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From the Section for Preventive Medicine, heochromocytoma fascinates and, at times, confounds clini-
Medical Center–University of Freiburg, cians. The symptoms due to hypersecretion of catecholamines can mimic
Faculty of Medicine, Albert-Ludwigs-Uni-
versity, Freiburg, Germany (H.P.H.N.); more than 30 medical disorders.1 This rare tumor can be lethal if left undi
the Division of Endocrinology, Diabetes, agnosed. Thus, rapid recognition is vital. Yet selecting a good approach to bio
Metabolism, and Nutrition, Department chemical testing and selecting imaging studies for purposes of localization can be
of Internal Medicine, Mayo Clinic, Roch-
ester, MN (W.F.Y.); and the Genomic confusing and complex. Although surgical resection is the treatment of choice, the
Medicine Institute, Lerner Research Insti- preparation for and timing of surgery are uncertain; furthermore, selection of
tute, and Taussig Cancer Institute, Cleve- the appropriate operative technique for a given tumor may be controversial. Finally,
land Clinic, Cleveland (C.E.). Address re-
print requests to Dr. Neumann at the recent progress in understanding the genetic basis for these tumors and how to
Section for Preventive Medicine, Faculty manage a specific case according to the gene involved adds to the complexity.
of Medicine, Albert-Ludwigs-University, Here, we highlight recent advances in the diagnosis and management of this rare
79104 Freiburg, Germany, or at hartmut
.neumann@uniklinikum-freiburg.de. neoplasm.
This article was updated on August 8,
2019, at NEJM.org. His t or y, Ter minol o gy, a nd His t ol o gic Fe at ur e s
N Engl J Med 2019;381:552-65.
DOI: 10.1056/NEJMra1806651 Max Schottelius (1849–1919), a pathologist in Freiburg, Germany, was the first
Copyright © 2019 Massachusetts Medical Society. person to describe the histopathological features of pheochromocytoma; in 2017,
Schottelius was finally profiled.2 He provided the histologic description of bi
lateral adrenal tumors in an 18-year-old woman who died in 1886 after a long
history of panic attacks, tachycardia, and sweating.3 This report was translated
into English and published in the series “Classics in Oncology” in 1984.4 In 2007,
we reported that this patient was the first described to have multiple endocrine
neoplasia type 2 (MEN-2); descendants of her brother were found to carry a re
arranged during transfection (RET) mutation.5 The adrenal tumors in this patient
were described by Schottelius as chromaffin tumors on the basis of staining with
Müller’s solution. The term pheochromocytoma dates back to 1912, when it was
used by the German pathologist Ludwig Pick.6
In the 2017 World Health Organization (WHO) classification, pheochromocy
toma is an adrenal tumor, and paraganglioma is an extraadrenal tumor; since the
two tumor types cannot be differentiated on the basis of histologic findings
(Fig. 1), anatomical location is used to distinguish between them.7,8 Tumor growth
shows the so-called zellballen pattern, consisting of well-developed tumor cells
showing nested growth, with an intervening stromal component of fibrovascular
tissue and peripheral sustentacular cells. Immunohistochemical examination shows
chief cells stained with chromogranin and sustentacular cells stained with S100.8
A B C
D E
toms of anxiety and panic attacks are common and anatomical documentation of the tumor. An
in the general population, and identifying the increase in plasma fractionated metanephrines
rare patient with pheochromocytoma or para (metanephrine and normetanephrine) has a
ganglioma is a challenge for clinicians. How mean sensitivity of 97% and a specificity of 93%
ever, with the widespread use of crosssectional across 15 studies.12 In contrast, measurement of
imaging, the incidental discovery of an adrenal fractionated catecholamines (epinephrine, nor
mass is becoming common.11 In addition, asymp epinephrine, and dopamine) is less sensitive, but
tomatic cases of pheochromocytoma and para clearly elevated values (>2 times the upper limit
ganglioma are increasingly being discovered on of the normal range) are also diagnostic.13,14
the basis of family and germlinemutation testing. However, mild elevations in the levels of frac
