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20 Hyperaldosteronism
Han MA, Smith PW, Wilhelm S, Asa SL, Fahey TJ 3rd, McKenzie TJ, Strong VE, Perrier
ND.American Association of Endocrine Surgeons Guidelines for adrenalectomy: executive
summary. JAMA Surg. 2022;157:870–7.
3. Reincke M, Bancos I, Mulatero P, Scholl UI, Stowasser M, Williams TA.Diagnosis and treatment of primary aldosteronism. Lancet Diabetes Endocrinol. 2021;9:876–92.
4. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A.Cardiometabolic outcomes and
mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet
Diabetes Endocrinol. 2018;6:51–9.
5. Funder JW, Carey RM, Mantero F, etal. The management of primary aldosteronism: case
detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin
Endocrinol Metab. 2016;101:1889–916.
6. Young WF, Stanson AW.What are the keys to successful adrenal venous sampling (AVS) in
patients with primary aldosteronism? Clin Endocrinol. 2009;70:14–7.
7. Williams TA, Burrello J, Sechi LA, Fardella CE, Matrozova J, Adolf C, Baudrand R, Bernardi
S, Beuschlein F, Catena C, Doumas M, Fallo F, Giacchetti G, Heinrich DA, Saint-Hilary
G, Jansen PM, Januszewicz A, Kocjan T, Nishikawa T, Quinkler M, Satoh F, Umakoshi H,
Widimský J Jr, Hahner S, Douma S, Stowasser M, Mulatero P, Reincke M.Computed tomography and adrenal venous sampling in the diagnosis of unilateral primary Aldosteronism.
Hypertension. 2018;72:641–9.
8. Burrello J, Burrello A, Stowasser M, Nishikawa T, Quinkler M, Prejbisz A, Lenders JWM,
Satoh F, Mulatero P, Reincke M, Williams TA. The primary Aldosteronism surgical outcome score for the prediction of clinical outcomes after adrenalectomy for unilateral primary
Aldosteronism. Ann Surg. 2020;272(6):1125–32.
9. Williams TA, Lenders JWM, Mulatero P, etal. Outcomes after adrenalectomy for unilateral
primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol. 2017;5:689–99.
187
Chapter 21
Pheochromocytoma andParaganglioma
CortneyY.Lee andAnnaM.Reagan
Introduction [1–3]
– Pheochromocytomas and paragangliomas (PPGL) are tumors that arise from
chromafn cells.
– Pheochromocytomas originate in the adrenal medulla and typically secrete cat-
echolamines (epinephrine, norepinephrine, dopamine).
– Paragangliomas develop from chromafn cells of the sympathetic paravertebral
ganglia of the thorax, abdomen, and pelvis or parasympathetic ganglia in the
neck. The location typically dictates if they are secreting. Head and neck paragangliomas often are non-functional.
– PPGL most commonly present between the third and fth decades of life.
– Prevalence of 0.2–0.6% of hypertensive patients in general outpatient clinics.
– Approximately 10–15% of PPGL are malignant.
Genetics [1, 2, 4]
– Approximately 40% of patients with PPGLs have a germline mutation.
– Because of this signicant percentage, all patients with PPGL should be consid-
ered for genetic testing.
– Patients with a genetic syndrome often present at a younger age and are more
likely to have bilateral and/or multifocal disease.
C. Y. Lee (*) · A. M. Reagan
Department of Surgery, University of Kentucky, Lexington, KY, USA
e-mail: cortney.lee@uky.edu; anna.reagan@uky.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_21
189© The Author(s), under exclusive license to Springer Nature
190
– The most common/widely known mutations (and associated syndromes) include:
SDHx (hereditary paraganglioma-pheochromocytoma), VHL (von HippelLindau), RET (MEN2), and NF1 (Neurobromatosis type 1).
– Knowledge of the mutation can help in preoperative planning, including screen-
ing for concomitant diseases (such as medullary thyroid cancer in MEN2), predicting risk of malignancy (SDHB has higher rate of malignancy compared to
other SDHx mutations), and determining risk of recurrence (twice as high in
familial PPGL).
