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Pheochromocytoma and Paraganglioma: Pearls
Pheochromocytoma and Paraganglioma: Pearls
Pheochromocytoma and Paraganglioma: Pearls
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series, 391
DOI 10.1007/978-1-84628-881-4_29, Springer-Verlag London Limited 2009
392
ENDOCRINE SURGERY
deaths in the USA annually were attributed to [14]. The hypotension further reduces their dia-
complications from pheochromocytomas [11]. stolic coronary blood flow immediately follow-
Of those whose diagnosis of pheochromocytoma ing a bolus of epinephrine or norepinephrine
was diagnosed on postmortem examination, thus exaggerating their risk of cardiovascular
three quarters of these deaths were secondary morbidity. The timing of the paroxysmal spells
to a sudden severe myocardial infarction or cer- varies greatly from cycling as frequently as
ebral vascular catastrophe. Tragically, one third every 715 min to daily or weekly episodes
of the sudden deaths occurred during or after [15]. These episodes may be initiated by nearly
unrelated minor operations [12]. any mechanism that applies pressure to the
tumor: increased intraabdominal pressure with
defecation, urination (particularly with para-
Clinical Presentation gangliomas of the urinary bladder), child birth,
vigorous physical exercise, sexual intercourse,
Pheochromocytomas typically occur in the or trauma. There are also chemical triggers to
fourth to fifth decade of life with a female pre- catecholamine release which may be stimulated
dominance. The majority, 8090% of pheochro- by glucagon administration or alcohol inges-
mocytomas, are thought to be sporadic in origin, tion. Importantly, patients may experience
with the remaining 1020% being associated severe or even lethal complications related to
with genetic disorders [13]. Each year as thou- paroxysmal spells brought about by invasive
sands of researchers study the genetic associa- procedures such as diagnostic needle biopsy,
tions of these tumors more genetic markers are angiography, general anesthesia, and unrelated
identified. As a result many of those initially surgical procedures [16]. Other symptoms that
thought to be sporadic may be reclassified patients may experience include nausea, lassi-
based on their genetic fingerprints in the years tude, heat intolerance, anxiety, abdominal pain,
to come. pallor, fever, or glucose intolerance.
Pheochromocytomas have been termed the
ten percent tumor since roughly 10% are
malignant, bilateral, multifocal, extra-adrenal, Diagnosis
inherited, incidentally discovered, and occur in
children. The diagnosis of a pheochromocytoma requires
The typical presentation is that of a wide the identification of the classic signs as well as
spectrum of symptoms due to catecholamine attention to clinical scenarios when hyperten-
excess with the overwhelming unifying symp- sion is unexplained, refractory, or otherwise
tom at presentation being refractory or severe seemingly out of place. Examples of these sce-
episodic hypertension. In addition most experi- narios include intermittent hypertension, espe-
ence paroxysmal spells that are characterized cially labile hypertension, pregnant patients
by the classic triad of headaches, palpitations, with new onset hypertension in the absence of
and extreme hypertension. Following these preeclampsia, hypertension in children or in
spells, patients may remain hypertensive and descendants of patients with pheochromocyto-
thus many are treated for years for presumed mas, or genetic endocrinopathies [17]. With the
essential hypertension. It may also be difficult increasing use of high-resolution imaging mod-
to obtain accurate blood pressure measure- alities more clinically silent adrenal lesions are
ments due to overwhelming peripheral vaso- identified. These patients should be screened
constriction and Raynauds type phenomenon. for pheochromocytoma since the incidence of
This profound increase in systemic vascular pheochromocytomas in a review of 42 inciden-
resistance combined with the direct adrenergic talomas at the University of California at San
effects on the heart may lead to myocardial Francisco was as high as 33% [18]. Suspicious
ischemia. This accounts for the increased inci- adrenal lesions should not be biopsied without
dence of sudden death in the patients identified confirmation of the absence of a pheochromo-
to have pheochromocytomas at postmortem cytoma to prevent a predictable severe compli-
examination [12]. Half of patients are normo- cation [16].
tensive between episodes and some patients Our initial study of choice to identify pheo-
have periods of hypotension following spells chromocytomas or paragangliomas is a 24-h
393
ENDOCRINE SURGERY
a b
Fig. 29.1. (A) An axial CT scan, demonstrating a 10-cm left pheochromocytoma with areas of central necrosis displacing the
pancreas and splenic vasculature anteriorly. (B) A coronal CT image of the same pheochromocytoma consuming the left upper
quadrant.