The approach to making a diagnosis may dif tionated metanephrines and catecholamines in
fer from center to center, but a consensus ap plasma and urine are common in persons who
proach is shown in Table 1. The diagnosis of do not have pheochromocytoma. Medications
pheochromocytoma or paraganglioma requires (e.g., tricyclic antidepressants, antipsychotic
both proof of excessive release of catecholamines agents, serotoninreuptake or norepinephrine
Table 1. Approach to Pheochromocytoma and Associated Syndromes According to the Clinical Scenario.*
Clinical Scenario Initial Biochemical Testing and Imaging Follow-up Biochemical Testing and Imaging
Signs and symptoms on presentation Perform abdominal contrast-enhanced CT Measure metanephrines postoperatively and
(e.g., resistant hypertension or or MRI; if abdominal imaging is negative, then annually; if bilateral pheochromocy
paroxysms of hypertension, palpita- consider MRI of skull base, neck, chest, tomas were removed with cortical-sparing
tions, perspiration, headaches, and and pelvis surgery, document normal glucocorticoid
markedly elevated metanephrines secretory function with cosyntropin-stimu-
or catecholamines) lation test
Incidentally discovered adrenal or retro- If levels of metanephrines are clearly elevated, If a pheochromocytoma or paraganglioma was
peritoneal mass with attenuation perform contrast-enhanced CT or MRI; if resected, measure metanephrines post
>10 Hounsfield units on unen- mass is >10 cm in diameter or is extraadre- operatively and then annually
hanced CT nal, search for additional paragangliomas
or metastatic disease with 123I-MIBG scin
tigraphy, 68Ga-DOTATATE–PET–CT, or
18F-FDG–PET–CT
* The term metanephrines refers to metanephrine and normetanephrine. CT denotes computed tomography, 18F-FDG 18F-fluorodeoxyglucose,
68Ga-DOTATATE 68Ga-labeled 1,4,7,10-tetraazacyclododecane–1,4,7,10-tetraacetic acid–octreotate, 123I-MIBG 123I-labeled metaiodobenzyl-
reuptake inhibitors, and levodopa) could cause be considered: first, typical symptoms combined
elevations in endogenous catecholamines, and with clearly elevated metanephrine or catechol
clinical circumstances (e.g., acute illness) could amine levels; second, incidental detection of an
lead to false positive test results. To effectively adrenal or retroperitoneal mass; and third, a
screen for catecholamine-secreting tumors, tri germline mutation in a susceptibility gene on
cyclic antidepressants and other psychoactive molecular genetic testing and the associated
agents should be tapered and discontinued at syndrome. In scenario 1, the tumor has to be
least 2 weeks before any hormonal assessments localized by means of either contrast-enhanced
are performed. computed tomography (CT) or T2-weighted
For medical imaging of pheochromocytoma magnetic resonance imaging (MRI). Standard
or paraganglioma (Table 1), three scenarios must imaging includes the entire retroperitoneum,
since nearly all extraadrenal, catecholamine- standard treatment for patients with pheochro
secreting tumors are located in the retroperito mocytoma in order to control blood pressure and
neum rather than in the pelvis or thorax. In prevent intraoperative hypertensive crises.21 Ad
scenario 2, CT without contrast material is impor renergic blockade is typically accomplished with
tant, because when CT attenuation is 10 Houns either a nonselective or a selective α-adrenergic
field units or less, a lipid-rich mass is present, receptor antagonist (e.g., nonselective α-adrener
which rules out the diagnosis of pheochromocy gic blockade with phenoxybenzamine, started at
toma or paraganglioma, and biochemical testing a dose of 10 mg by mouth two times a day and
is not needed.15 For masses with CT attenuation increased to up to 30 mg three times a day with
of more than 10 Hounsfield units, biochemical adjustment for low-normal blood pressure for
testing must be performed. When biochemical age; or selective α1-adrenergic blockade with
testing is abnormal, cross-sectional imaging doxazosin, started at a dose of 1 mg by mouth
with contrast-enhanced CT or MRI is indicated. daily and increased to up to 10 mg twice daily as
For scenario 3, see the discussion below on the needed to achieve target blood-pressure levels),
