Harold E. Carlson
I. GENERAL CONSIDERATIONS. Cancers of endocrine glands constitute about 3% of all malignancies. Most malignant neoplasms derived from endocrine organs are not associated with clinical endocrinopathies, although several do produce unique syndromes and biochemical markers.
A. Steroid hormones are usually produced by the tissue that normally produces them, such as the adrenal cortex and gonads, whether that tissue is healthy or cancerous. Occasionally, human chorionic gonadotropin (hCG)-producing tumors of the placenta or other organs (e.g., lung) have the capacity to transform androgens into estrogens. The mechanism of action for most steroid hormones depends on specific receptors in the target cell cytoplasm or nucleus.
B. Peptide hormones and catecholamines appear to act at the cell surface, where they attach to specific receptors and modify intracellular concentrations of cyclic nucleotides, calcium, and kinases.
1. Amine precursor uptake and decarboxylation (APUD) cells are theoretically derived from embryonic neuroectoderm (melanocytes, thyroid C cells, adrenal medulla, paraspinal ganglia, argentaffin cells of the intestine). These cells produce hormone mediators such as serotonin, catecholamines, histamine, and kinins. Neoplasia of these tissues gives rise to carcinoid tumors, pheochromocytoma, and medullary thyroid cancer; these tumors may also produce peptide hormones (e.g., adrenocorticotropic hormone [ACTH] and vasoactive intestinal polypeptide [VIP]) in addition to their natural products. Other peptide-producing endocrine tissues (e.g., parathyroid, pancreatic islet) demonstrate some APUD characteristics, even though they may not be derived from neuroectoderm.
2. Peptide hormones, such as ACTH, hCG, and calcitonin, are produced by a wide variety of neoplastic tissues that may or may not normally synthesize detectable amounts of these hormones. Many of these peptides are synthesized as a prehormone. A segment of prehormone is enzymatically cleaved to form a storage molecule, a prohormone. The prohormone is further cleaved into the active hormone that is secreted into the blood.
3. Gastrointestinal hormones, such as insulin, glucagon, somatostatin, VIP, and gastrin, are normally produced by gut endocrine cells and the pancreatic islets. Neoplasms of these tissues commonly produce one or more of these hormones; gut hormones are also normally produced in the brain and may be products of a wide variety of other neoplasms.
C. Multiple endocrine neoplasias (MEN) are inherited, mendelian-dominant, endocrine tumor syndromes. Two categories of the syndrome are recognized.
1. MEN-1 (Wermer syndrome; menin tumor-suppressor gene located at chromosome 11q13)
a. Pituitary tumors (acromegaly, nonfunctioning adenoma, prolactinoma, or ACTH-producing adenoma)
b. Pancreatic islet cell tumors, including gastrinoma, VIPoma, glucagonoma, and insulinoma
c. Parathyroid adenomas
2. MEN-2. Medullary carcinoma of the thyroid is present in all patients with this syndrome. Cushing syndrome may develop as a consequence of ectopic ACTH production by medullary carcinoma or pheochromocytoma.
a. MEN-2A (Sipple syndrome; ret oncogene located at chromosome 10q11)
(1) Medullary carcinoma of the thyroid
(2) Pheochromocytoma (bilateral)
(3) Parathyroid hyperplasia or adenomas
b. MEN-2B (ret oncogene located at 10q11)
(1) Medullary carcinoma of the thyroid
(2) Pheochromocytoma (bilateral)
(3) Multiple mucosal ganglioneuromas (lips, tongue, eyelids)
(4) Marfanoid body habitus, high-arched palate, pes cavus, diverticulae, and sugar-loaf skull often accompany the endocrine abnormalities in MEN-2B.
II. CARCINOID TUMORS
A. Epidemiology and etiology. Carcinoid cancers represent <1% of visceral malignancies. The cause of these tumors is unknown, but they are sometimes associated with MEN-1.
B. Pathology and natural history
1. Primary tumor. Carcinoid tumors belong to the APUD system of tumors (see Section I.B.1). The primary tumors are usually small and most commonly arise in the small intestine. They may also develop in the stomach, colorectum, lung, ovary, and rarely other organs. Appendiceal carcinoids are common but are usually of no clinical significance.
2. Metastases tend to develop primarily in the liver. Bone metastases, which are often osteoblastic, also occur. Carcinoid metastases are indolent or slowly progressive and evolve over many years. Carcinoid tumors tend to produce desmoplastic responses, which can result in mesenteric fibrosis and bowel obstruction (“parachute intestine”). Hormonally inactive tumors usually cause death by replacing hepatic tissue, which leads to liver failure.
3. Tumor products. Hormonally active tumors occur in 30% to 50% of patients and produce a variety of potentially lethal complications (carcinoid syndrome).
a. Small intestine carcinoids never produce the carcinoid syndrome in the absence of liver metastases; the responsible hormonal mediators are degraded in their first pass through the liver.
b. Benign and malignant lung carcinoids occur with about equal frequency; those that produce the carcinoid syndrome are malignant. Lung carcinoids can potentially produce hormonal effects without metastasizing; active tumor products may pass directly into the circulation without being filtered by the liver. Most patients with endocrinologically active lung carcinoids, however, also have liver metastases. Bronchial carcinoids that produce ACTH or growth hormone–releasing hormone (GH-RH) may be benign, and Cushing syndrome or acromegaly may be the only endocrine manifestation.
c. Symptomatic ovarian carcinoids are rarely associated with liver metastases.
d. Humoral mediators of the carcinoid syndrome are serotonin, histamine, kinins, prostaglandins, and other hormonally active tumor products.
(1) The major source of serotonin is dietary tryptophan, which normally is mostly metabolized to nicotinic acid. In carcinoid syndrome, tryptophan metabolism is directed to the production of serotonin (Fig. 15.1). Most patients with carcinoid syndrome develop chemical evidence of niacin deficiency, and some may develop clinically recognizable pellagra.
Figure 15.1. Hepatic metabolism of tryptophan and serotonin in carcinoid syndrome. The normal pathway (thin arrow) of tryptophan metabolism is impaired in carcinoid syndrome, resulting in excessive production of serotonin. *Monamine oxidase inhibitors interfere with the metabolism of serotonin and are contraindicated in patients with carcinoid syndrome. 5-HIAA, 5-hydroxyindoleacetic acid.
(2) Other hormones and hormone metabolites that are found in some patients with carcinoid include calcitonin, gastrin, GH-RH, and ACTH. These substances may or may not produce clinical syndromes, but they should be searched for in patients with carcinoid and serum calcium abnormalities, peptic ulcer, acromegaly, or Cushing syndrome.
C. Diagnosis
1. Symptoms: Endocrinologically inactive carcinoids. Most carcinoid tumors are endocrinologically inactive. Patients who have these tumors may have appendicitis, bowel obstruction, or a painful, enlarged liver that results from metastases. Bronchial carcinoids may produce cough, hemoptysis, or frequent pulmonary infections.
2. Symptoms: Endocrinologically active carcinoids
a. Humoral mediators produce attacks of flushing, diarrhea, hypotension, light-headedness, and bronchospasm in various combinations. Attacks may be spontaneous or precipitated by emotional stress, alcohol ingestion, exercise, eating, or vigorous palpation of a liver that contains metastatic deposits.
b. Heart failure from valvular lesions commonly occurs in patients with long-standing carcinoid symptoms and appears to be related to serotonin excess. Ileal carcinoids with hepatic metastases produce tricuspid and/or pulmonic valve stenosis and insufficiency. A patent foramen ovale or bronchial carcinoids with venous drainage into the left atrium can occasionally produce mitral valve disease.
3. Physical findings
a. The characteristic flush differs somewhat according to the site of the primary tumor.
(1) Ileal carcinoid. Purple flush involves the upper trunk and face and usually lasts <30 minutes.
(2) Bronchial carcinoid. Deep, dusky purple flush over the entire body
(3) Gastric carcinoid. Generalized urticaria-like, pruritic, and painful wheals, probably related to histamine production
b. Chronic skin changes may result from repeated episodes of flushing, especially with bronchial carcinoids, which cause thickening of the facial features, telangiectasis, enlargement of the salivary glands, and leonine facies. A pellagrous skin rash characterized by photosensitivity, atrophy of the lingual mucosa, and thickened skin may develop.
c. Right heart failure with evidence of tricuspid or pulmonic valve disease
d. Hepatomegaly
e. Cushing syndrome and, occasionally, acromegaly
4. Laboratory studies in all patients
a. Routine blood tests, particularly liver function tests (LFTs)
b. Liver MRI scan
c. Chest CT scan to search for bronchial carcinoids
d. Upper gastrointestinal barium series or endoscopy
e. Nuclear scanning using a radiolabeled somatostatin analog
f. A histologic diagnosis is essential for management. Biopsy the site that is associated with the least morbidity and that has been determined by noninvasive tests to be probably affected.