ENDOCRINE SURGERY
influence. With occlusion of the adrenal vein, the most port which is crucial to provide exposure
patient may rapidly vasodilate, requiring more of the retroperitoneum. The triangular ligament
vasopressor support and volume resuscitation. is divided to allow further medial rotation of the
In our experience however many patients do not liver and visualization of the peritoneum cover-
have this hemodynamic shift until the last see- ing the right adrenal and inferior vena cava
mingly insignificant venous attachments are (IVC). The peritoneum adherent to the liver
divided. edge is incised with the cautery and the superior
border of the adrenal gland is exposed. Simi-
larly, the peritoneum adjacent to the lateral edge
Operative Techniques of the IVC is incised. The dissection then pro-
ceeds progressively superiorly along the right
There are several surgical approaches for resec- side of the IVC to expose the short adrenal
tion of pheochromocytomas and paraganglio- vein which is isolated, clipped, and divided.
mas. A unifying feature of any surgical resection The remaining attachments are then divided
of a pheochromocytoma or paraganglioma is with electrocautery or a harmonic scalpel with
that physical manipulation of the tumor should careful attention to avoid violation of the cap-
be minimized to reduce the hemodynamic sule of the gland. Along the caudal most extent
swings that are present even in well-blocked of the gland there are predictable arterial
patients. It is also essential that the capsule of branches from the right renal artery and aorta
the tumor not be violated as this may lead to an which are typically best controlled with clips.
increased risk of local recurrence of otherwise The gland is then removed en bloc in a specimen
benign lesions. Lastly, any minimal access pro- bag and sent to pathology.
cedure should be terminated in favor of an open On the left side the trocars are placed simi-
exploration in cases of a difficult dissection, larly to the right; however, only three trocars
evidence of invasion, prohibitive adhesions, or may be necessary since the spleen does not
surgeon inexperience. require constant retraction when fully mobi-
lized. Exposure of the left adrenal gland begins
with mobilization of the splenic flexure of the
Anterior Transperitoneal colon and the division of the diaphragmatic
attachments of the spleen with electrocautery.
Laparoscopic Approach This allows for the development of a trough
between Gerotas fascia of the kidney and the
During the last 15 years, we have experienced a pancreas. As this exposure is further developed,
dramatic change in the approach to adrenalect- the medial aspect of the adrenal gland is visua-
omy with the advent of transperitoneal laparo- lized and often the left phrenic vein may be
scopic adrenalectomy. As its safety has been traced to its junction with the left adrenal vein.
demonstrated, its utility has been broadened The left adrenal vein arises from the left renal
from the first laparoscopic adrenalectomy for vein and is isolated, clipped, and divided. The
an aldosteronoma to the studies describing the phrenic vein may also be divided in a similar
utility of the laparoscopic approach for tumors fashion. The gland is then mobilized with elec-
up to 13 and even 15 cm [25]. The benefits of the trocautery or the harmonic scalpel. Similar to
laparoscopic approach have been well docu- the right adrenal gland the left adrenal gland
mented as in other abdominal procedures and also has predictable inferiorly based arterial
they include shorter hospital stay, decreased branches.
blood loss, decreased pain, smaller incisions,
and fewer complications [33].
The patients are positioned in a full lateral Anterior Open Approach
decubitus position with the side of the offending
gland up. A pneumoperitoneum is established. When patients have large tumors or a history of
On the right four trocars are placed along the multiple upper abdominal operations an open
right costal margin from the midline to the anterior adrenalectomy may be elected. On both
midaxillary line. A liver retractor (glass rod or the right and left we prefer a long subcostal
fan retractor) is placed through the medial incision. A mechanical retractor is utilized to
397
elevate the costal margin superiorly. On the right flexed to approximately 1008 and the knees are
the dissection proceeds very similarly to the bent 908. The position of the bed is then
description above for the laparoscopic approach. oriented such that the lower back is parallel to
However, further mobilization of the liver is the floor. A 1.5-cm incision is made at the tip of
required, and sometimes also a partial Kocher the twelfth rib. The fascia immediately inferior
maneuver to expose the IVC. The adrenal vein is to the tip of the twelfth rib is entered bluntly and
then exposed and controlled. The exposure of the the subfascial pocket is developed with finger
left adrenal gland may be obtained via either the dissection. A 5-mm trocar is placed with biman-
medial mobilization of the spleen as described ual direction 45 cm lateral to the initial inci-
above or more typically via entrance into the sion, which is near the tip of the eleventh rib.
lesser sac with cephalad retraction of the pan- Then a 10-mm trocar is placed 45 cm medial to
creas and spleen to expose the left adrenal gland the initial incision in a similar bimanual fash-
and its vascular attachments. ion. A 10-mm Hasson trocar is then placed in
the initial incision and a capnoretroperitoneum
is then established with a pressure between 20
Posterior and 28 mm Hg which does not cause hemody-
Retroperitoneoscopic namic embarrassment as would be expected
with a pneumoperitoneum at these pressures.
Approach After a retroperitoneal space is created beneath
the diaphragm with blunt dissection the upper
Although less common than the laparoscopic pole of the kidney is identified and is depressed
transperitoneal adrenalectomy, the posterior ret- with an instrument. It is occasionally necessary
roperitoneoscopic approach (PRA) is being per- to place a forth trocar to allow for the surgeon to
formed in more centers worldwide each year. It have two available trocars for dissection. On
provides the same benefits as the anterior laparo- both the right and the left the mobilization of
scopic approach in regard to small incisions, less the adrenal gland begins medially and caudally.
