clinical analysis of pheochromocytoma / paraganglioma in southern

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Vol. 20, No. 3, 2006
CLINICAL ANALYSIS OF PHEOCHROMOCYTOMA / PARAGANGLIOMA
IN SOUTHERN TAIWAN
Kuo-Ching Huang, Ming-Cheng Wang*, An-Bang Wu*, Feng-Hwa Lu*, Chin-Chung Tseng*, Jeng-Jong Huang*
Pheochromocytoma, albeit rare, is an important cause of secondary hypertension. Although potentially
curable, it can be lethal if it goes unrecognized. We reviewed the medical charts of 145 patients with ICD-9
coded as adrenal tumors from 1988 to 2004. A total of 140 patients were enrolled in this study. Eighteen
patients had pheochromocytoma, and five patients had paraganglioma. Among these 23 pheochromocytoma/
paraganglioma patients, 13 cases had hypertension. A total of 12 received an operation and had no intraoperative mortality. Eleven patients became normotensive after operation. The other one, who was concomitant
with diabetic nephropathy and chronic renal insufficiency, had persistent hypertension after operation and
progressed to end-stage renal disease. Urinary levels of vanillylmandelic acid (VMA) were checked in 14
patients. Comparing the estimated tumor sizes with the urinary levels of VMA, larger masses had higher VMA
levels (r=0.5668, P=0.0434). The pheochromocytoma/paraganglioma had the variable clinical presentations
and was a nearly curable hypertensive disease. Also, the urinary levels of VMA correlated with estimated
tumor sizes. (Acta Nephrologica 2006; 20: 166-174)
Key words: Adrenal tumor, pheochromocytoma, paraganglioma, hypertension, vanillylmandelic acid (VMA),
adrenalectomy
INTRODUCTION
Pheochromocytoma is a rare tumor and as an important cause of secondary hypertension, which may be curable after proper diagnosis and adequate treatment, but
can be lethal if not recognized. Although the true prevalence of pheochromocytoma is uncertain, it can be estimated as 0.1% to 0.5% of patients with hypertension.1,2
Pheochromocytomas derive from chromaffin cells of the
sympathetic nervous system, and it turns a dusky color
when treated with chromium salts. Although most of
the tumors are located at the adrenal glands, about 10%
of these chromaffin tumors are located at extra-adrenal
area and are often referred to as paragangliomas or chemodectomas.1 In order to realize clinical presentations
of this rare tumor in Southern Taiwan, we retrospectively analyzed the clinical features of 23 patients with
pheochromocytoma/paragangliomas in our hospital
from 1988 to 2004. Also, we surveyed the relationship
between the tumor sizes and levels of urinary VMA. In
addition, we reviewed the literature about pheochromocytoma/paraganglioma and described our cases and
other adrenal tumors.
MATERIALS AND METHODS
Patients
From October 1988 to September 2004, there were
151 patients with ICD-9 coded as adrenal tumors at National Cheng Kung University Hospital, Tainan, Taiwan,
and detailed medical charts of 145 patients were reviewed. Among these patients, five cases were suspected
to have pheochromocytoma by clinical pictures, but
could not be confirmed by laboratory data and/or imaging studies, and were excluded from our study. Totally,
140 patients with adrenal tumor were enrolled into our
study. Among those cases, 23 patients were diagnosed as
pheochromocytoma/paraganglioma. The diagnosis of 21
patients was proved by pathology, and the other two patients were proved by clinical diagnosis including clini-
Department of Internal Medicine, Chi-Mei Foundation Hospital, Liou-Ying, Tainan county; and Departments of *Internal Medicine,
and Family Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
Received: November, 2005 Revised: December, 2005
Accepted: June, 2006
Address reprint requests to Dr. Jeng-Jong Huang, Division of Nephrology, Department of Internal Medicine, National Cheng Kung
University Hospital, 138 Sheng-Li Rd, Tainan, 70428, Taiwan
Tel: +886-6-2766138
Fax: +886-6-2766175
E-mail: [email protected]
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Clinical analysis of pheochromocytoma/paraganglioma
cal presentations, imaging findings and increased VMA
levels, although there was no pathologic proof. Imaging studies and laboratory examinations
By clinical suspicion and physicians’ decisions, various imaging studies and laboratory examinations were
arranged as follows.
