Endocrine Malignancies

Thyroid CarcinomaParathyroid CarcinomaAdrenal Gland NeoplasmsReferences

Endocrine neoplasms are relatively uncommon, but those that do occur are often difficult to detect and treat effectively. According to 1991 estimates, there were 13,900 cases of endocrine cancers in the United States, 12% of which will ultimately prove fatal. In this review, we discuss the epidemiology, etiology, pathology, diagnosis, and current treatment of the most common endocrine maligancies: thyroid carcinoma, parathyroid carcinoma, adrenal gland cancers, and malignant pheochromocytomas.

Thyroid Carcinoma

Epidemiology, Incidence, and Distribution

The incidence of thyroid cancer appears to have increased in recent decades (Figure 1), although this malignancy remains rare, with only 12,400 new cases reported in 1991 [1,2]. The apparent increase in incidence is likely due to improved diagnosis and to the increased use of therapeutic irradiation. Certain thyroid cancers remain undiagnosed during a person's life; incidental thyroid cancers with or without metastases are found at autopsy in up to 10% of cases. Unsuspected or occult thyroid carcinomas are usually less than 0.5 cm in greatest dimension, papillary in nature, and are believed to follow an indolent course; they also have been noted to have a racial predilection. There is, for example, a higher prevalence of occult thyroid carcinoma among the Japanese than among the US population [3].

Thyroid cancer constitutes about 1% of all malignant tumors, and the differentiated types account for 0.8% of all human malignancies. Although thyroid nodules are relatively common, only about 5% to 15% of clinically detectable, solitary, hypofunctioning (cold) thyroid nodules are found to be malignant. Thyroid tumors are rare in children, and increase in frequency with age. In children with thyroid nodules, the prevalence of cancer has been estimated at 15% to 20%. In particular, the risk of carcinoma in a dominant thyroid nodule in a child under 14 years old is approximately 50% (range, 20% to 73%), whereas the risk in an adult is less than 15%, with a slightly greater risk after age 60 years. Well-differentiated thyroid carcinomas account for over 90% of the malignant lesions, primarily papillary or follicular. Medullary thyroid carcinomas account for 4% to 10% of the thyroid carcinomas in children; teratomas, lymphomas, and anaplastic carcinomas of the thyroid occur rarely.

Medullary thyroid carcinomas represent 5% to 10% of all thyroid neoplasms [4,5]. About 80% of patients with medullary thyroid carcinoma have a sporadic form of the disease, and the remaining 20% inherit medullary thyroid carcinoma as an autosomal dominant trait, as part of the distinct clinical syndromes of multiple endocrine neoplasia (MEN) type IIA or IIB or familial medullary carcinoma of the thyroid. MEN IIA occurs in association with pheochromocytoma and parathyroid adenoma, while MEN IIB occurs in association with pheochromocytoma and mucosal neuromas or neurofibromas. The incidence of anaplastic thyroid carcinoma appears to be decreasing, but this is most likely because better techniques for differentiating other thyroid tumors from anaplastic disease have become available.

Etiology

External low-dose radiation therapy to the head and neck during infancy and childhood, used frequently from the 1940s to the 1960s to treat a variety of benign diseases, has been shown to predispose to thyroid cancer. The average time between irradiation and recognition of the tumor is 10 years but may be longer than 30 years [6]. Patients exposed to head or neck irradiation experience an increased frequency of benign tumors, but malignancy occurs in up to 30% of cases. Treatment of malignant diseases with higher x-ray doses (more than 2,000 cGy), especially at a young age, also has been associated with an increased risk of both benign and malignant neoplasms of the thyroid.

Besides radiation-induced thyroid cancer, there are only sparse data on the etiology of this malignancy [7]. Prolonged thyroid-stimulating hormone (TSH) stimulation has been implicated as a potential risk factor; however, patients with primary hypothyroidism do not appear to exhibit increased frequency of thyroid carcinoma [8]. Thyroid-stimulatory immunoglobulins present in patients with Graves' disease have also been implicated [9], and associations between thyroid cancer and Hashimoto's thyroiditis, Graves' disease, and multinodular goiter have been reported. However, any causative relationship between these diseases remains poorly documented.

