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166
B. James and N. Chaves
– 2% in patients <70years old
– 7% in patients >70years old
– 1.1–8.7% in autopsy studies
– 0.6–5% in computer tomography studies.
Differential Diagnosis [1, 4–9]
• The etiology of an AI is variable, and it can include tumors from the adrenal
cortex, adrenal medulla, or from metastases to the adrenal gland.
• Adrenal Cortex
– Adrenocortical adenoma: a benign neoplasm of adrenocortical cells that may
be non-secretory or secretory.
Approximately 80% of cases are non-secretory.
Secretory adenomas may produce:
Glucocorticoids (independent of ACTH).
Mineralocorticoids (independent of the renin-angiotensin system).
Estrogens or androgens, very rare.
Cortisol-producing adenoma: autonomous cortisol secretion (See Chap.
19: Hypercortisolism).
5% have subclinical Cushing syndrome
Aldosterone-producing adenoma: autonomous aldosterone secretion (See
Chap. 20 Hyperaldosteronism).
Found in 1% of patients.
May be associated with familial syndromes.
Multiple endocrine neoplasia type 1 (MEN 1).
Familial adenomatous polyposis (FAP).
– Adrenocortical carcinoma (ACC): a rare, aggressive malignancy with an inci-
dence of 1 to 2 per million persons per year (See Chap. 22: Adrenal Metastasis
and Adrenocortical Carcinoma).
– Bilateral adrenocortical tumors: Less than 15% of AI cases are bilateral.
Most are benign lesions: bilateral cortical adenomas or nodular hyperplasia.
Other causes: metastatic lesions, invasive diseases, congenital adrenal
hyperplasia, and bilateral pheochromocytomas.
• Adrenal Medulla
18 Adrenal Incidentaloma: Differential Diagnosis andWorkup
– Catecholamine-secreting tumors arising from within the adrenal gland are
called pheochromocytomas (See Chap. 21: Pheochromocytoma and
Paraganglioma).
Pheochromocytomas can be benign or malignant and can occur at any age
(most common fourth to fth decade of life).
They are rare, with an incidence of 0.8 per 100,000 person-years.
40% are due to hereditary syndromes:
Von Hippel Lindau (VHL).
Multiple endocrine neoplasia type 2 (MEN2).
Neurobromatosis type 1 (NF1).
• Metastasis
– Adrenal glands are common sites for metastases.
– Metastases to the adrenal gland may be bilateral.
– The most common primary sites:
Lung: 35%.
Followed by gastrointestinal system, kidney, and breast.
History andPhysical [1, 2, 10]
167
• AIs are most commonly asymptomatic unless hormonally active.
• Focus on evaluating for hormonally active tumors and signs of malignancy
(Table18.1).
• Review of systems:
Table 18.1 Signs and symptoms of adrenal tumor type
Tumor type Symptoms Signs
Cortisol producing Muscle weakness, easy bruising/
bleeding, ushing, palpitations,
poor wound healing
Aldosterone
producing
Adrenocortical
carcinoma
Pheochromocytoma Episodic headaches, sweating,
Metastasis None related to adrenal tumor Consistent with primary tumor, may
Non-functional mass Mass effect: Vague abdominal pain May be able to palpate
a
Depends on the type of secreting hormone
Muscle cramping, muscle
weakness, fatigue, polydipsia,
polyuria
Mass effect, Cushing syndrome/
virilization
palpitations, pallor, anxiety,
ushing, sense of impending doom
a
Moon facies, buffalo hump, central
obesity, abdominal striae,
hypertension, hyperglycemia
Refractory hypertension,
hypokalemia
May be able to palpate, hormone
secretion signs
Hypertension, tachycardia,
congestive heart failure, tremors
have adrenal insufciency
168
B. James and N. Chaves
– Headaches, ushing, palpitations, tremor, anxiety, easy bruising or bleeding,
insomnia, fatigue, weakness, muscle cramping, poor wound healing, sudden
changes in weight, and hair loss.
– Symptoms associated with mass effect: abdominal pain, ank pain, early sati-
ety, nausea, and vomiting.
• Personal History:
– Hypertension, hypertensive crisis, cardiovascular disease, previous myocar-
dial or cerebrovascular accident, fractures, and hyperglycemia.
– Ask about age-appropriate cancer screening.
• Family History:
– History of adrenal masses or sudden death.
• Physical examination.
