A patient with a large recurrent pheochromocytoma demonstrating the pitfalls of diagnosis

NATURE REVIEWS | ENDOCRINOLOGY VOLUME 7 | DECEMBER 2011 | 749

Department of Endocrinology and Nephrology (J. Singer, R. Paschke), Surgical Department II (W. Kassahun), Department of Radiology, Liebigstraβe 20 (M. Seiwerts, G. Borte), Department of Nuclear Medicine, Liebigstraβe 18 (R. Kluge, T. Lincke), Department of Pathology, Liebigstraβe 26 (K. Schierle), University of Leipzig, 04103 Leipzig, Germany. Division of Endocrinology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA (C. A. Koch). Department of General Surgery, Delitzscher Straβe 141, Sankt Georg Hospital Leipzig, 04129 Leipzig, Germany (P. Lamesch). Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, Fetscherstraβe 74, University of Dresden, 01307 Dresden, Germany (G. Eisenhofer).

Correspondence to: R. Paschke ralf.paschke@ medizin.uni-leipzig.de

A patient with a large recurrent pheochromocytoma demonstrating the pitfalls of diagnosisJörg Singer, Christian A. Koch, Woubet Kassahun, Peter Lamesch, Graeme Eisenhofer, Regine Kluge, Thomas Lincke, Matthias Seiwerts, Gudrun Borte, Katrin Schierle and Ralf Paschke

Background. A 59-year-old man presented for a follow-up, 6 years after surgery for a large pheochromocytoma. He had suffered from diabetes mellitus, hypertension and abdominal pain in the right flank region. Previous postoperative follow-up did not reveal tumor recurrence.

Investigation. Measurement of plasma free metanephrine and normetanephrine by high-performance liquid chromatography and radioimmunoassay; 123I-metaiodobenzylguanidine (MIBG) scintigraphy; hybrid 123I-MIBG single-photon emission CT (SPECT)–CT; MRI; testing for plasma norepinephrine and epinephrine; intraoperative ultrasonography; histological staining for chromogranin A and synaptophysin; and postoperative 18F-dihydroxyphenylalanine (DOPA) PET scan.

Diagnosis. Recurrent pheochromocytoma.

Management. Laparotomy with tumor resection. Reduction of antihypertensive medications. Further follow-up by MRI, hybrid 123I-MIBG SPECT–CT and testing for plasma catecholamines and free metanephrines.

Singer, J. et al. Nat. Rev. Endocrinol. 7, 749–755 (2011); published online 6 September 2011; doi:10.1038/nrendo.2011.132

The caseA 59-year-old man presented for a regular follow-up about 6 years after surgical removal of a large pheochromocytoma

at an endocrinologic outpatient clinic. The patient did not complain of any symptoms and was normotensive under treatment with metoprolol and nitrendipine. At 53 years of age, he had initially presented to the clinic with sudden pain in the right upper abdomen. Ultrasonography and a CT scan showed a large tumor of the right adrenal gland with calcifications and signs of necrosis and indications of compression of the liver and kidney. At initial presen-tation, the patient had hypertension and type 2 dia betes mellitus. His BMI was 25.2 kg/m2. He had no clinical fea-tures of multiple endocrine neoplasia type 2 or neuro-fibromatosis type 1 and no history of renal stones or impaired renal function. An electrocardiogram showed single supra ventricular extrasystoles. Measurement of 24 h blood pressure revealed a mean systolic blood pres-sure of 163 mmHg and a mean diastolic blood pressure of 99 mmHg, accompanied by a mean heart rate of 86 bpm. Mild concentric left ventricular hypertrophy as well as a very slight pericardial effusion were diagnosed using echocardiography. No evidence of primary hyperpara-

thyroidism was found. Thyroid and neck ultrasonography results were normal.

During the initial work-up, a monoclonal gammo-pathy—excessive abnormal immunoglobulin levels in the blood—of unknown significance was identified. A 24 h urine analysis showed tremendously elevated epi-nephrine levels (Table 1). Blood samples showed markedly increased plasma norepinephrine and epinephrine levels. Unfortunately, the urinary norepinephrine level was not assessed preoperatively. 123I-metaiodobenzylguanidine (MIBG) scintigraphy showed tracer uptake, suggesting

Competing interestsThe authors, the journal Chief Editor J. Osório and the CME questions author C. P. Vega declare no competing interests.

