Pheochromocytoma

Background

The pheochromocytoma is a paraganglioma arising from the adrenal medulla. Bilateral disease is present in approximately 10% of patients. Bilaterality is much more common in familial pheochromocytoma, often found in association with the familial multiple endocrine neoplasia syndromes (MEN, types IIA and IIB).

Patients may present with hypertension which may be sustained or paroxysmal and is often severe with occasional malignant features of encephalopathy, retinopathy and proteinuria. Less commonly, severe hypertensive reactions may occur during incidental surgery, following trauma, exercise, or urination, which may be seen in cases of bladder pheochromocytoma. Other clinical features of pheochromocytoma include headache, sweating, palpitation, tachycardia and severe anxiety along with epigastric or chest pain. Orthostatic hypotension may be present and is secondary to reduced intravascular volume following chronic adrenergic stimulation.

Ninety-seven percent are found in the abdomen, 2%-3% in the thorax, and 1% in the neck.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

INCIDENCE 800 new cases/year/United States

AGE RANGE-MEDIAN 3-5th decades

DISEASE ASSOCIATIONS CHARACTERIZATION

A case of Sipple's syndrome with malignant pheochromocytoma treated with 131I-metaiodobenzyl guanidine and a combined chemotherapy with cyclophosphamide, vincristine and dacarbazine.

Sasaki M, Iwaoka T, Yamauchi J, Tokunaga H, Naomi S, Inoue J, Oishi S, Umeda T, Sato T.

Third Department of Internal Medicine, Kumamoto University Medical School, Japan

Endocr J 1994 Apr;41(2):155-60 Abstract quote

A 39-year-old woman with Sipple's syndrome and a malignant pheochromocytoma (PHE) is presented.

She is a member of a big family with this syndrome and had undergone bilateral, subtotal adrenalectomy because of bilateral PHE six years prior to the present admission. In 1989, a small nodule was identified in her right thyroid lobe by ultrasonography and was suspected to be a medullary thyroid carcinoma (MTC). Further examinations revealed the coexistence of multiple lung and liver masses. These tumors were considered to be metastases of PHE because of the increased urinary excretion of catecholamines as well as extremely high catecholamines both in the hepatic venous blood and in the cystic fluid of the liver tumor even though there was no apparent recurrences of PHE in the adrenal region. After surgical removal of the MTC in August, 1989, she was given 3.7 GBq of 131I-metaiodobenzyl guanidine (131I-MIBG) infusions twice--in October, 1989 and in August, 1990. 131I-MIBG showed a strong accumulation in the lung and liver masses on both occasions. Periodic increases in blood pressure and tachycardia with an excessive catecholamine secretion were observed over two weeks after the first treatment. However, this treatment was not effective in reducing urinary catecholamines nor the size of the metastatic tumors.

She, therefore, underwent chemotherapy with cyclophosphamide, vincristine and decarbazine in 1991, which slightly but significantly reduced urinary excretion of catecholamines and the size of the lung tumors. She had clinically stable period for one year after the treatment but rapid growth of these metastatic tumors occurred afterwards and she died in August, 1992.

MEN Type IIA and IIB
N Engl J Med 1993;329(21):1531-1538.

Risk of developing a contralateral tumor following unilateral adrenalectomy is approximately 50%

23% were found to be carriers of associated familial disorders. Therefore, all patients with pheochromocytomas should be screened for MEN-2 and von Hippel- Lindau

Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study.

Nguyen L, Niccoli-Sire P, Caron P, Bastie D, Maes B, Chabrier G, Chabre O, Rohmer V, Lecomte P, Henry JF, Conte-Devolx B;

French Calcitonin Tumors Study Group. Service d'Endocrinologie,

Eur J Endocrinol 2001 Jan;144(1):37-44 Abstract quote

OBJECTIVE: The aim of this prospective study is to update our knowledge of the chronology of pheochromocytoma occurrence in multiple endocrine neoplasia type 2 (MEN 2), and to better manage MEN 2 patients after the genetic diagnosis.

DESIGN: Eighty-seven non-index gene carrier MEN 2 patients were included in this prospective study: 84 patients with MEN 2A (from 52 families) and 3 with MEN 2B (from 3 families).

METHODS: Medullary thyroid carcinoma (MTC) was diagnosed by measuring plasma calcitonin in basal conditions or after pentagastrin stimulation. The search for pheochromocytoma consisted of clinical evaluation, 24 h determination of urinary catecholamines and adrenal imaging. The mean age at genetic diagnosis of MEN 2 was 14.0+/-7.0 years, the mean duration for the follow-up was 7.6+/-2.8 years.

RESULTS: All 87 patients had a MTC detected at the same time as the genetic diagnosis was made. Urinary catecholamine measurements led to the diagnosis of pheochromocytoma and a combination of imaging techniques enabled the correct localization of both unilateral or bilateral adrenal involvement. Pheochromocytoma was detected simultaneously with MTC in only seven patients, and seven others were detected throughout the follow-up. Of the 14 patients with pheochromocytoma, 11 had bilateral involvement: nine were initially bilateral and two became so during follow-up.

CONCLUSION: This study demonstrates that in MEN 2, MTC is the lesion which appears earliest. Pheochromocytoma develops later during the evolution of the disease, and necessitates regular clinical and biological monitoring throughout follow-up. Determination of urinary and/or plasma catecholamines and metanephrines should be performed to detect pheochromocytoma. Imaging techniques lead to the detection of both unilateral and bilateral pheochromocytoma, thus making video-assisted laparoscopic adrenalectomy possible.

Neurofibromatosis

Neurofibromatosis

von Hippel-Lindau disease

Cerebellar hemangioblastoma

Sturge-Weber's syndrome

Tuberous sclerosis

PATHOGENESIS CHARACTERIZATION

CHROMOSOMAL ABNORMALITIES

Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome.

Lui WO, Chen J, Glasker S, Bender BU, Madura C, Khoo SK, Kort E, Larsson C, Neumann HP, Teh BT.

Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
Oncogene 2002 Feb 7;21(7):1117-22 Abstract quote
By using comparative genomic hybridization (CGH), we characterized the genetic profiles of 36 VHL-related pheochromocytomas.

We then compared the results with those of sporadic and MEN 2-related pheochromocytomas. In 36 VHL-related tumors, loss of chromosome 3 and chromosome 11 were found in 34 tumors (94%) and 31 tumors (86%), respectively. There was significant concordance of deletions in chromosomes 3 and 11 (Kappa=0.64, P=0.0095), suggesting that they are involved in two different but necessary and complementary genetic pathways. The loss of chromosome 11 appeared to be specific for VHL-related pheochromocytoma as it was not present in any of the 10 VHL-related CNS hemangioblastomas studied and was significantly less common when compared with (a) sporadic pheochromocytomas from previously published results (13%; P=<0.0001), and (b) MEN 2-related pheochromocytomas from this and previously published studies (30%; P=0.0012).

In summary, this is the first report of a novel consistent genetic alteration that is selected and specific for VHL-related pheochromocytoma, besides the two hits of the VHL gene.

NEUROFIBROMIN

Neurofibromin and NF1 Gene Analysis in Composite Pheochromocytoma and Tumors Associated with von Recklinghausen's Disease.

Kimura N, Watanabe T, Fukase M, Wakita A, Noshiro T, Kimura I.

Department of Pathology and Laboratory Medicine (NK), Tohoku Rosai Hospital, Sendai.
Mod Pathol 2002 Mar;15(3):183-8 Abstract quote
Composite tumor of pheochromocytoma and neuroblastoma, or ganglioneuroma, or ganglioneuroblastoma (composite pheochromocytoma), also known as mixed neuroendocrine and neural tumor, are sometimes combined with neurofibromatosis type 1 (NF1).

To better understand the relationship between NF1 and composite pheochromocytoma, an immunohistochemical study using anti-neuro-fibromin that is an NF1 gene product and DNA sequence of NF1 Exon 31 were carried out in five cases of composite pheochromocytoma and in various tumors from five patients with NF1. Neurofibromin was not expressed in Schwann cells and sustentacular cells of composite pheochromocytomas and was very weakly or negatively expressed in neurofibroma of NF1 patients. However, it was strongly expressed in ganglionic cells and pheochromocytoma cells of the composite pheochromocytomas and also in mucosal ganglioneuromas, a gangliocytic paraganglioma, and in pheochromocytomas from the patients with NF1.

