THYROID, PARATHYROID, AND ADRENAL DISEASE
Richard E. Goldstein, M.D., Ph.D., F.A.C.S.
I. ADRENAL TUMORS
Introduction: As surgeons, we are mainly concerned with adrenal lesions either due to the issue
of adrenal carcinoma or due to excess hormone production. In terms of excess hormone
production, adrenal tumors can produce excess cortisol leading to a syndrome known as
Cushing’s Syndrome. Other tumors can produce excess aldosterone also known as Conn’s
Syndrome named after a paper by Jerome Conn in 1955. Much less common are virilizing
tumors, particularly tumors that might produce excess DHEA. Adrenocortical carcinomas are, in
general, very aggressive and approximately 50% of these are associated with excess hormone
production. All of the above lesions originate from the adrenal cortex. Tumors that originate
from the medullary tissue of the adrenal are generally associated with excess catecholamine
production and are known as pheochromocytomas.
Often patients referred to surgeons due to the finding of an incidental adrenal tumor
picked up on a CT scan that was performed for other reasons such as trauma. Overall, the
probability of an incidental adrenal tumor that is 5 cm in diameter being malignant is only 1 in
one thousand. However, if the lesion appears to be quite heterogeneous rather than a nice
smooth homogeneous pattern, then there needs to be increased concern about malignancy even in
those tumors that are less than 5 cm.
Embryology of the adrenal: Recall that the adrenal cortex is derived from mesodermal tissue and
the adrenal medulla arises from neural crest cells that invade the fetal cortex. These stain
yellow-brown with chrome salts and are hence called chromaffin cells. Tumors of the adrenal
medulla, as mentioned above, are referred to as pheochromocytomas.
Cushing’s Syndrome: The signs and symptoms of Cushing’s Syndrome include hypertension,
hypernatremia, truncal obesity, a characteristic buffalo hump, abdominal striae, easy bruisability,
muscle wasting and depression. Keep in mind that the most common causes of death for
untreated Cushing’s are sepsis and suicide.
Low Dose Dexamethasone Suppression Test: The primary test and the most cost effective test to
make a diagnosis of Cushing’s Syndrome is the low dose dexamethasone suppression test. The
low dose dexamethasone suppression test is designed to first make a diagnosis of excess cortisol
production from a tumor. The basic principle is that a low dose of dexamethasone is given over
a period of up to two days. Serum cortisol is measured. Failure of the serum cortisol level to
suppress is confirmatory of Cushing’s Syndrome. Next, the issue is to decide whether this
originates from a pituitary tumor producing excess ACTH, an adrenal tumor producing excess
cortisol, or an ectopic tumor producing either ACTH or CRH.
High Dose Dexamethasone Suppression Test: The source of the Cushing’s Syndrome is defined
by the high dose dexamethasone expression test. In this test a higher dose of dexamethasone is
given. If there is suppression of cortisol, this suggests a pituitary source. Failure to suppress
would point to either an adrenal or an ectopic source. If the plasma ACTH is elevated, that
would point to an ectopic source such as a thymic carcinoid.
Imaging for the adrenal lesion: Either CT scan or MRI is usually very adequate to identify an
adrenal source for Cushing’s Syndrome. Most of these tumors are > than 1 cm in diameter and if
the adrenal is the source they should be able to be identified.
Conn’s Syndrome: This is caused by an adrenal tumor, usually benign, that produces excess
aldosterone. Signs and symptoms include hypertension which is generally relatively mild but
can be severe, associated with hypernatremia, hypokalemia, thirst, weakness, and leg cramps.
Imaging of adrenal lesions for Conn’s Syndrome: Like Cushing’s Syndrome, these are often
caused by benign adenomas but in the case of Conn’s, these are often 1 to 2 cm in diameter. An
adenoma > than 5 m causing Conn’s Syndrome would be unusual. CT scan is usually very
helpful for the identification and one sees a very homogeneous small adenoma. Occasionally
bilateral adrenal vein sampling for aldosterone and cortisol is necessary to confirm that one side
is producing excess of aldosterone relative to the opposite adrenal.