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Learning objectivesUpon completion of this activity, participants should be able to: 1 Describe the clinical presentation of patients with

pheochromocytoma.2 Evaluate laboratory testing to diagnose pheochromocytoma. 3 Assess radiologic testing for pheochromocytoma.4 Analyze the perioperative management of pheochromocytoma.

CASE STUDY

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the presence of abnormal chromaffin tissue projecting to the right adrenal gland and no signs of metastasis.

Preoperatively, the patient received phenoxybenzamine with a final dose of 100 mg twice daily to treat his hyper-tension. Metoprolol was added to the regimen with a dose of 95 mg twice daily, and the patient received enalapril at a dose of 10 mg daily. Diabetes mellitus was treated with glimepiride and rosiglitazone. The patient was not receiv-ing any substances known to possibly interfere with the measurement of catecholamines and their metabolites before surgery.1 A laparotomy with tumor resection and right-sided adrenalectomy and an additional cholecys-tectomy due to chronic cholecystitis were performed 5 months after the initial examination. After 2 days, the patient underwent a second laparotomy for removal of the abdominal bandages left in place during the first operation to control diffuse bleeding related to removal of extensive adhesions around the liver.

Pathological investigation indicated a pheochromo-cytoma of 15 × 11 × 11 cm in size and a weight of 652 g. The capsule of the tumor appeared to be partly infiltrated and destroyed. However, the tumor did not infiltrate the sur rounding adipose tissue. A high rate of mitoses was pre sent with 4 per 10 high-power fields (HPF). A PASS (pheo chromocytoma of the adrenal gland scaled score) of 6 was calculated, on the basis of the system described by Thompson.2 The size of the removed pheochromo-cytoma did not differ significantly from that measured by CT, so rapid tumor progression during the 5 months from initial detection to removal seems very improbable. 1 month after surgery, treatment with antidiabetic drugs was no longer necessary. Further antihypertensive treat-ment consisted of 100 mg of metoprolol twice daily and

10 mg of the dihydropyridine calcium-channel blocker nitrendipine twice daily.

At follow-up, 10 months after the surgery, the patient was well, with plasma metanephrines (measured by radio immunoassay) within the normal range. However, 123I-MIBG scintigraphy showed an area with a dia meter of about 2 cm located in the right upper abdomen with enhanced tracer uptake (Figure 1a). No tumor was detected in this area by CT scans 10 and 19 months after sur gery and an MRI scan 21 months after surgery. How-ever, a second 123I-MIBG scan 21 months after sur gery showed the same result as the first scintigraphy performed 10 months after operation. Plasma meta nephrine levels, determined by radioimmunoassay 19 and 21 months after surgery, were slightly elevated (Table 1), whereas normeta-nephrine levels were within the normal range. Simi-larly, 24 h urinary metanephrine levels were also slightly elevated, whereas the normetanephrine con centration was normal.

MRI and CT scans 33 months after the initial surgery again showed normal results. Calcitonin and the neuro-endocrine tumor marker plasma chromogranin A, as well as a 24 h urinary catecholamine levels, were normal. At follow-up 36 months after surgery, blood pressure remained stable at 130/70 mmHg with metoprolol and nitrendipine at the initially prescribed doses. Urinary output of metanephrines remained elevated (Table 1). The monoclonal gammopathy of unknown significance was stable throughout follow-up. Genetic testing for VHL, RET, SDHB and SDHD yielded negative results.