Although there was no mutation in NF1 Exon 31, it could not be ruled out that there were mutations in other sites of the NF1 gene. Neurofibromin insufficiency may induce abnormal proliferation of Schwann cells in composite pheochromocytomas as well as in neurofibromatosis.

LABORATORY/
RADIOLOGIC/
OTHER TESTS CHARACTERIZATION

CT scan and MRI
The initial studies should be a chest film and abdominal computed tomographic (CT) scan

Magnetic resonance imaging (MRI), or rarely, vena cava catheterization with selective venous sampling for catecholamines may be indicated

CT and MRI scans are about equally sensitive (98%-100%)

MIBG scanning has a specificity of 100%

Radioisotope-guided surgery in patients with pheochromocytoma and recurrent medullary thyroid carcinoma: a comparison of preoperative and intraoperative tumor localization with histopathologic findings.

Adams S, Acker P, Lorenz M, Staib-Sebler E, Hor G.

Department of Nuclear Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main, Germany.

Cancer 2001 Jul 15;92(2):263-70 Abstract quote

BACKGROUND: The objective of this study was to appraise the detection of metastases of medullary thyroid carcinoma (MTC) and pheochromocytoma using radioguided surgery (RGS) and to compare the results with external imaging modalities, surgical palpation, and histopathologic findings.

METHODS: Twenty-five patients with recurrent MTC underwent preoperative scintigraphic imaging with 500 megabecquerels (MBq) of technetium 99m(V)-dimercaptosuccinic acid [(99m)Tc(V)-DMSA] and 222 MBq of indium 111 ((111)In)-pentetreotide. The radiopharmaceutical that showed the greatest preoperative tumor uptake was selected for intraoperative RGS. Surgery was performed 24 hours after the administration of (111)In-pentetreotide or 4 hours after the injection of (99m)Tc(V)-DMSA. Furthermore, three male patients underwent surgery who suffered from recurrent pheochromocytoma (injection of 180 MBq iodine 123-labeled metaiodobenzylguanidine [(123)I-MIBG] 4--5 hours before surgery).

RESULTS: Overall, lesion detection sensitivities in patients with MTC for computed tomography, (111)In-pentetreotide, and (99m)Tc(V)-DMSA were 32%, 34%, and 65%, respectively. Surgical palpation identified lymph node metastases of recurrent MTC with a sensitivity of 65%, whereas RGS localized 64 malignant lesions (sensitivity, 97%). Altogether, 71 lesions could be excised, 5 of which were adjudged false positive with respect to MTC metastases. Both surgical palpation and RGS localized all paravertebral subdiaphragmatic lesions (size > or = 2 cm) of recurrent pheochromocytoma seen in the preoperative MIBG scan.

CONCLUSIONS: RGS was capable of localizing more and smaller metastases of MTC compared with conventional imaging modalities and surgical palpation. However, the relatively high radioligand accumulation in the kidneys ((111)In-pentetreotide) and the dense hepatic and biliary signals using MIBG limited their use for intraoperative detection of tumors in the area of the adrenal gland.

Laboratory Markers

GENERAL

Biochemical Diagnosis of Pheochromocytoma

Which Test Is Best?

Jacques W. M. Lenders, MD, PhD; Karel Pacak, MD, PhD; McClellan M. Walther, MD; W. Marston Linehan, MD; Massimo Mannelli, MD; Peter Friberg, MD, PhD; Harry R. Keiser, MD; David S. Goldstein, MD, PhD; Graeme Eisenhofer, PhD

JAMA. 2002;287:1427-1434 Abstract quote

Context
Diagnosis of pheochromocytoma depends on biochemical evidence of catecholamine production by the tumor. However, the best test to establish the diagnosis has not been determined.

Objective
To determine the biochemical test or combination of tests that provides the best method for diagnosis of pheochromocytoma.

Design, Setting, and Participants
Multicenter cohort study of patients tested for pheochromocytoma at 4 referral centers between 1994 and 2001. The analysis included 214 patients in whom the diagnosis of pheochromocytoma was confirmed and 644 patients who were determined to not have the tumor.

Main Outcome Measures
Test sensitivity and specificity, receiver operating characteristic curves, and positive and negative predictive values at different pretest prevalences using plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid.

Results
Sensitivities of plasma free metanephrines (99% [95% confidence interval {CI}, 96%-100%]) and urinary fractionated metanephrines (97% [95% CI, 92%-99%]) were higher than those for plasma catecholamines (84% [95% CI, 78%-89%]), urinary catecholamines (86% [95% CI, 80%-91%]), urinary total metanephrines (77% [95% CI, 68%-85%]), and urinary vanillylmandelic acid (64% [95% CI, 55%-71%]). Specificity was highest for urinary vanillylmandelic acid (95% [95% CI, 93%-97%]) and urinary total metanephrines (93% [95% CI, 89%-97%]); intermediate for plasma free metanephrines (89% [95% CI, 87%-92%]), urinary catecholamines (88% [95% CI, 85%-91%]), and plasma catecholamines (81% [95% CI, 78%-84%]); and lowest for urinary fractionated metanephrines (69% [95% CI, 64%-72%]). Sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines using receiver operating characteristic curves. Combining different tests did not improve the diagnostic yield beyond that of a single test of plasma free metanephrines.

Conclusion
Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.

ACTH

Adrenocorticotropic hormone-secreting pheochromocytoma.

Sato M, Watanabe T, Ashikaga T, Taneda T, Yamawake N, Nishizaki M, Arimura A, Azegami N, Arita M, Fukuoka H, Kitamura H.

First Department of Internal Medicine, Yokohama Minami Kyosai Hospital.

Intern Med 1998 Apr;37(4):403-6 Abstract quote

A 41-year-old female had pheochromocytoma which secreted adrenocorticotropic hormone (ACTH). She was admitted to our hospital because of weight loss and excessive sweating. Not only urinary metanephrine but also plasma ACTH was extremely high. An abdominal echogram showed a cystic tumor in the left adrenal gland. An abdominal magnetic resonance imaging scan showed a hyperintense T2-weighted abnormality inside the tumor. Left adrenalectomy was done. The tumor consisted of benign pheochromocytoma cells diffusely stained with anti-ACTH antibody. The present case did not show any typical Cushingoid symptoms which are common in ACTH-secreting pheochromocytomas.

CATECHOLAMINES

Urine and serum catecholamine levels
Elevated 24-hour urinary excretion of free catecholamines (norepinephrine and epinephrine) or catecholamine metabolites (VMA and total metanephrines)

The measurement of plasma catecholamines has limited sensitivity and specificity

Plasma metanephrines have been reported to be more sensitive than plasma catecholamines

RET PROTO-ONCOGENE

Diagnosis and management of pheochromocytomas in patients with multiple endocrine neoplasia type 2-relevance of specific mutations in the RET proto-oncogene.

Frank-Raue K, Kratt T, Hoppner W, Buhr H, Ziegler R, Raue F.

Medizinische Universitatsklinik, Heidelberg, Germany.

Eur J Endocrinol 1996 Aug;135(2):222-5 Abstract quote

It has been suggested that specific mutations in the RET proto-oncogene correlate with clinical manifestation of the multiple endocrine neoplasia type 2 (MEN 2) syndrome.

We retrospectively analyzed 61 patients with MEN 2, 28 with associated pheochromocytoma, regarding the relevance of specific mutations in the RET proto-oncogene and the diagnostic sensitivity of catecholamine screening and localization procedures.

The present study shows that the position of the RET mutation is related to disease phenotype; codon 634 mutations are predictive of families predisposed to pheochromocytoma. In 18% of our patients, the diagnosis of pheochromocytoma preceded detection of medullary thyroid carcinoma. Therefore, mutation analysis of the RET gene should be performed in apparently "sporadic" cases of pheochromocytoma to confirm or exclude MEN 2. The most sensitive biochemical marker for pheochromocytoma in MEN 2 is 24-h urinary epinephrine excretion. Computed tomography, magnetic resonance imaging and MIBG scintigraphy are all highly sensitive methods to localize pheochromocytoma.

