Jaydira Del Rivero and Ann W. Gramza
INTRODUCTION
Endocrine tumors arise from hormone-secreting glands. They may be sporadic or part of a familial cancer syndrome (Table 33.1), the most common being the multiple endocrine neoplasia syndromes. With the exception of thyroid cancer, endocrine tumors are often difficult to diagnose and treat effectively. They may cause morbidity and mortality through local and distant metastasis or through systemic effects caused by hormones produced by tumor cells. While relatively uncommon as a group, thyroid cancer has increased in incidence over the last decade more than any other malignancy. The most common endocrine tumors include
Thyroid carcinoma
Pheochromocytoma and Paraganglioma
Carcinoid tumors
Pancreatic neuroendocrine tumors (NETs)
Adrenocortical carcinoma (ACC)
Parathyroid carcinoma
TABLE 33.1Hereditary Endocrine Cancer Syndromes
Familial Syndrome | Associated Malignancies | Gene Mutated |
MEN 1 (Werner syndrome) | Pituitary adenomas Functioning pancreatic neuroendocrine tumors (insulinoma, gastrinoma) Nonfunctioning pancreatic neuroendocrine tumors Parathyroid hyperplasia/adenomas causing hyperparathyroidism Peptic ulcers (with Zollinger-Ellison syndrome) Bronchial, thymic, gastric carcinoid | MEN 1 |
MEN 2A (Sipple syndrome) | Medullary thyroid cancer Pheochromocytoma Primary hyperparathyroidism (parathyroid hyperplasia) | RET |
MEN 2B | Medullary thyroid cancer Pheochromocytoma Marphanoid body habitus Multiple mucosal and digestive neurofibromas Megacolon | RET |
Familial MTC | MTC in kindreds with 4 to 10 or more affected members | RET |
Neurofibromatosis 1 | Carcinoids Pheochromocytomas/paragangliomas Pancreatic neuroendocrine tumors Gastrointestinal stromal tumors (GIST), | NF1 |
von Hippel-Lindau | Pheochromocytomas Pancreatic neuroendocrine tumors Hemangioblastomas Retinal angiomas Renal cell carcinomas Endolymphatic sac tumors Epididymal papillary cystadenomas | VHL |
Li-Fraumeni | Adrenocortical cancer Breast cancer Sarcoma Leukemia Brain tumors | TP53 |
Beckwith-Wiedemann | Adrenocortical carcinoma Wilms tumor Rhabdomyosarcoma Neuroblastoma Hepatoblastoma | Multiple in the 11p15 region |
Carney complex | Adrenocortical tumors Thyroid follicular neoplasms Pituitary adenomas Myxomas Schwannomas Sertoli cell tumors Leydig cell tumors | PRKAR1A |
Thyroid carcinoma Sarcoma Hepatoblastoma Pancreatic carcinoma Medulloblastoma Adenomatous colon polyps | APC | |
Cowden | Follicular thyroid cancer Breast cancer Endometrial carcinoma | PTEN |
Peutz-Jeghers | Thyroid cancer, benign ovarian sex cord tumors, calcifying Sertoli tumors of the testis, endometrial cancer, breast cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer | STK11/LKB1 |
Hyperparathyroidism-jaw tumor | Parathyroid cancer, ossifying fibromas of the jaw, cystic and neoplastic renal lesions, uterine tumors | HPRT2 |
THYROID CARCINOMA
General
Thyroid cancer is the most common endocrine malignancy, now over twice as common in the United States as it was 10 years ago, and it is now the fifth most common cancer in women in the United States.
The National Cancer Institute has estimated that 62,450 new cases of thyroid carcinoma are diagnosed in the United States annually, accounting for approximately 1950 deaths. The incidence of thyroid carcinoma is now about 9 per 100,000, with approximately 2.7 to 3.1 times as many women as men affected (in women at a rate >5% per year). The ratio of female to male patients is approximately 3:1.
Mortality has also been rising for the past two decades. The precise reasons for the increase in incidence and mortality are unknown.
The best-established risk factor for thyroid cancer is head and neck radiation exposure during childhood for diseases such as Hodgkin lymphoma; hereditary factors, family history of thyroid cancer and history of goiter or thyroid nodule, and/or preceding autoimmune thyroid disease are implicated in some patients as the cause of the increased risk of thyroid cancer.
Autoimmune thyroid disease is more prevalent in women and this may explain why thyroid cancer is more common in women that in men.
Thyroid cancer has been observed 20 to 25 years after radiation exposure among atomic bomb survivors, and in some regions of Japan the incidence of thyroid cancer in screened populations is as high as 0.1%—10-fold greater than expected based on US incidence rates.
Prognosis varies by thyroid cancer subtype, but the overall 5-year relative survival is nearly 98%. This is because more than 80% of cases are papillary thyroid cancer (PTC), the subtype with the best survival.
Differentiated Thyroid Cancer: Papillary, Follicular, Hurthle Cell
More than 90% of all thyroid cancers are a subtype of differentiated thyroid cancer (DTC) with papillary thyroid cancer (PTC) the most common subtype (80% to 85%).
PTC is generally unilateral, but may be multifocal within a lobe. Histologic subtypes of PTC that have a worse prognosis include tall cell variant, columnar cell variant, and diffuse sclerosing variant. A worse prognosis is also seen with highly invasive variants of follicular cancer, which is characterized by extensive vascular invasion and invasion into extrathyroidal tissues or extensive tumor necrosis with many mitoses. PTC metastasizes primarily via lymphatic invasion; vascular invasion is uncommon.
DTCs are derived from thyroglobulin-producing follicular cells (thyrocytes), often secrete thyroglobulin (TG) and are typically initially radioiodine (RAI) responsive. TG can be used as a tumor marker in antithyroglobulin antibody–negative patients.
