Bethesda Handbook of Clinical Oncology, 2nd Edition
Michael E. Menefee*
*Medical Oncology Clinical Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
†Cancer Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Endocrine tumors are relatively uncommon. These tumors may cause morbidity and mortality not only by local and distant spread of tumor cells but also through mediators produced by the tumor cells that may have systemic effects. The tumors are often difficult to diagnose and treat effectively.
This chapter discusses
- thyroid cancer
- cancer of the parathyroid gland
- adrenocortical cancer
- pancreatic endocrine tumors
- carcinoid tumors
- multiple endocrine neoplasia (MEN).
The epidemiology of endocrine tumors is outlined in Table 34.1.
TABLE 34.1. Incidence and Proportion of all Endocrine Cancers and Relative Proportions of Different Primary Thyroid Cancer Subtypes
Thyroid carcinoma is not a common type of cancer. However, it is the most common endocrine malignancy and remains a diagnostic as well as therapeutic challenge to the clinician.
- Thyroid carcinoma accounts for more than 90% of all endocrine tumors.
- There are approximately 20,000 new cases per year.
- The occurrence of thyroid carcinoma is greater in women than in men (2–3:1).
- Risk factors include:
- irradiation to the head and neck during childhood
- family history.
- Rearrangements of the tyrosine kinase domains of the RETand TRK genes with the amino terminal sequence of an unlinked gene are found in some papillary carcinomas.
- RETrearrangements are found in 3% to 33% of the papillary carcinomas that are not associated with irradiation and in 60% to 80% of those that occur after radiation.
- Most patients with thyroid carcinoma present with an asymptomatic thyroid nodule
- Hoarseness is caused by invasion of the recurrent laryngeal nerve or by direct compression of the larynx
- Cervical lymphadenopathy
- Horner syndrome.
Papillary Thyroid Carcinoma
- Papillary thyroid carcinoma is the most common subtype of thyroid carcinomas (60% to 75%).
- The carcinoma is well differentiated.
- Papillary thyroid carcinoma tends to be unilateral, although it may be multifocal within a lobe.
- The carcinoma metastasizes via lymphatic invasion; vascular invasion is uncommon.
- The prognosis is related to stage and age of the patient. Patients with early-stage disease have a prolonged survival. Ten-year survival in patients with distant metastases ranges from 30% to 50%.
- Variants include tall-cell, columnar, and diffuse sclerosis.
Follicular Thyroid Carcinoma
- Follicular thyroid carcinomas are well differentiated.
- The carcinoma affects a slightly older patient population than does papillary thyroid carcinoma.
- The carcinoma metastasizes at a late stage to the lungs and bones via a vascular route and may occur late.
- Lymph node involvement is rare.
- Prognosis is good, but is slightly less favorable than that of papillary thyroid carcinoma.
Medullary Thyroid Carcinoma
- Medullary thyroid carcinoma is a neuroendocrine tumor of the parafollicular (C) cells.
- It represents 3% to 5% of all thyroid carcinomas.
- The carcinoma may be a part of the MEN type 2 (MEN-2) syndrome; however, most cases are sporadic.
- Sporadic tumors tend to be solitary, whereas familial tumors tend to be bilateral and multifocal.
- The tumors secrete calcitonin.
- Approximately 50% of patients with this carcinoma present with regional lymphadenopathy.
- Distant metastases typically occur late in the disease and usually involve the lungs, liver, bones, and the adrenal glands.
Anaplastic Thyroid Carcinoma
- Anaplastic thyroid carcinoma accounts for 2% to 5% of all thyroid cancers; up to 50% of patients will have either antecedent or concurrent history of a well-differentiated thyroid carcinoma.
- It is a high-grade tumor, often with lymphovascular invasion and regional or distant spread at diagnosis.
- Hürthle cell carcinoma
- Radiation-induced carcinoma—25- to 30-year latency period between exposure and the development of cancer
- Metastatic tumors
- The TNM definitions and the staging for thyroid carcinoma are discussed in Tables 34.2 and 34.3.
TABLE 34.2. TNM Definitions for Thyroid Carcinoma
TABLE 34.3. Staging of Thyroid Cancer
Evaluation of a Thyroid Nodule
- Fine needle aspiration biopsy (FNAB) is a more cost-effective technique than ultrasonography.