We conclude that, in all families with MEN 2, mutational analysis of the RET proto-oncogene should be performed, both to identify gene carriers for MEN 2 and to identify specific mutations that are more strongly associated with pheochromocytoma.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

General

VARIANTS

EXTRA-ADRENAL TUMORS
Most often located within the abdomen and may have greater malignant potential than adrenal pheochromocytoma

Extra- adrenal tumors usually have a poorer prognosis than adrenal tumors

CYSTIC PHEOCHROMOCYTOMA

The "ring sign" of necrotic pheochromocytoma.

Velasquez G, Nath PH, Zollikofer C, Valdez-Davila O, Castaneda-Zuniga WR, Formanek A, Amplatz K.

Radiology 1979 Apr;131(1):69-71 Abstract quote

Pheochromocytomas are usually hypervascular tumors exhibiting dense stain during angiography. The cystic nature of the neoplasm or tumor necrosis can result in failure of opacification of the mass or a central lucent area. Four cases of pheochromocytoma are described where a central avascular zone was surrounded by a dense rim of contrast, giving a "ring sign." Since this appearance is best seen in the capillary and venous phases, delayed films are essential.

Cystic pheochromocytoma: radiologic diagnosis.

Munden R, Adams DB, Curry NS.

Department of Radiology, Medical University of South Carolina, Charleston 29425.

South Med J 1993 Nov;86(11):1302-5 Abstract quote

Cystic pheochromocytomas are unusual variants of adrenal pheochromocytomas.

Computed tomography and pathologic findings in the two cases reported here illustrate three cardinal principles in the diagnosis of cystic pheochromocytomas: (1) A suprarenal cystic tumor discovered on CT may be the result of hemorrhage and necrosis of an adrenal pheochromocytoma. (2) The cystic pheochromocytoma typically exhibits areas of low attenuation, with Hounsfield units in the range of 5 to 15 and rim enhancement on contrast administration. (3) Incidental adrenal lesions with these features discovered on CT scanning are an indication for catecholamine assays to screen for pheochromocytoma.

Tc-99m MIBG imaging in a huge clinically silent pheochromocytoma with cystic degeneration and massive hemorrhage.

Suga K, Motoyama K, Hara A, Kume N, Ariga M, Matsunaga N.

Department of Radiology, Yamaguchi University School of Medicine, Ube, Japan.

Clin Nucl Med 2000 Oct;25(10):796-800 Abstract quote

I-131 metaiodobenzylguanidine scintigraphy showed marked accumulation in the walls of a clinically silent, huge cystic adrenal mass with a prominent hemorrhage in a 48-year-old man. Although a careful reexamination of the histologic specimen finally lead to a diagnosis of pheochromocytoma, the appearances of this mass on computed tomography and magnetic resonance imaging were not specific for this neoplasm, and even pathologic analysis initially indicated, incorrectly, that this lesion was a hemorrhagic hemangioma.

This case shows that I-131 metaiodobenzylguanidine scintigraphy is useful for correctly diagnosing an adrenal mass with prominent cystic or hemorrhagic degeneration.

Pheochromocytoma in an incidentally discovered asymptomatic cystic adrenal mass.

Klingler PJ, Fox TP, Menke DM, Knudsen JM, Fulmer JT.

Department of Surgery, Mayo Clinic Jacksonville, FL 32224, USA.

Mayo Clin Proc 2000 May;75(5):517-20 Abstract quote

Cystic adrenal lesions can be either cortical or medullary, and distinguishing between these 2 types of lesions may be important in patient management. Pheochromocytomas, which are adrenal medullary neoplasms, typically manifest with hypertension, headaches, palpitations, tachycardia, sweating, and anxiety symptoms; however, 10% to 17% of patients with pheochromocytomas are asymptomatic.

We describe a 67-year-old woman with lifelong headaches and recent persistent cough in whom a left cystic adrenal mass was incidentally discovered by computed tomography of the chest. A moderate increase in normetanephrine and total metanephrine values in two 24-hour urine samples suggested a pheochromocytoma. Computed tomography with use of contrast medium revealed ring enhancement of the cyst wall, a finding consistent with an adrenal medullary tumor.

This report demonstrates the importance of repeated 24-hour urine samples to determine the metanephrine values together with contrast-enhanced computed tomography in a patient with nonspecific symptoms.

HISTOLOGICAL TYPES CHARACTERIZATION

General

Malignant tumors
Approximately 10% of pheochromocytomas are considered to be malignant

There are no histologic features that distinguish benign from malignant tumors

Microscopic evidence suggestive of include:
Local invasion of tissue or blood vessels
Tumor size
Mitotic index
DNA ploidy

VARIANTS

Adrenal Oncocytic Pheochromocytoma

Maomi Li, M.D., Ph.D.; Bruce M. Wenig, M.D.

From the Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York, U.S.A.

Am J Surg Pathol 2000;24:1552-1557 Abstract quote

We report a case of adrenal oncoctyic pheochromocytoma in a 37-year-old woman.

The patient presented with a 2-year history of an increase in abdominal girth. Computed tomographic studies revealed a large left adrenal mass, which was subsequently excised. Grossly, the tumor measured 17 � 14 � 8.5 cm, weighed 1150 g, and had a solid, brown cut surface. Histologically, it consisted of large polygonal tumor cells containing eosinophilic granular cytoplasm and arranged in nesting, alveolar, and trabecular patterns. Electron microscopy revealed closely packed mitochondria and dense-core membrane-bound granules in almost all tumor cells. The latter were immunohistochemically positive for chromogranin, synaptophysin, neuron-specific enolase, neurofilament, serotonin, bombesin, ACTH, vimentin, desmin, S-100 protein, and cytokeratins, including AE1/3, CAM 5.2, cytokeratin 7, and cytokeratin 20.

To the best of our knowledge, this is the first reported case of adrenal oncocytic pheochromocytoma confirmed by ultrastructural study. The immunoreactivity of this tumor adds several unusual features to the wide immunohistochemical spectrum of pheochromocytoma.

SPECIAL STAINS/
IMMUNOPEROXIDASE CHARACTERIZATION

Special stains

Immunoperoxidase
Positive for:
Neuroendocrine markers
S100 is positive in sustentacular cells

Negative for:
In general, cytokeratin is poorly expressed
Desmin

The role of calretinin, inhibin, melan-A, BCL-2, and C-kit in differentiating adrenal cortical and medullary tumors: an immunohistochemical study.

Zhang PJ, Genega EM, Tomaszewski JE, Pasha TL, LiVolsi VA.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19147, USA.
Mod Pathol. 2003 Jun;16(6):591-7. Abstract quote
Morphologic distinction between adrenal cortical and medullary tumors can be difficult. Previous studies have shown inhibin, melan-A, and BCL-2 to be useful markers for adrenal cortical tumors.

We have recently observed a high level of calretinin expression in normal adrenal cortex but not the medulla and therefore evaluated its diagnostic application for adrenal tumors in comparison with inhibin, melan-A, and BCL-2. C-kit is a transmembrane tyrosine kinase receptor. Immunodetection of c-kit expression has been recently used for tumor diagnosis, and c-kit-positive tumors can potentially benefit from kit kinase inhibitor treatment. Although c-kit expression was reported in adrenal medulla and pheochromocytoma, it has not been evaluated in adrenal cortical tumors.

In this study, 28 adrenal cortical tumors (12 carcinomas, 16 adenomas), 20 pheochromocytomas, and 20 extraadrenal paragangliomas were evaluated for calretinin, inhibin, melan-A, BCL-2, and c-kit expression by standard immunohistochemical assays on paraffin sections. The percentage of immunoreactivity in adrenal cortical tumors was as follows: calretinin, 96%; melan-A, 89%; inhibin, 92%; BCL-2, 20%; and c-kit, 5%. Normal adrenal medulla did not stain for c-kit but was positive for BCL-2. Eighty-six percent of pheochromocytomas stained for BCL-2 and none for calretinin, with the exception of the ganglioneuromatous areas in composite pheochromocytomas (n = 5). Extraadrenal paragangliomas showed reactivity with calretinin in 25%, melan-A in 5%, inhibin in 16%, BCL-2 in 38%, and c-kit in 8% of the cases.

