Update on the Management of Unusual Neuroendocrine Tumors: Pheochromocytoma and Paraganglioma, Medullary Thyroid Cancer and Adrenocortical Carcinoma
Jonathan R. Strosberg
Pheochromocytomas, paragangliomas, and medullary thyroid carcinomas (MTCs) originate in cells that share a common neuroectodermal origin. Like other neuroendocrine neoplasms, they are characterized by a propensity to secrete amines (epinephrine and norepinephrine) and peptide hormones (calcitonin). Improved understanding of underlying molecular pathways, such as muta- tions of the RET (rearranged during transfection) proto-oncogene, has led to new rational targeted therapies. Adrenocortical carcinomas (ACCs) originate in the steroid hormone-producing adrenal cortex. While tumors of the adrenal cortex are not, strictly speaking, part the “diffuse neuroendo- crine system,” they are often included in neuroendocrine tumor guidelines due to their orphan status. In this update on management of unusual neuroendocrine tumors, we review the biology and treatment of these rare neoplasms.
Semin Oncol 40:120-133 @ 2013 Elsevier Inc. All rights reserved.
PHEOCHROMOCYTOMA AND PARAGANGLIOMA
Overview
P heochromocytomas and paragangliomas are un- common tumors that originate from chromaffin cells of the adrenal medulla and autonomic para- ganglia. They share a common embryonic derivation from the neural crest. Approximately 70% of paragan- gliomas originate in the parasympathetic tissues of the head and neck.1 Paragangliomas originating in the ca- rotid body are sometimes referred to as chemodecto- mas, whereas jugulotympanic tumors are also known as glomus tumors. Nearly all head and neck paragan- gliomas are hormonally silent. Sites of abdominopelvic paragangliomas include periaortic and pericaval para- ganglia, as well as the organ of Zuckerkandl located at the aortic bifurcation. Pheochromocytomas, as well as the majority of abdominopelvic paragangliomas (some- times referred to as “extra-adrenal pheochromocyto-
Conflicts of interest: none.
http://dx.doi.org/10.1053/j.seminoncol.2012.11.009
mas”), derive from the sympathetic nervous system and secrete catecholamines.1
Epidemiology
The annual incidence of pheochromocytomas is ap- proximately 2-8 per 1,000,000.2,3 They represent 4% of patients presenting with adrenal incidentalomas and 0.1% of patients evaluated for hypertension. The peak incidence of pheochromocytomas is in the fourth to fifth decade and the gender distribution is roughly equal. Pheochromocytomas generally obey the “rule of 10”: roughly 10% are malignant,4 10% occur in chil- dren, 10% are nonfunctional, and 10% are bilateral. While previous studies indicated that approximately 10% were hereditary, it appears that germline muta- tions are found in a larger percentage of patients.5
Paragangliomas are roughly half as common as pheo- chromocytomas. In one series, 69% of cases originated in the head and neck, 10% in the thorax, and 22% in the abdomen and pelvis.1 Head and neck paragangliomas represent only 0.6% of all head and neck tumors. The rate of malignancy is particularly low among carotid body tumors (6%) and jugulotympanic tumors (2%- 4%).6 Multicentric paragangliomas occur in 10%-20% of sporadic cases, and in up to 80% of hereditary cases.7
Clinical Presentation
The classic triad of pheochromocytomas consists of episodic headaches, palpitations, and diaphoresis.4 The
hallmark clinical finding is hypertension, which can be paroxysmal or sustained. Other common signs and symptoms include tachycardia, syncope, tremors, dys- pnea, and panic-attack like symptoms. Although symp- toms often occur spontaneously, triggering factors can include anesthesia, exercise, and tyramine-containing foods. Hypertensive or stress-induced cardiomyopathy can occasionally occur in patients with longstanding symptoms.8
The average size of pheochromocytomas is approx- imately 5 cm.9 Malignant tumors, which measure ap- proximately 9 cm on average, tend to be larger than benign tumors. With widespread use of cross-sectional imaging, an increasing number of pheochromocytomas are diagnosed incidentally.9 Incidental tumors, as well as tumors detected while screening patients with he- reditary syndromes, tend to be smaller than symptom- atic ones.
Paragangliomas are less likely to be hormonally func- tional than pheochromocytomas, and more commonly present with symptoms related to tumor growth. Ca- rotid body tumors typically present as painless masses below the angle of the mandible. Horner’s syndrome may result from pressure on the sympathetic nerves. Jugulotympanic tumors may cause pulsatile tinnitus, dizziness, facial droop, or pain.7 Catecholamine-pro- ducing paragangliomas, typically arising below the neck, present most often with hormonal symptoms.
Genetics
Although hereditary tumors were once thought to represent approximately 10% of pheochromocytomas and paragangliomas, it now appears that nearly 30% of cases are associated with identifiable germline muta- tions.1º Hereditary pheochromocytomas are associated with multiple endocrine neoplasia type 2 (MEN 2), with von Hippel-Lindau (VHL) syndrome, and very rarely with neurofibromatosis type 1 (NF 1). In one series of 154 patients with pheochromocytomas, 20 (13%) had MEN 2, 15 (10%) had NF 1, and one patient had VHL.11 Hereditary paragangliomas are most often associated with mutations in genes encoding or stabi- lizing the succinate dehydrogenase (SDH) complex.
