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  1. 1. 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 73
  2. 2. 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 pheochromocytomas. 74
  3. 3. 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 75
  4. 4. 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 cancers. 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 gland. 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. 76
  5. 5. 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: Gender Tumor grade Age Tumor size 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 normal. 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 77
  6. 6. 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 occur sporadically. 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 78
  7. 7. 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 79
  8. 8. 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 parathyroid cancer. 80
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