Genetic alterations involved in the mitogen-activated protein kinase (MAPK) signaling pathway are found in at least 75% of PTC cases. BRAFV600E mutation is found in approximately 45% of PTCs, while rearranged during transfection (RET) are found in approximately 25%. Activating point mutations in the RAS oncogenes occur in approximately 10% of cases. RET rearrangements are found in approximately 25% and upregulation of vascular endothelial growth factor (VEGF) signaling is also common in metastatic disease.
Follicular thyroid cancer (FTC) is the second most common type of thyroid carcinoma, comprising 10% to 15% of thyroid cancers. FTC typically disseminates hematogenously, with metastases to bone and lung being most common in advanced disease.
RAS point mutations and the PAX8/PPARγ translocation are the most common genetic alterations in FTC.
Hurthle cell cancer (HCC) is also referred to as oxyphilic or oncocytic thyroid cancer, and represents approximately 5% of all DTCs. It is often considered a variant of FTC with less sensitivity to radioiodine and a more aggressive clinical course.
Most patients present with an asymptomatic thyroid nodule. Clinical symptoms may include the following:
•Hoarseness caused by invasion of the recurrent laryngeal nerve or by direct compression of the larynx
•Cervical lymphadenopathy
•Dysphagia
•Horner syndrome (miosis, partial ptosis, hemifacial anhidrosis)
Evaluation of any suspected thyroid nodule >1 cm should include a serum thyroid stimulating hormone (TSH) and thyroid ultrasound. Occasionally, thyroid nodules <1 cm require evaluation because of suspicious ultrasound findings, associated with lymphadenopathy, head and neck irradiation, or a family history of thyroid cancer.
If a nodule is seen on ultrasound
•If TSH is normal or high, a fine-needle aspirate (FNA) should be done.
•If the TSH is low, the nodule should be evaluated by radionuclide thyroid scan with either a 99mTc pertechnetate or 123I to see if it is hyperfunctioning. Hyperfunctioning nodules are benign and patients with them should be treated for hyperthyroidism.
Up to 30% of FNAs are indeterminate; therefore, a definitive diagnosis is often not made until the nodule is resected. A new gene expression classification assay was able to predict benign pathology when FNA cytology was indeterminate (e.g., BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8-PPARγ) and may allow a more conservative approach for those who would otherwise undergo a diagnostic surgical procedure. If the cytology reading reports follicular neoplasm, a lobectomy or total thyroidectomy should be considered.
Carcinoma is suggested by the following clinical findings: a history of head and neck radiation, family history of thyroid cancer, exposure to ionizing radiation, rapid growth of the nodule, hoarseness, vocal cord paralysis, and lymphadenopathy. There may also be specific features on ultrasound that are suggestive of possible malignancy.
Staging for DTC incorporates age. For patients ≤45 years old, the most advanced they can be is stage II given their excellent prognosis.
Total thyroidectomy is recommended for a DTC lesion >1 cm, a lesion that extends beyond the thyroid, or for patients with history of prior exposure to ionizing radiation to head/neck.
Unilateral lobectomy with en bloc resection of tumor may be considered for a DTC lesion <1 cm or for follicular lesion with no evidence of multicentric disease.
Total thyroidectomy with modified radical neck dissection should be done for regional lymph node metastases.
Thyroidectomy should be performed in patients with distant metastases to permit treatment with radioiodine, which can still be curative.
Mortality consequent to thyroidectomy in DTC is extremely low. Complications include recurrent laryngeal nerve damage in 2% of patients and hypoparathyroidism that is lifelong in 1% to 2% of patients.
TSH suppression via administration of “supra-therapeutic” levothyroxine is an essential component in the treatment of high-risk DTC, as residual cancer cells are usually initially responsive to TSH growth stimulation. Levothyroxine (T4, usual dosage range 125 to 200 μg by mouth daily) is administered to keep the TSH level suppressed below 0.1 mIU/L in high-risk (macroscopic tumor invasion, incomplete tumor resection, distant metastases) to intermediated risk patients (microscopic invasion of tumor into the perithyroidal soft tissues, cervical lymph nodes metastases, tumor with aggressive histology, or vascular invasion).
For low risk patients, the goal is to maintain TSH below the lower limit of normal 0.1 to 0.5 mIU/L.
Suppression of TSH below 0.1 mIU/L imposes long-term adverse effects on bone and can negatively impact quality of life, sometimes producing symptoms of thyrotoxicosis.
Treatment with radioiodine (I-131, RAI) is used to ablate normal residual thyroid tissue, treat micrometastases, and decrease cancer-related death, tumor recurrence, and development of distant metastases. Table 33.2 outlines indications for iodine-131 treatment after surgery.
Adjuvant external beam radiotherapy is sometimes recommended for those patients with gross or microscopic residual disease or those with high-risk histology and visible extrathyroidal extension. Locally recurrent disease not amenable to surgery or radioiodine therapy can also be treated with external beam radiotherapy.
TABLE 33.2Indications for Postsurgical Treatment with Iodine-131 in Patients with Thyroid Cancer
| Iodine-131 | |
Finding | Indicated | Not Indicated |
Low risk of cancer-specific mortality or relapse |
| X |
Incomplete excision of tumor | X |
|
Complete excision of tumor but high risk of mortality | X |
|
Complete excision of tumor but high risk of relapse due to | X |
|
Age (<16 y or >45 y) |
|
|
Histologic subtype (tall cell, columnar cell, diffuse sclerosing papillary variants; widely invasive or poorly differentiated follicular subtypes; Hurthle cell carcinomas) |
|
|
Extent of tumor (large tumor mass, extension beyond thyroid capsule, lymph node metastases) |
|
|
Distant metastases | X |
|
Elevated serum thyroglobulin >3 mo postsurgery | X |
|
Several VEGFR inhibitors have been shown to have activity in well-differentiated thyroid cancers and two—sorafenib and lenvatinib—have received FDA approval on the basis of randomized phase III trials for patients with advanced disease that is refractory to iodine-131.
