14 - Thyroid and Adrenal Carcinomas | Handbook of Cancer Chemotherapy

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 14 - Thyroid and Adrenal Carcinomas

Chapter 14

Thyroid and Adrenal Carcinomas

Haitham S. Abu-Lebdeh

Samir N. Khleif

Endocrine cancers account for 1.5% of all cancers diagnosed and for 0.4% of cancer deaths. Thyroid cancer is the most common endocrine malignancy, accounting for 90% of endocrine cancers and for 60% to 70% of the deaths from this group of diseases. Although the role of cytotoxic chemotherapy is limited in endocrine cancer, it is beneficial in select patients. Pancreatic islet cell carcinomas and other pancreatic malignancies are discussed in Chapter 9. Here, thyroid and adrenal carcinomas are discussed. The pathology, presentation, and biologic behavior of thyroid and adrenal carcinomas are important determinants of therapy and are briefly considered.

I. Thyroid carcinoma

A. Background

Incidence. Approximately 17,000 new cases of thyroid carcinoma are diagnosed each year, with approximately 1,200 deaths due to this cancer. The incidence of thyroid carcinoma is 5.9 per 100,000 women and 2.2 per 100,000 men, and the peak incidence is at age 40 in women and age 60 in men. The prevalence at autopsy is 5 to 15 per 100,000 subjects. The incidence of thyroid cancer is increasing each year. Thyroid carcinoma usually affects people between the ages of 25 and 65 years.
Etiology and prevention. In most instances, the cause of thyroid carcinoma is unknown, although experimentally prolonged stimulation by thyroid-stimulating hormone (TSH) may lead to the development of thyroid carcinoma. Some cases appear to be related to a dose-dependent phenomenon involving radiation to the neck during childhood. Thyroid malignancy has been observed 20 to 25 years after radiation exposure in atomic bomb survivors and in children treated with radiation therapy for benign conditions of the head and neck. The frequency increases exponentially with doses up to 12 Gy and then decreases, so that with doses over 20 Gy, the risk of developing malignancy becomes relatively low because such high doses lead to the destruction of cells rather than nonlethal damage of the deoxyribonucleic acid (DNA). In cases of accidental nuclear exposure, it is thought that the use of potassium iodide to block the thyroid uptake of radioactive iodine (RAI) in children is helpful in reducing the incidence of subsequent thyroid cancer. This measure was used in Eastern Europe after the Chernobyl accident. Although ionizing radiation for benign conditions of the head and neck is no longer being used, thyroid carcinomas related to prior exposure to radiation are still being seen. Some
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cases of thyroid carcinoma (usually medullary carcinoma) are familial, as seen in the multiple endocrine neoplasia (MEN) syndrome, associated with germline mutation of the RET proto-oncogene. Furthermore, mutations in the follicular thyroid cell signaling pathway are associated with tumor development. For example, RET/PTC gene rearrangements and Ras, BRAF and MEK-ERK pathway mutations are present in 70% of papillary thyroid cancer. Abnormalities in the p53-catenin pathway are associated with the development of anaplastic thyroid cancer. The least understood cancer is follicular carcinoma, but this is also associated with Ras and mutations on chromosome 3 (pax8-PPAR mutations).
Histologic types. The most common histologic types of thyroid carcinoma are as follows:
- Differentiated thyroid cancer (DTC). DTC includes papillary carcinoma (75% 80%) and follicular carcinoma (11%). DTCs are derived from thyroglobulin-producing follicular cells and are typically RAI responsive, especially in initial stages.
- Anaplastic or undifferentiated carcinoma (2%)
- Medullary carcinoma (4%). Medullary carcinomas are derived from thyroid parafollicular or C cells. These cells produce both immunoreactive calcitonin and carcinoembryonic antigen (CEA).
- H urthle cell carcinoma (3%). H urthle cell carcinoma used to be considered a variant of follicular carcinoma. It is now considered as a separate pathologic entity, and is characterized by relative RAI resistance.
- Thyroid lymphoma (5%)
Prognosis
- Cell types. Papillary and mixed papillary and follicular histologies are considered to have similar biologic and prognostic behaviors. Patients with these cancers have an excellent prognosis, with less than 15% mortality at 20 years. However, survival rates are significantly reduced if distant metastasis is detected. Patients with pure follicular carcinoma do not do as well as those with papillary elements, at least in part because there is a tendency for the follicular carcinoma to spread through the bloodstream, whereas the papillary carcinoma spreads more by lymphatic channels. The 10-year relative survival rates are 85% and 93%, respectively. Recent studies have shown that patients having follicular carcinoma with vascular invasion have a relatively bad prognosis, whereas patients with follicular carcinoma without vascular invasion do almost as well as those with papillary carcinoma. Approximately 25% of medullary carcinomas are familial, as part of three clinical syndromes (MEN2A, MEN2B, and familial non-MEN medullary thyroid carcinoma). Regional lymph node and distant metastases are common in patients with medullary carcinomas and occur in early stages of the disease. The 10-year survival rate after surgical resection is 40% to 60%. Patients with anaplastic thyroid carcinoma have an abysmal prognosis, with a
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  median survival time of 4 months, although occasional patients may be cured with combined radiotherapy and chemotherapy.
- Other factors. In addition to the cell type, the prognosis of thyroid carcinoma is shown to be worse if the following factors are present:
  - A large tumor size, especially more than 4 cm.
  - Patient age more than 40 years.
  - Distant metastases. DTC tends to metastasize to the lung or bone. Patients with bone metastases have survival rates of 53%, 38%, and 30% at 5, 10, and 15 years, respectively.
  - Abnormal DNA content in tumor cells in the papillary type; the more pronounced the aneuploidy, the more aggressively the cancer behaves.
  - Male sex, which may be related to the fact that men tend to be older at the time of diagnosis and are more likely to have a worse histologic type.
  In contrast to most other cancers, limited regional lymph node metastasis of DTC does not influence survival substantially, and radiation-induced thyroid carcinoma is not associated with a worse prognosis.

