Clinical Research

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Pheochromocytoma in VHL Disease

Pheochromocytoma in von Hippel–Lindau Disease: Distinct Histopathologic Phenotype Compared to Pheochromocytoma in Multiple Endocrine Neoplasia Type 2 Christian A. Koch, MD*, David Mauro, MD, PHD, McClellan M. Walther, MD, W. Marston Linehan, MD, Alexander O. Vortmeyer, MD, Ronald Jaffe, MD, Karel Pacak, MD, PHD, George P. Chrousos, MD, Zhengping Zhuang, MD, PHD, and Irina A. Lubensky, MD Abstract

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development (CAK, KP, GPC), Laboratory of Pathology, National Cancer Institute (DM), Urologic Oncology Branch, National Cancer Institute (MMW, WML), Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (AOV, ZZ, IAL), National Institutes of Health, Bethesda, MD; and Department of Pathology (RJ), University of Pittsburgh and Children’s Hospital, Pittsburgh, PA. *Present address: University of Leipzig, Department of Medicine III, Philipp-RosenthalStr. 27 04103 Leipzig, Germany. Address correspondence to Dr. Irina A. Lubensky, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Building 10, Room 5D37, 10 Center Drive, Bethesda, MD 20892. E-mail: [email protected] Endocrine Pathology, vol. 13, no. 1, 17–27, Spring 2002 © Copyright 2002 by Humana Press Inc. All rights of any nature whatsoever reserved. 1046–3976/02/13:17–27/ $12.75

Pheochromocytomas are rare neuroendocrine tumors that arise from chromaffin tissue. In a small subset of patients, pheochromocytomas occur as a manifestation of von Hippel– Lindau (VHL) disease. The histology of VHL-associated pheochromocytomas has not been reported in detail. In this article, we describe histopathologic features of 14 pheochromocytomas in eight patients with VHL disease and demonstrate that VHL-associated pheochromocytomas have a distinct histologic phenotype as compared with pheochromocytomas in patients with multiple endocrine neoplasia type 2 (MEN 2). VHL tumors are characterized by a thick vascular tumor capsule; myxoid and hyalinized stroma; round, small to medium tumor cells intermixed with small vessels; predominantly amphophilic and clear cytoplasm; absence of cytoplasmic hyaline globules; and lack of nuclear atypia or mitoses. In contrast to MEN 2, there is no extratumoral adrenomedullary hyperplasia in the VHL adrenal gland. Our findings of a distinct histologic phenotype of VHL pheochromocytoma may further help in subdividing patients who clinically present with multiple, bilateral pheochromocytomas. Key Words: Pheochromocytoma; adrenal; von Hippel–Lindau disease; multiple endocrine neoplasia type 2; sporadic; histopathology.

Introduction Pheochromocytomas are catecholamineproducing or nonfunctioning neuroendocrine tumors that arise in chromaffin tissue including the adrenal medulla. Most pheochromocytomas are sporadic, solitary, and unilateral. Multiple bilateral pheochromocytomas occur in hereditary tumor syndromes such as multiple endocrine neoplasia type 2 (MEN 2), von Hippel–Lindau disease (VHL), and neurofibromatosis type 1 (NF1). The epidemiologic incidence

of pheochromocytoma differs in these three syndromes: >50% in MEN 2, 10–34% in VHL disease, and <2% in NF1 [1–10]. For all three hereditary syndromes, the respective causative genes have been identified (reviewed in ref. 11). MEN 2A is the most common form of MEN 2 and comprises medullary thyroid carcinoma; pheochromocytoma; and, in approx 20% of patients, parathyroid hyperplasia/adenoma [1]. Pheochromocytoma patients with MEN 2 have an 17