Sorafenib is an inhibitor of several protein tyrosine kinases (VEGFR and PDGFR) and some intracellular serine/threonine kinases (e.g., C-Raf, wild-type and mutant B-Raf). Safety and effectiveness were established in a randomized trial involving 417 participants with locally recurrent or metastatic, progressive differentiated thyroid cancer that had not responded to radioactive iodine treatment. The sorafenib dose was 400 mg twice a day. The median progression-free survival (PFS) was 10.8 months with sorafenib compared to 5.8 months with placebo (P <0.0001). Partial responses were observed in 12.2% of patients receiving sorafenib compared with 0.5% in the placebo arm (P < 0.0001). The most common side effects with sorafenib were diarrhea, fatigue, alopecia, hand-foot skin reaction, rash, weight loss, anorexia, nausea, gastrointestinal and abdominal pains, and hypertension (see Table 33.3).
Lenvatinib is an inhibitor of the vascular endothelial growth factor receptor 2 (VEGFR2). The approval of lenvatinib was based on a multicenter, double blind, placebo-controlled trial that enrolled 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of progression within 12 months prior to randomization. Patients received lenvatinib 24 mg orally per day. Median PFS was 18.3 months in the lenvatinib arm and 3.6 months in the placebo arm (P <0.0001). Objective response rates were 65% and 2% in the lenvatinib and placebo arms, respectively. No statistically significant difference in overall survival between the two arms was demonstrated. The most common adverse reactions were hypertension, fatigue, diarrhea, arthralgia/myalgia, anorexia, weight loss, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. Adverse reactions led to dose reductions in 68% of patients receiving lenvatinib and 18% of patients discontinued lenvatinib for adverse reactions (see Table 33.3).
TABLE 33.3Systemic Therapy Regimens for Advanced or Metastatic Endocrine Cancers
Regimen | Malignancy |
Sorafenib 400 mg orally twice daily | Radioactive iodine refractory differentiated thyroid cancer |
Lenvatinib 14 mg orally daily | Radioactive iodine refractory differentiated thyroid cancer |
Vandetanib 300 mg orally daily | Medullary thyroid cancer |
Cabozantinib 140 mg orally daily | Medullary thyroid cancer |
Cyclophosphamide 750 mg/m2 day 1,Vincristine 1.4 mg/m2 day 1,Dacarbazine 600 mg/m2 day 1, and Dacarbazine 600 mg/m2 day 2, every 21–28 d | Malignant pheochromocytomaa |
Sunitinib 37.5 mg orally daily | Pancreatic neuroendocrine tumors, malignant pheochromocytomaa |
Everolimus 10 mg orally daily | Pancreatic neuroendocrine tumors, carcinoid |
Octreotide 150–250 µg SC TID or depot 20 mg IM every 4 weeks | Pancreatic neuroendocrine tumors, carcinoid |
Depot octreotide 30 mg IM every 28 d and Everolimus 10 mg daily | Pancreatic neuroendocrine tumors, carcinoid |
Streptozocin 500 mg/m2/d IV days 1–5 and5-Fluoruracil 400 mg/m2/d IV days 1–5 every 6 weeks | Pancreatic neuroendocrine tumors, carcinoida |
Streptozocin 500 mg/m2/d IV days 1–5 and Doxorubicin 50 mg/m2 IV days 1, 22 every 6 weeks | Pancreatic neuroendocrine tumors, carcinoida |
Capecitabine 750 mg/m2 twice daily on days 1–14 plus temozolomide 200 mg/m2 daily on days 10–14 | Pancreatic neuroendocrine tumors, carcinoida |
Mitotane orally continuously (starting dose = 1–2 g/d, increase to mitotane level of 14–20 mg/L or toxicity) | Adrenocortical carcinoma |
Mitotane orally continuously (starting dose = 1–2 g/d, increase to mitotane level of 14–20 mg/L or toxicity) andStreptozotocin (1 g on days 1–5 in cycle 1; 2 g on day 1 in subsequent cycles every 3 weeks) | Adrenocortical carcinoma |
Mitotane orally continuously (starting dose = 1–2 g/d, increase to mitotane level of 14–20 mg/L or toxicity) and Etoposide (100 mg /m2 IV days 2, 3, and 4), Doxorubicin (40 mg/m2 IV day 1), and Cisplatin (40 mg/m2 IV days 3 and 4) every 4 weeks | Adrenocortical carcinoma |
aLimited phase II data.
Medullary Thyroid Cancer
Medullary thyroid cancer (MTC) is a neuroendocrine tumor of the parafollicular or C cells of the thyroid gland. MTC accounts for approximately 4% of thyroid carcinomas. Its estimated incidence in the United States for 2010 is about 1,300 to 2,200 patients. Sporadic MTC accounts for about 80% of all cases of the disease. The typical age of presentation is in the fifth or sixth decade, and there may be a slight female preponderance.
Hereditary MTC is divided into three distinct clinical subtypes. Multiple endocrine neoplasia (MEN) 2A, or Sipple’s syndrome, is the most common subtype, accounting for approximately 70% to 80% of patients with hereditary MTC. MEN 2A is characterized by MTC in 100% of affected individuals, by pheochromocytoma in 50%, and by primary hyperparathyroidism in 20%. MTC is usually the first manifestation of the syndrome. Patients typically present with a thyroid nodule or neck mass by 15 to 20 years of age, but MTC can appear as early as 5 years of age. Sporadic tumors tend to be solitary, whereas familial tumors tend to be bilateral and multifocal.
