The medulla secrets catecholamine like
adrenaline and nor-adrenaline
 Both are endocrine hormones but the secretion
from the latter is guided by signals from pre-
synaptic cholinergic nerve fibers
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8. Physiology…
 The major adrenal mineralocorticoid hormones
are aldosterone, 11-deoxycorticosterone (DOC),
and cortisol
 Aldosterone secretion is regulated by
 Primarily, by the renin-angiotensin system (RAAS)
 Hyperkalemia
 ACTH and other hormones are weak stimulators
 Function of Aldosterone:
 Acts on principal and intercalated cells of distal
tubule and collecting duct to increase excretion of
potassium and retention of sodium/ water
respectively
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9. RAAS
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10. Physiology…
 The secretion of cortisol and androgens are
regulated by ACTH secreted by the anterior
pituitary, which, in turn, is under the control of
corticotrophin releasing hormone (CRH) secreted
by the hypothalamus
 Cortisol’s function include
 Mobilization of energy reserves in times of stress
 Immunosuppression
 Anti-inflammatory
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11. Hypothalamus-Pituitary-Adrenal axis
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12. Physiology…
 Adrenal androgens are produced in the zona
fasciculata and reticularis from 17-
hydroxypregnenolone in response to ACTH
stimulation
 They include dehydroepiandrosterone (DHEA)
and its sulfated counterpart (DHEAS),
androstenedione, and small amounts of
testosterone and estrogen
 They are peripherally converted to the more
potent testosterone, dihydrotestosterone and
estrogen in peripheral tissues
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13. Physiology…
 Catecholamine hormones epinephrine,
norepinephrine, and dopamine are produced by
the adrenal medulla from the substrate tyrosine
 They are also secreted else where by
postganglionic sympathetic neurons
 They prepare the body for fight-or-flight reaction
 They are degraded by COMT, MAO
 The end stage metabolite is Vanillymandelic
Acid (VMA)
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14. Adrenal mass
 Hyperplasia
 Primary Vs Secondary (as in Pituitary adenoma)
 Congenital Vs acquired
 Benign adenomas- functional or non-
functional
 Functional- Conn’s syndrome, Cushing’s syndrome
from adrenal adenomas, Sex hormone secreting
adenomas
 Pheochromocytomas
 Incidentalomas
 Malignant cancers
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15. Primary Hyperaldosteronism
(Conn’s Syndrome)
 Increased aldosterone secretion
 Age distribution, before age 30 or after 55
 In secondary hyperaldosteronism, renal artery
stenosis or low flow states can be causes
 Here ,the aldosterone production is autonomous
 Aldosterone producing adrenal adenoma (70%)
 Bilateral idiopathic hyperplasia (30%)
 Usually diagnosed as a secondary cause of
hypertension that is resistant to treatment
 Bring hypokalemia
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16. Conn Syndrome…
 Clinical presentation:
 Headache, muscle weakness, polyuria (due to
hypokalemia)
 Absence of edema
 Secondary hypertension
 Systolic >140 mm Hg or diastolic > 90 mm Hg that is resistant
to 3 drug regimen
 Lab:
 Hypokalemia (<3.2 mmol/L or <3 mmol/L if while on
diuretic)
 Metabolic alkalosis
 Increased plasma aldosterone concentration (PAC)
 Decreased plasma renin activity (PRA)
 Aldosterone-to-renin ratio used as a screening
 Increased ratio ( 25 to 30) is positive, but has limited use
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17. Conn Syndrome
 Confirmatory test:
 Sodium loading test
 Oral sodium or saline infusion to suppress aldosterone
secretion
 In Conn Syndrome- no suppression
 Imaging
 CT- to identify unilateral, bilateral, cancerous lesions
 NP-59 scintigraphy
 ‘Hot’ nodule- adenoma
 Diffuse uptake- hyperplasia
 Adrenal venous sampling, to determine bilateralism(gold
standard)
 Catheterization of adrenal veins to draw sample and determine
aldosterone to cortisol ratio after ACTH stimulation
 Significant difference in ratio between right & left, unilateral
disease 10/5/2021
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18. Conn syndrome
 CT image and NP-59 scan of left adrenal
adenoma
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19. Conn Syndrome…
 Treatment:
 Initial goals of reducing BP and limiting organ damage
 Resection for unilateral tumors, laparoscopic or open
 Medical for bilateral tumors
 Aldosterone antagonists like spironolactone ordered
 Preoperative control of hypertension and potassium
supplementation , postoperative prevention of
hyperkalemia are important
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20. Cushing’s Syndrome
 Complex symptom & signs resulting from
hypersecretion of cortisol regardless of etiology
 Causes:
 Iatrogenic exogenous glucocorticoids (commonest)
 Endogenous
1. Primary hypercortisolism- ACTH independent
 Adrenal adenoma
 Adrenocortical cancer
 Primary adrenal hyperplasia
2. Secondary hypercortisolism- ACTH dependent
 Pituitary microadenoma (Cushing Disease)-70%
 Ectopic paraneoplastic foci ( Eg. Small Cell Lung Ca)
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21. Cushing’s Syndrome…
 Clinical features:
 Obesity
 Peculiar fat deposition
 Skin bruises, striae, acne
 Secondary hypertension
 Hyperglycemia, DM
 Impotence
 Hirsutism
 Amenorrhea
 Osteoporosis
 Proximal muscle weakness
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22. Cushing’s Syndrome…
 Diagnosis:
Screening tests include
 24 hrs. urine cortisol measurement
 Midnight saliva cortisol levels
 Dexamethasone suppression test ( low dose)
Confirmatory tests
 Serum ACTH ( to identify the cause)
 High dose dexamethasone suppression test( to
identify the cause)
 CRH stimulation test ( to identify the cause)
 Imaging ( to localize the tumor)
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23. Cushing’s Syndrome…
 Diagnosis (screening):
 Diagnosis is likely if 24 hr. urine cortisol levels or
midnight saliva cortisol levels are raised
 Low dose Dexamethasone (1mg) can be given at
11pm to measure subsequent plasma cortisol on
the next morning
 Suppressions implies a normal finding
 Failure to suppress cortisol levels is indicative of
Cushing’s syndrome. ACTH level should be
determined next to know the cause of endogenous
hypercortisolism.