- Ultrasonographic evaluation is warranted in patients with a history of neck irradiation.
- The evaluation of palpable thyroid nodules is discussed in Fig. 34.1 and Table 34.4.
TABLE 34.4. Analysis of Thyroid Fine Needle Aspiration (FNA) Results
FIG. 34.1. Evaluation of a palpable thyroid nodule.
Prognostic Factors of Well-differentiated Thyroid Carcinoma
- Overall survival rate at 10 years for middle-aged adults is about 80% to 95%.
- Five percent to 20% of patients will have local or regional recurrences.
- Ten percent to 15% of patients will have distant metastatic disease.
- The prognostic indicators for recurrent disease and death are age at the time of diagnosis, histologic subtype, and extent of the tumor.
Treatment of Well-differentiated Thyroid Carcinoma
- If the lesion is <1.5 cm, lobectomy is appropriate.
- Lobectomy: contralateral lobe is not dissected, but is examined only for abnormalities.
- Subtotal thyroidectomy: leaves 2 to 4 g of the thyroid tissue in the upper part of the contralateral thyroid. It also preserves the recurrent laryngeal nerve and the blood supply to the upper parathyroid glands.
- Near-total thyroidectomy: leaves a much smaller portion of the thyroid tissue near the ligament of Berry. It also preserves the recurrent laryngeal nerve, but not the blood supply to the parathyroid glands.
- Total thyroidectomy: removes all thyroid tissue. It can cause permanent hypocalcemia. Replacement calcium and vitamin D supplementation should therefore be considered.
- The choice of surgery is a controversial topic.
- Iodine-131 is used in papillary or follicular thyroid carcinoma for the following reasons:
- Ablation of the normal, residual thyroid tissue after thyroid surgery, thereby increasing the sensitivity of subsequent iodine-131 total body scanning (TBS), and measurement of serum thyroglobulin for the presence of recurrent disease.
- Treatment of microscopic occult thyroid cancer in the neck or in the metastatic sites.
- Radioiodine treatment decreases cancer-related death, tumor recurrence, and development of distant metastases.
- The dose of iodine-131 varies from 30 to 150 mCi or higher.
- Table 34.5 discusses the indications for iodine-131 treatment after surgery.
- Fig. 34.2 provides the recommended follow-up of patients after total thyroid ablation.
TABLE 34.5. Indications for Ablative Treatment with Iodine-131 After Surgery in Patients with Thyroid Cancer
FIG. 34.2. Recommended follow-up of patients after total thyroid ablation based on serum thyroglobulin [assessment and iodine-131 total body scanning (TBS)]. (From Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med 1998;338:297–308, with permission.)
Complications of Iodine-131 Treatment
- Marrow suppression
- Testicular dysfunction
Chemotherapy has only a limited role in thyroid carcinoma. Doxorubicin is considered the most active agent; other single agents like UP-16, carboplatin, and cisplatin have low response rates.
External-beam radiation therapy has only a limited role in thyroid carcinoma. Indications include incomplete surgical resection and tumors that do not take up iodine-131.
- The growth of the thyroid tumor cells is controlled by thyrotropin, and the recurrence and survival rates are improved by inhibition of thyrotropin secretion with thyroxine.
- Levothyroxine should be given to all patients with thyroid carcinoma regardless of the extent of the surgery and other treatments.
- In patients without evidence of thyroid carcinoma, the level of the thyroid-stimulating hormone (TSH) should be maintained below the normal range (0.5 to 5 mU per mL).
- In patients with thyroid carcinoma, the level of the TSH should be maintained below 0.1 mU per mL.
Follow-up of Patients with Well-differentiated Thyroid Carcinoma
The goals after initial therapy are to maintain a euthyroid state and to detect recurrent or persistent disease.
- Clinical examination for recurrent nodes in thyroid bed
- Ultrasonography in patients with clinical findings suggestive of the disease and in those who are at high risk
- Serum thyroglobulin
- Thyroglobulin (Tg) is an important tumor marker in the follow-up of thyroid cancer (Fig. 34.2).
- Tg should be undetectable after thyroidectomy and radioablation.
- If there are detectable Tg levels after suppressive therapy, it is indicative of persistent or recurrent thyroid cancer.