MEN 2B is less common than MEN 2A, accounting for approximately 5% of MTC cases. It is characterized by a clinically more aggressive form of MTC that is manifest at a younger age (second decade) and that occurs in 100% of affected individuals, by pheochromocytoma in 50%, and by characteristic dysmorphic features including distinctive mucosal neuromas on the tongue, lips, and subconjunctival areas, diffuse ganglioneuromas of the gastrointestinal tract, and marfanoid habitus. Hyperparathyroidism is not associated with MEN 2B (see Table 33.1).
Familial MTC is the third clinical subtype of inherited MTC. It accounts for 10% to 20% of hereditary MTC cases and is defined by the presence of MTC in kindreds with four to 10 or more affected members and with objective evidence of the absence of adrenal and parathyroid gland involvement. This form of hereditary MTC is less aggressive and has an older age at onset, usually between 20 and 40 years, compared to MEN 2A and 2B
Patients typically present with an asymptomatic thyroid mass. Some may also have local symptoms such as dysphagia, dyspnea, or hoarseness.
Approximately 10% will present with systemic symptoms usually consisting of bone pain, flushing, and/or diarrhea.
Approximately 50% of patients present with regional lymphadenopathy.
Distant metastases typically occur in late-stage disease and usually involve lung, liver, bones, and adrenal glands.
Guidelines for evaluation of thyroid nodules should be followed as described for DTC.
If the FNA is suggestive of MTC, further evaluation should consist of calcitonin and CEA measurement and genetic testing for germline RET mutations.
Total thyroidectomy with central lymph node dissection is the appropriate surgery.
Surgery and/or external beam radiotherapy can be used for residual or recurrent disease treatment; however, the survival benefit for either modality is unclear.
Metastatic MTC is the most common cause of death in patients with MEN 2a, MEN 2b, or FMTC, and the tumor is relatively unresponsive to conventional doses of radiation therapy and to standard or novel chemotherapeutic regimens. Until recently, doxorubicin was the only US Food and Drug Administration (FDA)–approved treatment for patients with advanced thyroid cancer. Doxorubicin has resulted in transient tumor response rates in up to 20% of patients with MTC and is associated with significant toxicity. There is no treatment (apart from complete surgical removal) that has been shown to be effective for recurrent or persistent MTC.
Vandetanib, an oral inhibitor of VEGFR, RET, and epidermal growth factor receptor (EGFR) has been approved in April 2011 by the U.S. Food and Drug Administration (FDA) for the treatment of advanced (metastatic or unresectable locally advanced) medullary thyroid cancer based on an international randomized phase III trial. In a preliminary report of results (median follow-up 24 months), median PFS was improved in patients randomly assigned to vandetanib versus placebo (hazard ratio 0.45, 95% CI, 0.30 to 0.69). The overall response rate was 45%. Objective responses were durable on the basis of the median duration of response not being reached at 24 months of follow-up. Its toxicity profile is extensive including diarrhea, rash, nausea, hypertension, headache, fatigue, decreased appetite; Grade 3 toxicities reported are diarrhea, hypertension, and fatigue. Therefore, toxicity can limit its use in patients with small volume, asymptomatic or indolent disease.
Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), VEGFR2, and RET, demonstrated clinical activity in patients with medullary thyroid cancer (MTC). A double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC was performed. The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < 0.001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimated of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, PPE, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients. See Table 33.3 for vandetanib and cabozantinib dosing.
Both vandetanib and cabozantinib have recently been approved by the US FDA for the treatment of advanced MTC based on improvement in PFS in phase III trials. No improvement in overall survival has been demonstrated; therefore, patients with indolent disease should consider observation until their disease becomes necessary to treat.
Anaplastic Thyroid Cancer
Anaplastic thyroid cancer (ATC) is a rare, high-grade, aggressive malignancy that accounts for 2% to 5% of all thyroid carcinomas. Up to 50% of patients have antecedent or concurrent history of DTC. Disease-specific mortality is nearly 100%.
Patients typically present with a rapidly enlarging neck mass.
Approximately 90% will have locoregional or distant metastases at the time of diagnosis.
Treatment is primarily palliative and often aimed at preventing asphyxiation, the most common cause of death in these patients. It can consist of surgery, radiation, chemotherapy, or a combination of these modalities.
Surgical resection does not improve local control or survival in patients. If surgery is performed, it should be followed by locoregional radiotherapy usually within 2 to 3 weeks after surgery. Local control is desirable in patients with ATC because of the likelihood of asphyxia from the rapidly enlarging tumor.
Treatment with external beam radiotherapy with systemic therapy appears to achieve local control in two-thirds of patients with ATC, however, almost all subsequently die of distant metastases.
A number of novel agents have been preliminarily studied in ATC such as fosbretabulin assessed in phase II trial with increased overall survival in some patients. TKIs such as sorafenib, axitinib, gefitinib has been studied with no evidence of RECIST response; however, a limited number of patients were reported to have stable disease.
Other Thyroid Cancers
PHEOCHROMOCYTOMA
Epidemiology
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare rine tumors NETs that arise from chromaffin cells. Pheochromocytomas account for 90% of cases and arise in the adrenal glands, whereas paragangliomas, the extra-adrenal counterpart of pheochromocytomas, arise from ganglia along the sympathethic and parasympathetic chain (e.g., carotid body/skull base, urinary bladder, heart, organ of Zuckerkandl).
Most PHEOs represent sporadic tumors and 15% of these are associated with somatic mutations. However, about 35% are familial in origin and patients are found to harbor germline mutations in susceptibility genes.