Our results indicate that calretinin is the most sensitive among all the adrenal markers tested. Like melan-A and inhibin, calretinin is also a very specific marker in differentiating cortical from medullary adrenal tumors. In addition, calretinin can be used to confirm a composite pheochromocytoma. BCL-2 does not appear to be useful in differentiating adrenal cortical from medullary tumors. C-kit is not useful in the diagnosis of adrenal tumors, and kit kinase inhibitor might have a limited role in the treatment of adrenal tumors and paraganglioma because of the low frequency of c-kit expression in these tumors.

CD44

CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas.

August C, August K, Schroeder S, Bahn H, Hinze R, Baba HA, Kersting C, Buerger H.

Institute of Pathology, University Muenster, Germany.

Mod Pathol. 2004 Sep;17(9):1119-28. Abstract quote

The natural course of pheochromocytomas (PCC) cannot be predicted for certain on the basis of primary histology, their malignant character can only be confirmed by the occurrence of metastases during follow-up.

Based on the recently proposed PASS score for evaluation we examined 37 adrenal (36 sporadic and one familial) and six sporadic extra-adrenal paragangliomas (all designated as pheochromocytomas) with a 'malignant histology' to find additional predictive factors. Drawing upon the follow-up (18 months to 12 years, mean 5.8 years) metastasized (n=20) and nonmetastasized (n=23) courses could be distinguished. Metastasized PCC revealed significantly (P=0.03) more copy number changes on comparative genomic hybridization (CGH) (mean 8.3) than nonmetastasized tumors (mean: 4.3). The most frequent chromosomal alterations were losses on 1p (75.6%) and 3q (44%). Both were detected with identical frequency in metastasized and nonmetastasized PCC. A gain on 17q (P=0.025) was significantly predominant in malignant courses and suggests similarities in the genetic origin and progression of PCC and neuroblastomas. The proliferative activity (MIB-1 score) of metastasized PCC (n=20) was found to be significantly higher in metastasized tumors (mean 12.8% vs mean 3.5%). In contrast, the semiquantitatively scored membrane-bound staining of CD 44-S was stronger in tumors without metastases (mean 2.1 vs mean: 0.25) during the follow-up period (P<0.01). Although the results correspond to the established weight differences the tumor weight does not appear to be an independent prognostic factor.

Our study suggests that CD 44-S and MIB-1 immunostaining as well as the CGH results might complement the PASS score in predicting a metastasized course of PCC. Regardless of tumor weight, tumors with a 'malignant histology' are highly prone to metastasize when more than 5% of MIB1-positive nuclei are present or CD44-S immunostaining is negative, or both. PCC with 10 or more copy number changes on CGH must be referred to as malignant tumors.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS
Hum Pathol 1990;21:1168-1180
Hum Pathol 1985;16:580-589
There are no consistent criteria that differentiate benign tumors from malignant

Presence or absence of metastatic disease is the most important determinant

Large tumor size and extensive necrosis has been reported to be more frequent in malignant tumors

Classically, about 10% of cases are malignant

Grading

Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) to Separate Benign From Malignant Neoplasms: A Clinicopathologic and Immunophenotypic Study of 100 Cases.

Thompson LD.

Department of Endocrine and Otorhinolaryngic-Head & Neck Pathology, Armed Forces Institute of Pathology, Washington, DC, U.S.A.
Am J Surg Pathol 2002 May;26(5):551-66 Abstract quote
No comprehensive series has evaluated the histologic features of pheochromocytoma to separate benign from malignant pheochromocytoma by histomorphologic parameters only. Fifty histologically malignant and 50 histologically benign pheochromocytomas of the adrenal gland were retrieved from the files of the Armed Forces Institute of Pathology. The patients included 43 females and 57 males, with an age range of 3-81 years (mean 46.7 years). Patients usually experienced hypertension (n = 79 patients). The mean tumor size was 7.2 cm (weight was 222 g).

Histologically, the cases of malignant pheochromocytomas of the adrenal gland more frequently demonstrated invasion (vascular [score = 1], capsular [score = 1], periadrenal adipose tissue [score = 2]), large nests or diffuse growth (score = 2), focal or confluent necrosis (score = 2), high cellularity (score = 2), tumor cell spindling (score = 2), cellular monotony (score = 2), increased mitotic figures (>3/10 high power fields; score = 2), atypical mitotic figures (score = 2), profound nuclear pleomorphism (score = 1), and hyperchromasia (score = 1) than the benign tumors.

A Pheochromocytoma of the Adrenal gland Scaled Score (PASS) weighted for these specific histologic features can be used to separate tumors with a potential for a biologically aggressive behavior (PASS >/=4) from tumors that behave in a benign fashion (PASS <4). The pathologic features that are incorporated into the PASS correctly identified tumors with a more aggressive biologic behavior. Application of these criteria to a large cohort of cases will help to elucidate the accuracy of this grading system in clinical practice.

Survival

The operative mortality is less than 2%-3% for benign tumor resection

In malignant or recurrent tumors, overall survival may be less than 50%

Recurrence
Median time for recurrence following initial resection is approximately 6 years and may be as long as 20 years

Metastasis
Lymph nodes, bones, liver, and lungs
Liver involvement may be the result of direct extension from right-sided primary tumors

GENERAL

Extraadrenal and multiple pheochromocytomas. Are there really any differences in pathophysiology and outcome?

Lumachi F, Polistina F, Favia G, D'Amico DF.

Endocrine Surgery Unit, Clinica Chirurgica I, University of Padua, Italy.

J Exp Clin Cancer Res 1998 Sep;17(3):303-5 Abstract quote

In 15-20% of the cases pheochromocytoma (pheo) localizes in extraadrenal sites and in about 15% of all cases it seems to be multiple.

We analyze our 20-year experience in surgical treatment of pheos, studying the differences between typical and extraadrenal or multiple tumors. From 1977 to 1996 we operated 55 patients (patients) with pheos, 28 (50.9%) males and 27 females (mean age 41 years, range 10-63). Two groups have been distinguished: classic pheos (Group 1, 45 patients) and extraadrenal or multiple pheos (Group 2, 10 patients). Hypertensive crises were present in 37/45 (82.2%) patients of Group 1 and in 7/10 patients of Group 2. Five (11.1%) masses were nonfunctioning and incidentally discovered (4 in Group 1 and one in Group 2). In 4 cases association with familial syndromes was observed (3 MEN IIb, 1 von Recklinghausen syndrome); no further significant differences in clinical features and laboratory data were found between the two Groups. At immunohistochemical analysis 26/26 patients resulted positive for chromogranin A and NSE and 17/26 (11/20 in Group 1 and 4/6 in Group 2) resulted positive for S 100 protein. Five (11.1%) malignant pheos were discovered and removed (Group 1); average survival of these patients was 54.4 months, two patients underwent radioactive iodine (131-I-MIBG) therapy after surgery and only one patient is still alive at 24-month follow-up. Recurrence for benign sporadic pheo (Group 1) occurred in one patient 183 months after adrenalectomy.

Ectopic, associated with familial syndromes and multiple pheos are not uncommon and although recovery in surgically treated patients is excellent, lifelong follow-up is necessary also in benign tumors.

TENASCIN

Increased Expression of Tenascin in Pheochromocytomas Correlates With Malignancy

Kaisa Salmenkivi, M.D. ; Caj Haglund, M.D. ; Johanna Arola, M.D. ; P�ivi Heikkil�, M.D.

From the Department of Pathology, Haartman Institute, University of Helsinki and HUCH Laboratory Diagnostics, Helsinki University Central Hospital, Helsinki (K.S., J.A., P.H.); and the Department of Surgery (C.H.), Helsinki University Central Hospital, Helsinki, Finland.

Am J Surg Pathol 2001;25:1419-1423 Abstract quote

Tenascin is a significant extracellular matrix glycoprotein, which is upregulated in various neoplasias and pathologic processes. Pheochromocytomas are rare tumors of the sympathoadrenal system, whose malignancy is almost impossible to predict. There are no histologic or chemical markers available that would define the malignant behavior of these tumors, except the discovery of metastases.

