Endocrine Incidentalomas: Current Problems in Surgery

Current Problems in Surgery 53 (2016) 219–246
Contents lists available at ScienceDirect
Current Problems in Surgery
journal homepage: www.elsevier.com/locate/cpsurg
Endocrine incidentalomas
Lee F. Starker, MD, PhDa, Peter A. Prieto, MD, MPHa,
J. Spencer Liles, MDb, Hop S. Tran Cao, MDc,
Elizabeth G. Grubbs, MD, MSa, Jeffrey E. Lee, MDd,
Nancy D. Perrier, MDa, Paul H. Graham, MDa,n
Incidental thyroid nodule
Thyroid nodules are ubiquitous in the general population, with an estimated prevalence of
4%-7%.1 However, the true prevalence of thyroid nodules is likely far greater than reported.
Autopsy studies have demonstrated thyroid nodules in 50%-60% of adults.2 Most thyroid nodules
are indolent in nature and manifest as incidental findings discovered by the patient, their
primary care physicians, or in more contemporary times, by common diagnostic imaging.
Nonpalpable nodules detected during the evaluation of separate disorders are deemed
“incidentalomas,” and the appropriate evaluation of a patient with newly discovered thyroid
nodules is an essential part of any clinical practice.
Clinical evaluation
The primary objective in the evaluation of a newly diagnosed thyroid nodule is to exclude a
primary thyroid malignancy. Thyroid carcinoma may account for 4%-6.5% of all thyroid nodules,3
of which the majority are well-differentiated thyroid carcinomas. The risk of malignancy in
nonpalpable nodules is equal to that of similar-sized palpable nodules;4 therefore, incidenta-
lomas should be evaluated similarly. The initial patient encounter should include an assessment
of the patient's medical history for specific factors associated with an increased risk of
malignancy, including a history of childhood head and neck irradiation, total body irradiation,
family history of thyroid carcinoma, or a history of hereditary syndromes associated with thyroid
From the a University of Texas M.D. Anderson Cancer Center, Houston, TX; b University of South Alabama, Mobile, AL;
c
Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Houston, TX; and
d
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; nAddress reprint
requests to Paul H. Graham, MD, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center,
1400 Pressler St, Unit 1484, Houston, TX 77030. E-mail address: [email protected] (P.H. Graham)
http://dx.doi.org/10.1067/j.cpsurg.2016.04.001
0011-3840/& 2016 Elsevier Inc. All rights reserved.
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220 L.F. Starker et al. / Current Problems in Surgery 53 (2016) 219–246
cancer, including multiple endocrine neoplasia type 2 (MEN2), Cowden syndrome, Carney
complex, and familial polyposis.
The patient should be assessed for any signs or symptoms of potentially invasive thyroid
pathology including dysphagia, dyspnea, pain, globus sensation, or change in voice strength or
quality. Additionally, the patient should be evaluated for any manifestations of hyperthyroidism
or hypothyroidism. The neck examination should focus on the thyroid gland and adjacent
cervical lymph node basins for any firm or fixed nodules or masses. Flexible indirect
laryngoscopic evaluation of vocal cord movement can be employed selectively, predominantly
for patients with recent changes in voice quality, radiographic concern of compressive or
invasive tumors, or a prior history of neck or thoracic surgery in which the recurrent laryngeal
nerves were at risk for injury.5
The biochemical evaluation of a thyroid nodule should begin with a baseline assessment of
thyroid hormone function by measurement of serum thyroid-stimulating hormone (TSH) and
free thyroxine (T4) levels. A low or suppressed serum TSH is consistent with hyperthyroidism
and in the setting of thyroid nodules can be indicative of an autonomous, hyperfunctioning
nodule, or a toxic multinodular goiter. An elevated serum TSH is consistent with hypothyroidism,
and high levels have been described as independent predictors of both thyroid malignancy and
stage.6,7 Measurement of antithyroid peroxidase antibodies can help identify the presence of
chronic autoimmune (Hashimoto's) thyroiditis, where lymphocytic infiltration of the paren-
chyma can decrease thyroid function over time and produce a pseudonodular appearance to the
gland. Routine measurement of serum thyroglobulin (Tg), a tissue-specific marker used in the
surveillance of well-differentiated carcinomas, is not recommended in the initial evaluation of a
thyroid nodule because Tg levels are insensitive and nonspecific for cancer in the setting of an
intact thyroid gland.8 Likewise, routine measurement of serum calcitonin to screen for
medullary thyroid cancer may be nonspecific, as reference ranges are not standardized in the
setting of an intact thyroid gland.
Imaging
All patients with an incidentally discovered thyroid nodule should undergo dedicated
imaging to further characterize the nodule for any features concerning for thyroid cancer. The
primary imaging procedure of choice in a euthyroid patient is a comprehensive thyroid
ultrasound inclusive of the adjacent central and lateral neck compartments. Ultrasound provides
excellent anatomical detail of both the clinically apparent and the incidental thyroid nodule and
often discovers other unidentified nodules during the evaluation. Ultrasound discovers
incidental thyroid nodules in 50%-60% of patients with a clinically normal neck examination,9-11
and when compared with abnormal physical examination findings by primary care physicians,
ultrasound findings were different in up to 63% of cases,12 therefore providing more accurate
diagnostic information.
Several sonographic features are important in the characterization of a thyroid nodule,
specifically in predicting malignancy.13 Features suspicious for malignancy include nodule
hypoechogenicity as compared with adjacent normal thyroid parenchyma, increased intra-
nodular vascularity, presence of microcalcifications, indistinct infiltrative borders, and height
greater than width14 (Fig 1). The presence of any one of these features has a high sensitivity for
malignancy, and the presence of multiple features yields a positive predictive value for
malignancy of up to 97% in select series.15 Conversely, nodules exhibiting cystic or spongiform
appearances, hyperechogenicity, and comet-tail shadowing have high negative predictive values
for malignancy.
Ultrasound is also invaluable for the detection and aspiration of suspicious cervical
lymphadenopathy. Local-regional nodal metastases are often not clinically apparent, and when
discovered in the setting of a suspicious-appearing thyroid nodule, are concerning for metastatic
thyroid carcinoma. Preoperative identification by ultrasound is important for surgical planning
and may alter the extent of resection in as many as 39% of patients.16 Suspicious sonographic
L.F. Starker et al. / Current Problems in Surgery 53 (2016) 219–246 221
features include a rounded or cystic shape, loss of the characteristic fatty hilum, necrosis, and
calcifications.
In the hyperthyroid patient, functional imaging studies may be more useful than ultrasound
in the initial evaluation of a thyroid nodule. Thyroid scintigraphy with iodine-123 or
technetium-99 m pertechnetate radioisotopes is useful for differentiating diffuse gland hyper-
function from autonomous hormone production by a solitary thyroid nodule. Autonomous “hot”
nodules display more uptake than the surrounding thyroid parenchyma (Fig 2) and do not
typically require further evaluation by fine-needle aspiration (FNA), as the risk of malignancy is
low.1,17 Conversely, certain authors note that the risk of malignancy may not be as negligible as
previously reported and recommend additional screening for those patients not undergoing
surgical management of the hot nodule.18,19 Thyroid scintigraphy can also identify non-
functioning “cold” nodules that demonstrate less isotope uptake as compared with the
Fig. 1. Sonographic features suspicious for malignancy. (A) Hypoechogenicity, (B) microcalcifications, (C) infiltrative
borders, and (D) hypervascularity. (Color version of figure is available online.)
surrounding thyroid tissue. Nodules with low or indeterminate uptake should undergo further
evaluation by thyroid ultrasound to further characterize the nodule.
Incidental thyroid nodules are also commonly discovered by various advanced imaging
modalities, including computed tomography (CT), magnetic resonance imaging (MRI), and
positron emission tomography (PET), although these modalities are not typically used in the
primary evaluation of a thyroid nodule. Ultrasound provides excellent anatomical detail, is
readily available, and it has no associated radiation exposure risks, making the use of the other
modalities more selective. CT is useful in delineating compressive effects, substernal extension,
extrathyroidal tumor extension or invasion, and the degree of lymphadenopathy in locoregional
metastasis.20 MRI has similar utility, although it is used less frequently. PET imaging may identify
increased uptake in a thyroid nodule in up to 2.3% of patients undergoing whole body imaging.
The specificity for thyroid carcinoma is low, with only 27%-42% ultimately proving to be
papillary thyroid carcinoma,21,22 but the discovery should prompt further ultrasound evaluation.
Diagnosis
Ultimately, the imaging characteristics of a concerning thyroid nodule alone are not enough
to render a definitive diagnosis of malignancy, and tissue acquisition for a histologic diagnosis is
recommended for treatment planning. FNA is the procedure of choice for the diagnostic
assessment of suspicious thyroid nodules and is commonly performed by various clinical
providers, including radiologists, endocrinologists, and surgeons. FNA provides diagnostically
useful results in up to 80% of cases23 and with the incorporation of ultrasound guidance, reduces
insufficient cytology samples by one-half.24 The false-negative rate of a benign diagnosis is less
than 3%, and the positive predictive value for malignancy is greater than 97%.25
Typically, a small-bore needle (23-27 gauge) is passed into the nodule of concern under
image guidance. The specimen is then obtained by the application of syringe suction or by
repetitive passes through the nodule along the same biopsy tract. The aspirated material is then
immediately fixed onto slides or washed into liquid preservative for subsequent cytospin and
slide preparation. Multiple separate fine-needle passes are recommended per nodule of concern.
Other techniques include the use of large-bore needle aspiration (15-21 gauge) or core needle
biopsies for tissue acquisition. The larger specimens obtained in these techniques may lead to
Fig. 2. Toxic adenoma. Increased tracer uptake in a dominant, left-sided nodule on thyroid scintigraphy. (Photo courtesy
of Hubert Chuang MD).