Finally, at a follow-up investigation 5.8 years after surgery, results of measurement of plasma free meta-nephrines by high-performance liquid chromatography

Table 1 | Biochemical analysis

Investigations Normal range

Initial presentation

After first surgery After second surgery

19–21 months 3.6 years 5.8 years

Plasma free metanephrine (pg/ml)

NA ND 108 (NR: <96)* ND 229 (NR: <61)‡ 22 (NR: <61‡

Plasma free normetanephrine (pg/ml)

NA ND 44.3 (NR: <123)* ND 201 (NR: <112)‡ 86 (NR: <112)‡

Urine metanephrine (nmol over 24 h)

<1,732 ND 2,860 3,504 ND 289

Urine normetanephrine (nmol over 24 h)

<3,620 ND 2,848 3,250 ND 1,115

Plasma epinephrine (pg/ml) 30–83 1,444 ND ND 55 ND

Plasma norepinephrine (pg/ml)

165–498 2,556 ND ND 493 ND

Urinary epinephrine (nmol over 24 h)

<109 4,878 161 68 ND ND

Urinary norepinephrine (nmol over 24 h)

<620 ND 113 366 ND ND

Urinary dopamine (nmol over 24 h)

1,300–3,000

3,996 820 2,116 ND ND

Methoxytyramine (pg/ml) <22 ND ND ND 5 ND

Chromogranine A(pg/ml)

<110 ND ND 59 54 ND

*Measured by radioimmunoassay. ‡Measured by high-performance liquid chromatography. Abbreviations: NA, not applicable; ND, not determined; NR, normal range.

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(HPLC) showed clearly elevated plasma concentrations of metanephrine and normetanephrine (Table 1). Levels of metanephrine and normetanephrine measured by HPLC were more elevated than those measured by RIA at 3.6 years after initial surgery. The values yielded by HPLC suggested a small catecholamine-producing tumor with a possible size of about 2.1 cm in diameter (extreme ranges 1.1.–4.4 cm).3 123I-MIBG scintigraphy showed the same enhancement as previously described. However, this time, a concurrent 123I-MIBG single-photon emission CT (SPECT)–CT enabled detection of a hypodense area in the region of MIBG enhancement (Figures 1b and 2). A sub-sequent MRI scan identified a 2.0 × 1.2 cm hyperintense, partly cystic lesion in the vena cava and the vessel wall on T2-weighted images (Figure 3). In retro spect, this lesion was already visible on the MRI scans at 21 and 33 months after initial surgery, with a size of 1.7 × 1.0 cm. Additional laboratory testing for plasma norepinephrine and epi-nephrine revealed normal values (Table 1). The results of these tests provided a normetanephrine to norepinephrine ratio of 0.41 and a metanephrine to epinephrine ratio of 4.2, further increasing the probability of a pheochromo-cytoma, as discussed below.4 The metanephrine to epi-nephrine ratio, in particular, indicated that the increase in plasma metanephrine was unlikely to represent a false-positive result, leading to an intensive work-up including thorough revision of all radiologic investigations that were performed during the follow-up.

On the basis of these results, the patient underwent a second laparotomy for recurrent pheochromocytoma. The tumor could not be located by initial exploration of the previous surgical area. However, intraoperative ultrasonography identified a tumor with a diameter of about 3 cm infiltrating the inferior vena cava, just beneath the confluence of the hepatic veins. Tumor excision was performed. Histology showed a pheochromocytoma with infiltration of the vascular wall and neighboring adipose tissue (Figure 4a). Tumor tissue showed prominent stain-ing for chromogranin A and synaptophysin. The MIB1 proliferation index was <5% (Figure 4b).

Biochemical testing after surgery revealed normal-ized values for plasma metanephrine and plasma normetanephrine, as well as for urine meta nephrine and normeta nephrine (Table 1). A postoperative 18F-dihydroxyphenylalanine (DOPA) PET scan did not show any evidence of meta stases or extra-adrenal chro-maffin tissue. Postoperatively, the patient still required amlodipine 2.5 mg twice daily and ramipril 2.5 mg for hypertension. Further lifelong follow-up will include periodic testing for plasma cate cholamines and free metanephrines, MRI and hybrid 123I-MIBG SPECT–CT.

