Division of Endocrinology, Diabetes, and Metabolic Diseases (P.S.N., E.B.R., A.E.D.), Jefferson Medical College of Thomas Jefferson University; Section on Endocrinology (A.E.D.), Pennsylvania Hospital, Philadelphia, Pennsylvania 19106
Address correspondence and requests for reprints to: Anne E. de Papp, Department of Endocrinology and Metabolism, Pennsylvania Hospital, 700 Spruce Street, Duncan Building, Suite 506, Philadelphia, Pennsylvania 19106.
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Clinical Case Seminar |
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The past medical history was unremarkable except for congenital absence of the thumbs bilaterally. Her medications at the time of admission included Ciprofloxacin and Decadron nasal spray. The family history was remarkable for scleroderma in the father and a carotid body tumor in the mother. There was no family history of endocrinopathy or endocrine neoplasia.
Examination revealed a thin, anxious, and restless female. Her weight
was 54 kg, and her height was 164 cm. The blood pressure was 118/70 mm
Hg, with a pulse of 118 bpm, respirations of 30, and a rectal
temperature of 99.0 F. The skin was cold and mottled, with decreased
skin turgor. The fundi were normal with no hypertensive retinopathy.
Neck exam revealed no jugular venous distension, lymphadenopathy, or
thyroid nodules. The chest exam revealed right-sided rales. The cardiac
exam revealed a third heart sound and an apical systolic murmur. The
abdomen was soft and nontender, with no organomegaly or palpable
masses. The extremities revealed trace ankle edema, a fine tremor, and
absence of the thumbs bilaterally. A 5 cm soft tissue mass was palpable
in the right shoulder. There was no cervical, axillary, or inguinal
adenopathy. The neurological exam was nonfocal. Initial laboratory
studies are listed in Table 1. A plain
chest radiograph demonstrated mild cardiomegaly. An electrocardiogram
revealed sinus tachycardia with a rate of 116 bpm, and 2 mm ST segment
elevation in leads V3 and V4. An echocardiogram showed top normal left
ventricular cavity, moderate global hypokinesis, and mild pulmonary
hypertension, consistent with biventricular failure. A radionuclide
bone scan revealed an area of increased uptake in the right shoulder
and in the left, ninth rib.
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Differential diagnosis
In summary, this 37-yr-old white female presented with a chief complaint of cough, dyspnea, weakness, nausea, vomiting, and a soft tissue mass in the right shoulder. Manipulation of the shoulder mass provoked transient, severe hypertension. Her later hospitalization was complicated by the development of palpitations, diaphoresis, and nonsustained ventricular tachycardia. The presence of hypertension, coupled with hyperadrenergic symptoms should raise the suspicion of tumors of the adrenal medulla or the extraadrenal paraganglion system. The paraganglion system is composed of chromaffin cells that arise from the neural crest and migrate, along with sympathetic nerve ganglia, to form the adrenal medulla as well as extraadrenal paraganglia (1). Chromaffin cells are characterized by dark brown staining that occurs upon addition of chromium salts. This staining property is due to the presence of catecholamines stored within neurosecretory granules. Although most paraganglion tissue in the newborn involutes, embryologic rests of paraganglion cells are found in the paraaortic areas in conjunction with the sympathetic nerve ganglia from the base of the skull to the pelvis. Functional tumors arising from these extraadrenal rests of paraganglion cells are known as paragangliomas, or extraadrenal pheochromocytomas. These tumors are most commonly found within the abdomen and pelvis, in the organ of Zuckerkandl or in the urinary bladder (1).
The key feature of this patients presentation is that paraganglia cells are normally absent in the extremities. For a paraganglioma to be present in the shoulder signifies that the lesion is metastatic. The malignancy rate of paraganglion tumors varies with the site of origin of the primary tumor. Extraadrenal paragangliomas have a reported malignancy rate of up to 45% (1). In comparison, adrenal pheochromocytomas have a reported malignancy rate of 10%.
Many of the patients signs and symptoms can be explained on the basis of excess catecholamines. Pheochromocytomas can be remembered by the pneumonic "the 5 Ps " for pressure, pain, (i.e. headaches), palpitations, perspiration, and pallor. Conspicuously absent in this patients history were headaches or hypertension, which are present in over 70% of cases of pheochromocytoma. However, multiple other hyperadrenergic symptoms were manifest in this patient including: anxiety, tremulousness, breathlessness, nausea, vomiting, and diaphoresis. Her physical exam was remarkable for tachycardia, tachypnea, a low grade fever and cold, mottled extremities. Many of these signs can be attributed to the pharmacologic effects of excess catecholamines. The congenital thumb agenesis was most likely an unrelated finding, as there is no reported association between pheochromocytomas and thumb agenesis. The history, physical exam, and ancillary studies suggested a diagnosis of congestive heart failure. A specific catecholamine cardiomyopathy has been described and may present in the form of congestive heart failure in patients with pheochromocytoma (2). The cardiomyopathy is multifactorial and secondary to both catecholamine induced vasospasm as well as direct myocardial toxicity. Histologically, excess catecholamines have been shown to cause focal myocardial necrosis (2). The cardiomyopathy is often reversible with surgical resection of the tumor.
Many of the patients laboratory findings can similarly be explained by excess catecholamines. Laboratory evaluation revealed evidence of an increased anion gap metabolic acidosis. As there was no history to suggest toxin ingestion, diabetic ketoacidosis, or uremic acidosis, lactic acidosis is most likely. Lactic acidosis has been described as a complication of pheochromocytoma in the absence of obvious infection (3, 4). Lactic acidosis may result from impaired tissue perfusion secondary to the profound vasoconstrictive effects of norepinephrine as well as from the metabolic effect of excess catecholamines on intermediary metabolism. Fever and neutrophilia, in the absence of infection, can also be explained by excess catecholamines (4).
