Cancer of the Endocrine System
Summary of Key Points
Thyroid Cancer
Classification
• Differentiated thyroid cancer (DTC) includes papillary thyroid cancer (PTC), which accounts for 80% of all thyroid cancers, follicular thyroid cancer (FTC), which accounts for 10% to 20% of all thyroid cancers, and a rare type, Hürthle cell cancer.
• Medullary thyroid cancer (MTC) arises from the parafollicular C cells and accounts for 5% to 10% of all thyroid cancers.
• Anaplastic thyroid cancer is a rare, but rapidly fatal, form of thyroid cancer.
• Other histologic types of cancer, such as lymphoma, sarcoma, and metastatic cancers, can also be found within the thyroid.
Etiology
• Known risk factors for the development of thyroid cancer include radiation exposure and iodine deficiency.
• Thyroid cancer can also run in families or exist as part of familial syndromes (Gardner, Cowden, and Werner syndromes)
• More recently, the molecular pathogenesis of thyroid cancer has been investigated. The following are the most widely studied molecular markers for DTC to date:
• Well-differentiated histology has excellent 5-year survival (>95%).
• Older age and extent of invasion are related to prognosis.
• Lymph node involvement is associated with higher recurrence, but has questionable impact on survival.
• Many staging systems exist for DTC.
• Hürthle cell adenoma—larger size (>6 cm) predicts malignancy.
• Poorly differentiated tumors—recurrence lymph node metastases are common.
• Anaplastic cancers are extremely aggressive with 5-year survival less than 5%.
Presentation and Diagnosis
• The history should include radiation exposure, family history, and compressive symptoms (dysphagia, hoarseness, pain/pressure) from enlarging tumor.
• Concerning exam findings, include a fixed mass or lymphadenopathy.
• Incidental fining on computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound.
• Preoperative laboratory studies include thyroid-stimulating hormone (TSH), Tg.
• Fine-needle aspiration (FNA) biopsy is a key component of the workup of thyroid nodules. The Bethesda Criteria classify FNA results and determine the risk of cancer in the nodule.
• Preoperative imaging should cervical ultrasound. CT is used when aggressive variants are suspected to assist in operative planning.
Treatment
• Treatment begins with surgery. Most thyroid cancers are treated with total thyroidectomy. Compartment-oriented neck dissection is added when there is metastatic disease in the cervical lymph nodes.
• Adjuvant therapy for differentiated tumors is radioactive iodine (131I).
• Patients must be prepared for radioactive iodine ablation with a low iodine diet.
• And thyroid hormone withdrawal or recombinant human thyroid-stimulating hormone (rhTSH) if there is no evidence of metastatic disease.
• After surgery and radioactive iodine, thyroxine-suppression prevents the growth of microscopic disease.
• External beam radiation is utilized for persistent, recurrent, anaplastic, poorly differentiated tumors that are not iodine avid.
• Chemotherapy is mainly palliative for poorly differentiated or anaplastic tumors. Traditional chemotherapy has minimal response rates, but newer, targeted therapies, such as sorafenib or sunitinib, are showing promise.
Recurrence
• Surveillance for recurrent thyroid cancer includes measurements of TSH, Tg, and antithyroglobulin antibodies in addition to cervical ultrasound. The schedule of these tests is tailored to risk level.
• Treatment of recurrence can include external beam radiation or targeted therapies, depending on the iodine avidity of the tumor.
Medullary Thyroid Cancer
• Medullary thyroid cancer accounts for 5% to 10% of all thyroid cancers; 75% of cases are sporadic and 25% are familial (multiple endocrine neoplasia [MEN]-2, familial medullary thyroid carcinoma [FMTC]).
• The diagnosis is made by FNA with calcitonin washout. RET testing can identify inherited germline mutations. As in DTC, cervical ultrasound assists with operative planning. The tumor markers calcitonin and carcinoembryonic antigen (CEA) can be useful in following patients postoperatively for identifying recurrence and metastases.
• At a minimum, treatment of MTC should consist of total thyroidectomy plus central lymph node dissection. Lateral neck dissection is added when there are clinically positive nodes in the central neck and for high-risk patients.
• Traditional chemotherapy is not effective for metastatic MTC, but newer, targeted therapies for metastatic disease such as vandetanib, have shown some promise.
Adrenocortical Cancer
• The incidence of adrenocortical cancer is 1 to 2 per million people.
• Most adrenocortical cancers are sporadic, but they can also occur as part of familial syndromes such as MEN-1, Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and Carney complex.