MEN 2 is an autosomal-dominant syndrome caused by activating germline mutations in the RET (rear- ranged during transfection) proto-oncogene and char- acterized by a propensity to develop medullary thyroid cancers (MTCs), hyperparathyroidism, and pheochro- mocytomas. Individuals with MEN 2 have a 50% risk of developing pheochromocytomas, which are typically benign and frequently bilateral.1º Patients are usually diagnosed in their third or fourth decades.
VHL is an autosomal-dominant hereditary disease caused by mutations in the VHL tumor-suppressor gene, located on chromosome 3p25-26. The VHL pro- tein is involved in regulation of hypoxia-induced gene
expression. Pheochromocytomas develop in approxi- mately 10%-20% of VHL cases. Most VHL-associated tumors produce norepinephrine.10 The tumors are be- nign in almost all cases and bilateral in up to 50%. The most common type of VHL (type 1) is associated with a predisposition to develop retinal angiomas, brain he- mangioblastomas, and renal cell carcinomas. VHL type 2 patients are characterized by predisposition to de- velop pheochromocytomas.12 Depending on the spe- cific type of mutation, some patients (type 2A) develop pheochromocytomas without renal carcinomas but with other VHL-associated tumors, whereas others de- velop all types of VHL tumors including pheochromo- cytomas (type 2B), or pheochromocytomas exclusively (type 2C).
NF 1, formerly known as von Recklinghausen’s dis- ease, is an autosomal-dominant genetic syndrome caused by mutations of a tumor-suppressor gene on chromosome 17q11.2. The gene encodes neurofibro- min, which is involved in the inhibition of Ras activ- ity.13 The syndrome is characterized by cutaneous neu- rofibromas, café-au-lait spots, and iris hamartomas (Lisch nodules) among other signs. Several tumors, including duodenal carcinoids, gastrointestinal stromal tumors, and MTCs, have been described. Pheochromo- cytomas reportedly occur in only 0.1%-5.7% of patients with NF 1.14
Hereditary paraganglioma syndromes are autosomal- dominant diseases caused by mutations in genes encod- ing or stabilizing SDH complex subunits. Inactivation of SDH results in upregulation of hypoxia-inducible factor 1-alpha (HIF-1a).10 The SDH enzyme complex consists of four subunits encoded by the SDHA, SDHB, SDHC, and SDHD genes. Mutations of SDHD are associated with multifocal head and neck paragangliomas that are typically benign.15 Mutations in SDHC are exceedingly rare and characterized by solitary head and neck para- gangliomas.16 Mutations of SDHB are associated with development of pheochromocytomas and sympathetic paragangliomas, which are frequently malignant and tend to secrete norepinephrine.17 A newly recognized syndrome is caused by mutations in SDH assembly factor 2 (SDHAF2), which stabilizes SDHA.18 Patients typically present with head and neck paragangliomas.
There are currently few accepted guidelines to di- rect genetic testing. Patients younger than 45 and those with bilateral or multifocal tumors are more likely to harbor a germline mutation than patients with benign solitary tumors. Malignant tumors, particularly paragan- gliomas, are commonly associated with mutations of SDHB. Complex algorithms for genetic testing have been developed that are based on tumor location (ad- renal versus extraadrenal), hormone secretion (epi- nephrine v norepinephrine or dopamine) and pheno- type (malignant v benign). 10,19
Diagnostic Tests
Most pheochromocytomas and functional paragan- gliomas produce norepinephrine and/or epinephrine, which undergo intratumoral catabolisminto metaneph- rine and normetanephrine by catechol-O-methyltrans- ferase.20 These metabolites are, in turn, converted by the monoamine oxidase system into vanillylmandelic acid (VMA). Evaluation of patients who present with adrenergic signs or symptoms typically begins with plasma or urine measurements of catecholamines and their metabolites. However, there is a lack of consensus regarding the optimal diagnostic tests.
Plasma-fractionated metanephrines have a high level of sensitivity (97% and 99% in two studies).21,22 Normal levels are therefore reliable for excluding a catechol- amine-producing tumor. However, specificity is subop- timal at standard reference levels resulting in a rela- tively high rate of false positive tests. Moreover the technique for obtaining plasma catecholamines and metanephrines appears to influence the results. Mea- surements obtained in seated patients using standard venipuncture tend to be elevated compared to mea- surements obtained in patients who have rested for 20 minutes after placement of an indwelling venous can- nula. Due to the relatively low specificity, some experts recommend that plasma metanephrines only be or- dered in patients in whom there is a high index of suspicion for a catecholamine-secreting tumor.
Twenty-four-hour urinary metanephrines and cat- echolamines have a relatively high specificity (98% in one study)21 compared to plasma metanephrines but lower sensitivity. Consequently, they may be prefer- able in cases where the index of suspicion for pheo- chromocytoma is lower. It is important to note that certain medications, including tricyclic antidepres- sants, levodopa, decongestants, amphetamines, pro- chlorperazine, ethanol, and even acetaminophen, can cause false elevations in both plasma and urine tests.