- Thyroxine can suppress Tg secretion and mask recurrent disease.
- Combined rTSH-stimulated radioiodine and Tg testing is as sensitive as thyroid hormone withdrawal in detecting recurrent thyroid cancer and causes less morbidity.
- Tg may be more sensitive than whole-body scan in detecting cancer.
Treatment of Medullary Thyroid Carcinoma
- Chemotherapy and external-beam radiation are ineffective in treating medullary thyroid carcinoma.
- Total thyroidectomy with central nodal dissection is the treatment of choice.
Treatment of Anaplastic Thyroid Carcinoma
- The options available for the treatment of anaplastic thyroid carcinoma are limited, and prognosis is extremely poor.
- Surgery: Patients should be considered for aggressive local resection.
- Radiation treatment: Radiation therapy after surgery should be considered, although response rates are low.
- Chemotherapy: Paclitaxel is the single most effective agent.
Parathyroid carcinoma is an extremely rare cause of hyperparathyroidism. It is different from other endocrine tumors, which usually are hypofunctional. Clinically, it is important to distinguish this disease from other benign disorders of the parathyroid gland that result in hyperparathyroidism (see Table 34.6).
TABLE 34.6. Benign versus Malignant
- Parathyroid carcinoma accounts for less than 1% of all cases of hyperparathyroidism.
- Its incidence is approximately 0.015 per 100,000 population.
- It is equally prevalent in men and women.
- It occurs in the fifth or sixth decade of life.
- The recurrence rates of parathyroid carcinoma approach 50%.
- The 10-year survival rate is 49%.
- The morbidity and mortality are usually related to the hypercalcemia rather than to the complications of metastases.
- Familial tumor, renal failure, prior neck irradiation.
- Thick fibrous bands, a large number of mitotic figures, and trabecular pattern are characteristic of parathyroid carcinoma.
- There is invasion of the glandular capsule and vascular tissue.
- There is no American Joint Committee for Cancer (AJCC) staging for parathyroid carcinoma because of the low incidence of the disease.
- Symptoms of moderate to severe hypercalcemia, with calcium levels usually more than 14 mg per dL
- Palpable neck mass; if >3 cm, suggestive of carcinoma
- Elevated parathyroid hormone levels
- Vocal cord paralysis in more advanced disease
- Sites of metastases: lungs, cervical lymph nodes, and liver.
- Differential includes parathyroid adenoma and hyperplasia, with carcinoma being suggested by a large neck mass and markedly elevated calcium levels.
- Most cases are diagnosed at surgery; however, some cases are not diagnosed until after the initial resection has been completed or until the time of local recurrence or metastases.
- Fine needle aspiration (FNA) is inappropriate for diagnosis.
- Primary modality consists of an en blocresection of the tumor and involved structures, as well as of the ipsilateral lobe of thyroid.
- Recurrent tumor and oligometastases should be resected as well.
- Chemotherapy is of limited value.
- Agents with activity include DTIC (dacarbazine); 5-fluorouracil; cyclophosphamide.
- Management of hypercalcemia is essential while treating parathyroid carcinoma.
- Tumors are generally radioinsensitive.
- Radiation only has a palliative benefit.
ADRENAL CORTICAL CARCINOMA
- Adrenal cortical carcinoma is rare; it accounts for 0.05% to 0.2% of all cancers.
- It shows a bimodal age distribution, with the first peak in children younger than 5 years and with a second peak in adults in their fourth to fifth decade.
- The 5-year survival rate is 23%.
- The 10-year survival rate is 10%.
- The prognosis is better in children.
- The common sites of distant spread are liver, lungs, lymph nodes, and bone.
- The etiology of adrenal cortical carcinoma is not known.
- Differentiation between adenomas and carcinomas can represent a histologic challenge. However, carcinomas will tend to display mitotic activity, aneuploidy, and venous invasion.
- Carcinomas may also secrete abnormal amounts of androgens and 11-deoxysteroids.
MacFarlane classification of various stages of adrenal cortical carcinoma is given in Fig. 34.3.
FIG. 34.3. MacFarlane classification. From DeVita VT, Hellman JS, Rosenberg SA. Cancer: principles and practices of oncology, 6th ed. Philadelphia: Lippincott-Raven, with permission.