C. Y. Lee and A. M. Reagan
Presentation [3–5]
– Patients with pheochromocytoma typically present with symptoms secondary to
excess catecholamine production.
– The classic triad of symptoms includes headache, diaphoresis, and palpitations.
However, very few patients present with all three.
– Other presenting symptoms may include anxiety, hypertension, orthostatic hypo-
tension, hyperglycemia, and a sense of impending doom.
– Symptoms are typically episodic. Episodes usually last 10–20min and can be
spontaneous or brought on by physical activity. Patients are often asymptomatic
and normotensive between episodes.
– Of note, patients may also be asymptomatic and are found to have PPGL inci-
dentally on imaging. Therefore, any patient with an adrenal incidentaloma should
undergo biochemical evaluation for pheochromocytoma if Hounseld units
(HU) on non-contrasted CT images are >10. Likewise, HU <10 excludes
pheochromocytoma.
– Non-functional paragangliomas (often head and neck) will present as a mass or
incidentally on imaging.
Biochemical Diagnosis [1–4]
– The adrenal medulla secretes catecholamines such as norepinephrine and epi-
nephrine. However, catecholamines are sporadically released and have short
half-lives; therefore, they are not best for biochemical diagnosis.
– Metanephrines (metanephrines and normetanephrines) are metabolites of cate-
cholamines, have relatively stable plasma levels, are excreted in urine, and are
more sensitive than catecholamines when diagnosing PPGLs.
– Patients with suspected PPGL should be tested for plasma-free metanephrines or
24-h urine metanephrines (often termed “fractionated metanephrines” meaning
the lab will report both metanephrines and normetanephrines).
21 Pheochromocytoma andParaganglioma
191
– While metanephrines are superior to catecholamines for diagnosing pheochro-
mocytomas, catecholamines can be useful to check for dopamine, which can be
secreted by paragangliomas.
– Remember, some paragangliomas (particularly head and neck) are
non-functional.
Imaging [1–4]
– CT abdomen (to include aortic bifurcation) is the preferred initial imaging
method for the evaluation of known functional PPGL. If non-localizing, then
functional imaging can be considered.
– Imaging characteristics of PPGL include increased attenuation on nonenhanced
CT (often >20 HU), delay in contrast washout, and increased vascularity
(Figs.21.1a and 21.2a).
– MRI can be used to evaluate paragangliomas at the skull base or within the neck.
– Functional imaging such as
(Fig.21.1b) or Ga-68 DOTATATE-PET scan (Fig.21.2b, c) can be used if CT
imaging is negative or if patients are at an increased risk of metastatic disease.
– FDG-PET scan should be reserved for patients with metastatic disease.
– For patients with a known paraganglioma syndrome (such as an SDHx muta-
tion), whole-body MRI is used for screening (approximately every 2years).
123
I-metaiodobenzylguanidine (MIBG) scintigraphy
ab
Fig. 21.1 Bilateral pheochromocytomas (larger right, smaller left) in a patient with a germline
MAX mutation. Contrast-enhanced CT (a) and MIBG SPECT/CT fusion (b)
192
C. Y. Lee and A. M. Reagan
abc
Fig. 21.2 Large right pheochromocytoma with intense peripheral enhancement and central necrosis (a). Note normal (non-pathologic) DOTATATE uptake in left adrenal gland (b,c). Contrastenhanced CT (a), DOTATATE PET/CT (b), whole body DOTATATE MIP (c)
Preoperative preparation [1–4]
– Preoperatively, patients with functional PPGLs require α-adrenergic blockade
for at least 7–14days prior to surgery. During this time, patients will require
volume resuscitation as alpha-mediated vasoconstriction is relaxed and should
be counseled to increase uid intake and temporarily add a little extra salt to their
diet as directed by their physician.
– Morbidity and mortality are similar between phenoxybenzamine (non-selective)
and selective alpha-blockers (e.g., doxazosin).
– While not a rst-line option, calcium channel blockers are occasionally used for
preoperative blockade either in place of or in addition to alpha blockade.