Tests with the lowest level of diagnostic accuracy include plasma catecholamines, which are secreted ep- isodically and tend to fluctuate more than metaneph- rines, which undergo intratumoral production at a rel- atively constant rate.20 The sensitivity of urine VMA is poor and some authors suggest that it should not be routinely assessed.22 Obtaining multiple blood and urine measurements may add slightly to diagnostic sen- sitivity but at the expense of specificity. Most investi- gators, therefore, discourage multiple assays in favor of a single diagnostic test. At our institution, plasma meta- nephrines are generally performed as an initial screen- ing test. Normal levels are reliable at excluding a cate- cholamine-producing tumor, while levels elevated beyond four times the upper reference limit are usually diagnostic (100% specific).22
Radiographic Studies
Approximately 95% of catecholamine-producing tu- mors are found within the abdomen (roughly 90% in the adrenal glands and 5% in sympathetic abdominopel- vic paraganglia). As a result, computed tomography (CT) scans of the abdomen and pelvis are most fre- quently recommended for localization of disease after positive biochemical testing.23 Magnetic resonance im- aging (MRI) shares a high sensitivity for detection of tumors in the adrenal gland, which are usually hyper- intense on T2-weighted images and hypointense on T1-weighted images.24
Iodine 123-meta-iodobenzylguanidine (MIBG) is an analog of norepinephrine that is taken up by adrenergic tissues.25 MIBG scintigraphy with single-photon emis- sion computed tomography (SPECT) is recommended when the index of suspicion for a catecholamine-pro- ducing tumor remains high despite negative cross-sec- tional imaging, or for staging of large pheochromocy- tomas (>5 cm in diameter) that have a relatively high metastatic potential.26 The sensitivity of MIBG scan is approximately 75%-92%.27 Novel investigational imag- ing modalities include 18F-DOPA positron emission to- mography (PET)28 and 11C-hydroxyephedrine PET.29
Head and neck paragangliomas typically present with enlarging masses, often associated with cranial nerve palsies. Duplex ultrasound sonography,30 CT scans, CT angiography, MRI, and MR angiography are all methods that can be used to localize tumors and identify vascular supply.31 Digital subtraction angiogra- phy (DSA) is considered by some investigators to be an important method for delineating the vascular supply of the tumor.7
Histology
Needle biopsy of a pheochromocytoma is strongly contraindicated due to concerns regarding tumor seed- ing and hypertensive crisis.32 Head and neck paragan- gliomas are typically vascular and needle biopsies are relatively contraindicated.33 Therefore histological anal- ysis is typically performed on resected specimens. Mi- croscopic evaluation usually shows intermediate to large polygonal cells arranged in an alveolar or trabec- ular architecture. Spindle cells are rarely observed. The tumor cells typically either resemble normal chromaf- fin cells, or are larger with prominent nuleoli. Mitotic figures are rare, particularly in benign tumors.34 Even malignant tumors average only three mitotic figures per 30 high-powered fields (HPF).
Traditional chromaffin staining has been replaced with newer immunohistochemical tests. Pheochromo- cytomas are usually positive for vimentin and negative for cytokeratins. Chromogranin A can help distinguish pheochromocytomas from adrenocortical tumors. Syn- aptophysin is less specific in this respect. S-100 protein
is observed in sustentacular cells, particularly in pa- tients with alveolar architecture.
There are no universally accepted histological methods for distinguishing benign from malignant tumors other than presence of lymph node or distant metastases. In one study, confluent tumor necrosis and presence of vascular invasion and/or extensive local invasion were predictive of malignancy. Immu- nohistochemical staining for Ki-67 also can be help- ful: a cutoff value of >3% yields a specificity of 100% and a sensitivity of 50% in predicting malignancy.35 In another study of 32 pheochromocytomas and ab- dominal paragangliomas, all benign tumors had a Ki-67 index of <1%.36
Preoperative Procedures
Prophylactic therapy is required to prevent hyper- tensive crises and/or tachyarrhythmias. This approach is recommended for all patients with clinical or bio- chemical evidence of catecholamine secretion. An al- pha-adrenergic blocker is usually given 10-14 days preoperatively to normalize blood pressure.8 Phenoxy- benzamine, a nonselective alpha-blocker, can be ad- ministered starting at a dose of 10 mg once or twice daily, and increasing by 10-20 mg every 2-3 days as needed to control blood pressure and paroxysmal spells.4,37 Side effects include dizziness and nasal con- gestion. Use of selective alpha-blockers such as terazo- sin, prazosin, and doxazosin also has been described,38 and outcomes appear to be similar.39 On the second or third day of alpha-blockade, patients are encouraged to begin a high-sodium diet for volume expansion.37 Beta- adrenergic blockers or calcium channel blockers also can be started to control tachycardia but only after adequate alpha-blockade in order to avoid hypertensive crisis from unopposed alpha-adrenergic stimulation.40 Alpha-methyltyrosine inhibits tyrosine hydroxylase, a rate-limiting step in catecholamine biosynthesis, and is sometimes used as an adjunctive perioperative drug.41
Treatment of Localized Disease