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24. Cushing’s Syndrome…
Screening tests confirmatory
of Cushing’s Syndrome
Increased ACTH
Failure to suppress urinary
cortisol
Ectopic ACTH
secreting tumor
Urinary cortisol suppressed
Cushing’s disease
(Pituitary adenoma)
CRH secreting tumor
High dose
Dexamethasone
suppression test
Decreased ACTH
Adrenocortical tumors
ACTH- Adrenocorticotropic hormone
CRH- Corticotrophin releasing hormone
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25. Cushing’s Syndrome…
 Diagnosis (confirmatory tests)
 CRH can be determined to know the origin of ACTH
dependent hypercortisolism. CRH is administered
and levels of ACTH and cortisol are determined
serially.
 Those with ACTH dependent Cushing Syndrome will have a
higher rise of ACTH, whereas those with of primary adrenal
tumors will have blunted response
 Petrosal venous sampling can be done to further identify
pituitary adenomas
 High dose dexamethasone suppression test uses
2mg dose 6 hourly or 8mg overnight and measures
the 24 hrs. urine cortisol
 Failure to suppress by >50% confirms ectopic ACTH
 Radiologic evaluation 10/5/2021
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26. Adrenal Adenoma
 Are benign cortisol secreting tumors
 CT, MRI’s can be used for the diagnosis
 Adrenal cortex contralateral to tumor shows atrophy
 Radioscintigraphic imaging using NP-59 can be
used to identify adenomas from Hyperplasia
 Unilateral focal uptake in adenoma
 Symmetric uptake in hyperplasia
 “cold” nodules are likely to be cancerous
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27. Adrenal Adenoma…
 Treatment:
 Laparoscopic adrenalectomy
 Open adrenalectomy for large tumors
 Bilateral adrenalectomy for primary adrenal
hyperplasia
 Pre-operative and post-operative steroids are
essential to prevent adrenal insufficiency due to the
physiologically suppressed contralateral normal
adrenal gland
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28. Adrenocortical Cancer…
 Rare, worldwide incidence with 2 per million
 Bimodal age distribution
 Children and adults in 4th/5th decade affected
 Sporadic, but occasionally related with Li
Fraumeni and MENIN
 50% are non-functioning tumors, 30% are
functioning
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29. Adrenocortical Cancer…
 Clinical features:
 Non-functioning tumors present with abdominal
mass, pain, weight loss, anorexia
 Functioning tumors can secrete a number of
hormones and present with rapid onset of Cushing’s
syndrome as well as virilization features
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30. Adrenocortical Cancer…
 Laboratory diagnosis:
 Hypokalemia
 Urinary catecholamines ( to rule out
pheochromocytoma)
 Overnight 1 mg dexamethasone suppression test
(to rule out Cushing’s syndrome)
 24 hr. urine collection cortisol(to rule out Cushing’s
syndrome)
 Urinary 17-Ketosteroids
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31. Adrenocortical Cancer…
 Imaging: CT, MRI
 Features of malignancy include large size of tumor,
heterogeneity, presence of hemorrhage, adjacent
LAP, liver metastasis, local invasion of surrounding
structures
 Helps to diagnose distant metastasis
 Pathology- difficult to differentiate benign from
carcinoma
 Rather vascular and capsular invasion are used as
indicators
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32. Adrenocortical Cancer…
 Treatment:
 Open adrenalectomy: Resection of tumor enbloc
with surrounding LN and invaded structures
 Chemotherapy
 Mitotane- adjuvant treatment that has adrenolytic
effects
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33. Sex Hormone Secreting Tumors
 Clinical features:
 Virilizing adrenal tumors
 In females: hirsutism, amenorrhea, infertility, increased
muscle mass, deepening of voice, temporal balding
 In males, difficult to diagnose. They commonly present late
 In boys: precocious puberty (facial hair, deepening of voice,
enlargement of genitalia), accelerated growth
 Feminizing adrenal tumors
 In Males: gynecomastia, impotence, testicular atrophy
 In females: DUB, irregular menses, vaginal bleeding in post-
menopausals
 In girls: precocious puberty ( breast enlargement,
menarche)
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34. Sex Hormone Secreting Tumors
 Diagnosis:
 Virilizing tumors:
 Urine 17-ketosteroids raised
 Glucocorticoids increased
 Feminizing tumors:
 Urine 17-ketosteroid
 Estrogen increased
 Radiologic investigation
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35. Sex Hormone Secreting Tumors
 Treatment:
 Adrenalectomy
 Adrenolytic drugs:
 Mitotane
 Aminoglutethimide
 ketoconazole