The possible role of genetic factors is receiving a great deal of attention in familial cases of thyroid cancer. Two uncommon familial syndromes are associated with follicular thyroid carcinoma: Gardner's syndrome with polyposis of the large intestine, which is inherited as an autosomal dominant trait, and Cowden's disease, which is characterized by inherited multiple hamartomas. Genetic factors may also predispose people to radiation-induced thyroid neoplasms.

In a descriptive epidemiologic study of 7,696 patients with thyroid cancer in the United States between 1973 and 1981 [7], striking differences in incidence were noted among ethnic groups. Compared with white men and women, Puerto Rican Hispanics and blacks had significantly lower thyroid cancer rates. Conversely, New Mexican Hispanic men and Chinese, Japanese, Hawaiian, and Filipino men and women had significantly higher rates. Elevated thyroid cancer rates were also noted for residents of Hawaii, regardless of ethnic group, as well as for residents in areas bordering the Ring of Fire, such as Colombia, the Philippines, and Polynesia. An etiologic relationship between thyroid cancer and the presence of active volcanoes in this region has been postulated.

Pathology

Thyroid cancer is generally subdivided into a large group of well-differentiated neoplasms characterized by slow growth and high curability, and a small group of highly anaplastic tumors with a bleak outlook. The pathologic classification proposed by Woolner et al in 1961 [4] was adopted by the American Thyroid Association with a few modifications, and in 1974 was accepted by the World Health Organization.

Thyroid cancer is classified into four main types, according to morphology and biologic behavior: papillary, follicular, medullary, and anaplastic. This classification has an advantage over systems based purely on histologic patterns, in that it relates morphology to methods of treatment and prognosis. Primary lymphoma of the thyroid, metastases from other primary sites, and other uncommon thyroid tumors are also encountered, though rarely (Table 1)[10].

Lymphoid-cell origin

Papillary tumors arise from thyroid follicular cells and are in most cases unilateral. They vary in size from microscopic to large cancers that may invade the thyroid capsule and infiltrate contiguous structures. Papillary tumors tend to invade the lymphatics, but they have little tendency to invade the blood vessels; psammoma bodies are common. Follicular tumors, although frequently encapsulated, commonly exhibit vascular and capsule invasion microscopically. Hrthle-cell carcinomas are considered a type of follicular cancer.

Many tumors have both papillary and follicular elements histologically; they are called follicular variants of papillary carcinoma, and are classified as papillary lesions because their clinical behavior is typically indistinguishable from that of pure papillary cancers. Occasionally, both papillary and follicular tumors occur as small lesions surrounded by a dense fibrotic reaction; they are called occult sclerosing lesions and may be associated with lymph-node metastases.

Medullary thyroid carcinoma is derived from C-cells (or calcitonin-secreting cells)[5] that are of ectodermal neural crest origin. Medullary carcinoma of the thyroid primarily arises in the upper two thirds of the gland where the C-cells are normally found. C-cells secrete a 32–amino acid peptide called calcitonin, which serves as a useful biochemical marker in patients with this cancer. Medullary carcinoma of the thyroid occurs as a solid mass or clusters of C-cell hyperplasia interspersed between normal-appearing thyroid follicles. These can be visualized with calcitonin immunostaining, which shows variable amounts of fibrosis and deposits of amyloid in 60% to 80% of tumors. Even the smallest visible tumors can be associated with metastases.

Anaplastic thyroid tumors [11] are derived from follicular cells. The presence of argyrophilic cytoplasmic granules distinguishes follicular from parafollicular origin, and thus can differentiate anaplastic follicular thyroid lesions from undifferentiated variants of medullary carcinoma. Thyroglobulin, normally synthesized in the follicular epithelium of the thyroid, is present in well-differentiated papillary and follicular carcinomas and infrequently in anaplastic carcinomas, but not in medullary carcinoma cells. Therefore, thyroglobulin immunoreactivity also is considered to be indicative of follicular epithelial origin.

The absence of thyroglobulin immunoreactivity in anaplastic carcinomas does not exclude follicular epithelial origin, because undifferentiated carcinoma cells may have lost the ability to synthesize this glycoprotein. Occasionally, it is possible to show that a case of anaplastic carcinoma arose from preexisting well-differentiated thyroid carcinoma.