Workup for primary aldersteronism (Conn’s): The primary screening for Conn’s Syndrome
involves obtaining simultaneous serum measurements of aldosterone and rennin. Patients with
Conn’s Syndrome should have elevated aldosterone level and virtually unmeasurable rennin
levels. Further levels are meant to distinguish hyper aldosteronism from secondary. These can
include the measurement of postural studies and saline suppression tests.
Adrenal cortical carcinoma: Depicted in the slide presentation is a CT scan from a patient with
adrenal cortical carcinoma. Features noted are that of a large mass that is very heterogenous. In
this particular slide the mass is approximately 10 cm in maximal diameter.
Functional Adrenal Cancer: As noted previously, most adrenal cortical cancers are functional.
Glucocorticoid excess is found in 50% of these and the mental manifestations may be extremely
profound including depression and paranoia. Excess sex-steroid production is present in 25% of
patients with virilization most common. Aldosterone production is very unusual. The
combination of excess hormone production is highly suggestive of malignancy.
Surgical Management of adrenal cortical carcinoma: Unfortunately, approximately 50% of these
lesions are stage IV at the time of presentation, nevertheless, the only true hope for cure in these
patients is to perform a curative wide resection. Open transabdominal procedures are used.
Laparoscopic adrenalectomies are not appropriate in this setting. Adjuvant therapies have been
generally useless. They are, however, anecdotal reports on the insecticide related agent
mitotane. This particular chemical is toxic to adrenal tissues. Larger series have not
demonstrated efficacy of this drug.
Pheochromocytoma: In 1886 Dr. Felix Frankel autopsied Fraulein Minna Roll. The autopsy
demonstrated bilateral adrenal tumors that demonstrated positive chromaffin reaction. In 1926
Dr. Charles Mayo in Minnesota and Dr. Cesar Roux each independently resected
Clinical Presentations of Pheochromocytomas: These tumors are most known for causing
hypertension and it is estimated that 0.4 to 2% of all hypertensive patients have
Pheochromocytoma. The most common pattern of hypertension is that of sustained hypertension
with extreme paroxysms. Other manifestations include headache, flushing pale, palpitations,
sweating, blurred vision, abdominal pain, nausea and some vomiting. It should also be noted
that approximately 10% of patients with pheochromocytomas have no documented hypertension.
Genetic Aspects of pheochromocytomas: Ninety percent of these tumors are sporadic and 10%
are familial. The most common type of familial tumors include MEN2A (MTC, pheo, and
primary hyperparathyroidism; ninety to 100% develop MTC, 40% develop pheos), and MEN2B
(MTC, pheo, and neuromas), Carney’s Syndrome, and Neuroectodermal dysplasias.
The Neuroectodermal Dysplasias: Von Recklinghausen’s Disease, Sturge-Weber Syndrome,
tuberous sclerosis, von Hippel Lindau Disease with cerebellar hemangioblastomas, renal cysts,
angiomas of the retinas, pancreatic cysts, islet cell tumors
Screening for pheochromocytomas The most common and functional screening method is the
24-hour urine collection. The 24-hour urine is checked for total and fractionated catecholamines,
normetanephrine and metanephrines and VMA. Increasingly, plasma catecholamine and plasma
metanephrines are being screened and there is recent evidence that plasma metanephrines are
probably the most accurate screening test available.
Localization of pheochromocytoma: In the past angiography was used but over the last twenty
years unenhanced CT scans and MRI’s are fairly equivalent to each other and are much easier to
perform than angiography. MRI can be particularly useful in the setting of pregnancy or if one is
looking for extra-adrenal pheochromocytomas. Extra-adrenal pheochromocytomas account for
10% of pheochromocytomas and can occur anywhere along the sympathetic chain.
MIBG Scan: This is a radioisotope that is taken up by adrenal tissue in proportion to the amount
of adrenal tissue present. However, it is not used very often as it is very expensive and takes
several days to perform and most pheochromocytomas can be identified based on CT or MRI’s.