The number of genes associated with susceptibility to PHEOs/PGLs was recently increased to 19, and includes the von Hippel-Lindau (VHL) tumor suppressor gene, the RET proto-oncogene, the neurofibromatosis type 1 (NF1) tumor suppressor gene, the genes encoding the four succinate dehydrogenase complex (SDH) subunits (SDHA, -B, -C, -D), and the gene encoding the enzyme responsible for flavination of the SDHA subunit (SDHAF2). Additionally, new susceptibility genes, transmembrane protein 127 (TMEM127), MYC-associated factor X (MAX), and hypoxia-inducible factor 2α (HIF2A), have been identified. Others include the kinesin family member 1B, transcript variant β (KIF1Bβ), prolyl hydroxylase 1 and 2 (PHD1/EGLN2 and PHD2/EGLN1), Harvey Ras sarcoma viral oncogene (H-RAS), Kirsten Ras sarcoma viral oncogene (K-RAS), isocitrate dehydrogenase 1 (IDH1), fumarate hydratase (FH) and BRCA1-associated protein-1 (BAP1). Finally, germline mutations in malate dehydrogenase 2 (MDH2) and somatic mutations in alpha thalassemia/mental retardation syndrome X-linked (ATRX) genes were identified in PHEOs/PGLs (see Table 33.5)
TABLE 33.4Potential Clinical Manifestations of Pheochromocytomas
Mild labile hypertension to hypertensive crisis; sustained hypertension also common |
Myocardial infarction |
Cerebral infarction |
Classic pattern of paroxysmal hypertension (30%–50% of cases) |
Spells of paroxysmal headache |
Pallor or flushing |
Tremor |
Apprehension |
Palpitation |
Orthostasis |
Mild weight loss |
Diaphoresis |
TABLE 33.5Clinical Characteristics of Genetic Mutations Associated with PHEO/PGL
Gene | Syndrome | Germline/ somatic | Common PHEO/PGL sites | Malignancy | Other associated clinical characteristics/tumors |
SDHA | AD | Adrenal PHEOs or extra-adrenal PGLs | 0%–14% | Homozygous patients: Leigh syndrome Renal cell carcinoma Gastrointestinal stromal tumors Pituitary adenomas | |
SDHB | PGL4 | AD | Sympathetic PGLs (rarely adrenal PHEOs and head and neck PGLs) | 31%–71% | Renal cell carcinoma Gastrointestinal stromal tumors Pituitary adenomas Possibly breast carcinoma Possible papillary thyroid carcinoma |
SDHC | PGL3 | AD | Head and neck PGLs, sometimes multiple (rarely sympathetic PGLs or adrenal PHEOs) | Rare | Renal cell carcinoma Gastrointestinal stromal tumors Pituitary adenomas |
SDHD | PGL1 | AD | Head and neck PGLs, commonly multiple (rarely extra-adrenal abdominal PGLs or adrenal PHEOs) | <5% | Renal cell carcinoma Gastrointestinal stromal tumors Pituitary adenomas |
SDHAF2 | PGL2 | AD | Head and neck PGLs, sometimes multiple | Further study needed | |
VHL | VHL | AD | Adrenal PHEOs (rarely sympathetic or head and neck PGLs) | <5% | Hemangioblastomas Pheochromocytoma Renal cell carcinoma Pancreatic serous cystadenoma Endolymphatic sac tumor Pancreatic neuroendocrine tumors Epidydimal papillary cystadenomas Retinal angiomas |
NF1 | AD | Adrenal PHEOs (rarely sympathetic PGLs) | ~12% | Café-au-lait spots Neurofibromas Freckles Benign iris hamartomas Optic-nerve gliomas Sphenoid bone dysplasia/pseudoarthritis | |
RET | MEN2 | AD | Adrenal | Rare | MEN2A: Medullary thyroid cancer, pheochromocytoma, hyperparathyroidism MEN2B: Medullary thyroid cancer, pheochromocytoma, marphanoid habitus and mucosal ganglioneuromas |
MAX | AD PI | Adrenal | 20-25% | ||
TMEM127 | AD | Adrenal | <5% | Possibly linked to breast carcinoma Possibly linked to papillary thyroid carcinoma | |
HIF2A | Pacak-Zhuang | Somatic | Extra-adrenal PGLs, usually multiple PHEOs | None reported | Multiple somatostatinomas Polycythemia |
KIF1β | Somatic | Further study needed | None reported | ||
PHD2 | Yes | Germline | Multple PGLs | None reported | |
IDH | Somatic | Carotid PGL | None reported | Glioblastoma multiforme | |
FH | Germline | Adrenal PHEO | Polycythemia | ||
H-RAS | Somatic | Both PHEO and PGL | None reported |
Clinical Presentation
Clinical manifestations of PHEO/PGL are diverse, with similar symptoms occurring in other disease conditions. Most of the signs and symptoms are attributed to the direct actions of the over production of catecholamines. These include hypertension, headache, palpitations, and anxiety. Hypertension can be paroxysmal or sustained. Some patients may present with orthostatic hypotension. Biochemically silent tumors may be suspected from tumor mass effect or may be found incidentally on imaging studies (see Table 33.4).
The incidence of malignancy is about 10%, with metastases the only definite proof of malignancy, as there are no definitive histopathologic criteria for malignancy. Oncologists must read the literature carefully given that descriptions of benign and malignant are often combined.
The overall 5-year survival rate for patients with malignant pheochromocytoma is 36% to 44%. About 50% or more of SDHB mutation carriers will develop malignant paragangliomas, and up to 60% of patients with a malignant paraganglioma harbor a SDHB mutation.
Diagnosis
Measurement of 24-hour urinary-fractionated metanephrines is the most specific tool for diagnosis of pheochromocytoma.
Plasma-fractionated metanephrines measurement is the most sensitive test, but has a high rate of false positives.
Clonidine suppression test is recommended for indeterminate plasma catecholamine or metanephrine levels, both of which will not be suppressed in patients with pheochromocytoma.
CT and MRI are equally sensitive diagnostic tools for pheochromocytoma.
Labeled metaiodobenzylguanidine (131I-MIBG), which is structurally similar to norepinephrine, is taken up and concentrated in adrenergic tissue. It is highly sensitive and specific for malignant tumors and familial syndromes, but is inferior to bone scan for detecting bone metastases.