Patients with probable pheochromocytoma/paraganglioma received abdominal ultrasonography (echo), computed tomography (CT scan) (Fig. 1, 2 & 3; Cases 4, 6 &
14), and/or 131Iodine-metaiodobenzylguanidine (MIBG)
radionuclide scan. And urinary levels of vanillylmandelic acid (VMA) were collected in most of these patients. In the patients with probable aldosterone-secreting
tumors of adrenal cortex, CT scan and/or 131Iodine-6beta- iodomethyl-59-nor-cholesterol (NP59) scan were
arranged. In addition, all specimen or samples were analyzed at the Department of Pathology, National Cheng
Kung University Hospital, Tainan, Taiwan.
To explore the relationship between the tumor sizes
and levels of urinary VMA, we assumed that these tumors were olive shape and calculated estimated tumor
size by 4/3×π×(length×width×height/8).
Statistical Analysis
The correlation between the estimated tumor sizes
167
and urinary VMA levels was analyzed by regression. ANOVA was performed to compare the urinary VMA
levels with hypertensive patterns. Statistical significance was assumed at p < 0.05.
RESULTS
I. pheochromocytoma/paraganglioma
Clinical Features (Variable presentations of pheochromocytoma and paraganglioma):
Eighteen patients were diagnosed as pheochromocytoma, and the male to female ratio was 9:9. Sixteen
cases were diagnosed by pathological proof and the
other two were diagnosed by clinical presentations, imaging studies, and elevated urinary VMA levels. Also,
five patients were diagnosed as paraganglioma (Fig. 1,
Case 4), and the male to female ratio was 2:3 (Table 2).
The mean age was 46.0±13.6 years old (ranged from 22
to 68 years old) at diagnosis. Among these 23 patients,
two patients (8.7%) were diagnosed to have malignant
pheochromocytoma with multiple metastasis (Fig. 3,
Case 6). Three patients (13.0%) were diagnosed as multiple endocrine neoplasia (MEN) type II (Cases 8-10),
and two of them had small hyperplastic nodules (i.e. less
than 1 cm).
One case of the bladder paraganglioma initially
Fig. 1. (Case 4) Enhanced CT scan showed a right paraganglioma in aorticosympathetic
area (arrows) in a 36 year-old male.
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K. C. HUANG, M. C. WANG, A. B. WU, F. H. LU, C. C. TSENG, J. J. HUANG
Vol. 20, No. 3, 2006
Fig. 2. (Case 14) Enhanced computed tomography showed left pheochromocytoma (arrows) in a 40
year-old female.
Fig. 3. (Case 6) Enhanced CT scan showed a left huge pheochromocytoma (black arrows) with central
necrosis and multiple liver metastasis (white arrows) in a 55 year-old male.
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169
Table 1. Characteristics of 136 patients with adrenal tumors in National Cheng Kung University Hospital
Neuroblastoma
Adrenal
Meta
Number
(n = 9)
(n = 55)
Age, ranged
1.5–117 m
Sites (R/L/Bil.)
5/4/0
Male/female
Mean age
7/2
31 m
AldosteroneCortisol-secreting Pheochromoproducing cortical
Paraganglioma*
cortical adenoma
cytoma*
adenoma
(n = 42)
(n = 7)
( n = 18)
( n = 5)
32–84 yr
22-68 yr
19 m-45 yr
22-68 yr
36-68 yr
26/23/6
20/22/0
4/3/0
9/6/3
2/3
38/17
53.5 yr
11/31
43.6 yr
0/7
24.8 yr
11/12
46.3 yr
2/3
46 yr
Adrenal meta: adrenal metastastasis; R: right, L: left, Bil.: bilateral.