B. Diagnosis and staging

Any solitary thyroid nodule should be considered a possible malignant tumor until proved otherwise, especially in patients younger than 25 years and men older than 60 years. Although toxic nodular goiters are less likely to contain carcinoma, a nodule in the setting of hyperthyroidism does not automatically confer benignity. The overall incidence of cancer in a cold nodule is 5% to 10%. Because most thyroid tumors spread primarily by local extension and regional nodal metastasis, assessment of the extent of disease is concentrated on the neck. Presurgical studies include careful physical examination, thyroid function tests, thyroid ultrasound and cytology by fine needle aspiration (FNA). Unlike core needle biopsy, FNA biopsy yields an aspirate of cells and not a tissue fragment. FNA does not require local anesthesia and is considered safer and easier to perform. The accuracy of needle aspiration biopsy ranges between 50% and 97%, depending on the experience of the pathologist and the institution.

Other studies such as indirect laryngoscopy, radionuclide scanning, esophagogram, and computed tomography (CT) scan of the neck can be performed on a case-by-case basis. In a few instances, a core needle biopsy might be considered. If there is a strong clinical suspicion of thyroid lymphoma and FNA is not diagnostic, then a core needle biopsy should be considered as an alternative to a surgical biopsy that requires general anesthesia. Chest radiography should be performed before surgery to rule out pulmonary metastasis. If there is any clinical or laboratory suggestion of bone metastases, skeletal x-rays, CT scan, or a radionuclide bone scan should be performed. Patients with thyroid carcinoma are typically euthyroid. Thyroid carcinoma rarely destroys thyroid tissue to the point of frank hypothyroidism. However, elevated TSH levels with increased thyroid peroxidase antibodies may be

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seen with Hashimoto's thyroiditis, which may coexist in 20% of patients with thyroid lymphoma.

Table 14.1. Pathologic TNM staging system for thyroid cancer

Stage	Papillary or Follicular, Age <45	Papillary or Follicular, Age >45; Medullary, Any Age	Anaplastic, Any Age
I	M0	T1, N0, M0
II	M1	T2, N0, M0
III		T3, N0, M0 T1 3, N1a, M0
IV		T4, Any N, M0 T1 3, N1b, M0 Any T, Any N, M1	Any T, N, or M
T4 = Any tumor invading tissue beyond thyroid capsule. N1a = Metastasis to central lymph node compartment. N1b = Metastasis to other lymph nodes. M0 = no evidence for metastasis. M1 = distant metastasis is present.

The most widely accepted staging system is the pathologic TNM (pTNM) classification, which assesses tumor size and extent (T1, <2 cm; T2, 2 4 cm; T3, >4 cm), lymph node metastasis, and distant metastasis (Table 14.1). With the use of pTNM staging, any anaplastic thyroid cancer is considered stage IV, and there are no stage III or IV patients with DTC who are younger than 45 years. This staging system does not provide all the information needed. Other staging or riskgroup assignment systems are used for providing prognostic information.

C. Treatment

The therapeutic approach to patients with thyroid carcinoma depends considerably on the histologic type.