Clinical Presentation and Course

Thyroid cancer is usually detected in a euthyroid patient as a dominant anterior neck mass that moves on deglutition and is “cold” on scintiscan. The diagnosis of medullary carcinoma of the thyroid can be made by measuring calcitonin levels after provocative pentagastrin and/or calcium administration. Because of the potentially familial nature of medullary cancer, consideration should be given to screening a patient's first-degree relatives after a positive diagnosis. Recent advances in molecular biology may allow for genetic detection of this disease in the near future [12]. Fine-needle aspiration of a nodule followed by immunohistochemical staining for thyroglobulin or calcitonin can lead to a correct diagnosis in most cases.

In adults with differentiated papillary thyroid cancer, up to 40% may present with regional lymph-node metastases; these are mostly ipsilateral, but bilateral and mediastinal lymph-node metastases may be encountered in a few patients. Distant metastases occur in less than 1% of patients at the time of presentation. The most common sites of metastasis, in decreasing order of frequency, are the lungs, bones, and other soft tissues.

Older patients have a higher risk for distant metastases. Most children and teenagers also present with a solitary nodule of the thyroid, but cervical node involvement is more common in this age group than in adults; up to 10% of children and adolescents may have lung involvement at the time of diagnosis [13]. The prognosis for patients who have received head and neck irradiation is similar to that of random cases, even though the former group may present with more extensive disease [14].

Follicular thyroid carcinoma [15] occurs in older people, with peak incidence in the fifth decade of life. This disease occurs less often than papillary carcinoma, except perhaps in iodine-deficient areas or among patients with preexisting goiters. Follicular thyroid malignancies have a worse prognosis than papillary tumors, especially in patients with fixed/invasive lesions. Direct invasion of the strap muscles and trachea may occur and compromise resectability. Follicular tumors tend to metastasize to the lungs and bone (producing osteolytic lesions), often retain the ability to accumulate radioactive iodide, and can be treated with iodine [13].

Invasion of the capsule and/or blood vessels is generally used to classify follicular neoplasms as malignant. Patient age over 50 years, tumor size larger than 3.9 cm, high tumor grade with high nuclear DNA content, presence of marked vascular invasion, adjacent tissue invasion, and distant metastases at diagnosis all are associated with increased cancer mortality.

The biology, natural history, and optimal therapy for Hrthle-cell carcinoma continues to generate debate because of persisting difficulties in the differentiation of benign from malignant lesions. While most lesions appear benign, without capsular invasion or vascular invasion, many are more aggressive, showing obvious invasion and having a pronounced tendency to recur in the neck years after the original resection. Therefore, aggressive surgery with thyroidectomy is generally recommended, especially for tumors greater than 2 cm, but controversy over this treatment approach remains.

Pulmonary metastases in differentiated thyroid carcinoma are often classified radiographically as either “micronodular” or “macronodular” disease. Micronodular metastases present a miliary, diffusely reticular pattern predominating in the lower lung fields, and tend to concentrate radioiodine diffusely. Macronodular (coarse) metastases with nodular masses of unequal size (varying between 0.5 cm and 3.0 cm) occur more frequently. Radioiodine incorporation is heterogeneous, but often not present. Transition from micro- to macronodular metastasis may occur during the course of the disease.

The most common clinical presentation of sporadic medullary thyroid cancer is a solitary thyroid mass found incidentally during routine examination. Most patients present in the fourth or fifth decades of life with a male:female ratio of 1.4:1 [5,16]. Metastases to cervical and mediastinal lymph nodes are found in half of the patients and may be present at the time of initial presentation. Distant metastases to the lungs, liver, bones, and adrenal glands most commonly occur late in the course of the disease. Secretory diarrhea, often severe, is the most prominent of the hormone-mediated clinical features of medullary carcinoma. Rarely, ectopic production of adrenocorticotropic hormone (ACTH) and/or corticotropin releasing hormone (CRH) may cause paraneoplastic Cushing's syndrome.

Anaplastic carcinoma, in sharp contrast to differentiated thyroid carcinomas, confers a dismal prognosis, with median survival time after diagnosis ranging from 4 to 12 months. Most studies show a 2-year survival rate close to 0%, and long-term survival of more than 5 years is rare. Anaplastic thyroid carcinoma is a locally and systemically aggressive disease, with better survival rates seen only in those patients with well-localized anaplastic tumors. Favorable prognostic features seem to be unilateral tumors, tumor size less than 5 cm, no invasion of adjacent tissue, and absence of nodal involvement. Anaplastic carcinoma most commonly presents as a rapid growth of a thyroid mass, frequently in a preexisting goiter. A history of a long-standing thyroid enlargement is noted in about 80% of the patients.