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activating mutation in hot-spot areas of the RET protooncogene that contribute to the development of adrenomedullary hyperplasia (AMH) and adrenal pheochromocytoma [12]. RET mutations in codons 620, 631, 634, and 918 are frequently found in patients with MEN 2–associated pheochromocytoma [13]. Pheochromocytomas occur in patients with VHL type 2 disease. VHL type 2B is characterized by development of retinal angiomas, central nervous system (CNS) hemangioblastomas, and clear cell renal cell carcinomas and pheochromocytomas. VHL type 2A is a rare form of VHL disease characterized by a predisposition to develop pheochromocytomas without renal cell carcinoma, and infrequent hemangioblastomas and retinal angiomas. Patients with VHL type 1, the most common form of VHL disease, are predisposed to develop retinal angiomas, CNS hemangioblastomas, and clear cell renal cell carcinomas but not pheochromocytomas [14,15]. Germline mutations in the VHL gene responsible for each of these VHL phenotypes have been identified and cataloged [14]. The histopathology of MEN 2–associated pheochromocytomas has been characterized in detail [16–20], and the histology of exceedingly rare NF1-associated pheochromocytomas has been documented in individual case reports [21–30]. The histology of VHL-associated pheochromocytomas, however, has not been described. In this article, we describe the histopathology of pheochromocytoma in patients with VHL disease and compare it with the histopathology of pheochromocytoma in patients with MEN 2. We also address differences and similarities between NF1-associated and sporadic pheochromocytoma and VHL-associated pheochromocytoma.

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Materials and Methods Patients

Eight patients (three women and five men; mean age: 38 yr; range: 31–51 yr) with VHL disease type 2 were selected from the group of familial VHL patients with known VHL germline mutations followed on a clinical protocol at the Urologic Oncology Branch, National Cancer Institute, National Institutes of Health (NIH). Clinical and genetic data on the patients with VHL disease are given in Table 1. Three patients underwent bilateral adrenalectomy and five unilateral adrenalectomy (one had partial adrenalectomy) for multiple pheochromocytomas [31]. Three of the patients had VHL type 2A and five had VHL type 2B. For comparison, we selected four patients with MEN 2A and bilateral pheochromocytomas (four women; mean age: 36 yr; range: 25–42 yr) from the group of patients followed on a clinical protocol at the National Institutes of Child Health and Human Development, NIH. Each patient with MEN 2A had a documented germline mutation of the RET protooncogene in exons 10 or 11 including codons 620, 631, or 634. Ten sporadic pheochromocytomas removed by adrenalectomy from patients (six women and four men; mean age: 52 yr) followed on a clinical protocol at the Urologic Oncology Branch, National Cancer Institute, NIH were evaluated for comparison. Morphologic Examination of Tumors

We retrieved 14 formalin-fixed, paraffin-embedded pheochromocytomas and adrenal tissue from eight patients with VHL disease type 2 from the files of the Laboratory of Pathology at the National Cancer Institute, NIH. For comparison,

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Table 1. Clinical and Genetic Data in Eight Patients with VHL Disease with Pheochromocytoma Patient 1 2 3 4 5 6 7 8

Age (yr)/sex

Location

Metastases

42/M 34/F 35/M 44/F 38/M 41/M 32/M 31/F

Left adrenal Bilateral Right adrenal Left adrenal Right adrenal Right adrenal Bilateral Bilateral

None None None None None None None Liver, lung (patient died)

Follow-up (yr)

VHL mutation (nucleotide)

Other VHL tumorsa

VHL type

3 18 25 31 17 4 22 25

694, C to T 446, A to G 699, C to G 594/595 gc to tt Partial deletion 547, T to C Partial deletion 695, G to A

H/R/P/ Epi H/R/P H/R/P/A/E P, A H/R/P/Epi/A/E A H/R/P/Epi/A/E None

2B 2B 2B 2A 2B 2A 2B 2A

a H, hemangioblastoma; R, renal cancer; P, neuroendocrine tumor of the pancreas; Epi, epididymal cystadenoma; A, retinal angioma; E, endolymphatic sac tumor.