– Measure blood pressure, heart rate, and weight.
– Check for physical hormonal characteristics: moon facies, buffalo hump, cen-
tral obesity, supraclavicular fat, thinned skin, ecchymoses, proximal muscle
weakness, acne, hirsutism, tremor, and peripheral wasting.
Diagnostic Approach [3, 10–12]
• All tumors greater than 1cm require assessment for hormone excess and malig-
nancy (Table18.2).
– Laboratory assessment is done to evaluate: cortisol excess, pheochromocy-
toma, and primary hyperaldosteronism.
• Imaging: AIs are most commonly diagnosed with computed tomography (CT).
– They may also be detected via MRI and ultrasound.
Table 18.2 Laboratory tests for each clinical diagnosis
Clinical diagnosis Laboratory test
Cortisol excess • Low-dose dexamethasone suppression test
• 24h urine free cortisol
Pheochromocytoma • Serum fraction metanephrines
• 24h urine fractionated metanephrines and fractionated
catecholamines
Primary
hyperaldosteronism
Adrenocortical carcinoma • Low-dose dexamethasone suppression test
• Plasma aldosterone concentration
• Plasma renin activity
• Basic metabolic panel which includes potassium
• Serum dehyroepiandrosterone sulfate
18 Adrenal Incidentaloma: Differential Diagnosis andWorkup
169
– Imaging studies cannot distinguish between functional and non-functional
adrenal masses.
• Adrenal biopsy: should never be performed without conrmation that the tumor
is inactive and should only be performed if the result will alter treatment or if
tissue is needed for subsequent management (i.e., clinical trial for adrenal metastasis or concern for retroperitoneal sarcoma).
– If ACC is suspected, the mass should not be biopsied.
– Risks: hematoma, pancreatitis, pneumothorax, hematuria, abscess formation,
and seeding of tumor cells along the needle track.
Management [3, 10]
• Management depends on the size of the tumor and biochemical evaluation
(Fig.18.1).
• Team should consist of an endocrinologist, radiologist, pathologist, and endo-
crine surgeon.
• Depending on factors such as patient age and nal pathology, referral to genetic
counseling should be considered.
• Surgical approaches:
– Open:
Anterior transabdominal.
Posterior retroperitoneal.
– Minimally invasive:
Laparoscopic transabdominal.
Posterior retroperitoneoscopic.
Includes robotic and single-port options.
• Minimally invasive adrenalectomy is the gold standard for most adrenal masses.
• ACC: often performed via an open approach due to high risk of local recurrence
and peritoneal carcinomatosis with capsule disruption or inadequate en bloc
resection of involved surrounding structures.
• Small, benign, non-functional masses, that require no surgery: no need for
follow-up.
– Characteristics: non-functional adrenal mass, <4cm, benign imaging charac-
teristics, and non-contrast HU less than 10.
• Nodules 1–4cm with indeterminate imaging characteristics (e.g., CT HU>10).
– At least 1 repeat imaging at 6–12months.
170
B. James and N. Chaves
Adrenal Incidentaloma on
<4 cm with benign characteristics
(homogenous, regular borders, HU <10 on
(PAC/PRA; plasma free metanephrines and
normetanephrines; and overnight 1-mg
Fig. 18.1 Algorithm for the evaluation and management of an adrenal incidentaloma. *CT
HU<10; **CT HU>10; CT computed tomographic, HU Hounseld units; PAC plasma aldosterone concentration, PRA plasma renin activity. Permission was granted to utilize Fig.18.1. This
article was published in Endocrine Practice, volume 15. Zeiger MA, Thompson GB, Duh QY, etal.
American Association of Clinical Endocrinologists and American Association of Endocrine
Surgeons Medical Guidelines for The Management of Adrenal Incidentalomas. Figure18.1 only.
Copyright Elsevier. 2009
noncontrast CT scan)
Hormonally active
dexamethasone suppression test)
Ye s
Adrenalectomy
No follow-up
Benign*
imaging
≥4 cm on CT scan:
indeterminate or malignant
Adrenalectomy after hormonal
evaluation
Indeterminate**No
Follow-up with
imaging
• Autonomous cortisol secretion: most common excess to develop.
– May reevaluate at a 2- to 5-year interval.
• Myelolipomas and adrenal cysts with pathognomonic imaging features and no
symptoms of mass effect: do not resect.