care of asymptomatic germline mutation carri usually started at least 7 days before surgery.1,22
ers and relatives. Adrenergic blockade should be accompanied by
Once a pheochromocytoma or paraganglioma a high-sodium diet (e.g., 5000 mg per day) and
has been identified, the need for additional total- generous fluid intake (e.g., 2.5 liters per day).1
body imaging is questionable.16 Functional The β-adrenergic antagonist (e.g., oral admin
imaging (e.g., scintigraphy with 123I-labeled meta istration of extended-release metoprolol at a start
iodobenzylguanidine [MIBG] or positron-emis ing dose of 25 mg by mouth once daily and in
sion tomography [PET]–CT with 68Ga-labeled creased to up to 100 mg twice daily as needed
1,4,7,10-tetraazacyclododecane–1,4,7,10-tetraace for a target average heart rate of 80 beats per
tic acid–octreotate [DOTATATE] or 18F-labeled minute) should be administered to control tachy
l-dihydroxyphenylalanine [l-DOPA]) is very ef cardia after α-adrenergic blockade has been ef
fective in localizing pheochromocytomas and fective in normalizing blood pressure, because
paragangliomas (Fig. 1).17 Furthermore, the re with β-adrenergic blockade alone, severe hyper
sults of 68Ga-DOTATATE–PET–CT correlate with tension or cardiopulmonary decompensation may
biochemical measurements.18 The main indica occur as a result of unopposed α-adrenergic
tion for functional imaging is the search for stimulation.22 However, postoperative sustained
metastatic disease or identification of multiple hypotension can be a complication of preopera
chromaffin tumors. tive adrenergic blockade. In 2017, the concept
In contrast, head-and-neck paragangliomas of adrenergic blockade–free management was
are usually manifested as painless, slowly grow explored. A prospective study involving 110 pa
ing masses, mainly as carotid-body tumors and tients who received preoperative treatment with
vagal paragangliomas, or with conductive hear α-adrenergic blockade and 166 patients who did
ing loss and pulsatile tinnitus caused by jugulo not revealed no relevant differences regarding
tympanic paragangliomas. Lower-cranial-nerve maximal intraoperative systolic pressure, hyper
deficits are frequently seen in patients with tensive episodes, or major complications.23 In a
advanced head-and-neck paragangliomas. Cate patient who has not had adverse effects in asso
cholamine hypersecretion is rarely found in such ciation with long-term, episodic blood-pressure
patients.19,20 spikes without α-adrenergic blockade, it seems
unlikely that decompensation would occur in
the few days before surgery, and nitroprusside-
T r e atmen t
guided blood-pressure control during anesthesia
Surgical resection of pheochromocytoma or para may be justifiable. This opens the avenue for
ganglioma is the cornerstone of therapy. Most of operation without further delay. There is no con
these tumors are resected on the basis of bio sensus in support of this approach, not even
chemical and CT or MRI documentation. The among us, and the 2014 pheochromocytoma
major questions concern the timing of surgery guidelines issued by the Endocrine Society, as
and the surgical approach. well as many experts, continue to recommend
Combined α- and β-adrenergic blockade is preoperative adrenergic blockade for all patients.22
Until 1996, the surgical approach for pheo ly seen after surgery. Patients with these advanced
chromocytoma was open laparotomy and removal tumors may have less treatment-related morbid
of the entire adrenal gland with the tumor.24 On ity with the nonsurgical treatment options.
the basis of anecdotal evidence from many cen
ters in the United States, Europe, and Asia, this Suscep t ibil i t y Gene s
procedure is still frequently performed. In 1996,
Gagner and colleagues removed a pheochromo The RET proto-oncogene was identified in 1993
cytoma endoscopically.25 Over the subsequent as a risk factor for pheochromocytoma. Since
decades, endoscopic technology with transab then, at least 18 additional susceptibility genes
dominal or retroperitoneal access replaced the have been reported.33 In parallel with these inves
open surgical approach and became standard tigations, gene-specific clinical data have been
practice because of the shorter operative time, studied to guide clinical management strategies.