Laparoscopic adrenalectomy is the preferred surgi- cal technique for management of most pheochromocy- tomas. Relative contraindications include large size (>10 cm) and/or malignant appearance on imaging.9 In a large series of 102 patients with pheochromocyto- mas, 97 operations were laparoscopic, seven were open, and four converted from laparoscopic to hand- assisted or open.9 There were no perioperative deaths. Seven patients (6%) experienced recurrent disease in the operative bed requiring reoperation. In another series of 161 pheochromocytomas and abdominal para- gangliomas, resected laparoscopically, only one patient converted to open resection and only five patients developed locoregional and/or distant metastatic recur- rence.42
Resection of head and neck paragangliomas can be challenging due to their high vascularity and proximity to cranial nerves. Preoperative embolization of the tu- mor’s arterial supply within 48 hours of surgery may reduce blood loss.43 Concurrent resection of bilateral tumors is usually not recommended. Among patients who are not surgical candidates, definitive radiother- apy offers high rates of tumor control. In one series of 121 paragangliomas of the head and neck, 89 were treated with conventional radiotherapy, and 32 with stereotactic or intensity modulated techniques. The overall local control rate at 10 years was 94% and cause-specific survival was 95%.44 Among patients who have residual disease after surgical resection, adjuvant radiotherapy appears to confer a survival benefit.6
Postoperative Follow-up
There are no definitive guidelines for postoperative surveillance of pheochromocytomas and paraganglio- mas. Case series with long term follow-up suggest that recurrences occur nearly a decade, on average, follow- ing initial surgical therapy.11,45 Predictors of increased risk of metastatic recurrence, or development of sec- ond primary tumors, include large tumor size, high Ki-67 index, and hereditary syndromes. The National Comprehensive Cancer Network (NCCN) recommends biannual biomarkers for the first 1-3 years followed by annual evaluations thereafter. Imaging studies are rec- ommended as clinically indicated.46
Treatment of Metastatic Disease
Approximately 10% of pheochromocytomas, and 30%-40% of abdominopelvic paragangliomas metasta- size. Common sites of distant spread include the liver, lungs and bone. The prognosis of malignant pheochro- mocytomas is relatively poor: 5-year overall survival in one study was 44%.47 Surgical debulking is recom- mended for patients with locally advanced tumors or limited metastases who can be resected with curative or near-curative intent.48 If the tumor appears to be aggressive or symptomatic, chemotherapy can be ad- ministered. One commonly used regimen consists of cyclophosphamide, vincristine, and dacarbazine (CVD) based on a series of 18 patients in which 10 (55%) had a complete or partial response.49 Recently, the tyrosine kinase inhibitor (TKI) sunitinib has been associated with tumor regression in case reports.50,51
Another approach is use of therapeutic doses of radioiodinated MIBG in patients showing evidence of radiotracer uptake on MIBG scans. This form of therapy relies on uptake of MIBG by tumors of neuroectoder- mal origin, thereby enabling delivery of targeted sys- temic radiation. In one retrospective single-institution study, 33 patients with metastatic pheochromocytomas and paragangliomas received a mean dose of 549 mCi of 131I-MIBG. Radiographic response rates were ob-
served in 38% of patients and median survival was 4.7 years.52 Among 22 symptomatic patients, 19 appeared to experience palliation of hypertension, abdominal pain, sweating, and/or palpitations. In another multi- center retrospective review of 116 patients treated with 131I-MIBG, overall response rate was 30% and hormonal response was 45%.53 A prospective study of 50 patients with metastatic pheochromocytoma and paraganglioma evaluated high-doses of 131I-MIBG rang- ing from 492-3,191 mCi.54 The overall objective re- sponse rate was 22% and the estimated 5-year survival rate was 64%. High rates of hematologic toxicity were observed.
MEDULLARY THYROID CANCER
Overview
MTCs arise from the parafollicular (C cells) of the thyroid gland. They represent approximately 5% of all thyroid cancers.55,56 Parafollicular cells share a com- mon neuroectodermal origin with the adrenal medulla. They secrete calcitonin, a hormone that plays an im- portant role in the calcium regulation of certain animals but not in humans. Sporadic cases account for approx- imately 75% of all MTCs.57 Nearly all the remainder are associated with the MEN 2 syndromes.58 While MTCs are characterized by a high rate of locoregional metas- tases, they tend to progress indolently and are associ- ated with 10-year survival rates of approximately 80%. Recent advances in genetic screening have enabled early detection of hereditary MTCs and prophylactic thyroidectomy for affected kindreds.
Genetics
All MEN 2 variants are autosomal-dominant syn- dromes caused by germline mutations of RET, a proto- oncogene located on chromosome 10 that encodes a tyrosine kinase receptor which provides mitogenic and survival signals to C cells.59 The protein consists of an extracellular ligand-binding domain, a cadherin-like do- main, and a cystein-rich domain. Mutations occur in codons 8, 10, 11, and 13-16. An early manifestation of all MEN 2 syndromes is parafollicular C-cell hyper- plasia, which eventually progresses to multicentric neoplasia. MEN 2 has been divided into three distinct subgroups: MEN 2A, MEN 2B, and familial MTC (FMTC).
MEN 2A, also known as Sipple syndrome, is defined by a predilection toward MTC, pheochromocytoma, and primary parathyroid hyperplasia. The respective frequency of these tumors is 90% for MTC, 40%-50% for pheochromocytoma, and 10%-20% for parathyroid hyperplasia. The majority of mutations in MEN 2A kin- dreds involve the cysteine-rich domain of the RET pro- tein, including exons 10 and 11.60 Patients who are not
detected through genetic screening typically present in their third decade.
