Chapter 53: Pheochromocytoma and Adrenocortical Carcinoma

Pheochromocytomas and paragangliomas are catecholamine-producing tumors derived from the sympathetic or parasympathetic nervous system. These tumors may arise sporadically or be inherited as features of multiple endocrine neoplasia type 2, von Hippel–Lindau disease, or several other pheochromocytoma-associated syndromes. The diagnosis of pheochromocytomas identifies a potentially correctable cause of hypertension, and their removal can prevent hypertensive crises that can be lethal. The clinical presentation is variable, ranging from an adrenal incidentaloma to a hypertensive crisis with associated cerebrovascular or cardiac complications.

Pheochromocytoma is estimated to occur in 2–8 of 1 million persons per year, and ~0.1% of hypertensive patients harbor a pheochromocytoma. The mean age at diagnosis is ~40 years, although the tumors can occur from early childhood until late in life. The classic “rule of tens” for pheochromocytomas states that ~10% are bilateral, 10% are extra-adrenal, and 10% are malignant.

Pheochromocytomas and paragangliomas are well-vascularized tumors that arise from cells derived from the sympathetic (e.g., adrenal medulla) or parasympathetic (e.g., carotid body, glomus vagale) paraganglia (Fig. 53-1). The name pheochromocytoma reflects the black-colored staining caused by chromaffin oxidation of catecholamines; although a variety of terms have been used to describe these tumors, most clinicians use this designation to describe symptomatic catecholamine-producing tumors, including those in extra-adrenal retroperitoneal, pelvic, and thoracic sites. The term paraganglioma is used to describe catecholamine-producing tumors in the skull base and neck; these tumors may secrete little or no catecholamine. In contrast to common clinical parlance, the World Health Organization (WHO) restricts the term pheochromocytoma to adrenal tumors and applies the term paraganglioma to tumors at all other sites.

The etiology of sporadic pheochromocytomas and paragangliomas is unknown. However, 25–33% of patients have an inherited condition, including germ-line mutations in the classically recognized RET, VHL, NF1, SDHB, SDHC, and SDHD genes or in the more recently recognized SDHA, SDHAF2, TMEM127, and MAX genes. Biallelic gene inactivation has been demonstrated for the VHL, NF1, and SDH genes, whereas RET mutations activate receptor tyrosine kinase activity. SDH is an enzyme of the Krebs cycle and the mitochondrial respiratory chain. The VHL protein is a component of a ubiquitin E3 ligase. VHL mutations reduce protein degradation, resulting in upregulation of components involved in cell cycle progression, glucose metabolism, and oxygen sensing.

Its clinical presentation is so variable that pheochromocytoma has been termed “the great masquerader” (Table 53-1). Among the presenting manifestations, episodes of palpitation, headache, and profuse sweating are typical, and these manifestations constitute a classic triad. The presence of all three manifestations in association with hypertension makes pheochromocytoma a likely diagnosis. However, a pheochromocytoma can be asymptomatic for years, and some tumors grow to a considerable size before patients note symptoms.

The dominant sign is hypertension. Classically, patients have episodic hypertension, but sustained hypertension is also common. Catecholamine crises can lead to heart failure, pulmonary edema, arrhythmias, and intracranial hemorrhage. During episodes of hormone release, which can occur at widely divergent intervals, patients are anxious and pale, and they experience tachycardia and palpitations. These paroxysms generally last <1 h and may be precipitated by surgery, positional changes, exercise, pregnancy, urination (particularly with bladder pheochromocytomas), and various medications (e.g., tricyclic antidepressants, opiates, metoclopramide).

The diagnosis is based on documentation of catecholamine excess by biochemical testing and localization of the tumor by imaging. These two criteria are of equal importance, although measurement of catecholamines or metanephrines (their methylated metabolites) is traditionally the first step in diagnosis.

Biochemical testing

Pheochromocytomas and paragangliomas synthesize and store catecholamines, which include norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine. Elevated plasma and urinary levels of catecholamines and metanephrines form the cornerstone of diagnosis. The characteristic fluctuations in the hormonal activity of tumors results in considerable variation in serial catecholamine measurements. However, most tumors continuously leak O-methylated metabolites, which are detected by measurement of metanephrines.