Therapeutic Options and Factors in Selecting Therapy

In patients with disease confined to the neck, surgical excision is the first treatment of choice. Postoperative examination with radioiodine scanning allows the identification of residual regional or distant foci of disease. Radioiodine can be used therapeutically to ablate such tumor deposits [17]. The thoroughness of thyroid resection and the optimal scheme for radioiodine surveillance and treatment remain subjects of discussion. In adults, cervical lymph-node metastases are associated with a higher incidence of recurrence but not with a diminished rate of survival [18].

In a recent review of 101 patients with differentiated thyroid carcinoma and pulmonary metastases, Samaan et al analyzed potential prognostic factors and the efficacy of radioactive iodine treatment over time [19]. Uptake of radioactive iodine by lung metastases conferred a favorable prognosis, especially in patients with negative radiologic findings. The probability of radioactive iodine uptake was related to the degree of differentiation of the primary tumor. Pulmonary metastases were least common in patients with papillary carcinoma and most common in those with Hrthle-cell carcinoma. Patients less than 40 years old had a better prognosis than older patients. Patients under 20 years old with papillary and/or follicular thyroid cancer should have aggressive initial treatment because they tend to present with extensive regional disease and lymph-node metastases, and they have a high rate of tumor recurrence [20].

For most patients with differentiated thyroid cancer, we recommend a near-total thyroidectomy with modified neck dissection as needed, followed by a postoperative iodine 131 scan and appropriate treatment. Following this initial program, thyroxine replacement therapy is prescribed, and patients are carefully followed up with regular physical examinations, chest radiographs, and serum thyroglobulin determinations. The optimal strategy for subsequent radioiodine scanning and/or therapy should be individualized. External irradiation has a limited role in this disease and should be reserved for locally invasive, carefully selected neoplasms that do not concentrate iodine. Systemic chemotherapy is required for certain cases of widespread disease, although available regimens have not been very effective to date.

In medullary thyroid carcinoma, the usual treatment is total thyroidectomy with careful cervical node examination and appropriate dissection. This approach is especially important for patients with familial disease, who are more likely to harbor bilateral disease. These patients should have a preoperative evaluation for possible coexisting pheochromocytoma; if the tumor is present, appropriate control of catecholamine hypersecretion should precede thyroid surgery.

For resectable lesions in anaplastic carcinoma, thyroid lobectomy with wide margins of adjacent soft tissue on the side of the tumor is appropriate. Total thyroidectomy and radical neck dissection result in an increased complication rate and are not likely to increase survival time in this disease. Radiotherapy and chemotherapy are important alternative approaches, but further evaluation is needed to optimize their effectiveness [21].

Parathyroid Carcinoma

Incidence and Etiology

The prevalence of benign primary hyperparathyroidism has increased with the advent of multichannel autoanalyzers that permit the early detection of disease in asymptomatic patients. Nevertheless, the incidence of parathyroid carcinoma has not changed appreciably. This disease remains a rare cause of hypercalcemia; it is responsible for less than 2% of cases with primary hyperparathyroidism [22]. The etiology of parathyroid carcinoma is obscure. While regional head and neck irradiation is a significant factor in the genesis of parathyroid adenomas and benign hyperparathyroidism [23], a similar association is not apparent for malignant parathyroid disease [24]. Similarly, no association with prior iodine 131 exposure has been demonstrated.

Parathyroid carcinoma has rarely been reported in families with familial hyperparathyroidism. Thus, it may be prudent to screen the relatives of patients with parathyroid carcinoma for hypercalcemia to improve the chance of early diagnosis of parathyroid disease.

Clinical Presentation

Patients with parathyroid carcinoma tend to be younger than patients with benign hyperparathyroidism; the disease occurs with similar frequency in both sexes [22]. Most patients with malignant disease are symptomatic and have moderate to severe hypercalcemia (mean serum calcium level, 15 mg/dL; range, 10.0 to 24 mg/dL)[24]. Parathyroid hormone levels are generally very elevated.