Discussion of diagnosisPheochromocytomas are rare neuroendocrine tumors of the adrenal gland that produce and secrete cate chola-mines. If these tumors are located outside the adrenal gland, they are referred to as sympathetic or parasym-pathetic paragangliomas and commonly have less capa-bility of producing catecholamines than tumors of the adrenal glands, especially when located in the head and

neck region. The prevalence of these adrenal and extra- adrenal neuroendocrine tumors has been reported as 0.1% of patients suffering from sustained or medically refractory hypertension, but is likely to be underestimated when considering that many patients with pheochromo-cytomas do not have sustained hypertension or may even be normotensive. In Western countries, with 20% of the population suffering from sustained hypertension, the estimated prevalence of pheochromocytomas is about 1 in 6,500 in the general population. In patients presenting with an adrenal incidentaloma, pheochromo cytomas are found in approximately 5% of cases and may not cause any of the classical symptoms of catecholamine excess (hypertension, headache, hyperhidrosis, hyper glycemia, tachycardia). These tumors are, therefore, sometimes referred to as being clinically silent. Some of the symp-toms in patients with pheo chromocytoma resemble those seen in patients with hyper thyroidism and other neuro-endocrine tumors such as medullary thyroid cancer and insulinoma. On the other hand, certain medica-tions including commonly prescribed antidepressive drugs may cause symptoms of pheo chromocytoma and even biochemical features of catecho lamine excess. In this context, one has to be reminded that pheochromo-cytomas are rare tumors and the positive predictive value of symptoms of pheochromocy toma is, therefore, low; in other words, most patients presenting with symptoms of ph eochromocytoma do not have the tumor.1

Figure 1 | 123I-metaiodobenzylguanidine scintigraphy in the case patient. Planar posterior views 24 h after injection indicate suspicion of residual tumor mass a | after the first surgery and b | before the second surgery.

a b

a b

Figure 2 | 123I-metaiodobenzylguanidine (MIBG) scintigraphy with single-photon emission CT (SPECT)–CT in the case patient. Fusion of low-radiation dose CT with MIBG scintigraphy enables better anatomical correlation than MIBG scintigraphy alone in the axial (a) and coronal (b) view.

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Biochemical testingMeasurements of plasma free metanephrines (normeta-nephrine and metanephrine) and urinary fractionated metanephrines are the test of choice when pheochromo-cytoma is suspected.1,4–6 These O-methylated metabolites are produced continuously within tumors, providing diag-nostic advantages over measurements of catecholamines (epinephrine, norepinephrine), which can be secreted episodically or only in low amounts.7 The described case reveals several pitfalls of biochemical analyses. Meta-nephrines can be measured by several methods, includ-ing HPLC with electrochemical or mass spectrometric detection and immunoassays, such as RIA and ELISA.8 Although measurement of plasma metanephrines by RIA is considered to be a reliable screening approach for pheochromocytomas,9 few studies are available that have compared ELISA and HPLC. Nevertheless, novel data from interlaboratory proficiency programs indicate that immunoassays significantly underestimate plasma levels of meta nephrines compared with HPLC-based methods.10 Use of inappropriately established upper reference intervals exacerbates the problem, leading to increased potential for false-negative results. In the case patient, the minimally elevated levels measured by RIA compared with the highly elevated levels measured by HPLC illustrate this potential pitfall.

The calculation of metanephrine to epinephrine and normetanephrine to norepinephrine ratios was of further value for establishing the diagnosis in the case patient. Patients with pheochromocytoma have larger relative increases in metanephrines than in catecholamines, whereas false-positive results are associated with larger increases of catecholamines than of metanephrines.4 Of note, calcium-channel blockers such as nitrendi-pine, with which the case patient was treated for hyper-tension, can increase plasma catecholamine levels by sympathetic activation.1 In 30% of cases in which plasma free meta nephrines did not provide unequivocal results, a metanephrine to epinephrine ratio >4.2 and a nor-metanephrine to norepinephrine ratio >0.52 confirmed the presence of a pheochromocytoma.4 In selected patients with less than fourfold elevated plasma free meta-nephrine levels and less than twofold increased fraction-ated urinary metan ephrine levels above normal levels, measuring plasma chromogranin A, a neuroendocrine

tumor marker, can prove helpful,11 although in the case patient the concentration of this analyte was normal.

