Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

13. Thyroid and Adrenal Carcinomas

Haitham S. Abu-Lebdeh, Michael E. Menefee, and Keith C. Bible

Endocrine cancers account for 2.7% of all newly diagnosed cancers but only 0.44% of cancer deaths in the United States, largely due to the overall good prognosis of the most common endocrine malignancy, differentiated thyroid cancer. Thyroid cancers account for almost 95% of endocrine cancers and for two-thirds of the deaths from this group of diseases. Although the efficacy of cytotoxic chemotherapy is limited in differentiated thyroid cancers, it has an established role in anaplastic thyroid cancer, adrenocortical cancer, and pheochromocytoma/paraganglioma. Moreover, novel therapeutics—in particular tyrosine kinase inhibitors (TKIs)—have emerged as promising approaches to treating several endocrine cancers. Here, thyroid and adrenal neoplasms are discussed with emphasis on individualizing therapy for patients afflicted with these diseases. Neuroendocrine cancers, in particular pancreatic islet cell carcinomas (as well as other pancreatic malignancies), are discussed separately in Chapter 8.

I. THYROID CARCINOMA

A. Background

1. Incidence. About 37,000 new cases of thyroid carcinoma are diagnosed in the United States annually, accounting for approximately 1600 deaths. The incidence of thyroid carcinoma is now about 9 per 100,000, with approximately 2.7 times as many women as men affected. The peak incidence is at age 40 for women and age 60 for men. Thyroid cancers are increasing—in women at >5% per year; mortality is also up by one-third in the last decade, suggesting that the increasing incidence is real and not due to better screening/detection. Thyroid carcinoma is now over twice as common in the United States as it was 10 years ago, and it is now the seventh most common cancer in U.S. women.

2. Etiology and prevention. In most patients, the cause of thyroid carcinoma is unknown, but prior remote head and neck radiation exposure, hereditary factors, and/or preceding autoimmune thyroid disease are implicated in some patients. Radiation to the neck during childhood for diseases including Hodgkin lymphoma, enlarged thymus, or even skin diseases such as acne can be causative. Thyroid cancer has been observed 20 to 25 years after radiation exposure among atomic bomb survivors, and in some regions of Japan the incidence of thyroid cancer in screened populations is as high as 0.1%—10-fold greater than expected based on U.S. incidence rates. In cases of accidental radioisotope exposure, expeditious use of potassium iodide can block the thyroid uptake of radioactive iodine (RAI).

Some cases of thyroid carcinoma are familial. Medullary thyroid cancer (MTC) is seen in multiple endocrine neoplasia (MEN) syndrome types 2A and 2B and in the familial MTC (FMTC) syndrome associated with germline mutation of the RET proto-oncogene. In these syndromes, prophylactic thyroidectomy should be undertaken in at-risk individuals at young ages. Furthermore, there are kindreds of patients with increased heritable risk of differentiated thyroid cancers, known as familial non-MTC, but such kindreds are uncommon.

Prolonged stimulation by thyroid-stimulating hormone (TSH), as seen in endemic goiter and autoimmune thyroid disease, may also lead to the development of thyroid carcinoma. As autoimmune thyroid disease is more prevalent in women, this may in part explain why thyroid cancer is so much more common in women than men. Further, this may also help explain why many patients with thyroid cancer relate a family history of autoimmune thyroid disease and suffer from autoimmune thyroid disease themselves.

3. Histologic types. The most common types of thyroid carcinoma are as follows.

a. Differentiated thyroid cancer (DTC; 88%). DTC includes papillary thyroid cancer (PTC; 85%), follicular thyroid cancer (FTC; 12%), and Hürthle cell (3%) subtypes. DTCs are derived from thyroglobulin-producing follicular cells (thyrocytes) and are typically initially RAI responsive. Hürthle cell carcinoma, a histological variant of FTC often of more aggressive behavior, has variously been subsumed under the FTC classification rather than being considered a unique histotype. RET/PTC gene rearrangements or RAS, BRAF, or MEK-ERK pathway mutations are present in 70% of PTCs, and upregulation of vascular endothelial growth factor (VEGF) signaling is also common in metastatic disease. FTC may be associated with RAS mutations and mutations on chromosome 3 (pax8-PPAR mutations). DTCs most often secrete thyroglobulin; hence, it can be used as a tumor marker in antithyroglobulin antibody–negative patients.

b. Medullary thyroid cancer (UTC; 4%). MTCs are derived from thyroid parafollicular or C cells, the source of the hormone calcitonin. Activating mutations of the RET proto-oncogene are characteristic, with germ line activating RET mutations as seen in FMTC and MEN2 a predisposing factor. MTC most often produces both immunoreactive calcitonin and carcino-embryonic antigen, which can be used as tumor markers.

