The Washington Manual of Oncology, 3 Ed.

Endocrine Malignancies

Jessica L. Hudson • Jeffrey F. Moley

  I. THYROID CARCINOMA

1.  Definition. Thyroid cancer consists of a group of neoplasms including differentiated (papillary, follicular, Hurthle cell, and follicular variant of papillary); medullary (sporadic and hereditary); poorly differentiated, anaplastic; and lymphoma. The most common site of spread of thyroid cancer is the cervical nodes, with the central nodal compartment affected most often.
2.  Epidemiology. In 2013, there were 60,220 new cases of thyroid cancer in US, with a disproportionate number of females and patients under the age of 55. Studies from Asia reveal that thyroid cancer has become the most commonly diagnosed cancer in women. It is estimated that by 2014, thyroid cancer in females will outnumber that in males by 4:1. Despite the rising incidence of thyroid cancer, prognosis remains favorable, reflecting the indolent nature of the disease. The majority of thyroid cancer (90%) is well-differentiated thyroid carcinoma of papillary, follicular, or Hurthle cell pathology. Ten-year survival rates for patients with these subtypes are 93%, 85%, and 76%, respectively.
3.  Differentiated. Subtypes include papillary, follicular, Hurthle cell, and poorly differentiated. Papillary carcinoma is the most common, accounting for 85%, and commonly metastasizes to the lymph nodes. In contrast, follicular carcinomas are more prone to systemic metastases.
4.  Poorly differentiated. These tend to be more aggressive, more often are not iodine avid, and have a poorer prognosis.
5.  Anaplastic. These carcinomas are almost never curable. Management includes surgical excision, if possible, and experimental protocols or palliative radiation. Survival is usually measured in weeks to months.
6.  Medullary thyroid carcinomas (MTC). These can present as either sporadic tumors (75%) or as part of the multiple endocrine neoplasia syndromes (MEN2A and MEN 2B-25%). Sporadic and hereditary MTCs have similar clinical courses, but sporadic lesions often present later in life with neck masses largely due to lack of screening, almost always have lymph node metastases, and require extensive lymph node dissections. Hereditary MTCs are often detected as a result of familial screening, which allows for earlier detection and performance of preventative thyroidectomy in presymptomatic gene carriers.
7.  MEN2A and MEN2B. The hallmark of these syndromes is MTC, which may be bilateral and multifocal. The MEN2A syndrome is characterized by MTC (100% penetrance), hyperparathyroidism (<25% penetrance), pheochromocytoma (<40% penetrance), and Hirschsprung’s disease (<3%). The MEN2B syndrome is characterized by MTC (100% penetrance), pheochromocytoma (50% penetrance), megacolon (100% penetrance), and by characteristic facial and skeletal features (“marfanoid habitus”). The MEN2 syndromes are caused by germline gain of function mutations in the RET proto-oncogene. There are strong genotype–phenotype correlations. For example, Hirschsprung’s disease is only associated with mutations in codon 609, 611, 618, and 620, while MEN2B is usually associated with codon 918 mutation. Patients with inherited RET proto-oncogene mutations identified by genetic screening should have prophylactic thyroidectomy. Patients with established MTC should be treated with surgery after screening for pheochromocytoma preoperatively. Patients with metastatic MTC are also candidates for therapy with tyrosine kinase inhibitors. Controversy exists over the appropriate age for prophylactic thyroidectomy, extent of lymph node dissection based on calcitonin level, and timing of systemic therapy in metastatic disease.
8.  Presentation
9.  Subjective. Patients with thyroid cancer of any type usually present with a thyroid or nodal mass in the neck, which may be associated with hoarseness, dysphagia, or difficulty breathing.
10.  Objective. The physical exam reveals a mass in the thyroid that moves up and down with swallowing, but which may be fixed in position if there is significant local invasion. Cervical lymphadenopathy may be present. Frequently, there is an appreciable hoarse quality to the voice.
11.  Diagnosis. Generally made by fine-needle aspiration cytology.
12.  Workup
13.  Laboratory assessment. Specific diagnostic labs include thyroid function tests, thyroglobulin, and calcitonin levels. The tumor markers thyroglobulin levels and antithyroglobulin antibodies are used to follow patients after treatment for differentiated thyroid cancer. Following treatment, thyroglobulin is measured either with or without TSH level modulation (achieved either by thyroid hormone withdrawal or administration of recombinant thyroglobulin [Thyrogen^TM]). Calcitonin levels are followed in patients with MTC, and are used preoperatively to help determine the extent of node dissection, and postoperatively to screen for disease persistence, recurrence, and progression.
