GENERAL PRINCIPLES
In 1954, a family was described with hyperparathyroidism and tumors of the pituitary and pancreatic islet cells. Now known as multiple endocrine neoplasia type I (MEN I), it is one of the most well-known hereditary endocrine neoplastic syndromes. Since then, our knowledge about the genetics and pathology of endocrine tumors has grown tremendously and has led to various new diagnostic and therapeutic measures. Endocrine neoplasms are a heterogenous group of tumors. This chapter will cover the most common types, including pituitary, thyroid, parathyroid, adrenal cortex, gastroenteropancreatic neuroendocrine, and pheochromocytoma, as well as the MEN syndromes.
THYROID CARCINOMA
GENERAL PRINCIPLES
Multiple histologic subtypes of thyroid cancer exist (Table 25-1), and together they account for >90% of all endocrine malignancies. The normal thyroid is composed of two main cell types. One is the follicular cell type that concentrates iodine and produces thyroid hormone. The other cell type is the parafollicular cell that produces calcitonin. Follicular cells give rise to well-differentiated cancers (papillary, follicular, and Hürthle) and anaplastic tumors. Parafollicular cells give rise to medullary thyroid carcinoma (MTC).
Epidemiology
According to American Cancer Society, 44,670 patients were diagnosed with thyroid cancer in 2010 and 1,690 died from it. Thyroid cancer is nearly twice as common in women as in men.
Risk Factors
Previous radiation exposure is the main risk factor with an average lag time of 25 years to cancer presentation. Other risk factors include female sex and family history. MTCs are different in that radiation exposure is not a risk factor and can occur sporadically (two-thirds) or in individuals who have either MEN II syndrome or familial MTC(one-third).
DIAGNOSIS
Clinical Presentation
Initial presentation is typically a solitary thyroid nodule. The majority of thyroid nodules are benign, and the history and physical exam assist in directing further investigation. The probability of malignancy is higher if the nodule is found in men, individuals younger than 15 or older than 60 years, those with a positive family history, those with other diseases associated with MEN II (hyperparathyroidism, pheochromocytoma, or mucosal neuromas), and those with previous radiation exposure. A solitary, firm, immobile nodule or a rapid change in size is also of greater concern, as are symptoms of hoarseness, dyspnea, dysphagia, or new Horner syndrome. Symptoms of diarrhea and flushing are occasionally seen in advanced MTC due to hormone secretion.
Physical Examination
Exam should evaluate nodule size, firmness, mobility, and local lymphadenopathy. Nodules <1 cm in a patient without other risk factors may be followed with a repeat exam in 6 to 12 months. However, nodules >1 cm or a nodule of any size in a patient with one of the previously listed risk factors warrants further evaluation.
Diagnostic Testing
Ultrasound of the thyroid is recommended; central hypervascularity, irregular borders, and/or microcalcifications suggest malignancy. Fine-needle aspiration (FNA) is combined with ultrasound as the initial approach to establish diagnosis. If malignancy cannot be excluded by FNA, a lobectomy is usually performed to obtain adequate tissue for determining the correct diagnosis.
Radioactive isotope scans and serologic testing with thyroid-stimulating hormone (TSH) and serum thyroglobulin assays are only useful in postoperative follow-up; they are not useful in making the diagnosis of thyroid malignancy, as most nodules are hypoactive regardless of presence or absence of malignancy. Calcitonin levels, however, should be checked at presentation and at follow-up exams for patients with MTC, as calcitonin serves as a sensitive tumor marker. In addition, those with MTC need to be evaluated for the RET proto-oncogene mutation, and a 24-hour urine for vanillylmandelic acid, catecholamines, and metanephrines is needed to evaluate for possible pheochromocytoma as part of MEN II syndrome.
Imaging
Once a diagnosis of malignancy is made, all individuals should have a chest x-ray to evaluate for metastases to the lung. An extensive staging workup is necessary only in anaplastic thyroid cancers, as they are often metastatic at presentation. Patients with anaplastic tumors should receive complete imaging of the neck with ultrasound or MRI and have a contrast-enhanced CT scan of the chest. Consideration should also be given to abdominal imaging with CT or MRI.
Staging
The staging of thyroid cancer is different from other malignancies. In addition to tumor size, it also depends on tumor histology and the patient’s age at presentation. For example, in patients <45 years old, well-differentiated papillary or follicular cell carcinomas are never classified higher than stage II. On the other hand, all anaplastic tumors are classified as stage IV regardless of anatomic extent due to their aggressive nature and high potential for metastasizing. In MTC, staging information comes from evaluation of the total thyroidectomy and cervical lymph node dissection.