c. Anaplastic thyroid cancer (ATC; 2%). ATC is the most aggressive of all thyroid cancers, with only about 10% historical 1-year survival from diagnosis. ATC can arise de novo, but is generally thought to result from thyrocytes via dedifferentiation in DTC tumors. ATC (grade 4 thyroid cancer) is distinguished from the undifferentiated histotype (grade 3) in part by loss of TTF-1 expression, and abnormalities in p53 signaling are also common.

d. Thyroid lymphoma (5%). Thyroid lymphomas are uncommon and represent cancers of lymphoid tissues, as discussed in Chapters 21 and 22.

e. Thyroid sarcoma (1%). Thyroid sarcomas are also rare, and they should be treated in accordance with their underlying histology, as discussed in Chapter 16.

f. Squamous cell carcinoma of the thyroid (1%). Rarely, squamous cell cancers arise in the thyroid; they are best treated as in head and neck primary squamous cell carcinoma (see Chapter 5).

4. Prognosis

a. Cell types/histology. PTCs and mixed PTC/FTCs have similar, generally favorable biologic and prognostic behaviors. Most DTCs grow slowly, with recurrence risk 0.5% to 1.6% per year, and with less than 15% mortality at 20 years. Even patients with lung metastases have a 20-year survival rate exceeding 50%.

Pure FTCs have a somewhat worse prognosis than cancers with papillary elements, with 10-year survival in FTC and PTC at 85% and 93%, respectively. Recent studies have shown that FTCs with vascular invasion have a relatively worse prognosis, whereas FTC patients without vascular invasion do almost as well as PTC patients.

About 25% of MTCs are familial, as part of three clinical syndromes (MEN-IIa, MEN-IIb, and familial non-MEN MTC). Regional nodal and distant metastases are more common and occur in early stages of the disease in MTC, with 10-year survival after surgical resection of MTC at 40% to 60%.

Patients with ATC have an abysmal prognosis, with a median survival of only 4 months and a historical 10% survival 1 year from diagnosis.

b. Other factors. Prognosis is worse if tumor size is >4 cm, patient age >40 years of age and/or male gender, distant metastases are present, and/or DNA content is aneuploid. DTC tends to metastasize first to lymph nodes, then to lung, and somewhat less commonly bone—with 5-, 10-, and 15-year survivals of 53%, 38%, and 30%, respectively. Other sites of metastases in DTC include subcutaneous structures, liver, and also brain. In contrast to most other cancers, limited regional lymph node metastasis of DTC does not influence survival substantially, and radiation-induced DTC is not associated with a worse prognosis.

Several systems are used to predict outcomes in DTC, including for example, the MACIS scoring system (metastases, +3 if metastases; age, ≤39 years of age = 3.1, >40 = age in years × 0.08; completeness of resection, +1 if primary resection is incomplete; invasion, +1 if pathologically invasive; and size, 0.3 × largest dimension in centimeters) with median prognosis estimated based on the total score as indicated in Table 13.1.

B. Diagnosis and staging

Although physical examination is the primary screening modality for the detection of thyroid cancer, in populations at increased risk, neck ultrasound is an important supplemental approach. Any solitary thyroid nodule should be considered malignant until proved otherwise. Although toxic nodular goiters are less likely to contain carcinoma, a nodule in the setting of hyperthyroidism does not preclude malignancy.

Because most thyroid tumors spread primarily by local extension and regional nodal metastasis, assessment of the extent of disease in the neck is critical. In recent years, ultrasound has become integrated into endocrinology practices and is very helpful in assessing risk of cancer, and in facilitating expeditious outpatient fine needle aspiration (FNA) of suspicious thyroid nodules. FNA does not require local anesthesia and is considered safer and easier to perform than core biopsy, with accuracy between 50% and 97%, depending on the type of cancer, the experience of the pathologist, and the institution; however, there are times when formal core biopsies are required, including when lymphoma is suspected.

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Diagnostic RAI imaging is not now commonly used in the primary assessment of thyroid nodules, but remains a mainstay of assessment in patients with high-risk disease or with metastatic radioiodine-avid DTC after primary surgery. Chest radiography should be performed before surgery to rule out macroscopic pulmonary metastasis. If there is any clinical or laboratory suggestion of bone or other metastases, skeletal radiographs, computed tomography (CT) scan, positron emission tomography (PET) scan, and/or a radionuclide bone scan should be considered on a case-by-case basis.