14.  Imaging. Ultrasound will demonstrate the intrathyroidal tumor mass and adjacent lymph nodes. Computed tomography of the neck, chest, and abdomen may be helpful to distinguish pulmonary and mediastinal disease spread. Features of metastatic nodes in the neck include presence of calcifications; wide but short, rounded lesions; and obliteration of the fatty hilum. The only current recommended role for FDG/PET imaging is in patients with differentiated carcinoma with elevated thyroglobulin levels postoperatively and negative iodine imaging. In medullary carcinoma, computed tomography is highly favored over PET.
15.  Endoscopy. Laryngoscopy should be performed on all patients with hoarseness as this may reveal a vocal cord paralysis. If tracheal or esophageal invasion is suspected, bronchoscopy and/or endoscopy is warranted.
16.  Pathology. Routine light microscopy of the tissue specimen after staining with hematoxylin and eosin may identify the main cytologic subclasses of thyroid cancers. Special stains for calcitonin or immunoglobulin markers may be necessary if medullary carcinoma or lymphoma is suspected. Genetic mutations identified by molecular testing of tissue and aspirates, including BRAF, RAS, PAX8-PPAR gamma, and RET-PTC rearrangements, have been associated with differentiated thyroid cancer, though controversy exists over their utility in guiding surgical therapy.
17.  Treatment. Surgical resection is usually the treatment modality of choice for thyroid cancer confined to the neck, though the extent of dissection and the adjuvant therapies vary by disease subtype.
18.  Surgery. For differentiated thyroid cancer, total thyroidectomy is indicated for tumors >4 cm in diameter or tumors less than 4 cm with risk factors including age >45 years, cervical lymph node metastases, poorly differentiated histology, or extrathyroidal extension. There is controversy regarding whether or not to do prophylactic central lymph node dissection. However, the subcategory of minimally invasive follicular carcinoma generally follows an indolent course and can be treated adequately with lobectomy. For MTC, total thyroidectomy is generally recommended, and preoperative imaging and calcitonin levels should determine the extent of lymph node dissection. For anaplastic thyroid cancers, there is controversy as to whether or not surgery is ever indicated. The role of surgery for lymphoma is usually limited to tissue diagnosis only or in settings of airway compromise.
19.  Radioactive iodine (RAI). Thyroid tissue selectively takes up iodine and is the primary location of its use in the body. Therefore, targeted radioactive therapy is possible. RAI is typically recommended for primary tumors >4 cm, gross extrathyroidal extension, or elevated postoperative unstimulated thyroglobulin levels (>5 to 10 ng/mL). RAI may selectively be applied for primary tumors measuring 1 to 4 cm, high-risk histology, lymphovascular invasion, cervical lymph node disease, macroscopic multifocality, or postoperative unstimulated thyroglobulin levels <5 to 10 ng/mL. RAI is not typically indicated for small, intrathyroidal, unifocal lesions, or undetectable postoperative unstimulated thyroglobulin. Additionally, RAI is not indicated in the setting of gross residual disease. Exact timing of adjuvant RAI is institution specific.
20.  External beam radiation therapy. The role for this therapy in thyroid cancer is limited to tumors of the anaplastic subtype. This can be either adjuvant or palliative in nature.
21.  Hormonal therapy. Thyroid-stimulating hormone (TSH) is a trophic hormone that stimulates growth of thyroid cancer cells. Maintenance of low TSH levels is usually optimal in these patients. Total suppression by oral supplementation with levothyroxine used to be recommended for all patients; however, recent data suggest that doing so places populations such as the elderly at greater risk of cardiac tachyarrhythmias and bone demineralization. The current guidelines favor a stratified approach. In patients with known residual disease or at high risk for recurrence, TSH levels should be maintained below 0.1 mU/L. In low-risk patients with biochemical evidence but no structural evidence of disease, the TSH should be maintained between 0.1 and 0.5 mU/L. Disease-free patients should have TSH levels near the lower limit of the normal reference range. After several years of being disease free, patients can be maintained within the reference range. Chronic suppression of TSH can lead to deficiencies in calcium and vitamin D.
22.  Systemic therapy. Conventional chemotherapeutic agents have limited utility in the treatment of metastatic thyroid cancer. However, a role for oral tyrosine kinase inhibitors has clinically been demonstrated in randomized, placebo-controlled trials both in RAI-refractory differentiated thyroid cancer and in locally recurrent but unresectable or metastatic medullary thyroid cancer. Kinase therapy has been shown to be associated with improved progression-free survival but not cure. However, this therapy has significant side effects, the management of which is crucial to therapy compliance. The rate of disease progression is a key variable to determine candidacy for systemic therapy. Treatment should be favored in patients with progressive disease over those with stable or indolent disease. An additional option for systemic therapy is surgical tumor debulking, but there are limited data on this intervention, and the benefit to survival is yet to be determined.