pain, less blood loss, and early return to normal On the right the vena cava is then exposed by
unrestricted activity. However, it extends a mini- division of the tiny arterial branches that cross
mal access option to those who otherwise have the posterior surface of the vena cava. The right
hostile peritoneal cavities from previous upper adrenal vein is then able to be visualized so that
abdominal surgery. Most surgeons have chosen it may be clipped and divided. The gland is then
the transperitoneal approach because of their detached from its remaining attachments with
familiarity with the anatomy. Walz and collea- clips applied to arterial branches that cannot be
gues have reported on the largest series to date controlled with cautery or the harmonic scalpel.
which included 560 adrenalectomies in 520 On the left side the superior pole of the left
patients. The mortality was zero. The open con- kidney is identified after identical endoscopic
version rate was 1.7% with a mean operative time retroperitoneal exposure. The dissection
of 67 min. Major complications occurred in 1.3% around the gland also begins medially and caud-
with minor complications in 14.4% [34]. Walz ally allowing the gland to be lifted posteriorly
and colleagues have also reported their experi- exposing the left adrenal vein which is clipped
ence resecting 161 pheochromocytomas or and divided. The venous stump is also able to be
paragangliomas via the retroperitoneoscopic used for retraction as the gland is lifted and its
approach in 126 patients. In 22 of 24 patients vascular attachments are divided. The gland
with bilateral disease cortical function was pre- with the associated tumor is removed en bloc
served [35]. In carefully selected patients this via a silastic bag and sent to pathology [3436].
may prove to be a better option when compared
to laparoscopic transperitoneal approach, but
this has not been elucidated in the literature. Postoperative Management
Patients are positioned in a prone position
with the chest, pubis, and iliac crests supported The hemodynamic parameters of the patient are
by thick gel pads to allow the abdomen to often very stable by the completion of the opera-
hang thus allowing the kidneys to drop out tion. Occasionally vasopressors and ongoing
of the operative field. The patients hips are volume resuscitation will be required for a few
398
ENDOCRINE SURGERY
hours as the effects of the alpha blockade wear ephedrine which were used in approximately
off in the absence of the catecholamine drive. It 30%, while sodium nitroprusside, which was
is reasonable for patients to be monitored in an commonly used in earlier years, was required in
intensive care unit for 24 h such that subtle less than 10% of cases. Throughout this time,
changes in hemodynamics may be recognized there has been a profound change from resecting
promptly and treated. If a minimal access the pheochromocytomas through an open ante-
approach was utilized they may often be dismissed rior approach, to a laparoscopic method. In fact,
48 h after tumor removal if their recovery has been in 2006, all of the pheochromocytomas were
uncomplicated. Two weeks postoperatively a 24-h resected laparoscopically. Overall, 62% of these
urine collection for metanephrines and catechola- tumors were removed via the anterior transper-
mines is obtained to assure that all disease was itoneal laparoscopic approach, 33% were
removed and to serve as a baseline. We recom- resected through an open anterior approach,
mend annual 24-h urine collection for at least and 5% were removed via an open posterior
5 years as metastatic disease may be latent approach.
5 years or longer. At Mayo Clinic, 48 abdominal paraganglio-
mas were removed between 1992 and 2006.
There was a slight female predominance of
Mayo Clinic Rochester 56% compared to 44% in men. The average
age was 13 years younger at 41 than the corre-
Experience sponding group with pheochromocytomas. Pre-
operative symptoms were present in 73% at
Between 1995 and 2006, 173 patients, 98 (57%) initial presentation. Hypertension, present in
women and 75 (43%) men, underwent resection 77%, was the most common presenting symp-
of pheochromocytomas. Their age ranged from tom. CT, MRI, and MIBG were found to have
16 to 86 with a mean age of 54. Associated con- sensitivities for detecting abdominal paragan-
ditions were present in 23 (13%) including 8 gliomas of 95, 100, and 85%, respectively. We
multiple endocrine neoplasia (MEN) 2A, 5 MEN continue to prefer an open, anterior surgical
2B, 6 VHL, and 4 with neurofibromatosis. Overall approach for paragangliomas owing to the
59 (36%) of tumors were initially identified as variability of the blood supply and difficulties
incidentalomas. CT was the most common ima- often encountered in tumor mobilization.