Several issues should also be kept in mind in assessing disease extent and response to therapy. First, iodinated contrast materials should not be used in any DTC patients who may be candidates for therapeutic radioiodine, as the iodine load can saturate tumor binding sites and thereby render therapeutic RAI ineffective. In general, a 2-month delay of RAI is preferred after any iodinated contrast. Second, anatomic imaging in surveillance of patients and in following disease course is important. In DTC for instance, a negative iodine/thyroid scan does not exclude the possibility of metastatic disease, as small pulmonary nodules often escape detection using this modality. Further, some DTCs will become radioiodine refractory and will not image even in the presence of bulky metastases. Third, although tumor markers can be very helpful in patient surveillance in the postoperative setting in DTC and MTC, they must be used judiciously. Thyroglobulin can be neutralized by patient antithyroglobulin antibodies, and therefore the two tests should always be measured in tandem. If antithyroglobulin antibody is elevated, thyroglobulin levels are uninterpretable. Moreover, with time and interval therapies, thyroglobulin production by DTCs diminishes concordant with tumor dedifferentiation, thereby yielding misleading results and again emphasizing the importance of anatomic imaging in high-risk patients or those with advanced disease. Thyroglobulin levels are also less predictable in estimating disease extent in patients receiving novel therapies.

Also worthy of comment is that PET imaging should be used judiciously in thyroid cancer. In ATC, PET can be very helpful; however, some DTCs do not image well via PET. In DTC, PET avidity tends to correlate with more aggressive tumor behavior.

Patients with thyroid carcinoma are typically euthyroid; however, elevated TSH with increased thyroid peroxidase antibodies may be seen with Hashimoto thyroiditis, which may coexist in 20% of patients with thyroid lymphoma and also sometimes in DTC.

The most widely accepted tumor staging system, TNM, uses tumor size and extent, presence of lymph node spread, and distant metastasis (Table 13.2). Any ATC is considered stage IV (A, B, or C), and there are no TNM stage III or IV patients with DTC who are younger than 45 years. This staging system is suboptimal in thyroid cancer, prompting use of algorithms such as the MACIS system discussed above.

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C. Treatment

Therapeutic approach in thyroid cancer depends considerably on the histologic type, extent of disease, patient symptoms, and rate of disease progression. Careful management of disease residing in the neck so as to protect airway, esophagus, and other critical structures is also of paramount importance.

1. Differentiated thyroid cancer (DTC)

a. Surgery. Bilateral near-total or total thyroidectomy is the best initial approach in thyroid cancer, taking into consideration that with DTC the incidence of disease in the contralateral lobe is 20% to 87%. Further, total thyroidectomy is conducive to RAI surveillance, and simplifies follow-up in patients with high-risk disease. Limited lymph node involvement does not influence survival but is associated with an increase in local recurrence risk; 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 consequent to thyroidectomy in DTC is extremely low. Complications include recurrent laryngeal nerve damage that is permanent in 2% of patients and hypoparathyroidism that is lifelong in 1% to 2% of patients.

b. TSH suppression. TSH suppression via administration of “supratherapeutic” levothyroxine is an essential component in the treatment of high-risk DTC, as residual cancer cells are usually initially responsive to TSH growth stimulation. Levothyroxine (T4, usual dosage range 125 to 200 μg by mouth daily) is administered to keep the TSH level suppressed below 0.1 mIU/L in high-risk patients, including those with systemic metastases and/or residual disease following surgery. However, suppression of TSH below 0.1 mIU/L imposes long-term adverse effects on bone and can negatively impact quality of life, sometimes producing symptoms of thyrotoxicosis. Angina can also be provoked by suppressive dosage levothyroxine, as can tachycardia or sometimes even frank cardiac arrhythmia, so care must be used in the selection of patients in whom the risks of aggressive TSH suppression is justified.

c. Radiotherapy—RAI. Radiation can be applied in two general ways in the treatment of DTC: systemic RAI versus focal external beam or stereotactic radiotherapy. Destruction of residual normal thyroid tissue after thyroidectomy with RAI (131I) is termed radioactive remnant ablation (RRA). RRA is different from “RAI therapy”; in RAI therapy, larger doses of RAI are used to attempt to destroy persistent cancer, whereas RRA is used to eliminate residual normal thyroid tissue remaining after primary surgery. RRA is widely used in practice in the United States following thyroidectomy, but there has recently been increased scrutiny of the prudence of RRA in patients with anticipated excellent long-term prognosis as estimated using the prognostic algorithms (e.g., MACIS).

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 and also improves the utility of thyroglobulin in the detection of residual thyroid cancer (as remnant thyroid tissue is destroyed). An RRA dose of 30 mCi (1110 MBq) to 150 mCi (5550 MBq) is commonly used, with the lower dose of 30 mCi more typical, with an estimated 6 rem whole body exposure. For patients who are at a low risk of tumor recurrence, remnant ablation is controversial.