we also obtained eight pheochromocytoma and adrenal specimens from 4 patients with MEN 2 and 10 sporadic patients. The adrenal glands and tumors were evaluated on hematoxylin and eosin (H&E) stain by three pathologists (AOV, ZZ, IA) who were blinded to the clinical history and genotype of the respective patient. The histologic diagnosis of pheochromocytoma was confirmed by positive immunohistochemical stains for chromogranin A (1:1600) (Boehringer Mannheim, Indianapolis, IN) and synaptophysin (1:1000) (Zymed, San Diego, CA). Adrenal medullary hyperplasia (diffuse and nodular) was defined as an increase in the number of chromaffin cells and volume expansion of the medullary compartment resulting in increased proportion of the medulla relative to cortex when viewed in transverse section [32]. Results Multiple bilateral pheochromocytomas occur in patients with VHL disease and MEN 2. In these syndromes, the incidence of a pheochromocytoma in women is slightly higher than in men. The mean age at the time of diagnosis of pheochromocytoma is 34 for VHL disease and 38 for MEN 2, whereas the mean age at the diag-

nosis of solitary sporadic tumor is 52 (Table 1). Macroscopic and histologic features of VHL- and MEN 2–associated and sporadic pheochromocytomas are presented and compared in Table 2. Although adrenal pheochromocytomas in VHL disease and MEN 2 are similar in architecture, pheochromocytomas in patients with VHL disease have a distinct histology (Tables 2 and 3, Figs. 1 and 3). Tumors of adrenal medulla in both VHL 2A and 2B are characterized by a thick vascular tumor capsule; myxoid stroma; round, small to medium tumor cells intermixed with small vessels; prominent amphophilic and/or clear cytoplasm; absence of hyaline globules; neuroendocrine nuclei; and lack of nuclear atypia or mitoses (Table 3). There is no extratumoral AMH in the VHL adrenal gland. These histologic features are in contrast with those of the pheochromocytomas and AMH seen in patients with MEN 2 (Table 2, Figs. 2 and 3). Sporadic and VHL-associated tumors may show significant histologic overlap; both lack extratumoral AMH (Table 2). In our series, seven of eight patients with VHL disease had a benign clinical course, and one patient died and, at autopsy, had a metastatic malignant pheochromocytoma

20 Endocrine PathologyFeatures Volume 1 Spring 2002 Table 2. Patient Age and Macroscopic and Microscopic of VHL, 13, MENNumber 2, and Sporadic Pheochromocytomas VHL

MEN 2

Sporadic

Age (mean) (yr) No. of tumors Tumor size (cm) Location Tumor capsule Architecture Tumor vasculature

34 14 2–5 Adrenal (bilateral), (extraadrenal) Thick with numerous vessels Trabecular/solid Vessels intermixed with tumor cells

38 8 1–11 Adrenal (bilateral), extraadrenal Thin, absent Trabecular/solid Vessels in septae

Tumor cells Cytoplasm

Small, medium Amphophilic, clear, eosinophilic, no hyaline globules

Large, medium polygonal Eosinophilic, granular with hyaline globules (100%)

Stroma

Myxoid, with formation of cystic spaces, hyalinized Round, regular shape, salt-and-pepper-like chromatin, mitosis absent

Absent, minimal

Nuclei

Extratumoral adrenomedullary hyperplasia

Absent

Nuclear gigantism, round/oval, prominent nucleoli, rare mitotic figures, no atypical mitoses Present

52 10 3–5 Adrenal (unilateral) Thin, absent Trabecular/solid Vessels in septae or intermixed with tumor cells Medium, large Eosinophilic, basophilic without or with hyaline globules (33–50%) Hyalinized, with cystic degeneration Round or irregular, rare mitotic figures

Absent

Table 3. Microscopic Features of 14 Pheochromocytomas and Adrenals in Eight Patients with VHL Diseasea Patient no.

Tumor no. (size)

Architecture

Cell size

Cytoplasmb

Tumor vasculature

Stroma

Tumor capsule

1

1 (2 cm)

Solid

Small

Clear/amph

Prominent, intermixed with tumor cells

Myxoid/hyaline

2

2 (3 cm) 3 (3 cm)

Solid/trabec Solid/trabec

Small/med Small/med

Clear/amph Amph/clear

Myxoid Myxoid/hyaline

3

4 (5 cm) 5 (2 cm)

Solid Solid

Small/med Small/med

Amph/clear Amph/clear/eos

-“-d Prominent, intermixed with tumor cells -“Prominent, intermixed with tumor cells