ging modality utilized with no false positives,
only 3 false-negative and 155 true-positive
scans. MRI was utilized in approximately half Pathology
with 1 false positive, 2 false negatives, and 70
true-positive studies. MIBG scanning was used Pheochromocytomas and paragangliomas arise
selectively in 29 cases with 1 false-negative and 1 from the cells of the adrenal medulla or along
false-positive scan. The average size of tumors the ganglia of the paramedian sympathetic
resected was 4.8 cm, range 0.716 cm. Preopera- plexus due to their derivation from embryolo-
tive blockade with phenoxybenzamine was used gical neural crests cells. Ninety percent of these
in 95% with the remaining blocked with calcium tumors arise within the adrenal medulla. The
channel blockers such as nicardipine. Intrao- most common location of paragangliomas is
peratively, despite preoperative pharmacologic the organ of Zuckerkandl, at the aortic bifurca-
preparation, 80% of patients required vasoactive tion [37]. These tumors are collectively classi-
medications to maintain appropriate hemody- fied as chromaffin tumors due to their origin
namics. The average maximum systolic blood and staining characteristics [38]. They appear as
pressure was 192 with a maximum of 310, and dark purple tumors due to their rich blood sup-
the average minimum systolic blood pressure ply and may have cystic characteristics on their
was 84 with a nadir of 31. The most common surface due to underlying tumor necrosis
intraoperative agents used to control the (Fig. 29.4). In the setting of previous adrenal
patients hemodynamic parameters have evolved hemorrhage one may find a dense inflammatory
to the short-acting agents esmolol and pheny- rind surrounding the tumor or atypical adhe-
lephrine which were both used in just over 50% sions to surrounding organs from the resorbed
of cases. These were followed by labetalol and blood products. They typically range from 2 to
399
Pheochromocytoma
in Pregnancy
Fig. 29.4. Bivalved gross pathology photograph of 10 cm left
adrenal pheochromocytoma demonstrating the soft grey fish Hypertension during pregnancy may arise from
flesh appearance of the tumor with normal cortex and a variety of causes but, in contrast to pheochro-
medulla at the left of the image. mocytomas in pregnancy, few carry a mortality
rate of 40% to the mother with up to a 56% fetal
death rate [44]. The presentation during preg-
8 cm and weigh between 50 and 200 g. However nancy is similar to that described earlier with
both extremes are documented from the smal- the addition of supine hypertension as the
lest at 50 mg and less than a centimeter in gravid uterus compresses the tumor in the
incidentally identified tumors to nearly 6 kg in recumbent position. Thus, the typical lithotomy
a rare case of a 30-cm pheochromocytoma [39]. position during vaginal delivery would poten-
In sporadic cases the tumors are round or oval tially provide maximal compression of the
with occasional lobules despite the fact that they tumor. Additionally, the increased abdominal
arise as a single neoplasm. In the absence of pressure during labor may lead to massive cate-
malignant transformation these tumors tend to cholamine release with life-threatening compli-
have pushing rather than invading borders, cations [45]. The overwhelming majority of
and there is typically a plane separating sur- patients with hypertension during pregnancy
rounding structures visible on high-resolution will not be due to pheochromocytomas but
cross-sectional imaging. In contrast, 40% of instead be attributed to preexisting secondary
hereditary tumors are multiple either in the hypertension or preeclampsia. Preeclampsia is
same gland or bilaterally [40, 41]. In MEN 2 associated with sustained hypertension accom-
there is a hyperplastic change of the adrenal panied by proteinuria and is cured with deliv-
medulla that is akin to the precursor C-cell ery. Hypertensive pregnant patients should also
hyperplasia preceding medullary thyroid can- be evaluated with serum electrolytes, glucose,
cer, but malignancy of pheochromocytomas in creatinine, blood urea nitrogen, and urinalysis
MEN 2 is rare [42]. and culture to evaluate for secondary causes of
Malignancy of either pheochromocytomas or hypertension such as renal disease, diabetes,
paragangliomas is definitively diagnosed by and chronic pyelonephritis. When these studies
recurrence, local invasion, or distant metastasis are unrevealing and when hypertension is
(Fig. 29.5). Discriminating benign from malig- severe, positional or unexplained biochemical
nant on histologic evaluation has not generally screening for a pheochromocytoma should be
been thought to be reliable. Kimura et al. have performed with a 24-h urine collection for frac-
reported on a unique scoring system which tionated metanephrines and catecholamines.
assigns one or two points to the following cri- Once the diagnosis is confirmed pregnant
teria: (1) histologic pattern, (2) cellularity, (3) patients should be blocked. Blockade begins as
coagulation necrosis, (4) vascular or capsular described above with titration of an alpha
invasion, (5) Ki-67 immunoreactivity, and (6) blocker such as phenoxybenzamine followed
types of catecholamines produced. Specimens by the addition of a beta blocker as indicated
400
ENDOCRINE SURGERY
a b
a b
Fig. 29.5. (A) T2-weighted axial MRI of a paraganglioma displacing the right renal vascular pedicle anteriorly. (B) A T2-weighted
coronal MRI of the same paraganglioma compressing the inferior vena cava. (C) Intraoperative photograph of the above imaged
right paraganglioma which was displacing the right renal vein (RV) and inferior vena cava (IVC) anteriorly. (D) Intraoperative
photograph with the right kidney mobilized anteriorly to expose the retrocaval right-sided paraganglioma.
for tachycardia [45]. MRI is the best imaging during pregnancy. These tumors are rarely iden-
choice as it avoids the potential fetal risk of tified during the first trimester as there is not
radiation with CT or I-123 MIBG. sufficient uterine volume to compress the
The timing of surgery must account for the tumor. It is discouraged to perform any major
gestational age as with any abdominal procedure abdominal procedure during this time as it is the
401
highest risk period for miscarriage with any than 10% affected with pheochromocytomas.
major abdominal procedure. Although the sec- Overall 40% of those with MEN 2 will have a
ond trimester is the safest period during which pheochromocytoma [49].