Treatment with RAI (131I) is usually recommended for patients with DTC and known postoperative residual disease, patients with distant metastases, and/or 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 commonly given (3700 to 6475 MBq). Locally invasive cancer that is not completely resected is alternatively often treated with 150 to 200 mCi of RAI (5550 to 7400 MBq), while patients with distant metastasis are treated with 200 to 250 or even 300 mCi (7400 MBq). The potential exception to this schema is lung metastasis; a dose of up to 80 mCi of RAI (2960 MBq)whole body retention by dosimetry at 48 hours is generally used to avoid radiation-induced pulmonary fibrosis.

Effective and safe use of RAI treatment requires that tumor cells that are capable of concentrating iodide (i.e., DTC), and appropriate patient preparation to bring TSH levels up by either temporarily withholding thyroid hormone administration or via administration of recombinant TSH is necessary. In the former situation, due to its long half life, T4 is discontinued and T3 is initiated for a period of 6 weeks prior to the scan, with all thyroid medication withheld in the 2-week period prior to RAI administration. Ideally, TSH of 25 to 30 (μm/mL is required for successful ablation or radiotherapy. Alternatively, recombinant TSH can be used to stimulate thyroid cell uptake of RAI in the absence of T4 withdrawal; this approach maintains better quality of life but adds considerably to expense. A low iodine diet is also required for RAI efficacy, as dietary iodine can compete with RAI for uptake in normal thyrocytes and tumor and thereby reduce RAI therapeutic efficacy. Compliance with a low iodine diet is assessed via measurement of 24-hour urinary iodine excretion.

Patients receiving high dose RAI (150 to 300 mCi) must be treated at centers with special lead-lined containment rooms, with monitoring of treated patients to assure compliance with environmental radiation safety regulations and patient and population safety. The duration of hospitalization depends on the dose given, posttherapy method of transportation home, and contact of patient with the general public. Potential side effects of RAI include temporary bone marrow suppression (this can last weeks or even months with repeated high RAI dosage), transient nausea, sialoadenitis/dry mouth (with possible permanent cessation of salivary flow), skin reaction over the tissue concentrating the radioiodine, and pulmonary fibrosis. The use of very high cumulative RAI doses (usually when approaching 1000 mCi) have also rarely been associated with acute myelogenous leukemia, as well as rarely with bladder and breast cancers. Scintigraphy should be performed 4 to 10 days after RAI therapy to assess uptake of RAI by tumor and to detect residual carcinoma perhaps not otherwise seen using other imaging approaches.

d. Radiotherapy—focal approaches including external beam radiotherapy. The role of external radiation therapy in DTC is limited to treating progressive residual locoregional tumor in the neck that does not concentrate iodine and that is otherwise not amenable to effective surgery. External beam radiotherapy is also used for localized painful bony metastasis or other locally threatening disease. Stereotactic radiosurgical approaches (Gamma Knife, Elekta, Stockholm, Sweden; CyberKnife, Accuray, Sunnyvale, CA) are also used in patients with recurrent cancer at previously irradiated sites and when tumors are proximal to critical radiation-sensitive tumors.

e. Systemic therapies. Systemic cytotoxic chemotherapy has produced disappointing results in DTC. Recently, VEGF-receptor-inhibitory TKIs (e.g., sunitinib, sorafenib, pazopanib) have shown promise in phase II clinical trials. Although partial response rates as assessed by Response Evaluation Criteria in Solid Tumors criteria range from 20% to 50% using these agents, no survival advantage from use of TKIs in DTC patients has yet been demonstrated. Expert consensus nevertheless presently favors selective use of TKIs in treating patients with imminently threatening rapidly progressive metastatic DTC, and it is best in conjunction with a clinical trial.

2. Medullary thyroid cancer (MTC)

a. Surgery. MTC, like DTC, is best treated initially with surgery—with the caveat that patients with FMTC syndromes should be subject to early prophylactic thyroidectomy.

b. Radiotherapy. As MTC does not uptake iodine, RAI has no role. Locoregional radiation therapy, however, is useful in some patients as palliative therapy, as discussed previously.

c. Systemic therapies. Suppressive levothyroxine therapyis of no benefit in MTC. As MTC most often harbors receptors for somatostatin, somatostatin analogues such as octreotide have been preliminarily tested as therapeutic in MTC. The precise extent of benefit to be attained from the use of therapeutic octreotide in MTC remains uncertain; however, some patients appear to gain benefit.

Recently, orally bioavailable TKIs (e.g., vandetanib, sunitinib, sorafenib, pazopanib) that inhibit RET have been tested in phase II and III clinical trials in MTC, with promising initial results. Prolonged disease stabilization as well as impressive clinical responses have been reported, but impact on survival has not yet been established. Expert consensus supports the selective application of TKIs in patients with rapidly progressive imminently threatening MTC, and it is best in conjunction with ongoing clinical trials.