– After full alpha blockade, beta-blockade may be needed to control tachycardia.
– Beta blockade should not be initiated prior to alpha blockade as it allows for
unopposed α-adrenergic stimulation and can lead to hypertensive crisis.
– Medications should be adjusted until patients are normotensive and have a nor-
mal heart rate. With phenoxybenzamine, patients may experience nasal stufness and orthostatic hypotension, which is a clinical indicator of thorough
blockade.
Surgical Treatment [1–4]
– Minimally invasive adrenalectomy (laparoscopic or retroperitoneoscopic) is the
preferred surgical approach for most tumors.
– Open resection can be considered for paragangliomas, large tumors (>6cm), and
invasive pheochromocytoma.
– It is imperative to have an experienced anesthesia team due to uctuations in
hemodynamics during adrenalectomy for PPGL.Manipulation of the tumor can
21 Pheochromocytoma andParaganglioma
cause hypertension and patients often become hypotensive following division of
the adrenal vein.
– Adequate preoperative alpha blockade and volume resuscitation decreases intra-
operative hemodynamic instability.
– Patients with bilateral pheochromocytomas due to germline mutations should be
considered for cortical-sparing adrenalectomy (removal of only a portion of the
adrenal gland containing the pheochromocytoma with intent to avoid adrenal
insufciency by leaving functioning cortex) (Fig.21.3).
Pathology 6 [1–3, 6]
– Tumor biopsy is contraindicated prior to surgical resection of a primary PPGL
because percutaneous biopsy has been associated with signicant risks including
bleeding, hypertensive crisis, and death.
– The classic histologic pattern consists of nested (Zellballen) tumor cells that are
epithelioid and spindled. Sustentacular cells surround the nests, best seen with an
immunostain (Fig.21.4).
– Contrary to most other malignancies, cytology and/or histology cannot prove the
presence of malignant disease. However, certain pathologic scores (e.g., PASS)
can guide degree of suspicion.
– PPGL are only conrmed malignant when they have metastasized.
193
Fig. 21.3 Multiple
bilateral
pheochromocytomas in a
patient with a germline
MAX mutation. Total right
adrenalectomy containing
at least 3 dominant
pheochromocytomas
(>2cm each). Corticalsparing (partial) left
adrenalectomy containing
two small
pheochromocytomas
(~1cm each)
194
ab
Fig. 21.4 (a) Low power view: Well-circumscribed nodule (right) arising from medulla with adjacent normal adrenal gland (left). (b) High power view: Nested (Zellballen) pattern of pheochromocytoma with intervening vessels. Tumor cells are epithelioid to polygonal with abundant cytoplasm.
Nuclear pleomorphism and hyperchromasia are focally seen. No mitoses or necrosis
C. Y. Lee and A. M. Reagan
Follow Up [1, 2]
– For patients who have undergone surgical resection, plasma or urine metaneph-
rines should be measured at follow-up to assess for persistent disease.
– Annual biochemical testing is recommended to evaluate for recurrent or meta-
static disease.
– Patients with known PPGL syndromes should undergo yearly biochemical eval-
uation. Depending on the mutation, screening whole-body MRI should also be
considered every 2years.
Treatment ofMetastatic Disease [4]
– Radiation, chemotherapy, and high specic activity (therapeutic)
all be considered for metastatic or locally unresectable tumors.
– Even in the presence of metastatic disease, resection of the primary tumor can be
benecial. Pros and cons should be discussed by an experienced multidisciplinary team.
131
I-MIBG may
References
1. Lenders WJ, Duh Q, Eisenhofer G. Pheochromocytoma and paraganglioma: an endocrine
society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42. https://doi.
org/10.1210/jc.2014- 1498.
2. Shah MH, Goldner WS, Hochstetler C.Neuroendocrine and adrenal tumors, version 2.2021,
NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2021;19(7):839–68.
https://doi.org/10.6004/jnccn.2021.0032.