Vascular invasion and extension into the cortex may be seen with both benign and malignant tumors.
Treatment
Surgery, remains the only curative treatment option with pheochromocytoma/paraganglioma. Minimally invasive adrenalectomy is recommended for most adrenal pheochromocytomas and open resection for large or invasive tumors to ensure complete resection and avoid local recurrence.
Patients with hormone secreting tumors should undergo preoperative blockade for 7 to 14 days with α-adrenergic receptor blockers such as phenoxybenzamine or doxazosin to prevent perioperative cardiovascular complications.
Many patients require the addition of β-blockers, which are indicated for persistent tachycardia; however, to prevent hypertensive crisis secondary to unopposed vasoconstriction, β-blockers should not be given before α-antagonists. In patients in whom elevated blood pressure and arrhythmia cannot be controlled with α- and β-blockade, α-methyl-para-tyrosine (metyrosine, Demser) a competitive inhibitor of tyrosine hydroxylase can be used.
Importantly, normal postoperative biochemical test results do not exclude microscopic disease. Long-term periodic follow-up is recommended especially important if the tumors harbor mutations of disease-causing genes.
Radiation has a limited role in the treatment of pheochromocytoma, but may be used for bone and soft-tissue metastases.
Therapeutic doses of 131I-MIBG in patients showing evidence of radiotracer uptake on MIBG scans have provided both radiographic and symptomatic responses.
Combined chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD) has emerged as a standard option. Results of a nonrandomized, single-arm trial included fourteen patients with confirmed malignant PHEO with metastatic disease and elevated urinary catecholamine secretion. After optimization of antihypertensive therapy, patients received cyclophosphamide, 750 mg/m2 on day 1; vincristine, 1.4 mg/m2 on day 1, and dacarbazine, 600 mg/m2 on days 1 and 2, every 21 days. Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine produced a complete plus partial response rate of 57% (median duration, 21 months; range, 7 to more than 34). Complete and partial biochemical responses were seen in 79% of patients (median duration, more than 22 months; range, 6 to more than 35). All responding patients had objective improvement in performance status and blood pressure.
A long-term follow-up study was conducted in 18 patients treated with CVD at the National Institutes of Health. Combination chemotherapy with CVD produced a complete response rate of 11% and a partial response rate of 44%. Median survival was 3.8 years for patients whose tumors responded to therapy and 1.8 years for patients whose tumors did not respond (P = 0.65). All patients with tumors scored as responding reported improvement in their symptoms related to excessive catecholamine release and all had objective improvements in blood pressure. In this 22-year follow-up there was no difference in OS between patients whose tumors objectively shrank and those with stable or progressive disease. However, patients reported improvement in symptoms, had objective improvements in blood pressure, and had tumor shrinkage that made surgical resection possible. CVD therapy is not indicated in every patient with metastatic PHEOs/PGLs, but should be considered in the management of patients with symptoms and where tumor shrinkage might be beneficial.
Anecdotal reports suggest that the efficacy of chemotherapy may be high in patients with mutations in SDHB. Although the CVD regimen led to an overall response of approximately 50%, it is not clear if the administration of CVD impacts overall survival, as nearly all patients develop progressive and ultimately fatal disease.
Responses have also been reported with the targeted agent sunitinib.
See Table 33.3 for detailed chemotherapy regimens.
NEUROENDOCRINE TUMORS
NETs are cancers of the interface between the endocrine system and the nervous system. These rare tumors are distinguished from most other solid tumors by their ability to secrete biologically active molecules that can produce systemic syndromes. The 2010 WHO classification separates NETs into well-differentiated and poorly differentiated based on tumor grade, mitotic count, and Ki-67 proliferation index. The most common types of NETs are carcinoid tumors and pancreatic NETs, both of which are typically well differentiated.
Carcinoid Tumors
Incidence in the United States is approximately 2 per 100,000 individuals.
Carcinoids are slow-growing malignant tumors that arise from enterochromaffin cells of the aerodigestive tract.
They are traditionally categorized by their embryonic origin and are most commonly found in the foregut (bronchial) and small intestine.
The typical carcinoid syndrome consists of flushing and diarrhea and is seen most often with small intestine carcinoid tumors.
Carcinoid syndrome is observed in 10% of patients, especially those with liver metastases, retroperitoneal disease, or disease outside of the GI tract where excessive hormones can bypass metabolism in liver.
Features of foregut, midgut, and hindgut carcinoids are outlined in Table 33.6.
TABLE 33.6Carcinoid Features
Origin | Common Sites | Symptoms | Secretory Products |
Foregut | Stomach, duodenum | Abdominal pain, anemia, bleeding, atypical carcinoid syndrome uncommon | 5-HTP, histamine, tachykinins, other hormones, and peptides |
| Bronchus | Pulmonary symptoms, atypical carcinoid syndrome uncommon |
|
Midgut | Small bowel | Abdominal pain, carcinoid syndrome with liver metastases | Serotonin, other hormones, and peptides |
| Appendix | Asymptomatic, usually found incidentally, carcinoid syndrome with liver metastases |
|
Hindgut | Distal colon, rectum | Bowel habit changes, pain, obstruction, bleeding, carcinoid syndrome rare | Rare |
Abdominal and rectal carcinoids tend to be small (2 cm). Surgery involves segmental resection with mesenteric lymphadenectomy.
Appendiceal carcinoid is often discovered incidentally. If it is >2 cm or there is invasion or positive margins, right hemicolectomy is recommended. Right hemicolectomy is more controversial for tumors that are <2 cm and confined to the appendix.
Liver metastases can be treated locally with surgical debulking, hepatic arterial embolization, chemoembolization, cryotherapy, or radiofrequency ablation.