5. Laboratory studies in patients with symptoms have traditionally consisted of 24-hour urine collections for 5-hydroxyindoleacetic acid (5-HIAA), particularly in patients with midgut carcinoids. Serotonin is a product of tryptophan metabolism and is metabolized to 5-HIAA (Fig. 15.1). Fasting plasma 5-HIAA has been shown to be at least as sensitive and specific as urinary 5-HIAA. Platelet or urine serotonin measurements may also be useful, particularly in foregut carcinoids, in which 5-HIAA production may be minimal.
a. Causes of elevated urine or plasma 5-HIAA include the following:
(1) Carcinoid syndrome
(2) Other tumors that produce 5-HIAA include biliary, pancreatic islet, and medullary thyroid cancers.
(3) Dietary intake of nuts, bananas, avocados, or pineapples within 48 hours of urine collection or 8 hours of plasma sampling
(4) Medications that must be stopped 1 day before 5-HIAA measurement include mephenesin and guaifenesin.
(5) Malabsorption syndromes (celiac disease, Whipple disease, and tropical sprue) rarely increase 5-HIAA urine excretion above 20 mg per 24 hours.
b. Causes of falsely low 5-HIAA excretion. Phenothiazines interfere with the color reaction of the urine test and must be stopped 2 to 3 days before the collection of urine.
c. Interpretation. A urine level of 5-HIAA >9 mg per 24 hours in patients without malabsorption or >30 mg per 24 hours in patients with malabsorption is pathognomonic for carcinoid unless interfering foods or drugs have been ingested. The magnitude of 5-HIAA excretion in the urine roughly corresponds to the tumor volume; 5-HIAA excretion can also be used to monitor therapy. Normal values for plasma 5-HIAA are laboratory-dependent.
d. Chromogranin A (CgA) is a soluble protein found in secretory granules in a variety of neuroendocrine cell types. Plasma CgA is elevated in nearly all patients with carcinoid tumors, but is nonspecific, since it is also elevated in patients with other neuroendocrine tumors such as pancreatic islet tumors, small cell lung cancer, medullary thyroid cancer, and pheochromocytoma. Serum CgA may also be elevated in patients receiving proton pump inhibitors.
D. Management. The most important principle of management of metastatic carcinoid tumors is therapeutic restraint. These patients often survive for >10 years without antitumor treatment. Patients with endocrinologically active tumors are at especially high risk for complications from any procedure requiring anesthesia. Therapy should be focused on controlling the endocrine symptoms.
1. Surgery is useful for patients with localized primary carcinoids or metastatic tumors that produce obstruction. For patients with incidental appendiceal carcinoids that are ≤2 cm in diameter (which rarely metastasize), appendectomy is adequate treatment.
Partial hepatectomy has been recommended by some physicians, particularly if the metastases are confined to one lobe of the liver. The mortality rate of hepatectomy and the long natural history of the disease, however, often dissuade the physician from recommending the procedure. Palliation of liver metastases may also be accomplished with cryosurgery or radiofrequency ablation.
2. Hepatic artery occlusion performed surgically or by catheterization and embolization of hepatic metastases has been successfully used to palliate endocrine symptoms or pain. Objective regression of manifestations occurs in 60% of patients for a median of 4 months. Side effects of arterial occlusion include fever, nausea, and LFT abnormalities. Both the response rate and the median duration of response appear to improve when occlusion is followed by sequenced chemotherapy (see Section II.D.4).
3. Radiation therapy (RT) is used to palliate liver or bone pain caused by far-advanced metastatic disease unresponsive to other treatments. However, carcinoid tumors are relatively radioresistant.
4. Chemotherapy is used late in the course of disease for treatment of symptomatic metastases and for patients with severe endocrine symptoms that do not respond satisfactorily to pharmacologic maneuvers (see Section II.D.5). There is no general agreement on when (or even if) chemotherapy should be started in patients with malignant carcinoid. Single-agent therapy with 5-fluorouracil (5-FU), streptozocin, cyclophosphamide, doxorubicin (Adriamycin), dacarbazine, temozolomide, or interferon-α (IFN-α) has been associated with response rates of about 25%, with variable median durations of response. Endocrine symptoms may be palliated, but the effect of chemotherapy on survival is not known.
a. Combination chemotherapy regimens (such as streptozocin and doxorubicin) have not clearly had a more beneficial effect compared with single agents. Cisplatin in combination with etoposide is useful for anaplastic forms of neuroendocrine carcinomas. Combinations of IFN-α (3 to 10 million units three to seven times weekly) and octreotide have not been consistently more effective than monotherapy with either agent alone; a flu-like syndrome may be problematic in patients on long-term IFN treatment, and autoimmune thyroid disease may develop in some patients.
b. Hepatic arterial occlusion or embolization, with or without chemotherapy, has been performed for symptomatic hepatic metastases from carcinoid tumors or islet cell carcinomas. Substantial or complete relief from the endocrine syndromes is achieved in about 80% of selected patients, with a median duration of 18 months.
5. Pharmacologic management. It is probably not possible to control the symptoms of carcinoid syndrome completely with aggressive dietary tryptophan restriction and high-dose antiserotonin drugs alone.
a. Somatostatin analogs such as octreotide and lanreotide reduce the production of 5-HIAA and ameliorate symptoms in about 90% of patients. The drugs have a tumoristatic effect as well and prolong the time to tumor progression. The octreotide dosage is usually 100 to 600 mcg SC daily in two to four divided doses. Long-acting depot forms of octreotide and lanreotide are also available; octreotide LAR 10 to 30 mg IM or lanreotide autogel 60 to 120 mg SC are given every 28 days. Side effects of both octreotide and lanreotide include abdominal cramping, cholelithiasis, and hyperglycemia.
b. Hypotension, the most life-threatening complication of carcinoid syndrome, is mediated by kinins (and perhaps prostaglandins) and can be precipitated by catecholamines. β-Adrenergic drugs (e.g., dopamine, epinephrine) must be strictly avoided because they may aggravate hypotension. Pure α-adrenergic (methoxamine, norepinephrine) and vas oconstrictive (angiotensin) agents are preferred for treating hypotension in carcinoid syndrome.
(1) Methoxamine (Vasoxyl) is given IM at a dose of 0.5 mL (10 mg) or IV at a dose of 0.25 mL (5 mg) over 1 to 2 minutes (using a tuberculin syringe). The dose is repeated as necessary to maintain the blood pressure.
(2) Angiotensin amide (Hypertensin), rather than methoxamine, is recommended by some anesthesiologists.
(3) Corticosteroids may prevent episodes of hypotension.
c. Flushing is mediated by kinins and histamine and may respond to several agents, including the following:
(1) Prochlorperazine (Compazine), 10 mg PO four times daily
(2) Phenoxybenzamine (Dibenzyline), 10 to 20 mg PO twice daily
(3) Cyproheptadine (Periactin), 4 to 6 mg PO four times daily
(4) Prednisone, 20 to 40 mg PO daily, is useful for flushing as a result of bronchial carcinoids and occasionally for patients with other kinds of carcinoids.
(5) The combined use of H1- and H2-receptor antagonists has been effective in patients with carcinoid flush and documented hypersecretion of histamine. Diphenhydramine hydrochloride (Benadryl), 50 mg PO four times daily, plus cimetidine (Tagamet), 300 mg PO four times daily, have been used with success in some patients.
(6) Methyldopa (Aldomet) is useful in some patients.
(7) Monoamine oxidase inhibitors are contraindicated in carcinoid syndrome because they block serotonin catabolism and can aggravate symptoms (Fig. 15.1).
d. Bronchospasm is mediated by histamine and managed with aminophylline. Adrenergic agents, such as albuterol, do not appear to worsen bronchospasm for carcinoid and may also be used with caution, since they may cause hypotension.
e. Diarrhea is mediated by serotonin and is often difficult to control. A recommended sequence for treatment before the use of octreotide is as follows:
(1) Belladonna alkaloids and phenobarbital combination (Donnagel-PG), 15 mL every 3 hours as needed
(2) Loperamide (Imodium) or diphenoxylate and atropine (Lomotil) as needed
(3) Cyproheptadine (Periactin), 4 to 6 mg PO four times daily
(4) Methysergide maleate (Sansert), started at 8 to 12 mg/d and gradually increased to 20 to 22 mg/d if needed
(5) Ondansetron, 8 mg PO three times daily
f. Preparation for anesthesia. Patients with carcinoid syndrome are at high risk for the development of flushing, bronchospasm, and hypotension (carcinoid crisis) during surgery. Stimulation of adrenergic hormone release and use of drugs that induce hypotension (morphine, succinylcholine, and curare) must be minimized.
(1) Preoperative period. Patients should be given octreotide 100 mcg SC three times daily for 2 weeks prior to surgery to block the release of tumor products.
(2) During and after surgery. Octreotide should be given intravenously at a rate of 50 mcg/h, starting before anesthesia. Increased doses may be given if flushing or hypotension occurs. Octreotide should be tapered gradually over 1 week postoperatively.