In our search for new markers, we investigated the immunohistochemical expression of tenascin in a large number of pheochromocytomas and paragangliomas. Seven tumors were metastasized and were thus considered malignant. Normal adrenal medulla was tenascin negative. A striking difference was seen between malignant and benign pheochromocytomas. All malignant pheochromocytomas expressed stromal tenascin strongly or moderately, whereas most benign pheochromocytomas (28 of 37, 70%) showed no or only weak immunopositivity. The staining was strong or moderate also in 13 of 28 (46%) of the tumors that showed histologically suspicious features, here called borderline tumors. Paragangliomas showed a more heterogeneous staining pattern, and no significant difference was found between benign and malignant paragangliomas.

To our knowledge, this is the first study to demonstrate the expression of tenascin in pheochromocytomas and particularly the enhanced expression in malignant pheochromocytomas. We therefore suggest that tenascin may be associated with the malignant transformation and metastasis of pheochromocytomas. It is also a potential marker predicting more aggressive behavior in pheochromocytomas.

TREATMENT

Localized benign tumors

Complete surgical resection consisting of total adrenalectomy

The use of prophylactic contralateral adrenalectomy is not recommended for patients with unilateral tumors with MEN syndrome

Preoperative and intraoperative medical management of the effect of excessive adrenergic stimulation is necessary

Intraoperatively, blood pressure is controlled by titration of small doses of phentolamine or nitroprusside and cardiac arrhythmias may be treated with propranolol or lidocaine

The abdomen and retroperitoneum are examined thoroughly for the presence of extra-adrenal disease

After one week or more following surgery, repeated biochemical assays for catecholamines and/or metabolites are performed to confirm that all functioning pheochromocytoma has been removed

Regional tumors

Regional lymphatic metastasis or local extension should be treated by aggressive surgical resection with an attempt to remove all gross evidence of disease

If regional disease remains, the hypertension and symptoms due to catecholamine excess should be treated by adrenergic blockade and catecholamine synthesis inhibition as necessary

Radiation therapy or combination chemotherapy may be palliative for symptoms or morbidity due to local invasion by tumor.

Most active chemotherapy regimen appears to be the combination of cyclophosphamide, vincristine, and dacarbazine (CVD) and may produce partial remissions of moderate duration in symptomatic patients

Metastatic disease

Aggressive surgical resection of accessible recurrent disease or metastases that will render the patient free of gross disease with the potential for normal biochemical determinations should be attempted

No evidence that partial surgical debulking of tumor results in improved survival or reduction in symptoms but surgical intervention or radiation therapy may be indicated for palliation of local complications due to metastatic disease

Long-term medical management of symptoms using adrenergic blockade and catecholamine synthesis inhibition is indicated

Most active chemotherapy regimen appears to be the combination of cyclophosphamide, vincristine, and dacarbazine (CVD)

CHEMOTHERAPY
Combination of cyclophosphamide, vincristine, and dacarbazine (CVD)