Genetic testingAs genetic testing for VHL, RET (associated with mul-tiple endocrine neoplasia type 2), SDHB and SDHD germline mutations yielded negative results, inherited pheochromo cytoma was unlikely in the described case. Patients with large pheochromocytomas, such as the case patient, are at increased risk of malignancy, which can occur with any germline mutation in the afore mentioned genes,12–15 most frequently with SDHB germline muta-tions. Patients with von Hippel Lindau syndrome can have extra-adrenal and malignant pheochromo cytoma.1 To differentiate between benign and malignant pheo-chromocytomas, previous studies have investigated dif-ferent gene expression and molecular pattern profiles to separate the two classes of tumors. Thouënnon et al.5 used pan-genomic microarrays and identified four genes (QPCT, PAM, NPY, CAMK2N1) with significantly differ-ent expression in benign compared with malignant pheo-chromocytomas. However, expression of these genes was not analyzed in the case patient.

ImmunohistochemistryPreparations from both surgeries were histologically investigated and also stained for chromogranin A and synaptophysin. Both markers are expressed by neuro-endocrine cells and help to establish the diagnosis.16 The MIB1 antibody stains the Ki-67 protein, which is expressed in proliferating cells. The determination of the MIB1 proliferation index helps distinguish between benign and malignant neuroendocrine tumors.17

ImagingCT and MRI scans have a sensitivity of approximately 90% and a specificity of 70–80%1 for the diagnosis of adrenal pheochromocytomas with a diameter of ≥5 mm.7 Sensitivity is decreased for the detection of extra-adrenal pheochromocytomas and in postsurgical areas where recurrent disease can be obscured.7 A study by Fiebrich et al.18 compared sensitivities between 18F-DOPA PET, 123I-MIBG scintigraphy and CT–MRI imaging and found patient-based sensitivities of 90%, 65% and 67%, as well as lesion-based sensitivities of 73%, 48% and 44%, respectively. As a patient can have more than one lesion, and not all lesions are detected, lesion-based sensitivity is generally lower than patient-based sensitivity. Because of limitations in specificity of CT–MRI imaging, additional 123I-MIBG scanning is recommended. The sensitivity of 123I-MIBG scanning varies between 75%19 and 92%.20 Lack of sensitivity can be improved by hybrid MIBG SPECT–CT approaches, as used in the case patient, as well as by 18F-fluorodopamine (FDA) PET, which seems to be superior to 123I-MIBG scanning.18,21

The described case illustrates several pitfalls concerning imaging studies for localization of a pheochromo cytoma. In the described case patient, residual tissue of the pheo-chromocytoma after the first surgery was difficult to detect owing to an apparent lack of correlation between

a b

Figure 3 | T2-weighted MRI scans in the coronal (a) and axial (b) plane of the case patient showing tumor growth inside the inferior vena cava.

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123I-MIBG and MRI–CT scans. 123I-MIBG SPECT–CT or 18F-DOPA PET–CT enable earlier morphologic clari-fication of SPECT or PET abnormalities and should be used to ensure complete resection. The tumor recurrence in the vena cava of the case patient indicates that initial imaging studies should thoroughly assess possible evi-dence of infiltration of neighboring structures including larger vessels. The lack of a capsule in parts of the tumor without any histological evidence for an infiltration of adjacent structures was obviously attributed to the dif-ficult removal of the tumor, but a positive finding on postoperative 123I-MIBG imaging should have prompted a more thorough search for a morphologic correlate on contrast CT, MRI or preferably on MIBG–SPECT. False-negative results for 131I-MIBG scanning range from about 0% to 27%, but false-positive results are only found in up to 5% of patients (specificity 95–100%)22 and are even less probable in a post operative situation. Using 123I-MIBG scintigraphy, false-negative results range from 0% to 17%, with a specificity of 95–100%.22 Extra-adrenal and small adrenal pheochromocytomas are more prone to yield a false-negative result, with Bhatia et al.19 reporting a sensi-tivity of only 58% for extra-adrenal pheochromocytomas with 123I-MIBG scintigraphy.