fewer intraoperative and postoperative complica Here, we delineate the most extensively studied
tions, and shorter hospital stay.26 Although it has clinical phenotypes (e.g., tumor location, number
been shown that pheochromocytomas with a of tumors, and patient age at tumor manifesta
diameter of 5 cm or more can be safely removed tion) of the 10 currently clinically relevant syn
endoscopically,27 their safe removal is still a matter dromes (Table 2) that have been identified:
of debate and should be considered on an indi MEN-2, caused by germline mutations of the
vidual basis according to tumor characteristics RET proto-oncogene34; von Hippel–Lindau dis
and surgical expertise. For bilateral adrenal pheo ease, caused by mutations in the VHL tumor-
chromocytoma, the concept of organ-sparing suppressor gene35; neurofibromatosis type 1,
surgery was introduced in 1999 to avoid a post caused by mutations in the NF1 tumor-suppressor
operative requirement for glucocorticoid and gene36; paraganglioma syndromes 1 through 5,
mineralocorticoid replacement.28 Approximately caused by mutations of the succinate dehydroge
one third of one adrenal gland is sufficient for nase genes SDHD (syndrome 1),37 SDHAF2 (syn
normal glucocorticoid and mineralocorticoid drome 2),38 SDHC (syndrome 3),39 SDHB (syndrome
secretion.29 Much like retroperitoneal tumors, 4),40 and SDHA (syndrome 5)41; and the hereditary
tumors in unusual locations such as pelvic para pheochromocytoma syndromes caused by muta
vesicular and thoracic paravertebral regions have tions in the genes encoding transmembrane pro
been removed with the use of minimally invasive tein 127 (TMEM127)42 and MYC-associated factor
surgery 30 (see the video, available with the full X (MAX).43 Other susceptibility genes, which have
text of this article at NEJM.org; and the illustra not yet undergone rigorous genotype–clinical out
A video tive case in the Supplementary Appendix, avail come evaluation, include EGLN1 (PHD2), EGLN2
showing endoscopic
removal of a thoracic able at NEJM.org). (PHD1), KIF1B, IDH1, HIF2A, MDH2, FH, SLC25A11,
paraganglioma is For a patient with a head-and-neck paragan and DNMT3A.44-53 Various publicly available gene-
available at glioma, finding the best treatment option often variation databases that are relevant to pheo
NEJM.org
represents a challenge, and an individualized chromocytoma or paraganglioma susceptibility
interdisciplinary approach is essential. Treatment genes (e.g., LOVD-based SDHx variant database
options include surgery, stereotactic radiosur [www.LOVD.nl]) may be useful for clinicians
gery, external radiation therapy, and a wait-and- and researchers.54
scan strategy. Determining the exact location and
presence of tumor extension, as well as staging Pheo chromo c y t om a-A sso ci ated
before any kind of treatment, is essential. Carotid- S y ndrome s
body tumors are most frequently classified with
the use of the Shamblin classification, whereas The clinical features of pheochromocytoma-asso
the Fisch classification is used for jugulotym ciated syndromes (Table 2) have been known for
panic paragangliomas, both of which guide sur more than 100 years, starting with neurofibro
gical management.31,32 Surgical resection is the matosis 1, von Hippel–Lindau disease, and MEN-2.
only potentially curative treatment option. With With the identification of susceptibility genes
advanced cervical paragangliomas (Shamblin containing various germline mutations, these
class III) and jugular paragangliomas (Fisch class and additional syndromes have been defined and
C and D), lower-cranial-nerve deficits are frequent differentiated. Unilateral or bilateral pheochro
Head and
Adrenal Neck Extraadrenal Multiple Metastatic Family
Gene Syndrome Nonchromaffin Tumors Transmission Tumors Tumors Tumors† Tumors Tumors‡ History§
frequency (percent)
VHL VHL Retinal and CNS hemangio Autosomal dominant >50 <1 10–24 >50 1–9 25–50
blastomas, RCC, pancreatic
neuroendocrine tumor,
ELST
NF1 NF1 Cutaneous neurofibromas, Autosomal dominant >50 <1 1–9 25–50 1–9 10–24
malignant peripheral-nerve-
sheath tumor, breast cancer
RET MEN-2 Medullary thyroid carcinoma, Autosomal dominant >50 <1 <1 >50 <1 25–50
hyperparathyroidism
SDHA PGL5 Rarely also pituitary adenoma, Autosomal dominant 25–50 25–50 25–50 1–9 1–9 1–9
GIST, RCC
SDHB PGL4 Rarely also pituitary adenoma, Autosomal dominant 25–50 25–50 25–50 10–24 25–50 10–24
GIST, RCC
SDHC PGL3 Rarely also pituitary adenoma, Autosomal dominant 1–9 >50 <1 10–24 Not reported 10–24
GIST
SDHD PGL1 Rarely also pituitary adenoma, Autosomal dominant, 10–24 >50 10–24 >50 1–9 25–50
GIST, RCC maternal imprinting
maternal imprinting
MAX No name Rarely also RCC Autosomal dominant >50 <1 1–9 >50 1–9 25–50
TMEM127 No name Autosomal dominant >50 1–9 <1 25–50 10–24 1–9
Downloaded from nejm.org at PONTIFICIA UNIVERSIDAD JAVERIANA on August 7, 2019. For personal use only. No other uses without permission.