         FDA-approved kinase inhibitors for MTC at the time of this publication include Vandetanib and Cabozantinib. Clinical trials would be ideal for all other subtypes. If no clinical trial is available, one could consider as commercially available kinase inhibitors such as axitinib, pazopanib, sunitinib, or vandetanib.

         Specific to the treatment of anaplastic thyroid carcinoma, the disease often presents with a locally advanced, unresectable tumor. Adjuvant and neoadjuvant chemotherapy is usually employed. This is usually undertaken in the setting of a multidisciplinary team and guided either toward aggressive or palliative care. Current regimens include Doxorubicin, Paclitaxel, Cisplatin, or Paclitaxel plus Carboplatin.

6.  Surveillance and maintenance: patients with differentiated thyroid cancer. This should be followed with physical exam, TSH and thyroglobulin levels, and antithyroglobulin antibodies at 6 and 12 months postoperatively, then annually until disease free. Periodic neck ultrasounds should be performed. Additional courses of RAI can be considered in select responsive tumors in high-risk patients. Patients with medullary thyroid cancer should have physical exam, calcitonin and CEA levels and ultrasound or CT imaging in patients with elevated serum markers.
7. PARATHYROID CARCINOMA
8.  Definition. Extremely rare malignant tumor of the parathyroid gland, much less common than benign parathyroid hyperplasia or adenomas.
9.  Epidemiology. There are fewer than 100 cases per year in the United States. The five-year survival is 90%, whereas 10-year survival is 50%. Recurrence rates of this indolent malignancy are close to 50% even with en bloc resection. Mortality is usually due to the metabolic complications of malignant hyperparathyroidism.
10.  Presentation
11.  Subjective. Patients often present with a multitude of symptoms associated with primary hyperparathyroidism, such as nephrolithiasis, osteoporosis, hypertension, mood disturbances, fatigue, muscle weakness, or other subtle symptoms. Patients tend to have severe hyperparathyroidism (serum calcium >15 mg/dL), which may manifest with more severe symptoms or hyperparathyroid crisis.
12.  Objective. Parathyroid carcinoma is extremely rare, and suspicion is usually raised intraoperatively. Preoperatively, patients may have a palpable neck mass (50%) or symptoms of local invasion, such as hoarseness.
13.  Diagnosis. Histologic diagnosis at the time of surgery, usually with evidence of vascular or capsular or gross invasion of adjacent structures.
14.  Workup. Identical to benign disease (serum calcium and parathyroid hormone levels, ultrasound, 99mTc-sestamibi scintigraphy). Patients with persistent elevation of parathyroid hormone levels following surgery should undergo a metastatic workup including whole body imaging by computed tomography, FDG/PET, and/or Sestamibi scan.
15.  Treatment
16.  Surgical. Radical en bloc resection with ipsilateral thyroid lobectomy with adjacent lymph nodes.
17.  Systemic therapy. Very little research, generally poor results.
18.  Surveillance and maintenance. Patients should be followed with measurement of calcium and parathyroid hormone levels. Imaging should be done in patients with suspected recurrence of persistent disease.