Difficulties in identifying a morphologic correlate for positive MIBG results have previously been reported. For example, Pacak et al.7 described a similar situation with a patient in whom 123I-MIBG scintigraphy, as well as 18F-FDA PET, showed a focus of activity in the right adrenal bed in the area of a previous right adrenalec-tomy. The CT scan revealed multiple surgical clips in the right adrenal area causing artifacts that obviated detailed examination of the area. An additional abdominal MRI scan was also unable to locate any tumor mass in this location. The combination of results from 123I-MIBG scintigraphy, 18F-FDA PET and biochemical testing including vena cava blood sampling justified surgery in the reported case and revealed multiple nodes of pheo-chromocytoma tissue in the right adrenal surgical bed, some infiltrating the vena cava.7

Treatment and managementStandard preoperative preparation for surgical removal of a pheochromocytoma includes blood pressure con-trol using α blockers such as phenoxybenzamine or doxazosine, with phenoxybenzamine having a longer half-life and, therefore, a higher risk for postoperative hypotension if saline is not adequately administered as long as vasodilatation exists. After appropriate pre-operative α blockage, one can also use β-blocker therapy if necessary, for instance, to control reflex tachycardia.1

Laparoscopic adrenalectomy can be performed for small tumors, as the risk of malignancy and potential seeding of tumor cells is low. For tumors exceeding 6 cm in size, the risk of malignancy increases to >25% and even higher when certain genetic predispositions are present, such as germline mutations in the SDHB gene. In such patients, as in the described case, open adrena-lectomy or laparotomy should be performed to avoid potential tumor seeding and to obtain a better in situ

look intra operatively for complete tumor removal. 123I-MIBG scintigraphy cannot only help localize addi-tional extra-adrenal tumor tissue in these patients but also predicts whether a patient with malignant pheo-chromocytoma would be a candidate for 131I-MIBG therapy, including experimental agents such as arsenic trioxide.13 Traditional therapeutic regimens for malig-nant pheochromocytoma besides 131I-MIBG therapy include certain chemotherapy approaches, including the Averbuch protocol.1,23 The success rates of these therapies are generally suboptimal considering the aim of tumor shrinkage, for which surgical debulking repre-sents the first and most important treatment modality. In less dedifferentiated tumors, such as the one described, biochemical improvement or control of catecholamine excess and related symptoms can also be achieved by surgery, although medically refractory hypertension may not completely resolve depending on the duration of catecholamine excess and other contributing factors (that is, metabolic syndrome and genetic predisposition for hypertension). Patients with a surgically removed pheo-chromocytoma and treated catecholamine excess with undetectable plasma free and urinary fractionated meta-nephrines and catecholamines might, therefore, require long-term antihypertensive drugs. Patients should be followed long-term with annual monitoring of clinical symptoms and signs of pheochromocytoma, biochemi-cal evaluation with plasma free and urinary fractionated metanephrines and, in selected cases, methoxytyramine as well as 24 h urinary dopamine.

About 10–15% of all pheochromocytomas are malig-nant,1,2,5,12–15,24–28 with an overall 5-year survival of approxi mately 40–50%.23 According to the current WHO definition, the only proof of malignancy is the occurrence of distant metastases at sites where chromaffin tissue is normally absent. Chromaffin cells are usually found in the adrenal gland and in association with the paragan-glia of the sympathetic nervous system. Tumors with extensive invasion of surrounding tissues and those with local recurrence can also be fatal. Local recurrence of a pheochromocytoma can occur years after initial sur-gical tumor removal.2,25–28,29 Amar et al.24 reported four patients with evidence of a first metastasis more than 20 years after resection of the primary tumor, demon-strating the necessity of lifelong follow-up in patients with pheochromocytoma or paraganglioma.

Distinguishing benign from malignant tumors is very important, as it substantially influences the type and fre-quency of follow-up procedures. Malignant local tumor recurrence or invasion of surrounding tissues can be especially difficult to separate from benign local tumor growth from residual cells after surgical removal of a large tumor. These remaining cells, although benign, might initiate recurrence of a benign but also of a malignant pheochromocytoma. A benign pheochromocytoma on first presentation can also evolve into a malignant tumor owing to consecutive somatic mutations of genes affect-ing growth regulation such as IGF‑1, genes that trigger proliferation such as MEN1, genes that inhibit apopto-sis, such as BIRC5 and BCL2.12 In the described patient,

CASE STUDY



the speed of tumor growth over 6 years was low, from 1.7 × 1.0 cm to 2.0 × 1.2 cm, in spite of invasive growth.