Catecholamines and metanephrines can be measured by different methods, including high-performance liquid chromatography, enzyme-linked immunosorbent assay, and liquid chromatography/mass spectrometry. When pheochromocytoma is suspected on clinical grounds (i.e., when values are three times the upper limit of normal), this diagnosis is highly likely regardless of the assay used. However, as summarized in Table 53-2, the sensitivity and specificity of available biochemical tests vary greatly, and these differences are important in assessing patients with borderline elevations of different compounds. Urinary tests for metanephrines (total or fractionated) and catecholamines are widely available and are used commonly for initial evaluation. Among these tests, those for the fractionated metanephrines and catecholamines are the most sensitive. Plasma tests are more convenient and include measurements of catecholamines and metanephrines. Measurements of plasma metanephrine are the most sensitive and are less susceptible to false-positive elevations from stress, including venipuncture. Although the incidence of false-positive test results has been reduced by the introduction of newer assays, physiologic stress responses and medications that increase catecholamine levels still can confound testing. Because the tumors are relatively rare, borderline elevations are likely to represent false-positive results. In this circumstance, it is important to exclude dietary or drug-related factors (withdrawal of levodopa or use of sympathomimetics, diuretics, tricyclic antidepressants, alpha and beta blockers) that might cause false-positive results and then to repeat testing or perform a clonidine suppression test (i.e., the measurement of plasma normetanephrine 3 h after oral administration of 300 μg of clonidine). Other pharmacologic tests, such as the phentolamine test and the glucagon provocation test, are of relatively low sensitivity and are not recommended.

Diagnostic imaging

A variety of methods have been used to localize pheochromocytomas and paragangliomas (Table 53-2). CT and MRI are similar in sensitivity and should be performed with contrast. T2-weighted MRI with gadolinium contrast is optimal for detecting pheochromocytomas and is somewhat better than CT for imaging extraadrenal pheochromocytomas and paragangliomas. About 5% of adrenal incidentalomas, which usually are detected by CT or MRI, prove to be pheochromocytomas upon endocrinologic evaluation.

Tumors also can be localized by procedures using radioactive tracers, including ¹³¹I- or ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy, ¹¹¹In-somatostatin analogue scintigraphy, ¹⁸F-DOPA positron emission tomography (PET), or ¹⁸F-fluorodeoxyglucose (FDG) PET. Because these agents exhibit selective uptake in paragangliomas, nuclear imaging is particularly useful in the hereditary syndromes.

Differential diagnosis

When the possibility of a pheochromocytoma is being entertained, other disorders to consider include essential hypertension, anxiety attacks, use of cocaine or amphetamines, mastocytosis or carcinoid syndrome (usually without hypertension), intracranial lesions, clonidine withdrawal, autonomic epilepsy, and factitious crises (usually from use of sympathomimetic amines). When an asymptomatic adrenal mass is identified, likely diagnoses other than pheochromocytoma include a nonfunctioning adrenal adenoma, an aldosteronoma, and a cortisol-producing adenoma (Cushing's syndrome) (Table 53-3).

About 5–10% of pheochromocytomas and paragangliomas are malignant. The diagnosis of malignant pheochromocytoma is problematic. The typical histologic criteria of cellular atypia, presence of mitoses, and invasion of vessels or adjacent tissues are insufficient for the diagnosis of malignancy in pheochromocytoma. Thus, the term malignant pheochromocytoma is restricted to tumors with distant metastases, most commonly found by nuclear medicine imaging in lungs, bone, or liver—locations suggesting a vascular pathway of spread. Because hereditary syndromes are associated with multifocal tumor sites, these features should be anticipated in patients with germ-line mutations of RET, VHL, SDHD, or SDHB. However, distant metastases also occur in these syndromes, especially in carriers of SDHB mutations.

Treatment of malignant pheochromocytoma or paraganglioma is challenging. Options include tumor mass reduction, alpha blockers for symptoms, chemotherapy, and nuclear medicine radiotherapy. The first-line choice is nuclear medicine therapy for scintigraphically documented metastases, preferably with ¹³¹I-MIBG in 200-mCi doses at monthly intervals over three to six cycles. Averbuch's chemotherapy protocol includes dacarbazine (600 mg/m² on days 1 and 2), cyclophosphamide (750 mg/m² on day 1), and vincristine (1.4 mg/m² on day 1), all repeated every 21 days for three to six cycles. Palliation (stable disease to shrinkage) is achieved in about one-half of patients. Other chemotherapeutic options are sunitinib and temozolomide/thalidomide. The prognosis of metastatic pheochromocytoma or paraganglioma is variable, with 5-year survival rates of 30–60%.