lower rates of inadequate specimens but are less commonly used owing to concern for
procedural bleeding and patient discomfort.
FNA indications
The 2009 Revised ATA Thyroid Cancer Guidelines provide recommendations for FNA of
thyroid nodules based on sonographic and clinical features.17 Generally, routine FNA of
subcentimeter nodules is not recommended unless patients demonstrate a high-risk clinical
history or clinically evident abnormal lymph nodes. FNA of nodules 1.0-1.5 cm in size should
focus on lesions with suspicious ultrasonographic features, whereas FNA of mixed cystic-solid
nodules is recommended when greater than 2.0 cm. Aspiration should focus on the solid
component of heterogenous nodules because a malignancy is more likely to be discovered in this
portion. Purely cystic nodules do not require biopsy as they carry a low risk of malignancy,
although aspiration may prove therapeutic as well. Patients with multiple nodules should have
each nodule evaluated individually, as the prevalence of thyroid cancer is the same as in patients
with solitary nodules.26 In patients with excessive numbers of thyroid nodules, aspiration of the
most concerning nodule in each lobe at the initial encounter is appropriate, with further
evaluation of the remaining nodules reserved for separate serial encounters.
FNA results and Bethesda criteria
Further management of the incidental thyroid nodule should be based on cytologic results
from the fine-needle aspiration25 (Table 1). An aspiration lacking sufficient tissue to make a
cytologic diagnosis is considered nondiagnostic. Repeat FNA with ultrasound guidance and
immediate on-site cytologic assessment of specimen adequacy is recommended for improved
diagnostic yield. Additionally, the use of core needle biopsy may increase diagnostic yield.
Regardless of these added techniques, up to 7% would continue to result in nondiagnostic
specimens. As neither benign nor malignant results can be inferred from the specimen, surgical
excision is recommended for larger nodules or those with concerning imaging features. Serial
surveillance can be considered for smaller or less-concerning nodules.
Most FNA will result in benign cytology. Possible benign diagnoses include adenomatous or
hyperplastic nodules, colloid adenomas, simple and complex cysts, and thyroiditis with
pseudonodular appearance. Benign thyroid nodules can be managed nonsurgically unless they
demonstrate rapid serial enlargement, compressive symptoms secondary to their overall size, or
autonomous thyroid hormone production.
Surgical resection is commonly performed for solitary toxic adenomas and toxic goiters.
Graves thyrotoxicosis can be treated by multiple modalities, including antithyroid thionamide
medications, radioactive iodine ablation, or surgery. Surgery is preferred in instances when
patients have adverse reactions to antithyroid medications or have contraindications to
receiving radioactive iodine therapy. Thionamides can cause elevation of liver transaminases
and decrease in absolute neutrophil counts; therefore, serial biochemical assessment is
necessary to evaluate for medication tolerance. Radioactive iodine treatment is contraindicated
in pregnant patients and in those patients where therapy could worsen existing ophthalmopathy.
Table 1
Bethesda diagnostic categories and associated risk of malignancy.
Category Risk of malignancy
Nondiagnostic
Benign o3%
Follicular lesion or atypical cells of undetermined significance 5%-10%
Follicular neoplasm 20%-30%
Suspicious for malignancy 50%-75%
Malignant 100%
Additionally, larger compressive goiters as a result of Graves disease are unlikely to resolve
without operative management.
The false-negative rate of a benign aspiration is low, although some studies have noted a
concern for false-negative rates of up to 13% in nodules greater than 3 cm in size.27,28 Repeat
aspirations of stable nodules are not indicated, as the novel detection of malignancy is
uncommon. Routine ultrasound surveillance of known thyroid nodules should be performed in
6-month to 1-year intervals, with lengthening intervals appropriate after a period of stable
surveillance. Repeat aspiration may be indicated for nodules that have demonstrated a change in
clinical symptoms, ultrasonic characteristics, or increase in size. As most thyroid nodules would
demonstrate growth over time,29 significant change is defined as an increase in nodule volume
of greater than 50% or a 20% increase in nodule diameter with a minimal increase in 2 or more
dimensions of at least 2 mm. Again, even in previously benign nodules that have grown over
time, malignancy is rare.30,31 Only a small portion of patients demonstrate an overall decrease in
nodule size, with little difference demonstrated by the addition of thyroid hormone therapy to
shrink the thyroid nodule. Additionally, any decrease in size may be nonspecific for benign
disease as up to 13% of papillary cancers decrease in size with T4 treatment.32
Atypical cells of undetermined significance (ACUS) and follicular lesions of undetermined
significance (FLUS) are indeterminate cytologic categories in which specimens do not fully
demonstrate benign features, yet they lack the characteristics to fully categorize them as
malignant. ACUS lesions demonstrate nuclear atypia, and FLUS demonstrate mixed macro-
follicular and microfollicular patterns, oncocytic changes, or specimens with poor fixation. These
cytopathologic patterns can be seen in multinodular goiters, follicular adenomas, thyroiditis, and
follicular and papillary carcinomas. This category was originally formed to encompass no more
than 7% of cytologic specimens,33 yet higher percentages are reported in clinical practice.34
Diagnostic variability among cytopathologists may account for the range in incidences, and
secondary cytology reviews are often inconsistent with the initial diagnosis.35 The risk of
malignancy in this category has been reported as high as 32%, with ACUS noted to have higher
rates of malignancy than FLUS.36 Repeat aspiration with molecular testing vs surgical excision
should be considered for these indeterminate results.
The cytologic diagnosis of follicular neoplasm is also considered an indeterminate category
consisting of microfollicular and cellular neoplasms ranging from benign follicular adenomas,
follicular carcinomas, and follicular-variant of papillary carcinomas. The inability of FNA to
determine capsular or vascular invasion precludes the definitive diagnosis between follicular
adenomas and carcinomas, although the demonstration of papillary features in a follicular
neoplasm may be indicative of a follicular-variant of papillary thyroid carcinoma. The
designation of Hurthle cell neoplasm is similar to follicular neoplasm in the inability of FNA
to distinguish between benign and malignant disease, but in Hurthle cell neoplasms the
predominant cells of concern are large, polyclonal cells with abundant oxyphilic cytoplasm. The
diagnosis of Hurthle cell neoplasm has been reported to have a higher incidence of malignancy
than follicular neoplasm.37
The only definitive way to exclude malignancy in an indeterminate specimen is through
pathologic assessment of a dedicated tissue specimen usually acquired by diagnostic thyroid
lobectomy. Therefore, a higher number of thyroid lobectomies are performed for what
ultimately results as benign pathology. Newer techniques for the molecular evaluation of FNA
samples have been developed to further characterize the risk of malignancy in an indeterminate
nodule beyond what the cytologic assessment provides. Molecular marker panels test common
mutations specific to thyroid cancer, including BRAF, RAS, RET/PTC, and PAX8/PPAR gamma.
A positive result can confer a risk of malignancy of up to 88% in an indeterminate nodule38 and
aid in the decision to perform an upfront total thyroidectomy instead of diagnostic lobectomy.39
The addition of gene fusion panels increases sensitivity and specificity of up to 90% and 93%,
respectively.40 Commercially available testing is offered through several proprietary platforms.
Alternative testing is available through gene expression classifier panels that measure
expression of greater than 140 genes via messenger RNA to classify indeterminate nodules as
benign or suspicious. A negative pattern on the gene expression classifier correlates with a high
negative predictive value for malignancy, whereas a suspicious pattern is less specific for
malignancy.41 Results from either form of testing must be incorporated into the complete clinical
picture to determine the risks and benefits of pursuing surgical intervention.
A malignant designation on FNA cytology incorporates a variety of carcinomas, including
well-differentiated thyroid cancers and their variants, medullary and anaplastic thyroid cancer,
lymphoma, and metastases to the thyroid. Surgical management varies slightly according to
each type. WTCs diagnosed by or suspicious for malignancy on cytology should undergo surgical
resection, although the extent of thyroidectomy is debated. Total thyroidectomy is well accepted
for carcinomas greater than 1.0-1.5 cm in size and those with locoregional metastasis or
significant risk factors, but a survival advantage to total thyroidectomy over thyroid lobectomy
for smaller, low-risk lesions is not well described.42 Additionally, select providers have
demonstrated only a small portion of low-risk microcarcinomas that progress to clinically
significant disease and reserve surgical management for those tumors with an interval size
increase by 3 mm or more, the novel appearance of lymph node metastases, or tumor size
reaching 12 mm or larger.43 Therapeutic compartment-oriented lymph node dissection is
performed for regional metastases, whereas prophylactic central neck dissection is less
standardized but favored for advanced primary tumors (T3 and T4) and concerning features.
Medullary thyroid carcinoma is treated by total thyroidectomy and formal dissection of involved
lymph node compartments. Prophylactic compartmental lymph node dissection is based upon
preoperative serum calcitonin and carcinoembryonic antigen levels.44 The presence of
hereditary disease should be evaluated through RET proto-oncogene testing and the exclusion
of associated pheochromocytomas and primary hyperparathyroidism (PHPT). Thyroid lym-
phoma is treated nonoperatively with chemotherapy or radiation or both, and any surgical
intervention is typically reserved for tissue acquisition to establish the diagnosis. Anaplastic
thyroid cancer is primarily treated by external-beam radiotherapy and chemotherapy, as the
tumor is commonly widely advanced at presentation, but locally confined ATC can be treated by
total thyroidectomy with wide resection.
Follow-up and surveillance
Continued surveillance is recommended for thyroid nodules not necessitating excision