Preoperative Management: The preoperative management of pheochromocytomas is extremely
important, probably more important than the surgery itself. The hallmark of preoperative
management is the drug phenoxybenzamine. This is an α-blocker. It started 10 to 14 days prior
to resection. As an α-blocker it will tend to counteract excess norepinephrine. Beta-blockade is
occasionally used but less so than in the past. It’s main indication is for tachycardias > 140 bpm
or arrhythmias, however, due the ability of anesthesiologists to use short acting beta blockers in
the operating room it is often not started preoperatively. The third drug is metyrosine. This
actually inhibits the enzyme, tyrosine hydroxylase, that catalyzes the step of tyrosine to dopa,
which is a precursor of both norepinephrine and epinephrine. Thus, use of this drug directly
attacks excess catecholamine synthesis.
Operative Approaches: In the past an incision that was used for all adrenal cases was either the
wide bucket handle incision that is a large transverse incision across the abdomen or a vertical
midline incision. In the 1970’s and 1980’s a posterior approach, going through the 11th or 12th
base of the rib and resecting the adrenal gland from a retroperitoneal approach was very popular.
This was particularly true for small adenomas, namely Cushing’s or Conn’s tumors. Since 1995
an increasing popular approach has been laparoscopic resection of the adrenal. This has been
increasingly applied to all cases except very large benign tumors or tumors that are felt to be
highly likely to be malignant.
II. THYROID GLAND
Introduction: Thyroid nodules are much more common than the average person thinks and the
prevalence of nodules goes up with age. While approximately 5% of individuals will have
palpable thyroid nodules by age 50, almost 50% of the population will have at least one thyroid
nodule that can be detected by ultrasound. However, the probability that a nodule is malignant is
probably, in general, only approximately only 5%. As a rule, although women are more likely to
have thyroid nodules, a thyroid nodule in a male is slightly more likely to be malignant than that
in a female.
Evaluation of thyroid nodules: In the past radionucleotide scanning of thyroid nodules was one
of the most predominant modes for evaluation. One of the problems is that while it is recognized
that a cold thyroid nodule probably has at most a 20% chance of being malignant, (whereas a hot
thyroid nodule has < 4% chance of being malignant) most thyroid nodules are cold; therefore,
scanning as the first step in the evaluation is generally not helpful.
What is now used is fine needle aspiration (FNA) of the nodule using either 22 or 25
gauge needles. Increasingly this is done with ultrasound guidance. This should be done in
combination with obtaining thyroid functions tests, namely TSH and a freeT4. In general,
thyroid cancer can be broken down in the following categories:
Well-differentiated thyroid cancer (DTC), which comprises papillary thyroid cancer
along with follicular thyroid cancer. Together these 2 entities comprise 90% of thyroid
Medullary thyroid cancer
Anaplastic thyroid cancer
Thyroid lymphoma and sarcoma
Some tumors such as renal cell or melanoma can present with metastatic lesions to the
Thyroid nodules and age: Prior to age 18, males and females have approximately the same
incidences of benign and malignant thyroid lesions, however, after that age the rates increase
markedly overall for females compared to males, although the rates go up in both genders. After
age 60 the rates start to approach each other again.
Papillary thyroid cancer: This is the most common type of thyroid cancer. It tends to be a firm
unencapsulated neoplasm. It is multicentric in 80% of the cases. It is also characterized by
psammoma bodies and ground glass “orphan-Annie” nuclei.
Some features that are characteristic of papillary thyroid cancer and affect outcome:
In particular, females have a better outcome than males. Tumors with higher grade do worse
than lower grade, younger patients do better than older patients and those with smaller tumors do
better than those with larger tumors. In fact, there have been a number of risk group formulas in
addition to the TNM categories that can help a physician define the potential risk of a patient.
The only known risk factor for papillary thyroid cancer is radiation.
Operative Procedures: There are a number of operative procedures that can be applied to
patients with thyroid cancer. In general, the minimal procedure for a small, well-differentiated
thyroid cancer would be a thyroid lobectomy and resection of the isthmus; however, in general if
there is a recognized differentiated cancer at the time of the surgical procedure, near total
thyroidectomy would be the most appropriate procedure. For patients who have medullary
thyroid cancer, particularly those who have MEN2 Syndrome, all C cells are potentially at risk
and total thyroidectomy would be indicated.
The addition of lymph node dissections are controversial, particularly for papillary
thyroid cancer where it is difficult to demonstrate that the presence of cervical metastatic disease
alters outcome. Nevertheless it is useful to recognize that papillary thyroid cancer often spreads
by lymphatics pathways to the regional lymph nodes of the neck. Follicular thyroid cancer tends
to spread by hematogenous routes to distant sites. Medullary and anaplastic thyroid cancer can
spread by both routes.