Patients with carcinoid syndrome should be treated with a somatostatin analog (SSA) such as octreotide. Octreotide has also demonstrated antitumor activity, potentially improving time to progression.
The U.S. Food and Drug Administration (FDA) has recently approved telotristat ethyl (targets tryptophan hydroxylase, an enzyme that mediates the excess serotonin production within NET cells), an orally administered therapy for the treatment of carcinoid syndrome diarrhea in combination with SSA therapy in adults inadequately controlled by SSA therapy.
Carcinoids are resistant to most chemotherapeutic agents. Active agents include 5-fluorouracil, capecitabine, streptozocin, doxorubicin, and interferon. Chemotherapy is typically reserved for patients who are progressing with no other treatment options. See Table 33.3 for detailed systemic therapy regimens.
Radiation therapy is for palliation only.
Pancreatic Neuroendocrine Tumors
Pancreatic NETs, also known as islet cell tumors, arise from the hormone-secreting cells of the pancreas. Up to 75% are nonfunctioning and not associated with clinical syndromes. The functioning pancreatic NETs and are categorized by the hormone and clinical syndrome they produce. Pancreatic NETs comprise approximately 3% of all pancreatic tumors, are generally well differentiated, and are malignant. They are associated with familial syndromes in up to 25% of cases (see Table 33.1).
Gastrinoma (Zollinger-ellison Syndrome)
Gastrinoma is a tumor that secretes gastrin. Primary tumors predominate in the pancreatic head but may also develop in the small intestine or stomach.
Gastrinoma occurs in 0.1% to 1% of patients with peptic ulcer disease.
They are usually diagnosed between the third and sixth decades but can occur at any age.
Approximately 20% of gastrinomas are associated with the familial syndrome MEN 1, and 80% are sporadic. Sporadic tumors often have somatic mutations in the MEN1 gene.
Approximately one-third of patients with gastrinoma have metastatic disease at diagnosis.
Diagnosis and Clinical Presentation
Patients typically present with severe, often refractory peptic ulcer disease accompanied by abdominal pain and diarrhea.
Diagnosis is made by a fasting gastrin level: >1,000 pg/mL with a gastric acid pH <5.0 or gastrin level that increases by ≥200 pg/mL within 15 minutes of intravenous infusion of secretin.
Other common diagnostic procedures include ultrasonography, CT scan, MRI, endoscopic ultrasonography, angiography, and octreotide scan.
Medical therapy is standard for gastrinoma associated with MEN 1, given that tumors are often multifocal and incurable. Some surgeons will offer resection with the intent of reducing future morbidity from metastatic disease.
Surgical resection with exploratory laparotomy is curative in up to 50% of patients with sporadic gastrinoma without metastatic disease.
The goal of medical therapy is to control gastrin secretion and acid production. Therapies include proton pump inhibitors, somatostatin analogs (e.g., octreotide), and tumor embolization.
Both sunitinib and everolimus were approved for the treatment of progressive, well-differentiated pancreatic NETs. Approval was based on improved PFS.
Cytotoxic chemotherapy can also be used for metastatic disease. Active chemotherapeutic agents include streptozotocin, doxorubicin, temozolomide, 5-fluorouracil, and dacarbazine.
See Table 33.3 for detailed chemotherapy regimens.
For those patients with liver metastases, liver-directed therapies such as embolization, radiofrequency ablation, and cryosurgery are options.
Insulinoma is the most common type of functioning pancreatic NET.
It occurs most commonly in the fifth decade of life, with a slight female predominance.
Most insulinomas are solitary and approximately 10% are malignant, as defined by the presence of metastases.
Diagnosis and Clinical Presentation
Three criteria, known as Whipple triad, suggest insulinoma:
Symptoms known or likely to be caused by hypoglycemia (confusion, personality change, palpitations, diaphoresis, tremulousness)
Hypoglycemia during symptoms
Relief of hypoglycemia symptoms when glucose is raised to normal
An inappropriately high level of insulin during an episode of hypoglycemia establishes the presence of insulinoma.
Asymptomatic patients may be diagnosed after prolonged fasting by testing levels of serum glucose, insulin, and C-peptide every 6 to 12 hours.
Surgery is the treatment of choice for insulinoma and is most often curative.
Patients with recurrent disease that includes liver metastases can be treated with surgical resection (when possible) or liver-directed therapy such as chemoembolization or radiofrequency ablation.
Refractory hypoglycemia can be treated with oral diazoxide, which inhibits pancreatic secretion of insulin and stimulates release of catecholamine and glucose from the liver.
Both sunitinib and everolimus have been approved for the treatment of progressive, well-differentiated pancreatic NETs. Approval was based on improved PFS.
Cytotoxic chemotherapy can also be used for metastatic disease. Active chemotherapeutic agents include streptozotocin, doxorubicin, temozolomide, 5-fluoruracil, and dacarbazine.
See Table 33.3 for detailed chemotherapy regimens.
VIPoma (Verner-morrison Syndrome)
VIPoma is a rare NET that usually originates in the pancreas and produces vasoactive intestinal peptide (VIP).
Elevated serum VIP establishes the presence of VIPoma.
Patients present with watery diarrhea, hypokalemia, and hypo- or achlorhydria.
Diarrhea may be treated effectively with somatostatin analogs, which decrease VIP secretion. Interferon-α can also be used.
Patients with recurrent disease that includes liver metastases can be treated with surgical resection (when possible) or liver-directed therapy such as chemoembolization or radiofrequency ablation.
Both sunitinib and everolimus have been approved for the treatment of progressive, well-differentiated pancreatic NETs. Approval was based on improved PFS. See Table 33.3 for detailed chemotherapy regimens.
Glucagonoma is a rare tumor of the pancreas that results in overproduction of the hormone glucagon.
Serum levels of glucagon >500 pg/mL are diagnostic of glucagonoma.