Involvement of peripheral target organs, such as kidneys or bone, is no longer considered characteristic of benign hyperparathyroidism, but is somewhat common in patients with functioning parathyroid cancer. Unlike patients with benign disease, patients with parathyroid carcinoma are more likely to have a palpable mass in the neck. Rare cases of nonfunctioning parathyroid carcinoma usually present as neck masses; their clinical course is similar to that in patients with functioning tumors [25]. Careful pathologic examination is needed to establish the diagnosis, but clinical concern about parathyroid cancer should be raised in patients with hyperparathyroidism who have a palpable neck mass and severe hypercalcemia, patients with recurrent hyperparathyroidism, or patients with associated unilateral vocal cord paralysis.

Parathyroid carcinoma is a slow-growing but tenacious malignancy, and the hypercalcemia it engenders may have catastrophic consequences [26]. The average time from initial surgery to the first recurrence is approximately 3 years but may be as long as 10 years. Local invasion of adjacent structures and lymph nodes can be present at initial operation. The thyroid gland is the most common site of involvement, followed by the recurrent laryngeal nerve, strap muscles, esophagus, and trachea. Distant metastases can be present at initial surgery; local spread to contiguous structures in the neck may be followed later by distant metastases to the lung, bone, and liver. Only 50% of patients are still alive 5 years after diagnosis. Death usually results from complications of the hypercalcemia rather than from the tumor burden.

Pathology

It is difficult to distinguish benign from malignant parathyroid tumors histologically. The principal features of this cancer include a trabecular pattern, mitotic figures, thick fibrous bands, and capsular or blood vessel invasion. Ultrastructural features of parathyroid carcinoma have been described, but these findings do not always help establish the diagnosis of malignancy. Other important features include lymphatic or hematogenous metastases and histologic evidence of tumor infiltration into the surrounding tissues (including macroscopic adherence or vocal cord paralysis)[27].

Although cytologic evidence of mitoses is necessary to confirm malignancy, mitotic activity alone is an unreliable indicator of such malignancy. On occasion, some highly differentiated tumors without distinct nuclear atypia are initially considered to be adenomas but are later reclassified when recurrence or metastases appear. On the other hand, a few parathyroid tumors may be classified as malignant because of their atypia, but neither metastasis nor relapse develops. One view is that the only reliable microscopic findings of malignancy are invasion of surrounding structures or metastasis to lymph nodes or other organs. Thus, ultimate diagnosis of parathyroid carcinoma can be made with confidence only after recurrence or metastatic spread occurs.

DNA aneuploidy determined by flow cytometry is a valuable adjunct marker in the diagnosis of malignancy and is associated with a poor prognosis [28,29]. Aneuploid parathyroid carcinomas are likely to show more malignant behavior than those with a diploid DNA pattern. It should be pointed out, however, that DNA aneuploidy may be found in some benign lesions. Therefore, this feature should be interpreted with caution [30].

Adenomas can be subdivided into two groups-typical and atypical. If an atypical adenoma possesses one or more of the histologic features usually considered requisite for a diagnosis of parathyroid carcinoma or is grossly adherent to an adjacent structure at the time of operation, it might represent a case of low-grade parathyroid carcinoma. Patients with these tumors should be monitored more carefully than those with the typical benign form.

Treatment

Intraoperative identification of malignancy and appropriate initial surgery are critical in the therapy for parathyroid carcinoma. Because there is no evidence that preoperative localization studies shorten operating time or prevent surgical failures, these studies are not required during initial surgery [31].

Resection of the tumor along with the ipsilateral lobe of the thyroid and abnormal central nodal tissue is indicated. A wide excision of locally recurrent tumor, an en bloc radical neck dissection and mediastinum dissection for lymphatic metastases, and an aggressive surgical resection of metastases whenever possible are recommended. Although these operations are not always curative, they usually offer palliation of the marked hypercalcemia for a considerable although variable period. Neck dissection is needed when there is evidence of regional node metastases.

After surgery, regular surveillance of serum calcium and parathyroid hormone (PTH) levels is essential. Thallium 201 isotope scanning has been used to aid in the localization of recurrent disease, but its reliability remains limited. Chest radiographs and computed tomographic (CT) scanning are useful for delineating pulmonary metastases. Isolated metastases may be resected to lengthen survival time and control hypercalcemia. As with benign, functioning parathyroid tumors, preoperative localization may be needed for patients who have had prior neck exploration.