557
The n e w e ng l a n d j o u r na l of m e dic i n e
mocytomas develop in up to 50% of patients Figure 2 (facing page). Frequencies of Gene Mutations
with these syndromes.55,56 Once the pathogenic in Patients with Pheochromocytoma or Paraganglioma.
RET mutation is identified in a patient with Data are from the joint Freiburg, Germany, and Padua,
pheochromocytoma, clinicians must be aware Italy, registries, which contain information about more
that virtually all mutation carriers will have than 3300 patients with chromaffin tumors.7,55,61,73,74
medullary thyroid carcinoma, whereas 20% of Panel A shows the relative percentages of germline
mutations among all mutation carriers, according to
patients with MEN-2A, but not MEN-2B, will decade of age at presentation. In Panels B through G,
have hyperparathyroidism. It would be rare for a the relative percentages of patients with mutations in
patient with MEN-2B (characterized chiefly by various genes and patients without mutations are shown
the RET p.M918T mutation) to first present with in pie charts. The overall percentages of mutation car-
pheochromocytoma, since the typical components riers are shown in Panel B; the percentages for head-
and-neck paragangliomas (HNP), extraadrenal tumors,
are manifested relatively early, even in infancy, bilateral adrenal tumors, and metastatic tumors are
such as early-onset medullary thyroid carcinoma; shown in Panels C through F, respectively. In Panel G,
ganglioneuromas typically involving the tongue, the pie chart for mutation-positive tumors shows the
lips, and eyelids; skeletal deformities (e.g., kypho relative frequencies of mutations in susceptibility
scoliosis and marfanoid habitus); joint laxity; genes among mutation carriers. Proportions of less
than 1% are not shown.
and intestinal ganglioneuromatosis.56
By contrast, in patients with von Hippel–
Lindau disease, especially type 2, pheochromo tance is autosomal dominant for pheochromo
cytomas and paragangliomas are common, may cytoma-predisposing germline mutations. This
be part of the patient’s initial presentation, even means that offspring of a carrier have a 50%
in early infancy, and are often associated with likelihood of inheriting the parent’s mutation.
mutations in codons 98, 161, and 167.33,57,58 Mis However, SDHD and SDHAF2 are maternally im
sense VHL mutations predict von Hippel–Lindau printed (the gene is not expressed from the
disease type 2. Truncating VHL mutations are maternal allele). This means that inheriting a
often associated with renal-cell carcinoma and mutation from the mother only rarely results in
in rare cases are associated with pheochromocy tumor development,72 which explains why one or
toma (von Hippel–Lindau disease type 1). Other more generations appear to be skipped.
features of von Hippel–Lindau disease include reti
nal and central nervous system (CNS) hemangio Cl inic a l H a l l m a r k s of
blastomas and pancreatic neuroendocrine tumors.59 Her edi ta r y Pheo chromo c y t om a
Neurofibromatosis 1 is characterized by neuro a nd Pa r ag a ngl iom a
fibromas, café au lait spots, axillary freckling,
iris hamartomas (Lisch nodules), bony abnormali In addition to family history, classic hallmarks
ties, CNS gliomas, macrocephaly, and cognitive of hereditary pheochromocytoma and paragan
deficits, but pheochromocytomas and paragan glioma include an early age at onset, extraadrenal
gliomas are present in only 1 to 3% of affected and multiple primary tumors, and associated non
persons.60-62 Patients with mutations of SDHx, paraganglial tumors (Table 2 and Fig. 2). The
TMEM127, or MAX generally have only pheochro age at diagnosis is about 15 years younger for
mocytomas and paragangliomas. A minority of syndromic pheochromocytomas and paraganglio
SDHx mutation carriers have had gastrointestinal mas than for sporadic cases, with von Hippel–
stromal tumors (GISTs), renal-cell carcinomas, Lindau disease diagnosed at the earliest age.74
or pituitary adenomas.63-69 The autosomal domi Paraganglioma occurring in an unusual location,
nant Carney–Stratakis syndrome is characterized such as the organ of Zuckerkandl, thorax, or
by the association of pheochromocytoma, para urinary bladder, should suggest the possibility
ganglioma, or both with GISTs, and the so-called that the patient has a syndrome associated with
3PAs syndrome (pheochromocytoma, paragan the tumor.