because of the risk of false-negative cytology. Nodules should be followed for changes in
sonographic features or for interval growth. Significant interval growth has been described as an
increase in nodule volume of greater than 50% or a 20% increase in nodule diameter with a
minimal increase in 2 or more dimensions of at least 2 mm.17 Nodules with significant growth
should be reevaluated for repeat FNA or excision, although the rates of a new diagnosis of
thyroid cancer are only 0.3%-1.2%.30,31 The development of suspicious sonographic features may
be more indicative of malignancy than size increase.30 The overall duration of surveillance is not
well described, but a repeat ultrasound is typically recommended 6-12 months following the
initial evaluation, after which surveillance intervals can be extended to 2-5 years for stable,
benign nodules.
Conclusion
The proper management of a newly discovered thyroid nodule is an essential aspect of any
general and endocrine surgery practice. Thyroid incidentalomas are common, and with the
increasing use of diagnostic imaging studies, they are being discovered with increased
frequency. Additionally, the incidence of thyroid cancer in the United States is rising, making
the appropriate evaluation of the thyroid incidentalomas increasingly important. Through a
thorough clinical examination, specific biochemical testing, and dedicated thyroid imaging and
cytology, treating providers are equipped with the proper tools to render effective surgical care
to the endocrine patient.
Incidental hypercalcemia
PHPT is a disease of inappropriate calcium regulation secondary to one or multiple abnormal

parathyroid glands. Normal parathyroid tissue senses decreases in serum calcium levels through
calcium-sensing receptors and secrete parathyroid hormone (PTH) to maintain a steady calcium
state. Pathologic parathyroid tissue fails to fully respond to the appropriate negative feedback
regulation of extracellular calcium homeostasis, resulting in inappropriately elevated serum PTH
levels. Chronic PTH elevation leads to the development of sustained serum hypercalcemia,
persistent stimulation of widespread tissue PTH receptors, and the eventual progression of
multiple deleterious end-organ effects. Historically, it has been the clinical manifestations of the
kidneys and the skeletal system that have led to the initial presentation and evaluation of
parathyroid disease. In the modern era, though, PHPT is commonly discovered as asymptomatic
hypercalcemia on routine biochemical screening. Determining whether incidental hyper-
calcemia is true parathyroid pathology curable by surgery is an important part of the endocrine
surgery practice, and a commonly encountered endocrine incidentaloma.
Epidemiology
PHPT is one of the most common causes of hypercalcemia. The incidence has been noted
from 48-77 cases per 100,000 person-years 45,46 and is more common among women in their
fifth and sixth decades of life, with a median age of 60.4 years.47 PHPT is most commonly the
result of neoplastic enlargement of a solitary parathyroid gland, or adenoma, composed of a
mixture of chief cells and oncocytic cells surrounded by a fine capsular network. In
approximately 5%-10% of cases, multiple parathyroid glands are affected. Adenomas are
distinguished grossly and histologically from 4-gland hyperplasia by the presence of at least 1
normal parathyroid gland. Parathyroid carcinoma is a rare cause of PHPT 48 and is distinguished
by nuclear atypia, fibrous band formation, and capsular and vascular invasion.
Diagnosis
A basic knowledge of parathyroid physiology is important in understanding the biochemical

diagnosis of PHPT and excluding alternate causes of hypercalcemia. Hypercalcemia in PHPT is a
result of multiple PTH-mediated systemic effects on bone resorption, renal tubular calcium
resorption, vitamin D synthesis, and intestinal calcium absorption. PTH acts on the skeletal
system to stimulate osteoclast activity to promote bone resorption and elevate extracellular
calcium levels. Its actions on the kidneys lead to an increase in calcium reabsorption and
phosphorus excretion at the distal tubules, as well as stimulates the hydroxylation of the vitamin
D-25-OH precursor to vitamin D 1,25-OH, the most active metabolite. This in turn promotes
increased intestinal absorption of dietary calcium.
The diagnosis of PHPT is established by demonstrating an elevated serum PTH level in the
setting of hypercalcemia. PTH is more commonly measured by immunometric assays directed to
measure intact PTH and its active fragments. Variations in PTH levels exist among different
manufactured assays and specimen types,49 but normal reference ranges typically fall at
approximately 10-60 pg/mL.50 Calcium is measured as total serum calcium concentrations or
less often as free ionized serum calcium. PTH levels may register within the normal range of an
assay, but when associated with elevated serum calcium levels, should normally be suppressed
to low or undetectable levels. Therefore, mid-to-high-normal levels of PTH are often considered
inappropriately elevated in the setting of hypercalcemia. Additionally, PTH levels may be
elevated in the setting of normal serum calcium in an entity known as normocalcemic PHPT. The
appropriate diagnosis of this entity requires exclusion of elevated PTH levels as a consequence of
secondary hyperparathyroidism.51
Correctly establishing the diagnosis of PHPT is paramount to proper management as other
conditions can mimic the hypercalcemia of PHPT, but undergoing parathyroidectomy in these
situations would fail to cure the underlying hypercalcemia. Commonly excluded alternatives
include calcium-altering medications, hypercalcemia secondary to malignancy, familial
disorders of calcium-sensing receptors, and secondary causes of hyperparathyroidism. Well-
known medications that can raise serum calcium levels include thiazide diuretics and lithium
therapy. Thiazides diuretics reduce urinary calcium excretion and can cause mild elevations in
serum calcium levels.52 Likewise, lithium therapy may also reduce urinary calcium excretion but
additionally can raise the calcium set point for inhibition of hormone secretion by the
parathyroid glands.53 If possible both medications should be discontinued for at least 3 months
before a repeat biochemical evaluation, although the calcium-altering effects of lithium therapy
may be long-lasting despite discontinuation of the medication.
Occult malignancy is also one of the most common etiologies of hypercalcemia. The
diagnosis should be considered in any individual with a prior or current history of cancer. Its
effects can be attributed to the direct osteolysis of bone by metastases, activation of osteoclast
precursors into osteoclasts through various cytokines, or production of extrarenal calcitriol
or PTH-related protein. Hypercalcemia of malignancy commonly manifests with very high
serum calcium concentrations but is distinguished from PHPT by very low to undetectable
PTH levels.
Familial hypocalciuric hypercalcemia (FHH) is a rare hereditary disorder that leads to mild
hypercalcemia that is often difficult to distinguish from PHPT. FHH is an autosomal dominant
disease resulting from one of several different inactivating mutations in the calcium-sensing
receptor gene that leads to increased renal calcium absorption and renders the parathyroids less
sensitive to serum calcium concentrations. This alteration results in mild serum hypercalcemia
with normal to mildly elevated PTH levels. Factors that distinguish FHH from PHPT include low
24-hour urinary calcium excretion and calcium-creatinine clearance ratio,
Ca/Cr Clearance Ratio ¼ [24-hour Urine Ca x Serum Cr] C [Serum Ca x 24-hour Urine Cr],
in FHH. The 24-hour urinary calcium excretion is usually less than 200 mg/24-hours, and
calcium-to-creatinine clearance ratios less than 0.01 are typically confirmatory, although not
definitive, for FHH. Ratios greater than 0.02 are more indicative of PHPT.
Secondary hyperparathyroidism occurs when the parathyroid glands appropriately respond
to lower levels of serum calcium caused by various conditions limiting calcium absorption or
impairing renal function. Common conditions include decreased gastrointestinal absorption
secondary to vitamin D deficiency, malabsorption syndromes, or surgical bypass procedures and
impaired calcitriol production and urinary calcium leakage because of chronic kidney disease.
Assessment of renal function (by glomerular filtration rate or serum creatinine), vitamin D-25-
OH levels, and 24-hour urine calcium quantities help distinguish between the different
etiologies and should be included in the comprehensive evaluation.
Other potential causes of hypercalcemia to be taken into consideration during the evaluation
of PHPT include milk alkali syndrome, chronic states of physical inactivity, hypervitaminosis D,
tertiary hyperparathyroidism, and systemic inflammatory or granulomatous diseases.
Surgical indications
Classic symptoms of PHPT are the systemic effects of increased PTH secretion and elevated
serum calcium levels. They are commonly referred to by their end-organ effects, “bones, stones,
groans, moans, and neuropsychiatric overtones.” Historically, it was the manifestations of the
skeletal and renal systems that led patients to present for further medical evaluation. The many
clinical manifestations of PHPT are summarized in Table 2.
The constitutional clinical symptoms associated with PHPT are broad, and in many instances,
subjective in nature. They represent common symptoms of many possible disease processes and
can be difficult to attribute solely to PHPT. Therefore, caution should be employed in pursuing
surgery solely for constitutional symptoms unless the diagnosis and manifestations are certain.
In contemporary times, PHPT is more commonly diagnosed secondary to the discovery of
Table 2
Clinical manifestations of hypercalcemia and primary hyperparathyroidism.
System
Renal Polyuria, polydipsia, nephrolithiasis, nephrocalcinosis, diabetes insipidus, and renal insufficiency
Gastrointestinal Anorexia, nausea, peptic ulcer disease, constipation, and pancreatitis
Skeletal Bone pain, arthralgias, osteopenia or osteoporosis, osteitis and fibrosa cystica
Neurologic Fatigue, weakness, decreased cognitive function, poor memory, stupor, and depression
Cardiovascular Hypertension, bradycardia, and shortened QT
asymptomatic hypercalcemia on routine laboratory testing; therefore, separate objective factors