Note. Two female with adrenal cortical adenocarcinoma, one with adrenal lymphoma, and one with adrenal myolipoma
(a total of 4 cases) were not presented in this Table.
presented with painless gross hematuria, but he was attacked by sudden increase of blood pressure during cystoscopic examination (Case 1). Another case of bladder
paraganglioma with hypertension suffered from sigmoid
cancer with bleeding, and her bladder tumor (paraganlioma) was confirmed during a cancer operation (Case
2). One case of left carotid body paraganglima initially
presented with palpable neck mass (Case 3). Two cases
of intra-abdominal pargaglioma were thought to have a
hepatic tumor in abdominal ultrasonography (Case 4 and
5).
About initial presentations, Case 21 with paroxysmal hypertension initially presented with anxiety and
was treated as anxiety for one year. Later, she was found
to have fluctuating high blood pressure. Concomitant
primary megaureter and pheochromocytoma were diagnosed after survey (Table 2).3 A 36-year-old male patient
with two years of hypertension history had symptoms
mimicking myocardial infarction when he was sent to
our Emergency Room (Case 22).4 Case 23 was referred
to our Outpatient Department for hypertension, increased urinary VMA levels, and adrenal mass proven
by angiography. One month later, she was sent to our
Emergency Room with death on arrival.5
In imaging study, twelve (85.7%) of 14 patient receiving examination of CT scan had positive findings. In addition, seven (77.8%) of nine patients had positive
results of 131I-MIBG scan. Among these patients, two
was paraganglioma (Table 3).
Imaging study laboratory findings (Relationship between tumor sizes and levels of VMA):
Among the 21 patients with pathological proof, the
urinary levels of VMA were checked in 14 patients,
and seven of them had the elevated VMA levels, ranged
from 13.2 to 96.4 mg/day. The highest urinary VMA
level (96.4 mg/day) was noted in a patient with huge
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malignant pheochormocytoma. Because of central necrosis of neoplasm, it was difficult to compare the urinary estimated tumor size with the level of VMA in this
patient. Comparing the tumor sizes with urinary VMA
levels, it showed that the larger tumor mass had significantly higher VMA level (r = 0.5668, P < 0.0434), see
Fig. 4.
Treatment and outcome:
Thirteen patients had hypertension with a mean
duration of 4.8 years, ranging from six months to 18
years. Among these patients, four cases had paroxysmal
hypertension, and seven cases had other hypercatecholaminic symptoms/signs, such as palpitation or perspiration. Twelve of the 13 hypertensive patients received
operations. Their preoperative blood pressure ranged
from150/90 mmHg to 240/140 mmHg. After operation,
11 patients (91.7%) become normotensive. The one diabetic female with chronic renal insufficiency and heavy
proteinuria (i.e. diabetic nephropathy) had persistent
hypertension after operation. Six months later, she had
intracranial hemorrhage, and then progressed to endstage renal disease later. All surgical patients did not have intra-operative
mortality. But one case was complicated with renal artery thrombosis and received subsequent nephrectomy
(Case 4). One case of paraganglioma was found incidentally during septic survey, and she died of septic shock
later (Case 5). Two cases (Cases 6 and 7) of malignant
pheochromocytoma expired due to disease progression
three months and two months later, respectively. II. Features of Adrenal metastatic tumors:
Among these 140 patients with adrenal tumors,