TREATMENT
Treatment of the three main types of thyroid cancer varies significantly. Radioactive iodine, external-beam radiation, surgery, and systemic chemotherapy each have their role in comprehensive therapeutic regimens.
Well-differentiated thyroid carcinoma (i.e., papillary, follicular, and Hürthle) is mainly treated by surgical resection in all stages. Patients younger than 40 years have an excellent prognosis with thyroidectomy alone. Factors increasing the chance of recurrence include advanced age and tumor size >1 cm. For these patients, a total thyroidectomy is recommended; otherwise, unilateral lobectomy can be considered for smaller tumors. Recurrent laryngeal nerve damage resulting in hoarseness is an uncommon complication of thyroid lobectomy. A total thyroidectomy carries the additional risk of hypocalcemia from hypoparathyroidism. In more advanced disease, dissection of the central and lateral cervical lymph nodes should be considered.
Radioiodine therapy with 131I induces cytotoxicity and is the key adjuvant therapeutic agent. External-beam radiation therapy, on the other hand, rarely has a role in differentiated thyroid carcinomas. There are two main indications for use of 131I. The first is to ablate residual normal thyroid tissue post–total thyroidectomy to improve the sensitivity of subsequent diagnostic 131I scans in detecting recurrence. The second is to treat metastatic disease and destroy microscopic malignant foci. Follow-up imaging with 131I determines treatment efficacy by revealing residual normal tissue as well as carcinoma. Treatment ends when there is no further radioactive iodine uptake present.
Adjuvant hormonal therapy with exogenous thyroid hormone is also routinely used in well-differentiated thyroid carcinomas to suppress TSH, since both normal and neoplastic thyroid tissue depend on TSH for growth. In addition, thyroid hormone is also necessary to prevent symptoms of hypothyroidism. One should keep in mind, however, the potential side effects of higher rates of bone loss and an increased incidence of atrial fibrillation. Suppression of TSH to undetectable levels for the initial 5 to 10 years is reasonable. After this time, if there is no evidence of recurrent disease, exogenous thyroid hormone supplementation may be decreased, such that the TSH levels rise to the lower limits of normal.
Chemotherapeutic agents are rarely administered because they are typically less effective and have a worse side-effect profile than radioactive iodine.
MTC is sporadic in most cases, but ~20% of cases are part of inherited tumor syndromes (MEN IIA and IIB and familial MTC). This possibility makes ruling out a RET proto-oncogene mutation, hyperparathyroidism, and pheochromocytoma essential to the initial preoperative management, along with calcitonin measurement. Total thyroidectomy with bilateral central neck dissection is the mainstay of therapy for MTC because of the high frequency of bilateral disease. Although MTC is somewhat indolent in its progression, no effective systemic chemotherapy regimens exist, and MTC cells take up radioactive iodine poorly. For this reason, patients with genetic predisposition to the disease (i.e., RET mutations) should be highly encouraged to undergo prophylactic total thyroidectomy with central lymph node dissection. Complications of local MTC invasion mirror those of anaplastic tumors, yet progression is less rapid. Doxorubicin is the most effective cytotoxic chemotherapeutic agent, but an objective response is <40%, with no patients having a complete response.
Anaplastic thyroid carcinoma is poorly responsive to therapy and is often locally invasive, if not metastatic, at the time of presentation. These poor prognostic features mean that this histology is always classified as stage IV at diagnosis regardless of size, grade, node involvement, or metastasis. The invasive nature makes tumor resection difficult or even impossible. At initial presentation, the tumor may encompass the carotid arteries, esophagus, and/or trachea. Recurrent or superior laryngeal nerve damage may also occur. The complications of local invasion account for the major morbidity of this cancer, often leading patients to require gastrostomy tubes or a tracheostomy.
Resection. If imaging reveals limited disease, resection should be pursued for improved local control and delay of complications, although survival is not altered.
Radiation/Chemotherapy. Radioactive iodine is rarely taken up by anaplastic carcinoma cells, so external-beam radiation therapy is a necessary component of treatment. Administration should be undertaken concurrently with systemic radiosensitizing chemotherapy. Doxorubicin is the most commonly used agent.
End-stage care typically includes managing local complications, with ~50% of patients dying from airway obstruction.