Differentiated thyroid carcinoma (DTC)
- Surgery is the only definitive therapy. Although the surgical approach may differ among surgeons and institutions, many surgeons prefer a bilateral, near-total, or total thyroidectomy, taking into consideration that with DTC, the incidence of disease in the contralateral lobe is 20% to 87%. Limited lymph node involvement does not substantially influence the survival rate, but it is associated with an increase in local recurrence and therefore routine central compartment neck dissection should be considered. Total thyroidectomy with modified neck dissection is often preferred for those who have lateral cervical lymph node involvement. Mortality after thyroidectomy in DTC approaches 0%. Complications include permanent recurrent laryngeal nerve damage in 2% of patients and permanent hypoparathyroidism in 1% to 2%.
- TSH suppression is an essential component in the treatment of DTC because there is good evidence that
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  cells are usually responsive to TSH. TSH suppresses the growth of malignant as well as normal thyroid tissue, and therefore the recurrence rate is reduced; in a few patients, metastatic lesions are diminished markedly. This hormonal suppression can be achieved by the administration of exogenous thyroid hormone. Usually 125 to 200 g of levothyroxine (T4) daily is used to keep the TSH level in the range of 0.1 to 0.4 mIU/L. Complete TSH suppression (0.01 0.1 mIU/L) should be reserved for high-risk patients to avoid long-term adverse effects on bone and heart. Side effects and dose-limiting factors include symptoms of thyrotoxicosis, angina, and cardiac arrhythmia.
- Radiotherapy. Destruction of residual normal thyroid tissue after thyroidectomy with radioactive iodine (RAI-[¹³¹I]) is termed radioactive remnant ablation (RRA). RRA is different from RAI therapy. In RAI therapy larger doses of RAI are used to destroy persistent cancer or distant metastasis. RRA is widely used in the United States. When ablation is carried out postoperatively, it is usually done 4 to 6 weeks after thyroidectomy. RRA allows for better subsequent imaging with RAI when looking for metastasis. It also improves the sensitivity for thyroglobulin measurements (since remnant thyroid tissue is destroyed) and may destroy microscopic cancer cells within the remnant. A dose of 30 mCi (1,110 MBq) to 150 mCi (5,550 MBq) of RAI is usually used. Most centers use the lower dose of 30 mCi, which is estimated to expose the whole body to approximately 6 mSv. For patients who are at low risk (tumor size <1 cm), ablation is controversial. Many physicians still ablate to allow for an easier follow-up. RRA is strongly recommended for patients who are at high risk of recurrence ormetastasis (patients older than 45 years or with large lesions or multifocal disease). Once ablation is successful, patients are placed on suppressive therapy.
  