Pheochromocytomas occasionally are diagnosed in pregnancy. Endoscopic removal, preferably in the fourth to sixth month of gestation, is possible and can be followed by uneventful childbirth. Regular screening in families with inherited pheochromocytomas provides an opportunity to identify and remove asymptomatic tumors in women of reproductive age.

About 25–33% of patients with a pheochromocytoma or paraganglioma have an inherited syndrome. At diagnosis, patients with inherited syndromes are a mean of ~15 years younger than patients with sporadic tumors.

Neurofibromatosis type 1 (NF1) was the first described pheochromocytoma-associated syndrome (Chap. 48). The NF1 gene functions as a tumor suppressor by regulating the Ras signaling cascade. Classic features of neurofibromatosis include multiple neurofibromas, café au lait spots, axillary freckling of the skin, and Lisch nodules of the iris (Fig. 53-2). Pheochromocytomas occur in only ~1% of these patients and are located predominantly in the adrenals. Malignant pheochromocytoma is not uncommon.

The best-known pheochromocytoma-associated syndrome is the autosomal dominant disorder multiple endocrine neoplasia type 2 (MEN2) (Chap. 52). Both types of MEN2 (2A and 2B) are caused by mutations in RET (rearranged during transfection), which encodes a tyrosine kinase. The locations of RET mutations correlate with the severity of disease and the type of MEN2 (Chap. 52). MEN2A is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism; MEN2B also includes MTC and pheochromocytoma as well as multiple mucosal neuromas, marfanoid habitus, and other developmental disorders, though it typically lacks hyperparathyroidism. MTC is found in virtually all patients with MEN2, but pheochromocytoma occurs in only ~50% of these patients. Nearly all pheochromocytomas in MEN2 are benign and located in the adrenals, often bilaterally (Fig. 53-3). Pheochromocytoma may be symptomatic before MTC. Prophylactic thyroidectomy is being performed in many carriers of RET mutations; pheochromocytomas should be excluded before any surgery in these patients.

Von Hippel–Lindau syndrome (VHL) is an autosomal dominant disorder that predisposes to retinal and cerebellar hemangioblastomas, which also occur in the brainstem and spinal cord (Fig. 53-4). Other important features of VHL are clear cell renal carcinomas, pancreatic neuroendocrine tumors, endolymphatic sac tumors of the inner ear, cystadenomas of the epididymis and broad ligament, and multiple pancreatic or renal cysts.

The VHL gene (among other genes) encodes an E3 ubiquitin ligase that regulates expression of hypoxia-inducible factor 1. Loss of VHL is associated with increased expression of vascular endothelial growth factor (VEGF), which induces angiogenesis. Although the VHL gene can be inactivated by all types of mutations, patients with pheochromocytoma predominantly have missense mutations. About 20–30% of patients with VHL have pheochromocytomas, but in some families the incidence can reach 90%. The recognition of pheochromocytoma as a VHL-associated feature provides an opportunity to diagnose retinal, central nervous system, renal, and pancreatic tumors at a stage when effective treatment may still be possible.

The paraganglioma syndromes (PGLs) have been classified by genetic analyses of families with head and neck paragangliomas. The susceptibility genes encode subunits of the enzyme succinate dehydrogenase (SDH), a component in the Krebs cycle and the mitochondrial electron transport chain. SDH is formed by four subunits (A–D). Mutations of SDHB (PGL4), SDHC (PGL3), SDHD (PGL1), and SDHAF2 (PGL2) predispose to the PGLs. The transmission of the disease in carriers of SDHB and SDHC germ-line mutations is autosomal dominant. In contrast, in SDHD and SDHAF2 families, only the progeny of affected fathers develop tumors if they inherit the mutation. PGL1 is most common, followed by PGL4; PGL2 and PGL3 are rare. Adrenal, extra-adrenal abdominal, and thoracic pheochromocytomas, which are components of PGL1 and PGL4, are rare in PGL3 and absent in PGL2 (Fig. 53-5). About one-third of patients with PGL4 develop metastases.