Parathyroid carcinomas only rarely are located in the superior mediastinum or within the thymus. Putnam et al described a patient with mediastinal, nonfunctional parathyroid carcinoma that originated in the thymus and was treated with extended en bloc resection followed by prophylactic radiation therapy and chemotherapy [32]. Multiple metastases may not be amenable to surgical resection. Morbidity and mortality are generally caused by the effects of unremitting hypercalcemia rather than tumor growth. Medical treatments such as calcitonin, plicamycin (Mithracin), and bisphosphonates offer only temporary and palliative control of hypercalcemia.

Radiation therapy has not been very helpful in controlling primary and metastatic lesions [22], nor has chemotherapy. In a case report of a patient who had parathyroid cancer metastatic to the lung and severe hypercalcemia (serum calcium level, 18.6 to 20.0 mg/dL), the combination of fluorouracil, cyclophosphamide (Cytoxan, Neosar), and dacarbazine resulted in complete remission for 5 months [33]. Because of the variable clinical course of this disease, it is important to individualize therapeutic strategies. Nevertheless, surgical resection where possible remains the most effective treatment for both local and metastatic disease.

Adrenal Gland Neoplasms

Adrenocortical Carcinoma

Epidemiology: Adrenocortical carcinoma is a rare and often highly malignant neoplasm that is usually diagnosed late in its course, resulting in short life expectancy for the patient. The etiology is unknown, but some cases have occurred in families with a hereditary cancer syndrome. The incidence is estimated at two per million population per year. Adrenocortical carcinoma accounts for about 0.2% of cancer deaths. Close to 50% of the tumors produce hormonal and metabolic syndromes that lead to their discovery.

Clinical Presentation: Approximately half of adrenocortical carcinomas are functioning and present with clinical features consistent with several syndromes of hormone hypersecretion (glucocorticoids, androgens, mineralocorticoids, and estrogens [34]. Thus, the symptoms and signs of Cushing's syndrome, virilizing or feminizing syndromes, and hyperaldosteronism may be the presenting features. The other 50% of the tumors are nonfunctioning, and are discovered as a result of metastases or when the primary tumor becomes large enough to produce abdominal symptoms. Smaller tumors may be discovered incidentally when unrelated abdominal complaints are investigated radiographically [34,35]. Nonfunctioning tumors occur predominantly in males and older patients, whereas functioning tumors are seen more frequently in women and younger patients [36].

Cushing's syndrome is the most common clinical presentation for adults with functioning adrenocortical carcinoma. The clinical manifestations of excess cortisol are rapidly progressive and include weight gain, muscle weakness, easy bruising, irritability, insomnia, and centripetal obesity. The rare cases of Cushing's syndrome in children are often due to adrenal carcinoma. Obesity is the most common presenting sign, but it is more generalized than it is in adults because the effect on muscle tissue in the lower limbs is less evident in childhood.

Mixed syndromes, such as Cushing's and virilization, strongly suggest adrenal carcinoma. The combination of hirsutism, acne, amenorrhea, and rapidly progressing Cushing's syndrome in a young woman is a characteristic presentation. The androgen excess can moderate the severity of the catabolic effects of hypercortisolism. Skin and muscle atrophy, in particular, may not be as apparent in these patients.

In a male child who was normal at birth and who later develops precocious virilization, an adrenal carcinoma should be suspected. Similarly, in prepubertal girls, adrenocortical cancer represents a common cause of virilization. Feminization in the adult male, albeit rare, should immediately suggest adrenal carcinoma. In men, estrogen-secreting tumors are associated with gynecomastia, breast tenderness, testicular atrophy, impotence, and decreased libido. In women, estrogen-secreting tumors can cause tenderness and dysfunctional uterine bleeding; in prepubertal girls, precocious puberty may be seen.

Aldosterone-producing adrenocortical carcinomas are extremely rare, and the clinical manifestations are those of mineralocorticoid excess with hypertension and hypokalemia.

Treatment: Early diagnosis and complete surgical excision provide the best expectation for long-term survival, which is dismal overall. The survival rate for patients with adrenocortical cancer is 23% at 5 years and 10% at 10 years [37]. There is no significant difference between functioning and nonfunctioning tumors.