3. Anaplastic thyroid cancer (ATC) has been historically associated with only 10% overall survival 1 year from diagnosis. As a result, improved therapies are sorely needed. Although locoregional recurrence is a major issue, most deaths result primarily from systemic disease.

a. Surgery. Surgery alone is seldom curative in ATC, and when undertaken should be followed at least by locoregional radiotherapy. Surgery also has an uncertain role in treating patients with stage 4C (metastatic) disease. In locoregionally confined disease (stage 4A/B), surgery has the potential to protect vital structures within the neck otherwise imminently threatened by tumor invasion and should be considered.

b. Radiotherapy. Radiotherapy has an established role in the locoregional treatment of ATC. In stage 4C ATC, where no possibility of cure is anticipated, radiotherapy represents an attractive alternative to surgery, and it is best to use an accelerated regimen.

In stage 4A and 4B disease where a “curative intent” approach is elected, a more protracted radiation therapy course best utilizing intensity modulated radiation therapy (IMRT) should be strongly considered. In this latter circumstance, administration of concomitant radiosensitizing chemotherapy should be considered, as chemotherapy has the potential also to treat occult systemic disease.

c. Systemic therapies for ATC. Discouragingly, ATC is almost universally disseminated when diagnosed, accounting for its dire prognosis even when apparently only regionally spread. Most (about 60%) of all ATCs are unresectable or metastatic at the time of presentation.

(1) Single-agent chemotherapy. The two classes of cytotoxic agents with the greatest evidence in support of efficacy in ATC are anthracyclines (e.g., doxorubicin) and taxanes (e.g., paclitaxel), each with response rates in advanced disease as high as 50%. Improved survival may be achieved in patients with advanced disease who respond to these agents. Furthermore, there is accumulating rationale that the use of these agents in combination with IMRT in the adjuvant setting may also extend survival.

bullDoxorubicin at a dosage of 60 to 75 mg/m2 intravenously (IV) every 3 weeks has resulted in objective responses in 20% to 45% (median, 34%) in patients with advanced ATC. Alternatively, weekly doxorubicin at a dosage of 20 mg/m2 IV is similarly or perhaps even slightly more effective—and preferred in debilitated patients.

bull Taxanes (paclitaxel and docetaxel) also have activity in ATC, with paclitaxel (60 to 90 mg/m2/week) shown to have a transient response rate of 53%.

bull Novel agents including combretastatin and TKIs (e.g., sunitinib, sorafenib, pazopanib) have also produced anecdotal responses in phase II ATC trials, and are currently under active evaluation as candidate ATC therapeutics, especially combined with cytotoxins. In particular, TKIs produce frequent clinical responses in DTC and are considered emerging therapeutics in these cancers.

(2) Combination chemotherapy. Combination chemotherapy has been used in ATC, but it is uncertain whether multiagent therapy impacts survival more than single-agent therapies.

bull Cisplatin 50 mg/m2 IV plus doxorubicin 50 mg/m2 IV every 3 weeks is sometimes used in ATC but has not yet been shown to improve survival over single agents.

bull Doxorubicin 50 mg/m2 IV combined with docetaxel 50 mg/m2 IV (with growth factor support) administered every 3 weeks has also been used in advanced ATC, as has doxorubicin 50 mg/m2 IV combined with paclitaxel 220 mg/m2 IV administered every 3 weeks. However, combination therapy carries higher risk and side effects than monotherapy, and has not yet been shown to have a survival advantage in ATC.

At present, even if a patient with advanced ATC responds to chemotherapy, a prolongation of the median survival time by several months is generally all that can be achieved. Therefore, novel therapies should be strongly considered, with particular interest presently in combination regimens involving either TKIs or combretastatin. For a list of active trials visit www.clinicaltrials.gov.

II. ADRENAL CARCINOMA

A. Adrenal cortical carcinoma (ACC)

1. Incidence and etiology. ACC is a rare tumor, with approximately 300 new cases occurring annually in the United States. It accounts for 0.05% to 0.2% of all cancers and for 0.2% of cancer deaths. It has a prevalence of 0.5 to 2 per 1 million of the population worldwide. There is a bimodal distribution with the overwhelming majority of patients being affected during the fourth and fifth decades of life. However, a second peak can be seen in the pediatric population in children under the age of 5 years, and adults of any age can be affected. The incidence in women is slightly higher than in men (1.2:1.0). Tumors can be either functional (hormone-producing) or nonfunctional. Functional tumors are more common in women, but also occur commonly in men. The overwhelming majority of ACC cases are sporadic; however, this malignancy can occur more frequently in certain genetic syndromes including Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, MEN-1, and familial adenomatous polyposis. There have been no clear and consistent, modifiable lifestyle risk factors that have been identified that influence the risk of developing ACC.