MEN 2B, typically caused by a methionine to threo- nine mutation at codon 918 of RET (exon 16), is asso- ciated with MTC and pheochromocytoma but not hy- perparathyroidism.61 MTC in the setting of MEN 2B tends to be aggressive and occur at an early age, some- times presenting in the first year of life. Patients typi- cally have a marfanoid habitus. They also may develop mucosal neuromas involving the lips and tongue, and ganglioneuromatosis of the intestine. FMTC typically presents in the fourth decade and is characterized by a strong predisposition to MTC without the other clinical manifestations of MEN 2. The disease course tends to be less aggressive than in other MEN syndromes.58
Germline mutations of the RET gene also are be found in patients lacking a suspicious family history. In one series of 481 apparently sporadic cases, 35 patients (7%) were found to harbor a germline RET mutation.62 However, in another series of 67 unselected cases, only 1.5% were found to have germline mutations.63 Be- cause hereditary MTC can be prevented with prophy- lactic thyroidectomy, the American Thyroid Associa- tion recommends that all patients with MTC be offered germline RET testing.64
Somatic mutations of the RET gene occur in nearly half of sporadic MTCs.65 The majority of these are the M918T mutation. In one series of 100 sporadic cases, 43 patients had an identifiable RET mutation in their tumors. RET mutations were associated with increased risk of nodal and distant metastases, as well as a signif- icantly inferior survival rate.66
Clinical Presentation
Sporadic MTCs typically present with a solitary thy- roid nodule. Median age is approximately 50, with a female preponderance of 60% to 40%.67 Most tumors occur in the upper and central areas of the thyroid where C cells are present at higher concentrations.68 The diagnosis is usually made on fine-needle aspiration. On average, more than 50% of patients have locore- gional lymph node involvement at diagnosis and many present with palpable cervical adenopathy.69 Large pri- mary tumor size and multifocality of tumors increases the risk of lymph node involvement.70 Distant metasta- ses are observed in approximately 10%-20% of patients at diagnosis.57 These patients may present with hor- monal symptoms such as flushing and diarrhea, caused by excess secretion of calcitonin.
Radiographic Studies and Staging
When patients present with a solitary nodule, ultra- sonography of the neck is recommended to assess the tumor and locoregional lymph nodes.64,71 Ultrasonog- raphy typically reveals a hypoechogenic solid nodule with frequent microcalcifications. When lymph nodes
are identified or when calcitonin levels are >400 pg/ mL, cross-sectional imaging studies with neck, chest, and three-phase abdominal CT scans or contrast-en- hanced MRIs are recommended to rule out distant metastases.72
The recent edition of the American Joint Committee on Cancer (AJCC) included a proposed staging classifi- cation for MTCs that distinguishes between stage I tumors (<2 cm), stage II tumors (2-4 cm), stage III tumors (>4 cm or metastatic to level VI lymph nodes, or microscopically invading extrathyroidal tissue), and stage IV tumors (distant metastases or lymph node involvement outside level VI or gross soft-tissue exten- sion).73 In one study of 1,252 patients in the Surveil- lance, Epidemiology, and End Results (SEER) registry, 10-year overall survival rates for patients with localized, locoregional, and distant metastatic disease were 96%, 76%, and 40%, respectively.67
Histology
MTCs characteristically consist of eosinophilic po- lygonal cells arranged in nests and separated by stroma. Cellular pleomorphism or even multinucleated cells may be seen. The nuclei are typically uniform and the nuclear-to-cytoplasmic ratio is low. The tumor stroma characteristically contains amyloid, possibly derived from degenerated calcitonin.58 Several pathological variants have been described, including papillary, pseu- dopappilary, and follicular. The rare small cell variant is associated with an inferior prognosis.74 By immunohis- tochemistry, the majority of MTCs express low-molec- ular-weight cytokeratins,75 calcitonin, and calcitonin gene-related peptide. In addition, many tumors express carcinoembryonic enzyme (CEA).76 The Ki-67 prolifer- ative index has been found to correlate both with risk of postoperative recurrence and with overall survival.77
Treatment of Localized Disease
MTCs are multicentric in most hereditary cases and in up to 30% of sporadic cases.78 Locoregional lymph node involvement is detected histologically in the ma- jority of cases.57,79 For example, in one study of patients with palpable unilateral MTCs who underwent bilateral lymph node dissection, metastases were discovered in 81% of central node dissections, 81% of ipsilateral node dissections, and 41% of contralateral node dissec- tions.69 These tumor characteristics influence surgical management guidelines. A total thyroidectomy is rec- ommended for all cases of MTC, even among patients who appear to have small unifocal tumors. Moreover, evidence suggests that meticulous compartment-ori- ented lymph node dissection increases the odds of biochemical remission and improves long-term progno- sis.80 There is a lack of consensus, however, on the extent of lymph node dissection that would optimize cure rates while minimizing surgical morbidity.
The initial site of lymph node involvement is typi- cally the central compartment (level VI).69 As a result, most experts recommend that level VI lymph node dissection be performed in all cases; however, the NCCN considers central lymph node dissection to be optional in patients with unilateral tumors <1cm in size. Among patients with bilateral thyroid disease or tumors ≥1cm, the NCCN recommends bilateral central lymph node dissection (level VI).72 More extensive bi- lateral modified neck dissection (levels II-V) is recom- mended for patients with macroscopic lymph nodes metastases on examination or scans.
Other guidelines recommend routine bilateral neck dissection for hereditary MTC and ipsilateral neck dis- section for sporadic forms with contralateral dissection only when the ipsilateral lymph nodes are involved. A recent study reported high rates of contralateral lymph involvement even in patients with sporadic unilateral tumors, and recommended that complete bilateral neck dissection be performed routinely in all cases, except those where ipsilateral and central lymph node involvement was ruled out surgically.79
Because of the association between pheochromocy- toma and MTC in patients with MEN 2 syndromes, screening for a catecholamine-secreting tumor is rec- ommended prior to thyroid surgery. This can be done either by excluding MEN 2 via germline RET testing, or by measuring plasma/urine metanephrines.81 If a pheo- chromocytoma is detected, it should be resected prior to thyroidectomy.