Since 1960, mitotane (o,p´-DDD [Lysodren]) has been one of only a few agents effective against adrenocortical carcinoma. Mitotane exerts a specific cytolytic effect on adrenocortical cells, and has been used to treat unresectable or metastatic adrenocortical carcinomas, both functioning and nonfunctioning. While reduction of hormone production can be obtained in two thirds of patients with functioning tumors, only 15% to 30% of patients have objective tumor regression, with a median duration of about 7 months [38]. Tumor regression is a more accurate indicator of clinical benefit, as steroid response merely reflects the action of mitotane on steroid biosynthesis. Because of the frequent recurrence of adrenal carcinoma, mitotane has been advocated for all patients after apparent complete surgical excision. However, the efficacy of adjuvant mitotane remains disappointing [35,39]. Although some patients achieve tumor regression with mitotane levels of 10 µg/mL, serum levels above 14 µg/mL are more often required; drug toxicity remains a difficult problem with such high doses.

Doxorubicin (Adriamycin, Rubex) has been of benefit in a limited number of patients. Innovative programs are clearly needed for this disease. Suramin, a sulfonated drug that is cytotoxic to human adrenocortical carcinoma cell lines, has been used with some benefit in the treatment of metastatic and inoperable adrenocortical cancer [40]. Postoperative irradiation of the tumor bed with wide margins has been found useful by some but not all investigators [41]. Effective palliation of metastatic disease, especially painful bone lesions, may be obtained with radiotherapy. Hormone hypersecretion can be controlled medically in most cases. The antifungal agents ketoconazole (Nizoral), aminoglutethimide (Cytadren), and metyrapone (Metopirone) are very effective in reducing steroid production and in palliating the often debilitating associated clinical symptoms. These drugs may be used alone or in conjunction with mitotane.

Adrenal Medulla Pheochromocytoma

Epidemiology and Incidence: Pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells in the adrenal medulla or extra-adrenal sympathetic ganglia. They most commonly present with intermittent, episodic, or sustained hypertension and constitute a surgically correctable cause of hypertension in 0.1% to 1% of hypertensive persons [42]. The condition occurs in all age groups, but the peak incidence is the third to fifth decades. There is no sex predilection in adults, but in children, the disease is slightly more common in boys.

Approximately 10% of cases are inherited as an autosomal dominant trait, either independently or as a part of MEN type II; bilateral tumors are more common in this setting. In children, pheochromocytomas are rare but tend to be bilateral, because they are more likely to arise from inherited syndromes. Pheochromocytomas can be associated with other neuroectodermal disorders, such as neurofibromatosis, von Hippel-Lindau disease, cerebellar hemangioblastoma, Sturge-Weber's syndrome, and tuberous sclerosis.

Clinical Features: Pheochromocytomas can cause life-threatening cardiovascular disturbances by the release of excessive amounts of catecholamines. Patients with pheochromocytomas can present with a range of symptoms, from mild labile hypertension to a hypertensive crisis, myocardial infarction, or cerebral vascular accident [43], any of which can result in sudden death. Hypertension is the most common manifestation of pheochromocytoma. The classic pattern of paroxysmal hypertension occurs in 30% to 50% of cases. Sustained hypertension, resembling essential hypertension, may also occur. In some cases, extreme fluctuations in blood pressure may be superimposed on sustained hypertension. In children with pheochromocytomas, the hypertension is most often sustained.

A characteristic presentation in adults includes “spells” of sudden intense headaches, pallor or flushing, tremors, apprehension, palpitations, hypertension, and diaphoresis. The paroxysms may last for a few minutes to several hours and may occur several times a day or much less frequently. The attacks can be precipitated by a particular body position, straining at stool, exercise, emotional distress, or anxiety. In the rare cases of pheochromocytoma of the urinary bladder, the paroxysm may be provoked by voiding and may be associated with micturition syncope. Some patients may present with angina pectoris or acute myocardial infarction caused by coronary artery spasm and increased myocardial oxygen demand. Orthostatic hypotension can result from diminished plasma volume and blunted sympathetic reflexes. Atrial and ventricular arrhythmias can be encountered. Congestive heart failure due to catecholamine cardiomyopathy and persistent hypertension, although rare, may occur.

The majority of patients with pheochromocytomas have mild weight loss, but obesity does not rule out the condition. Patients may have symptoms of hypermetabolism, such as heat intolerance, increased caloric requirements, or diaphoresis. Basal metabolic rate may be elevated, but thyroid function is normal. Some patients may have impaired glucose tolerance or deterioration of diabetic control; the altered carbohydrate metabolism is thought to be caused in part by the alpha-adrenergic effect of norepinephrine and epinephrine.