most urgent procedures are performed, blockade Once the biochemical diagnosis of a hyper-
with meticulous follow-up from the twenty- secretory chromaffin tumor is identified in a
fourth week on until a safe gestational age for patient with confirmed MEN 2 syndrome bilat-
delivery is advised. At the time of delivery a eral adrenal hyperplasia is certain [50]. This
Cesarian section and combined tumor excision hyperplasia is a precursor to tumor develop-
is recommended [45]. In one report following ment but the time course of this is variable
appropriate blockade an uneventful Cesarian [42]. There is a controversy regarding extent of
section was followed 2 weeks later by a laparo- adrenalectomy in these scenarios. In one series
scopic adrenalectomy [46]. acute Addisonian crisis developed in 23% of
patients following bilateral adrenalectomy
[51]. In another report, at least 50% of patients
did not require contralateral adrenalectomy
Pheochromocytoma within 5 years and no episodes of acute hyper-
in Children tensive crisis developed following unilateral
adrenalectomy [52]. Therefore, it has become
Pheochromocytomas cause 1% of hypertension clear over time that initial bilateral adrenalect-
in children [47]. During 40 years at a referral omy for patients with MEN 2 should be avoided
center for pheochromocytomas 58 patients were due to the potential severe consequences. Our
treated between the ages of 4 and 20 with 48% current practice is to perform a unilateral adre-
being associated with a known genetic syndrome nalectomy with close follow-up, delaying the
[48]. The presentation in children is similar with contralateral adrenalectomy until the patient is
the exception that the hypertension is more often symptomatic and the tumor is visibile by cross-
sustained. The diagnosis is confirmed just as sectional imaging. This is due to the report of
described in adults and imaging follows with 33% of MEN 2 patients developing a contralat-
CT, MRI, or MIBG scans. When localizing these eral pheochromocytoma within 5 years and only
tumors it must be considered that more tumors 52% within 12 years. Overall the average length
are bilateral and extra-adrenal due to the of time to the development of a contralateral
increased proportion of hereditary syndromes pheochromocytoma in MEN 2 following unilat-
in children. However, it is encouraging that eral adrenalectomy is 13 years. Cortical sparring
malignancy is identified less frequently than in adrenalectomy has been increasingly performed
the cases of hereditary chromaffin tumors in for hereditary pheochromocytomas with the
adults. largest series of 59 patients reported from the
MD Anderson experience between 1962 and
2003 [52].
Genetic Syndromes
Von Hippel Lindau Disease
MEN Type 2 Syndrome
Von Hippel Lindau disease (VHL) is an auto-
MEN type 2 (MEN 2) syndrome is linked in somal dominant syndrome characterized by a
nearly all cases to mutations in the ret proto- predisposition to tumors of the central nervous
oncogene and is characterized by medullary system, kidneys, pancreas, adrenal glands,
thyroid carcinoma, pheochromocytomas, pri- and sympathetic ganglia. The occurrence of
mary hyperparathyroidism, and mucocuta- pheochromocytomas varies among kindreds
neous neuromas [13]. In contrast to medullary between 7 and 20% [53, 54]. In our experience
thyroid carcinoma which is present in nearly from 1975 to 2000, 109 patients with VHL were
100% of those with this autosomal dominant evaluated and 17 (16%) were found to have
syndrome, pheochromocytomas have a variable adrenal masses or paragangliomas. The ages
penetrance. In some kindreds 100% may be ranged from 16 to 47 years with an average of
affected while other families may have less 30 years. The majority, 60%, were asymptomatic
402
ENDOCRINE SURGERY
and 83% of tumors were identified by CT fol- are exclusively found in head and neck tumors
lowing biochemical evaluation. Only 2 of 17 and are rare, less than 4% of tumors. They are
underwent bilateral total adrenalectomy result- nonfunctioning, single, and benign in nearly
ing in life-long corticosteroid replacement. every case.
There were no deaths or recurrences with a
mean follow-up of 6.8 years (range 3 months
to 37 years) [55].
Associated Conditions
In addition to the conditions described above
Succinated Dehydrogenase pheochromocytomas also develop in associa-
tion with the neuroectodermal disorders of
Mutations (SDHB, SDHC, SDHD) von Recklinghausens neurofibromatosis, Stur-
geWeber syndrome, tuberous sclerosis, and
In 2002 Neumann and colleagues of the Frei-
Carneys syndrome. Carneys syndrome was
bergWarsawColumbus Pheochromocytoma
Study Group reported on the genetic evalua- described in 1977 by Dr. Aidan Carney and in
his 1999 review of his experience combined with
tions of 271 unrelated patients with nonsyndro-
the world literature he reported on 79 patients
mic pheochromocytomas who had no family
history of the disease [56]. They identified with a combination of gastric epithelioid leio-
myosarcoma, pulmonary chondroma, and para-
genetic mutations known to be associated with
gangliomas. Among this group 10% had func-
chromaffin tumors in 66 (24%). The mutations
tional paragangliomas [5759].
identified were 66% VHL, 35% SDH, and 20%
RET. The mutations in the SDH (mitochondrial
complex II) occur in the B, C, and D subunits.