are used to guide which patients may benefit from surgical intervention. Expert consensus
guidelines have been published to assist in characterizing which patients may benefit from
parathyroidectomy. The fourth International Workshop for Asymptomatic Primary Hyper-
parathyroidism is the most current iteration of these guidelines and lists the biochemical and
clinical indications to pursue parathyroidectomy in the asymptomatic patient (Table 3).
Surgical approach
Surgical planning should begin only after a diagnosis of PHPT and a surgical indication have
been established. The goal of parathyroid surgery is to restore normocalcemia in the patient
while minimizing the risk of potential surgical complications, including injury to the recurrent
laryngeal nerve, permanent hypoparathyroidism, and persistent hyperparathyroidism. The
extent of exploration includes bilateral, unilateral, and focused or minimally invasive approaches
and is dependent on the results of the preoperative evaluation and surgeon experience.
The traditional surgical approach to PHPT includes a bilateral cervical exploration with comparative
evaluation of all parathyroid glands. The normal parathyroid gland is approximately 40-50 mg in
weight, commonly flattened and ovoid, and approximately 5 mm in maximal dimension. Abnormal
benign parathyroid glands are typically enlarged, more full or round in nature, and typically darker
hued, although morphologic variations are common. Ideally at least 4 glands should be identified, and
all parathyroid glands should be compared before resection of any presumed abnormal tissue. The
abnormal gland(s) is excised and often confirmed by frozen section. Particular care should be given
not to rupture the capsule so as to prevent tissue seeding and possible parathyromatosis. In the case
of 4-gland hyperplasia, a subtotal parathyroidectomy is often performed with resection of 3.5 glands
and preservation of a viable, in-situ parathyroid remnant. Viable remnant tissue should be
confirmed before resection of the remaining parathyroid glands in case a separate gland is needed
for the subtotal resection. Total parathyroidectomy and autotransplantation should be avoided to
prevent higher rates of permanent postoperative hypoparathyroidism.
As most cases of PHPT are caused by single parathyroid adenomas, bilateral exploration can
potentially be avoided if a solitary focus of concern can be identified preoperatively. A focused
Table 3
Guidelines for surgery in asymptomatic primary hyperparathyroidism.
Measurement Surgical indication
Serum calcium 41.0 mg/dL (0.25 mmol/L) above upper limit of normal
Renal Creatinine clearance o60 cc/min
24-h urinary calcium 4 400 mg/24 h
Presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound, or CT
Skeletal BMD by DXA: T-score o 2.5 at lumbar spine, total hip, femoral neck, or distal 1/3 radius
Vertebral fracture by x-ray, CT, or MRI
Age, y o50
BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry. Bilezikian et al.68
exploration or minimally invasive parathyroidectomy should be distinguished from general

unilateral exploration and is performed when dissection is directed toward a localized, solitary
gland of concern. Multiple variations in technique are used including radioguided localization
and video-assisted approaches, but all approaches should theoretically minimize dissection and
the risk of contralateral recurrent laryngeal nerve injury and hypoparathyroidism.
Intraoperative PTH (ioPTH) assays are used as an adjuvant tool in minimally invasive
parathyroid surgery to confirm resection of all hyperfunctioning parathyroid tissue and denote
biochemical cure. Original criteria described by Irvin and colleagues defined surgical success as a
decline in ioPTH from baseline preincision or preexcision levels by 50% or more 10 minutes after
resection of all hyperfunctioning tissue of concern.54 Failure of ioPTH levels to decline
appropriately after resection of a targeted gland indicates a concern for multigland disease
secondary to either multiple adenomas or 4-gland hyperplasia, and further cervical exploration
should be performed. This approach has shown an overall accuracy of 97% in providing
surgical cure.
Among the various imaging modalities used for the localization of abnormal parathyroid
glands, head and neck ultrasound, technetium-99 sestamibi scintigraphy, and 4-dimensional CT
are the more commonly performed studies (Fig 3). Ultrasound of the neck is an inexpensive and
noninvasive modality useful for localizing parathyroid adenomas, which are often seen as
homogeneous, hypoechogenic foci adjacent to the thyroid. Ultrasound is also useful for
identifying potential concomitant thyroid pathology that may require coordinated resection at
the time of parathyroidectomy. Sestamibi scintigraphy takes advantage of prolonged retention of
99mTc-sestamibi tracer in the mitochondria of hyperfunctioning parathyroid tissue to aid in
gland localization. Performance, as well as localization of potential ectopic glands, is enhanced
when combined with sestamibi-single photon emission CT. Four-dimensional CT cross-sectional
imaging provides precise localization of a lesion by the rapid contrast uptake and washout
associated with parathyroid adenomas. It is particularly useful in the reoperative setting55 or
when other modalities fail to localize a gland of concern. Of note, parathyroidectomy based
solely on concordant imaging studies is associated with high rates of biochemical cure.56
Successful correction of PHPT is determined by return of normal calcium homeostasis and

improvement of the renal and skeletal manifestations over time. Persistent PHPT is denoted by
failure to reestablish normocalcemia within 6 months following parathyroidectomy. The most
common reasons for persistent disease are failure to localize the hyperfunctioning gland of
concern at the time of surgery or failure to resect all pathologic tissue secondary to multigland
Fig. 3. Parathyroid imaging modalities. (A) Gray-scale ultrasound with Doppler flow demonstrating a hypoechoic nodule
adjacent to the thyroid lobe with characteristic polar vessel. (B) Sestamibi-SPECT demonstrates persistent tracer uptake
in an upper-mediastinal ectopic adenoma. (C) Multiphase (4D) computed tomography demonstrates rapid contrast
enhancement of a partially cystic adenoma inferior to the right thyroid lobe. SPECT, single photon emission computed
tomography. (Color version of figure is available online.)
disease.57 The diagnosis of PHPT should be reconfirmed for persistent disease, and the benefits
of surgery should be weighed against the heightened risk of reoperation. Additionally, the risk of
complications associated with reoperative surgery can be influenced by whether a minimally
invasive approach vs a bilateral exploration was performed at the initial surgery.58 Most
abnormal glands at the time of reoperation are found in the normal anatomical location.59 Cure
rates can be seen in up to 89% of reoperative cases in experienced centers,58 although
experienced parathyroid surgeons are better adept to cure PHPT at the initial operation with
lower complication rates and decreased overall costs.60,61 Recurrent PHPT is a return of the
biochemical diagnosis, with or without recurrent symptoms, after a period of calcium
normalization for at least 6 months. Again, the risks of reoperative surgery should be weighed
carefully, and repeat localization imaging should be performed, as a focused approach with
ioPTH assays can be successfully employed in more than one half of cases.62 Patients having
undergone successful cure of their PHPT should be monitored for biochemical recurrence with
annual laboratory testing. Patients with asymptomatic PHPT not meeting any surgical indication
should be assessed at regular intervals for signs of progressive disease.
Familial and hereditary PHPT
Most cases of PHPT manifest as sporadic disease, although hereditary forms may be present
in up to 10% of cases.50,63 The most common hereditary conditions associated with PHPT include
MEN 1 and 2A. MEN1 is an autosomal dominant disease secondary to mutation in the MEN1
gene. In MEN1, parathyroid disease is most commonly the main presenting condition of the
syndrome. Parathyroid disease typically manifests in the second to fourth decades of life, with
near-complete penetrance by age 40-50 years.64 Disease is predominately multiglandular, and
bilateral cervical exploration with subtotal parathyroidectomy is appropriate as recurrent
hypercalcemia is common.65 Additionally, thymectomy should be performed for possible
supernumerary or ectopic parathyroid tissue, as well as to potentially decrease the risk of thymic
carcinoid.66,67 Cryopreservation of parathyroid tissue should be considered as available. MEN2A
is caused by activation of the RET proto-oncogene, and in MEN2A, disease may be
multiglandular or single-glandular. A 4-gland exploration is typically performed and often in
the context of concomitant total thyroidectomy for medullary thyroid cancer. A pheochromo-
cytoma should be ruled out before any surgical intervention. Familial isolated PHPT and familial
hyperparathyroidism-jaw tumor syndrome are other more rare causes of hereditary PHPT.
Conclusion
PHPT is one of the most common causes of hypercalcemia and is often discovered
incidentally on routine laboratory testing. Careful discernment of a full biochemical evaluation is
essential in appropriately confirming the diagnosis, and recognition of multiple surgical
indications helps identify those patients for whom parathyroidectomy might benefit. The use of
various specialized imaging modalities and intraoperative hormone assays commonly minimize
the extent of surgical dissection and expedite surgical cure, but a working knowledge of a
4-gland exploration is necessary for situations of nonlocalizing imaging, inappropriate ioPTH
decreases, or hereditary component. Regardless of the advances in the evaluation of PHPT, the
goal to provide safe, durable surgical care remains at the forefront of parathyroid surgery.
Adrenal incidentaloma
An adrenal incidentaloma (AI) is an adrenal mass encountered on radiographic studies

performed for separate extra-adrenal complaints. With the increasing use of advanced
diagnostic imaging, adrenal masses both smaller and larger than 1 cm in size are commonly
discovered in clinical practice. An adrenal nodule can be demonstrated in up to 4.4% of all
high-resolution CT scans.69 Additionally, bilateral adrenal nodules may be encountered in up to