  Treatment with RAI (131I) (RAI therapy) is usually recommended for patients with DTC and known postoperative residual disease, patients with distant metastases, and patients with locally invasive lesions. For patients with nodal metastases that are not large enough to excise, a dose of 100 to 175 mCi of RAI is given (3,700 6,475 MBq). Locally invasive cancer that is not completely resected is treated with 150 to 200 mCi of RAI (5,550 7,400 MBq). Patients with distant metastasis are treated with 200 mCi (7,400 MBq). The exception is lung metastasis; a dose of up to 80 mCi of RAI (2,960 MBq) whole body retention as determined by dosimetry at 48 hours is generally used to avoid radiation-induced fibrosis. Effective use of RAI treatment requires the following:
  - Tumor cells that are capable of receiving and concentrating iodide (i. e., DTC), and
  - Appropriate patient preparation by either withholding thyroid hormone administration for a short period
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    of time to provide the iodine-concentrating cells with the highest endogenous TSH stimulation or by using recombinant thyroid-stimulating hormone (rhTSH) to stimulate thyroid cell uptake of RAI.
  T3 is cleared from the body much more rapidly than T4. The shorter period of withdrawal minimizes the period of hypothyroidism. Accordingly, patients are switched from suppression therapy with T4 to a corresponding dose of T3 for 4 weeks to allow metabolic disposal of the T4. This is followed by 2 weeks of T3 withdrawal. Ideally, TSH of at least 25 to 30 m/mL is required for successful ablation or radiotherapy. Potential side effects expected after radioiodine therapy include temporary bone marrow depression, nausea, sialoadenitis with possible permanent cessation of salivary flow (radiation mumps), skin reaction over the tissue concentrating the radioiodine, and pulmonary fibrosis. The use of high doses (cumulative effect) may be associated with acute myelogenous leukemia, bladder and breast cancer, and transient bone marrow depression. Patients with lung metastases treated with RAI have a 20-year survival rate of 54%. Scintigraphy should be performed 4 to 10 days after therapy to detect any residual carcinoma. Most DTCs grow very slowly. The rate of recurrence is 0.5% to 1.6% per year. Therefore, lifelong annual serum thyroglobulin assays are recommended. Several centers also advocate the use of neck ultrasounds for follow-up. The role of external radiation therapy in DTC is limited. It is considered for residual cervical tumors that do not concentrate iodine. It is also used for localized painful bony metastasis, or metastatic lesions that are not amenable to surgery such as in the pelvis, vertebra or central nervous system (CNS).
Medullary thyroid carcinoma. With familial medullary carcinoma, the disease is almost always bilateral. Regional lymph node involvement is common in early stages. Therefore, total thyroidectomy, central lymph node dissection, and lateral ipsilateral modified radical neck dissection are required. The overall 10-year survival rate after surgical resection is 40% to 60%. Serum calcitonin levels should be measured 8 to 12 weeks postoperatively to assess disease burden and residual cancer. Search for germline and not somatic RET proto-oncogene mutations identifies most familial cases. For other family members with a positive RET proto-oncogene, surgery is recommended as early as at an age of 2 years. Postoperative annual evaluation is recommended by measuring levels of calcitonin and CEA, both of which are secreted by the medullary thyroid carcinoma cells, as a follow-up for residual disease or recurrence. Suppressive therapy is of no benefit because medullary cells do not have TSH receptors. RAI and cytotoxic chemotherapy are of little utility. Cisplatin, streptozocin, carmustine, methotrexate, and fluorouracil have shown little, if any, benefit. However, some studies have shown doxorubicin chemotherapy to produce occasional responses of metastatic disease (see Section I.C.4).
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Local radiation therapy is useful in some patients as palliative therapy.
Anaplastic thyroid carcinoma. Most anaplastic tumors are unresectable at the time of presentation. A more complete thyroid resection is associated with longer survival than biopsy alone. Combination chemotherapy or chemotherapy plus radiation therapy has shown encouraging results for local control, and few partial and complete remissions have been seen.
Chemotherapy
- Single-agent chemotherapy. The most widely applied cytotoxic agents are doxorubicin, bleomycin, cisplatin, and etoposide. Each of these medications has demonstrated some activity against anaplastic and medullary thyroid carcinomas. Improved survival may be achieved in patients who respond to sequential exposure to these agents. Doxorubicin has proved to be the best single chemotherapeutic agent with the highest response rate.
  - Doxorubicin in a dosage of 60 to 75 mg/m² IV every 3 weeks has resulted in objective responses in 20% to 45% (median 34%) of patients with advanced refractory metastatic thyroid carcinoma. The response rate is probably highest for the medullary type and lowest for undifferentiated thyroid carcinoma. A high single dose of doxorubicin, which should be increased in patients with no response, appears to be essential for a therapeutic effect. Because of its apparently lower cardiotoxicity, epirubicin, although almost as effective as doxorubicin, may be given at higher doses and over longer periods and is therefore preferred by some investigators.
- Combination chemotherapy. Combination chemotherapy usually includes doxorubicin.
  - Cisplatin 40 mg/m² IV plus doxorubicin 60 mg/m² IV every 3 weeks has yielded a higher rate and quality of response than doxorubicin alone. These results included complete remission in 12% of patients, several of whom may be expected to survive for more than 2 years. Toxicity was no worse with the combination therapy. Other combination-chemotherapy regimens are doxorubicin, bleomycin, vincristine, and melphalan, with a response rate of 36%, and doxorubicin, bleomycin, and vincristine, with an improved 64% response rate.
  - Doxorubicin 10 mg/m² IV has been used in combination with external beam radiotherapy 90 minutes before the first radiation treatment and weekly thereafter. In this combination, the radiotherapy was given at a dose of 1.6 Gy/treatment twice a day for 3 consecutive days weekly for 6 weeks. Patients with undifferentiated thyroid carcinoma treated in this manner showed an improvement in the median survival as compared with historical control subjects.
  - Carboplatin 300 mg/m² IV infusion and epirubicin 75 mg/m² IV bolus every 4 to 6 weeks for 6 courses used in a small study in association with rhTSH or thyroxine dose adjustments to stimulate the biological activity of thyroid cancer cells showed improved prognosis over historical controls.
  In general, the highest response is observed in patients with pulmonary metastasis. If anaplastic thyroid carcinoma responds to chemotherapy, a prolongation of the median survival time from 3 to 5 months to 15 to 20 months can be achieved. The benefit of chemotherapy is modest at best; therefore, novel therapies targeting specific tumor signaling pathway are under way. These include angiogenesis inhibitors targeting vascular endothelial growth factors, tyrosine kinase inhibitors which target RET/PTC oncogene signal, proteasome inhibitor (bortezomib), and DNA methylation inhibitor (decitabine). For a list of active trials visit www.clinicaltrials.gov.
Non Hodgkin's lymphoma. Non Hodgkin's lymphoma is more thoroughly addressed in Chapter 23. The discussion here briefly highlights its significance concerning thyroid malignancies. By definition, lymphoma of the thyroid is, at the time of diagnosis, confined to the gland or to the gland and regional lymph nodes. The major histologic type is non Hodgkin's lymphoma. Autoimmune thyroiditis is a predisposing factor. Lymphoma of the thyroid usually presents with rapid enlargement of the gland within a few weeks and is bilateral in 25% of patients. If the tumor is confined to the thyroid, surgical excision alone yields a 5-year survival rate of 70% to 90%. Once the lymphoma extends beyond the thyroid gland, however, surgical therapy does not improve survival, and radiation therapy and chemotherapy are indicated.