fifty-five patients with adrenal tumor were diagnosed as
adrenal metastasis by clinical features and imaging studies (Table 1). Among these patients, the original malig-
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Vol. 20, No. 3, 2006
Table 2. Clinical characteristics of 23 patients with pheochromocytoma (pheo)/ paraganglioma
Case Age/Sex Diagnosis (Site)
Initial Presentations
Other Conditions
HTN
Sigmoid cancer, cured
Renal artery thrombosis
during and resulting in
right nephrectomy
1
39/M
Paraganglioma, bladder
2
54/F
Paraganglioma, bladder
4
36/M
Paraganglioma, intraabdominal,
extradrenal (R)
Persistent HTN for 18 yrs, paroxysmal
headache & palpitation
5
68/F
6
55/M
Paraganglioma, intraabdominal
and extradrenal (R)
Conscious change, fever, right upper abd. Expired due to sepsis
pain, and liver mass noted in echo
7
43/M
8
29/F
10
27/F
3
9
41/F
56/F
Paraganglioma,
left carotid body
Chest pain, palpable left abdominal mass Expired 3 Ms later due to
progression
MEN, type 2
Family history of MEN, type 2
MEN, type 2
Family history of MEN, type 2
Malignant pheo (R), with lung,
bone meta
MEN, type 2
49/M
Pheo (R)
12
22/M
Pheo (R)
14
40/F
Pheo (R)
64/M
Pheo (R)
15
45/M
Pheo (R)
16
62/M
Pheo (L)
17
40/F
Pheo (L)
19
39/F
Pheo (L)
18
63/F
Left neck mass for 2 Ms
Malignant pheo (L), liver, celiac
trunk meta
11
13
Painless hematuria for 1 M, headache,
flushing, and palpitation during micturation (HTN during cystoscopy)
Pheo (R)
20
41/M
Pheo (L)
21
44/F
Pheo (R)
22
36/M
Pheo (R)
23
68/F
Pheo (L)
Bone pain
Expired 2 Ms later due to progression
Family history of MEN, type 2
Paroxysmal HTN, palpitation, headache
& face flush for 7 yrs
HTN and headache for 1/2 yrs
Septic shock 2 yrs after
adrenectomy
Adrenal incidentoma
Persistent HTN and severe headache for
2 yrs
Paroxysmal HTN and
headache for 2 yrs
ICH before diagnosis
Persistent HTN for 4 yrs, Adrenal incidentoma
Tachycardia & HTN for 1 yr
Persistent HTN for 10 yrs, chronic renal
insufficiency
Paroxysmal HTN & palpitation
Severe abdominal pain after drinking
snake wine, retro- peritoneal hemorrhage shock
ICH post adrenalectomy,
Diabetic nephropathy
progressed to ESRD*
Paroxysmal HTN, palpitation
& sweating for 1 yr
Left hydronephrosis due
to primary megaureter
HTN & high VMA, Referred for survey
Death on arrival
HTN, paroxysmal
headache, MI-like symptoms
R: right, L: left, MEN: multiple endocrine neoplasia, HTN: hypertension, ICH: intracerebral hemorrhage,
ESRD: end- stage renal disease, meta: metastasis, MI: myocardial infarction.
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171
Table 3. Laboratory and imaging findings in 23 patients with pheochromocytom/ paraganglioma
Case
1
2
3
VMA
(mg/day)
Computed tomography
–
P
8.7
–
Pathology
P
7.5×5×2.5 cm3
–
4×2.5×5 cm
Not mention tumor size
3
4
10.6
P
6
96.4
–
8
–
N
Nodular hyperplasia
10
6.6
N
11
9.1
–
0.7×0.5×0.5 cm ,
Nodular hperplasia,
5.5×4×2 cm3
5
7
9
12
–
–
–
21.4
P
15
7.3
17
18
19
20
21
22
23
–
P
13.2
16
–
33
13
14
–
1.84
50.7
0.7
18
3.5
5.6→16.2
15.2
–*
P
P
P
P
P
P
P
P
P
P
4.5×3×3 cm
3
Fine needle aspiration
16×22×18 cm
3
Data in other hospital
–
3
5.3×5×2.5 cm
3
7×5×4 cm3
4×4×3 cm3
Estimated tumor
size (cm3)
49.1
–
25
2×1.5×1.5 cm
7×6×5 cm
7×7×6 cm
3
2.2×1.6×1.0 cm
3
3.5×3.5×3.5 cm
3
4.5×3.5×2.5 cm
3
Size not mentioned
No pathologic proof
No pathologic proof
–
–
P
3316
P
–
–
–
–
–
0.1
–
–
–
–
23.0
N
73.3
P
2.4
N
153.9
P
22.4
–
34.7
109.9
3
P
21.2
25.1
3
I-131 MIBG
scan
1.8
–
–
–
P
20.6
P
–
–
–
–
–
–
I-131 MIBG: Iodine-metaiodobenzylguanidine, P: Positive finding, N: Negative finding, –: Not done.