• Most are asymptomatic, but 40% to 60% are functional (hormone production), and this may be the presenting symptom(s).
• The diagnosis is by urinary/plasma biochemical testing and imaging: CT, fluorodeoxyglucose (FDG)-PET.
• Often, the diagnosis is not made definitively until after resection of suspicious masses, and pathology provides definitive diagnosis. FNA of adrenal masses is rarely indicated.
• Surgery is the mainstay of treatment for adrenocortical cancer and should consist of en bloc resection of the adrenal gland with adjacent organs/tissue that is involved; cardiopulmonary bypass may be necessary for caval involvement.
• Long-term surveillance, consisting of physical exams and CT scans, is necessary to monitor for disease recurrence.
• Mitotane alone or in combination with other chemotherapeutic agents improves recurrence-free survival.
• Radiotherapy may improve local control, but there are no clear recommendations.
• Hormonal control can also limit disease spread and consists of mitotane, ketoconazole, metyrapone, etomidate.
• Excision or reoperation is recommended for recurrent or metastatic disease.
• The prognosis is poor, with overall 5-year survival of less than 40%.
Malignant Pheochromocytoma
• The incidence of malignant pheochromocytoma is 2 to 8 per 1,000,000 adults.
• Most malignant pheochromocytomas are sporadic, but 10% are part of inherited syndromes such as MEN syndromes, neurofibromatosis type I, von Hippel-Lindau syndrome, and succinate dehydrogenase gene mutations.
• Pheochromocytomas present with the classic triad of functional tumors-headache, tachycardia, and sweating, but they are asymptomatic in more than 50%, presenting as an incidental adrenal mass.
• The diagnosis is established with urinary or plasma fractionated metanephrines and catecholamines.
• Tumors are localized with CT/MRI; metaiodobenzylguanidine (MIBG) to identify extraadrenal metastases.
• Treatment begins with surgery to resect entire gland with clear margins. Surgery can also be useful in debulking for metastatic disease.
• Metastatic or unresectable disease can be treated with 131I-MIBG or chemotherapy.
• Radiotherapy is used for palliation in bone and lymph node metastases.
• Medical therapy to prepare patients for surgery or control symptoms of catecholamine excess can include phenoxybenzamine, nicardipine, or metyrosine.
MEN Syndromes
• MEN-1 presents first with hyperparathyroidism in their 30s and 40s. Other manifestations include pituitary tumors and neuroendocrine tumors of the pancreas (such as gastrinoma) and upper gastrointestinal tract.
• MEN-1 is inherited in an autosomal-dominant fashion. Mutations in the MENIN tumor suppressor gene cause this disease, but expression is variable.
• Treatment of parathyroid hyperplasia is subtotal parathyroidectomy and bilateral cervical thymectomy.
• MEN-1 patients with pancreatic and duodenal tumors are treated with distal pancreatectomy, enucleation of pancreatic head tumors, duodenotomy, and mucosal resection of multiple duodenal tumors.
• MEN-2A is characterized by pheochromocytoma, MTC, and primary hyperparathyroidism (hyperplasia).
• MEN-2B is characterized by more aggressive MTC, pheochromocytoma, and mucosal ganglioneuromas.
• The MTC in MEN-2 syndromes arises from C-cell hyperplasia and germline RET mutations.
• Specific codon mutations in the RET gene determine the disease phenotype in MEN-2 syndromes, and help risk-stratify patients.
• Prophylactic thyroidectomy should be offered to mutation carriers; the timing of thyroidectomy is determined by the specific codon mutation.
• Pheochromocytomas are often bilateral in MEN-2 syndromes, but onset is asynchronous. Consequently, prophylactic adrenalectomy is not indicated. Those MEN-2 patients who develop bilateral disease can be treated with bilateral adrenalectomy and hormone replacement or cortical-sparing adrenalectomy.
Carcinoid Tumors
• The incidence of carcinoid tumors is 5.25 in 100,000 people.
• Tumors are identified with specific immunohistochemical staining for NSE or chromogranin A. Chromogranin A also serves as a blood marker for the disease.
• Several classification systems exist for carcinoid tumors, including the World Health Organization (WHO) classification and European Neuroendocrine Tumor Society (ENETS) staging system.
• Carcinoids arise from the Kulchitsky cells in crypts of Lieberkühn of the gut or disseminated in the endobronchial mucosa, and are classified by location.
• The diagnosis is made definitively by tissue diagnosis, but urinary 5-hydroxyindoleacetic acid (5-HIAA), serum NSE, and chromogranin A are serum markers of the disease.