15% of cases. These figures likely underestimate the true prevalence of adrenal nodules in the
general population as autopsy studies have noted incidental adrenal nodules in 6%-10% of
cases.70,71 The prevalence of AIs has been noted to increase with age and in association with
certain medical comorbidities, although this may be a function of selection bias secondary to
increased diagnostic imaging within these populations.
Once detected, the health care practitioner is tasked with the appropriate management of the
newly discovered findings. The clinical evaluation of the incidentaloma should be based on 2
main considerations—(1) whether the adrenal tumor is functional or producing excess
endogenous adrenal hormones and (2) whether the adrenal mass is concerning for a primary
or secondary malignancy. Ultimately, most lesions are benign, nonfunctioning adrenocortical
adenomas that require no further intervention,72 but both considerations must be fully
evaluated in determining whether any surgical intervention is necessary.
Clinical features
The clinical evaluation of the adrenal patient should begin with a thorough history and
physical examination to assess for any of the well-known signs or symptoms of adrenal
pathology. Functional tumors account for 10%-15% of all incidentolamas,73,74 and clinical features
of hormone excess correlate to the histologic level affected. Functional adrenal tumors of the
adrenocortex include aldosterone-producing adenomas, cortisol-secreting adenomas, and rarely
androgen-secreting adenomas. Patients with aldosterone-producing adenomas may present
with polyuria, muscle cramping, and palpitations, but symptoms are more often related to
persistent hypertension (HTN) and increased cardiovascular risks associated with the hyper-
tensive state.75 Cortisol-producing adenomas may cause varying degrees of the stereotypical
Cushing phenotype of central obesity, proximal muscle weakness, facial rounding, skin striae,
acne, and hirsutism. Androgen-secreting tumors rarely cause clinically apparent virilization, but
when seen in conjunction with the overproduction of other adrenal hormones, virilizing
symptoms should prompt a concern for primary adrenocortical carcinoma. Pheochromocytomas
are functional tumors of the adrenal medulla and can manifest with a variety of symptoms
related to catecholamine excess, including paroxysmal HTN, intermittent headaches, flushing,
and tachycardia. Despite biochemical evidence of excess hormone production, it is not
uncommon for patients discovered in the incidental setting to be clinically asymptomatic or
minimally symptomatic at presentation.
Biochemical assessment
As the clinical manifestations of adrenal hormone overproduction are not always apparent, a
full adrenal biochemical assessment is necessary. In our practice, a full adrenal panel is obtained
at the initial patient evaluation. The laboratory panel includes evaluation of plasma electrolytes,
plasma aldosterone concentration (PAC), plasma renin activity, adrenocorticotropic hormone
(ACTH), cortisol, dehydroepiandrosterone sulfate, and plasma fractionated metanephrines and
normetanephrines. A more in-depth assessment is based on the initial panel results and any
clinical suspicion for a specific functional tumor. Further evaluation is described below according
to specific functional tumor.
Aldosterone-producing adenoma
Before testing, all mineralocorticoid receptor blockers (eg, spironolactone and eplerenone)
should be held to avoid inaccurate results. The hypokalemia stereotypical to this syndrome
can be absent in over half of patients and so is often unreliable for screening.76,77 Screening
tests typically demonstrate a plasma renin activity suppressed to levels below 1 ng/mL and
PAC elevated to greater than 15 ng/dL, resulting in an elevated aldosterone-to-renin ratio
greater than 20-30.76 Subsequent confirmatory testing for primary hyperaldosteronism is

obtained with monitored saline-infusion suppression testing, 24-hour urinary aldosterone levels
following salt loading, fludrocortisone suppression testing, or captopril challenge tests. With
saline-infusion suppression testing, an elevated PAC of greater than 10 ng/dL following
intravenous infusion of 2 L of normal saline over a 4-hour time period confirms the diagnosis.
Likewise, a 24-hour urine aldosterone concentration greater than 12 mcg/24 h following a 3-day
high-salt diet confirms primary hyperaldosteronism.78
Confirmation of primary hyperaldosteronism should then prompt an evaluation for unilateral
vs bilateral sources of aldosterone excess. In most circumstances, abdominal imaging alone
would not be able to provide definitive evidence regarding the source of excess aldosterone
production. The location of a functional gland may not correlate with the side of an identified
radiographic lesion, especially as the incidence of nonfunctional adenomas increases within the
aging population. Additionally, bilateral adrenal lesions may be present on initial imaging
studies requiring bilateral adrenal hyperplasia to be distinguished from unilateral aldosterone-
producing adenomas. An instance in which laterality can be established with more certainty
though is in the young patient with a solitary adenoma. An adrenal nodule in patients less than
35 years of age with primary hyperaldosteronism is consistently an aldosterone-producing
adenoma as a separate, nonfunctional adrenal nodule is uncommon in this age group.79
Determination of bilateral vs unilateral sources of aldosterone excess is achieved through
adrenal venous sampling. There are slight variations in adrenal venous sampling protocols
among institutions regarding the use of cosyntropin stimulation and the timing of blood
sampling,78,80 but regardless of technique, confirmation of successful adrenal vein cannulation is
essential to validate the study. Appropriate cannulation is demonstrated by an individual adrenal
vein to inferior vena cava cortisol ratio of greater than 3:1, although with cosyntropin
stimulation, it is more commonly greater than 10:1.80,81 Following confirmation of successful
bilateral adrenal vein cannulation, a cortisol corrected ratio can be calculated by the ratio of
aldosterone to cortisol of the affected side to the nonaffected side. A cortisol corrected ratio
greater than 4 with cosyntropin stimulation is generally accepted as confirmatory for a unilateral
source of hormone overproduction, whereas values of less than 4 are more consistent with
bilateral aldosterone excess.
Cortisol-producing adenoma
Cushing syndrome because of a cortisol-producing adenoma is identified by elevated cortisol

levels in at least 2 of 3 commonly performed screening studies—low-dose dexamethasone
suppression tests, midnight salivary cortisol levels, and 24-hour urinary cortisol levels. The 1 mg
dexamethasone suppression tests is commonly performed and can accurately detect hyper-
cortisolism with sensitivities and specificities of 73%-100% and 90%-97%, respectively.73,82 An
abnormal 24-hour urinary-free cortisol (24-UFC) test includes urinary cortisol levels 3-4 times
greater than the upper limit of normal on the corresponding assay. Physiologic causes of
hypercortisolism, renal insufficiency, and falsely elevated levels secondary to high fluid intake
should be considered when evaluating 24-hour samples. Midnight salivary cortisol testing
assesses for loss of the normal late-night cortisol nadir and should be used with caution in
patients with abnormal sleep-wake cycles. The upper-limit thresholds vary per assay used, but
sensitivities and specificities greater than 90% for the diagnosis of Cushing syndrome make it a
practical screening option for patients.83
An AI that autonomously secretes cortisol at levels high enough to suppress corticotropin but
that fails to produce overt Cushing syndrome can be classified as causing subclinical Cushing
syndrome (SCS). This is the most frequent hormonal imbalance encouutered with incidenta-
lomas.84 The optimal management of SCS is unknown, but multiple small series suggest
improved outcomes for patients' metabolic symptoms (including HTN, diabetes mellitus, and
obesity) with operative management.84-86 In a study of patients with SCS randomized to either
undergo laparoscopic adrenalectomy vs nonoperative surveillance, patients who underwent
resection were noted to have improvement or normalization of their diabetes mellitus, HTN, and
obesity87 suggesting an overall benefit for pursuing surgical management.
Pheochromocytoma
Biochemical testing for catecholamine-secreting tumors is routinely assessed by plasma