Glucagonoma leads to diabetes, weight loss, anemia, and increased risk of thromboembolism.
Patients commonly present with necrolytic migratory erythema, which may be treated with zinc supplements and amino acid infusion.
Surgery, somatostatin analogs, anticoagulants, and targeted therapy/chemotherapy (as described for the other pancreatic NETs) are therapeutic options for glucagonomas.
Somatostatinoma is a tumor of the endocrine pancreas that secretes excess somatostatin. The tumor inhibits secretion of insulin, other pancreatic hormones, pancreatic enzymes, and gastric acid production.
Surgery is the treatment of choice, but targeted therapy/chemotherapy (as described for the other pancreatic NETs) is indicated for unresectable disease.
ADRENOCORTICAL CARCINOMA
Epidemiology
ACC is a rare malignancy arising from the adrenal cortex, with 1.5 to 2 cases per million population per year.
It has a bimodal age distribution, with a first peak in children younger than 5 years and a second peak in adults in their fourth to fifth decade.
ACC remains a difficult to treat disease, with a 5-year survival of 10% to 25% and an average survival from diagnosis of ≈14.5 months.
Most cases are sporadic, but it can be a component of a hereditary syndrome (Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, MEN-1) (see Table 33.1).
Clinical Presentation
Symptoms may arise from the effects of local mass or distant metastases. Approximately 50% of patients present with evidence of hormonal excess consisting of
Diagnosis
Imaging studies can usually distinguish benign adenomas from ACC. Because ACC have lower lipid content than benign adenomas they usually have higher density values on CT scans; while on MRI they are usually iso-intense with liver on T1 images, and have intermediate to high intensity on T2 images.
Biochemical evaluation (urinary steroids and suppression tests) should be conducted if clinically warranted.
FNA cannot differentiate an adrenal adenoma from ACC, and should only be done if the adrenal mass is suspected to be a metastasis from another malignancy.
Diagnosis is often confirmed upon surgical resection; however, histologic differentiation of adrenocortical adenomas and carcinomas is challenging.
Carcinomas tend to display mitotic activity, aneuploidy, and venous invasion. Carcinomas may also secrete abnormal amounts of androgens and 11-deoxysteroids.
Treatment
A tumor with local invasion and nodal involvement, tumor invading adjacent organs, or any tumor with distant metastases constitutes stage IV disease.
En bloc resection is initially appropriate for stages I to III.
Debulking of unresectable or stage IV disease should be considered, particularly for symptom relief from hormone-secreting tumors; local recurrence and metastatic disease require further resection when feasible.
In general, adrenal tumors >6 cm (or <6 cm but suspected of being malignant) should be resected via open adrenalectomy. Because surgery remains the only proven curative option for a patient with ACC it must always be aggressively pursued at presentation and at relapse and a laparoscopic approach should never be used.
Adjuvant mitotane may improve survival for patients with stage I to III disease who have undergone a complete resection.
Several small and one large retrospective studies suggest mitotane given as an adjuvant therapy and continued indefinitely can at a minimum delay and possibly prevent a recurrence of disease.
Replacement steroids can be started with the initiation of mitotane or when clinical and laboratory parameters indicate adrenal insufficiency. Both fludrocortisone and hydrocortisone should be given.
An international prospective randomized trial comparing mitotane to placebo in this patient population is currently ongoing.
For advanced disease, mitotane monotherapy induces hormonal response rates in up to 75% of patients with functional tumors, with no change in OS.
Combination chemotherapy with mitotane plus etoposide, doxorubicin, and cisplatin (EDP) demonstrated better rates of response and disease-free survival (DFS) than mitotane plus streptozotocin in patients with advanced disease based on the FIRM-ACT trial (First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment). The study found a significantly better response rate (23.2% vs. 9.2%, P<0.001) and PFS (5.0 months vs. 2.1 months; hazard ratio, 0.55; P<0.001) with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events.
Radiofrequency ablation may also be implemented for local control or metastases in patients with unresectable disease.
See Table 33.4 for detailed chemotherapy regimens.
PARATHYROID CARCINOMA
Clinically, it is important to distinguish this disease from other benign disorders that cause hyperparathyroidism. Parathyroid carcinoma accounts for less than 1% of cases of hyperparathyroidism.
Epidemiology and Natural History
Parathyroid carcinoma occurs in <1 per million individuals per year, predominantly diagnosed in the fifth or sixth decade of life.
Germline or somatic mutations of the HRPT2 tumor suppressor gene are detected in the majority of cases.
Ten-year survival rate is approximately 70%; however, 40% to 60% will recur after initial surgery.
Morbidity and mortality are usually related to hypercalcemia rather than complications of metastases.
Clinical Presentation
Patients typically present with the following:
Symptoms of hypercalcemia, with calcium levels usually >14 mg/dL
Elevated parathyroid hormone levels
Palpable neck mass in up to 70%
Metastases to cervical lymph nodes, lungs bone, or liver in approximately 10%
Diagnosis
Parathyroid carcinoma is difficult to diagnose preoperatively; differential includes parathyroid adenoma and hyperplasia.
Most parathyroid carcinomas are diagnosed at surgery; however, some are not diagnosed until local recurrence or metastases. This is because there are no definitive histopathologic features to differentiate carcinoma from adenoma.
FNA is inappropriate for diagnosis.
Treatment
Treatment consists of parathyroidectomy with en bloc resection of tumor and involved structures. This may include the ipsilateral lobe of thyroid. Radical lymph node dissection is not recommended.
Recurrent tumor and oligometastases should also be resected.
Parathyroid tumors are generally not radiosensitive.
Small retrospective studies suggest there may be improved local control with postoperative radiotherapy for high-risk patients.
Radiation may have palliative benefit.
Chemotherapy efficacy is limited to case reports, and there is no standard regimen.
Management of hypercalcemia is essential while treating parathyroid carcinoma.
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