FOLLOW-UP
For routine follow-up of well-differentiated thyroid carcinoma, physical exam, TSH, thyroglobulin level measurement, and chest x-ray are recommended twice yearly for 4 years, then once yearly for 10 years. Thyroglobulin levels are expected to be <5 ng/mL if complete thyroid ablation has been successful. For MTC, serum calcitonin and carcinoembryonic antigen levels should initially be followed at 2 to 3 months postoperatively, and then yearly. Abnormal serum markers should trigger diagnostic imaging evaluation.
PROGNOSIS
Well-differentiated thyroid carcinomas have an excellent prognosis. Cure rates reach nearly 100% at 10 years, even with capsular invasion, as long as there is no vascular involvement. The two most important predictors of mortality are age (>45) and tumor stage at the time of initial therapy. Relative survival at 10 years for papillary, follicular, and Hürthle cell carcinomas is 93%, 85%, and 76%, respectively. Anaplastic tumors carry a grim prognosis, often leading rapidly to death within the first few years after diagnosis regardless of treatment. MTCs have 5-year survival rates >80% in stage I and II disease but <40% in stage III or IV disease.
Thirty percent of patients will have a recurrence, the majority locally, with distant recurrence mainly involving the lungs.
PARATHYROID CARCINOMA
GENERAL PRINCIPLES
Although adenomas of the parathyroid glands are a common endocrine abnormality, parathyroid carcinoma is quite rare. Primary hyperparathyroidism is categorized pathologically into three groups: single parathyroid adenoma (83% to 85%), multi-glandular hyperplasia (15%), and parathyroid carcinoma (0.5% to 3%). Unlike benign hyperparathyroidism, which is found primarily in the postmenopausal female population, parathyroid carcinoma is found equally in both genders at younger ages. With an incidence of only 0.015 in 100,000, parathyroid cancer is classified as one of the rarest human cancers. Although no etiologic causes are known, parathyroid cancer is seen in the autosomal dominant disease of MEN I.
DIAGNOSIS
Patients with parathyroid carcinoma often present with either hypercalcemia or a neck mass. On physical exam, 30% to 50% of patients with parathyroid carcinoma have palpable masses in the central neck region. A hyperfunctional parathyroid tumor leads to excessive production of parathyroid hormone and, ultimately, the clinical syndrome of primary hyperparathyroidism. Clinical signs and symptoms include fatigue, renal stones, bone disease, and neuromuscular/neuropsychiatric disturbances related to hypercalcemia. Grossly elevated calcium levels lead to nausea, vomiting, polyuria, and dehydration. Cytologic examination of a needle aspirate is considered an unreliable criterion for diagnosis of malignancy. Definitive diagnosis of parathyroid carcinoma is made in the operating room, where local invasion and metastasis can be assessed.
TREATMENT
The mainstay of treatment is surgical exploration of the neck and complete en bloc resection of the tumor along with the ipsilateral thyroid lobe and central cervical lymph nodes.1 There is no proven role for adjuvant chemotherapy or radiation therapy. Likewise, the only effective therapy for recurrent or meta-static disease is complete resection.
The management of severe hypercalcemia includes saline hydration, furosemide diuresis, and bisphosphonates. Octreotide and calcimimetic agents are occasionally used to lower calcium in patients refractory to other therapeutic interventions.
PROGNOSIS
Hypercalcemia is the major cause of morbidity and mortality. The prognosis for parathyroid carcinoma depends on the adequacy of the initial en bloc resection. The most common site of recurrence is local followed by lung, liver, and bone, in order of decreasing incidence. Early recurrence correlates with death from the disease. The overall survival is ~85% at 5 years and 50% to 70% at 10 years.2
PITUITARY NEOPLASMS
GENERAL PRINCIPLES
Pituitary neoplasms are rare endocrine malignancies that arise from epithelial origin in the adenohypophysis. Pituitary adenomas account for 10% to 15% of intracranial tumors. Previously classified by histopathology (acidophilic, basophilic, chromophobic), pituitary adenomas are now classified by the hormones they secrete, that is, prolactin, growth hormone, adrenal corticotropin hormone (ACTH), gonadotropins, and TSH. Tumors that do not secrete hormones above physiologic levels are termed nonfunctional adenomas.
Epidemiology
Incidence peaks in the third and fourth decades of life. In general, males and females are affected equally, with the exception of some subtypes, such as ACTH and prolactin-secreting adenomas, which are more common in females.