Patients with mutations in the C subunits are Summary
identified only in head and neck paraganglio-
mas such as carotid body glomus tumors The classic triad of headaches, sweating, and
whereas the B and D subunits are additionally hypertension should raise the suspicion of any
associated with paragangliomas and pheochro- clinician caring for a patient with what may be a
mocytomas. The risk factors associated with the life-threatening pheochromocytoma. With the
presence of one of these mutations was young increased use of high-resolution imaging these
age at presentation and the presence of multi- tumors are being identified more frequently
focal or extra-adrenal tumors. Of the 23 SDH before they are symptomatic and while they
mutations 12 were SDHB and 11 were SDHD. are small enough for laparoscopic or retroper-
None of these 23 had glomus tumors at presen- itoneoscopic resection. The evaluation is based
tation but 4 (17%) were found to have them on the cornerstone of 24-h urine total metane-
identified during follow-up. Since nearly one phrines and catecholamines. However, the
quarter of these seemingly sporadic pheochro- increased sensitivity of plasma fractionated
mocytomas were identified to have germ-line metanephrines and catecholamines now pro-
mutations this has led us to pursue genetic test- vides for a more convenient screening tool as
ing in a stepwise fashion to better identify patients are followed for life. It remains almost
patients who need more specific screening and impossible for the pathologist to differentiate
follow-up [56]. In general, the median age of the 90% of benign from the 10% which are
initial diagnosis for SDH mutations is 30, and malignant in the absence of local invasion or
by age 40, the likelihood of an SDHB or SDHD distant metastasis. As more genetic associations
mutation has been 45 and 75%, respectively. with these tumors are identified the routine
Tumors with SDHB mutations are likely to be follow-up will clearly be broadened for those
extra-adrenal in 60%, malignant in 3040%, and carrying the mutations discussed above, and
multiple in 10%. This compares to SDHD hopefully this will lead to earlier treatment of
tumors of which 90% occur in the head and the conditions associated with these tumors to
neck, 20% are extra-adrenal, 30% are multiple, extend the lives of those affected. Modern pre-
and 10% are malignant. SDHD mutations carry operative blockade and careful anesthetic man-
maternal imprinting thus only paternal trans- agement currently provides intraoperative sta-
mission leads to clinical effect. SDHC mutations bility to allow for resection via laparoscopic or
403
retroperitoneoscopic routes. With the resection 19. Sawka AM, Jaeschke R, Singh RJ, Young WF, A compar-
of these tumors the adrenergic symptoms are ison of biochemical tests for pheochromocytoma;
measurement of fractionated plasma metanephrines com-
cured and the life-threatening complications of pared with the combination of 24-hour urinary metane-
extreme catecholamine surges are meticulously phrines and catecholamines. J Clin Endocrinol Metab.
prevented. 2003;88:553.
20. Young WF, Kaplan NM. Clinical presentation and diag-
nosis of pheochromocytoma. UpToDate. 2007;15.2:120
21. Eisenhofer G, Goldstein DS, Walther MM, Friberg P,
References Lenders JWM, Keiser HR, Pacak K. Biochemical diag-
nosis of pheochromocytoma: how to distinguish true-
1. Frankel F. Ein fall von doppelseitigen vollig latent ver- from false-positive test results. J Clin Endocrinol Metab.
laufen nebennierentumor und gleichseitiger nephritis 2003;88:265666.
mit veranderungen am circulation sappart und retinitis. 22. Sawka AM, Prebtani AP, Thabane L et al. A systematic
Virchows Arch A. 1886;103:244. review of the literature examining the diagnostic effi-
2. Mayo CH, Paroxysmal hypertension with tumor of ret- cacy of measurement of fractionated plasma free meta-
roperitoneal nerve. J Am Med Assoc. 1927;89:1047. nephrines in the biochemical diagnosis of pheochromo-
3. Welbourne RB. Early surgical history of phaechromo- cytoma. BMC Endocr Disord. 2004;4:2.
cytoma. Br J Surg. 1987;74:594. 23. Lenders J, Pacak K, Walther M, et al. Biochemical diag-
4. Graham JB. Pheochromocytoma and hypertension. An nosis of pheochromocytoma: Which test is best? JAMA.
analysis of 207 cases. Int Abstr Surg. 1951;92:105. 2002;287:1427.
5. Kvale WF, Roth GM, Manger WM, Priestley JT. Pheo- 24. Young WF. Phaeochromocytoma: How to catch a moon-
chromocytoma. Circulation. 1956;14:622. beam in your hand. Eur J Endocrinol. 1997;136:28.
6. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeo- 25. Shen WT, Sturgeon C, Clark OH, Duh QY, Kebebew E.
chromocytoma. Lancet. 2005 Aug 2026;366(9486): Should pheochromocytoma size influence surgical
66575. approach? A comparison of 90 malignant and 60 benign
7. Meijer WG, Copray SC, Hollema H, Kema IP, Zwart N, pheochromocytomas. Surgery. 2004 Dec;136(6):1129-37.
Mantingh-Otter I, Links TP, Willemse PH, de Vries EG. 26. Bravo EL, Evolving concepts in the pathophysiology,
Catecholamine-synthesizing enzymes in carcinoid diagnosis, and treatment of pheochromocytoma.
tumors and pheochromocytomas. Clin Chem. 2003 Endocr Rev. 1994;15:356.