*She was referred to our hospital for surgery due to hypertension, high VMA and positive angiography (pheo). But she
died on arrival (Emergency Room).
131
nancies included lung cancer (31 patients, 56.4%), hepatoma (seven, 12.7%), colorectal cancer (six, 10.9%),
gastric cancer (two, 3.7%), renal cell carcinoma (two,
3.7%), and metastatic tumor of unknown origin (two,
3.7%). Most of these patients with suspected adrenal
metastatsis did not receive pathological examinations
due to poor general condition. However, 11 malignant
patients with suspected solitary adrenal metastasis had
received operation, and the pathology revealed ‘benign’
adrenal tumors in four patients.
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III. Features of other adrenal tumors:
Forty-two patients were diagnosed as aldosteroneproducing adrenal cortical adenoma (i.e. Conn’s
syndrome). The diagnosis of aldosterone-producing
adenoma was made by clinical pictures (i.e. hypokalemia and metabolic alkalosis) and NP59 scintigraphy or
adrenal CT scan. The male to female ratio was 11:31. The mean age was 43.6 + 10.8 years old (ranged from
22 to 68 years old) at diagnosis. Most of these patients
(28/42) were around 30-49 years old. Twenty patients
with aldosterone-producing adenoma were found in
right-sided adrenal gland and 22 in left-sided. About
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Vol. 20, No. 3, 2006
Fig. 4. Estimated tumor sizes of 13 cases with pheochromocytoma/paraganglioma significantly correlated with urinary
VMA levels. Note Case 6 with malignant pheochromocytoma had a huge tumor mass with central necrosis and the highest
VMA level. His data was excluded due to difficulty to evaluate the exact tumor size and metastasic lesion.
their initial presentations, hypertension was found in 34
patients (81.0%), periodic weakness in seven (16.7%),
headache in four (9.5%), dizziness in three (7.1%), and
angina pectoris in three. Three patients had no clinical symptoms/signs (i.e. incidentaloma). Thirty-seven
patients (88.1%) were noted to have hypokalemia (i.e.
serum potassium level < 3.5 mEq/L). The other five
patients had normal serum potassium level, and two of
them were found incidentally by ultrsonographic screen
(i.e. incidentaloma).
Seven female patients were diagnosed as adrenal
cortisol-secreting adenoma. The mean age was 24.8
± 13.2 years old, aged from 19 months to 45 years old.
Two females (3 yrs and 38 yrs) were diagnosed as adrenal cortical carcinoma, presenting with abdominal mass,
but they did not have hypertension or hypokalemia. In
addition, nine children including seven boys and two
girls, with the age ranged from 15-month-old to 10-yearold, were diagnosed as neuroblastoma (Table 1). A
60-year-old male was a case of adrenal lymphoma, and
a 64-year-old female was a case of adrenal myolipoma
(not shown in Table 1).
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DISCUSSION
Pheochromocytomas most frequently occurred in the
age of third and fourth decades, with slightly female predominance.1,2,6,7 Pheochromocytoma is a tumor of neuroectodermal origin that arises from the chromaffin cells
(i.e. pheochromocytes) of the sympathoadrenal system.
Paraganglioma is used to characterize tumor originating
in chromaffin cells adjacent to sympathetic ganglia or
in other extra-adrenal sites.8 Because 10% of patients
with pheochromocytoma were malignant, 10% were extraadrenal, 10% were bilateral, 10% were childhood, and
10% were inherited, pheochromocytomas are called a
10% tumor. From our study, most of these patients were
found in the third and fourth decades, and with an equal
sex ratio. And 8.7% of patients with pheochromocytoma
were malignant, 21.7% were extra-adrenal, 13.0% were
inherited, which was compatible with the result from
Kaohsiung Medical University (Kaohsiung, Taiwan) and
other literature reviewed.8,9
Pheochromocytoma and paraganglioma have variable clinical presentations. In our series, more than one
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Acta Nephrologica
Clinical analysis of pheochromocytoma/paraganglioma
half (13/23) of the patients had hypertension. These patients also can present with painless hematuria, metastatic lesion or palpable mass, anxiety, severe hypertension
during procedure, intracranial hemorrhage, myocardial
infarction, and even death on arrival (Case 23).