DIAGNOSIS
Clinical Presentation
Initial symptoms include headache, visual disturbance, and increased intracranial pressure, as well as syndromes related to the type of hormone secreted (Cushing’s syndrome, acromegaly, hirsutism, hyperprolactinemia, or hyperthyroidism).
Diagnostic Testing
Initial evaluation involves a dedicated gadolinium-enhanced MRI of the pituitary and laboratory evaluation for active adenomas with a panel consisting of growth hormone (GH), insulin-like growth factor 1 (IGF-1), prolactin (PRL), TSH, free T4, T3, ACTH, cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Diagnosis is made on imaging, substantiated by hormone levels in active adenomas, and, when appropriate, confirmed pathologically by transsphenoidal biopsy or resection. No TNM staging classification exists for these rare tumors, and prognostic markers include levels of hormone secreted, size of tumor, and extent of suprasellar extension.
TREATMENT
Management of pituitary adenomas depends on the type, but in general, transsphenoidal surgical resection is the favored curative approach. The exceptions are prolactin-secreting microadenomas, which are managed by dopamine agonists, or inactive adenomas, which remain stable in size on serial imaging. The goals of surgery are to alleviate mass effect while preserving pituitary function and abating endocrine hyperactivity. Postoperative management depends on the type of pituitary adenoma.
Prolactin-Secreting Adenomas
Prolactin-secreting adenomas are the most commonly diagnosed pituitary tumor, representing ~30% of cases. Symptoms of hyperprolactinemia include galactorrhea and hypogonadism (oligomenorrhea or amenorrhea, dry vaginal mucosa, sterility, decreased libido, and impotence).3 Prolactinomas are usually slow-growing microadenomas in premenopausal women, but can grow to a larger size (macroadenomas) in men and postmenopausal females. Macroadenomas can cause mass effect, classically manifested by visual disturbances (bitemporal hemianopsia) and headaches.
The differential diagnosis of hyperprolactinemia includes pregnancy, prolactin-stimulating drugs, hypothyroidism, and renal failure. The definitive diagnosis requires radiographic evidence of an adenoma and a persistently elevated prolactin level (>200 ng/mL in females and >100 ng/mL in males), with the other etiologies of hyperprolactinemia having been ruled out.
Treatment of prolactinomas is dependent on size. Microadenomas are treated medically, since most do not increase in size and surgery is rarely curative. Medical treatment is achieved with dopamine agonists (e.g., bromocriptine), where the response rates are 70% to 80% for tumor shrinkage and 80% to 90% for restoration of ovulation. In cases where dopamine agonist therapy is not tolerated (~30% of cases) or fertility is not a concern, oral contraceptives containing estrogen and progesterone can be used to treat the symptoms of hypogonadism. In cases of macroadenomas with significant suprasellar involvement or in pregnancy (which stimulates growth of adenomas), surgery or radiation therapy can be used, often in combination with dopamine agonists.
Follow-up should include yearly prolactin levels. If prolactin increases to >250 ng/mL or neurological symptoms develop, repeat MRI is indicated. For patients with macroadenomas, visual field testing and MRI at 6 months after commencement of therapy should be performed. When prolactin levels are normalized for 2 years and at least 50% tumor reduction is observed, a trial of tapering the dopamine agonist may be considered.
Growth Hormone–Secreting Adenomas
Growth hormone–secreting adenomas account for 30% of pituitary adenomas. Growth hormone excess results in acromegaly (coarse facial features, macro-glossia, and acral growth). Growth hormone leads to an increase in IGF-1, which affects bone and tissue growth and can ultimately lead to organomegaly, hypertension, cardiomyopathy, arthropathies, and restrictive lung diseases. Symptoms include arthralgias, oily skin, hyperhidrosis, headaches, and fatigue.
The diagnosis is suggested by a physical exam showing acromegaly, elevated IGF-1 levels (preferred over fasting GH because the levels are more stable), oral glucose suppression test failing to suppress IGF-1, elevated GH, and a pituitary adenoma evident on MRI.
The treatment of choice is a transsphenoidal resection. In patients not eligible for surgery, external-beam radiation may be used. Medical treatment with dopamine agonists or somatostatin analogs such as octreotide are not curative, but may be used for symptomatic control of acromegaly.
Follow-up should include monitoring GH and IGF-1 levels. Monitoring for hypopituitarism after radiation is also essential.