Familial pheochromocytoma (FP) has been attributed to hereditary, mainly adrenal tumors in patients with germ-line mutations in the genes TMEM127, MAX, and SDHA. Transmission is also autosomal dominant, and mutations of MAX, like those of SDHD, cause tumors only if inherited from the father.

In addition to family history, general features suggesting an inherited syndrome include young age, multifocal tumors, extra-adrenal tumors, and malignant tumors (Fig. 53-6). Because of the relatively high prevalence of familial syndromes among patients who present with pheochromocytoma or paraganglioma, it is useful to identify germ-line mutations even in patients without a known family history. A first step is to search for clinical features of inherited syndromes and to obtain an in-depth, multigenerational family history. Each of these syndromes exhibits autosomal dominant transmission with variable penetrance, but a proband with a mother affected by paraganglial tumors is not predisposed to PLG1 (SDHD mutation carrier). Cutaneous neurofibromas, café au lait spots, and axillary freckling suggest neurofibromatosis. Germ-line mutations in NF1 have not been reported in patients with sporadic pheochromocytomas. Thus, NF1 testing need not be performed in the absence of other clinical features of neurofibromatosis. A personal or family history of MTC or an elevation of serum calcitonin strongly suggests MEN 2 and should prompt testing for RET mutations. A history of visual impairment or tumors of the cerebellum, kidney, brainstem, or spinal cord suggests the possibility of VHL. A personal and/or family history of head and neck paraganglioma suggests PGL1 or PGL4.

A single adrenal pheochromocytoma in a patient with an otherwise unremarkable history may still be associated with mutations of VHL, RET, SDHB, or SDHD (in decreasing order of frequency). Two-thirds of extra-adrenal tumors are associated with one of these syndromes, and multifocal tumors occur with decreasing frequency in carriers of RET, SDHD, VHL, and SDHB mutations. About 30% of head and neck paragangliomas are associated with germ-line mutations of one of the SDH subunit genes (most often SDHD) and are rare in carriers of VHL, RET, and TMEM127 mutations (Fig. 53-6F).

Immunohistochemistry is helpful in the preselection of hereditary pheochromocytoma. Negative immunostaining with antibodies to SDHB, TMEM127, and MAX may predict mutations of the SDH, TMEM127, and MAX genes, respectively.

Once the underlying syndrome is diagnosed, the benefit of genetic testing can be extended to relatives. For this purpose, it is necessary to identify the germ-line mutation in the proband and, after genetic counseling, to perform DNA sequence analyses of the responsible gene in relatives to determine whether they are affected. Other family members may benefit when individuals who carry a germ-line mutation are biochemically screened for paraganglial tumors.

Asymptomatic paraganglial tumors, now often detected in patients with hereditary tumors and their relatives, are challenging to manage. Watchful waiting strategies have been introduced. Head and neck paragangliomas—mainly carotid body, jugular, and vagal tumors—are increasingly treated by radiation, since surgery is frequently associated with permanent palsy of cranial nerves II, VII, IX, X, XI, and XII. Nevertheless, tympanic paragangliomas are symptomatic early, and most of these tumors can easily be resected, with subsequent improvement of hearing and alleviation of tinnitus.

Adrenocortical carcinoma (ACC) is a rare malignancy with an annual incidence of 1–2 per million population. ACC is generally considered a highly malignant tumor; however, it presents with broad interindividual variability with regard to biologic characteristics and clinical behavior. Somatic mutations in the tumor-suppressor gene TP53 are found in 25% of apparently sporadic ACC. Germline TP53 mutations are the cause of the Li-Fraumeni syndrome associated with multiple solid organ cancers including ACC and are found in 25% of pediatric ACC cases; the TP53 mutation R337H is found in almost all pediatric ACC in Brazil. Other genetic changes identified in ACC include alterations in the Wnt/β-catenin pathway and in the insulin-like growth factor 2 (IGF2) cluster; IGF2 overexpression is found in 90% of ACC.