fractionated metanephrines and 24-hour urinary metanephrines. Fractionated plasma meta-
nephrines demonstrate a higher sensitivity than urinary studies for detecting pheochromocy-
tomas (97% vs 90%), whereas 24-hour total urinary metanephrines are more specific (98% vs
85%) and may lead to fewer false-positive results.73,88 Plasma fractionated metanephrines are
preferred in our practice owing to the ease in obtaining the specimen, but urinary
metanephrines are used for confirmation of equivocal plasma results and in the assessment of
dopamine-secreting tumors. Interfering medications including tricyclic antidepressants, acet-
aminophen, beta blockers, caffeine, and thiazide diuretics should be held before testing, and
indeterminate results can be further assessed through clonidine-suppression testing.89
Approximately 25% of patients with pheochromocytomas harbor a germline mutation90-92;
therefore, genetic testing should be considered in patients with early onset ( o45 years) tumors,
bilateral pheochromocytomas, a family history of pheochromocytoma or paraganglioma, or
other clinical findings suggestive of a hereditary syndrome (eg, MEN2, neurofibromatosis type 1,
and von Hippel-Lindau [VHL]). Individual mutation testing vs combination mutation panels are
available for RET, VHL, NF1, TMEM 127, MAX, FH, and succinate dehydrogenase subtypes (SDHB,
SDHC, SDHD, and SDHAF2).
Imaging
An AI’s specific imaging phenotype provides valuable information regarding tumor behavior
and the risk for malignancy. Specific radiographic features including tumor size, attenuation on
noncontrasted imaging, and enhancement on multiphase imaging help delineate between
benign adenomas and more concerning tumors.
Size is an important feature for predicting malignancy in an incidentaloma, in particular
when tumors are larger than 4 cm in greatest dimension. Angeli and colleagues72 noted a greater
than 90% sensitivity of detecting adrenocortical carcinoma in lesions larger than 4 cm, and
resection of adenomas larger than 4 cm in size is commonly performed in clinical practice.
It should be noted though that less than 25% of adrenal nodules larger than 4 cm in size were
found to be malignant in the aforementioned series. Conversely, multiple separate series have
reported the detection of adrenocortical carcinomas in adrenal masses less than 4 cm in
size,93,94; therefore, it is important to note that size should not be used as a sole criterion for
surgical resection.
Beyond considering absolute size, an AI’s appearance on multiphase imaging provides
important information regarding its potential behavior (Fig 4). CT is the most common modality
used in the initial evaluation of the incidentaloma. Benign lesions are associated with a round
shape, homogenous density, and well-demarcated borders on CT. Additionally, benign lipid-rich
adenomas characteristically demonstrate Hounsfield units (HU) less than 10 on unenhanced CT
phases. Sensitivities to these features alone are reported between 71% and 100%.95
Unfortunately, up to 30% of adenomas may be lipid poor, diminishing the ability to fully
categorize these lesions as benign based on low attenuation characteristics.96 Conversely,
adrenocortical carcinomas, pheochromocytomas, or metastases to the adrenal should be
suspected with increased size ( 4 4 cm), densities of greater than 10 HU on unenhanced imaging
phases, hypervascularity, heterogeneous density, and less than 50% washout of intravenous
contrast on 10-minute delayed contrast phases.97 In a single-institution review of more than 150
patients with adrenal masses having had both noncontrasted CT imaging and surgical resection,
the mean HU was significantly lower for adrenal adenomas than for adrenal carcinomas,
metastatic lesions, and pheochromocytomas.98 The only patients in the nonadenoma groups
Fig. 4. Multiphase imaging of a lipid-rich adenoma (left) and a suspicious mass (right). (Rows: (A) precontrast,
(B) arterial, and (C) 15-minute delay). Left: the images on the left demonstrate the imaging features characteristic of a
benign, lipid-rich adenoma, including small size, homogeneous texture, and well-defined borders. Additionally,
multiphase sequencing displays low (o10) precontrast Hounsfield units (HU) and rapid washout of contrast from
arterial to delayed phases. Right: the images on the right demonstrate common features concerning for a malignant
neoplasm, including a larger size (5.3 cm), heterogenous texture, increased precontrast density (425 HU), and delayed
absolute washout. (Color version of figure is available online.)
with a noncontrast CT HU less than 10 were those with benign adrenal myelolipomas, in whom
HUs were less than 40 and were therefore easily distinguishable. In this series, a noncontrast
CT HU r 10 or a combination of tumor size r 4 cm and HU r20 excluded nonadenomas in
100% of cases.
MRI is performed for a variety of indications and is often the identifying source of an AI. Its
ability to delineate soft tissue invasion, lipid content, and vascularity of a lesion makes it a
helpful modality for characterizing the tumor type and determining resectability. Examples of
specific MRI features include loss of out-of-phase signal-intensity for benign, lipid-rich
adenomas,99 hyperintensity of ACC and pheochromocytomas on T2-weighted images,100 and
loss of signal intensity for ACC on out-of-phase images because of the occasional intracellular fat
component. Additionally, the lack of ionizing radiation exposure to the patient makes MRI an
attractive option when CT is contraindicated or when serial imaging is needed.
Functional imaging studies including PET and iodine-123 metaiodobenzylguanidine
scintigraphy are not routinely obtained in the initial evaluation of an AI, as cross-sectional
imaging typically provides sufficient diagnostic information for treatment planning. In certain
circumstances, though, functional imaging may be useful to further characterize indeterminate
CT or MRI results, determine functionality in bilateral lesions, and localize extra-adrenal primary
or metastatic disease. 18F-fluorodeoxyglucose (18F-FDG) PET imaging is capable of predicting
malignant adrenal tumors with near 100% sensitivity and specificity.101,102 A small portion of
benign adrenal lesions may demonstrate increased FDG uptake as compared to background
activity,102 so the clinical history and cross-sectional imaging characteristics should be taken
into account for any management decisions. Additionally, 18F-FDG PET may be more specific
than 123-I MIBG in detecting associated metastases.103
Role for biopsy
Although FNA is readily obtainable in most clinical settings and carries minimal procedural
risk,104 it is seldom indicated. Cytology cannot reliably distinguish between primary adrenal
adenomas and carcinomas, and it is our practice not to routinely biopsy primary adrenal masses. The
primary role of a biopsy, therefore, is to differentiate adrenal tissue from extra-adrenal sources,
including metastatic disease or infectious processes. Although resection of a primary adrenal
malignancy or functional tumor in a patient able to tolerate surgery is recommended, a metastasis
to the adrenal may not be best served by metastectomy. A diagnostic biopsy in this scenario may be
indicated for complete staging and appropriate treatment planning. It should be cautioned, though,
that any adrenal biopsy should be preceded by the exclusion of a pheochromocytoma to prevent the
potential for serious complications related to sudden catecholamine release.
Treatment
Surgical resection is indicated for all functional adrenal tumors, and preoperative and
postoperative medical optimization is often necessary. Patients with aldosterone-producing
adenomas require strict electrolyte management and often substantial potassium repletion
before surgical intervention. Pheochromocytomas should be managed preoperatively with
alpha-adrenergic blockade to control hypertensive symptoms, and medication is titrated to the
point of eliciting slight orthostasis. Phenoxybenzamine and doxazosin are common alpha-
blockers used in the preoperative optimization of pheochromocytomas, and beta-adrenergic
blockade is routinely added to treat resultant tachycardia. Calcium channel blockers can be used
for additional blood pressure control. Thorough hydration is recommended in the few days
preceding resection to counter potential hypotension in the immediate postoperative period.
Patients with Cushing syndrome are monitored postoperatively for signs of adrenal insufficiency
secondary to possible contralateral gland suppression. Postoperative cosyntropin stimulation
tests can identify the need for steroid supplementation if there is a clinical concern for adrenal
insufficiency.
Nonfunctional masses concerning for primary adrenocortical carcinoma should undergo

complete resection as long as the patient is healthy enough to tolerate surgery. The benefit of
surgical debulking for advanced-stage disease or for palliation of symptoms is less certain, and
the role of neoadjuvant treatment should be considered for borderline resectable disease.105
Patients with a tumor concerning for adrenocortical carcinoma should be treated in centers of
expertise for best outcomes. Adrenalectomy in the treatment of nonadrenal malignancies
metastatic to the adrenal gland can be beneficial in certain situations, as prolonged survival has
been reported for resection of isolated, often metachronous, adrenal metastasis related to
certain primary malignancies. Additionally, laparoscopic resection in this setting has been
shown not to alter recurrence or overall survival.106 Again, evaluation in centers with experience
in adrenal metastectomy is recommended.
Patients with adrenal tumors with minimal concern for malignancy can undergo either
laparoscopic or open resection. Minimally invasive techniques have positive effects in
postoperative pain, length of hospital stay, blood loss, and mobility. The laparoscopic
transabdominal and the posterior retroperitoneoscopic approaches are the most common
minimally invasive procedures performed. The retroperitoneoscopic approach is preferred in our
experience as it has been shown to decrease operative times, blood loss, and postoperative
length of stay when compared with a transabdominal laparoscopic approach.107 Robotic
techniques can be employed as well, and both transabdominal and retroperitoneal approaches
are described. The 3-dimensional optics and ergonomic advantages of a robotic procedure
promote better visualization and may aid in maintaining a vascularized remnant during cortical-
sparing adrenalectomy.108 Regardless of the approach, the operative surgeon must be able to
come to an acceptable risk-benefit balance providing for the best patient outcome and recovery
while not placing the patient in danger or comprising the oncologic outcome.
Patients with a suspected primary malignancy are typically approached by open techniques,
as minimally invasive techniques in this group remain controversial. A meta-analysis looking at
laparoscopic resections of small adrenocortical carcinomas (o10 cm) demonstrated that
laparoscopic adrenalectomy by skilled surgeons was not inferior to open surgery when
oncological standards (margin-free resection, avoidance of tumor spillage) were respected,
although the open procedure remained the gold standard.109 This was also reviewed in a separate
study of more than 300 patients with ACC, which compared prereferral laparoscopic or open
adrenalectomy to open resection at the referral institution. Despite a smaller tumor size, patients
treated laparoscopically developed peritoneal carcinomatosis more frequently compared to those
treated with an open approach. When controlling for tumor stage, patients with an open
approach experienced superior recurrence-free and overall survival, indicating an oncologic
benefit of open resection over the short-term benefits of minimally invasive surgery.110
The optimal surveillance frequency for AIs differs among various consensus groups. Repeat
cross-sectional imaging is recommended anywhere from 3-12 months after the initial
evaluation, with the shorter intervals used for lesions with indeterminate imaging features
and the longer intervals for smaller, benign-appearing lesions. The American College of
Radiology recommends no further follow-up if the adrenal nodule is stable at a 1-year follow-
up,111 whereas the American Association of Clinical Endocrinologists and American Association
of Endocrine Surgeons recommend annual imaging for 1-2 more years.112 Incidentalomas with
growth of greater than 5 mm between interval scans or to an absolute size greater than 4 cm
should be considered for surgical resection, although up to 20% of adrenal nodules will increase
in size and the risk of conversion to malignancy is considered to be low. Additionally, the
secondary risk of malignancy from the chronic radiation exposure of surveillance imaging has
been suggested to outweigh the benefit of long-term repeat imaging.73 Repeat biochemical
assessment is recommended for up to 5 years, as up to 28% of AIs may develop hormonal
alterations during the surveillance period.113
Conclusion
AIs are commonly discovered on routine diagnostic imaging and must be fully assessed to
exclude hormonally active adrenal tumors and primary and metastatic adrenal malignancies. A
full biochemical assessment for excess hormone production often consists of both screening and
confirmatory testing, whereas determination of malignant potential is predominantly based on
size and specific imaging characteristics on various imaging modalities. Following appropriate
preoperative optimization, functional tumors should undergo resection to prevent the multiple
deleterious systemic effects of hormonal excess, and adrenal tumors concerning for malignancy
should undergo full staging to assess for resectability, followed by complete resection via an
open approach. Nonfunctioning adenomas should be followed with serial imaging and
biochemical testing to evaluate for nodular growth or the development of excess hormone
production.
Pancreatic incidentaloma
Pancreatic incidentalomas (PIs) are asymptomatic lesions within the pancreas found by
imaging, endoscopy, and abnormal laboratory testing discovered while investigating complaints
unrelated to the pancreas.114 Described as either cystic or solid, these lesions occur throughout
the pancreas and consist of a variety of disorders ranging from benign simple cysts to aggressive
adenocarcinoma. PIs are found in roughly 2% of people undergoing routine axial imaging, and
with the increasing use of high-quality imaging, incidentalomas are now believed to account for
nearly 50% of all consultations to pancreatic surgeons and between 6% and 23% of
pancreatectomies performed.115 The overall incidence of a PI is estimated between 0.01% and
0.6%, with malignant or premalignant lesions comprising 70%-94% of all incidentalomas.114-118
Resection is indicated when there is suspicion of malignancy or premalignancy based on clinical
history, laboratory evaluation, imaging characteristics, and pathologic sampling. Thus, the ability
to accurately identify and resect premalignant and malignant lesions is essential to the
appropriate management of PIs. Tumors of the endocrine pancreas are designated pancreatic
neuroendocrine tumors (PNETs) and are the focus of this review, although much of the
evaluation and diagnostic evaluation is similar among PIs.
Epidemiology
Pancreatic lesions are broadly categorized as cystic and solid pancreatic neoplasms.
Pancreatic adenocarcinoma and PNETs comprise the vast majority of solid PIs, but the list of
potential etiologies is extensive and contains both nonneoplastic and neoplastic processes
(Table 4). Malignant neoplasms include pancreatic adenocarcinoma, ampullary adenocarcinoma,
PNETs, primary pancreatic lymphoma, and metastases from other tumors, including renal cell
carcinoma, melanoma, and adenocarcinoma from the breast, lung, ovary, and stomach.
Pancreatoblastomas, solid pseudopapillary tumors of the pancreas, solid-appearing cystadeno-
mas, and acinar cell carcinomas are primary neoplasms of the pancreas that occur with much
less frequency. Nonneoplastic solid lesions of the pancreas include focal pancreatitis (acute,
chronic, or autoimmune), intrapancreatic splenules, and systemic disorders such as tuberculosis
and sarcoidosis.
Pancreatic adenocarcinoma is the fourth most common cause of cancer-related deaths in the
United States and accounts for 16%-30% of all PIs. It is the predominant tumor to exclude during the
evaluation of a PNET. It has a peak incidence in the seventh and eighth decades of life and affects
men and women equally. Known risk factors include increased age, cigarette smoking, African-
American race, heavy alcohol use, and chronic pancreatitis.119 Despite aggressive treatment,
pancreatic adenocarcinoma has a poor 5-year overall survival of only 5%, although patients with
incidentally identified pancreatic adenocarcinoma may have improved overall survival relative to
those who present with symptoms, secondary to diagnosis at an earlier stage.118
Table 4
Differential diagnosis of a solid pancreatic incidentaloma.
Adenocarcinoma (ductal, ampullary, cholangiocarcinoma) 18.6%-30%