II. Adrenal carcinoma

A. Adrenocortical carcinoma (ACC)

Incidence and etiology. ACC is a rare tumor, with fewer than 200 new cases occurring yearly in the United States. It accounts for 0.05% to 0.20% of all cancers and for 0.2% of cancer deaths. It has a prevalence of 2 per 1 million population worldwide. The peak incidence of ACC is during the fourth and fifth decades of life. The incidence in women in most reports is approximately 2.5 times higher than that in men, who tend to be older at diagnosis. Women have a tendency to develop a functional (hormone-secreting) carcinoma, whereas men usually develop a nonfunctional malignancy. There is no family predilection, and no etiologic factors have been established, although loss of genes on chromosome 17 and gene rearrangements on chromosome 11 are associated with ACC. Most cancers are monoclonal, suggesting that a genetic alteration in a progenitor cell contributes to tumorigenesis. Sometimes, it occurs in the context of tumor-predisposing syndromes such as Beckwith-Wiedemann syndrome or LiFraumeni syndrome, which is caused by an inactivating
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mutation in the TP53 tumor suppressor gene on chromosome 17.

Clinical picture. Adrenal carcinoma may present in several modes.

Forty percent to 60% of patients present with functioning tumor, with endocrine signs and symptoms of Cushing's syndrome; virilization, or feminization maybe detected. Such manifestations are due to an increase in the production of a wide variety of steroid hormones. Ten percent of ACCs are associated with virilization and 12% with feminization. Adrenal carcinoma is the cause of 10% of all cases of Cushing's syndrome.
Other frequent presenting symptoms include upper abdominal pain, weight loss, palpable abdominal mass, anorexia, and malaise. Usually, these symptoms are associated with advanced disease.

An abdominal mass maybe detected incidentally by abdominal imaging for some other purpose.

Table 14.2. Diagnosis of malignancy in adrenocortical neoplasms

Reliability	Clinical Criteria	Pathologic Criteria
Diagnostic of malignancy	Weight loss, feminization, nodal or distant metastases	Tumor weight >100 g, tumor necrosis, fibrous bands, vascular invasion, mitoses
Consistent with malignancy	Virilism, Cushing's syndrome and virilism, no hormone production	Nuclear pleomorphism
Suggestive of malignancy	Elevated urinary 17-ketosteroid levels	Capsular invasion
Unreliable	Hypercortisolism, hyperaldosteronism	Tumor giant cells, cytoplasmic size variations, ratio between compact and clear cells
Adapted from Page DL, DeLellis RA, Hough AJ. Tumors of the adrenal. In: Hartmann WH, Sobin LH, eds. Atlas of tumor pathology. Washington, DC: Armed Forces Institute of Pathology, 1986.

Pathology and diagnosis. Most malignant adrenal masses represent carcinomatous metastatic lesions, primarily from the lung and breast. Whether the coincidental finding of an adrenal mass requires complete screening of the patient for a hidden primary adrenal tumor depends on the clinical situation. There may be some difficulty distinguishing adenoma from carcinoma (Table 14.2). CT scan and magnetic resonance imaging (MRI) are helpful in diagnosing ACC. A CT finding of a large unilateral adrenal mass
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with irregular borders and a heterogeneous and hypervascular interior is almost always an indication of adrenal cancer. On MRI, adrenal cancer has intermediate to high signal intensity on T2-weighted images in contrast to benign lesions, which have low signal intensity. In addition, MRI is a helpful tool in delineating ACC before surgery. Iodocholesterol scanning is rarely indicated. It shows poor uptake in carcinomas as compared with adenomas. ACC can be further divided into two categories according to the pathologic patterns of cellular arrangement and the cellular pleomorphism:
- Well-differentiated ACC, which occurs more commonly in women and usually presents with a functioning tumor, and
- Anaplastic ACC, which is more common in men and is often associated with a lack of hormone production.

Staging and prognosis. Most patients (70%) present with stage III or IV disease. ACC is a highly malignant cancer with an overall 5-year mortality rate of 75% to 90%, depending on the stage and morphology of the disease. The most commonly used staging system (derived from the TNM classification system) for ACC is presented in Table 14.3.

Metastases of ACC most commonly occur in the lung (60%), lymph nodes (43%), liver (53%), and bone (10%). The median survival time of patients with well-differentiated carcinoma is 40 months, whereas patients with anaplastic carcinoma have a more dismal median survival time of 5 months. The median survival time of patients with stage I, II, or III disease is 24 to 28 months and for stage IV disease, it is 12 months. Intratumoral hemorrhage, number of mitotic figures per high-power field, and tumor size correlate with survival rates.

Table 14.3. TNM staging system for adrenocortical cancer

Stage	Size (cm)	Nodes or Local Invasion	Metastasis
I	5	-	-
II	>5	-	-
III	Any	+	-
IV	Any	Either present or absent	+
, absent; +, present.

Treatment. Because of the extremely low incidence of this disease, few medical centers have sufficient experience treating it, and an effort should be made to refer these patients to centers that have clinical trials pertaining to this disease. This caveat notwithstanding, several guidelines regarding its treatment can be given.