• CT or MRI can localize the carcinoid tumors, or OctreoScan can be used as these tumors have somatostatin receptors.
• The carcinoid syndrome occurs in metastatic carcinoid and presents as flushing, diarrhea, and bronchoconstriction. Right-sided valvular heart disease is also a manifestation of the disease.
• Treatment begins with resection of primary tumor with nodal metastases.
• Debulking/metastasectomy is beneficial for controlling symptoms in patients with liver disease or bulky disease.
• Radiation therapy is rarely used for primary therapy, but can be palliative.
• Antihormonal therapy consists of octapeptide analogs of somatostatin; Sandostatin LAR is a helpful, long-acting formulation octapeptide analogs of somatostatin.
• The liver is a common site for metastatic carcinoid, and there are several options for hepatic-directed therapy, including surgery and embolization (chemoembolization or radioembolization).
• Metastatic disease can also be treated with targeted agents or emerging radionuclide therapy.
Pancreatic Neuroendocrine Tumors
• Pancreatic neuroendocrine tumors (NETs) can be sporadic or inherited (MEN).
• Pancreatic NETs are diagnosed on CT/MRI imaging; ultrasound or endoscopic ultrasound (EUS) can help guide biopsy.
• The ENETS staging system is proposed to help stage pancreatic NETs.
• Insulinomas are diagnosed by fasting hypoglycemia with elevated plasma insulin levels; 10% are malignant, and surgical resection (enucleation) is curative.
• Glucagonoma is characterized by migratory necrotizing erythema, insulin-resistant diabetes, glossitis, ileus, and constipation; 50% to 80% are metastatic.
• Because of the higher rate of metastatic disease, surgical resection is curative in less than one-third of patients with glucagonoma.
• Somatostatinoma is characterized by diabetes, diarrhea, and gallbladder disorders.
• Treatment for somatostatinoma includes cytoreductive surgery and chemotherapy.
• Gastrinoma is characterized by ulcer disease in spite of adequate treatment and diarrhea.
• Gastrinoma is diagnosed by hypergastrinemia with elevated basal acid output or positive secretin test; tumors are localized with CT, MRI, or octreotide scan; these tumors are frequently metastatic.
• Targeted therapies such as everolimus and sunitinib have been FDA approved for first-line treatment of pancreatic NETs.
Parathyroid Carcinoma
• The incidence of parathyroid carcinoma is 5.73 per 10 million people.
• The etiology of parathyroid cancer has recently been attributed to pericentromeric inversion resulting in overexpression of the cyclin D1 gene.
In hyperparathyroidism-jaw tumor syndrome, there are mutations in the HRPT2 tumor suppressor gene (parafibromin).
• Clinical characteristics of parathyroid carcinoma include the constitutional symptoms of primary hyperparathyroidism, including muscle weakness, fatigue, nausea, vomiting, increased thirst, and frequent urination, in addition to bone pain and fractures.
• In parathyroid carcinoma, serum calcium is quite elevated (14.6 to 15.9) with elevated serum parathyroid hormone (PTH) (commonly 10-fold higher than the upper limit of normal).
The diagnosis is made by laboratory measurement of Ca and PTH, and then 99m-technetium sestamibi scan and neck ultrasound can localize the tumor ± washout for PTH measurement in FNA material.
• Pathological features of parathyroid carcinoma include local invasion and lymph node metastases.
• Treatment of parathyroid carcinoma should include en bloc resection of the parathyroid mass with ipsilateral thyroid lobe ± ipsilateral neck dissection followed by postoperative calcium and activated vitamin D supplementation.
• Medical therapy for hypercalcemia precipitated by parathyroid carcinoma should start with hydration and loop diuretics; calcimimetics (Cinacalcet) or bisphosphonates can later be added to lower the serum calcium levels.
• Adjuvant therapy includes chemotherapy, such as dacarbazine, 5-FU, cyclophosphamide; radiotherapy is of limited efficacy.
• Patients with features of hyperparathyroid-jaw-tumor syndrome or a family history should undergo genetic counseling and HRPT2 testing.
• After surgery, one-third of patients are cured, one-third have recurrence after prolonged disease-free survival, and one-third experience a short, aggressive course; the 5-year survival is 83.9%.
1. Which type of thyroid cancer is least likely to respond to radioactive iodine treatment?
2. A patient has a rapidly expanding thyroid mass that feels firm and fixed by exam. In addition to ultrasound, FNA, and TSH measurement, additional workup might include:
3. In order for radioactive iodine to be effective treatment for micro-metastatic thyroid cancer, which of the following must be true?