2. Clinical manifestations. Adrenal carcinoma may present in several modes.

a. Hormonal excess. Forty to sixty percent of patients present with a functioning tumor, with signs and symptoms of hypercortisolism (20% to 40%), and virilization (40% to 50%) being the most common with feminization (10%) and hyperaldosteronism (1%) occurring much less frequently. Many ACC patients may have elevated adrenal hormones without overt clinical signs of excess.

b. Abdominal mass. An adrenal mass may present as a palpable or, more rarely, visible lesion in a patient with a large mass and a thin body habitus. More often, the mass is either detected during an evaluation for the presence of unexplained abdominal pain or due to signs or symptoms of hormonal excess or constitutional symptoms (weight loss, anorexia, malaise, fatigue) that are suggestive of an underlying malignancy. An adrenal mass may also be detected as an incidental finding when abdominal imaging for some other purpose is being performed.

3. Pathology and diagnosis. Most malignant adrenal masses represent metastatic lesions from another primary cancer. The greater diagnostic dilemma is created by the presence of a solitary adrenal nodule or mass. While there are radiographic criteria that can help distinguish benign adrenal lesions from malignant ones, these are not absolute. Furthermore, it can be very difficult to discern an adrenal adenoma from ACC based on tumor histology alone. CT scans and magnetic resonance imaging (MRI) are helpful in diagnosing ACC. A CT scan finding of a large unilateral adrenal mass 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. Furthermore, MRI is a helpful tool in detecting vascular invasion. PET scans have demonstrated some promise in the staging and follow-up of patients with ACC. Other nuclear traces, such as (11)C-metomidate, also are very sensitive and specific for the identification of adrenal cortical tumors, but are not routinely available for clinical use.

Histologically, differentiating ACC from clear cell renal cell carcinoma can also prove challenging without the appropriate clinical background. The molecular pathogenesis is not as well defined for ACC as it is with other solid tumors, in part due to its rarity. Nonetheless, some studies have detected genetic alterations in patients with familial ACC which may also be relevant in sporadic forms of ACC. In particular, mutations in beta catenin, the insulinlike growth factor pathways, and p53 have been identified as mutated and overexpressed in ACC, and to a lesser degree, adrenal adenomas.

4. Staging and prognosis. The most commonly used staging system (derived from the TNM classification system) for ACC is presented in Table 13.3.

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 ACC 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 12 months. Intratumoral hemorrhage, number of mitotic figures per high-power field, and tumor size correlate with survival rates.

5. Treatment. Due to the extremely low incidence of this disease, few clinicians or 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.

a. Surgery. Surgical resection provides the best opportunity for cure or prolonged survival for patients who have localized disease. Furthermore, patients who have metastatic disease that is amenable to surgical resection and who undergo successful metastasectomy have improved survivals compared to those receiving systemic therapy. This is a paradigm shift from the typical oncology patient with metastatic disease for whom surgery is usually not a consideration. That said, many patients have either local invasion that is too extensive or metastases that cannot be resected who will require systemic therapy.

Surgery for the primary tumor should be performed, ideally, by a surgeon with a great deal of experience resecting ACCs. An area of evolving controversy is the role of laparoscopic resection for adrenal masses. Until data mature from ongoing trials evaluating open versus laparoscopic adrenalectomy, open should remain the standard of care.

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b. 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 to 55 Gy over 4 weeks), but the benefit is uncertain, and there is no proof that it improves survival.

c. Systemic therapy. Systemic therapy for ACC consists of controlling excessive hormonal production, in appropriate patients, and treating the carcinoma with cytotoxic therapy. ACC has historically been refractory to many chemotherapeutics, in part due to its high expression of drug-resistance proteins. Nevertheless, progress has been made with the use of combination chemotherapy. Indications for chemotherapy include recurrent, metastatic, and nonresectable ACC. Agents used are the following.

(1) Adrenal cortical suppressants

(a) Mitotane (o,p′-DDD; Lysodren) has been used to treat ACC since 1960. It inhibits steroid biosynthesis and, with prolonged use, destroys adrenal cells. The cytotoxic effects of mitotane against ACC are not well established. Much of the benefit derived from mitotane is primarily due to its adrenolytic effects and subsequent reduction in excessive hormone production. Now that many ACC patients are diagnosed at earlier stages, the effects of mitotane for advanced disease are less certain and cytotoxic agents are usually warranted, although often mitotane remains a part of the therapeutic strategy. The drug is highly lipid soluble and is subsequently concentrated in both normal and malignant adrenal cortical cells. Reports of its plasma half-life range from 18 to 159 days.