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Adrenal Gland

Multiple Endocrine Neoplasia Syndrome

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences

Internet Links

Last Updated September 7, 2004

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
CT scan and MRI	The initial studies should be a chest film and abdominal computed tomographic (CT) scan Magnetic resonance imaging (MRI), or rarely, vena cava catheterization with selective venous sampling for catecholamines may be indicated CT and MRI scans are about equally sensitive (98%-100%) MIBG scanning has a specificity of 100%
Radioisotope-guided surgery in patients with pheochromocytoma and recurrent medullary thyroid carcinoma: a comparison of preoperative and intraoperative tumor localization with histopathologic findings. Adams S, Acker P, Lorenz M, Staib-Sebler E, Hor G. Department of Nuclear Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main, Germany.	Cancer 2001 Jul 15;92(2):263-70 Abstract quote BACKGROUND: The objective of this study was to appraise the detection of metastases of medullary thyroid carcinoma (MTC) and pheochromocytoma using radioguided surgery (RGS) and to compare the results with external imaging modalities, surgical palpation, and histopathologic findings. METHODS: Twenty-five patients with recurrent MTC underwent preoperative scintigraphic imaging with 500 megabecquerels (MBq) of technetium 99m(V)-dimercaptosuccinic acid [(99m)Tc(V)-DMSA] and 222 MBq of indium 111 ((111)In)-pentetreotide. The radiopharmaceutical that showed the greatest preoperative tumor uptake was selected for intraoperative RGS. Surgery was performed 24 hours after the administration of (111)In-pentetreotide or 4 hours after the injection of (99m)Tc(V)-DMSA. Furthermore, three male patients underwent surgery who suffered from recurrent pheochromocytoma (injection of 180 MBq iodine 123-labeled metaiodobenzylguanidine [(123)I-MIBG] 4--5 hours before surgery). RESULTS: Overall, lesion detection sensitivities in patients with MTC for computed tomography, (111)In-pentetreotide, and (99m)Tc(V)-DMSA were 32%, 34%, and 65%, respectively. Surgical palpation identified lymph node metastases of recurrent MTC with a sensitivity of 65%, whereas RGS localized 64 malignant lesions (sensitivity, 97%). Altogether, 71 lesions could be excised, 5 of which were adjudged false positive with respect to MTC metastases. Both surgical palpation and RGS localized all paravertebral subdiaphragmatic lesions (size > or = 2 cm) of recurrent pheochromocytoma seen in the preoperative MIBG scan. CONCLUSIONS: RGS was capable of localizing more and smaller metastases of MTC compared with conventional imaging modalities and surgical palpation. However, the relatively high radioligand accumulation in the kidneys ((111)In-pentetreotide) and the dense hepatic and biliary signals using MIBG limited their use for intraoperative detection of tumors in the area of the adrenal gland.
Laboratory Markers
GENERAL
Biochemical Diagnosis of Pheochromocytoma Which Test Is Best? Jacques W. M. Lenders, MD, PhD; Karel Pacak, MD, PhD; McClellan M. Walther, MD; W. Marston Linehan, MD; Massimo Mannelli, MD; Peter Friberg, MD, PhD; Harry R. Keiser, MD; David S. Goldstein, MD, PhD; Graeme Eisenhofer, PhD	JAMA. 2002;287:1427-1434 Abstract quote Context Diagnosis of pheochromocytoma depends on biochemical evidence of catecholamine production by the tumor. However, the best test to establish the diagnosis has not been determined. Objective To determine the biochemical test or combination of tests that provides the best method for diagnosis of pheochromocytoma. Design, Setting, and Participants Multicenter cohort study of patients tested for pheochromocytoma at 4 referral centers between 1994 and 2001. The analysis included 214 patients in whom the diagnosis of pheochromocytoma was confirmed and 644 patients who were determined to not have the tumor. Main Outcome Measures Test sensitivity and specificity, receiver operating characteristic curves, and positive and negative predictive values at different pretest prevalences using plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid. Results Sensitivities of plasma free metanephrines (99% [95% confidence interval {CI}, 96%-100%]) and urinary fractionated metanephrines (97% [95% CI, 92%-99%]) were higher than those for plasma catecholamines (84% [95% CI, 78%-89%]), urinary catecholamines (86% [95% CI, 80%-91%]), urinary total metanephrines (77% [95% CI, 68%-85%]), and urinary vanillylmandelic acid (64% [95% CI, 55%-71%]). Specificity was highest for urinary vanillylmandelic acid (95% [95% CI, 93%-97%]) and urinary total metanephrines (93% [95% CI, 89%-97%]); intermediate for plasma free metanephrines (89% [95% CI, 87%-92%]), urinary catecholamines (88% [95% CI, 85%-91%]), and plasma catecholamines (81% [95% CI, 78%-84%]); and lowest for urinary fractionated metanephrines (69% [95% CI, 64%-72%]). Sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines using receiver operating characteristic curves. Combining different tests did not improve the diagnostic yield beyond that of a single test of plasma free metanephrines. Conclusion Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.
ACTH
Adrenocorticotropic hormone-secreting pheochromocytoma. Sato M, Watanabe T, Ashikaga T, Taneda T, Yamawake N, Nishizaki M, Arimura A, Azegami N, Arita M, Fukuoka H, Kitamura H. First Department of Internal Medicine, Yokohama Minami Kyosai Hospital.	Intern Med 1998 Apr;37(4):403-6 Abstract quote A 41-year-old female had pheochromocytoma which secreted adrenocorticotropic hormone (ACTH). She was admitted to our hospital because of weight loss and excessive sweating. Not only urinary metanephrine but also plasma ACTH was extremely high. An abdominal echogram showed a cystic tumor in the left adrenal gland. An abdominal magnetic resonance imaging scan showed a hyperintense T2-weighted abnormality inside the tumor. Left adrenalectomy was done. The tumor consisted of benign pheochromocytoma cells diffusely stained with anti-ACTH antibody. The present case did not show any typical Cushingoid symptoms which are common in ACTH-secreting pheochromocytomas.
CATECHOLAMINES
Urine and serum catecholamine levels	Elevated 24-hour urinary excretion of free catecholamines (norepinephrine and epinephrine) or catecholamine metabolites (VMA and total metanephrines) The measurement of plasma catecholamines has limited sensitivity and specificity Plasma metanephrines have been reported to be more sensitive than plasma catecholamines
RET PROTO-ONCOGENE
Diagnosis and management of pheochromocytomas in patients with multiple endocrine neoplasia type 2-relevance of specific mutations in the RET proto-oncogene. Frank-Raue K, Kratt T, Hoppner W, Buhr H, Ziegler R, Raue F. Medizinische Universitatsklinik, Heidelberg, Germany.	Eur J Endocrinol 1996 Aug;135(2):222-5 Abstract quote It has been suggested that specific mutations in the RET proto-oncogene correlate with clinical manifestation of the multiple endocrine neoplasia type 2 (MEN 2) syndrome. We retrospectively analyzed 61 patients with MEN 2, 28 with associated pheochromocytoma, regarding the relevance of specific mutations in the RET proto-oncogene and the diagnostic sensitivity of catecholamine screening and localization procedures. The present study shows that the position of the RET mutation is related to disease phenotype; codon 634 mutations are predictive of families predisposed to pheochromocytoma. In 18% of our patients, the diagnosis of pheochromocytoma preceded detection of medullary thyroid carcinoma. Therefore, mutation analysis of the RET gene should be performed in apparently "sporadic" cases of pheochromocytoma to confirm or exclude MEN 2. The most sensitive biochemical marker for pheochromocytoma in MEN 2 is 24-h urinary epinephrine excretion. Computed tomography, magnetic resonance imaging and MIBG scintigraphy are all highly sensitive methods to localize pheochromocytoma. We conclude that, in all families with MEN 2, mutational analysis of the RET proto-oncogene should be performed, both to identify gene carriers for MEN 2 and to identify specific mutations that are more strongly associated with pheochromocytoma.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
EXTRA-ADRENAL TUMORS	Most often located within the abdomen and may have greater malignant potential than adrenal pheochromocytoma Extra- adrenal tumors usually have a poorer prognosis than adrenal tumors
CYSTIC PHEOCHROMOCYTOMA
The "ring sign" of necrotic pheochromocytoma. Velasquez G, Nath PH, Zollikofer C, Valdez-Davila O, Castaneda-Zuniga WR, Formanek A, Amplatz K.	Radiology 1979 Apr;131(1):69-71 Abstract quote Pheochromocytomas are usually hypervascular tumors exhibiting dense stain during angiography. The cystic nature of the neoplasm or tumor necrosis can result in failure of opacification of the mass or a central lucent area. Four cases of pheochromocytoma are described where a central avascular zone was surrounded by a dense rim of contrast, giving a "ring sign." Since this appearance is best seen in the capillary and venous phases, delayed films are essential.
Cystic pheochromocytoma: radiologic diagnosis. Munden R, Adams DB, Curry NS. Department of Radiology, Medical University of South Carolina, Charleston 29425.	South Med J 1993 Nov;86(11):1302-5 Abstract quote Cystic pheochromocytomas are unusual variants of adrenal pheochromocytomas. Computed tomography and pathologic findings in the two cases reported here illustrate three cardinal principles in the diagnosis of cystic pheochromocytomas: (1) A suprarenal cystic tumor discovered on CT may be the result of hemorrhage and necrosis of an adrenal pheochromocytoma. (2) The cystic pheochromocytoma typically exhibits areas of low attenuation, with Hounsfield units in the range of 5 to 15 and rim enhancement on contrast administration. (3) Incidental adrenal lesions with these features discovered on CT scanning are an indication for catecholamine assays to screen for pheochromocytoma.
Tc-99m MIBG imaging in a huge clinically silent pheochromocytoma with cystic degeneration and massive hemorrhage. Suga K, Motoyama K, Hara A, Kume N, Ariga M, Matsunaga N. Department of Radiology, Yamaguchi University School of Medicine, Ube, Japan.	Clin Nucl Med 2000 Oct;25(10):796-800 Abstract quote I-131 metaiodobenzylguanidine scintigraphy showed marked accumulation in the walls of a clinically silent, huge cystic adrenal mass with a prominent hemorrhage in a 48-year-old man. Although a careful reexamination of the histologic specimen finally lead to a diagnosis of pheochromocytoma, the appearances of this mass on computed tomography and magnetic resonance imaging were not specific for this neoplasm, and even pathologic analysis initially indicated, incorrectly, that this lesion was a hemorrhagic hemangioma. This case shows that I-131 metaiodobenzylguanidine scintigraphy is useful for correctly diagnosing an adrenal mass with prominent cystic or hemorrhagic degeneration.
Pheochromocytoma in an incidentally discovered asymptomatic cystic adrenal mass. Klingler PJ, Fox TP, Menke DM, Knudsen JM, Fulmer JT. Department of Surgery, Mayo Clinic Jacksonville, FL 32224, USA.	Mayo Clin Proc 2000 May;75(5):517-20 Abstract quote Cystic adrenal lesions can be either cortical or medullary, and distinguishing between these 2 types of lesions may be important in patient management. Pheochromocytomas, which are adrenal medullary neoplasms, typically manifest with hypertension, headaches, palpitations, tachycardia, sweating, and anxiety symptoms; however, 10% to 17% of patients with pheochromocytomas are asymptomatic. We describe a 67-year-old woman with lifelong headaches and recent persistent cough in whom a left cystic adrenal mass was incidentally discovered by computed tomography of the chest. A moderate increase in normetanephrine and total metanephrine values in two 24-hour urine samples suggested a pheochromocytoma. Computed tomography with use of contrast medium revealed ring enhancement of the cyst wall, a finding consistent with an adrenal medullary tumor. This report demonstrates the importance of repeated 24-hour urine samples to determine the metanephrine values together with contrast-enhanced computed tomography in a patient with nonspecific symptoms.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	800 new cases/year/United States
AGE RANGE-MEDIAN	3-5th decades