E. Special clinical problems associated with carcinoid syndrome
1. Bowel obstruction may result from dense fibrosis of the mesentery. Surgical relief is often impossible. Patients may improve with simple nasogastric decompression and fluid replacement.
2. Right ventricular failure results from tricuspid and pulmonic valve lesions. These changes develop with far-advanced carcinoid syndrome, which has a poor prognosis independent of the heart lesions. Because of the high surgical risk in these patients, valve replacement may not be warranted. Heart failure should be medically managed with diuretics.
3. Pellagrous skin lesions may be treated with daily oral vitamin preparations containing 1 to 2 mg of niacin.
III. THYROID CANCER
A. Epidemiology and etiology
1. Incidence. Thyroid cancer accounts for about 3% of visceral malignancies; there are 45,000 new cases and 1,700 cancer deaths in the United States annually. The risk increases with age. Women are affected more than men in a ratio of 3:1.
2. Radiation exposure. Radiation fallout and RT given to the neck region in intermediate doses (<2,000 cGy) for benign conditions (such as acne in teenagers, or enlarged tonsils or thymus glands in children) increase the risk for thyroid cancer, particularly the papillary type.
a. The lag time between radiation exposure and the onset of thyroid cancer averages 25 years but ranges from 5 to 50 years. Many patients younger than 20 years of age with thyroid cancer have a history of neck irradiation.
b. About 4% of patients with thyroid cancer have a history of radiation to the neck. Between 5% and 10% of patients who have a history of neck irradiation develop thyroid cancer; 25% have an abnormal thyroid by palpation.
c. Thyroid cancers after neck irradiation are often multifocal but have an indolent course and a prognosis similar to that of spontaneous tumors.
d. Neck irradiation also increases the risk for hyperparathyroidism and parotid gland tumors.
3. Hereditary factors. Medullary cancer of the thyroid may arise sporadically or as a dominantly inherited syndrome of MEN-2 (see Section I.C.2). Thyroid tumors (including papillary and follicular carcinomas), as well as breast neoplasms, also occur frequently in Cowden multiple hamartoma syndrome and in familial adenomatous polyposis (including Gardner syndrome). Several oncogenes and tumor-suppressor genes have been implicated in the pathogenesis of thyroid neoplasms.
4. Thyroid-stimulating hormone (TSH). An increased risk for thyroid cancer may be present in patients with chronic TSH elevation, such as patients with congenital defects in thyroid hormone formation.
B. Pathology and natural history. The more aggressive histologic subtypes of thyroid cancer tend to affect older patients.
1. Papillary cancers (80% of thyroid cancers in adults) affect younger patients. Histologically, the tumor cells may be arranged in either papillary or follicular patterns; the diagnosis of papillary carcinoma is based on nuclear features, not on the presence or absence of follicles. Psammoma bodies may be present in histologic sections in about 40% of these tumors. Regional lymph nodes that drain the thyroid are involved in half of patients. Distant metastases to lungs, bone, skin, and other organs occur late, if at all.
2. Follicular cancers (10% of thyroid cancers) have a peak incidence at 40 to 50 years of age. They tend to invade blood vessels and to metastasize hematogenously to visceral sites, particularly bone. Lymph node metastases are relatively rare, especially compared with papillary cancers.
3. Anaplastic cancers (1% to 2% of thyroid cancers) occur most often in patients older than 60 years of age. Anaplastic thyroid cancers are aggressive cancers, which rapidly invade surrounding local tissues and metastasize to distant organs.
4. Medullary thyroid cancers (5% to 10% of thyroid cancers) secrete calcitonin and carcinoembryonic antigen (CEA). ACTH, histaminase, and an unidentified substance that produces diarrhea may also be secreted by these tumors. Amyloid may be seen on histologic examination and is composed of calcitonin arranged in fibrils. Metastases are mostly found in the neck and mediastinal lymph nodes and may calcify. Widespread visceral metastases occur late.
5. Hürthle cell cancer is a variant of follicular carcinoma and has a relatively aggressive metastatic course.
6. Other tumors found in the thyroid include lymphomas (1% to 2% of all thyroid cancers), a variety of soft tissue sarcomas, and metastatic cancers from kidney, colon and other primary sites. Small cell cancers of the thyroid are actually lymphomas in most cases.
C. Diagnosis
1. Symptoms and signs
a. Symptoms. Some patients with thyroid cancer complain of an enlarging mass in the neck. Hoarseness may be the result of recurrent laryngeal nerve paralysis. Neck pain or dysphagia occasionally is a complaint. Patients without symptoms may have thyroid cancer discovered at thyroidectomy done for other reasons or as an incidental finding in the course of radiologic examinations of the neck (see Section III.C.3.a).
b. Physical findings. Thyroid cancer may be found on routine physical examination as a mass in the thyroid or in the midline up to the base of the tongue (thyroglossal duct remnant). Thyroid masses <1 to 2 cm in diameter often are not palpable. Patients with thyroid cancer may have a single palpable nodule; others have a normal, multinodular, or diffusely enlarged thyroid gland. Cervical lymph nodes are sometimes palpable. Anaplastic cancer is often manifested by obvious masses infiltrating the skin and soft tissues of the neck or by respiratory distress.
2. Laboratory studies
a. Routine studies. Chest radiographs and serum alkaline phosphatase levels may be obtained to look for evidence of metastatic disease in the lung, liver, or bone. Liver and bone scans and selected skeletal radiographs are indicated when the alkaline phosphatase level is elevated.
b. Thyroid scans may be obtained in nonpregnant patients with palpable abnormalities of the thyroid who have a suppressed serum TSH, in order to document the existence of a “hot” nodule. Nonfunctional “cold” nodules are found in 90% of patients with palpable nodules, both benign and malignant, but only about 10% of cold nodules prove to be cancer. Routine isotope scanning of all thyroid nodules is therefore not indicated unless serum TSH is low.
c. Thyroid ultrasonography is useful in determining the size and location of a nodule, diagnosing cystic lesions, detecting nonpalpable nodules or lymphadenopathy, and documenting the presence of features suggestive of malignancy (e.g., microcalcifications within the nodule, irregular borders, increased internal vascularity). Purely cystic lesions, found in about 10% of patients with palpable nodules, are reported to be malignant in <1% of cases. Benign and malignant lesions cannot be confidently distinguished by ultrasonography if they contain mixed solid and cystic components or are entirely solid.
d. Serum calcitonin assay. Patients with a family history of medullary thyroid cancer or other features of MEN-2 should have serum calcitonin measured. Normal basal values may require a calcitonin stimulation test using pentagastrin or calcium infusion. Patients with elevated serum calcitonin require neck exploration regardless of findings on physical examination or sonography.
3. Thyroid gland biopsy
a. Needle aspiration biopsy is invaluable for cytologic diagnosis of thyroid nodules and for preventing unnecessary thyroidectomies. Many authorities recommend needle biopsy as the first step in the evaluation of any thyroid lump. The accuracy of needle biopsy of the thyroid is >90% for benign lesions; the false-negative rate is 5% to 10%. Only about 10% of nodules are cancerous. Roughly, if 100 patients with nodules underwent needle biopsy rather than immediate thyroidectomy, and if patients with clearly benign histopathology were excluded from surgery, 1 cancer would be missed, 9 cancers would be appropriately resected, and 10 patients with benign lesions would have undergone unnecessary surgery. Therefore, the needle biopsy saves 80 of 100 patients from unnecessary surgery at the expense of missing one cancer, which is usually indolent and can be detected later. Patients with nonpalpable nodules >1.5 cm in diameter found on radiologic examinations should generally undergo sonogram-guided needle aspiration biopsy, as should those patients with smaller nodules that appear suspicious for malignancy on sonography.
b. Open biopsy. Nodules interpreted as suspicious on needle biopsy should be removed.
D. Survival and prognostic factors
1. Papillary adenocarcinomas. Decreased survival is not noted when compared with age-matched populations until 12 years after the diagnosis. Only about 5% of patients die as a result of thyroid cancer. Even with distant metastases, patients often survive many years without therapy. The raw 10-year survival rate is 95% for patients <40 years of age and 75% for patients >40 years of age.
a. Factors that have no adverse effect on prognosis
(1) Gender
(2) Radiation-related neoplasms
(3) Regional lymph node metastases (increased recurrences, but normal survival)
b. Factors that adversely affect prognosis, which both increase the recurrence rate and decrease the survival rate
(1) Age > 45 years
(2) Size of nodule >4 cm (compared with <2.5 cm)
(3) Tumor extends through the thyroid capsule
(4) Presence of symptoms such as hoarseness or dysphagia
(5) Distant metastases
(6) Residual tumor fails to take up 131I
(7) Subtotal thyroidectomy (compared with total or “near-total” thyroidectomy) for tumors >1.0 cm in diameter
(8) Probably, postoperative therapy with thyroid hormone alone (compared with thyroid hormone and 131I) in patients with tumors >2 cm in diameter.
2. Follicular adenocarcinoma without vascular invasion has essentially the same survival rate as papillary carcinoma for age-matched populations. With significant vascular invasion, the 10-year survival rate drops to 35%.