Adrenal Corticotropin Hormone–Secreting Adenomas
These less common pituitary adenomas result in Cushing’s disease. Cushing’s disease is more common in women. The clinical presentation is most often a result of an endocrinopathy and less commonly secondary to a mass effect. Increased ACTH results in adrenal hyperplasia and hypercortisolism. Hypercortisolism results in centripetal obesity, moon facies, buffalo hump, hirsutism, abdominal striae, and acne (i.e., Cushing’s syndrome). Clinical signs include hypertension, bone loss, myopathies, diabetes, and psychiatric disorders.
Diagnosis is made by confirming hypercortisolism with 24-hour urinary cortisol. The pituitary origin of cortisol is demonstrated by failure of the low-dose dexamethasone suppression test to suppress serum cortisol to <10 μg/dL. Finally, serum ACTH should be elevated to rule out an adrenal adenoma. Ectopic ACTH syndrome is excluded if the high-dose dexamethasone suppression test results in reduction of cortisol levels to <50% of baseline. If the above laboratory testing is inconclusive, inferior petrosal sinus sampling for ACTH can be performed to confirm the pituitary etiology. Imaging studies are less reliable, as 50% of ACTH-secreting adenomas may not be detectable by MRI; nonetheless, MRI remains essential to guiding therapy and is performed in all cases.
Treatment of choice is transsphenoidal resection, with cure rates ranging from 76% to 94%. External-beam radiation can be used for poor surgical candidates or as adjuvant therapy to surgery. Medical therapy with ketoconazole or mitotane can be used for symptom control in those unable to tolerate surgery or in relapsed cases.
Follow-up requires replacement hormonal therapy for up to 1 year after surgery and monitoring for hypopituitarism after radiation.
Gonadotropin-Secreting Adenomas and Nonsecreting Pituitary Adenomas
These adenomas account for 30% of pituitary tumors. They are associated with an older population. Most are nonsecretory, but demonstrate secretory granules containing FSH and LH. Clinical presentation typically presents secondary to a mass effect, with symptoms of headaches, visual changes, and hypopituitarism.
Diagnosis is suggested by increased LH and FSH and by MRI findings of a macroadenoma. Postmenopausal women may have naturally elevated FSH and LH, and diagnosis relies on final surgical pathology.
The treatment is primarily transsphenoidal resection. Adjuvant external-beam radiation therapy may be considered in patients with residual tumor on imaging postoperatively. Follow-up several months postoperatively with repeat MRI is essential since most tumors are nonsecretory.
TSH-Secreting Adenomas
TSH-secreting adenomas are the least common pituitary tumor, comprising ~1% of pituitary adenomas. Clinical presentation is typically with symptoms of hyperthyroidism (heat intolerance, diarrhea, weight loss, or exophthalmos) or mass effect.
Diagnosis is made by demonstrating increased TSH despite elevated T4 and T3. MRI may confirm the presence of an adenoma.
Treatment is primarily transsphenoidal resection. Adjuvant external-beam radiation is used in refractory cases. Palliative medical therapy with octreotide has been used in refractory cases, with response rates of 90%. Follow-uprequires monitoring of TSH, T4, and T3 levels.
ADRENAL CORTICAL TUMORS
GENERAL PRINCIPLES
The majority are benign, nonfunctioning adenomas found incidentally on imaging. Others are benign hormone-secreting adenomas causing diseases such as Cushing’s. Only 50% of adrenal tumors are endocrinologically active. The third type of adrenal tumor is an adrenal cortical carcinoma that is a very rare and extremely aggressive tumor type.
DIAGNOSIS
Clinical Presentation
Adrenal “incidentalomas” can be found on 1% to 3% of CT scans of the abdomen. The differential diagnosis includes benign adenomas and metastases. The chance of malignancy is directly related to the size of the mass (<3cm, benign; >6 cm, malignant), with most carcinomas presenting as large masses.
Adrenal adenomas can secrete cortisol, sex hormones, or aldosterone, or can be inactive. The clinical presentation is dependent on the predominant hormone secreted. The most common clinical presentation is Cushing’s syndrome, which results from a cortisol excess. Sex hormone excess can lead to acne, oligomenor-rhea, and virilization/hirsutism in women and feminization in men. Rarely, these carcinomas may produce aldosterone, resulting in hypertension and hypokalemia.
Diagnostic Testing
Initial evaluation involves staging with imaging with a CT of the abdomen and pelvis, and determination of hormone levels, which are used to monitor for recurrence and progression.