Paragangliomas can be divided into four groups,
including: brachiomeric, intravagal, aorticosympathetic,
and visceral-autonomic paragangliomas. The carotid
body was included in the branchiomeric group. Our
Case 3 with carotid body paraganglioma had a palpable
mass for two months, but she did not have hypercatecalaminic symptoms (Table 2). Inactive paragangliomas
are frequently located in the neck and skull base; and the
carotid body paraganglioma are often called chemodectomas.10 Surgical resection is the curative modality and
has nearly no perioperative mortality.11 In addition, radiotherapy provides a high probability of tumor control
with relatively minimal risks for patients with chemodectomas of carotid body and is the treatment of choice
for advanced chemodectomas.12,13
Among these 23 patients, two cases had urinary
bladder paragangliomas. A 39 year-old male (Case 1)
presented with hypertension. And a 54 year-old female
(Case 2) had flushing and painless hematuria, and she
presented with severe hypertension during cystoscopy. In 2000, Cheng L, et al. reported that the paraganglioma
of urinary bladder occurs mostly in young adult women.14 These tumors in advanced histology are at risk of
recurrence, metastasis, and dying of the disease.14,15
In hypertensive patients with “three P” symptoms/signs (i.e. paroxysmal headache, perspiration or
palpitation), urinary VMA is frequently employed as
a screening method for pheochromocytom and is high
specific (90-98%), but less sensitive (40-60%).16,17 Catecholamines are metabolized by monoaminooxidase and
catecholmethyltransferase, and VMA is the main urinary
metabolite of norepinephrine and epinephrine.18 In previous study, these patients with persistent hypertension
had higher urinary VMA levels than that with paroxysmal one.19 The diagnostic sensitivity and specificity of
CT scan are 98% and 70%, respectively; and 78% and
100% for 131I–MIBG radionuclide scan, respectively.4
In our series, the levels of urinary VMA correlated with
the estimated tumor sizes (Fig. 4). In some studies, the
cure rate of hypertension was around 80%.20,21 In our series, except one patient with diabetic nephropathy, their
hypertension were cured postoperatively.
About 10% (2/23) of pheochromycytomas are malignant, and the prognosis of these patients was very
poor. The histopathological distinction between benign
and malignant lesions is difficult, and reliable prognostic
markers are lacking. Paragangliomas were more often
malignant than pheochromocytomas.8 166-76/620.indd 173
173
Most of the adrenal tumors in our series were metastatic from solid tumors, and most common causes of
original malignancies were lung cancer, followed by
hepatoma, and then colorectal cancer. In the Western
population, the leading original malignancies of adrenal
metastasis are lung cancer, breast cancer, renal cell carcinoma, and colorectal cancer.22 Among our 11 patients
with underlying malignancies and receiving operation
for solitary adrenal tumor, four of them were found to
have benign adrenal tumors. The adrenal tumors found
incidentally were named as incidentalomas. Among
those adrenal incidentaloma found in patients with underlying malignancies, three-fourth were metastatic.23
CONCLUSIONS
From this retrospective study, the most common
adrenal tumors were adrenal metastasis. Adrenal cortical
adenomas were the secondary leading cause of adrenal
tumors, and hypokalemia were the most common finding. Pheochromocytoma/paraganglioma had the variable
clinical presentations. It was a nearly curable hypertensive disease and had a low peri-operative mortality
rate. CT scan and 131I-MIBG radionuclide scan were
the sensitive diagnostic modalities. In addition, urinary
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