– Consider resection if indeterminate imaging, symptoms related to mass effect,
substantial growth on surveillance, and/or hemorrhage.
References
1. Sherlock M, Scarsbrook A, Abbas A, etal. Adrenal incidentaloma. Endocr Rev. 2020;41:6.
https://doi.org/10.1210/endrev/bnaa008.
2. Duh QY.Adrenal gland: new guidelines for adrenal incidentalomas. Nat Rev Endocrinol.
2016;12(10):561–2. https://doi.org/10.1038/nrendo.2016.148.
18 Adrenal Incidentaloma: Differential Diagnosis andWorkup
3. Yip L, Duh Q-Y, Wachtel H, et al. American Association of Endocrine Surgeons guidelines for adrenalectomy: executive summary. JAMA Surg. 2022;157(10):870–7. https://doi.
org/10.1001/jamasurg.2022.3544.
4. Cramer JD, Fu P, Harth KC, Margevicius S, Wilhelm SM.Analysis of the rising incidence of
thyroid cancer using the surveillance, epidemiology and end results national cancer data registry. Surgery. 2010;148(6):1147–53. https://doi.org/10.1016/j.surg.2010.10.016.
5. Shiroky JS, Lerner-Ellis JP, Govindarajan A, Urbach DR, Devon KM.Characteristics of adrenal masses in familial adenomatous polyposis. Dis Colon Rectum. 2018;61(6):679–85. https://
doi.org/10.1097/DCR.0000000000001008.
6. Lam AKY. Adrenocortical carcinoma: updates of clinical and pathological features after
renewed world health organisation classication and pathology staging. Biomedicines.
2021;9(2):1–25. https://doi.org/10.3390/biomedicines9020175.
7. Mantiri BJ, Sigumonrong Y.Bilateral adrenal tumor: a case report and current challenges. Int J
Surg Case Rep. 2021;84(May):106134. https://doi.org/10.1016/j.ijscr.2021.106134.
8. Vassiliadi DA, Partsalaki E, Tsagarakis S.Approach to patients with bilateral adrenal incidentalomas. Curr Opin Endocrinol Diabetes Obes. 2020;27(3):125–31. https://doi.org/10.1097/
MED.0000000000000536.
9. Copeland PM. The incidentally discovered adrenal mass: an update. Endocrinologist.
1999;9(6):415–23. https://doi.org/10.1097/00019616- 199911000- 00003.
10. Jason DS, Oltmann SC. Evaluation of an adrenal Incidentaloma. Surg Clin North Am.
2019;99(4):721–9.
11. Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European
Society of Endocrinology Clinical Practice Guideline in collaboration with the European
Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016;175(2):G1–G34. https://
doi.org/10.1530/EJE- 16- 0467.
12. Arellano RS, Harisinghani MG, Gervais DA, Hahn PF, Mueller PR.Image-guided percutaneous biopsy of the adrenal gland: review of indications, technique, and complications. Curr
Probl Diagn Radiol. 2003;32(1):3–10. https://doi.org/10.1067/cdr.2003.120002.
171
Chapter 19
Hypercortisolism
LatoyaA.Stewart andLilahF.Morris-Wiseman
Overview [1–6]
• Hypercortisolism describes a state of glucocorticoid excess.
• The eponym Cushing syndrome (rst described by Harvey Cushing in 1912)
refers to pathological hypercortisolism with characteristic clinical sequelae.
• There are two mechanisms of hypercortisolism:
– Exogenous (most common), resulting from the prolonged use of glucocorti-
coids to treat inammatory conditions or for transplantation immunosuppression.
– Endogenous, resulting from adrenal cortisol overproduction.
• Perioperative identication of exogenous hypercortisolism is critical for treat-
ment of patients who may be at risk for postoperative adrenal insufciency
(related to the stress of a surgical procedure).
• This chapter will focus on endogenous hypercortisolism which is subdivided
into adrenocorticotropic hormone (ACTH)-dependent and independent disease.
L. A. Stewart · L. F. Morris-Wiseman (*)
Division of Endocrine Surgery, Department of Surgery, Johns Hopkins University School of
Medicine, Baltimore, MD, USA
e-mail: lstewa47@jhmi.edu; lmorri54@jhu.edu
Switzerland AG 2024
R. M. Gartland, J. A. Lee (eds.), Endocrine Surgery Clerkship, Contemporary
Surgical Clerkships, https://doi.org/10.1007/978-3-031-62091-1_19
173© The Author(s), under exclusive license to Springer Nature
174
L. A. Stewart and L. F. Morris-Wiseman
Adrenal Cortex Anatomy [1]
• The adrenal glands are comprised of two embryologically distinct tissues—cor-
tex (mesoderm) and medulla (ectoderm/neural crest cells).