glioma, and pituitary adenoma) is associated with Anatomical locations of pheochromocytomas
SDHx mutations.70,71 and paragangliomas differ widely among the
The concept of genetic predisposition may be syndromes (Table 2). Adrenal pheochromocyto
confusing to patients and their families. Inheri mas occur almost exclusively in patients with
No mutation RET VHL NF1 SDHA SDHB SDHC SDHD SDHAF2 MAX TMEM127
A Mutations
100
90
80
70
60
Percent
50
40
30
20
10
0
1 2 3 4 5 6 7– 9
Decade
B All C HNP
F Metastatic G Mutation-Positive
germline mutations in RET. In contrast, in pa ablation, chemotherapy, and external irradiation.
tients with mutations in VHL, NF1, MAX, and Surgical resection of as much tumor tissue as
TMEM127, pheochromocytomas are common, possible should be the initial approach.83 Most
but retroperitoneal paragangliomas are also ob patients with metastatic pheochromocytoma or
served. Patients with SDHx mutations frequently paraganglioma have sporadic tumors, whereas
have head-and-neck paragangliomas, but pheo among patients with heritable pheochromocy
chromocytomas and retroperitoneal paragangli toma in whom metastatic disease develops,
omas are seen mainly in carriers of SDHD, SDHB, tumors caused by SDHB mutations account for
and SDHA mutations. The rare thoracic paragan up to 43% of cases, followed by VHL, SDHD, and
gliomas are associated mostly with mutations in NF1 mutations.84 Overall survival and disease-
SDHB, SDHD, or VHL. Multiple primary tumors specific survival are surprisingly favorable, at 25
often occur in patients with germline mutations years and 34 years, respectively.80
in RET, VHL, SDHD, or MAX.
M ajor Needs of A ffec ted
Me ta s tat ic Pheo chromo c y t om a Pat ien t s
The diagnosis of malignant pheochromocytoma The key concerns from the patient’s perspective
is problematic. Pathologists have correlated his include early diagnosis, the effect of germline
tologic features such as growth patterns, mitoses, mutation on treatment, best surgical option,
and atypia of cells and nuclei with malignant postoperative care guided by genetic features,
biologic features in pheochromocytomas and and appropriate care and surveillance of rela
paragangliomas, and these findings form the tives. Early diagnosis in patients with sporadic
basis for scoring systems (e.g., Pheochromocy pheochromocytomas or paragangliomas relies on
toma of the Adrenal Gland Scaled Score [PASS] keen clinicians who recognize signs and symp
and Grading System for Adrenal Pheochromocy toms of catecholamine-secreting tumors. Once
toma and Paraganglioma [GAPP]).75,76 However, it the diagnosis is established, it is important to
remains difficult to predict the clinical behavior consider when genetic testing in the context of
of individual tumors, and no single risk-stratifi genetic counseling should be performed, since
cation scheme is endorsed or in widespread all patients with pheochromocytoma or para
use.77,78 Only metastases are the proof for a ma ganglioma should undergo genetic analysis. Af
lignant pheochromocytoma or paraganglioma, ter detection of the mutation, the specific gene
and the updated WHO classification of endo guides the tailoring of imaging studies and
crine tumors has replaced the term “malignant subsequent medical management (Table 1). For
pheochromocytoma” with “metastatic pheochro example, imaging studies are performed for
mocytoma.”8 Metastases are located where chro medullary thyroid carcinoma if RET is mutated;
maffin tissue is normally not found (e.g., lymph for hemangioblastomas of the eyes and CNS and
nodes, lung, liver, and bones), and frequently, for tumors of the ears, kidneys, and pancreas if
metastases are not confirmed histologically but VHL is mutated; and for other chromaffin tu
are instead documented on nuclear imaging.79 mors or the rare kidney cancers, pituitary adeno
When pheochromocytoma is the primary tumor, mas, or GISTs if SDHx, MAX, or TMEM127 is
the typical metastatic sites are bones and lymph mutated. An important question is whether
nodes, whereas when paraganglioma is the screening for mutations should be performed
primary tumor, hepatic metastases are more before a pheochromocytoma is resected. Bilat
common.80 As a cautionary note, recurrent and eral adrenal tumors can occur metachronously,
metastatic disease may occur after intraoperative with intervals of more than a decade, especially
rupture of the tumor capsule, a complication in patients with RET germline mutations.55 Thus,
that can lead to incurable tumor spread.81,82 operative planning for preservation of sufficient
Treatment options for metastatic pheochro adrenal cortex will be guided by the results of
mocytoma include surgical resection, use of gene testing.