21 Pheochromocytoma andParaganglioma
3. Fishbein L, Del Rivero J, Jimenez C.The North American neuroendocrine tumor society consensus guidelines for surveillance and management of metastatic and/or unresectable pheochromocytoma and paraganglioma. Pancreas. 2021;50(4):469–93. https://doi.org/10.1097/
MPA.0000000000001792.
4. Yip L, Duh Q, Wachtel H, Jimenez C, Sturgeon C, Lee C, etal. American association of endocrine
surgeons guidelines for adrenalectomy executive summary. JAMA Surg. 2022;157(10):870–7.
5. Yeh MW, Livhits M, Duh Q.The adrenal glands. In: Townsend CM, Beauchamp RD, Evers
BM, Mattox KL, editors. Sabiston textbook of surgery: the biological basis of modern surgical
practice. 21st ed. St. Louis: Elsevier; 2022. p.964–97.
6. Guilmette J, Sadow P.A guide to pheochromocytomas and paragangliomas. Surg Pathol Clin.
2019;12:951–65.
195
Chapter 22
Adrenocortical Carcinoma andAdrenal
Metastasis
NicciOwusu-Brackett andBarbraS.Miller
Adrenocortical Carcinoma
Overview [1–3]
• Adrenocortical carcinoma (ACC) is rare with an incidence of 0.5–2 cases per
million in the population. ACC is most commonly identied during childhood
and between the ages of 40 and 50years.
• Adrenal malignancies are primarily identied incidentally on imaging studies
performed for unrelated symptoms. ACCs account for 2% of adrenal
incidentalomas.
Pathogenesis [4–8]
• 10% of ACCs are caused by germline genetic mutations; therefore, routine referral for consideration of genetic testing is recommended.
N. Owusu-Brackett (*)
Complex General Surgical Oncology, Division of Surgical Oncology, Department of Surgery,
The James Cancer Hospital and Solove Research Institute, Wexner Medical Center, The Ohio
State University, Columbus, OH, USA
e-mail: nicci.owusu-brackett@osumc.edu
B. S. Miller
OSU Comprehensive Adrenal Program, Division Director of Clinical Operations, Division of
Surgical Oncology, Department of Surgery, The James Cancer Hospital and Solove Research
Institute, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
e-mail: Barbra.Miller@osumc.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_22
197© The Author(s), under exclusive license to Springer Nature
198
N. Owusu-Brackett and B. S. Miller
• At least 40% of ACCs produce excess hormone. Cortisol and androgens are the
hormones most commonly secreted. Intermediary products in the steroid synthesis pathway may also be produced in excess.
• ACCs secreting cortisol or multiple hormones are associated with worse
outcomes.
Evaluation
History/Physical Examination
• A thorough history and physical examination should be performed, including a
family history.
• Patients with functional tumors may present with symptoms according to the
specic adrenal hormone produced in excess. Table22.1 lists the symptoms and
signs associated with each hormone.
• Patients with non-functional tumors may present with nonspecic symptoms
such as fatigue, weight gain or loss, abdominal pain, early satiety, or lower
extremity swelling. Some patients have no symptoms.
• Patients with advanced local or metastatic disease (lung, liver, bone) may present
with shortness of breath from pleural effusions, point tenderness of the spine, or
neurologic impairment due to nerve impingement or vertebral body fractures.
Laboratory Findings
• A comprehensive biochemical evaluation should be performed in all patients
with adrenal abnormalities. In those with indeterminate nodules/masses, intermediaries and end-products of the steroid synthesis pathway should be evaluated
as these can be used as tumor markers during long-term surveillance in those
diagnosed with ACC. Table 22.2 lists the typical biochemical evaluation for
patients found to have adrenal abnormalities on imaging.
Table 22.1 Symptoms and signs of hormone excess
Hormone Symptoms/signs
Aldosterone Hypertension, hypernatremia, hypokalemia, edema
Cortisol Moon facies, buffalo hump, striae, fatigue, hyperglycemia, weight gain,
hirsutism, easy bruising, hypercoagulability, emotional lability, hypertension,
hypokalemia
Androgens and
estrogens
Changes to secondary sexual characteristics