The definitive diagnosis is obtained by surgical pathology. High urinary free cortisol and serum cortisol, low ACTH, and lack of suppression in a high-dose dexamethasone suppression test occur in the instance of cortisol-secreting carcinoma. Virilizing sex hormone–secreting carcinomas demonstrate high levels of testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S) while feminizing tumors demonstrate high estradiol levels. Some tumors are nonsecretory, and definitive diagnosis relies on pathologic diagnosis.
The staging of adrenal carcinoma depends on tumor size, nodal involvement, and presence of distant metastasis. Tumors <5 cm with no nodal involvement are stage I; those >5 cm without nodal involvement, stage II; those with nodal involvement, stage III; and those with distant metastasis, stage IV.
TREATMENT
Surgical resection is the treatment of choice, even in advanced disease. Debulking of the tumor and metastectomy are often considered. Adjuvant chemotherapy can be considered in advanced disease, but it is thought to be minimally effective, as there is not enough evidence to support any single regimen.
In patients ineligible for surgery, most chemotherapeutic regimens will include mitotane, which selectively targets the adrenal cortex and results in selective chemical ablation.4 Overall response rate to mitotane is ~33%, but its effect on overall and disease-free survival has not been conclusively determined. Other medical therapies aimed at palliating symptoms include ketoconazole and aminoglutethimide.
Finally, adjuvant external-beam radiation therapy may also be effective for local control after resection or for symptomatic metastasis.
PROGNOSIS
The prognosis of adrenal carcinoma depends on initial stage and resectability. For surgically resectable tumors, the median overall survival is almost 6 years, but with medical therapy alone <10% of patients live to 6 years. Follow-up with repeat CT scans and hormone levels at 6 month intervals is recommended.
DIFFUSE ENDOCRINE SYSTEM TUMORS
Some endocrinologically active tumors are not localized to any one organ, but share the common embryonic origin of the neural crest and neuroectoderm. These include gastroenteropancreatic neuroendocrine tumors, pheochromocytomas, and the MEN syndromes.
GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS
GENERAL PRINCIPLES
Tumors of the gastroenteropancreatic axis are classified according to their secretory products: insulinoma, gastrinoma, somatostatinoma, glucagonoma, vasoactive intestinal peptide-oma (VIPoma), and carcinoid. Some are nonsecretory and classified as extrapulmonary small-cell carcinomas. Half of neuroendocrine tumors are of the carcinoid variant, followed by gastrinomas, insulinomas, VIPomas, and glucagonomas, in order of decreasing incidence.
DIAGNOSIS
Most neuroendocrine tumors are malignant and are commonly identified at the time of metastatic disease, with the exception of insulinomas, which are slow growing. Clinical presentation depends on the hormones secreted and the site of disease. The initial laboratory analysis should focus on specific hormones associated with those clinical symptoms as outlined in Table 25-2.
TREATMENT
Tumor localization is essential for successful management of limited disease. CT and MRI may detect larger tumors, but often scintigraphy or angiography with venous hormone sampling may be required to localize tumors. Therapy varies from surgical resection for localized tumors, to medical therapies and dietary changes to palliate symptoms, to chemotherapy and arterial embolization. Chemotherapy has variable activity depending on the type of gastroenteropancreatic tumor. Typical agents used include 5-FU, streptozotocin, doxorubicin, and dacarbazine. Octreotide is commonly used in the treatment of gastroenteropancreatic malignancies for symptom relief (e.g., flushing, wheezing, and diarrhea); it also has a direct inhibitory effect on tumor growth and is used in the perioperative setting as suppressive therapy.
CARCINOID TUMORS
GENERAL PRINCIPLES
Carcinoid tumors are the most common neuroendocrine tumors, with a yearly incidence of 1.5 in 100,000 in the United States. Benign and malignant tumors occur at approximately equal frequency, and either type may be symptomatic. They can secrete various vasoactive substances, including histamine, serotonin, catecholamines, and prostaglandins. The small bowel is the most common location for these tumors, but they may occur in the appendix, colon, rectum, lung, stomach, or ovary as well.5 Symptomatic carcinoid tumors usually result from small bowel tumors with metastases to the liver and do not occur with rectal carcinoid. Carcinoid syndrome is due to excessive production of serotonin and other bioactive compounds that then have direct access to the systemic circulation.
