 Case Presentation
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A 19-year-old woman was admitted to the hospital because of
intermittent palpitation for 1 year.
The patient, an overseas Chinese residing in Canada, had
been robust before until 1 year prior to admission, when she
began to suffer from paroxysmal palpitation, perspiration and
headache. These attacks occurred about 2-3 times a day and
lasted about 20-30 minutes. No known precipitating factors had
been remarked. She visited a hospital in Canada 10 months
before this admission, and was noted to have hypertension (the
blood pressure was 170/100mmHg). After serial work-up, she was
informed of having a significantly high level of
vanillylmandelic acid (VMA) in urine: 182 μmol/24hrs (normal:
<31 μmol/d ). Labetalol 25mg bid po was prescribed, which
could partially mitigate her symptoms. One month later, she
returned to Taiwan and visited some other hospital for further
evaluation, where abdominal CT and a scintigram following 131I
labeled metaiodobenzylguanidine (MIBG) both failed to
demonstrate the existence of pheochromocytoma, the most likely
diagnosis of this patient. Doxazosin 1.5 mg qd and nifedipine
5 mg hs po were prescribed to relieve her symptoms. Ten days
later, she came to this hospital for further investigation of
her disease.
The temperature was 36.9°C, the pulse was 76, and the
respirations were 20. The blood pressure was 160/90 mmHg.
There was no bruit or tumor perceptible over her neck, chest
or abdomen. The other physical examinations were unremarkable.
Laboratory tests were performed
(Tables 1 ~ 3).
| Table 1.
Hematologic Laboratory Values.
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|
|
WBC
(K/μL) |
RBC
(M/μL) |
Hb
(g/dL) |
HcT
(%) |
MCV
(fL) |
MCH
(pg) |
MCHC
(g/dL) |
Platelet
(K/μL) |
|
On Admission |
6.94 |
3.84 |
11.8 |
33.8 |
88.0 |
30.7 |
34.9 |
199.0 |
|
On 20th Hospital Day |
6.3 |
3.42 |
10.4 |
31.1 |
90.9 |
30.4 |
33.4 |
224.0 |
| Table 2.
Blood Chemical and EnzymeValues. |
|
|
D-BIL
mg/dL |
Alb
g/dL |
TP
g/dL |
T-BIL
mg/dL |
AST
U/L |
ALT
U/L |
UN
mg/dL |
CRE
mg/dL |
UA
mg/dL |
|
On Admission |
0.2 |
4.7 |
7.8 |
0.5 |
17.0 |
16.0 |
9.3 |
0.6 |
|
|
On 20th Hospital Day |
0.1 |
3.6 |
6.0 |
0.4 |
16.0 |
12.0 |
6.3 |
0.7 |
2.9 |
| Table 3.
Electrolytes and Lipid Profiles |
| |
Na
mmol/L |
K
mmol/L |
Cl
mmol/L |
Ca
mmol/L |
P
mg/dL |
Mg
mg/dL |
Mg
mmol/ |
T-CHO
mg/dL |
LDL
mg/dl |
mg/dL |
| On Admission |
130 |
4.0 |
99.0 |
2.4 |
3.6 |
- |
45.0 |
247.0 |
145 |
93.0 |
| On 20th Hospital Day |
139 |
3.9 |
- |
2.24 |
3.5 |
0.76 |
- |
- |
- |
- |
After
admission, elevated VMA and norepinephrine levels in urine
were noted. The metabolic and endocrinologic profiles were as
followings: (Table 4, 5)
| Table 4.
Endocrinologic Laboratory Values in Blood. |
| |
On Admission |
Normal Range |
| Glu AC (mg/dL) |
115 |
70~115 |
| Glu 2hr PC (mg/dL) |
122 |
<140 |
| Free T4(CIA) (ng/dL) |
0.87 |
0.6 ~ 1.75 |
| hsTSH(CIA) (μIU/mL) |
1.95 |
0.4 ~ 4 |
| RIA:T3 (ng/dL) |
206 |
80~200 |
| Microsomal Antibody (AMA) |
1:40 - |
< 1:80 (+) (1:N) |
| Thyroglobulin Antibody (ATA) |
1:40 - |
< 1:80 (+) (1:N) |
| Cortisol- 8am (μg/dL) |
10.3 |
am: 5 ~ 25;
pm: 2.5 ~ 12.5 |
| Cortisol- 4pm (μg/dL) |
6.87 |
am: 5 ~ 25;
pm: 2.5 ~ 12.5 |
| ACTH- 8am (pg/mL) |
10.6 |
10 ~ 65 |
| ACTH- 4pm (pg/mL) |
7.4 |
10 ~ 65 |
| DHEA-SO4 (μmol/L) |
3.7 |
♂ 4.6 ~ 13.4,
♀ 4.6 ~ 15.4 |
| Plasma renin activity (ng/ml/hr) |
6.40 |
1-5 |
| Aldosterone (ng/dL) |
66.75 |
5-30 |
| E2 (pg/ml) |
194. |
20~100 follicular,
100~ 350
luteal phase |
| FSH (IU/L) |
1.6 |
5~24 |
| LH (IU/L) |
0.88 |
4.5~ 24.3 |
| Table 5.