3. Medullary carcinoma without lymph node involvement is nearly always cured with surgery. With lymph node involvement, the 5-year survival rate decreases to 45%.
4. Anaplastic carcinoma. Nearly all patients die within 6 to 8 months. Aggressive therapy involving surgery, external RT, and chemotherapy may prolong survival in patients without distant metastases.
5. Thyroid lymphoma. Depending on the stage and histologic subtype, 5-year survival is 35% to 80%.
E. Management. No uniform opinion exists regarding the management of indolent varieties of thyroid cancer.
1. Surgery. Total or near-total thyroidectomy is the treatment of choice for all types of thyroid cancer. Overall, subtotal thyroidectomy is associated with double the recurrence rate and a lower survival rate than total thyroidectomy for papillary and follicular cancers. Subtotal thyroidectomy or lobectomy may be sufficient, however, for low-risk patients with small tumors (<1 cm). Medullary cancer of the thyroid is often bilateral, and total thyroidectomy is imperative.
a. Neck nodes that appear to be involved clinically or on sonography should be removed. Routine radical or modified radical neck dissection, however, does not improve the rate of survival or recurrence, except in medullary carcinoma, and is responsible for increasing the rate of major complications. Selective neck dissection may be pursued, depending on the extent of disease.
b. Complications. The major complications of thyroidectomy are hypoparathyroidism and vocal cord paralysis; death is rare. Combinations of these problems and other complications occur in 5% to 10% of patients subjected to total thyroidectomy; the incidence is doubled to tripled if neck dissection is added to the procedure.
2. Thyroxine. TSH suppression after thyroidectomy is essential because TSH stimulates the growth of most papillary and follicular tumors. Thyroxine is given in a dose sufficient to suppress serum TSH to low-normal or subnormal levels. Patients must be monitored for clinical signs of hyperthyroidism and the dose of thyroxine decreased to keep the patient clinically euthyroid. If 131I is given, thyroxine is begun afterward.
3. Radioactive iodine. Fears of the leukemogenic potential of 131I have abated because little increase in the incidence of acute leukemia has been found in many long-term studies. 131I given postoperatively (usually about 30 to 100 mCi) to ablate thyroid remnants may improve survival in patients with papillary and follicular tumors. Thyroid tumors that do not take up 131I are not ablated by the isotope. See Chapter 2, Section IV.A.
a. Indications for 131I. The true value of 131I is not known and is difficult to determine because the isotope has been given to patients with thyroid cancer as part of standard practice for many years. Radioactive iodine may not be necessary in all postoperative patients, particularly those with localized, small tumors (<1 cm). Clear indications for postoperative 131I treatment include the presence of the following:
(1) Tumors >4 cm in diameter
(2) Tumors with gross extrathyroidal extension
(3) Distant metastases
(4) Most follicular thyroid cancer or Hürthle cell cancer, except for small, minimally invasive follicular carcinomas
In addition, 131I therapy may be given to patients with tumors 1 to 4 cm in diameter if additional features indicate a higher risk of recurrence (e.g., aggressive histology such as tall cell or columnar cell types, presence of lymph node metastases, and age >45 years).
b. Administration. 131I may be given either when the patient demonstrates biochemical evidence of hypothyroidism or after treating the patient with recombinant human TSH. Both methods are based on the principle that TSH stimulates 131I uptake in both residual thyroid tissue and residual carcinoma and that it permits ablation of both.
(1) Waiting for hypothyroidism means allowing the patient to become hypothyroid following thyroidectomy. In some cases, patients are given tri-iodothyronine (T3) in a dose of 25 mcg PO twice daily for about 3 weeks to avoid prolonged hypothyroidism. T3 is then discontinued and serum TSH is measured 7 to 10 days later. If serum TSH exceeds 30 μU/mL, serum thyroglobulin is measured and 131I is given.
(2) Giving TSH. Recombinant human TSH (Thyrogen) is currently approved for diagnostic use and for stimulating 131I uptake in thyroid remnants following thyroidectomy. The use of TSH in the therapy of residual or recurrent cancer is being investigated.
4. Patient follow-up. In most patients with papillary or follicular cancer, serum levels of thyroglobulin (Tg) correlate with residual thyroid tissue (either normal or neoplastic) and can be used as a tumor marker after all normal thyroid remnants have been ablated. Current evidence suggests that serum thyroglobulin levels >1 to 2 ng/mL in patients receiving replacement thyroxine therapy indicate the presence of residual tumor.
Following initial therapy, most patients are monitored every year by assessing the serum Tg response to injected recombinant human TSH. Patients with residual tumor may demonstrate a Tg response even when the baseline serum Tg is <1 ng/mL. Low-risk patients with no Tg response to recombinant human TSH can be followed with measurement of unstimulated serum Tg levels. An 131I scan may also be performed following the administration of recombinant human TSH, but the scan is less sensitive than the Tg response in documenting the presence of residual tumor and often adds little useful information.
Localization of residual or recurrent tumor may also be achieved using sonography of the neck, MRI scans of the neck or other areas, or PET scans; of these, careful sonography is probably the most useful. The use of iodinated contrast agents (e.g., in CT scanning) should be avoided, if possible, because the large load of stable iodine will preclude the use of 131I for 1 to 3 months.
If additional treatment with radioactive iodine is to be given, thyroxine therapy is stopped and the patient is given T3 as detailed in Section III.E.3.b.1. T3 is then discontinued and serum TSH is allowed to rise; when serum TSH exceeds 30 μU/mL, serum Tg is measured and 131I is given. Alternatively, thyroxine therapy may be continued, and recombinant human TSH given to stimulate 131I uptake; this use of rhTSH is currently investigational.
5. Relapsing disease develops in about 12% of patients who have no evidence of disease after primary therapy. Tumors that are not treatable by the combination of surgery, thyroxine therapy, and repeat doses of 131I respond poorly to external-beam RT and chemotherapy.
a. External-beam RT is probably indicated as adjuvant therapy after surgery for anaplastic thyroid cancer and for patients with progressing residual cancers that do not take up 131I.
b. Chemotherapy for symptomatic, widespread metastatic thyroid cancer that is unresponsive to 131I has not been particularly useful.
F. Special clinical problems associated with thyroid cancer
1. Hypoparathyroidism complicates total thyroidectomy in 10% to 30% of patients; it is rare after 131I therapy. Hypoparathyroidism is transient in the majority of cases, and serum calcium levels normalize in 1 or 2 weeks.
a. Acute therapy. Serum calcium levels and clinical evidence of hypocalcemia are checked daily following surgery for 1 to 2 days. If the serum calcium level is <8 mg/dL, oral calcium citrate (1 g four or five times daily) or calcium carbonate (2.5 g/d) is given; either preparation will provide about 1 g of elemental calcium per day. If the patient manifests tetany or the serum calcium is ≤6 mg/dL, intravenous calcium gluconate or lactate is given (1 g every 4 to 6 hours) and serum calcium levels are monitored more frequently.
b. Chronic therapy. Patients with persistent hypocalcemia >1 to 2 weeks after thyroidectomy usually require chronic calcium supplements. If hypocalcemia recurs after 2 more weeks of therapy that has been followed by weaning off supplements, vitamin D therapy is necessary as well. Calcitriol is started at a dose of 0.25 mcg/d PO; calcium citrate or carbonate is continued. Serum calcium measurements are repeated weekly; if <8 mg/dL, the calcitriol is increased in 0.25-mcg increments weekly until the calcium level has normalized. Ergocalciferol or cholecalciferol may also be used; they are much less expensive than calcitriol but may cumulate and cause vitamin D intoxication. Serum calcium should be maintained in the borderline low range (8.0 to 9.0 mg/dL) to avoid hypercalciuria.
2. History of neck irradiation. Patients who have a history of neck radiation exposure and no palpable abnormalities should be followed by careful annual physical examination and sonography. Radiation-induced thyroid cancer typically has an indolent course and does not necessitate anxiety-provoking management.
IV. PHEOCHROMOCYTOMA
A. Epidemiology and etiology. Pheochromocytomas (PCCs) are rare tumors; they belong to the APUD system and produce symptoms by elaborating catecholamines. Extra-adrenal pheochromocytomas are called paragangliomas.Certain hereditary syndromes are associated with an increased risk for PCC or paraganglioma.
1. Dominantly inherited MEN-2 (see Section I.C)
2. Dominantly transmitted PCC
3. Neurofibromatosis-type 1 (von Recklinghausen disease)
4. von Hippel–Lindau disease of central nervous system and retinal hemangioblastomas, renal cell carcinomas, and polycythemia
5. Familial paraganglioma syndromes due to mutations in succinic dehydrogenase subunits B and D
Recent reports indicate that as many as 30% of patients with an apparently sporadic pheochromocytoma may, in fact, harbor a germ line mutation in one of these genes. Screening for these mutations should be performed in patients with bilateral, extra-adrenal, or malignant pheochromocytomas, patients with a family history of one of the syndromes, patients diagnosed with a pheochromocytoma before the age of 20 years, or patients with other phenotypic features of one of the hereditary syndromes.
