contents
18.1 Introduction . . . 189 18.2 Extra-adrenal Primary
Pheochromocytoma . . . 189 18.2.1 Frequency and Patterns
of Extra-adrenal Disease . . . 189 18.2.2 Diagnosis of Ectopic Sites . . . 189 18.2.3 Localization of Tumor . . . 190 18.2.4 Therapy . . . 191
18.3 Malignant Pheochromocytoma . . . 191 18.3.1 Incidence and Prevalence . . . 191 18.3.2 Diagnosis . . . 191
18.3.3 Localization and Treatment Planning . . . 192 18.3.4 Therapy . . . 192
References . . . 194
18.1 Introduction
Pheochromocytomas are rare tumors that are usually benign lesions within the adrenal gland. However, pri- mary tumors can occur outside of the adrenal gland, and tumors that arise either within the adrenal gland or outside of it can be malignant. This tumor is often described by the “rule of 10’s,” that is, 10% familial, bi- lateral,extra-adrenal,malignant,and occurring in chil- dren.However,this memory tool underestimates the in- cidence of both malignancy and extra-adrenal primary tumors, each of which probably occur in closer to 20%
of patients with pheochromocytoma [15].
18.2 Extra-adrenal Primary Pheochromocytoma 18.2.1 Frequency and Patterns
of Extra-adrenal Disease
Extra-adrenal tumors occur along the sympathetic chain,at any site from the base of the skull to the pelvis.
The most common site for extra-adrenal pheochro-
mocytomas, which are also sometimes, and probably more correctly, called paragangliomas particularly when they do not make appreciable amounts of cate- cholamines, is the organ of Zuckerkandl. They have been localized in the neck, posterior chest, atrium, re- nal hilum and bladder (Fig. 1). A common location of extra-adrenal tumors is between the aorta and vena cava at the level of the left renal vein, cephalad to the organ of Zuckerkandl tumors arising on either side of the superior mesenteric artery or more distally to the aortic bifurcation, where it can also be mistaken for a lymph node metastasis. Middle mediastinal tumors, which may involve the heart, occur more frequently than was previously recognized.Extra-adrenal tumors have a higher reported malignancy rate of 25–40%, al- though not all reports agree on the differential ag- gressiveness of the extra-adrenal sites [7, 10].
18.2.2 Diagnosis of Ectopic Sites
The increased recognition of ectopic sites of primary pheochromocytomas is due to a variety of changes in the diagnostic options. First, there is the improved ac- curacy of biochemical testing for pheochromocytoma.
With the current testing, particularly with the wide- spread availability of plasma metanephrine testing, the diagnosis of excess catecholamine synthesis and secretion can be more certain.With that increased lev- el of certainty, our improved imaging can be selective- ly and diligently applied. Current imaging, including high-resolution computerized tomographic (CT) and magnetic resonance scanning (MRI), and nuclear im- aging with
123I-MIBG or somatostatin receptor scintig- raphy can localize tumors in many sites that were sim- ply not practical in the past, particularly if the bio- chemical diagnosis was equivocal [5, 18].
Patients with disease at ectopic sites typically pres-
ent with the same symptoms as those with adrenal
pheochromocytoma. Most patients have hyperten-
Gerard M. Doherty
sion, and describe “spells,” which classically include hypertension, but which also may have a variety of symptoms that are consistent within each patient for their episodes. These spells may include paroxysmal headache,dizziness,anxiety,tachycardia,nausea or vi- sual changes. The spells may occur seemingly sponta- neously, or may predictably follow some activities.
This can be particularly true for some of the ectopic sites, where spells can be caused by local mechanical changes, such as micturition, sexual intercourse, or defecation causing spells from tumors adjacent to the bladder [17]. Patients may occasionally present with severe systemic illness or death from hormone release from a previously occult tumor.
Pheochromocytomas can also produce hormones other than catecholamines, including adrenocorti- cotropin (ACTH), calcitonin, somatostatin, vasoactive intestinal peptide (VIP) or serotonin. The production of these unusual hormones and their syndromes can lead to an extensive work-up to identify the respon- sible tumor.
18.2.3 Localization of Tumor
Once the biochemical diagnosis of pheochromocy- toma has been made, the tumor must be localized.