The PASS system helps predict malignancy in patients with pheochromocytoma according to several histo-logical features,25 but substantial interobserver and intra observer variation in interpretation of the criteria weaken the reliability of this system for predicting malig-nancy,28 similarly to the Weiss scoring system for adreno-cortical tumors.29 A PASS ≥4 indicates a high probability of malignancy,30 as in the case patient, who had a PASS of 6. Extra-adrenal location and tumor size >6 cm have been shown to carry an increased risk of malignancy, but these observations cannot be used to reliably predict malig-nant disease.27,28,30 Also, numerous molecular markers

have been suggested to distinguish between benign and malignant pheochromocytomas,5,12 but none has been validated in prospective studies.

The patient was additionally diagnosed with a mono-clonal gammopathy of unknown significance (MGUS). According to current recommendations, the patient did not receive any treatment for MGUS, but repeated measurement of γ-globulin levels was performed during follow-up to detect eventual progression. The association between pheochromocytoma and MGUS has not previ-ously been reported. It is unclear whether MGUS can contribute to tumor development in certain patients via immunomodulatory or immunosuppressive effects.

ConclusionsThe presented case illustrates some of the possible pit-falls of diagnosis and provides insights into the speed of growth of an adrenal pheochromocytoma over a 6-year time interval. The case demonstrates a combination of problems of follow-up biochemical screening in a patient operated for a large pheochromocytoma at increased risk of malignant disease. The importance of advanced bio-chemical investigations is indicated by the more defini-tive diagnosis provided by HPLC compared with RIA measurements of plasma metanephrines. Moreover, normal levels of catecholamines but increased levels of metanephrines in the case patient illustrate the impor-tance of primarily considering O-methylated metabo-lites, although both measurements should be taken into account. Finally, the difficulty in assessing the presence of disease after initial surgical resection and reaching a diagnosis of malignancy are highlighted.

a b

Figure 4 | Histology and immunhistochemistry of tissue samples taken at the second surgery of the case patient. a | Pheochromocytoma infiltrating the wall of the inferior vena cava of the case patient. b | Staining of the pheochromocytoma located inside the inferior vena cava of the case patient for the MIB1 (Ki-67) antibody. Calculation of the MIB1 proliferation index shows a rate of <5% proliferation.

1. Lenders, J. W., Eisenhofer, G., Mannelli, M. & Pacak, K. Phaeochromocytoma. Lancet 366, 665–675 (2005).

2. Thompson, L. D. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am. J. Surg. Pathol. 26, 551–566 (2002).

3. Eisenhofer, G. et al. Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin. Chem. 51, 735–744 (2005).

4. Eisenhofer, G. et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J. Clin. Endocrinol. Metab. 88, 2656–2666 (2003).

5. Thouënnon, E. et al. Identification of potential gene markers and insights into the pathophysiology of pheochromocytoma malignancy. J. Clin. Endocrinol. Metab. 92, 4865–4872 (2007).

6. Sawka, A. M. et al. A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma. BMC Endocr. Disord. 4, 2 (2004).

7. Pacak, K. et al. A “pheo” lurks: novel approaches for locating occult pheochromocytoma. J. Clin. Endocrinol. Metab. 86, 3641–3646 (2001).

8. Peaston, R. T., Graham, K. S., Chambers, E., van der Molen, J. C. & Ball, S. Performance of

plasma free metanephrines measured by liquid chromatography-tandem mass spectrometry in the diagnosis of pheochromocytoma. Clin. Chim. Acta 411, 546–552 (2010).

9. Unger, N. et al. Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients with adrenal mass. Eur. J. Endocrinol. 154, 409–417 (2006).

10. Pillai, D. & Callen, S. Pilot quality assurance programme for plasma metanephrines. Ann. Clin. Biochem. 47 (Pt 2), 137–142 (2010).

11. Algeciras-Schimnich, A., Preissner, C. M., Young, W. F. Jr, Singh, R. J. & Grebe, S. K. Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic accuracy of plasma fractionated metanephrines for pheochromocytoma. J. Clin. Endocrinol. Metab. 93, 91–95 (2008).

12. Qin, Y., Buddavarapu, K. & Dahia, P. L. Pheochromocytomas: from genetic diversity to new paradigms. Horm. Metab. Res. 41, 664–671 (2009).