Pancreatic neuroendocrine tumor (PNET) 9%-19%
Solid and pseudopapillary tumor 0%-9%
Acinar cell carcinoma —
Primary pancreatic lymphoma —
Metastases —
Pancreatitis (acute, chronic, and autoimmune) —
Solid cystadenoma —
Tuberculosis —
Intrapancreatic accessory splenule —
PNETs comprise less than 3% of all primary pancreatic neoplasms120 and 9%-19% of all PIs. The
majority (40%-60%) are discovered incidentally through various imaging modalities. They are
classified as either functional or nonfunctional tumors based on the presence of endogenous
hormone oversecretion. Roughly 25% of patients with PNETs present with symptoms of
hormone oversecretion and almost 50% are deemed functional on biochemical analysis.116,121
The peak incidence is in the fourth to sixth decades of life except when associated with a
hereditary condition such as MEN1 or VHL syndrome, where the diagnosis is established
frequently at a younger age.
PNETs exhibit a wide spectrum of clinical activity ranging from an indolent, benign nature
(63%-70% of incidental PNETs) to an aggressive, malignant behavior (30%-37% of all incidental
PNETs).116 PNETs are predominately categorized as well-differentiated neuroendocrine tumors
of low-to-intermediate grade. Poorly differentiated tumors are less common but more
aggressive, with frequent metastases and poorer survival.122 Malignant potential is based on
local invasion, evidence of nodal or systemic metastases, recurrent disease, and grading based on
mitotic figures or Ki-67 proliferative index. Staging is based on the European Neuroendocrine
Tumor Society (ENETS)123 and American Joint Committee on Cancer (AJCC) classification.
Clinical evaluation
The clinical evaluation of PNETs should begin with a detailed medical history to elicit specific
risk factors for the development of pancreatic disease (Table 5). A social history of prolonged
tobacco and alcohol use has been directly linked to pancreatic adenocarcinoma, and a family
history of adenocarcinoma is important to note as roughly 10% of pancreatic adenocarcinomas
arise in a hereditary fashion. Additionally, patients with Peutz-Jehgers syndrome, familial
pancreatitis, familial malignant melanoma syndrome, Lynch syndrome, and hereditary breast-
ovarian cancer syndrome are at increased risk.119 Likewise, PNETs are found as part of various
hereditary syndromes, including MEN1, VHL, and neurofibromatosis. Patients should be
questioned about affected first-degree relatives or for abnormalities in other known sites of
disease. MEN1 is characterized by the development of pituitary tumors, hyperparathyroidism,
and PNETs, whereas VHL is characterized by the development of benign and malignant tumors
of the eye, spinal cord, brain, kidney, pancreas, and adrenal gland.121
In the setting of a true PI, patients are likely not to report any overt symptoms, but on
detailed questioning may report vague signs of an underlying issue. Abdominal discomfort, early
satiety, and subtle weight loss are more suggestive of an underlying malignant process or mass
effect. When a PNET is suspected, determining functionality is important, and evaluation should
focus on signs or symptoms of hormone overexpression. Symptoms of gastrin oversecretion
(gastrinoma) include abdominal pain, diarrhea, nausea, and recurrent peptic ulcer disease.
Oversecretion of insulin (insulinoma) causes severe hypoglycemia that presents as confusion,
dizziness, altered mental status, diaphoresis, and anxiety. Excess glucagon production
Table 5
Evaluation of solid pancreatic incidentalomas.
Demographic Laboratory Radiographic Treatment
L.F. Starker et al. / Current Problems in Surgery 53 (2016) 219–246