B. Pathology and natural history
1. PCC originates in the adrenal medulla (90% of patients) or in the paraganglia of the sympathetic nervous system. The paraganglia range from the organ of Zuckerkandl at the aortic bifurcation to the carotid bifurcation. Bilateral PCC frequently occurs in inherited syndromes and in 10% of noninherited cases.
2. Metastases to bone, liver, and lung occur in 10% of cases of PCC despite a histologically benign appearance. Metastases frequently have an indolent growth pattern but are lethal because they often produce cardiovascular complications.
3. Hyperglycemia is common in patients with PCC. Patients also have an increased incidence of gallstones.
4. Paraneoplastic complications of PCC
a. Polycythemia
b. Hypercalcemia
c. Cushing syndrome
C. Diagnosis
1. Symptoms and signs
a. Symptoms. The most common symptoms of PCC are episodes of various combinations of the following: headache, sweating, tachycardia, palpitations, pallor, nausea, and feeling of impending death. Episodes may be triggered by exercise, emotional upset, alcohol ingestion, physical examination in the area of the tumor, or micturition. Vague complaints of anxiety, tremulousness, fever, dyspnea, or angina are often mistaken for psychosomatic illness or thyrotoxicosis. Weight loss is common, but one-third of patients are overweight.
b. Hypertension is present in 90% of patients. The hypertension is fixed (66% of patients) or paroxysmal (33%). Orthostatic hypotension occurs in 70% of patients.
c. Catecholamine cardiomyopathy. Patients may have cardiovascular collapse after a vague history of arrhythmias and anxiety.
d. Patients with small tumors, such as might be found when screening patients with a family history of a hereditary PCC syndrome or when evaluating patients with incidentally discovered adrenal masses, are often asymptomatic; the lack of symptoms does not exclude PCC.
2. Selection of patients for study. All patients with an incidentally discovered adrenal mass should be screened for PCC. Young patients without hypertension but with documented atrial arrhythmia, evidence of an unexplained hypermetabolic state, or cardiomyopathy should be screened for PCC and thyrotoxicosis. The presence of PCC should be sought in patients with hypertension and any of the following:
a. Age < 45 years (PCC is a remediable, although rare, cause of hypertension)
b. A family history of a hereditary PCC syndrome
c. Episodic attacks typical of the syndrome
3. Chemical tests
a. Catecholamine metabolites. Measurement of plasma-free metanephrines appears to be the most sensitive technique (98%) to detect PCC. Ideally, the sample should be drawn following an overnight fast and after the patient has been at rest, preferably supine, for 15 to 30 minutes. There is a 5% false-positive rate using this assay. Twenty-four–hour urine collections for measurement of fractionated metanephrines are nearly as sensitive and specific as plasmafree metanephrines. Plasma catecholamine assays are also available but require meticulous technique in sample collection and handling. Elevated levels of catecholamines or their metabolites suggest the presence of PCC and mandate further studies. A large number of drugs affect either the metabolism or the assay of catecholamines. All drugs, except perhaps mild tranquilizers, sedatives, and analgesics, should be discontinued 72 hours before sample collection, if possible. To control hypertension during the evaluation, diuretics, angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers may be given.
(1) Misleading elevations in urinary catecholamine metabolites. Phenothiazines and tricyclic antidepressants increase levels during acute therapy but may decrease catecholamine excretion during chronic therapy. Increased excretion of metabolites is commonly found with drugs that are catecholamines (e.g., isoproterenol) or catecholamine releasers (e.g., ephedrine, amphetamines, methylxanthines). Other agents include methyldopa, labetalol, phenoxybenzamine, acetaminophen, buspirone, and monoamine oxidase inhibitors (which affect the total metanephrines [TMN] level).
(2) Misleading low TMN values may result from incomplete urine collections or from the use of α-methylparatyrosine, clonidine, reserpine, or guanethidine.
b. Pharmacologic tests (e.g., production of a vasodepressor response with phentolamine) are hazardous, have a poor predictive value, and no longer have a role in the diagnosis of PCC. Failure to suppress plasma catecholamines by clonidine, however, may be useful in diagnosis.
4. Radiographic techniques are used for localization of tumor in patients with a chemical diagnosis of PCC.
a. Chest radiographs may reveal a paraganglionic tumor.
b. CT scan may identify PCC.
c. MRI scan shows a characteristic bright, hyperintense image on T2-weighted images in PCC.
d. Isotope scanning with 123I-metaiodobenzylguanidine may be useful in demonstrating PCC, especially in extra-adrenal sites. Octreotide scanning appears to be less sensitive. Positron emission tomography scanning utilizing 18F-fluorodeoxyglucose or 18F-fluoroDOPA has been reported to be particularly useful in cases of malignant PCC.
D. Management
1. Pharmacologic control of PCC is essential before invasive diagnostic tests or surgery is done.
a. Phenoxybenzamine (Dibenzyline), given in initial doses of 10 to 20 mg PO twice daily, is a pure α-adrenergic blocker that controls both episodic and fixed hypertension; doses are increased until blood pressure and episodes are well-controlled. Other α-adrenergic blockers may also be used (e.g., doxazosin in doses up to 20 mg/d).
b. Propranolol (Inderal), 10 to 40 mg PO given four times daily, is a β-adrenergic blocker that is useful for treating sweating, hypermetabolism, and arrhythmias. Propranolol should be used only after adequate α-adrenergic blockade is established to avoid worsening of hypertension.
c. α-Methylparatyrosine metyrosine (Demser) blocks catecholamine synthesis in doses of 2 to 4 g/d PO.
d. Labetalol, a combined α- and β-adrenergic blocker, can also be used in doses of 200 to 600 mg given twice daily.
e. Calcium channel blockers such as amlodipine (10 to 20 mg/d), nifedipine (30 to 90 mg/d), and verapamil (180 to 540 mg/d) may also be used.
2. Surgery
a. Before surgery
(1) Long-acting α- and β-adrenergic blockers should be continued preoperatively and throughout surgery.
(2) Close attention should be paid to maintaining fluid and electrolyte balance. Preoperative volume expansion may be useful.
(3) Central venous and arterial catheters should be placed to monitor blood volume and pressure changes closely.
b. During surgery
(1) Close ECG monitoring is necessary to manage arrhythmias.
(2) Hypertensive episodes, which may occur while the tumor is being manipulated, are managed with nitroprusside infusion or rapid intravenous boluses of phentolamine (Regitine, 1 to 2 mg IV).
(3) Hypotensive episodes, which occur after the tumor’s blood supply has been isolated, should be treated with intravenous fluids and norepinephrine.
(4) Obvious tumors and paraspinal ganglia should be carefully inspected. All visible tumor is removed. In patients with metastatic PCC, as much tumor as possible is removed to reduce catecholamine secretion.
(5) In patients with bilateral PCC or a familial syndrome predisposing to bilateral tumors (e.g., VHL or MEN-2), selective removal of the PCC while sparing the adrenal cortex has been utilized to avoid iatrogenic adrenal insufficiency.
c. After surgery
(1) Hypertension may develop as a result of fluid overload during surgery and is treated with intravenous furosemide and fluid restriction until the blood pressure is controlled.
(2) If hypertension persists for 2 or 3 days postoperatively, residual PCC must be suspected.
(3) All patients should have plasma-free metanephrines or 24-hour urine metanephrines measured about 1 week after surgery. Unsuspected residual tumors and tumor recurrences should be surgically removed.
(4) Plasma or urine metanephrines should be repeated at yearly follow-up examinations for at least 10 years in cases of sporadic PCC and indefinitely in patients with familial, bilateral, or extra-adrenal tumors.
3. Metastatic disease
a. RT is useful for palliating locally symptomatic metastases.
b. The usefulness of chemotherapy for unresectable disease is not established, although the combination of cyclophosphamide, vincristine, and dacarbazine produces objective responses in many patients. Symptoms of catecholamine excess are managed pharmacologically (see Section IV.D.1).
c. Some patients may respond to therapeutic doses of 131I-metaiodobenzylguanidine.
V. ADRENAL CORTICAL CARCINOMA
A. Epidemiology. Adrenal cancer causes 0.2% of cancer deaths. The average age at diagnosis is 40 years, but the tumor occurs at all ages. About 60% of the patients are women. Adrenal cortical cancer may occur as a component of Li-Fraumeni syndrome, MEN-1, Gardner syndrome, and Beckwith-Wiedemann syndrome.
B. Pathology and natural history. Adrenal cancers are highly aggressive; they frequently metastasize to lungs, liver, and other organs and are large and bulky at the time of diagnosis. About 70% to 80% of these tumors produce functional corticosteroids, including cortisol, aldosterone, androgens, and estrogens.