Patients may have cholelithiasis or severe constipation and abdominal distension caused by the inhibitory effect of catecholamines on gut motility. Paraneoplastic syndromes are occasionally present; Cushing's syndrome is seen most often and results from ectopic production of ACTH [44]. Other peptides of less clinical significance are produced, including somatostatin, calcitonin, oxytocin, and vasopressin. Polycythemia can be caused by excessive erythropoietin production or contraction of blood volume.

Diagnosis: The diagnosis of pheochromocytoma relies on an appropriate medical history and documentation of excessive catecholamine production [45]. Measurement of 24-hour urinary catecholamines and their metabolites, vanilmandelic acid (VMA) and metanephrine, is commonly used [46]; current methodology provides highly sensitive and reliable quantification of catecholamines. The metanephrine level is considered the most specific single test. Catecholamine measurements are very useful both for the initial diagnosis and for postoperative surveillance of patients with pheochromocytoma. It is important to remember that false-positive results may be caused by increased catecholamine excretion from severe physical or mental stress, or by certain medications. The VMA assay is the least specific and most susceptible to interfering substances.

Serum catecholamine measurements are more susceptible to false elevations due to stress-related physiologic fluctuations. The evaluation of serum catecholamines after clonidine suppression, however, provides a very useful diagnostic tool that is more convenient than urine collections. Dynamic provocative tests are very rarely indicated at this time.

Almost all pheochromocytomas are localized in the abdomen, mostly in the adrenal medulla. Other tumors tend to be localized in the posterior mediastinum, although they may occur in any distribution of the sympathetic ganglia. After the diagnosis is established biochemically, radiologic methods are used for preoperative localization of the lesion. At the present time, CT and magnetic resonance techniques are the most widely used.

Iodine 131 methyliodobenzylguanidine (iodine-131-MIBG) scintigraphy has recently become available and provides a “functional” image. This technique is most helpful in the detection of occult contralateral or extra-adrenal lesions. Positron emission tomography with hydroxyephedrine is a promising newer approach under investigation [47].

Preoperative Medical Management: Patients undergoing surgical excision of pheochromocytoma must be adequately prepared to prevent hypertensive crises during the induction of anesthesia and manipulation of the tumor [46]. Phenoxybenzamine (Dibenzyline), an oral, long-acting, noncompetitive alpha-adrenoceptor-blocking agent, is a widely used, very helpful first drug. Propranolol, a beta-adrenoceptor blocker, is usually added after a few days to prevent tachycardia or arrhythmias. The tyrosine hydroxylase inhibitor metyrosine (Demser) may be added in patients whose hypertensive responses are not well controlled with alpha and beta blockers alone. It is important to remember that the use of beta blockers alone is hazardous, because they may precipitate a paradoxic rise in blood pressure. For inoperable tumors, a similar program with alpha-adrenoceptor and beta-adrenoceptor blockers as well as metyrosine can be used for chronic medical control.

Malignant Pheochromocytoma

Pheochromocytomas are rare tumors that are almost always benign. Only about 10% of these tumors are considered malignant. The histologic differentiation between benign and malignant lesions is extremely difficult and often impossible. Thus, specific diagnosis often must await the development of lymph node, hepatic, bone, or other distant metastases. Recurrent symptoms of pheochromocytoma, often many years after the original diagnosis, suggest the possibility of malignancy. Biochemical confirmation of recurrent catecholamine hypersecretion and localization of metastatic lesions with iodine-131--MIBG scan constitute diagnostic proof.

The treatment of choice for malignant pheochromocytoma remains problematic. Chemotherapy using streptozocin (Zanosar)-based regimens or combined cyclophosphamide, vincristine, and dacarbazine programs have yielded promising responses [48,49]. Treatment with iodine-131--MIBG has met with only limited success [50]. Radiotherapy can achieve significant palliation, especially for painful bone lesions. In most cases, uncontrolled catecholamine hypersecretion eventually escapes biochemical blockade, and fatal hypertensive crisis ensues. In those rare cases in which limited and resectable lesions can be identified, surgery can effect complete and lasting remission of the disease. Clearly, improved strategies for control of malignant pheochromocytoma are needed.

References:

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