Pancreatic adenocarcinoma Elderly (470) CA19-9 Solid, hypoenhancing, Resection
infiltrative
Pancreatic neuroendocrine Ages 40-69, younger in familial Chromogranin A Solid (90%), hyperenhancing on Resection
tumor syndromes Insulin arterial/delayed images with
Gastrin calcifications
Glucagon
VIP
Lymphoma – – Large, heterogenous with Chemotherapy, radiation
peripancreatic
lymphadenopathy and minimal
ductal dilation
Metastatic disease History of renal cell carcinoma, Corresponding tumor markers Hypoenhancing Appropriate systemic
melanoma, or adenocarcinoma chemotherapy, Rarely, a role
of the stomach, breast, lung, or for resection.
ovary
Solid and pseudopapillary Females (20–30s) Mixed cystic and solid Complete resection
tumor components
Autoimmune pancreatitis History of autoimmune diseases IgG-4 Delayed enhancement of Corticosteroids
affected pancreas, mild
dilatation of the main pancreatic
duct over a long segment
Acute pancreatitis alcohol Amylase/lipase Hypoenhancing Bowel rest, lifestyle
modifications, observation
VIP, vasoactive intestinal peptide.
239
(glucagonoma) results in recent-onset diabetes, deep vein thromboses, depression, cachexia and
a rash known as necrolytic migratory erythema. Severe watery diarrhea and associated
hypokalemia with dehydration are found with excessive levels of vasoactive intestinal protein
(VIPoma). Lastly, symptoms from somatostatinomas are exceptionally rare and may consist of
diarrhea, steatorrhea, gallstones and weight loss.
Biochemical analysis is helpful to corroborate a diagnosis suggested by imaging, and
commonly assessed labs include serum CA19-9, chromogranin A, specific functional hormones,
and IgG-4 levels. CA19-9, a sialylated Lewis A blood group antigen, is the most clinically useful
biomarker for pancreatic adenocarcinoma. CA19-9 is shed from pancreatic and hepatobiliary
cells during inflammation and malignancy, and therefore lacks specificity for pancreatic
adenocarcinoma but is a reliable diagnostic marker and has some predictive value in the setting
of resectable disease.119 Serum chromogranin A levels are elevated in at least 60% of PNETs and
studies have demonstrated a correlation between elevated levels and shorter survival in the
setting of metastatic disease. In patients with suspicious lesions and symptoms of hormone
overexpression, measuring serum gastrin, insulin, glucagon, and vasoactive intestinal peptide
levels is mandated. Serum IgG-4 is useful in diagnosing autoimmune pancreatitis as levels are
elevated in up to 75% of affected patients.
Imaging and biopsy
Although the history and physical examination contribute to the initial evaluation, the most
critical components of the diagnostic evaluation are obtained through cross-sectional imaging
and endoscopy.124 Pancreatic-specific high-resolution, contrast-enhanced imaging is often
needed to further characterize the incidentaloma. Triple phase CT includes noncontrasted,
arterial, and venous (delayed) phases with thin-cut, high-resolution sections of the abdominal
cavity. Owing to its high vascular content, the pancreatic parenchyma enhances rapidly during
arterial contrast, whereas pathologic lesions, having varying degrees of associated vasculature,
frequently become discernable. Pancreatic adenocarcinoma is typically hypovascular with a
dense peritumoral stroma and therefore appears hypoenhancing on contrasted images relative
to the background parenchyma, whereas PNETs are hypervascular and enhance avidly
throughout arterial and delayed venous images.
Owing to these characteristics, imaging by helical CT scanners with multidetector-rows
(MDCT) have a sensitivity up to 96% in detecting pancreatic adenocarcinoma125 and 73%-84% in
detecting PNETs.116,126 Evidence suggests that MDCT is equal to or superior to abdominal
ultrasonography and MRI for the evaluation and diagnosis of a pancreatic mass, and owing to the
ease of use and wide availability, is the preferred initial imaging modality for characterizing a
pancreatic mass. Furthermore, MDCT not only helps in mass identification and diagnosis, it also
helps determine resectability by demonstrating the tumor's relationship to the portal-
mesenteric vasculature. The sensitivity of CT decreases for smaller tumors (o 2 cm) and iso-
enhancing tumors. In these instances, further evaluation by MRI and endoscopic ultrasound
(EUS) is critical for accurate diagnosis of the lesion.124
MRI has excellent soft tissue contrast resolution and can be helpful in characterizing iso-
enhancing pancreas lesions and in identifying and differentiating liver metastases from benign
liver lesions. In the setting of a hyperenhancing lesion on CT that is equivocal, MRI T2-weighted
images can help to differentiate a PNET from benign lesions such as an intrapancreatic accessory
spleen or a serous cystadenoma. Somatostatin-receptor scintigraphy with single photon
emission CT and PET/CT with radioactively labeled somatostatin analogues can be beneficial
in diagnosing primary PNETs and evaluating for metastases when other modalities are
equivocal.116 Arterial stimulation and venous sampling can be used for regional localization of
functional tumors when conventional imaging fails to identify a tumor.
EUS with FNA has had a profound effect on the evaluation of pancreatic masses and is
considered a helpful adjunct to cross-sectional imaging when imaging is inconclusive and tissue
sampling is needed before proceeding with treatment planning (Fig 5). EUS is more sensitive
Fig. 5. Endoscopic ultrasound (EUS). (A) EUS of a 4-mm mass in the body of the pancreas. (B.) EUS-guided fine-needle
aspiration of the mass.
than CT for PNETs smaller than 2 cm in size and for insulinomas.126 For PNETs, tissue acquisition
can confirm neuroendocrine origin, diagnose regional metastases, and establish a Ki-67
proliferative index. Tissue sampling is critical to distinguish between certain similar appearing
hypervascular lesions such as intrapancreatic accessory splenules and solid-appearing serous
cystadenomas. With hypoenhancing lesions concerning for adenocarcinoma, some studies have
suggested that EUS-FNA can provide additional information regarding venous invasion and
nodal involvement and provides a means of tissue acquisition before delivery of systemic
chemotherapy.119 Focal areas of pancreatitis, either acute or autoimmune, and primary
pancreatic lymphoma can appear hypoenhancing on CT and must be distinguished from
pancreatic adenocarcinoma.116 Primary pancreatic lymphoma should be suspected when
imaging shows diffuse peripancreatic lymphadenopathy without evidence of tumor invasion
or ductal obstruction and is confirmed with flow cytometry of the FNA sample.
Management and follow-up
Accurate diagnosis of a solid PI is paramount, as appropriate treatment can vary between

surgical resection to medical management. As stated earlier, the vast majority of solid PIs are
adenocarcinoma or PNETs, and when these diagnoses are suggested by evaluation or proven on
biopsy, surgical resection is indicated when anatomically feasible and if the patient is a suitable
candidate. When pancreatic adenocarcinoma appears localized to the pancreas on imaging,
surgical resection remains the mainstay of treatment and the only chance of cancer cure.
Pancreaticoduodenectomy should be utilized for tumors of the head and uncinate process,
whereas lesions in the tail should be resected via distal pancreatectomy with splenectomy.
Surgical resection should be considered in sporadic, nonfunctional PNETs owing to the
substantial malignant potential of these tumors and the lack of effective systemic treatment
options. Regional nodal dissection should be considered in all surgical cases, and in the setting of
oligometastatic disease of functional or nonfunctional PNETs, surgical resection of all disease, if
feasible and safe, is indicated. Pancreatic enucleation can be entertained with small (1-2 cm),
peripheral lesions not involving the main pancreatic duct. Additionally, nonoperative
observational management can be considered in nonfunctional PNETs smaller than 2 cm with
a Ki-67 less than 2%, and no evidence of local invasion, nodal involvement, or metastatic disease,
as observational series have demonstrated little risk of tumor growth and no development of
nodal metastasis during surveillance.127-129,116 Close observation with serial imaging is
recommended at 6-month intervals. All sporadic functional PNETs, regardless of size, should
be resected if the tumor appears resectable and if the patient is an appropriate surgical
candidate. Sporadic insulinomas are generally small, solitary tumors with low malignant
potential that can commonly be managed by enucleation when smaller than 2 cm and not
involving the main pancreatic duct. When larger, involving the main duct, or associated with
regional lymphadenopathy, traditional resection techniques should be performed. In either
approach, multiple tumors should be excluded intraoperatively. Gastrinomas frequently arise in
the duodenum and necessitate duodenotomy for local resection. VIPomas, glucagonomas, and
somatostatinomas typically require traditional resection. Surgical debulking of unresectable
disease can be considered to palliate symptoms of a functional tumor. Otherwise, beneficial
effects have been demonstrated with octreotide, lanreotide, everolimus, sunitinib, hepatic
regional therapy, and some cytotoxic systemic chemotherapy agents. For patients with high-
grade poorly differentiated neuroendocrine carcinoma, medical therapy is advised as the
primary treatment modality. Postresection surveillance involves physical examination, appro-
priate biochemical analysis, and cross-sectional imaging every 6-12 months for up to 10 years.
Management of hereditary PNETs differs from their sporadic counterparts because they are
predominately multifocal and distributed throughout the pancreas. MEN1 is the most common
hereditary syndrome associated with PNETs, and imaging surveillance would identify disease in
up to 56% of patients, a third of which may be functional.130 Unlike sporadic PNETs, gastrinomas
tend to be the most common functional tumor and are typically smaller, multifocal, and exhibit
earlier lymph node metastasis.131 Proton-pump inhibitor therapy and parathyroidectomy for
hypercalcemia secondary to PHPT can improve symptoms in a significant proportion of patients.
Surgical resection is indicated for larger tumors, lymph node metastases, and pancreatic
tumors.64 Tumors in the duodenum and not the pancreas tend to be the source of gastrin
hypersecretion; therefore, duodenal exploration and lymphadectomy should be performed to
better achieve eugastrinemia.132 The other functional tumor variants should undergo anatomical
resection. The best management of nonfunctional PNETs in MEN1 is debated. Most guidelines
recommend surgical resection for tumors larger than 2 cm in size and conservative surveillance
with tumors smaller than 1 cm; management of tumors 1-2 cm in size varies.64,133,134 Advanced
disease in hereditary PNETs is treated with the same nonoperative modalities as sporadic
disease.
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Endocrine Incidentalomas: Current Problems in Surgery

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Current Problems in Surgery 53 (2016) 219–246

Contents lists available at ScienceDirect

Current Problems in Surgery

journal homepage: www.elsevier.com/locate/cpsurg

Incidental thyroid nodule

FNA results and Bethesda criteria

Category Risk of malignancy

Follow-up and surveillance

Continued surveillance is recommended for thyroid nodules not necessitating excision

PHPT is a disease of inappropriate calcium regulation secondary to one or multiple abnormal

A basic knowledge of parathyroid physiology is important in understanding the biochemical

asymptomatic hypercalcemia on routine laboratory testing; therefore, separate objective factors

Measurement Surgical indication

exploration or minimally invasive parathyroidectomy should be distinguished from general

Follow-up and surveillance

Successful correction of PHPT is determined by return of normal calcium homeostasis and

Familial and hereditary PHPT

An adrenal incidentaloma (AI) is an adrenal mass encountered on radiographic studies

high-resolution CT scans.69 Additionally, bilateral adrenal nodules may be encountered in up to

greater than 20-30.76 Subsequent conﬁrmatory testing for primary hyperaldosteronism is

Cushing syndrome because of a cortisol-producing adenoma is identiﬁed by elevated cortisol

Biochemical testing for catecholamine-secreting tumors is routinely assessed by plasma

Role for biopsy

Nonfunctional masses concerning for primary adrenocortical carcinoma should undergo

Follow-up and surveillance

Adenocarcinoma (ductal, ampullary, cholangiocarcinoma) 18.6%-30%

Demographic Laboratory Radiographic Treatment

L.F. Starker et al. / Current Problems in Surgery 53 (2016) 219–246

VIP, vasoactive intestinal peptide.

Imaging and biopsy

Management and follow-up

Accurate diagnosis of a solid PI is paramount, as appropriate treatment can vary between

1. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med. 1993;328(8):553–559.

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