Patients with large adrenal tumors suspicious of malignancy should be managed by a multidisciplinary specialist team, including an endocrinologist, an oncologist, a surgeon, a radiologist, and a histopathologist. FNA is not indicated in suspected ACC: first, cytology and also histopathology of a core biopsy cannot differentiate between benign and malignant primary adrenal masses; second, FNA violates the tumor capsule and may even cause needle canal metastasis. Even when the entire tumor specimen is available, the histopathologic differentiation between benign and malignant lesions is a diagnostic challenge. The most common histopathologic classification is the Weiss score, taking into account high nuclear grade; mitotic rate (>5/HPF); atypical mitosis; <25% clear cells; diffuse architecture; and presence of necrosis, venous invasion, and invasion of sinusoidal structures and tumor capsule. The presence of three or more elements suggests ACC.

Although 60–70% of ACCs show biochemical evidence of steroid overproduction, in many patients, this is not clinically apparent due to the relatively inefficient steroid production by the adrenocortical cancer cells. Excess production of glucocorticoids and adrenal androgen precursors are most common. Mixed excess production of several corticosteroid classes by an adrenal tumor is generally indicative of malignancy.

Tumor staging at diagnosis (Table 53-4) has important prognostic implications and requires scanning of the chest and abdomen for local organ invasion, lymphadenopathy, and metastases. Intravenous contrast medium is necessary for maximum sensitivity for hepatic metastases. An adrenal origin may be difficult to determine on standard axial CT imaging if the tumors are large and invasive, but CT reconstructions and MRI are more informative (Fig. 53-8) using multiple planes and different sequences. Vascular and adjacent organ invasion is diagnostic of malignancy. 18-Fluoro-2-deoxy-D-glucose positron emission tomography (18-FDG PET) is highly sensitive for the detection of malignancy and can be used to detect small metastases or local recurrence that may not be obvious on CT (Fig. 53-8). However, FDG PET is not specific and therefore cannot be used for differentiating benign from malignant adrenal lesions. Metastasis in ACC most frequently occurs to liver and lung.

There is no established grading system for ACC, and the Weiss score carries no prognostic value; the most important prognostic histopathologic parameter is the Ki67 proliferation index, with Ki67 <10% indicative of slow to moderate growth velocity, whereas a Ki67 ≥10% is associated with poor prognosis including high risk of recurrence and rapid progression.

Cure of ACC can only be achieved by early detection and complete surgical removal. Capsule violation during primary surgery, metastasis at diagnosis, and primary treatment in a nonspecialist center are major determinants of poor survival. If the primary tumor invades adjacent organs, en bloc removal of kidney and spleen should be considered to reduce the risk of recurrence. Surgery can also be considered in a patient with metastases if there is severe tumor-related hormone excess. This indication needs to be carefully weighed against surgical risk, including thromboembolic complications, and the resulting delay in the introduction of other therapeutic options. Patients with confirmed ACC and successful removal of the primary tumor should receive adjuvant treatment with mitotane (o,p'DDD), particularly in patients with a high risk of recurrence as determined by tumor size >8 cm, histopathologic signs of vascular invasion, capsule invasion or violation, and a Ki67 proliferation index ≥10%. Adjuvant mitotane should be continued for at least 2 years, if the patient can tolerate side effects. Regular monitoring of plasma mitotane levels is mandatory (therapeutic range 14–20 mg/L; neurotoxic complications more frequent at >20 mg/L). Mitotane is usually started at 500 mg tid, with stepwise increases to a maximum dose of 2000 mg tid in days (high-dose saturation) or weeks (low-dose saturation) as tolerated. Once therapeutic range plasma mitotane levels are achieved, the dose can be tapered to maintenance doses mostly ranging from 1000 to 1500 mg tid. Mitotane treatment results in disruption of cortisol synthesis and thus requires glucocorticoid replacement; glucocorticoid replacement dose should be at least double of that usually used in adrenal insufficiency (i.e., 20 mg tid) because mitotane induces hepatic CYP3A4 activity resulting in rapid inactivation of glucocorticoids. Mitotane also increases circulating CBG, thereby decreasing the available free cortisol fraction. Single metastases can be addressed surgically or with radiofrequency ablation as appropriate. If the tumor recurs or progresses during mitotane treatment, chemotherapy should be considered; the established first-line chemotherapy regimen is the combination of cisplatin, etoposide, and doxorubicin plus continuing mitotane. Painful bone metastasis responds to irradiation. Overall survival in ACC is still poor, with 5-year survival rates of 30–40% and a median survival of 15 months in metastatic ACC.