Thick; prominent vessels Thick Thick

4

6 (3 cm)

Solid/trabec/cystic

Small/med

Amph/clear/clear

5

7 (2 cm) 8 (2 cm)

Solid Solid

Small Small/med

Amph/clear Clear/amph

6

9 (5 cm)

Solid/trabec

Small/med

Amph/clear

7

10 (5 cm)

Solid

Small/med

Amph/clear

Prominent, intermixed with tumor cells -“Prominent, intermixed with tumor cells Prominent, intermixed with tumor cells Prominent, intermixed with tumor cells

11 (3 cm)

Solid/trabec

Small/med

Amph/clear/eos

12 (2.5 cm) 13 (3 cm)

Solid Solid

Small Small/med

Amph/clear Amph/clear

14 (5 cm)

Solid/trabec

Small/med

Amph/clear

8c

-“-“Prominent, intermixed with tumor cells -“-

Myxoid/hyaline Myxoid/hyaline

AMH Absent Absent Absent

Hyaline/myxoid

Thick Thick; prominent vessels Absent

Absent

Myxoid/hyaline Absent

Thick Thick

Absent Absent

Myxoid/hyaline

Thick

Absent

Myxoid/hyaline

Thick; prominent vessels Thick; prominent vessels -“Thick

Absent

Myxoid Myxoid Myxoid/hyaline Myxoid/hyaline

Thick; prominent vessels

Absent Absent

Absent Absent Absent Absent

a AMH, adrenomedullary hyperplasia; trabec, trabecular; med, medium; amph, amphophilic; eos, eosinophilic. All 14 tumors showed minimal to no nuclear atypia and no mitoses (0/5 high-power fields [HPF]). No cytoplasmic hyaline globules were present in 14 tumors. b Cells with clear cytoplasm were present in all 14 tumors. The number of clear cells per tumor varied from focal in tumor 9 and 1% in tumor 3 to 60% in tumor 1 and 90% in tumor 8. c Patient 8 developed metastases to the lungs, liver, and skull bones 25 yr after the initial diagnosis of pheochromocytoma. Metastatic tumor showed marked cytologic atypia, pleomorphism, and 4–10 mitoses/5 HPF. d Same as above.

Pheochromocytoma in VHL Disease

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Fig. 1. Histopathology of the VHL-associated pheochromocytoma. (A) Two tumor nodules in the adrenal gland of a patient with VHL are separated by a normal adrenal medulla (original magnification: ×20). (B) A thick tumor capsule with prominent vessels in a VHL pheochromocytoma is shown (original magnification: ×400). (C) Edematous/myxoid stroma may be prominent in a VHL pheochromocytoma (original magnification: ×400). (D) Tumor cells with clear and amphophilic cytoplasm are intermixed with numerous vessels in a VHL pheochromocytoma (original magnification: ×400).

to the liver, lungs, and skull bones on 25-yr follow-up. This patient’s primary adrenal pheochromocytoma did not look different from the tumors of the other seven patients with VHL disease (Table 3). None of our MEN 2 and sporadic patients had a malignant pheochromocytoma on 9-yr follow-up. Discussion We have described histopathologic features of VHL-associated pheochromocytomas and found that, as compared to MEN 2–associated tumors of the adrenal medulla,

VHL pheochromocytomas have a morphologically distinct phenotype (Tables 2 and 3, Figs. 1–3). The characteristic histologic findings in the majority of VHL-associated pheochromocytomas include a thick vascular tumor capsule; myxoid and hyalinized stroma; small to medium, round tumor cells closely intermixed with small vessels; predominantly amphophilic and clear cytoplasm; absence of cytoplasmic hyaline globules; neuroendocrine nuclei; and rare or absent nuclear atypia and mitoses (Tables 2 and 3, Figs. 1 and 3). Cells with clear cytoplasm may predominate in a VHL-associated pheochromo-