 III. ADRENAL TUMORS

1.  Definition. Benign adrenal tumors are very common, being present in up to 9% of the population. This classification includes adenomas, lipomas, myelolipomas, cysts, and benign pheochromocytomas. Malignant tumors of the adrenal gland include malignant pheochromocytoma, adrenocortical carcinoma (ACC), and metastases. The most common sources of adrenal metastases include lung, renal, melanoma, and thyroid cancer. Tumors arising from the medulla include neuroblastoma and pheochromocytoma. Tumors arising from the cortex are largely nonfunctional and also include aldosteronomas, cortisol-secreting adenomas, and tumors that secrete both cortisol and male hormones, the latter of which is usually malignant, such as ACC. Pediatric patients may develop adrenal neuroblastomas.
2.  Epidemiology. Incidental adrenal lesions are reportedly found in 1% to 4% of abdominal CTs. Additionally, lesions were found in up to 9% of adult autopsies. In patients with other known malignancies at the time of death, 27% had adrenal metastases. Physicians must weigh the risk of malignancy against the morbidity and cost of additional interventions. Of the histologic diagnoses of adrenal incidentalomas, adenomas account for 55%, metastatic lesions account for 31%, pheochromocytomas and adrenal cancers for 4.3%, hyperplasia for 2%, and lipomas/myelolipoma for 1.4%.

       In addition to assessing functionality, the workup for incidentalomas is aimed at detecting ACC. Tumor size is a predictor of likelihood of ACC. The prevalence is roughly 2% for lesions <4 cm, 6% for lesions from 4.1-cm, and 25% for lesions >6 cm. Patients with ACC generally have a very poor prognosis. Long-term survival is related to the tumor stage at the time of diagnosis and the ability to undergo surgical resection by a skilled surgeon. Nevertheless, the five-year survival remains approximately 20% to 25%.

       Pheochromocytomas are neuroendocrine tumors of the adrenal gland, arising from the medulla. These tumors can store, synthesize, and secrete catacholamines. Approximately 10% are bilateral, 10% are extra-adrenal, 10% occur in children, 10% are familial (MEN2A, VHL, and NF-1), and 10% are malignant, though the extra-adrenal pheochromocytomas, or paragangliomas, have a higher incidence of malignancy (15% to 35%). A small subset of malignant pheochromocytomas has metastases at the time of initial diagnosis, but a significant number go on to develop metastases after treatment. Unfortunately, even with histologic immunohistochemical evaluation, differentiating between benign and malignant pheochromocytomas in the absence of metastases is challenging. Additional research is needed and long-term follow-up is essential.