The disruption of blood supply to the parathyroid glands during central neck dissection requires removal of at least several parathyroid glands during thyroidec- tomy. Some surgeons resect all four parathyroid glands with autotransplantation of fragments into individual muscle pockets. A novel strategy involves resection and autotransplantation of the two parathyroid glands ipsilateral to the primary tumor and the contralateral lower parathyroid, leaving the contralateral upper para- thyroid in situ. Parathyroid fragments can be trans- planted into the sternocleidomastoideoles in most cases. The exception is MEN 2A patients who are at risk for future hyperparathyroidism. These patients should therefore undergo transplantation of parathyroid tissue into the non-dominant forearm where it is more easily accessible in case of future graft hyperplasia.81
Postoperative Follow-up
All patients with MTC should be monitored with serial serum calcitonin and CEA measurements starting roughly 2 months after surgery and continuing semian- nually. Calcitonin appears to have two components, one with a rapid metabolism (half-life of 3 hours) and another with a slow metabolism (half-life of 30 hours).82 Elevated levels of calcitonin in the postoper- ative period are both sensitive and specific for residual
or recurrent disease.83 Conversely, normalization of calcitonin is termed “biochemical cure.” The doubling time of tumor markers correlates strongly with prog- nosis. In one study, patients with a CEA and calcitonin doubling time of less than two years had stable radio- graphic disease at 1-year intervals, whereas those with a shorter doubling time had evidence of radiographic disease progression by Response Evaluation Criteria in Solid Tumors (RECIST).84 In another study, doubling time of calcitonin correlated with recurrence within 5 years of surgery and with overall survival at 3 years.83 There is evidence that tumors with higher secretion of CEA versus calcitonin may represent a more immature and aggressive phenotype.85
The optimal approach to a patient with biochemical evidence of residual or recurrent disease is unclear. Several studies have suggested that among patients with recurrent locoregional disease after initial thyroid- ectomy, re-exploration, and lymph node dissection usu- ally fails to normalize calcitonin levels. Watchful wait- ing may be a preferable approach given that 10-year survival rates approach 80%-90% even in patients who experience biochemical recurrences after initial thyroidectomy.78,86 Several experts have advocated surgical neck re-exploration only among patients with radiographic evidence of resectable locore- gional recurrence.78
External Beam Radiotherapy
There is significant controversy regarding the role of adjuvant external beam radiotherapy (EBRT) among patients with locoregional neck disease. In one retro- spective series evaluating a 45-year institutional expe- rience, no survival benefit was observed among pa- tients who had received adjuvant EBRT for control of locoregional disease.87 However, in another series, the locoregional relapse-free survival rate was 86% at 10 years among patients who received EBRT versus 52% for those who did not.88 In an analysis of the SEER database, EBRT was associated with improved overall survival on univariate analysis but not on multivariate analysis controlling for other known prognostic fac- tors.89 The NCCN recommends consideration of thera- peutic EBRT among patients with grossly incomplete tumor resection and adjuvant EBRT for patients with gross extrathyroidal extension (T4) with positive mar- gins and following resection of moderate to high vol- ume disease with extranodal soft tissue extension.72
Prophylactic Thyroidectomy in MEN 2
Genetic screening in family members of MEN 2 pa- tients is strongly recommended since MTC is a life- threatening disease that can be prevented with prophy- lactic thyroidectomy. Patients lacking evidence of a mutated gene require no further screening. Recent advances in understanding genotype-phenotype corre-
lations have led to the development of published guide- lines that suggest the appropriate timing of thyroidec- tomy in children.56,64 Thyroidectomy during the first year of life is recommended for children with MEN 2B (very high risk), most commonly associated with mu- tations in codon 918. Thyroidectomy between ages 2 and 4 years is suggested for patients with mutations in codon 634 (high risk). Thyroidectomy between ages 5 and 10 is recommended for children with lower risk mutations. Serum CEA and calcitonin should be mea- sured prior to prophylactic thyroidectomy. Elevated levels should prompt consideration of central neck dissection.81
Treatment of Metastatic Disease
New targeted therapies have emerged based on im- proved understanding of signaling pathways. Activat- ing mutations of the RET tyrosine kinase receptor are observed in virtually all hereditary MTC cases and ap- proximately 50% of sporadic cases. Moreover, immu- nohistochemical analysis demonstrates overexpression of the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EGFR) in MTC patients.90 In recent years, several TKIs targeting these pathways have been tested in MTC with encouraging results.
The only agent, thus far, to demonstrate benefit in a phase III clinical trial has been vandetanib, an oral TKI of RET, VEGFR, and EGFR. In an international placebo- controlled study, 331 patients with metastatic MTC were randomized to receive vandetanib 300 mg daily versus placebo.91 The primary endpoint, progression- free survival (PFS), was significantly improved among patients assigned to the vandetanib arm (hazard ratio, 0.46; P <. 001). At a median follow-up of 24 months, the median PFS was not yet reached for the vandetanib group (but was estimated to be 30.5 months) com- pared to 19.3 months in the placebo group. Objective response rates were also significantly higher in the vandetanib arm (45% v 13%; P <. 001). Common ad- verse effects included rash, diarrhea, nausea, hyperten- sion, and headaches. Significant QTc prolongation on electrocardiogram was observed in 8% of cases.