• Adrenal cortical tissue produces different classes of corticosteroids (steroid
hormones).
• Glucocorticoids are produced in the zona fasciculata (middle layer) of the adre-
nal cortex.
Physiology [1, 2]
• Hypothalamic neurons release corticotropin-releasing hormone (CRH) into the
hypothalamic-pituitary portal system in response to stress, leading to ACTH
secretion by the anterior pituitary gland.
• ACTH is released in a pulsatile fashion following a circadian rhythm and binds
to G protein-coupled receptors on the cell surface, which stimulates glucocorticoid secretion after a series of intracellular oxidative reactions. For this reason,
ACTH and cortisol levels are typically highest within 1h of waking, then gradually decline throughout the day.
• Cortisol, the primary glucocorticoid, generates a catabolic state in peripheral tis-
sues, causing alterations in carbohydrate, protein, and lipid metabolism, which
ultimately increases blood glucose levels.
Clinical Presentation [1, 2, 6–9]
• Hypercortisolism may be detected through obtaining a thorough history and
physical including investigation into symptoms, comorbid conditions, current
medications, blood pressure measurement, and skin exam (Table19.1).
• Signs and symptoms of cortisol excess include easy bruising, proximal muscle
weakness, changes in fat distribution (ex, buffalo hump and truncal obesity),
Table 19.1 Symptoms, physical exam ndings, and sequelae of hypercortisolism
History/review of systems Physical exam ndings Sequelae/objective ndings
Fatigue
Depressed mood
Emotional lability
Menstrual irregularities
Decreased libido
Impaired memory/cognition
Sleep disturbances
Easy bruising
Proximal muscle weakness
Weight gain
Moon facies
Facial plethora
Buffalo hump
Central adiposity
Peripheral edema
Striae
Acne
Hirsutism
Hypertension
Hyperlipidemia
Atherosclerosis
Hyperglycemia/insulin resistance
Osteoporosis/bone density loss
Impaired immunity
Hypokalemia
Hypercoagulability
Infertility
19 Hypercortisolism
striae, facial plethora, hirsutism, osteoporosis, and mood disturbance. These
symptoms may seem nonspecic in isolation; maintain a high degree of suspicion for hypercortisolism if patients present with multiple symptoms
simultaneously.
• Hypertension, hyperglycemia, insulin resistance, and an immunocompromised
and hypercoagulable state are also sequelae of cortisol excess.
• Hypercortisolism is associated with an increased mortality risk, particularly
from cardiovascular complications.
175
Differential Diagnosis [1, 2, 5, 9]
• Exogenous hypercortisolism (prolonged use of glucocorticoids).
• Endogenous hypercortisolism (cortisol overproduction by the adrenal glands).
– ACTH dependent (~90%):
Hypersecreting pituitary corticotrope adenoma, also known as Cushing
disease (80–90%).
Ectopic ACTH secretion by neuroendocrine tumors (ex, bronchial, pancreatic), or other neoplasm (10–20%).
– ACTH independent (~10%):
Adrenal adenoma (~90%).
Adrenal cortical carcinoma (ACC) (<10%).
Bilateral adrenal hyperplasia (<1%).
Diagnostic Workup (Fig.19.1) [1–6, 8, 10]
Biochemical
• Hypercortisolism is a biochemical diagnosis:
– Though over 90% of circulating cortisol is bound to plasma proteins, unbound
cortisol can be detected in urine and saliva. 24-h urine-free cortisol with concurrent creatinine measurement is the initial screening test (greater than 3x
normal values is diagnostic).
• Once hypercortisolism is conrmed, determine whether disease is ACTH-
dependent vs independent:
– Measure plasma ACTH levels (normal 10–60pg/mL for 8am sample). ACTH
<5pg/mL is highly indicative of an ACTH-independent process (adrenal neoplasm). Non-suppressed ACTH levels in a patient with hypercortisolism indicate an ACTH-dependent disease.
176
L. A. Stewart and L. F. Morris-Wiseman
Fig. 19.1 Diagnostic workup of hypercortisolism