1.  Presentation
2.  Subjective. Sixty percent of primary malignant tumors are functional and therefore manifest according to their hormone profile. However, many of these symptoms present on a spectrum and over a prolonged period of time, delaying the diagnosis. Most patients present after an astute clinician has a high degree of suspicion or as an incidental finding from imaging for another reason (“incidentaloma”).
3.  Objective. Rarely is an adrenal tumor identifiable on physical exam; however, the functional overexpression of cortisol, virilization hormones can lead to impressive physical exam findings (i.e., Cushing’s syndrome with virilization). In the case of ACC, patients may report abdominal or flank pain or fullness or fevers due to hemorrhage within large lesions.
4.  Diagnosis. Usually, a correlation of diagnostic imaging and biochemical testing without preoperative biopsy. Often, the assistance of an endocrinologist is valuable.
5.  Workup
6.  Laboratory studies. The laboratory workup for an adrenal mass is extensive but targeted, aimed at elucidating the functional capacity of the tumor, which affects preoperative management. Additionally, hormonal markers can be used for postoperative surveillance. Basic screening for hypercortisolism includes either a low-dose dexamethasone suppression test or a 24-hour urine cortisol assessment. For aldosterone, serum potassium and blood pressure are assessed first. If these are abnormal, then plasma renin activity and aldosterone levels are obtained. For pheochromocytomas, screening is accomplished best by plasma metanephrines and plasma normetanephrines.
7.  Imaging. As stated earlier, many adrenal tumors are found incidentally on computed tomography performed for other indications. Unfortunately, these are often of insufficient quality. The ideal imaging modality is a thin-section, high-resolution CT or MRI of the adrenal gland, ideally with an institution-specific adrenal protocol. CT scanning is usually sufficient in 90% of lesions >1 cm in diameter. MRI is of particular utility when there is clinical concern for pheochromocytoma because of the ability to distinguish between adenomas. ¹³¹I-metaiodobenzylguanidine (MIBG) scintigraphy is an additional imaging modality that can be employed to identify both intra- and extra-adrenal pheochromocytomas.

         The appearance of an adrenal lesion on imaging is crucial to the correct diagnosis and therefore warrants review. Regarding specific characteristics, adrenal adenomas tend to be homogeneous and have smooth contours with sharp margins. On noncontrasted CT, the tissue density measures <10 Hounsfield units (HU), while on contrasted CT, it measures <25 HU. On MRI, there is signal dropout on opposed phase chemical shift imaging. Comparatively, ACCs have a nonhomogeneous enhancement pattern with central necrosis, irregular borders, calcifications, sparing of local lymph nodes, and/or invasion into surrounding structures, especially the inferior vena cava. On noncontrasted CT, the tissue densities are >10 HU. ACCs tend to measure >6 cm at the time of diagnosis, though a cutoff of 4 cm for diagnosis is associated with 93% sensitivity and 24% specificity. For pheochromocytoma, CT tissue densities normally range from 40 to 50 HU, and on MRI, the hallmark feature is high signal intensity on T-2-weighted images without signal dropout on opposed phase chemical shift imaging. Extracapsular invasion into adjacent structures is suggestive of malignant pheochromocytoma.

         The role of PET in adrenal cancer is limited to staging for ACC, and in the case of metastatic adrenal lesions, as clinically indicated for the primary malignancy.

3.  Biopsy. After excluding a pheochromocytoma, it is considered safe to perform a biopsy of an adrenal lesion. Typically, this is performed by image guidance in cases of concern for metastases or lymphoma, if the diagnosis would alter management. Usually, tissue diagnosis is not necessary prior to resection of obviously malignant adrenal masses.
4.  Treatment. Any adrenal lesion with concerning characteristics or measuring >4 cm should be considered for surgical resection. Benign but functional lesions are also treated with surgery, but will not be covered. This discussion will focus on malignant pheochromocytoma, ACC, and adrenal metastases.
5.  Surgery. There is a role for surgery in solitary adrenal metastases, specifically if the patient is symptomatic (i.e., flank pain), there is control of the primary tumor, and the adrenal metastasis is considered fully resectable. There is improved survival in patients after solitary metastasis adrenalectomy due to adenocarcinoma when compared with other pathologic subtypes. There does seem to be improved quality of life when adrenalectomy is performed in symptomatic metastatic disease. While debatable, this can be performed via either an open or a laparoscopic approach.