C. Diagnosis
1. Symptoms and signs
a. Hormonally inactive tumors are discovered as large abdominal masses in patients with abdominal pain, weight loss, or evidence of metastases.
b. Hormonally active tumors present with the following:
(1) Rapid virilization (hirsutism, clitoromegaly, oligomenorrhea, or amenorrhea) in women
(2) Gynecomastia in men
(3) Precocious puberty
(4) Cushing syndrome with hypertension and glucose intolerance
2. Adrenal function tests. Patients with clinical or laboratory evidence (hypokalemic alkalosis) of hypercortisolism should have the dexamethasone suppression test and the 24-hour urine collection for 17-ketosteroids or serum dehydroepiandrosterone sulfate (DHEAS) performed. The differential diagnosis of causes of Cushing syndrome is shown in Table 15.1.
a. Dexamethasone suppression test. The 1-mg overnight dexamethasone suppression test is useful as an initial screening test in outpatients. Following the administration of 1 mg of dexamethasone at 11:00 p.m., serum cortisol is measured before 9:00 a.m. the next morning; serum cortisol is usually suppressed to <3.6 mcg/dL in normal individuals without Cushing syndrome.
Patients who do not suppress normally using the 1-mg dose should have a baseline measurement of serum cortisol and plasma ACTH at 7:00 to 8:00 a.m. on another day. An elevated serum cortisol level together with a suppressed plasma ACTH concentration suggests a primary adrenal cause of the patient’s Cushing syndrome.
b. Twenty-four–hour urine collection is obtained for urinary-free cortisol (upper limit of normal is <50 mcg per 24 hours in most laboratories) and 17-ketosteroids (upper normal limit is <14 to 26 mg per 24 hours, depending on the age and sex of the patient). The level of urinary-free cortisol is elevated in Cushing syndrome, no matter what the cause. Levels of 17-ketosteroids in excess of 50 mg in 24 hours make the diagnosis of adrenal carcinoma likely; levels >100 mg in 24 hours are diagnostic. Serum DHEA-sulfate can be measured as an alternative to urine 17-ketosteroids and is elevated in most cases of adrenal carcinoma.
Table 15.1 Differential Diagnosis of Causes of Cushing Syndrome
ACTH, adrenocorticotropic hormone; N, normal; ↓, decreased; ↓↓, markedly decreased; ↑, increased; ↑↑, markedly increased.
aAdrenal gland enlargement is determined by CT scan.
3. Further studies
a. Chest CT scan to search for metastases
b. Abdominal CT scan or MRI to look for abdominal masses not clinically evident. Small (<4 cm) benign adrenal masses are common incidental findings on CT examination; laboratory findings and follow-up CT scans may help in the differential diagnosis.
c. Biopsy
(1) In patients with metastatic disease, biopsy is performed on the most readily accessible site (e.g., superficial lymph nodes or liver with evidence of metastases).
(2) If only intra-abdominal disease is evident, surgery is necessary for biopsy proof of the diagnosis.
D. Management. The median survival for untreated patients is 3 months. Treated patients may survive much longer, depending on the extent of disease.
1. Surgery should be used to resect as much tumor as possible. The contralateral adrenal gland should be inspected and removed if there is evidence of tumor.
2. RT is used to palliate symptoms from local metastatic sites. Adjuvant tumorbed RT has been reported to reduce tumor recurrence.
3. Chemotherapy may be useful for reducing tumor bulk and controlling endocrine symptoms. Mitotane produces objective tumor regression or improvement of endocrine symptoms in 30% of cases. The combination of mitotane with etoposide, doxorubicin, and cisplatin has provided responses in 50% of patients. The use of mitotane as an adjuvant to surgery in localized disease may improve results. Pharmacologic management of hypercortisolism is discussed in Chapter 27, Section VIII.C.
VI. ISLET CELL TUMORS
A. General aspects. Islet cell tumors of the endocrine pancreas are uncommon. In addition to the specific endocrine manifestations associated with each kind of tumor, some have been associated with ectopic production of ACTH (Cushing syndrome) and other hormones. Many of these tumors are malignant and metastasize to the liver and regional lymph nodes.
1. Diagnosis. The diagnosis of islet cell tumor is usually suspected because of endocrine or biochemical abnormalities. Signs and symptoms of islet cell tumors are described according to the specific type. After abnormal hormonal products are detected, the following studies are done in all patients to determine the tumor’s location and extent:
a. LFTs and liver imaging, preferably with MRI
b. Liver biopsy is the diagnostic method of choice if liver imaging suggests the presence of tumor.
c. CT or MRI scans of the pancreas and duodenum may reveal isolated tumors. Selective angiograms have a yield of <50%. Endoscopic ultrasonography is useful in localizing tumors in the head of the pancreas or duodenal wall.
d. Somatostatin receptor scanning using radioiodinated octreotide frequently demonstrates primary and metastatic islet cell tumors. More than 90% of PETs (pancreatic endocrine tumors) possess somatostatin receptors. Detection of somatostatin receptors by this method correlates well with response to treatment with octreotide.
e. Selective arterial secretagogue injection is an extremely useful technique in which the desired pancreatic hormone (e.g., gastrin, insulin) is measured in the hepatic vein immediately following selective injection of pancreatic hormone stimulants such as calcium or secretin into individual branches of the celiac artery axis; although technically difficult, it is highly effective in localizing the source of hormonal hypersecretion.
f. Exploratory laparotomy is indicated if there is clinical or laboratory evidence of an islet cell tumor, even if preoperative localization is unrevealing.
2. Management
a. Surgery. Intraoperative pancreatic ultrasonography and intraoperative duodenoscopy are used to localize tumors. Benign tumors are excised. Cytoreductive surgery should be performed in all patients with malignant tumors when feasible. In patients with liver metastases, partial hepatectomy, cryotherapy, and radiofrequency ablation have all been used for palliation, with some increase in both survival and quality of life. Hepatic artery embolization is helpful in carefully selected patients, with or without postocclusion chemotherapy (see Section II.D.2).
b. Chemotherapy has been useful in half of patients with metastatic disease, by both decreasing tumor mass and ameliorating otherwise refractory endocrine symptoms. The presence of metastases to the liver or other sites does not justify instituting cytotoxic therapy in itself because such patients can still survive several years (e.g., a median of about 4 years for gastrinomas with liver metastases if gastric acid secretion is controlled). Chemotherapy is generally reserved for patients with documented progressive liver metastases or without control of symptoms by octreotide and other medical measures.
(1) Octreotide and lanreotide are somatostatin analogs that inhibit hormone release from gastrinomas, insulinomas, VIPomas, glucagonomas, and GH-RHomas (tumors producing growth hormone–releasing hormone) and often relieve the symptoms of the associated clinical syndrome. Both drugs may slow tumor progression in some patients. Sustained-release forms can be given as a monthly intramuscular or subcutaneous injection.
(2) Streptozocin has been the drug of choice for islet cell tumors and is associated with a 30% response rate. Although most other single chemotherapeutic agents are much less effective, recent trials suggest that both sunitinib and everolimus significantly prolong progression-free survival.
(3) Combination chemotherapy with streptozocin and doxorubicin or 5-FU achieves a 40% to 60% response rate for an average duration of about 18 months. Alternatively, the combination of 5-FU and streptozocin can be sequenced with the combination of doxorubicin and dacarbazine after hepatic artery occlusion (see Section II.D.4).
(4) IFN-α in doses of about 5 million units three times weekly may control symptoms and biochemical abnormalities in some patients and may slow tumor progression in a minority.
B. Gastrinoma (Zollinger-Ellison syndrome). About 60% of these tumors are malignant, 90% are multiple, and about 30% are associated with MEN syndromes; the majority are located in the duodenum, with smaller numbers in the pancreas. Duodenal gastrinomas have a 40% to 70% risk of spread to local lymph nodes, but a low (5%) risk of hepatic metastases, while pancreatic gastrinomas are more likely to spread to the liver. Prognosis is poorer in cases with hepatic metastases.
1. Diagnosis
a. Symptoms include severe peptic ulcer disease and, often, severe diarrhea.
b. Laboratory studies
(1) Upper gastrointestinal contrast radiographic studies and endoscopy show severe ulceration and hypertrophic gastric folds.
(2) Fasting serum gastrin level (normal value is <100 pg/mL) is usually elevated to >500 pg/mL. If gastrinoma is suspected but serum gastrin levels are not elevated, gastrin stimulation with calcium or secretin may be attempted. Calcium infusion (12 mg/kg of calcium gluconate over 3 hours) causes the gastrin level to more than double in patients with gastrinoma; the paradoxical increase in gastrin after secretin stimulation is used by some authorities to diagnose gastrinoma. Other causes of increased gastrin levels (use of proton pump inhibitors, atrophic gastritis, vagotomy, retained antrum after Billroth II gastrojejunostomy, and G-cell hyperplasia) must be differentiated from gastrinoma. Atrophic gastritis is differentiated by gastric acid studies.
(3) Gastric secretory studies. After an overnight fast, a nasogastric tube is placed, and four 15-minute aliquots are removed for analysis. Acid secretion of >10 mEq/h and a volume of >100 mL/h suggest gastrinoma. These studies clearly distinguish gastrinoma from atrophic gastritis.
c. Tumor location and extent. See Section VI.A.1.