Other promising agents include cabozantinib, a small-molecule TKI targeting VEGFR, c-MET, and RET. In a dose-escalation phase I study, 10 of 35 patients (29%) achieved a partial response.92 Another investiga- tional TKI, motesanib, targets VEGF, platelet-derived growth factor receptor (PDGFR), and RET. In a phase II study of 91 patients, 44 (48%) had stable disease for at least 6 months, and two patients had partial re- sponses.93 Sorafenib and sunitinib also have been stud- ied in small clinical trials.94,95 It is unclear whether they are active in patients who have progressed or are in- tolerant of vandetanib.
The role of cytotoxic chemotherapy has not been well established given the small size and retrospective nature of most series. In one study of seven patients treated with CVD, two patients experienced a partial radiographic and biochemical response.96 In another series, 20 patients were treated with a regimen consist- ing of doxorubicin and streptozocin alternating with 5-fluorouracil and dacarbazine. Objective responses were reported in three patients (15%).97
ADRENOCORTICAL CARCINOMA
Overview
The annual incidence of adrenocortical carcinomas (ACCs) is approximately 1-2 per million.98 There is a bimodal age distribution with peak occurrences in early childhood and in the fourth to fifth decades of life. The female to male ratio is approximately 1.5 to 1.99 The majority of cases are sporadic; however, ACCs can occur in association with several hereditary syn- dromes including Beckwith-Wiedemann syndrome, Li- Fraumeni syndrome, and multiple endocrine neoplasia type 1 (MEN 1).100-104 Inactivating mutations of the p53 tumor-suppressor gene (chromosome 17p13),105,106 as well as alterations at the 11p15 locus (site of the IGF-2 gene),107,108 are detected with high frequency in spo- radic cases.
Clinical Presentation
Approximately 60% of patients present with evi- dence of adrenal steroid hormone excess, usually Cush- ing’s syndrome with or without virilization.109-112 Signs and symptoms associated with hypersecretion of corti- sol include weight gain, moon facies, cervical fat pads, acne, abdominal striae, weakness (primarily in proxi- mal muscles), osteoporosis, hypertension, hyperglyce- mia, and hypokalemia. Androgen-secreting tumors in women may produce hirsutism and oligo/amenor- rhea.109 In men, estrogen-secreting tumors may induce gynecomastia and testicular atrophy. Patients with al- dostoerone-secreting tumors may present with hyper- tension and hypokalemia. Hormonally inactive ACCs are often diagnosed after evaluations for nonspecific symptoms such as flank or abdominal pain, and weight loss. 109,113
Radiographic Studies
On CT scans with IV contrast, ACCs often appear inhomogeneous and poorly circumscribed. On unen- hanced CTs, the Hounsfield unit (HU) number is usu- ally higher in carcinomas than in adenomas, and a threshold value of 10 HU has been proposed as a means of distinguishing benign from malignant tumors.114 Be- cause the lung and liver are the most common sites of metastatic spread, thoracic and abdominal scans are integral to the staging workup of ACCs. MRIs may more
easily identify local invasion and involvement of the inferior vena cava than CT scans.115,116 ACCs are usually isointense to liver on T1-weighted images and show increased intensity on T2 sequences. On fluorodeoxy- glucose (FDG) PET scans, hypermetabolic uptake is typically observed in malignant tumors but rarely in benign adenomas.117,118
Histology
The histological architecture of ACC generally re- sembles the normal adrenal cortex. The most common pattern consists of sheets of cells interrupted by a sinusoidal network.119 Immunohistochemical staining is generally negative or weakly positive for cytokera- tins. ACCs are also typically negative for chromogranin A, which helps distinguish them from tumors of the adrenal medulla.120 Immunostains that help distinguish ACC from renal neoplasms include steroidogenic fac- tor-1 (positive in nearly all cases of ACC and negative in renal neoplasms), and epithelial membrane antigen (negative in ACC and positive in most renal neo- plasms).121
Preoperative pathologic assessment of a suspected primary adrenal neoplasm is rarely indicated. Needle biopsies are relatively contraindicated due to the risk of capsule rupture and peritoneal seeding, as well as the risk of inducing hypertensive crisis in patients with pheochromocytomas. Even on analysis of a surgical specimen, the pathological distinction between a ma- lignant and benign adrenal tumor may be difficult. The most commonly used diagnostic tool is the Weiss score,122,123 which assesses the mitotic rate (>5 mito- ses/50 HPF), nuclear atypia, vascular and capsular in- vasion, and presence of necrosis.
Hormonal Evaluation
Patients with Cushing’s syndrome secondary to a cortisol-producing adrenal tumor will typically have elevated serum cortisol with suppressed serum adreno- croticotropin (ACTH). Confirmatory tests should in- clude either a 24-hour urine free cortisol, an overnight 1-mg dexamethasone suppression test, or a midnight salivary cortisol.109 For evaluation of masculinization or feminization symptoms, tests include serum dehydro- epiandrosterone sulfate (DHEA-S), androstenedione, testosterone, and 17-OH-progesterone.109 For evalua- tion of mineralocorticoid excess, a plasma aldosterone concentration greater than 15 ng/dL with an aldoste- rone to renin ratio >20 is suggestive of autonomous aldosterone secretion.