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- Surgery. In up to half the number of patients, ACCs can be resected, although incompletely in some patients; however, the remainder of patients have either local invasion that is too extensive or metastases to the abdomen, liver, lung, or other locations. Of the patients whose tumors are resected for cure, 40% remain disease free. The remainder die, usually with extensive metastatic disease, within an average of less than 1 year. Patients who undergo complete resection should initially be followed up on a monthly basis (with measurements of steroid levels if they have a functioning tumor) to detect recurrence. Serial MRI may also be used to evaluate for recurrence.
- Radiotherapy. Radiation therapy provides symptomatic relief from pain due to local or metastatic disease, especially bony metastases. It has also been used to prevent local recurrence after surgical resection (40 55 Gy over 4 weeks), but the benefit is uncertain, and there is no proof that it improves survival.
- Chemotherapy. Indications for chemotherapy include recurrent, metastatic, and nonresectable ACC. Agents used are the following:
  - Adrenocortical suppressants
    - Mitotane (o, p'-DDD, Lysodren). An unconventional chemotherapeutic agent and a close chemical relative of the insecticide 1,1-bis (p-chlorophenyl)-2,2,2-trichloroethane (DDT), mitotane has been used to treat ACC since 1960. It inhibits steroid biosynthesis and with prolonged use destroys adrenal cells. The cytotoxic effect of mitotane has been considered transient and inconsistent. Included in its effects is the destruction of the adrenocortical cells. The part that is most affected by this action is the zona reticularis and the least affected is the zona glomerulosa. Forty percent of the medication is absorbed from the gastrointestinal tract. The drug is highly lipid soluble and is subsequently concentrated in both normal and malignant adrenocortical cells. Reports of its plasma half-life range from 18 to 159 days.
      - Dosage and administration. Treatment with mitotane is started at 2 to 6 g/day PO in three divided doses, then gradually increased monthly by 1 g/day until 9 to 10 g/day is reached or until the maximum tolerated dose is achieved with no side effects. Blood levels of o, p'-DDD should be maintained at more than 14 g/mL to demonstrate a therapeutic response. Mitotane serum level was shown in a retrospective study to be the only significant prognostic factor for tumor response. Levels of more than 20 g/mL have a higher incidence of toxicity. Starting at a small dose and increasing it gradually may delay achieving adequate plasma levels;
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        frequently, starting at a higher dose of 6 to 9 g may be tolerated and may shorten the time required to achieve a therapeutic effect.
      - Response and follow-up. Objective tumor regression usually occurs within 6 weeks of the initiation of therapy and is seen in 70% of patients as a decrease in excessive hormone production. However, the reduction in hormone production is not regularly accompanied by an objective tumor response. In approximately 30% to 40% of patients, the tumor size is reduced significantly, but complete remission is unlikely. The median duration of response is 10.5 months. If no clinical benefit is demonstrated at the maximum tolerated dose after 3 months, the case may be considered a clinical failure. Postoperative adjuvant therapy with mitotane has resulted in no improvement in survival. The combination of mitotane and radiation therapy has not conferred any additional benefit over mitotane alone.
      - Side effects. Nausea and vomiting occur in 80% of patients. Severe neurotoxicity, which may occur during long-term treatment, presents as somnolence, depression, ataxia, and weakness in 40% of patients. Reversible diffuse electroencephalographic changes may also occur. Adrenal insufficiency occurs in 50% of patients (without replacement), and dermatitis develops in 20% of patients. Because the maximal dosage is often limited by the severity of, and the patient's tolerance to, the side effects, the total dose may range widely from patient to patient.
      - Glucocorticoid replacement. During mitotane treatment, it is necessary to prevent hypoadrenalism. Replacement can be achieved by administering cortisone acetate 25 mg PO in the morning and 12.5 mg PO in the evening or equivalent glucocorticoid plus fludrocortisone acetate 0.1 mg PO in the morning. Plasma cortisol should be used to monitor adrenal function during mitotane use. If severe trauma or shock develops, mitotane should be discontinued immediately and larger doses of corticosteroids (e.g., hydrocortisone 100 mg t.i.d.) should be administered.
    - Non-responders to mitotane. These patients can be treated with other adrenocortical suppressants including metyrapone (750 mg PO every 4 hours), which reduces cortisol production by inhibiting 11 -hydroxylase. However, this
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      results in accumulation of deoxycorticosterone and can induce hypertension and hypokalemic alkalosis.
      