(i) Dosage and administration. Treatment with mitotane is started at 2 to 6 g/day by mouth 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 between 14 and 20 μg/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 (μg/mL have a higher incidence of toxicity. Starting at a small dose and increasing it gradually may delay achieving adequate plasma levels; frequently, starting at a higher dose of 6 to 9 grams may be tolerated and may shorten the time required to achieve therapeutic effect.

(ii) 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.

(iii) Glucocorticoid replacement. During mitotane treatment, it is necessary to provide replacement therapy for the adrenal insufficiency that is induced by mitotane. Therapy will often need to be maintained for several weeks to months after mitotane is discontinued until adrenal function returns. Replacement can be achieved by administering the equivalent of hydrocortisone 20 mg orally in the morning and 10 mg in the evening. 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 three times a day) should be administered. Fludrocortisone may also be required to maintain adequate mineralocorticoid homeostasis.

(b) Alternative adrenal cortical suppressants. Many patients cannot tolerate mitotane at a dose sufficient to achieve therapeutic levels. These patients can be treated with other adrenal cortical suppressants including metyrapone (750 mg by mouth every 4 hours), which reduces cortisol production by inhibiting 11β-hydroxylase. However, this results in accumulation of deoxycorticosterone and can induce hypertension and hypokalemic alkalosis.

Another agent is aminoglutethimide (250 mg by mouth 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). Aminoglutethimide 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 up to 800 mg/day. It is a potent adrenal inhibitor that produces clinical alleviation of the signs and symptoms within 4 to 6 weeks.

(2) Cytotoxic chemotherapy. Very few patients will have a sustained, objective response to single-agent mitotane. More commonly, cytotoxic drugs are being used in patients who show no response to mitotane or in combination with mitotane in the first-line setting. The optimal regimen has not clearly been identified; however, cisplatin-containing regimens have consistently demonstrated the greatest activity.

The most commonly used regimen is etoposide 100 mg/m2 IV on days 5 to 7, doxorubicin 20 mg/m2 on days 1 and 8, and cisplatin 40 mg/m2 on days 1 and 9 every 4 weeks, combined with mitotane 4 gm/day for 3 to 8 months. This resulted in objective response in almost 50% of patients treated during a phase II clinical trial; an international, randomized, phase II study is ongoing to confirm this benefit. For patients with marginal performance status who may not be a candidate for triple therapy or doxorubicin, single-agent cisplatin or a platinum doublet, most commonly with etoposide, or an agent such gemcitabine, can be considered.

bull Cisplatin 75 to 100 mg/m2 was combined with mitotane 4 g by mouth daily. This resulted in a 30% objective response that lasted for 7.9 months. The survival duration in this study was 11.8 months.

bull Etoposide 100 mg/m2 IV on days 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.

Another regimen that was used frequently in the past and still can be considered for refractory patients is a combination of streptozocin 1 gm/day by mouth for 5 days then 2 gm every 3 weeks combined with mitotane 1 to 4 gm by mouth daily. Clinical trials are of high priority in this patient population due to a lack of durable, effective regimens.

d. Alternative modalities

(1) 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.

(2) Thermal ablation. Both cryoablation and radiofrequency ablation have been used to palliate patients with oligometastasis. These procedures can be limited by the location and size of the tumors.

III. PHEOCHROMOCYTOMA AND PARAGANGLIOMA

A. Description and diagnosis

Pheochromocytomas arises from chromaffin cells mainly in the adrenal medulla (90% of cases), whereas paraganglias are histologically indistinguishable tumors that arise at other sites (e.g., carotid body/skull base, urinary bladder, heart, and organ of Zuckerkandl). About 800 cases are diagnosed in the United States every year, and although it is found in up to 0.3% of autopsy subjects, it is responsible for less than 0.5% of all cases of hypertension. Pheochromocytoma can be hereditary, as part of the MEN syndrome (MEN-IIa, MEN-IIb), or familial with no other manifestation of the MEN syndrome. When part of the MEN syndrome, it is almost always benign. It may also occur in conjunction with Von Hippel-Lindau disease, tuberous sclerosis, Sturge-Weber syndrome, and Carney syndrome. Patients with pheochromocytoma can present with sustained or episodic hypertension, but hypertension does not usually correlate with the amount of catecholamine production. The diagnosis of pheochromocytoma relies 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, and/or [131I]metaiodobenzylguanidine (MIBG) scintigraphy. Although pheochromocytoma is a rare tumor, early detection and treatment are crucial, owing to its high morbidity and potential mortality (stroke, myocardial infarction). The incidence of malignancy is about 10%, with the only definite proof of malignancy being metastatic disease, as there are no definitive histopathologic criteria for malignancy. The overall 5-year survival rate for patients with malignant pheochromocytoma is 36% to 44%.