The patients corrected calcium was elevated. Hypercalcemia is associated with pheochromocytoma in approximately 5% of cases. This may be due either to parathyroid hyperplasia, as in multiple endocrine neoplasia (MEN) type II A syndrome or, secondarily, to liberation of parathyroid hormone-like protein (PTH-rP) (5). Pheochromocytomas have the ability to synthesize and release multiple peptide hormones including PTH-rP, calcitonin gene-related protein, adrenocorticotropic hormone (ACTH), endorphins, enkephalins, erythropoietin, and vasoactive intestinal polypeptide (6). Local osteolytic hypercalcemia, secondary to bony metastases was also a possibility in this case.
Lastly, the family history deserves mention, as it is suggestive of a familial syndrome. The patients mother had a history a carotid body tumor, also known as a chemodectoma. The carotid body is the single largest extraadrenal collection of paraganglia cells in the adult. Carotid body tumors have been reported in association with familial pheochromocytomas and, rarely, as part of the MEN type II syndrome (7). Although there was no family history to suggest a diagnosis of MEN II A, MEN II B, von Hippel-Lindau, or neurofibromatosis, further genetic testing of family members may be indicated.
In summary, this patient had evidence of malignant pheochromocytoma complicated by a catecholamine cardiomyopathy. The bone scan was worrisome for metastatic disease in both the left rib and right shoulder. In series of malignant pheochromocytomas, bone lesions are often the first site of metastases. Bone metastases to the ribs, pelvis, spine and proximal, long bones occur in order of decreasing frequency (8). To confirm biochemical evidence of excess catecholamines, plasma and urine catecholamines should be obtained. No single test has perfect sensitivity and specificity, thus combination testing is often utilized. To localize the site of the primary lesion, computed tomography (CT) of the abdomen would be the procedure of choice, as most functional chromaffin tumors arise below the diaphragm. Lastly, nuclear medicine scans such as 131I-met-iodobenzylguanidine scintigraphy (MIBG) or indium-111-labeled octreotide scanning would be helpful to define the extent of disease and to localize metastatic deposits.
Clinical course
Because of the history of a right shoulder paraganglioma and signs
of adrenergic excess, plasma and urine catecholamines were obtained
(Table 2). A subsequent CT scan of the
abdomen and pelvis (Fig. 2
) revealed an 11x9x8 cm left
adrenal mass. An indium labeled octreotide scan (Fig. 3
) confirmed uptake in the left adrenal and
right shoulder. No uptake was seen in the rib cage to correspond to
that seen on bone scan. The patient was started on alpha blockade with
phenoxybenzamine and alpha methyl-paratyrosine. The use of beta
blockers repeatedly resulted in profound hypotension. Surgical
resection of the primary adrenal lesion was attempted. Laparotomy
revealed an 11 cm pheochromocytoma of the left adrenal gland with
invasion of the pancreatic parenchyma. On the fifth post-operative day,
the patient developed an episode of acute cardiovascular collapse. She
was resuscitated and maintained for 49 days before she expired.
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Malignancy has been reported in approximately 10% of patients with pheochromocytomas. Many studies have tried to define factors predictive of malignancy, but the only definite criterion is still the presence of metastases in sites where chromaffin tissue is normally absent. Common sites of metastases include; bones, lungs, liver, and regional lymph nodes (9). Histologic features are not specific for malignancy, but vascular and capsular invasion favor malignancy and are associated with a poor prognosis. DNA flow cytometry studies suggest that nondiploid tumors are more likely to be aggressive and therefore should be monitored more carefully (6). Biochemically, norepinephrine excretion predominates in malignant as well as benign pheochromocytomas. Dopamine excretion is frequently associated with malignancy, possibly due to cellular dedifferentiation. Dopamine excretion is also more frequent in patients with large tumor masses or at the end stage of their disease, thus portending an unfavorable prognosis (10). Elevated serum levels of neuroendocrine tumor markers, such as neuron specific enolase, neuropeptide Y and chromogranin A have all been linked to malignancy (10), although their usefulness in predicting malignancy has not been proven. Finally, the extraadrenal presence of chromaffin tissue is highly suspicious for malignancy because as many as 50% of extraadrenal pheochromocytomas have been reported to be malignant.
Malignant pheochromocytomas occur mostly between the third and fifth decade and have been associated with other conditions like Von Recklinghausens disease (neurofibromatosis), von Hippel-Lindau disease, MEN type II, and multiple neuroectodermal tumors. Treatment should consist of aggressive surgical resection, and symptoms should be controlled with alpha and beta blockers as needed. Radiation therapy to bony metastases is palliative. MIBG was originally promising as a new mode of treatment for malignant pheochromocytomas, but reports indicate that less than 50% of patients derive a beneficial effect (6). Chemotherapy with cyclophosphamide, vincristine, and dacarbazine has been shown to induce a partial remission in some patients, but it is not curative and is only effective for a finite period (11). For this reason, chemotherapy should be reserved for patients with surgically inaccessible metastatic disease that is producing symptoms of excess catecholamines that cannot be controlled pharmacologically.
The progression of malignant pheochromocytomas is variable, with survival ranging from months to decades. Metastases to lungs and liver are generally more aggressive than metastases to bones and lymph nodes. Overall median survival is 5 yr, but prolonged survival even with widely metastatic disease has been reported.
Received July 29, 1997.
Revised August 27, 1997.
Accepted September 5, 1997.
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