targeted radiolabeled carriers (e.g., 131I-MIBG or Favorable surgical outcomes include complete
90
Y-DOTATATE and 177Lu-DOTATATE), thermal tumor resection, no permanent complications,
limited postoperative pain, good cosmetic re the mean penetrance of pheochromocytoma or
sults, and a short hospital stay. Minimally inva paraganglioma in RET mutation carriers is 50%
sive surgery performed by expert surgeons is key by the age of 44 years, whereas for carriers of
in achieving these goals. mutations that increase susceptibility to von
An organized, long-term postoperative care Hippel–Lindau disease type 2, the mean pene
program is essential for patients with germline trance is 50% at the age of 52 years.55,57 SDHA
mutations and should be in the hands of endo mutation penetrance is 39% by the age of 40
crinologists. The goals of such programs (Table 1) years in probands, as compared with only 10%
include surveillance and early detection of pheo at the age of 70 years, with a lifetime disease
chromocytomas and paragangliomas and sur penetrance of 1.7% in mutation carriers who are
veillance for and management of associated non relatives of probands.73,85,86 Unlike SDHA muta
chromaffin tumors such as medullary thyroid tion penetrance, SDHB mutation penetrance is
carcinoma and primary hyperparathyroidism in similar in probands and relatives, at 22% by the
patients with MEN-2; hemangioblastomas of the age of 60 years, which also reflects lifetime pene
retina, cerebellum, and spine, along with renal- trance, whereas lifetime penetrance is 8% for
cell carcinomas and pancreatic neuroendocrine SDHC and 43% for SDHD by the age of 60 years.85,87
tumors, in patients with von Hippel–Lindau dis Penetrance estimations are pending for MAX,
ease; peripheral-nerve-sheath tumors and breast TMEM127, and SDHAF2 and for the newer genes.
cancer in patients with neurofibromatosis 1; and Postoperatively, asymptomatic patients should
GISTs, renal-cell carcinomas, and pituitary tu undergo annual biochemical testing and cross-
mors in patients with SDHx and MAX mutations. sectional digital imaging of the operated area
annually for at least 3 years. The intervals for
subsequent surveillance imaging remain open to
Te s t ing of R el at i v e s
a nd A s ymp t om at ic Ger ml ine- debate, but at most specialized centers, imaging
Mu tat ion C a r r ier s is performed every 2 to 3 years (Table 1). Special
guidelines are available for postoperative sur
All first-degree relatives of a mutation carrier veillance of patients with asymptomatic extra
should be offered predictive (or cascade) testing paraganglial tumors.59,60,88
in the context of genetic counseling. Testing of
relatives results in a 50% likelihood of identify Pr egna nc y in Pat ien t s
ing mutation carriers, who are typically asymp w i th Pheo chromo c y t om a
tomatic. These asymptomatic mutation carriers or Pa r ag a ngl iom a
should be offered clinical surveillance and man
agement specific to the gene (Table 1).22 The age Pheochromocytoma during pregnancy is regard
at onset and gene-specific, age-related pene ed as one of the great challenges in medicine. Of
trance guide management to look for pheochro paramount importance is interdisciplinary coop
mocytoma, paraganglioma, and nonchromaffin eration of obstetricians, endocrinologists, and
tumors in order to identify these neoplasms at surgeons. Pregnant patients have symptoms that
an early stage, when they are resectable. are similar to those in patients who are not
It is important that both patients and clini pregnant and may have had hypertension before
cians understand the concept of disease pene becoming pregnant. The tumors can become
trance. Some studies provide penetrance figures symptomatic in any period of gestation. The
that include all mutation carriers of a given diagnosis should be suspected clinically and
gene, whereas others provide only data subsets confirmed biochemically. For imaging, ultraso
for the clinical type of a syndrome such as MEN-2A nography and MRI without contrast material are
and MEN-2B, for asymptomatic carriers, or for recommended. Any nuclear medicine imaging is
specific gene mutations. Common features of all contraindicated. Pharmacologic treatment, most
susceptibility genes for pheochromocytoma or ly α-adrenergic blockade, is a challenge, since
paraganglioma are age dependency and incom uteroplacental circulation must be adequately
plete penetrance; thus, disease does not develop preserved. Endoscopic removal of the tumor is
in all carriers of gene mutations. For example, the option of choice and has been repeatedly
A
should be detected well before a pregnancy is
planned. In this context, molecular genetics is
an ideal tool. The proof of principle is shown in
Figure 3, which presents the case of an 18year
old woman who underwent resection of an asymp
tomatic paraganglioma after identification of a
germline VHL mutation and had an uneventful
pregnancy 5 years later.