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Fig. 2. Histopathology of the MEN 2–associated pheochromocytoma is in contrast to the VHL counterpart. (A) Adrenomedullary hyperplasia with a nuclear atypia in MEN 2 is shown (original magnification: ×100). (B) Tumor capsule is absent in a MEN 2 pheochromocytoma, and tumor cells impinge on the adrenal cortex (original magnification: ×400). (C) Small vessels are located in the stromal septae between the nests of large eosinophilic tumor cells in a MEN 2 pheochromocytoma (original magnification: ×400).

cytoma (Table 3). Such cells intermixed with small vessels are also characteristically seen in other VHL-associated neoplasms such as renal cysts and renal cell carcinoma, macrocystic adenoma and neuroendocrine tumor of the pancreas, and cystadenoma of the epididymis [33–35]. Cytoplasmic clearing is secondary to the deposition of glycogen and lipids [34]. These histologic features are different from those of MEN 2A pheochromocytoma, the most common hereditary pheochromocytoma syndrome to be distinguished from VHL type 2 (Table 2, Figs. 2 and 3). Based on our tumor samples and

the literature [16,20], MEN 2A pheochromocytoma often consists of large and polygonal eosinophilic cells with characteristic intracytoplasmic hyaline globules, nuclear atypia is common, the tumor capsule is thin or absent, and small vessels are located in stromal septae between nests of tumor cells (Figs. 2 and 3, Table 2). Normal extratumoral adrenal medulla in patients with VHL pheochromocytoma is in contrast to the presence of diffuse or nodular AMH seen in the adrenal gland of patients with MEN 2 (Figs. 1 and 2, Tables 2 and 3). Thus, a small nodule in the adrenal medulla seen on an H&E slide

Pheochromocytoma in VHL Disease

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Fig. 3. Cytomorphologic differences between VHL- and MEN 2–associated pheochromocytomas (original magnification: ×400). (A,B) VHLassociated pheochromocytoma is composed of round, small, and medium neuroendocrine cells with prominent clear and amphophilic cytoplasm. (C,D) In MEN 2 pheochromocytoma, tumor cells are large and polygonal and may show nuclear atypia and rare mitoses. Cells with prominent eosinophilic granular cytoplasm and intracytoplasmic hyaline globules are characteristic for MEN 2 tumors.

of a VHL patient is a pheochromocytoma, whereas such a nodule may represent AMH or a pheochromocytoma in a patient with MEN 2. Although size of the nodule (e.g., <1 cm) is used by some researchers to distinguish between AMH and pheochromocytoma in patients with MEN 2 [16], we believe that the division into hyperplasia and neoplasia on the basis of histologic criteria alone is arbitrary and needs to be confirmed by molecular analysis. The presence of a morphologically distinct phenotype of VHL pheochromocytoma is interesting in view of the fact that patients with VHL disease or MEN 2–

associated pheochromocytoma have distinct genetic alterations. Patients with VHL disease usually have germline mutations in the VHL tumor suppressor gene accompanied by a deletion, point mutation, or hypermethylation of the wild-type allele of the gene [14]. Thus, analysis of tumors for germline mutations in the VHL gene may be helpful in the differential diagnosis of hereditary pheochromocytoma. Some patients with VHL disease have a VHL germline deletion and somatic point mutation in the respective VHL tumor [36]. Distribution of VHL mutation with predominance of nucleotide (nt) 712/713

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has been documented in some VHL families [3,15,37]. Each of the eight patients with VHL type 2 in our series had a different VHL germline mutation, and no patient had a mutation in nt 712/713 (Table 1). Pheochromocytoma patients with MEN 2 have an activating mutation in hot-spot areas of the RET protooncogene that contribute to the development of AMH and adrenal pheochromocytoma [12]. RET mutations in codons 620, 631, 634, and 918 are frequently found in patients with MEN 2–associated pheochromocytoma, and such mutations were detected in patients with MEN 2 in the present study [12]. Bilateral and unilateral adrenal and extraadrenal pheochromocytomas are a rare manifestation of another hereditary syndrome, NF1. Patients with NF1 develop tumors secondary to germline mutations of the NF1 tumor suppressor gene accompanied by inactivation of the wild-type allele of the gene. Mutation analysis of the NF1 gene in patients presenting with a pheochromocytoma is not practical because of the large gene size and structure, rarity of pheochromocytoma in NF1, and clinically distinct pathognomonic abnormalities such as neurofibromas and café au lait spots in NF1 patients. A review of the literature demonstrates that most NF1-associated pheochromocytomas share histologic features with MEN 2–associated tumors (thin or absent tumor capsule, large and polygonal eosinophilic tumor cells with irregular nuclei and small vessels located within the stromal septae), whereas they are usually histologically distinct from VHLassociated pheochromocytomas (Table 2) [21–30]. However, normal extratumoral adrenal medulla is a common feature of both VHL and NF1 adrenal glands and is in contrast to the presence of diffuse or nodular AMH in the adrenal gland of patients with MEN 2 (Figs. 1 and 2, Table 2).