- Endocrine dysfunction:
- Features of hypercortisolism
- Mineralocorticoid excess.
- Approximately 50% of patients present with evidence of hormonal excess.
- Symptoms arising from local mass effect or distant metastases are evident.
- Adrenal incidentalomas are being detected more often, with improved quality and with more frequent utilization of imaging studies. SeeFig. 34.4.
FIG. 34.4. Evaluation of an adrenal mass in a patient with suspected pheochromocytoma. From DeVita VT, Hellman JS, Rosenberg SA. Cancer: principles and practices of oncology, 6th ed. Philadelphia: Lippincott-Raven, with permission.
- Biochemical evaluation is performed if clinically warranted (i.e., urinary steroids, suppression tests).
- En blocresection is appropriate for all stages initially, and further surgical resection should be attempted for local recurrence and for metastatic disease whenever feasible.
- Radiofrequency ablation may be implemented for local control or metastases in patients with unresectable disease.
- Mitotane has induced hormonal response rates in up to 75% of patients with functional tumors, without any change in overall survival.
- Other active agents include doxorubicin, etoposide, and cisplatin.
- Pheochromocytoma is found in less than 0.2% of all patients with hypertension.
- Classically, approximately 10% of pheochromocytomas are malignant; however, the true number may be higher.
- Approximately 10% of pheochromocytomas are bilateral; it tends to occur more frequently in the familial syndromes.
- Approximately 10% of the disease is extraadrenal; malignancy is more likely to be found in extraadrenal tumors.
- Approximately 10% of the disease is associated with a familial genetic syndrome [e.g., MEN-2 or von Hippel–Lindau (VHL)].
- Pheochromocytomas generally are indolent tumors.
- It metastasizes most commonly to the lungs, brain, and bone.
- Morbidity and mortality is related to the secretory products of the tumor.
- The etiology of pheochromocytoma is not known.
- Pheochromocytomas arise from chromaffin cells, most of which nest in the adrenal medulla.
- Both malignant and benign tumors have the capability of vascular invasion and extension into the cortex.
- The only absolute criterion for malignancy is the presence of secondary tumors in sites where chromaffin cells do not usually exist.
- The clinical features of pheochromocytomas are summarized in Table 34.7.
TABLE 34.7. Clinical Features
- Metabolic assessment:
- Twenty-four-hour urinary catecholamines, vanillylmandelic acid (VMA), and metanephrine (most specific)
- Clonidine suppression test is recommended for intermediate catecholamine levels. Catecholamine levels will not be suppressed in patients with pheochromocytoma.
- Radiologic assessment:
- Both computerized tomography (CT) scan and magnetic resonance imaging (MRI) are equally sensitive.
- Labeled metaiodobenzylguanidine (131I-MIBG) is structurally similar to norepinephrine and is taken up and concentrated in adrenergic tissue. It is highly sensitive and specific, particularly for malignant tumors and the familial syndromes.
- Bone scan is superior to 131I-MIBG in detecting bone metastases.
- Diagnostic evaluation helps to differentiate between benign and malignant tumors (Table 34.7).
- Surgery is the mainstay of treatment and should be considered for primary, recurrent, and metastatic disease.
- Appropriate preoperative evaluation and α ± β-blockade are required to minimize risk of a hypertensive crisis.
- The laparoscopic approach is acceptable if no obvious tumor invasion or metastases are visualized during imaging studies (see Fig. 34.5).
FIG. 34.5. Diagnosis and treatment of pheochromocytoma. (From Abeloff MD, et al. Clinical oncology, 3rd ed. Philadelphia: Elsevier Churchill Livingstone, with permission.)
- Cyclophosphamide, vincristine, and dacarbazine (CVD)
- Biochemical response of 79%
- Fifty-seven percent reduction in measurable disease
- Median duration of response is greater than 20 months
- Small study (14 patients).
- Radiation has a limited role; it may be used for bone metastases and soft-tissue metastases.
Neuroendocrine tumors are rare tumors that are distinguished from many other solid tumors by their ability to produce biologically active molecules that can produce systemic syndromes. The two primary subgroups of neuroendocrine tumors are carcinoid tumors and pancreatic endocrine tumors.
- The incidence of carcinoid tumors in the United States is 1 to 2 cases per 100,000 individuals.