Apr;49(4):58693. 27. Bessell-Browne R, OMalley ME. CT of pheochromocy-
8. Stenstrom G, Svardsudd K. Pheochromocytoma in Swe- toma and paraganglioma: risk of adverse events with i.v.
den 19581981. An analysis of the National Cancer Reg- administration of nonionic contrast material. AJR Am J
istry Data. Acta Med Scand. 1986;220:225. Roentgenol. 2007 Apr;188(4):970-4.
9. Sheps SG, Jiang N-S, Klee GG. Diagnostic evaluation of 28. Qiao HS, Feng XL, Yong L, Yong Z, Lian ZJ, Ling LB. The
pheochromocytoma. Endocrine Metab Clin North Am. MRI of extraadrenal pheochromocytoma in the abdom-
1988;17:397 inal cavity. Eur J Radiol. 2007 Jun;62(3):335-41.
10. Pederson LC, Lee JE. Pheochromocytoma. Curr Treat 29. Lumachi F, Tregnaghi A, Zucchetta P, Cristina Marzola
Options Oncol. 2003 Aug;4(4):32937. M, Cecchin D, Grassetto G, Bui F. Sensitivity and posi-
11. Graham JB. Phaeochromocytoma and hypertension. Int tive predictive value of CT, MRI and 123I-MIBG scinti-
Abstr Surg. 1951;92:105. graphy in localizing pheochromocytomas: a prospective
12. St. John Sutton MG, Sheps SG, Lie JT. Prevalence of study. Nucl Med Commun. 2006 Jul;27(7):5837.
clinically unsuspected pheochromocytoma. Review of 30. van der Horst-Schrivers AN, Kerstens MN, Wolffenbuttel
a 50-year autopsy series. Mayo Clin Proc. 1981;56:354. BH. Preoperative pharmacological management of
13. Mittendorf EA, Evans DB, Lee JE, Perrier ND. Pheochro- phaeochromocytoma. Neth J Med. 2006 Sep;64(8):2905.
mocytoma: advances in genetics, diagnosis, localization, 31. Proye C, Thevenin D, Cecat P, et al. Exclusive use of
and treatment. Hematol Oncol Clin North Am. 2007 calcium channel blockers in preoperative and intrao-
Jun;21(3):50925. perative control of phaeochromocytomas: hemody-
14. Baxter MA, Hunter P, Thompson GR, London DR. namics and free catecholamine assays in ten consecutive
Phaeochromocytomas as a cause of hypotension. Clin patients. Surgery. 1989;106:114954.
Endocrinol (Oxf) 1992;37:304. 32. Engelman K, Jequier E, Udenfriend S, Sjoerdsma A.
15. Ganguly A, Grim CE, Weinberger MH, Henry DP. Rapid Metabolism of alpha-methyltyrosine in man: relation-
cyclic fluctuations of blood pressure associated with an ship to its potency as an inhibitor of catecholamine
adrenal pheochromocytoma. Hypertension. 1984;6:281. biosynthesis. J Clin Invest. 1968;47:56876.
16. McCorkell SJ, Niles NL. Fine-needle aspiration of cate- 33. Jaroszewski DE, Tessier DJ, Schlinkert RT, Grant CS,
cholamine producing adrenal masses: A possibly fatal Thompson GB, van Heerden JA, Farley DR, Smith SL,
mistake. AJR Am J Roentgenol. 1985;145:113. Hinder RA. Laparoscopic adrenalectomy for pheochro-
17. Young WF, Maddox DE. Spells: in search of a cause. mocytoma. Mayo Clin Proc. 2003 Dec;78(12):15014.
Mayo Clin Proc. 1995;70:757. 34. Walz MK, Alesina PF, Wenger FA, Deligiannis A, Szuc-
18. Lee JA, Zarnegar R, Shen WT, Kebebew E, Clark OH, zik E, Petersenn S, Ommer A, Groeben H, Peitgen K,
Duh QY. Adrenal incidentaloma, borderline elevations Janssen OE, Philipp T, Neumann HP, Schmid KW,
of urine or plasma metanephrine levels, and the sub- Mann K. Posterior retroperitoneoscopic adrenalect-
clinical pheochromocytoma. Arch Surg. 2007 omy-results of 560 procedures in 520 patients. Surgery.
Sep;142(9):8703. 2006 Dec;140(6):9438.
404
ENDOCRINE SURGERY
35. Walz MK, Alesina PF, Wenger FA, Koch JA, Neumann 48. Barontini M, Levin G, Sanso G. Characteristics of pheo-
HP, Petersenn S, Schmid KW, Mann K. Laparoscopic chromocytoma in a 4- to 20-year-old population. Ann
and retroperitoneoscopic treatment of pheochromocy- NY Acad Sci. 2006 Aug;1073:307.
tomas and retroperitoneal paragangliomas: results of 49. Howe JR, Norton JA, Wells SA. Prevalence of pheochro-
161 tumors in 126 patients. World J Surg. 2006 mocytoma and hyperparathyroidism in multiple endo-
May;30(5):899908. crine neoplasia type 2A: Results of long-term follow-up.