2. Management
a. Therapy with proton pump inhibitors controls symptoms in most patients.
b. Total gastrectomy is rarely necessary because ulcer symptoms can be controlled with proton pump inhibitors. Curative tumor excision may be possible in patients without hepatic metastases, and tumor debulking may improve quality of life in those with limited spread to the liver.
c. Chemotherapy is used for metastatic disease (see Section VI.A.2.b).
C. Insulinomas are most likely to occur between the ages of 40 and 60 years. About 80% to 85% are benign, 5% to 10% are malignant, and 5% to 10% are multifocal; 80% are hormonally functional. Insulinomas are sometimes found in association with gastrinomas. A family history of diabetes mellitus is present in 25% of patients.
Insulinomas occur with equal frequency in the head, body, and tail of the pancreas; about 3% develop outside the pancreas. Malignant tumors are more frequent in male patients. When malignant, they metastasize to the liver primarily.
1. Diagnosis. The differential diagnosis of hypoglycemia is discussed in Chapter 27, Section XII.A.
a. Symptoms. Fasting hypoglycemia, often alleviated by meals, is usually the presenting feature of insulinoma. Symptoms include diaphoresis, nervousness, palpitations, hunger pangs, anxiety, asthenia, confusion, weakness, seizures, and coma. Many patients have personality or other psychiatric changes noticed by the family. Weight gain is occasionally reported. Weight loss and liver failure may develop with metastases to the liver.
b. Laboratory studies. Simultaneous measurements of fasting blood glucose, insulin and C-peptide levels during hypoglycemia are the cornerstone for diagnosis of insulinoma.
(1) Fasting hypoglycemia. An overnight fast is begun at 10:00 p.m. Blood glucose, insulin, and C-peptide measurements are then obtained at 6:00 a.m., noon, 6:00 p.m., and midnight. Inappropriately elevated levels of plasma insulin (>6 μU/mL) and C-peptide (>0.6 ng/mL) in the presence of hypoglycemia (glucose <55 mg/dL) usually is diagnostic of insulinoma or sulfonylurea ingestion. If symptoms of hypoglycemia develop at any time, blood glucose, insulin, and C-peptide levels should be measured; if the glucose concentration is <40 mg/dL, the test should be terminated by giving the patient food or a 50-mL intravenous bolus of 50% dextrose.
(2) Other insulin assays. Proinsulin and C-peptide are absent from commercial insulin preparations; their measurement by radioimmunoassay determines the role of exogenous insulin administration in the causation of hypoglycemia. In fasting patients, proinsulin levels are normally <20% of total insulin; a higher percentage of proinsulin is indicative of insulinoma.
c. Tumor location and extent. See Section VI.A.1.
2. Management
a. Surgery. Surgical removal of the tumor is the treatment of choice for insulinoma.
b. RT as an adjuvant to surgery has not been shown to be helpful.
c. Chemotherapy may be used for advanced disease (see Section VI.A.2.b).
d. Treatment of hypoglycemia
(1) Diazoxide, 150 to 600 mg PO daily, is effective in managing hypoglycemic symptoms. The drug can induce hyperglycemia, hyperosmolar coma, or ketoacidosis; urine sugar and ketones should be monitored daily. A mild diuretic, such as hydrochlorothiazide, 50 mg daily, should be given to counteract the sodium-retaining effect of diazoxide. Other complications of diazoxide therapy include cytopenias, lanugo hair growth, rashes, eosinophilia, and hyperuricemia.
(2) Corticosteroids (prednisone, 40 mg/d, or hydrocortisone, 100 mg/d) may be given to patients who do not respond to diazoxide.
(3) Subcutaneous injections of octreotide or lanreotide (or a monthly injection of a sustained-release preparation) inhibit insulin secretion and restore euglycemia in about half of insulinoma patients. By suppressing glucagon and growth hormone secretion, somatostatin analogues will occasionally worsen hypoglycemia.
(4) Calcium channel blockers (e.g., verapamil, 80 mg t.i.d.) inhibit insulin secretion and have been successfully used to prevent hypoglycemic episodes.
(5) Patients with unresponsive hypoglycemia and unresectable insulinoma may be approached with several other, usually unsatisfactory, alternatives including continuous intravenous infusion of 10% dextrose solutions through a Broviac or Hickman catheter, hepatic irradiation, or infusion of 5-FU into the hepatic artery.
D. Glucagonomas are usually malignant, and most have metastasized at the time of discovery. The disease is suspected in patients who have diabetes mellitus that is moderately resistant to insulin and who have the following abnormalities:
1. Diagnosis
a. Symptoms and physical findings
(1) Dermatosis: A peculiar erythematous migratory skin rash that had waxed and waned over many years (often >6 years), especially involving perioral and perigenital regions (also the fingers, legs, and feet), occurs in 80% of patients.
(2) Depression or other personality changes reported by family members
(3) Diarrhea; abdominal pain
(4) Deep vein thrombosis (half of patients)
(5) Oral cavity ulcerations and sore tongue are common.
(6) Weight loss
b. Laboratory studies
(1) Hyperglycemia (usually mild)
(2) Normocytic anemia
(3) Elevated fasting blood glucagon levels (normal is <130 pg/mL)
c. Tumor location and extent. See Section VI.A.1.
2. Management. See Section VI.A.2. Prophylactic measures to prevent venous thrombosis during the perioperative period are mandatory.
E. Pancreatic cholera syndrome (VIPoma). These islet cell tumors secrete VIP (vasoactive intestinal peptide); half are malignant.
1. Diagnosis
a. Symptoms include severe watery diarrhea, muscle weakness due to hypokalemia, flushing, psychosis, and hypotension.
b. Laboratory studies
(1) Serum chemistry studies show hypokalemia and, often, hypercalcemia.
(2) Gastric secretory studies show achlorhydria or hypochlorhydria.
(3) Serum levels of VIP are elevated (normal is <60 pg/mL).
c. Tumor location and extent. See Section VI.A.1.
2. Management
a. Surgery. Removal of solitary tumors controls manifestations of the pancreatic cholera syndrome, including hypercalcemia. Debulking of extensive tumor may palliate the diarrhea.
b. Chemotherapy (see Section VI.A.2.b) is useful for controlling symptoms in patients with metastatic tumor. Long-acting somatostatin analogs (octreotide or lanreotide) usually lower VIP levels and stop the diarrhea.
F. Other pancreatic endocrine tumors
1. Somatostatinoma. Somatostatin (somatotropin-release inhibiting factor) inhibits numerous endocrine and exocrine secretory functions. Half of patients with somatostatinoma have other endocrinopathies as well. This rare tumor produces diabetes mellitus, diarrhea, steatorrhea, gastric achlorhydria, weight loss, and in many cases, gallstones. Metastases are present in most cases at presentation. Cases are discovered by accident; symptoms are investigated, the tumor is found, and then the assays to confirm the diagnosis of somatostatinoma are performed. No definite procedure for diagnosis has been established. Routine evaluation of diabetic patients for somatostatinoma is not worthwhile unless severe malabsorption is present. See Section VI.A.2 for treatment recommendations.
2. PPoma. Pancreatic polypeptide (PP) inhibits gallbladder contraction, and thus PPomas are usually silent biochemically. It appears that many cases of so-called nonfunctional islet cell tumors are actually PPomas. These tumors are usually found incidentally while evaluating the patient for abdominal symptoms. Caution must be exercised in interpreting elevated PP levels because they can occur in other conditions such as the MEN-1 syndrome. Benign tumors should be excised. Malignant PPomas respond to octreotide and streptozocin.
3. GH-RHomas are large tumors that excessively produce growth hormone–releasing hormone. About one-third of these rare tumors originate in the pancreas, and more than half originate in the lung. The diagnosis can be suspected in patients with acromegaly but without an imaged pituitary tumor or with an abdominal mass. The diagnosis can be confirmed with elevated plasma GH-RH levels. Surgical resection is performed if possible. Octreotide effectively lowers plasma GH-RH levels.
VII. OTHER ENDOCRINE CANCERS
A. Parathyroid carcinoma is rare. Patients usually present with a neck mass and severe hypercalcemia; occasional patients with nonfunctioning tumors are normocalcemic. Tumor growth is slow and tends to involve the neck and upper mediastinum; widespread metastases are uncommon. Many patients with parathyroid carcinoma have either somatic or germ line mutations in the HRPT2 gene, located at chromosome 1q25; the gene product, parafibromin, appears to function as a tumor suppressor.
1. Diagnosis
a. Patients with parathyroid cancer usually have stigmata of hypercalcemia, including polyuria, polydipsia, constipation, mental status changes, hyperparathyroid bone disease, hypercalciuria, nephrocalcinosis, or renal stones.
b. High serum calcium levels are typical (often >15 mg/dL). Patients appear to tolerate these high levels relatively well, although hypercalcemic nephropathy and progressive bone disease ultimately complicate the course. Serum levels of parathyroid hormone are usually grossly elevated.
c. The diagnosis is established by biopsy of obvious neck masses in patients with evidence of hyperparathyroidism.
d. Patients with parathyroid carcinoma should be considered for DNA testing for germ line mutations in the HPRT2 gene.