DISEASE ASSOCIATIONS	CHARACTERIZATION
A case of Sipple's syndrome with malignant pheochromocytoma treated with 131I-metaiodobenzyl guanidine and a combined chemotherapy with cyclophosphamide, vincristine and dacarbazine. Sasaki M, Iwaoka T, Yamauchi J, Tokunaga H, Naomi S, Inoue J, Oishi S, Umeda T, Sato T. Third Department of Internal Medicine, Kumamoto University Medical School, Japan	Endocr J 1994 Apr;41(2):155-60 Abstract quote A 39-year-old woman with Sipple's syndrome and a malignant pheochromocytoma (PHE) is presented. She is a member of a big family with this syndrome and had undergone bilateral, subtotal adrenalectomy because of bilateral PHE six years prior to the present admission. In 1989, a small nodule was identified in her right thyroid lobe by ultrasonography and was suspected to be a medullary thyroid carcinoma (MTC). Further examinations revealed the coexistence of multiple lung and liver masses. These tumors were considered to be metastases of PHE because of the increased urinary excretion of catecholamines as well as extremely high catecholamines both in the hepatic venous blood and in the cystic fluid of the liver tumor even though there was no apparent recurrences of PHE in the adrenal region. After surgical removal of the MTC in August, 1989, she was given 3.7 GBq of 131I-metaiodobenzyl guanidine (131I-MIBG) infusions twice--in October, 1989 and in August, 1990. 131I-MIBG showed a strong accumulation in the lung and liver masses on both occasions. Periodic increases in blood pressure and tachycardia with an excessive catecholamine secretion were observed over two weeks after the first treatment. However, this treatment was not effective in reducing urinary catecholamines nor the size of the metastatic tumors. She, therefore, underwent chemotherapy with cyclophosphamide, vincristine and decarbazine in 1991, which slightly but significantly reduced urinary excretion of catecholamines and the size of the lung tumors. She had clinically stable period for one year after the treatment but rapid growth of these metastatic tumors occurred afterwards and she died in August, 1992.
MEN Type IIA and IIB	N Engl J Med 1993;329(21):1531-1538. Risk of developing a contralateral tumor following unilateral adrenalectomy is approximately 50% 23% were found to be carriers of associated familial disorders. Therefore, all patients with pheochromocytomas should be screened for MEN-2 and von Hippel- Lindau
Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study. Nguyen L, Niccoli-Sire P, Caron P, Bastie D, Maes B, Chabrier G, Chabre O, Rohmer V, Lecomte P, Henry JF, Conte-Devolx B; French Calcitonin Tumors Study Group. Service d'Endocrinologie,	Eur J Endocrinol 2001 Jan;144(1):37-44 Abstract quote OBJECTIVE: The aim of this prospective study is to update our knowledge of the chronology of pheochromocytoma occurrence in multiple endocrine neoplasia type 2 (MEN 2), and to better manage MEN 2 patients after the genetic diagnosis. DESIGN: Eighty-seven non-index gene carrier MEN 2 patients were included in this prospective study: 84 patients with MEN 2A (from 52 families) and 3 with MEN 2B (from 3 families). METHODS: Medullary thyroid carcinoma (MTC) was diagnosed by measuring plasma calcitonin in basal conditions or after pentagastrin stimulation. The search for pheochromocytoma consisted of clinical evaluation, 24 h determination of urinary catecholamines and adrenal imaging. The mean age at genetic diagnosis of MEN 2 was 14.0+/-7.0 years, the mean duration for the follow-up was 7.6+/-2.8 years. RESULTS: All 87 patients had a MTC detected at the same time as the genetic diagnosis was made. Urinary catecholamine measurements led to the diagnosis of pheochromocytoma and a combination of imaging techniques enabled the correct localization of both unilateral or bilateral adrenal involvement. Pheochromocytoma was detected simultaneously with MTC in only seven patients, and seven others were detected throughout the follow-up. Of the 14 patients with pheochromocytoma, 11 had bilateral involvement: nine were initially bilateral and two became so during follow-up. CONCLUSION: This study demonstrates that in MEN 2, MTC is the lesion which appears earliest. Pheochromocytoma develops later during the evolution of the disease, and necessitates regular clinical and biological monitoring throughout follow-up. Determination of urinary and/or plasma catecholamines and metanephrines should be performed to detect pheochromocytoma. Imaging techniques lead to the detection of both unilateral and bilateral pheochromocytoma, thus making video-assisted laparoscopic adrenalectomy possible.
Neurofibromatosis
Neurofibromatosis
von Hippel-Lindau disease
Cerebellar hemangioblastoma
Sturge-Weber's syndrome
Tuberous sclerosis

PATHOGENESIS	CHARACTERIZATION
CHROMOSOMAL ABNORMALITIES
Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome. Lui WO, Chen J, Glasker S, Bender BU, Madura C, Khoo SK, Kort E, Larsson C, Neumann HP, Teh BT. Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden	Oncogene 2002 Feb 7;21(7):1117-22 Abstract quote By using comparative genomic hybridization (CGH), we characterized the genetic profiles of 36 VHL-related pheochromocytomas. We then compared the results with those of sporadic and MEN 2-related pheochromocytomas. In 36 VHL-related tumors, loss of chromosome 3 and chromosome 11 were found in 34 tumors (94%) and 31 tumors (86%), respectively. There was significant concordance of deletions in chromosomes 3 and 11 (Kappa=0.64, P=0.0095), suggesting that they are involved in two different but necessary and complementary genetic pathways. The loss of chromosome 11 appeared to be specific for VHL-related pheochromocytoma as it was not present in any of the 10 VHL-related CNS hemangioblastomas studied and was significantly less common when compared with (a) sporadic pheochromocytomas from previously published results (13%; P=<0.0001), and (b) MEN 2-related pheochromocytomas from this and previously published studies (30%; P=0.0012). In summary, this is the first report of a novel consistent genetic alteration that is selected and specific for VHL-related pheochromocytoma, besides the two hits of the VHL gene.
NEUROFIBROMIN
Neurofibromin and NF1 Gene Analysis in Composite Pheochromocytoma and Tumors Associated with von Recklinghausen's Disease. Kimura N, Watanabe T, Fukase M, Wakita A, Noshiro T, Kimura I. Department of Pathology and Laboratory Medicine (NK), Tohoku Rosai Hospital, Sendai.	Mod Pathol 2002 Mar;15(3):183-8 Abstract quote Composite tumor of pheochromocytoma and neuroblastoma, or ganglioneuroma, or ganglioneuroblastoma (composite pheochromocytoma), also known as mixed neuroendocrine and neural tumor, are sometimes combined with neurofibromatosis type 1 (NF1). To better understand the relationship between NF1 and composite pheochromocytoma, an immunohistochemical study using anti-neuro-fibromin that is an NF1 gene product and DNA sequence of NF1 Exon 31 were carried out in five cases of composite pheochromocytoma and in various tumors from five patients with NF1. Neurofibromin was not expressed in Schwann cells and sustentacular cells of composite pheochromocytomas and was very weakly or negatively expressed in neurofibroma of NF1 patients. However, it was strongly expressed in ganglionic cells and pheochromocytoma cells of the composite pheochromocytomas and also in mucosal ganglioneuromas, a gangliocytic paraganglioma, and in pheochromocytomas from the patients with NF1. Although there was no mutation in NF1 Exon 31, it could not be ruled out that there were mutations in other sites of the NF1 gene. Neurofibromin insufficiency may induce abnormal proliferation of Schwann cells in composite pheochromocytomas as well as in neurofibromatosis.