Tumor Staging and Grading
The World Health Organization (WHO) has pub- lished a tumor-node-metastasis (TNM) staging system for ACCs that distinguishes between tumors smaller ≤5 cm in size (stage I), tumors >5 cm (stage II), tumors
with locoregional lymph node involvement or invading periadrenal fat (stage III), and tumors invading adjacent organs or metastatic to distant sites (stage IV).119 The WHO classification is prognostic for overall survival. In one study, the 5-year survival rates for patients with stages I through IV were 66%, 58%, 24%, and 0%, respectively. Tumor grade is also an important prog- nostic factor. Mitotic rates above 20 mitoses per 50 HPF are associated with a shorter disease-free interval compared to lower mitotic rates.
Treatment of Localized Disease
For non-metastatic ACCs (stages I-III), surgical treat- ment is generally recommended.110 An en bloc adrenal- ectomy and regional lymphadenectomy with curative intent (R0 resection) should be attempted with an effort to avoid disruption of the tumor capsule.98 Tu- mor thrombus in the renal vein or inferior vena cava is not considered a contraindication to surgery.98,124 En bloc resection of the kidney is recommended for any patients with invasion of the renal capsule. The risk of local recurrence may be higher with laparoscopic ad- renalectomies, especially with larger or invasive tu- mors, and open adrenalectomies are therefore recom- mended as standard of care.125
Patients with locoregional recurrences after adrenal- ectomy can be considered for re-operation, particularly if complete resection can be achieved. Debulking of metastatic tumors can be considered in patients with low-grade tumors who are symptomatic from hormone secretion and in whom a complete or near complete removal of tumors is feasible.
Adjuvant Treatment
Due to the rarity of ACCs, there have been no published randomized, prospective trials of adjuvant therapy. The majority of retrospective reports have examined the use of adjuvant mitotane, an oral ad- renocorticolytic agent.126 The largest study retrospec- tively analyzed 177 patients with resected ACCs (stages I-III) treated in Italy and Germany.127 In the Italian cohort, nearly half received adjuvant mitotane (47/102 patients) at doses ranging from 1-5 g/d, whereas none of the 75 German patients received adjuvant mitotane. The median duration of treatment was 29 months. In follow-up, disease-free survival and overall survival were significantly longer in the treatment cohort versus the control cohorts, suggesting that adjuvant mitotane may be effective. However, given the retrospective nature of this analysis, there is little consensus on the role of adjuvant mitotane. Moreover, the optimal doses and duration of treatment have not yet been standard- ized. Because mitotane suppresses endogenous cortisol production and simulates the catabolismof cortisol, supraphysiologic replacement steroid doses are recom-
mended (eg, hydrocortisone 30-40 mg/d in divided doses) in order to prevent adrenal insufficiency.
There are little data on adjuvant radiotherapy follow- ing adrenalectomy. Radiation of the surgical bed may be considered in patients who are at high risk for local recurrence, eg, those with close or positive surgical margins, or disruption of the adrenal capsule. How- ever, the potential benefits of this approach are un- proven.
Treatment of Metastatic Disease
Mitotane has been evaluated in multiple small, sin- gle-arm studies and retrospective series. Objective ra- diographic response rates have been reported in approximately 25% of patients.111,128 Palliation of symp- toms resulting from excess corticosteroids may occur in the majority of cases. In the absence of randomized, prospective studies, it is unclear whether mitotane treatment is associated with a survival benefit. Several studies recommend target blood mitotane concentra- tions of 14-20 mg/dL.129 The therapeutic window of mitotane is low and toxicities increase sharply with blood levels exceeding 20 mg/dL. Side effects are mainly gastrointestinal and neurologic, including nau- sea and dizziness and somnolence.130
Corticosteroid replacement is necessary in patients who experience adrenal suppression due to mitotane, and in all patients with non-cortisol-producing ACCs.
Several studies have evaluated the combination of mitotane with other cytotoxic agents, including cispla- tin and etoposide. One of the larger studies analyzed the combination of mitotane (4 g/d) with cisplatin, etoposide, and doxorubicin (EDP), yielding an overall response rate of 49% (by WHO criteria) and a complete hormonal response in nine of 16 patients with func- tioning tumors.131 Another study examined the combi- nation of mitotane with streptozocin and reported an objective response rate of 36%.132
The above two cytotoxic regimens were recently compared in the phase III FIRM-ACT study, the largest ever conducted for treatment of advanced ACCs.133 In this trial, 304 patients were randomized to receive mitotane combined with EDP, or mitotane combined with streptozocin as first-line therapy. The objective response rate was found to be significantly higher in the EDP-mitotane group (23.2% v 9.2%) as was the PFS (5.0 months v 2.1 months). There was a trend towards improved overall survival with EDP-mitotane (14.8 months v 12.0 months), which did not reach statistical significance (P = . 07).
Medical Treatment of Corticosteroid Excess
Patients who experience symptoms secondary to adrenocortical steroid secretion may require treatment for palliation of symptoms such as hypertension, hypo- kalemia hyperglycemia, muscle atrophy, and cognitive
changes. Mitotane is often used as a first-line agent due to its tumorlytic effects but may be insufficient. Other adrenostatic agents include ketoconazole, metyrapone, aminoglutethimide, and etomidate. Ketoconazole is most commonly used at doses of 400-1,200 mg/d due to its easy availability and relatively tolerable toxicity profile.
CONCLUSIONS
Recent years have seen significant advances in evi- dence-based treatments for rare NETs. The identifica- tion of RET mutations in MTC followed by develop- ment of targeted RET inhibitors represents a triumph of translational research. Moreover, the successful com- pletion of randomized studies, such as the FIRM-ACT trial for advanced ACC, illustrates that large phase III trials are feasible with multinational cooperation.
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