Since most pheochromocytomas are located in the adrenal gland, the initial localizing test should be a cross-sectional study of the adrenals, either a high- resolution CT scan or an MRI.If that study shows a uni- lateral adrenal mass, without suggestion of malignan- cy or other extra-adrenal findings,then no further test- ing is necessary. In a consecutive series from the University of Michigan, 48 patients with a biochemical diagnosis of pheochromocytoma and a unilateral ad- renal mass on CT or MRI, none had additional disease defined by the
123I-MIBG scan. Forty-seven of the 48 patients had a single unilateral focus of uptake de- fined on MIBG scan, and the remaining patient had a
Fig. 1a–c. Studies from a woman with ectopic pheochromo- cytoma during pregnancy. This patient’s worsening hyper- tension led to a biochemical evaluation that diagnosed her pheochromocytoma. Initial imaging of her adrenal glands with ultrasound and an abdominal MRI showed no evidence of the source of her disease. When a chest X-ray (a) showed this left thoracic mass (arrow), the localization was clear. A subsequent MRI of the chest (b, c) provided improved anatomic delineation before resection in the second trimester of the pregnancy (tumor at arrows). Mother and daughter have subsequently done well
false-negative MIBG scan [8]. Thus, we now reserve the MIBG scan for patients whose disease is either not apparent on the cross-sectional imaging, or who have additional abnormalities (bilateral adrenal masses or extra-adrenal lesions). In these patients,
123I-MIBG scans or somatostatin receptor scintigraphy can iden- tify the site(s) of disease to allow treatment planning [5].
18.2.4 Therapy
The best therapy for extra-adrenal pheochromocy- toma is resection, as this is the only potentially cura- tive option. Careful attention to the preoperative lo- calization allows operative planning to include all sites of disease. Once the diagnosis of pheochromocytoma has been firmly established with biochemical testing, and localization studies have been completed, prepa- rations can be made for the operative treatment of the tumor(s). Regardless of the site or number of tumors, all patients should be prepared with an alpha-adren- ergic antagonist for 1–2 weeks preoperatively. One proven method is phenoxybenzamine (Dibenzyline), which can be administered three times a day. Starting with a total dose of 30 mg per day, we increase the dose every 3rd day by 30 mg. The endpoint of therapy is or- thostatic hypotension, although a clinical sign that the dose is adequate is the development of nasal conges- tion. This may be achieved with the starting dose, although some patients have required as much as 360 mg per day. An experienced and prepared anes- thesiologist should be considered as an essential mem- ber of the team. Central venous and arterial pressure lines are placed for monitoring during induction of anesthesia and throughout the operative procedure.
The operative approach should be planned to resect the evident disease. As with most adrenal pheochro- mocytomas, many extra-adrenal pheochromocy- tomas can now be resected using minimally invasive techniques (laparoscopy or thoracoscopy). This tech- nology must be applied judiciously by a surgeon fa- miliar with both the disease and the techniques, in or- der to achieve optimal outcome for the patient.
18.3 Malignant Pheochromocytoma
18.3.1 Incidence and Prevalence
Malignant pheochromocytomas currently account for 10–15% of all cases, although various authors have re-
ported an incidence ranging from 5% to as high as 46%. Extra-adrenal pheochromocytomas have been associated with a higher incidence of malignancy in most series reported ranging from 20% to 40%, but this is not uniform [10]. When collected series of pheochromocytomas are evaluated, and trying to account for selective referral bias, an overall incidence of 15% appears to be a reliable estimate [15].
18.3.2 Diagnosis
There are no certain histologic criteria that distinguish benign from malignant tumors. Even upon retrospec- tive review, the distinction is often impossible since vascular and capsular invasion as well as mitotic figures can be readily identified in both benign and malignant pheochromocytomas. Tumors without evi- dence of capsular or vascular invasion have metasta- sized to distant sites while some tumors with local cap- sular or even major venous invasion have apparently been cured by surgical excision. Malignancy can be positively diagnosed only when there is local invasion of tumor into surrounding soft tissue, or when the presence of tumor in non-chromaffin-bearing tissue outside the region of the sympathetic chain is identi- fied. Tumors that are at increased risk for malignancy are those that are extra-adrenal (30–40% risk vs. 10%
adrenal), and those pheochromocytomas that secrete only dopamine.
The median time of recurrence or identification of metastases is 5–6 years. Long-term follow-up is there- fore advised which should include regular blood pres- sure monitoring as well as annual biochemical studies for catecholamine and their metabolites. Our current approach is to evaluate using plasma metanephrine measurements at least annually, except in those tu- mors that make only dopamine or ACTH, in which case specific biochemical follow-up plans must be made depending upon the initial biochemical presen- tation [2–4, 13].
The most common site for metastatic lesions is
bone, where they commonly present as lytic lesions of
the spine, skull or ribs. Other sites include liver, lung,
and retroperitoneal or mediastinal lymph nodes. Ma-
lignant pheochromocytomas usually are slow grow-
ing tumors and long-term survival has been reported
(although rare) provided that control of symptoms
caused by increased catecholamines is possible.