DIAGNOSIS
Clinical Presentation
Appendiceal and small(<1 cm) rectal tumors rarely metastasize, cause symptoms, or affect survival. Small bowel tumors are more likely to be problematic. One-third of small intestine tumors are multicentric, and the chance of metastases increases with increased tumor size (tumors >2 cm have a high rate of metastasis). In general, the progression of small intestinal carcinoid tumors is indolent. However, once metastasis of tumor cells occurs, prognosis is considerably worse. Five-year survival with localized disease, with only nodal involvement, and, finally, with liver metastases is ~95%, 65%, and 20%, respectively. Urinary 5-hydroxyindoleacetic acid levels inversely correlate with survival.
Approximately 40% of carcinoid tumors found in living patients are hormonally active, leading to carcinoid syndrome in 10% of cases. This syndrome rarely occurs without liver metastasis. Symptoms may include facial flushing and edema, abdominal cramping and diarrhea, bronchospasm, hypotension, and cardiac valvular lesions (typically on the tricuspid and/or pulmonic valve if the tumor secretions originate in the bowel). Alcohol, stress, or exercise may precipitate symptoms. Tumors that are not endocrinologically active can also cause devastating effects such as bowel obstruction, appendicitis, or painful livermetastases.
Diagnostic Testing
Anelevated 24-hour urinary 5-hydroxyindoleacetic acid level is often used for diagnosis, but it is not useful for detecting carcinoid at the early stages when it is curable. Levels >25 mg/d are the typical finding (normal value of excretion is <9 mg/d). Patients should avoid excessive intake of nuts, bananas, avocados, and pineapples for ~2 days before testing, as these may result in erroneously high levels.
Plasma chromogranin A level may also be a useful test with a high sensitivity and without significant variability or need for a 24-hour urine collection.
Routine blood tests, with attention to liver function tests, hepatic and upper gastrointestinal system imaging, a chest x-ray, and eventual tissue acquisition should all be part of the workup. If available, somatostatin receptor scintigraphy is a useful imaging test. There is no accepted staging system for carcinoid.
Finally, pathologic diagnosis is confirmed with positive stains for chromogranin, synaptophysin, and neuron-specificenolase.
TREATMENT
For localized disease, surgical resection is the standard curative modality, with a 5-year overall survival of 70% to 90%. In metastatic disease, overall survival is ~2 years, with the focus of therapy on palliating symptoms both surgically and medically. As survival with untreated carcinoid tumors can exceed 10 years, therapy is usually focused on controlling symptoms. Dietary tryptophan restriction, along with serotonin antagonists and other symptom-controlling drugs, is the initial mainstay of therapy.
The somatostatin analog octreotide, used at doses of 100 to 600 mcg SC/d in two to four divided doses, is effective at symptom alleviation in nearly 90% of patients. A depot formulation of octreotide available as monthly dosing has become standardized. Histamine blockers, prochlorperazine, and cyprohepta-dine may decrease flushing. Atropine, diphenoxylate, and cyproheptadine can be used for diarrhea. Monoamine oxidase inhibitors (MAOIs) are contraindicated.
Surgery can be risky, as anesthesia often precipitates attacks. However, resection is indicated and highly successful in localized carcinoid tumors. Preoperative administration of octreotide is necessary to prevent carcinoid crisis.
Radiation and various chemotherapy regimens are typically reserved for symptomatic control of metastases in advanced disease.
PHEOCHROMOCYTOMA
GENERAL PRINCIPLES
Pheochromocytomas arise from chromaffin cells primarily in the adrenal medulla (90%), although they can also arise along the aorta, within the carotid body, intracardiac, and even within the urinary bladder. The “rule of 10” is also useful in recognizing general features of pheochromocytomas: 10% are malignant, 10% are extra-adrenal, and 10% are bilateral. This widespread distribution reflects the location of chromaffin cells associated with the sympathetic ganglia. Pheochromocytoma is present in only 0.1% of hypertensive patients who undergo urinary catecholamine quantification.
The incidence of malignancy in pheochromocytomas ranges from 5% to 45% in several series. Extra-adrenal tumors are more commonly malignant. Pheochromocytomas are associated with several inherited disorders. Bilateral adrenal medullary pheochromocytomas are elements of the inherited MEN IIA and MEN IIB neuroendocrine syndromes. Although ~25% of patients with von Hippel–Lindau disease develop pheochromocytomas, <1% of patients with neurofibromatosis and Von Recklinghausen disease are found to have the tumor.