B
C onclusions
More than 130 years have passed since the first
patient with documented pheochromocytoma was
described. The evolution in diagnosis and treat
ment has been dramatic. The clinical presentation
has evolved from classic symptoms of paroxys
mal hypertension, palpitations, and headaches
to the incidental discovery of an adrenal mass on
crosssectional imaging and detection of asymp
tomatic pheochromocytomas on the basis of
germlinemutation testing. The biochemical
C methods for case detection have become more
sensitive and specific. Effective tumor localiza
tion has been facilitated by advances in cross
sectional imaging with CT and MRI and in
functional imaging with 123IMIBG scintigraphy
or 68GaDOTATATEPETCT. The development of
minimally invasive surgical techniques has im
proved operative outcomes. Individualized treat
ment and tumor surveillance have been remark
ably advanced on the basis of the identification
of 19 genes in which germline mutations cause
pheochromocytoma or paraganglioma.
Figure 3. Presymptomatic Resection of a Juxta-Adrenal Paraganglioma These endocrine neoplasms are rare, and many
after Mutation Identification in an 18-Year-Old Woman. clinicians will never encounter them. Neverthe
The patient’s brother and father had pheochromocytoma. Genetic testing less, it is important for clinicians to remain
of the patient revealed germline mutation VHL c.298T→C. After the muta-
vigilant and to suspect, confirm, localize, and
tion was identified, the patient underwent VHL-informed MRI surveillance
for von Hippel–Lindau disease, which revealed the juxta-adrenal paragan- resect these tumors, because the associated
glioma. Five years later, the patient had an uneventful pregnancy and gave symptoms and hypertension are curable with
birth to a healthy child. In Panel A, MRI with gadolinium contrast medium surgical removal. If the tumor is not diagnosed
(axial plane) shows the tumor (arrow). In Panel B, PET (frontal view) shows and removed, there is a risk of lethal paroxysm
an 18F-L-DOPA–avid paraganglioma (arrow). Panel C shows the 1-cm scar
and cardiac disorders. These tumors have malig
(arrow) after endoscopy with single-incision access was used to remove the
tumor. nant potential, and early resection is the way to
prevent metastatic disease.
The evidence to date shows that more than
performed with good outcomes for mother and 40% of patients presenting with pheochromocy
child; the preferred timing is the second trimes toma or paraganglioma, irrespective of age at
ter of pregnancy.8991 An alternative approach is onset and family history, carry germline muta
medical management during pregnancy and re tions. Ideally, all persons presenting with these
section of the pheochromocytoma several weeks neoplasms should undergo genepanel testing in
after delivery. Ideally, however, such tumors the context of genetic counseling, so that pro
spective gene-specific management can be initi trast medium associated with current tumor-
ated proactively. If a patient is found to carry a surveillance strategies.
mutation, all first-degree relatives should be of No potential conflict of interest relevant to this article was
fered mutation-specific testing. Although gene- reported.
Disclosure forms provided by the authors are available with
informed surveillance, with early detection and the full text of this article at NEJM.org.
cure, is a triumph of gene-informed precision We thank Tobias Krauss, M.D., Juri Ruf, M.D., Stephan Meckel,
care, it would be much more desirable to provide M.D., and Martin Walz, M.D., for providing clinical, radiographic,
and histologic images; and Giuseppe Opocher, M.D., Francesca
a targeted preventive therapy in order to avoid Schiavi, Ph.D., and Birke Bausch, M.D., for providing genetic
the risks of cumulative radiation doses and con data presented graphically.
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