HISTOLOGICAL TYPES	CHARACTERIZATION
General
Malignant tumors	Approximately 10% of pheochromocytomas are considered to be malignant There are no histologic features that distinguish benign from malignant tumors Microscopic evidence suggestive of include: Local invasion of tissue or blood vessels Tumor size Mitotic index DNA ploidy
VARIANTS
Adrenal Oncocytic Pheochromocytoma Maomi Li, M.D., Ph.D.; Bruce M. Wenig, M.D. From the Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York, U.S.A.	Am J Surg Pathol 2000;24:1552-1557 Abstract quote We report a case of adrenal oncoctyic pheochromocytoma in a 37-year-old woman. The patient presented with a 2-year history of an increase in abdominal girth. Computed tomographic studies revealed a large left adrenal mass, which was subsequently excised. Grossly, the tumor measured 17 � 14 � 8.5 cm, weighed 1150 g, and had a solid, brown cut surface. Histologically, it consisted of large polygonal tumor cells containing eosinophilic granular cytoplasm and arranged in nesting, alveolar, and trabecular patterns. Electron microscopy revealed closely packed mitochondria and dense-core membrane-bound granules in almost all tumor cells. The latter were immunohistochemically positive for chromogranin, synaptophysin, neuron-specific enolase, neurofilament, serotonin, bombesin, ACTH, vimentin, desmin, S-100 protein, and cytokeratins, including AE1/3, CAM 5.2, cytokeratin 7, and cytokeratin 20. To the best of our knowledge, this is the first reported case of adrenal oncocytic pheochromocytoma confirmed by ultrastructural study. The immunoreactivity of this tumor adds several unusual features to the wide immunohistochemical spectrum of pheochromocytoma.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS	Hum Pathol 1990;21:1168-1180 Hum Pathol 1985;16:580-589 There are no consistent criteria that differentiate benign tumors from malignant Presence or absence of metastatic disease is the most important determinant Large tumor size and extensive necrosis has been reported to be more frequent in malignant tumors Classically, about 10% of cases are malignant
Grading
Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) to Separate Benign From Malignant Neoplasms: A Clinicopathologic and Immunophenotypic Study of 100 Cases. Thompson LD. Department of Endocrine and Otorhinolaryngic-Head & Neck Pathology, Armed Forces Institute of Pathology, Washington, DC, U.S.A.	Am J Surg Pathol 2002 May;26(5):551-66 Abstract quote No comprehensive series has evaluated the histologic features of pheochromocytoma to separate benign from malignant pheochromocytoma by histomorphologic parameters only. Fifty histologically malignant and 50 histologically benign pheochromocytomas of the adrenal gland were retrieved from the files of the Armed Forces Institute of Pathology. The patients included 43 females and 57 males, with an age range of 3-81 years (mean 46.7 years). Patients usually experienced hypertension (n = 79 patients). The mean tumor size was 7.2 cm (weight was 222 g). Histologically, the cases of malignant pheochromocytomas of the adrenal gland more frequently demonstrated invasion (vascular [score = 1], capsular [score = 1], periadrenal adipose tissue [score = 2]), large nests or diffuse growth (score = 2), focal or confluent necrosis (score = 2), high cellularity (score = 2), tumor cell spindling (score = 2), cellular monotony (score = 2), increased mitotic figures (>3/10 high power fields; score = 2), atypical mitotic figures (score = 2), profound nuclear pleomorphism (score = 1), and hyperchromasia (score = 1) than the benign tumors. A Pheochromocytoma of the Adrenal gland Scaled Score (PASS) weighted for these specific histologic features can be used to separate tumors with a potential for a biologically aggressive behavior (PASS >/=4) from tumors that behave in a benign fashion (PASS <4). The pathologic features that are incorporated into the PASS correctly identified tumors with a more aggressive biologic behavior. Application of these criteria to a large cohort of cases will help to elucidate the accuracy of this grading system in clinical practice.
Survival	The operative mortality is less than 2%-3% for benign tumor resection In malignant or recurrent tumors, overall survival may be less than 50%
Recurrence	Median time for recurrence following initial resection is approximately 6 years and may be as long as 20 years
Metastasis	Lymph nodes, bones, liver, and lungs Liver involvement may be the result of direct extension from right-sided primary tumors
GENERAL
Extraadrenal and multiple pheochromocytomas. Are there really any differences in pathophysiology and outcome? Lumachi F, Polistina F, Favia G, D'Amico DF. Endocrine Surgery Unit, Clinica Chirurgica I, University of Padua, Italy.	J Exp Clin Cancer Res 1998 Sep;17(3):303-5 Abstract quote In 15-20% of the cases pheochromocytoma (pheo) localizes in extraadrenal sites and in about 15% of all cases it seems to be multiple. We analyze our 20-year experience in surgical treatment of pheos, studying the differences between typical and extraadrenal or multiple tumors. From 1977 to 1996 we operated 55 patients (patients) with pheos, 28 (50.9%) males and 27 females (mean age 41 years, range 10-63). Two groups have been distinguished: classic pheos (Group 1, 45 patients) and extraadrenal or multiple pheos (Group 2, 10 patients). Hypertensive crises were present in 37/45 (82.2%) patients of Group 1 and in 7/10 patients of Group 2. Five (11.1%) masses were nonfunctioning and incidentally discovered (4 in Group 1 and one in Group 2). In 4 cases association with familial syndromes was observed (3 MEN IIb, 1 von Recklinghausen syndrome); no further significant differences in clinical features and laboratory data were found between the two Groups. At immunohistochemical analysis 26/26 patients resulted positive for chromogranin A and NSE and 17/26 (11/20 in Group 1 and 4/6 in Group 2) resulted positive for S 100 protein. Five (11.1%) malignant pheos were discovered and removed (Group 1); average survival of these patients was 54.4 months, two patients underwent radioactive iodine (131-I-MIBG) therapy after surgery and only one patient is still alive at 24-month follow-up. Recurrence for benign sporadic pheo (Group 1) occurred in one patient 183 months after adrenalectomy. Ectopic, associated with familial syndromes and multiple pheos are not uncommon and although recovery in surgically treated patients is excellent, lifelong follow-up is necessary also in benign tumors.
TENASCIN
Increased Expression of Tenascin in Pheochromocytomas Correlates With Malignancy Kaisa Salmenkivi, M.D. ; Caj Haglund, M.D. ; Johanna Arola, M.D. ; P�ivi Heikkil�, M.D. From the Department of Pathology, Haartman Institute, University of Helsinki and HUCH Laboratory Diagnostics, Helsinki University Central Hospital, Helsinki (K.S., J.A., P.H.); and the Department of Surgery (C.H.), Helsinki University Central Hospital, Helsinki, Finland.	Am J Surg Pathol 2001;25:1419-1423 Abstract quote Tenascin is a significant extracellular matrix glycoprotein, which is upregulated in various neoplasias and pathologic processes. Pheochromocytomas are rare tumors of the sympathoadrenal system, whose malignancy is almost impossible to predict. There are no histologic or chemical markers available that would define the malignant behavior of these tumors, except the discovery of metastases. In our search for new markers, we investigated the immunohistochemical expression of tenascin in a large number of pheochromocytomas and paragangliomas. Seven tumors were metastasized and were thus considered malignant. Normal adrenal medulla was tenascin negative. A striking difference was seen between malignant and benign pheochromocytomas. All malignant pheochromocytomas expressed stromal tenascin strongly or moderately, whereas most benign pheochromocytomas (28 of 37, 70%) showed no or only weak immunopositivity. The staining was strong or moderate also in 13 of 28 (46%) of the tumors that showed histologically suspicious features, here called borderline tumors. Paragangliomas showed a more heterogeneous staining pattern, and no significant difference was found between benign and malignant paragangliomas. To our knowledge, this is the first study to demonstrate the expression of tenascin in pheochromocytomas and particularly the enhanced expression in malignant pheochromocytomas. We therefore suggest that tenascin may be associated with the malignant transformation and metastasis of pheochromocytomas. It is also a potential marker predicting more aggressive behavior in pheochromocytomas.
TREATMENT
Localized benign tumors	Complete surgical resection consisting of total adrenalectomy The use of prophylactic contralateral adrenalectomy is not recommended for patients with unilateral tumors with MEN syndrome Preoperative and intraoperative medical management of the effect of excessive adrenergic stimulation is necessary Intraoperatively, blood pressure is controlled by titration of small doses of phentolamine or nitroprusside and cardiac arrhythmias may be treated with propranolol or lidocaine The abdomen and retroperitoneum are examined thoroughly for the presence of extra-adrenal disease After one week or more following surgery, repeated biochemical assays for catecholamines and/or metabolites are performed to confirm that all functioning pheochromocytoma has been removed
Regional tumors	Regional lymphatic metastasis or local extension should be treated by aggressive surgical resection with an attempt to remove all gross evidence of disease If regional disease remains, the hypertension and symptoms due to catecholamine excess should be treated by adrenergic blockade and catecholamine synthesis inhibition as necessary Radiation therapy or combination chemotherapy may be palliative for symptoms or morbidity due to local invasion by tumor. Most active chemotherapy regimen appears to be the combination of cyclophosphamide, vincristine, and dacarbazine (CVD) and may produce partial remissions of moderate duration in symptomatic patients
Metastatic disease	Aggressive surgical resection of accessible recurrent disease or metastases that will render the patient free of gross disease with the potential for normal biochemical determinations should be attempted No evidence that partial surgical debulking of tumor results in improved survival or reduction in symptoms but surgical intervention or radiation therapy may be indicated for palliation of local complications due to metastatic disease Long-term medical management of symptoms using adrenergic blockade and catecholamine synthesis inhibition is indicated Most active chemotherapy regimen appears to be the combination of cyclophosphamide, vincristine, and dacarbazine (CVD)
CHEMOTHERAPY	Combination of cyclophosphamide, vincristine, and dacarbazine (CVD)