      Another agent is aminoglutethimide (250 mg PO every 6 hours initially, with a stepwise increase in dosage to a total of 2 g/day or until limiting side effects that resemble those of mitotane appear). The latter drug inhibits conversion of cholesterol to pregnenolone. Neither of these medications has antitumor effects, but they are effective in relieving the signs and symptoms of excessive hormonal secretion. Combining both in smaller doses might reduce the side effects seen in taking higher doses of either agent alone. Another medication that can be used is ketoconazole 600 mg/day. It is a potent adrenal inhibitor that produces clinical alleviation of the signs and symptoms within 4 to 6 weeks. In addition, it may cause regression of pulmonary and hepatic metastases, although the mechanism is not clear. Other drugs that might be of benefit in controlling symptoms include those that block the action of steroids in their target tissues, including antimineralocorticoid and antiandrogenic agents and, more recently, antiglucocorticoid agents such as mifepristone (RU 486). None of these medications has an effect on tumor regression.
  - Cytotoxic chemotherapy. Cytotoxic drugs are usually used in patients who show no response to mitotane. Because of the small number of patients who require such therapy, the experience with this treatment is limited despite many clinical trials. No cytotoxic monotherapy has shown definite effectiveness in the treatment of ACC, although doxorubicin, cisplatin, and suramin have been reported to produce partial responses in patients with metastatic disease.
    - Cisplatin 75 to 100 mg/m² was combined with mitotane 4 g PO daily.
      
      This resulted in a 30% objective response that lasted for 7.9 months. The survival duration in this study was 11.8 months. Few combinationchemotherapy regimens have been effective.
    - Etoposide 100 mg/m² IV on day 1 to 3 plus cisplatin 100 mg/m² IV given in cycles every 4 weeks plus mitotane led to partial remission in 33% of 18 patients with ACC.
    The most used regimen is
    - Etoposide 100mg/m² on days 5 to 7, doxorubicin 20 mg/m² on days 1 and 8, cisplatin 40 mg/m² on days 1 and 9 every 4 weeks, combined with mitotane 4 g/day (EPD + M) for 3 to 8 months.
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    This was associated with approximately 50% response rate. Another frequently used regimen is a combination of streptozotocin 1 g/day for 5 days then 2 g every 3 weeks combined with mitotane 1 to 4 g daily. A third regimen is used as salvage therapy for patients failing the protocolmentioned in the preceding text; this includes vincristine 1.5 mg/m² on day 1, cisplatin 100 mg/m² on day 2, teniposide 150 mg/m² on day 4, and cyclophosphamide 600 mg/m² on day 1 (OPEC) every 4 weeks for 6 months. This salvage regimen improved survival rates as compared to historical controls. Other combinations of natural-product chemotherapy with mitotane are being tested; this may be pharmacologically advantageous because mitotane has been shown to be a multidrug resistance blocking agent. The role of vascular endothelial growth factor inhibitors, thalidomide and tyrosine kinase inhibitors are being evaluated in treatment of ACC as well.
- Arterial embolization. Another modality used for palliation of ACC is arterial embolization. It is used to decrease the bulk of the tumor, suppress tumor function, and relieve pain. Embolic agents used include polyvinyl alcohol foam and surgical gelatin.

B. Pheochromocytoma

Description and diagnosis. Pheochromocytoma is a tumor that arises from chromaffin cells mainly in the adrenal medulla (90% of cases), paraganglia, as well as in other sites (e.g., urinary bladder, heart, and organ of Zuckerkandl). It is an uncommon tumor, with an estimated 800 cases diagnosed in the United States every year. It is found in up to 0.3% of autopsy subjects and is responsible for less than 0.1% to 0.5% of all cases of hypertension. Pheochromocytoma can be hereditary, as part of the MEN syndrome (MEN 2A, MEN 2B), or familial with no other manifestation of the MEN syndrome; when part of the MEN syndrome, it is almost always benign. Also, it may be found as part of von Hippel-Lindau disease, tuberous sclerosis, Sturge-Weber syndrome and Carney's syndrome. The incidence of malignant pheochromocytoma is approximately 10% of all pheochromocytomas. The only definite proof of malignancy is the presence of tumor in secondary sites where chromaffin tissue is not normally present. The diagnosis of pheochromocytoma depends on a thorough history and physical examination, increased catecholamine levels in the plasma and the urine (including epinephrine, norepinephrine, dopamine, and total metanephrines), cross-sectional imaging such as CT or MRI, or [¹³¹I]metaiodobenzylguanidine ([¹³¹I]MIBG) scintigraphy. The overall 5-year survival rate for patients with malignant pheochromocytoma is 36% to 44%. Although pheochromocytoma is a rare tumor, early detection and treatment are crucial, owing to its high morbidity and potential mortality (stroke and myocardial infarction). Patients with pheochromocytoma can present with sustained or episodic hypertension. Hypertension does not usually
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correlate with the amount of catecholamine production, and its severity varies widely among patients.
Treatment
- Surgery. Surgery is the only definitive therapy for pheochromocytoma, for localized and regional unilateral or bilateral disease. Surgery requires careful preoperative preparation to achieve control of the blood pressure, blood volume, and heart rate. Phenoxybenzamine, an -adrenergic receptor blocker, is started 1 to 2 weeks before surgery in a dose of 10 to 20 mg PO three or four times daily. Some patients require the addition of -blockers (e.g., propranolol 80 to 120 mg/day), which are indicated for persistent supraventricular tachycardia or the presence of angina. To prevent hypertensive crisis secondary to unopposed vasoconstriction, the -blocker should never be given before the -antagonist. Other -adrenergic blockers are used for the same purpose, including prazosin, which is a selective 1-antagonist that has also been used successfully for preoperative preparation of pheochromocytoma. Metyrosine 250 mg four times daily (maximum 4 g/day) can also be used, but is associated with frequent side effects. Intraoperatively, blood pressure can be controlled by titration with nitroprusside.
  