2. Management
a. Surgery. Surgical extirpation of as much tumor as possible is necessary. Periodic repeated surgical debulking is warranted to try to control both the local effects of the tumor and hypercalcemia.
b. Hypercalcemia may be difficult to manage unless the tumor can be removed. Attempts should be made to normalize blood calcium levels; because this may be impossible, however, the alternative therapeutic goal is to reduce blood levels to the asymptomatic range. The management of patients with hypercalcemia is discussed in Chapter 27, Section I. Chronic therapy with zoledronate (4 mg IV) or pamidronate (30 to 90 mg IV) every 7 to 30 days may be necessary. The calcimimetic agent, cinacalcet, may be used (30 to 60 mg/d PO) to suppress parathyroid hormone production and alleviate the hypercalcemia.
B. Pineal gland neoplasms are extremely rare and are usually found in boys and young men. Dysgerminoma is the most common tumor of the pineal gland, although gliomas, choriocarcinoma, and melanomas also occur. Most tumors are localized, but spread along the flow tract of cerebrospinal fluid often occurs. See Chapter 14, Section VII, for diagnosis and management.
VIII. METASTASES TO ENDOCRINE ORGANS
A. Adrenal gland metastases. The adrenal gland is frequently the site of metastatic tumors, particularly from lung cancer, breast cancer, and melanomas. Adrenal insufficiency, although rare, can develop with bilateral adrenal metastases.
1. Diagnosis
a. Symptoms and signs. Patients with adrenal insufficiency develop malaise, asthenia, weakness, anorexia, decreased ability to taste salt, and salt craving. Hyperpigmentation of the skin and mucous membranes, particularly the gums, and orthostatic hypotension may occur.
b. Laboratory findings include hyponatremia, hyperkalemia, and elevated blood urea nitrogen. Diagnosis is established by the following steps:
(1) Obtaining a baseline serum cortisol level that is low (<5 mcg/dL)
(2) Repeating the serum cortisol 1 hour after administering 0.25 mg of cosyntropin IV. Failure of the cortisol level to rise to a peak value of at least 19 to 20 mcg/dL is diagnostic of adrenal insufficiency.
2. Management. Patients with adrenal insufficiency should be treated with fludrocortisone acetate (0.1 mg once or twice a day) and hydrocortisone (20 to 30 mg/d) or prednisone (5 to 7.5 mg daily). The correct dose of fludrocortisone is determined by measuring orthostatic blood pressure changes and blood electrolyte levels. If the orthostatic drop in blood pressure is >10 mm Hg, the fludrocortisone is increased by 0.05-mg increments every few days until orthostasis is corrected. If the patient develops hypertension, hypokalemia, or alkalosis, the fludrocortisone dose is decreased.
Surgical excision may be considered in patients with an apparently isolated adrenal metastasis.
B. Thyroid gland metastases. The thyroid gland is occasionally involved with metastases but is rarely the presenting site for metastatic tumors. Non-Hodgkin lymphomas and carcinomas of the breast, ovary, cervix, kidney, esophagus, colon, lung, and melanoma have been reported to produce thyroid metastases. Diagnosis is established, if necessary, by needle biopsy of the thyroid masses. Therapy depends on the presence of local symptoms, the nature of the primary tumor, and the presence of metastases elsewhere in the body.
C. Testicular metastases. Acute leukemia, melanoma, and carcinomas of the lung, prostate, bladder, and, occasionally, kidney can metastasize to the testes. A peritesticular mass, intratesticular mass, or stony-hard enlarged testis (particularly characteristic of leukemic infiltration) is found on physical examination. Biopsy is necessary to establish the diagnosis; a transinguinal approach is mandatory.
D. Ovarian metastases. Ovarian metastases may complicate melanomas and primary tumors of the breast, stomach, colon, lung, and, occasionally, other organs. Ovarian metastases are usually asymptomatic but occasionally are the presenting feature of the primary tumor. An ovarian mass is palpable on pelvic examination. Biopsy must be done to determine the diagnosis if no other sites of cancer are evident.
E. Pituitary metastases cannot be distinguished on clinical or biochemical grounds from pituitary adenomas. Patients with cancer have been reported to have a 28% incidence of sellar or suprasellar metastases at autopsy while the general population has about a 10% incidence of pituitary adenomas at postmortem examination. Radiologic discrimination antemortem is not possible. Primary cancers of the breast account for more than half of the cases of pituitary metastases and lung cancer for 20%; the remainder are caused by other carcinomas, melanomas, sarcomas, and leukemias. The triad of headache, extraocular nerve palsy, and diabetes insipidus is highly suggestive of sellar metastases whether or not the patient has a known cancer. Surgical exploration and decompression may be necessary unless precluded by progressive widespread metastases.
Suggested Reading
Carcinoid and Islet Cell Tumors
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Ehehalt F, Saeger HD, Schmidt CM, et al. Neuroendocrine tumors of the pancreas. Oncologist 2009;14:456.
Gustafsson BI, Kidd M, Modlin IM. Neuroendocrine tumors of the diffuse neuroendocrinesystem. Curr Opin Oncol 2008;20:1.
Jensen RT, Delle Fave G. Promising advances in the treatment of malignant pancreatic endcrine tumors. N Engl J Med 2011;364:564.
Kulke MH. Clinical presentation and management of carcinoid tumors. Hematol Oncol Clin North Am 2007;21:433.
Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am 2009;89:1105.
Nakakura EK, Bergsland EK. Islet cell carcinoma: neuroendocrine tumors of the pancreas and periampullary region. Hematol Oncol Clin North Am 2007;21:457.
Pinchot SN, Holen K, Sippel RS, et al. Carcinoid tumors. Oncologist 2008;13:1255.
Poncet G, Faucheron J-L, Walter T. Recent trends in the treatment of well-differentiated endocrine carcinoma of the small bowel. World J Gastroenterol 2010;16:1696.
Thyroid Cancer
Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167.
Fialkowski EA, Moley JF. Current approaches to medullary thyroid carcinoma, sporadic and familial. J Surg Oncol 2006;94:737.
Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single-institution experience using aggressive multimodal therapy. Thyroid 2011;21:25.
Green LD, Mack L, Pasieka JL. Anaplastic thyroid cancer and primary thyroid lymphoma: a review of these rare thyroid malignancies. J Surg Oncol 2006;94:725.
Sabet A, Kim M. Postoperative management of differentiated thyroid cancer. Otolaryngol Clin North Am 2010;43:329.
Pheochromocytoma
Adjallé R, Plovin PF, Pacak K, et al. Treatment of malignant pheochromocytoma. Horm Metab Res 2009;41:687.
Adler JT, Meyer-Rochow GY, Chen H, et al. Pheochromocytoma: current approaches and future directions. Oncologist 2008;13:779.
Havekes B, King K, Lai EW, et al. New imaging approaches to phaeochromocytomas and paragangliomas. Clin Endocrinol 2010;72:137.
Mittendorf EA, Evans DB, Lee JE, et al. Pheochromocytoma: advances in genetics, diagnosis, localization and treatment. Hematol Oncol Clin North Am 2007;21:509.
Pacak K. Perioperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 2007;92:4069.
Petri B-J, Van Eijck CHJ, de Herder WW, et al. Phaeochromocytomas and sympathetic paragangliomas. Br J Surg 2009;96:1381.
Adrenal Cortical Carcinoma
Fassnacht M, Allolio B. Clinical management of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab 2009;23:273.
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Lacroix A. Approach to the patient with adrenocortical carcinoma. J Clin Endocrinol Metab 2010;95:4812.
Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol 2009;27:4619.
Young WF Jr. The incidentally discovered adrenal mass. N Engl J Med 2007;356:601.
Parathyroid Carcinoma
Adam MA, Untch BR, Olson JA. Parathyroid carcinoma: current understanding and new insights into gene expression and intraoperative parathyroid hormone kinetics. Oncologist 2010;15:61.
Sharretts JM, Kebebew E, Simonds WF. Parathyroid cancer. Semin Oncol 2010;37:580.
Metastases to Endocrine Glands
DeWaal YRP, Thomas CMG, Oei ALM, et al. Secondary ovarian malignancies. Frequency, origin and characteristics. Int J Gynecol Cancer 2009;19:1160.
Gittens PR, Solish AF, Trabulsi EJ. Surgical management of metastatic disease to the adrenal gland. Semin Oncol 2008;35:172.
Komninos J, Vlassopoulou V, Protopapa D, et al. Tumors metastatic to the pituitary gland: case report and literature review. J Clin Endocrinol Metab 2004;89:574.
Papi G, Fadda G, Corselllo SM, et al. Metastases to the thyroid gland: prevalence, clinicopathological aspects and prognosis: a 10-year experience. Clin Endocrinol 2007;66:565.