Adjuvant therapy and differentiated thyroid cancer: Once the thyroid gland has been resected in
the setting of either capillary or follicular thyroid cancer the two main adjuvants of therapy are
thyroxine suppressive therapy and radioactive iodide ablation. The goal of thyroxine therapy is
to replace the thyroid hormone thyroxine at a level high enough to suppress endogenous TSH
production. TSH is a growth factor and the goal is to keep the TSH less than the lower limits of
Radioactive Iodine (I-131): Radioactive iodine is transported into both normal and malignant
papillary and follicular cancers. In order to administer radioactive iodine thyroxine needs to be
withheld for approximately 4 to 6 weeks so that the TSH is significantly elevated. Radioactive
iodine has no effect on medullary thyroid cancer.
Follicular thyroid cancer: Pure follicular thyroid cancer is fairly rare and may be becomingly
increasingly rare. It tends to occur in patients who are 10 to 15 years older than patients with
papillary thyroid cancer. Small occult follicular thyroid cancers are rare and can metastasize via
hematogenous routes to bone, lung and brain.
Anaplastic thyroid cancer: Anaplastic thyroid cancer is rare but extremely deadly. It is
considered to be the most deadly epithelial cancer. Average life expectancy from the time of
diagnosis is only approximately 3 months. There is no proven effective adjuvant therapy for
these tumors. Nevertheless, protocols that involve hyperfractionated radiation and doxirubicin or
Adriamycin are being used.
Medullary thyroid cancer: As noted before, medullary thyroid cancer originates from
neuroendocrine or C cells. These cells secrete calcitonin and sometimes CEA. Hereditary
medullary thyroid cancer associated either as a familial medullary thyroid cancer syndrome or
MEN2A or MEN2B and is frequently multifocal. However, the majority of medullary cancers
Ret proto-oncogene: Familial medullary thyroid cancer (FMTC), MEN2A, and MEN2B are all
associated with mutations in the ret proto-oncogene. This gene codes for a protein with a
tryosine-kinase activity. It is located on chromosome 10. Genetic screening can be performed
looking for this mutation. All patients with medullary thyroid cancer should be genetically
screened for this mutation.
III. PRIMARY HYPERPARATHYROIDISM
Introduction: Parathyroid surgery in the United States started in 1926 with an operation on a
civilian sea captain, Charles Martell, at Massachusetts General Hospital. Unfortunately the
procedure was not successful. The first successful parathyroidectomy for primary
hyperparathyroidism was performed at Barnes Hospital in 1928. Primary hyperparathyroidism is
associated with the rhyme, “stones, bones, groans and moans”. The pathophysiology is generally
caused by benign adenomas of the parathyroid glands that have a set point error and this results
in an elevated intact parathyroid hormone (PTH) level that brings about an elevated serum
calcium level. The combination of the elevated intact parathyroid hormone level and calcium
level is what is responsible for the signs and symptoms, namely higher rates of kidney stones,
osteoporosis and spontaneous bone fracture, fatigue, depression, odd aches and pain and
occasional complaints of loss of memory. The incidence increases with age and, like thyroid
disease, there is a decided gender preference. It is now estimated that one in 500 women will
develop this compared to 1 in 2000 men. It is now estimated that 80-85% of patients will have
single adenomas, 2-5% will have multiple adenomas, 10-15% will have disease caused by four-
gland hyperplasia. Parathyroid carcinoma is very rare and accounts for less than 1% of the cases.
Parathyroid surgery in 1990: The standard procedure for primary hyperparathyroidism consisted
of bilateral exploration of the neck under endotracheal anesthesia. One would try to identify all
four parathyroid glands. If only one appeared enlarged, a diagnosis of adenoma was made and
the one enlarged gland was resected. This generally resulted in cure rates of 97 – 99%.
Preoperative non-invasive imaging studies were not particularly good. Due to the embryology of
the parathyroid glands, occasionally the parathyroid adenoma would not be identified and it
potentially could be located down in the anterior or posterior mediastinum or one could have an
undescended parathyroid adenoma high in the neck by the hyoid bone.