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The presence of a morphologically distinct phenotype of VHL pheochromocytoma is important in that there is an overlap in VHL, MEN 2, and NF1 pheochromocytomas on clinical grounds. All hereditary pheochromocytomas may be multifocal, bilateral intraadrenal, and extraadrenal. Adrenal pheochromocytomas occur multifocally and bilaterally in 15– 44% of patients with VHL disease, in 65– 78% of patients with MEN 2, and in 10% of patients with NF1 [2,5,6,9,12,16,33, 38–45]. In our series, 3 of 8 patients (38%) with VHL type 2 disease, all 4 patients (100%) with MEN 2, and 4 of 18 patients (22%) from the literature-based NF1 series had a bilateral pheochromocytoma [26– 28]. In up to 30% of patients with VHLassociated pheochromocytomas, the tumors are reported to be extraadrenal [2,3,5,6] compared with 13% of patients with MEN 2–associated pheochromocytomas [2,33], and 6% of patients with NF1-associated pheochromocytomas [9]. The presence of a morphologically distinct phenotype of VHL pheochromocytoma is also interesting in view of the fact that many VHL- and MEN 2–associated pheochromocytomas have been shown to have distinct biochemical features. Patients with VHL-associated pheochromocytomas predominantly have elevated plasma norepinephrine and normetanephrine concentrations, indicating a more noradrenergic biochemical phenotype. Patients with MEN 2–associated pheochromocytomas have predominantly epinephrine and metanephrine elevations in plasma and urine, thereby featuring a more adrenergic biochemical phenotype [48,49]. Most hereditary pheochromocytomas have a benign clinical course. However, malignant pheochromocytomas have been described in VHL and MEN 2 cases [3,17,41,42,50]. The diagnosis of malignancy in pheochromocytoma is not based

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Pheochromocytoma in VHL Disease

on tumor morphology but is established on clinical grounds by the presence of distant metastases. In our series, one of eight patients with VHL disease had a malignant pheochromocytoma with metastases to the liver, lungs, and bone on 25-yr follow-up. A histologic review of the primary bilateral adrenal tumors (tumors 13 and 14) demonstrated minimal to no nuclear atypia and no mitoses (Table 3). Metastatic tumor at autopsy, however, showed marked cytologic atypia, pleomorphism, and 4– 10 mitoses/5 HPF. None of the four patients with MEN 2 had a malignant pheochromocytoma on 9-yr follow-up. When followed up for more than 23 yr, as many as 25% (2/8, 4/19) of patients with MEN 2– associated pheochromocytoma may reveal clinical metastases [17,42,50]. At present, there are no markers that can reliably distinguish benign from malignant pheochromocytomas [51]. Although most VHL-associated pheochromocytomas may be distinguished morphologically from MEN 2 pheochromocytomas, there is an overlap in histology between multiple VHL- and MEN 2–associated tumors and solitary sporadic pheochromocytomas in some cases (Table 2) [20,44,52–54]. Thus, germline mutation screening for VHL and RET is recommended in patients presenting with pheochromocytoma. In summary, the presence of a distinct morphologic phenotype of VHL-associated pheochromocytoma should allow for its histologic distinction from MEN 2– associated pheochromocytoma. This histologic difference of VHL pheochromocytoma alone or in combination with biochemical and genetic profiles of the tumor should aid in assigning patients with multiple, bilateral pheochromocytomas into the appropriate hereditary syndrome group.

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