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36. Pheochromocytoma
 A rare tumor, 1.9 % prevalence based on
screening
 Peak at 4th-5th decade of life
 ‘known to be “the ten percent tumor”
 10% are bilateral
 10% are malignant
 10% occur in pediatric patients
 10% are extra-adrenal
 10% are familial
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37. Pheochromocytoma…
 Many familial syndromes associated with it, the
commonest being are MEN-2Aand MEN-2B
followed by VHL genes
 Clinical feature:
 The classic triad is headache, palpitation,
diaphoresis
 Other non-specific complaints are anxiety,
tremsulousness, paresthesia, flushing, chest pain,
SOB, abdominal pain, nausea, vomiting
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38. Pheochromocytoma…
 Clinical features…
 The above symptoms can be induced by exercise,
micturition, defecation
 Cardiovascular complications- MI, cerebrovascular
accident
 Hypertension- is very important sign, it can be
paroxysmal or sustained
 Sudden death can occur in undiagnosed patients
who undergo other surgeries or biopsies
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39. Pheochromocytoma…
 Diagnosis:
 Can be biochemical or radiologic
 Biochemical:
 24 hrs. urine sample for catecholamine and their
metabolites (E.g. Homovanillic acid, Vanillymandelic acid)
 Urinary metanephrine
 Plasma free metanephrine- most reliable
 Fractionated urinary catecholamine (nor-epinephrine,
epinephrine, dopamine)- confirmatory test
 Abnormal clonidine suppression test- In
Pheochromocytoma there won’t be suppression
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40. Pheochromocytoma…
 Radiologic- to localize and assess extent of spread
 CT
 MRI
 Scintigraphy with MIBG (Metaiodobenzyl guanide)
 Radiolabeled MIBG helps to localize extra-adrenal
tumors when biochemistry is positive
 Also genetic testing recommended
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41. Pheochromocytoma…
 Malignant pheochromocytomas can be difficult to
diagnose as there is no histologic criteria
 Diagnosed in the presence of evidence for local
invasion to surrounding structures or distant
metastasis ( bone, liver, LN, lung, peritoneum)
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42. Pheochromocytoma…
 Treatment:
 Medical for BP control and volume repletion
 α-blocker like phenoxybenzmine started 1-3 weeks
before surgery
 β-blocker like propranolol pre-operatively for
patients with tachycardia and arrhythmia
 Volume repletion after surgery to prevent
hypotension from loss of vasoconstriction
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43. Pheochromocytoma…
 Treatment…
 Surgical – Open or laparoscopic Adrenalectomy
done depending on the size of tumor
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44. Adrenal Incidentaloma
 Adrenal lesion discovered during imaging
performed for unrelated reason
 Incidence 0.4 to 4.4%
 Majority are non-functional (36-94%), but sub-
clinical Cushing’s syndrome may be associated
 Adrenal can be also a metastasis site for lung,
breast neoplasms, melanoma, Renal cell
Carcinoma, lymphoma
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45. Adrenal Incidentaloma…
 DDx
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46. Adrenal Incidentaloma
 Approach for diagnosis: All of the following
screening tests should be done
Low dose overnight Dexamethasone suppression
test OR 24 hrs. urine cortisol AND Determination
of 17-ketosteroids
24-hrs. urine collection for catecholamine,
metanephrine, VMA OR plasma metanephrine
Serum electrolytes, plasma aldosterone, plasma
renin
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47. Adrenal Incidentaloma
 Confirmatory tests can be done based on results
 Radiologic- CT, MRI, NP-59 radionucleotide
imaging
 NP-59 uptake implicates benign lesion
 NP-59 absence is predictive of non-adenomatous
lesion
 FNAB has very limited role
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48. Adrenal Incidentaloma…
 Approach to management:
1. Functional tumor is indication for adrenalectomy
2. Non- functional
 If past history of cancer is present adrenalectomy
or systemic therapy can be given depending on
the case. If there is no such history, risk
assessment should be done
3. Risk assessment for being malignant
 Management depends on the size of tumor and
imaging features that predict malignancy. In
absence of malignancy features, the lesions can
be followed biannually
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49. Reference
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 Schwartz, 1928. Principles of Surgery, 9th Ed. (F.
C. Brunicardi et al Eds.) Mc Graw Hill Education

50. QUESTIONS?