There have been 3 developments in the past 10 years that have changed the field of
parathyroid surgery. The first of these has been the development of the Sestamibi (MIBI) scan.
Second has been the development of a quick intraoperative parathyroid assay that can measure
the fall in the parathyroid level after the resection of an adenoma within 15 minutes. This is
based on the fact that PTH has a half-life of only approximately 5 minutes. The third
development has been that of a hand-held gamma probe, often more associated with sentinel-
node biopsies for melanoma and breast cancer. However, this same probe can identify MIBI in
the operating room and can be used to track down to the adenoma.
Parathyroid scanning: In a standard scan the technetium 99m isotope Sestamibi is administered
to a patient and 15 minutes later initial images are obtained. The isotope is taken up by thyroid
and parathyroid tissue as well as the salivary glands but is cleared by thyroid tissue faster that it
is cleared from an abnormal parathyroid tissue. A delayed film is then obtained in
approximately two hours. One should see wash out form the thyroid gland but persistent
retention of the isotope in the enlarged thyroid adenoma.
Parathyroid surgery in the first decade of the 21st century: The combination of these
developments has allowed many patients to be candidates for unilateral explorations of their
neck. If the have a parathyroid scan that is positive then one can set up a surgical date for them
in which one plans to only explore the side of the neck that has the adenoma identified on pre-
operative scanning. One particular type of unilateral approach that is utilized extensively is the
minimally invasive radioguided parathyroidtomy or MIRP. This is based on a positive
preoperative scan. The patient comes back on the day of their surgery in the holding room they
are re-injected with Sestamibi. Some patients can have the procedure under local anesthesia
rather than general anesthesia. A small incision is used, only 2 – 4 cm, and the surgeon is guided
down to the parathyroid adenoma using the hand held gamma probe. Many patients could be
candidates to leave the hospital on the same day. The surgeons at the University of Louisville
have performed over 250 of these procedures. The overall rate of success exceeds 97%. Another
procedure being offered is the video-assisted parathyroidectomy. This utilizes a small incision
(1.5 cm) and a small angled scope.
Secondary and tertiary hyperparathyroidism: Patients with long standing renal disease who have
aberrant Vitamin D metabolism can have chronic stimulation of the parathyroid glands that
results in secondary or tertiary hyperparathyroidism. This results in parathyroid hyperplasia and
an elevated parathyroid hormone level. In some cases surgical intervention is indicated in these
patients. The 2 most common options are either a subtotal parathyroidectomy or total
parathyroidectomy with auto transplantation of parathyroid tissue.
In a subtotal parathyroidectomy all 4 glands are identified. Three glands are completely
removed and the fourth gland is cut back so that approximately 1 ½ times the normal gland is
left in vivo.
The other option is to completely resect all 4 parathyroid glands which is known as a total
parathyroidectomy and, at the time of the surgical procedure, to autotransplant approximately 1
½ times of a normal gland into a patients forearm. The appropriateness of these options for a
patient is often based on individual patient characteristics.
MEN1, MEN2A, and Hyperparathyroidism: Approximately 40-60% of patients with MEN
Syndrome will develop primary hyperparathyroidism. This is generally caused by 4-gland
hyperplasia but is not due to the same pathophysiology as those patients with renal disease.
Nevertheless, the 2 options discussed above for patients with renal disease are the primary
surgical options available for patients with primary hyperparathyroidism and MEN Syndrome.
Again, the choice of surgical procedure is based on several characteristics of the individual
patient. In addition, an upper thymectomy is often added as small, ectopically located
parathyroid cells can be present.
Parathyroid Cancer: Parathyroid cancer is very rare and accounts for less than 1% of patients
with primary hyperparathyroidism. It is generally associated with patients that are elderly, have
markedly elevated calcium levels, and may be found to have rock-hard and fibrotic large masses
at the time of their surgical procedures. The most important item in the surgical procedure is to
not violate the parathyroid capsule if parathyroid cancer is suspected. The procedure, if a
parathyroid cancer is suspected, to do is an en bloc resection of the thyroid lobe that includes the
parathyroid gland. There is little effective adjuvant therapy for patients with metastatic