- Abdominal and rectal carcinoids tend to present with tumors of small size (<2 cm) and are amenable to surgical resection, with 5-year survival rates of approximately 95%.
- Small-bowel carcinoids present at a more advanced stage, but if resectable, the 20-year survival rates for these carcinoids are still approximately 80%. If unresectable, median survival is approximately 5 years.
- It is difficult to differentiate between malignant and benign carcinoid tumors on the basis of histology.
- Malignancy is determined only if there is lymph node invasion or distant metastatic disease.
- Carcinoid syndrome, a result of excess production and secretion of serotonin, may result in multiple symptoms including flushing, diarrhea, abdominal cramps, cough, bronchospasm, valvular heart disease, and pellagra in severe cases.
- Eighty-five percent of tumors originate from the gut (predominantly from the appendix).
- The lungs are the second most common site of involvement and represent approximately 2% of lung cancers.
- Twenty-four-hour urine for 5-hydroxyindoleacetic acid
- CT scan or MRI of the abdomen
- Octreotide scan
- This scan has higher sensitivity for detecting pancreatic tumors as well as metastatic disease.
- It may predict which patients will respond to therapy with a somatostatin analog.
- Appendiceal tumors
- For tumors <2 cm: appendectomy
- For tumors >2 cm: right hemicolectomy with lymph node dissection
- Small intestine and rectal tumors
- Segmental resection with mesenteric lymphadenectomy
- Hepatic disease
- Debulking by surgery, cryotherapy, or radiofrequency ablation
- Transplantation may be of benefit to patients without extrahepatic disease.
- Symptoms of hormonal excess are mitigated with somatostatin analogs, steroids, and other agents.
- Carcinoids tend to be resistant to most chemotherapeutic agents.
- Active agents include 5-fluorouracil (5-FU), doxorubicin, interferon α-2a and α-2b, and these agents achieve response rates between 10% and 20%
- Combining chemotherapeutic agents offers minimal clinical and survival benefit while increasing toxicity.
- Radiation therapy is reserved for palliation.
Pancreatic Endocrine Tumors
Gastrinoma (Zollinger–Ellison Syndrome)
- Gastrinoma accounts for 60% to 80% of all pancreatic endocrine tumors.
- Gastrinoma occurs in 0.1% to 1% of patients with peptic ulcer disease.
- It is usually diagnosed between the third and sixth decades, but can occur at any age.
- Twenty percent of gastrinomas are familial and 20% develop MEN-1.
- Approximately one third of patients with gastrinoma have metastatic disease at diagnosis.
- Male-to-female ratio is 1.5 to 2.0:1.
- Gastrinomas are well differentiated, with few mitoses.
- The malignant potential of gastrinomas is determined by the presence of distant metastases and not by histologic grade. Most tumors are malignant.
- Primary tumors predominate in the pancreatic head but may also develop in the small intestine or stomach.
- Excess production of gastrin results in increased secretion of gastric acid.
- Severe, often refractory, peptic ulcer disease is a characteristic feature.
- Secretory diarrhea is commonly seen.
- Abdominal pain is a common symptom.
- A gastric acid pH <3.0 in the setting of hypergastrinemia (1,000 pg per mL) indicates gastrinoma.
- Gastrin level that increase by more than 200 pg per mL within 15 minutes of an intravenous infusion of secretin is suggestive of gastrinoma.
- Ultrasonography, CT scan, MRI, endoscopic ultrasonography (EUS), angiography, and octreotide scanning are the commonly used diagnostic procedures.
- Surgery is potentially curative, but is only an option in 20% of patients.
- With the advent of better, effective medical therapies, surgery seems to be having a limited role. Controversy exists about operating on patients with MEN-1.
- Resection of the primary tumor can reduce the rate of liver metastases.
- Proton pump inhibitors are the drugs of choice
- Somatostatin analogs (e.g., octreotide)
- Chemotherapeutic agents with activity include 5-FU, etoposide, doxorubicin, DTIC, streptozotocin, and α-interferon (α-IFN)
- Tumor embolization.
- The role of radiation in the adjuvant setting remains undefined.
- It may be effective in palliation in patients with unresectable disease.
- Insulinoma occurs most commonly in the fifth decade of life.