B. Treatment

1. Surgery. Surgery, the only definitive therapy for pheochromocytoma, requires careful preoperative preparation to achieve control of blood pressure and prevent hypertensive crisis and potentially fatal outcome from surgery. Phenoxybenzamine, an α-adrenergic receptor blocker, is started 1 to 2 weeks before surgery in a dose of 10 to 20 mg by mouth three or four times daily. Many patients require the addition of β-blockers, which are indicated for persistent tachycardia; however, to prevent hypertensive crisis secondary to unopposed vasoconstriction, β-blockers should not be given before α-antagonists.Other α-adrenergic blockers including prazosin, a selective α1-antagonist, have also been used successfully for preoperative preparation of pheochromocytoma. Metyrosine 250 mg 4 times daily (maximum 4 gm/day) can also be used but is associated with frequent side effects. Intraoperatively, blood pressure can be controlled by titration with nitroprusside. Surgical isolation of unperturbed primary tumors is also critical; therefore, referral to expert surgeons commonly treating this neoplasm should be made if pheochromocytoma or paraganglioma is suspected. Contralateral adrenalectomy of a normal gland is generally not recommended in patients with a high incidence of bilateral disease (e.g., MEN-II), despite the high risk of subsequent involvement. In patients with metastatic disease, there is no evidence to support improved survival after local debulking. Catecholamine and metanephrine levels should be measured 1 week after surgery to confirm total removal of the tumor. Surgical mortality is estimated around 2% and usually correlates with the severity of hypertension. Patients whose localized benign disease is fully resected should have normal life expectancy; however, close postoperative follow-up is mandatory because of the possibility of residual tumor and as 10% of patients have metastasis with another 10% with multiple primary tumors at the time of diagnosis. Follow-up should include history, physical, catecholamine and metanephrine measurements, and CT imaging initially at 3-month intervals then yearly thereafter.

2. Chemotherapy. Chemotherapy is reserved for inoperable metastatic, imminently threatening disease, as its efficacy is limited.

bull 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 repeated in 3 to 4 weeks resulted in objective response in 61% of patients, with catecholamine/metanephrine levels decreasing in 74% of patients, and with median response duration averaging 28 months and minimal overall toxicity.

bull Streptozocin alone and in combination with other chemotherapeutics has yielded favorable results in the treatment of neuroendocrine tumor in the gastrointestinal tract, and has also sometimes been used in pheochromocytoma.

Emerging approaches to treating recurrent malignant pheochromocytoma and paraganglioma include TKIs (e.g., sunitinib, pazopanib), currently being evaluated in multicenter phase II trials based on encouraging anecdotal experience with these agents.

3. Radiation therapy. [131I]MIBG is generally actively taken up and concentrated by pheochromocytoma cells with high sensitivity and specificity. Consequently, high-dose radiotherapeutic [131I] MIBG has been historically used to treat pheochromocytoma in metastatic MIBG-avid tumors. However, this approach has considerable bone marrow toxicity and is unfortunately of limited palliative benefit, so it is best used in conjunction with clinical trials. External beam radiotherapy, Gamma Knife, and CyberKnife stereotactic approaches can provide local control in focally symptomatic or threatening metastases.

Selected Readings

Thyroid Carcinoma

AACE/AME Task Force on Thyroid Nodules. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodule. Endocr Pract. 2006;12(1):63–102.

Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2009;19:1167–1214.

Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. American Thyroid Association Guidelines Task Force. Thyroid. 2009;19:565–612. Review. Erratum in: Thyroid. 2009;19:1295.

Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer. 2009;16:17–44.

Adrenal Cortical Carcinoma

Bornstein SR. Stratakis CA Chrousos GP. Adrenal cortical tumors: recent advances in basic concepts and clinical management. Ann Intern Med. 1999;130:759–771.

Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenal cortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer.2005;12(3):657–666.

Mansmann G, Lau J, Balk E, Rothberg M, Miyachi R, Bornstein SR. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev. 2004;25(2):309–340.

Strosberg JR, Hammer GD, Doherty GM. Management of adrenocortical carcinoma. J Natl Compr Canc Netw. 2009;7:752–758.

Tabarin A, Bardet S, Bertherat J, et al. Exploration and management of adrenal incidentalomas. French Society of Endocrinology Consensus. Ann Endocrinol (Paris). 2008;69:487–500.

Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356:2372–2380.

Pheochromocytoma

Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med. 1988;109:267–273.

Carling T. Multiple endocrine neoplasia syndrome: genetic basis for clinical management. Curr Opin Oncol. 2005:17:7–12.

Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat. Clin Pract Endocrinol Metab. 2007;3:92–102.

Vanderveen KA, Thompson SM, Callstrom MR, et al. Biopsy of pheochromocytomas and paragangliomas: potential for disaster. Surgery. 2009:146:1158—1166.