4. Regarding lymph node metastases in differentiated thyroid cancer, which of the following is true?
A Lymph node metastases rarely occur.
B Lymph node metastases are associated with worse survival.
C Lymph node metastases are associated with higher recurrence rates.
D Lymph node metastases are associated with worse survival and higher recurrence rates.
5. Regarding adrenocortical cancer, which of the following is not a concerning finding on CT?
6. A 65-year-old woman presents with an adrenal mass that measures 10 cm and is highly suspicious of adrenocortical cancer. Which of the following is the most appropriate treatment?
7. Which of the following is not associated with malignant pheochromocytoma?
8. Which of the following studies is the least accurate for the evaluation of malignant pheochromocytoma?
9. A 46-year-old woman presents with abdominal pain to the emergency department. Her serum pregnancy test is negative, and all labs are normal except for an elevated white blood cell count of 15.4. CT findings are consistent with acute appendicitis. She is taken to the operating room for laparoscopic appendectomy, and recovers well. Pathology confirms the presence of a carcinoid tumor at the base of the appendix, 2.4 cm in greatest diameter with mesoappendiceal involvement. What is the next best step in management?
A Octreotide scan to look for metastatic disease
B Initiation of adjuvant 5-FU–based chemotherapy
10. A 71-year-old man with a history of a resected low-grade carcinoid tumor of the ileum presents with flushing, diarrhea, and abdominal pain. His CT shows diffuse, hypervascular, low-attenuation lesions in both lobes of the liver. Biopsy confirms the presence of metastatic carcinoid. No other metastatic disease is identified. No pancreatic lesions are noted. Which of the following has the best chance at delaying disease progression for this patient?
1. Answer: D. Medullary thyroid cancer arises from the parafollicular C cells, which do not concentrate iodine. The other cancer types arise from follicular cells and have some chance of concentrating iodine, although less so as these cells become de-differentiated.
2. Answer: D. A rapidly growing thyroid mass is concerning for a poorly differentiated, aggressive, or anaplastic subtype of thyroid cancer. These tumors have a high likelihood for local invasion and distant metastases. A CT scan can help operative planning to determine the extent of resection and additional organ involvement (e.g., trachea and esophagus), while a PET scan can indicate distant sites of metastasis. FNA is often not adequate for anaplastic tumors or thyroid lymphomas; core needle biopsy is necessary if FNA cannot make the diagnosis.
3. Answer: C. Radioactive iodine is targeted to the micro-metastatic disease that cannot be detected by preoperative imaging or intraoperatively. For it to be effective, all thyroid tissue must be removed, otherwise it will serve as a sink for the radioactive iodine.
4. Answer: C. The significance of lymph node metastases in differentiated thyroid cancer remains controversial. The best data indicate that, although lymph node metastases do not confer a worse survival, they do increase the likelihood for recurrence.
5. Answer: D. The diagnosis of adrenocortical cancer is often not made until final pathology becomes available. Therefore it is necessary to evaluate preoperative imaging for suspicious findings. Irregular borders, heterogeneity, Hounsfield units > 20, and calcifications are all suspicious for adrenocortical cancer. Cancers also tend to retain contrast on delayed images and therefore will not wash out.
6. Answer: C. When preoperative imaging features are suspicious of adrenocortical carcinoma, the optimal treatment is open adrenalectomy to obtain negative margins.
7. Answer: B. MEN-1 is associated with pheochromocytoma but the other syndromes listed are associated with malignant pheochromocytoma.
8. Answer: C. CT and MRI are useful studies to evaluate any adrenal mass and to determine any concerning features for malignancy. MIBG is a nuclear medicine scan that can identify extraadrenal or metastatic sites for pheochromocytomas. Similarly, pheochromocytomas are PET avid, and this is a useful study in patients with metastatic cancer. Ultrasound has poor resolution for adrenal masses.
9. Answer: C. The best oncologic treatment of a carcinoid tumor of this size is right hemicolectomy with adequate resection of the mesentery to include the draining lymph nodes (lymphadenectomy). Octreotide scan is useful in the preoperative workup of suspected metastatic carcinoid, and chemotherapy is unnecessary if the tumor is completely resected with no evidence of further disease.
10. Answer: B. A randomized, double blind, placebo-controlled trial of octreotide LAR in midgut neuroendocrine tumors showed a significant prolongation in progression-free survival (PFS) from 6 months in the placebo arm to 14.3 months in the octreotide LAR arm. Targeted agents such as everolimus have shown a survival benefit in metastatic neuroendocrine tumors.