- There is a slight female predominance in the occurrence of insulinoma.
- Approximately 10% of cases are malignant.
- Gastrinomas account for 20% to 40% of pancreatic endocrine tumors.
- Malignancy is defined by the presence of metastases. Most tumors are benign.
- Whipple triad:
- Neuroglycopenic and/or adrenergic symptoms
- Relief from symptoms and hypoglycemia when the latter is corrected.
- Most tumors are solitary.
- An inappropriately high level of insulin during an episode of hypoglycemia establishes the presence of insulinoma.
- In patients who are asymptomatic at the time of diagnosis, a prolonged fasting period, with serum sampling for glucose, insulin, and C-peptide levels every 6 to 12 hours, helps diagnose insulinoma.
- Surgery is the treatment of choice; it may result in a complete cure.
- Dietary management with small, frequent meals
- Oral diazoxide inhibits pancreatic secretion of insulin and stimulates the release of catecholamine as well as glucose from the liver.
- Streptozotocin, 5-FU, and doxorubicin are shown to be active in patients with malignant disease.
VIPoma (Verner–Morrison Syndrome)
- Elevated serum vasoactive intestinal peptide establishes the presence of VIPoma.
- VIPoma manifests with watery diarrhea, hypokalemia, and achlorhydria.
- Surgery is the treatment of choice, with limited roles for chemotherapy and or radiation; somatostatin analogs treat diarrhea effectively.
- Glucagonomas are tumors that secrete excess glucagon. Serum levels of glucagons >500 pg per mL are diagnostic.
- Glucagonomas cause diabetes, weight loss, anemia, and increased risk for thromboembolism.
- Necrolytic migratory erythema is a common presenting symptom of glucagonomas.
- Surgery, somatostatin analogs, anticoagulants, and chemotherapy are therapeutic options for glucagonomas.
- Zinc supplementation and amino acid infusions may reduce the rash.
- Tumors secrete excess somatostatin, resulting in inhibition of the secretion of insulin and pancreatic enzyme, and in the production of gastric acid.
- Surgery is the treatment of choice.
- Chemotherapy is the therapeutic option for unresectable disease.
MULTIPLE ENDOCRINE NEOPLASIA I AND II
MENs are characterized by the occurrence of tumors involving two or more endocrine glands within one patient. MENs are uncommon, but because they are inherited as autosomal dominant traits, they have important implications for other family members. First-degree relatives have about a 50% risk of developing the disease (see Tables 34.7 and 34.8 and Fig. 34.6).
FIG. 34.6. Suggested diagram for treatment of individuals from kindreds of MEN-2a. (From Norton, JA. Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 5th ed. Philadelphia: Lippincott-Raven, 1997:1659–1677, with permission.
TABLE 34.8. Syndromes of Multiple Endocrine Neoplasia
Bellantone R, Lombardi CP, Raffaelli M, et al. Is routine supplementation therapy (calcium and vitamin D) useful after total thyroidectomy? Surgery 2002;132(6):1109–1112.
Grant CS, Hay ID, Gough IR, et al. Local recurrence in papillary thyroid carcinoma: is extent of surgical resection important? Surgery 1998;104:954–962.
Hundahl SA, Fleming ID, Fremgen AM, et al. A national cancer database report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995. Cancer 1998;83:2638–2648.
Icard P, Chapuis Y, Andreassian B, et al. Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 1992;112:972–979.
Ladenson PW. Recombinant thyrotropin for detection of recurrent thyroid cancer. Trans Am Clin Climatol Assoc 2002;113:21–30.
Lairmore TC, Ball DW, Baylin SB, et al. Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 1993;217:595–603.
Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990;322:1195–1201.
Mazzaferri EL. Treating differentiated thyroid carcinoma: where do we draw the line? Mayo Clin Proc 1991;66:105–111.
Neumann HP, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 1993;329:1531–1538.
Norton JA. Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 5th ed. Philadelphia: Lippincott-Raven, 1997:1659–1677.
Sanders LE, Cady B. Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg 1998;133:419–425.
Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med 1998;338:297–308.
Sclafani LM, Woodruff JM, Brennan MF. Extraadrenal retroperitoneal paragangliomas: natural history and response to treatment. Surgery 1990;108:1124–1129.