13. Majumdar, S. et al. Compound heterozygous mutation with a novel splice donor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma. Pediatr. Blood Cancer 54, 473–475 (2010).

14. Bausch, B., Borozdin, W. & Neumann, H. P. Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N. Engl. J. Med. 354, 2729–2731 (2006).

15. Ricketts, C. J. et al. Tumor risks and genotype–phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum. Mutat. 31, 41–51 (2010).

16. Lloyd, R. V. Adrenal cortical tumors, pheochromocytomas and paragangliomas. Mod. Pathol. 24 (Suppl. 2), S58–S65 (2011).

17. Morimoto, R. et al. Immunohistochemistry of a proliferation marker Ki67/MIB1 in adrenocortical carcinomas: Ki67/MIB1 labeling index is a predictor for recurrence of adrenocortical carcinomas. Endocr. J. 55, 49–55 (2008).

18. Fiebrich, H. B. et al. 6-[F-18]Fluoro-L- dihydroxyphenylalanine positron emission tomography is superior to conventional imaging with 123I-metaiodobenzylguanidine scintigraphy, computer tomography, and magnetic resonance imaging in localizing tumors causing catecholamine excess. J. Clin. Endocrinol. Metab. 94, 3922–3930 (2009).

19. Bhatia, K. S. et al. Reznek RH. 123I-metaiodobenzylguanidine (MIBG) scintigraphy for the detection of adrenal and extra-adrenal phaeochromocytomas: CT and MRI correlation. Clin. Endocrinol. (Oxf.) 69, 181–188 (2008).

20. Jacobson, A. F., Deng, H., Lombard, J., Lessig, H. J. & Black, R. R. 123I-metaiodobenzylguanidine scintigraphy for the detection of neuroblastoma and pheochromocytoma: results of a meta-analysis. J. Clin. Endocrinol. Metab. 95, 2596–2606 (2010).

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21. Timmers, H. J. et al. Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J. Clin. Endocrinol. Metab. 94, 4757–4767 (2009).

22. Havekes, B. et al. New imaging approaches to phaeochromocytomas and paragangliomas. Clin. Endocrinol. (Oxf.) 72, 137–145 (2010).

23. Huang, H. et al. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 113, 2020–2028 (2008).

24. Amar, L. et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J. Clin. Endocrinol. Metab. 92, 3822–3828 (2007).

25. Gao, B. et al. Development and validation of pheochromocytoma of the adrenal gland scaled score for predicting malignant

pheochromocytomas. Urology 68, 282–286 (2006).

26. Gao, B. et al. A logistic regression model for predicting malignant pheochromocytomas. J. Cancer Res. Clin. Oncol. 134, 631–634 (2008).

27. Shen, W. T., Sturgeon, C., Clark, O. H., Duh, Q. Y. & Kebebew, E. Should pheochromocytoma size influence surgical approach? A comparison of 90 malignant and 60 benign pheochromocytomas. Surgery 136, 1129–1137 (2004).

28. Strong, V. E. et al. Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis. Surgery 143, 759–768 (2008).

29. Pohlink, C. et al. Does tumor heterogeneity limit the use of the Weiss criteria in the evaluation of adrenocortical tumors? J. Endocrinol. Invest. 27, 565–569 (2004).

30. Wilhelm, S. M., Prinz, R. A., Barbu, A. M., Onders, R. P. & Solorzano, C. C. Analysis of large versus small pheochromocytomas: operative

approaches and patient outcomes. Surgery 140, 553–559; discussion 559–60 (2006).

AcknowledgmentsWritten consent for publication was obtained from the patient. C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.

Author contributionsJ. Singer, C. A. Koch, G. Eisenhofer, M. Seiwerts, G. Borte, K. Schierle and R. Paschke researched the data for the article. J. Singer, C. A. Koch, W. Kassahun, P. Lamesch, G. Eisenhofer, M. Seiwerts, G. Borte and R. Paschke provided a substantial contribution to discussions of the content. J. Singer, C. A. Koch and R. Paschke wrote the article. All authors reviewed and/or edited the manuscript before submission.

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