18.3.3 Localization and Treatment Planning Once the diagnosis of malignant pheochromocytoma is established or suspected,
123I-MIBG scintiscanning has proven effective in detecting the extent of the dis- ease in most patients (Fig. 2). In some centers, MIBG is used routinely in all pheochromocytoma patients be- fore any operative procedure to rule out occult metas- tases, although a recent study from our institution shows that in most pheochromocytoma patients, this is not necessary [8]. CT and MRI may give additional anatomic information that may be helpful in deter- mining resectability in patients whose disease is lim- ited to soft tissue.Octreotide scanning and technetium bone scans have also proved useful in some cases [5].
Bone metastases, in vertebral bodies, skull or ribs are the most common location for spread of the disease.
They can be identified by any of the scintiscanning techniques.
18.3.4 Therapy
18.3.4.1 Medical Blockade of End-Organ Effects
All patients with malignant pheochromocytomas
should initially be treated with an alpha-adrenergic
blocking drug with the exception of those rare tumors
secreting only dopamine. We prefer phenoxybenza-
mine, gradually increasing the dose to control hyper-
tension. Starting with a total dose of 30 mg per day, we
increase the dose every third day by 30 mg. The end-
point of therapy is orthostatic hypotension, although
a clinical sign that the dose is adequate is the develop-
ment of nasal congestion. Small doses of a beta-block-
ing drug, even when epinephrine levels are not exces-
sively high, may also prove beneficial. In patients
whose symptoms or blood pressure cannot be readily
controlled with an alpha-blockade, additional antihy-
pertensive therapy may be required. For patients with
unresectable metastatic disease,alpha-methyltyrosine
should be considered. This drug inhibits the synthesis
of catecholamines and may, in conjunction with an
adrenergic blockade, offer long-term control of cate-
Fig. 2. MIBG scan can demonstrate the sites of systemic disease, as in this patient with diffuse intra-abdominal and intra-tho- racic nodal disease (double arrows) and bone metastasis (single arrow). (Images courtesy of Dr. Barry Shulkin, University of Michigan)cholamine-related symptoms. Some patients with un- resectable disease may live for a number of years, pro- viding their catecholamine secretion is controlled.
18.3.4.2 Extirpative Therapy
After appropriate blockade, management of recur- rences includes wide local excision of surgically re- sectable disease as a first line of treatment (Fig. 3). Un- fortunately, this may only be palliative because of the presence of bone metastases. However, when tumor is limited to soft tissue, surgical excision may offer long- term palliation and even cure.Complete resection may require retroperitoneal lymph node dissection, liver resection, or soft tissue resection that includes other intra-abdominal organs (kidney, bowel, distal pan- creas).Careful preoperative planning and imaging can help to “draw the dotted lines” sufficiently widely around the tumor to give the best opportunity for cure [10].
18.3.4.3 Systemic Therapy
Until the past decade, no effective chemotherapeutic regimen had been reported. No single agent such as Adriamycin or streptozotocin has ever been shown to be beneficial. However, a combination of cyclophos- phamide, vincristine and dacarbazine has resulted in a high incidence of both biochemical improvement (decrease in catecholamines) and tumor growth inhi- bition [1,12,14,16].This combination is currently con- sidered the drug regimen of choice when chemother- apy is indicated (Table 1).
18.3.4.4 Palliative Care
External beam radiation treatment is effective for the palliation of bone pain. Cytotoxic therapy including cyclophosphamide,vincristine and dacarbazine offers
Fig.3a–c. Preoperative imaging can be critical to appropriate operative planning. This woman with a large right adrenal pheochromocytoma with necrosis (a) had a significant thrombus in the inferior vena cava demonstrated on preop- erative ultrasound (b, arrow). Exploration with extensive mo- bilization and control of the IVC, and intraoperative ultra- sound allowed resection of the tumor en bloc with the in- volved IVC (c, with the Satinsky clamp enclosing the region of IVC to be resected)
only limited improvement in survival rates [1, 12, 14, 16]. Therapeutic
131I-MIBG has been used to treat pa- tients with functioning metastases with encouraging results in selected patients with respect to decrease in both tumor size and circulating catecholamines [6, 9, 11, 14]. Less than a third of patients are candidates for treatment,which is based on the tumor’s ability to con- centrate sufficient
131I-MIBG to be irradiated effec- tively.Although regression of tumor has been well doc- umented in some cases, the duration of effect has been limited to approximately 2 years and no patient has been cured.
References
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Table 1. Clinical reports of therapy with cyclophosphamide, dacarbazine and vincristine
Authors Year Patients (N) Biochemical response Tumor responses
(CR+PR) (CR+PR)
Averbuch [1] 1988 14 11 8
Tada [15] 1998 3 3 NR
Sisson [13] 1999 6 3 3