36. Walz MK, Peitgen K, Hoermann R, Giebler RM, Mann K, Surgery. 1993;114:1070.
Eigler FW. Posterior retroperitoneoscopy as a new mini- 50. Webb TA, Sheps SG, Carney JA. Differences between
mally invasive approach for adrenalectomy: results of 30 sporadic pheochromocytoma and pheochromocytoma
adrenalectomies in 27 patients. World J Surg. 1996 in multiple endocrine neoplasia, type 2. Am J Surg
Sep;20(7):76974. Pathol. 1980;4:121.
37. Young WF Jr. Paragangliomas: clinical overview. Ann 51. Tibblin S, Dymling J-F, Ingemansson S, Telenius-Berg
NY Acad Sci. 2006 Aug;1073:219. M. Unilateral versus bilateral adrenalectomy in multiple
38. Lack EE. 2000. Tumours of adrenal and extra-adrenal endocrine neoplasia IIA. World J Surg. 1983;7:201.
paraganglia. In: Solae E, Kloppel G, Sobin LH, editors. 52. Yip L, Lee JE, Shapiro SE, Waguespack SG, Sherman SI,
Histological Typing of Endocrine Tumors, 2nd. ed. Ber- Hoff AO, Gagel RF, Arens JF, Evans DB. Surgical man-
lin: Springer. 3848. agement of hereditary pheochromocytoma. J Am Coll
39. Kondo T, Ito F, Kihara T, Nakamura R, Goya N, Naka- Surg. 2004 Apr;198(4):52534.
zawa H, Toma H. A case of massive adrenal malignant 53. Maher ER, Yates JR, Harries R, et al. Clinical features
pheochromocytoma: management of a large pheochro- and natural history of von Hippel-Lindau disease. Q J
mocytoma. Hinyokika Kiyo. 1995 Sep;41(9):66973. Med. 1990;77:11511163.
40. Orchard T, Grant CS, van Heerden JA, Weaver A. 54. Lamiell JM, Salazar FG, Hsia YE. Von Hippel-Lindau
Pheochromocytoma Continuing evolution of surgical disease affecting 43 members of a single kindred. Med-
therapy. Surgery. 1993;114:1153. icine (Baltimore). 1989;68:129.
41. van Heerden JA, Sheps SG, Hamberger B, et al. Pheo- 55. Baghai M, Thompson GB, Young WF Jr, Grant CS,
chromocytoma: Current status and changing trends. Michels VV, van Heerden JA. Pheochromocytomas
Surgery. 1982;91:367. and paragangliomas in von Hippel-Lindau disease: a
42. Califano D, DAlessio A, Colucci-DAmato GL, De Vita role for laparoscopic and cortical-sparing surgery.
G, Monaco C, Santelli G, Di Fiore PP, Vecchio G, Fusco Arch Surg. 2002 Jun;137(6):6828.
A, Santoro M, de Franciscis V. A potential pathogenetic 56. Neumann HP, Bausch B, McWhinney SR, Bender BU,
mechanism for multiple endocrine neoplasia type 2 syn- Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C,
dromes involves ret-induced impairment of terminal Zerres K, Januszewicz A, Eng C, Smith WM, Munk R,
differentiation of neuroepithelial cells. Proc Natl Acad Manz T, Glaesker S, Apel TW, Treier M, Reineke M,
Sci USA. 1996 Jul 23;93(15):79337. Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke
43. Kimura N, Wananabe T, Noshiro T, Soichiro S, Miura Y. A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska
Histological grading of adrenal and extra-adrenal pheo- M, Szmigielski C, Eng C; Freiburg-Warsaw-Columbus
chromocytomas and relationship to prognosis: A Pheochromocytoma Study Group. Germ-line mutations
clinicopathological analysis of 116 adrenal pheochro- in nonsyndromic pheochromocytoma. N Engl J Med.
mocytomas and 30 extra-adrenal sympathetic paragan- 2002 May 9;346(19):145966.
gliomas including 38 malignant tumors. Endo Patho. 57. Carney JA, Sheps SG, Go VLW, et al. The triad of gastric
2005;16(1):2332. leiomyosarcoma, functioning extra-adrenal paragan-
44. Schenker JG, Granat M. Pheochromocytoma and preg- glioma, and pulmonary chondroma. N Engl J Med.
nancy An updated appraisal. Aust NZ J Obster Gynae- 1977;296:15171519.
col. 1982;22:1. 58. Carney JA. The triad of gastric leiomyosarcoma, func-
45. Freier DT, Thompson NW. Pheochromocytoma and preg- tioning pulmonary chondroma, and extra-adrenal
nancy: The epitome of high risk. Surgery. 1993;114:1148. paraganglioma: a five-year review. Medicine. 1983;62:
46. Dugas G, Fuller J, Singh S, Watson J. Obstetrical and 159169.
pediatric anesthesia: Pheochromocytoma and preg- 59. Carney JA. Gastric stromal sarcoma, pulmonary chon-
nancy: A case report and review of anesthetic manage- droma, and extra-adrenal paraganglioma (Carneys
ment. Can J Anesth. 2004;51:134. triad): natural history, adrenocortical component, and
47. Ciftci, A.O. et al. Pheochromocytoma in children. possible familial occurrence. Mayo Clin Proc. 1999;
J Pediatr Surg. 2001;36:447452. 74:543552.