         For ACC, open adrenalectomy is the preferred operation, aiming for radical en bloc resection of the involved adrenal gland and the surrounding tissues and lymphadenectomy. This could involve the kidney, liver, spleen, and/or inferior vena cava. Avoiding violation of the adrenal capsule reduces the risk of local recurrence. When ACC was not diagnosed preoperatively, retrospective data indicated an increased risk of local recurrence and disease dissemination after undergoing laparoscopic adrenalectomy when compared with open.

         For pheochromocytomas, surgical resection should always be considered, even in the presence of metastatic disease, if only to alleviate symptoms via tumor debulking. Attempts are made to remove local and distant metastatic lesions, which can often be identified preoperatively by MIBG. Specific to hepatic lesions, consideration may need to be given to cryotherapy or transarterial chemoembolization.

2.  Hormonal. Hormonal therapy for adrenal lesions is targeted at treating or preventing hormone imbalances, rather than targeting the tumors themselves. Nevertheless, it is a crucial component of managing these patients. In the setting of cortisol-producing lesions, all patients should be treated postoperatively with exogenous glucocorticoids for 6 to 18 months to allow the hypothalamic–pituitary–adrenal axis to re-equilibrate. Patients with subclinical or clinical Cushing’s disease should also receive preoperative glucocorticoids. With aldosterone excess, supplementation of mineralocorticoids should be considered.

         In the treatment of pheochromocytoma, malignant or otherwise, alpha-adrenergic blockade is necessary 1 to 3 weeks preoperatively in order to prevent intraoperative blood pressure lability. Recent research suggests possible further improvement with the addition of the tyrosine kinase inhibitor metyrosine. If the tumor cannot be fully resected, the alpha-blockade should be continued postoperatively.

3.  Systemic. For metastatic lesions of the adrenal gland, systemic therapy is guided by the primary tumor guidelines.

         For ACC, a derivative of the insecticide DDT, called mitotane, has been used for adjuvant therapy. It acts to suppress the adrenal cortex directly and therefore has an extensive side-effect profile. It is not yet known whether adjuvant systemic treatment is effective in ACC, and therefore patient selection criteria do not yet exist. At the time of this publication, multiple research trials are ongoing to assess for additive effects of mitotane with more traditional chemotherapeutic agents. Some such combinations include etoposide, doxorubicin, and cisplatin plus mitotane as well as gemcitabine and 5-fluorouracil or capecitabine plus mitotane.

         For inoperable pheochromocytomas, a variety of protocols have been suggested for systemic therapy. Historically, this has included cyclophosphamide, vincristine, and dacarbazine (CVD). More recent approaches have suggested lomustine and 5-fluoruracil for indolent lesions, and etoposide and a platinum-based agent for aggressive lesions.

4.  Radiation. For treatment of malignant pheochromocytomas, there is a role for neoadjuvant radiation for tumor debulking, palliation, and management of painful bony metastases. In patients who showed radioactive uptake of the noradrenaline analogue MIBG by preoperative imaging, adjuvant administration of radioactive MIBG has been given as a radiopharmaceutical for pheochromocytoma. Most patients experienced symptomatic improvement, which then led to survival benefits proportional to their biochemical response. Since the transition of MIBG from a diagnostic to a therapeutic intervention, and given the poor treatment response to systemic chemotherapy, some suggest that MIBG is the most useful treatment in unresectable pheochromocytomas. Likewise, radiolabeling analogues of somatastatin, such as octreotide, have been used. Research is still ongoing about the possible combination of these two radiopharmaceutical treatments. Total body radiation dosing limits apply, and the side-effect profile is directly proportional to the dose received.
5.  Surveillance and maintenance. Patients with adrenal lesions that do not meet the criteria for surgical resection warrant repeat imaging initially 3 and 6 months after diagnosis, then annually. Subsequent hormonal evaluation should be completed every 5 years unless there is a change in the clinical conditions.

SUGGESTED READINGS

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