  Catecholamine and metanephrine levels should be measured 1 week after surgery to confirm total removal of the tumor. Surgical mortality is estimated to be approximately 2% and usually correlates with the severity of hypertension. Patients whose localized disease is fully resected should have normal life expectancy. Close postoperative follow-up is mandatory because of the possibility of postoperative residual tumor and because 10% of patients have metastasis, and another 10% have multiple primary tumors at the time of diagnosis.
  
  Follow-up should include a history, physical examination, and catecholamine and metanephrine measurements at 3 months, followed by a similar evaluation yearly for life. Redevelopment of any sign or symptom suggesting pheochromocytoma or a rising trend in catecholamine levels requires imaging, including [¹³¹I]MIBG scintigraphy. A few centers recommend that [¹³¹I]MIBG scintigraphy be done yearly, regardless of the catecholamine levels or the clinical picture; this is not frequently practiced in the United States. The recurrence rate of pheochromocytoma postoperatively is 5% per year. Contralateral adrenalectomy of a normal gland is generally not recommended in patients with a high incidence of bilateral disease (e.g., MEN 2), despite the high risk of subsequent involvement. In patients with metastatic disease, there is no evidence to support improved survival after local debulking.
- Chemotherapy. This is reserved for locally invasive, metastatic, and inoperable lesions. Response to chemotherapy or radiotherapy is evaluated by regression of tumor size and a decrease in the catecholamine levels. Owing to the small number of patients with
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  pheochromocytoma, limited data are available regarding the effect of chemotherapy. Because of the functional and biologic similarities between pheochromocytoma and neuroblastoma, the combination of cyclophosphamide and dacarbazine, which induces an 80% response in neuroblastoma, was used in two series to treat pheochromocytoma. The chemotherapy regimen consisted of cyclophosphamide 750 mg/m² IV plus vincristine 1.4 mg/m² IV on day 1 and dacarbazine 600 mg/m² IV on days 1 and 2; it was repeated in 21- to 28-day cycles.
  
  Analysis of 23 patients showed objective tumor size regression in 61% of patients, and the urinary catecholamine levels decreased in 74% of patients. The median response time averaged 28 months. Improvement of blood pressure control and performance status occurred with minimal toxicity. Because streptozocin has yielded favorable results in the treatment of neuroendocrine tumor in the gastrointestinal tract, it was used as a single agent in a patient with malignant pheochromocytoma. Streptozocin showed promising results, with a 73% reduction in urinary vanillylmandelic acid level and significant tumor size regression.
- Radiation therapy. [¹³¹I]MIBG is actively taken up and concentrated by pheochromocytoma cells with high sensitivity and specificity. Consequently, a high dose of [¹³¹I]MIBG is used to treat pheochromocytoma. This treatment has shown some evidence of response in terms of tumor size regression and decreased catecholamine levels. The uptake of [¹³¹I] MIBG by pheochromocytoma requires the presence of an active neuronal pump mechanism, which limits the use of this agent to patients with pheochromocytoma who have the ability to concentrate [¹³¹I]MIBG in the cells. Therefore, initial screening of the ability of the pheochromocytoma to concentrate small doses of [¹³¹I]MIBG is necessary to determine the probable efficacy of the treatment. High doses such as 800 mCi (37 MBq) have been used in a small study, achieving complete response in three patients; two had prior evidence of skeletal and soft tissue metastasis. In addition, combination [¹³¹I]MIBG and chemotherapy produced additive effects in reducing tumor burden. External radiation to doses of 4,000 to 5,000 cGy over 4 to 5 weeks may provide local control to an inoperable tumor and may be used to control local bone metastasis.
- Supportive pharmacologic therapy. -Blockers should be used to prevent severe hypertension-related morbidity and mortality, especially in untreated patients and those receiving chemotherapy. Another pharmacologic agent that can be used is -methyl-L-tyrosine (metyrosine), which inhibits tyrosine hydroxylase, a rate-limiting step in catecholamine biosynthesis. Metyrosine allows the use of lower doses of -blockers and has been shown to be effective in catecholamine-induced cardiomyopathy. Other medications include -blockers,
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  which are used to control arrhythmia, angiotensin-converting enzyme inhibitors, and calcium-channel blockers, which are also used for hypertension control as discussed previously.