DIAGNOSIS
Clinical Presentation
The most common presenting complaint is severe hypertension unrelated to physical or emotional stress. The production of catecholamines results in the clinical symptoms of episodic or sustained hypertension and anxiety attacks. Pheochromocytomas have been known to produce other hormones, including ACTH, somatostatin, calcitonin, oxytocin, and vasopressin. Classically, patients describe spells of hypertension, palpitations, headaches, and diaphoresis. Other presenting findings include lactic acidosis, hypovolemia, and unexplained fever. Clinically, the cluster of symptoms can be recalled by remembering the five Ps: pain, pressure, palpitation, perspiration, and pallor.However, it should be appreciated that many patients do not exhibit these “classic” episodes and may have persistent hypertension, rather than episodic.
Diagnostic Testing
Traditionally, diagnosis has been based on a 24-hour measurement of catecholamines and metabolites in the urine, including vanillylmandelic acid and metanephrines. New data suggest that a random plasma metanephrine level is extremely sensitive (~99%) in diagnosing pheochromocytoma and is an excellent choice for initial screening. Although rarely used in clinical practice today, the clonidine suppression test has been used in the past. Normally, clonidine suppresses plasma levels of epinephrine and norepinephrine. In the presence of pheochromocytomas, no such suppression is observed.
Localization of a pheochromocytoma is accomplished by chest and abdominal imaging with CT or MRI. Nuclear scanning after the administration of labeled metaiodobenzylguanidine can be done if the tumor is not localized by CT or MRI. Metaiodobenzylguanidine is structurally similar to norepinephrine and is selectively taken up by adrenergic tissue.
TREATMENT
After diagnosis, tumor localization and operative preparation are indicated, as surgical resection represents the mainstay of curative therapy.
Preoperative alpha-adrenergic blockade is necessary for patients with pheochromocytomas. Traditionally, phenoxybenzamine has been used to control hypertension. Propranolol may be used to control tachycardia, but must always follow alpha-adrenergic blockade to avoid hypertensive exacerbation due to unopposed vasoconstriction. Intraoperative hypertensive episodes are controlled with alpha-adrenergic blockers or sodium nitroprusside.
Malignant pheochromocytomas are difficult to distinguish from benign pheochromocytomas by pathology alone. Natural history, secondary tumor sites, and recurrence help determine the nature of the pheochromocytoma. Aggressive disease may require combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine. Routine follow-up consists of blood pressure measurements and urinary catecholamines in addition to regularly scheduled CT, MRI, or metaiodobenzylguanidine scanning to monitor for recurrence.
MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES
MEN syndromes are a group of rare genetic disorders that confer an increased risk of malignancy of endocrine tissues. These disorders are grouped by the major cell type of malignancy that the affected patients are at risk for developing (Table 25-3). They share a common cell of origin (amine precursor uptake and decarboxylation [APUD] neuroendocrine cells) and are inherited in an autosomal dominant pattern.
Multiple endocrine neoplasia I (Werner syndrome)
This syndrome has high penetrance, with parathyroid glands most frequently involved. One-third of gastrinomas are associated with MEN I, and pituitary adenomas can also be discovered. The MEN I gene locus has been mapped to 11q13 and codes for a tumor suppressor gene. Inheritance of the mutation is autosomal dominant. Morbidity and mortality are predominately related to duodenopancreatic malignancies. Treatment is directed by sites of tumor involvement. Patients require close follow-up for evidence of additional sites of involvement in the pituitary, parathyroid, pancreas, duodenum, adrenals, thymus, and lungs.
Multiple endocrine neoplasia IIA (Sipple syndrome) and IIB
MEN II syndromes demonstrate an autosomal dominant inheritance of an activating mutation of the RET proto-oncogene, located on chromosome 10. Nearly all patients develop medullary thyroid carcinoma (MTC), which is typically multifocal and bilateral and occurs at a young age. Other features of these syndromes are expressed variably and are reported in Table 25-3. Treatment is directed by sites of tumor involvement. All patients presenting with MTC should be considered for genetic screening for RET proto-oncogene mutations. Furthermore, all patients with MTC should be evaluated for possible pheochromocytoma before undergoing thyroidectomy to avoid a life-threatening hypertensive crisis.
Familial non-multiple endocrine neoplasia medullary thyroid carcinoma (FMTC)
This disease is also associated with an autosomal dominant inheritance of the RET proto-oncogene; however, these patients develop MTC without other abnormalities associated with MEN II syndromes. Patients with MEN IIA and FMTC almost invariably develop MTC at an early age, and therefore, prophylactic thyroidectomy should be considered in patients with a known mutation.
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