Catecholamines in Urine. |
| |
On Admission |
On 15th Hospital Day |
On 35th Hospital Day |
Normal Range |
| Dopamine (μg/24h) |
361.4 |
742.4 |
472.9 |
50~450 |
| Epinephrine (μg/24h) |
15.6 |
24.2 |
65.5 |
<22.4 |
| Norepinephrine (μg/24h) |
1173.2 |
1195.2 |
164.5 |
12.1~85.5 |
| VMA (mg/24h) |
18.1 |
28.0 |
8.3 |
1~7 |
Abdominal
CT revealed a peripancreatic tumor compatible with
pheochromocytoma. The adrenal glands were normal in size. Positron
emission tomography
exhibited a large, hypermetabolic ringed lesion at
right subhepatic region. Surgical excision of the tumor was
indicated and phenoxybenzamine was prescribed to control her
blood pressure before the operation. Propranolol was added
because of the palpitation. She underwent excision of the
tumor on 30th hospital day and a soft, well encapsulated tumor
of 5.5 cm with central necrosis was identified. The pathology
showed paraganglioma with central scar, hemorrhage, vascular
invasion and necrosis. The post-operative 24-hours urine VMA
and norepinephrine declined discernibly (Table 5. ). The blood
pressure after surgery dropped to 120/80 mmHg, while no
antihypertensive medication was administered. She remained
symptom-free during the 1-year follow-up at the outpatient
clinics, with no reliance upon any medications.
<病案分析>
本病例為一相當典型的嗜鉻細胞瘤(pheochromocytoma)的患者。
在臨床上的表現, 為程度不一的陣發性症狀發作; 大多數這類病人會有持續的高血壓,, 再加上陣發性的更高血壓的發作,
並伴隨不適感。 少數病人則在每次發作之間, 完全沒有任何不適症狀或高血壓的表現,
因此很難在這些時候找到catecholamine釋放或分泌的證據。 因而必須借助CT或MRI scan 的幫忙,
來達成診斷。 但絕大多數的病人是像本例之患者, 在陣發性症狀發作時會表現出頭痛、冒汗、心悸、不安、 噁心嘔吐,
甚至會有視力障礙的現象。 有些患者也有體重減輕的表現。
臨床上, 當病人有以下表現時, 必須考慮到pheochromocytoma
的可能性: 當病人有陣發性症狀發作時; 當病人年紀很輕就有高血壓時;
當一個成年高血壓患者其血壓對藥物反應不佳時;當病人有新陳代謝加速或同時有糖尿病時; 或當病人在接受麻醉、 手術或生產時,
有血壓巨幅上升或休克的表現時, 均應考慮到此病的可能性。 而在家族史上一等親有pheochromocytoma,
multiple endocrine neoplasia (MEN), 或medullary thyroid
cancer時, 也必須仔細檢查診斷, 是否有pheochromocytoma 的存在。
鑑別診斷上, 有一些疾病也會伴隨有交感神經之刺激,
而與pheochromocytoma不易區分。 例如: 嚴重的anxiety或panic states, 高血壓、
或因手術、腦中風、 急性肺水腫等引起之高血壓危症, 停經後症候群所伴隨之熱潮紅、 甲狀腺機能亢進、 偏頭痛、
或服用一些減肥藥物及感冒藥中含有交感神經興奮劑等等, 以上這些可能會與pheochromocytoma混淆的情況,
在臨床上必須多加注意, 以免引起不必要的困擾。
本病患在臨床表現與實驗室檢查上,
均強烈支持pheochromocytoma的診斷; 但在imaging studies上, 卻遭到困難。 一般而言,
超過95%的pheochromocytoma是位於腹腔內, 而其中的85%是在adrenal gland上。
腹腔內adrenal gland以外的好發部位, 包括腎臟附近、 膀胱壁、 以及所謂的organ of
Zuckerkandl—位於inferior mesenteric artery 的level,
是新生兒出生後一年內體內製造catecholamines的主要來源, 年齡漸長之後會逐漸萎縮。胸腔內的好發部位,
則包括心臟與後縱膈腔等處。 至於多發性的病灶則相當罕見,
除非是具有家族病史且在孩童時期就發病的pheochromocytoma或所謂MEN的患者,
否則常是惡性轉移的現象。這個病人後來在本院重新作腹部較低位置的CT scan與PET,
在腹腔比較下方腎臟附近的位置發現到疑似腫瘤, 且經由手術證實為pheochromocytoma,
更進一步證明絕大多數的pheochromocytoma位於腹腔, 若詳細檢查仍無法在腹腔找到病灶時,
才須考慮其他的部位。
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 繼續教育考題
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1.
(C) |
What is the most common
cause of secondary hypertension in general population? |
| A | Primary aldosteronism |
| B | Cushing's syndrome |
| C | Renal parenchymal hypertension |
| D | Renovascular hypertension |
| E | Pheochromocytoma |
2.
(D) |
When should we suspect
the existence of secondary hypertension, Except: |
| A | Hypertension developed before
the age of 35 or after 55 |
| B | A history of use of adrenal
steroids or estrogens |
| C | A history of weight gain or
weight loss |
| D | A family history of angina
pectoris or cerebrovascualr insufficiency |
| E | Arterial pressure is not
controlled after initial therapy |
3.
(E) |
Which of the
following tests should always be included as basic tests for initial
evaluation of hypertension, Except: |
| A | Urine protein, blood and
glucose |
| B | Serum creatinine and/or blood
urea nitrogen |
| C | Fasting glucose, serum
potassium and total cholesterol |
| D | Electrocardiogram |
| E | Serum calcium and phosphate |
4.
(C) |
Which statement about
pheochromocytoma is False? |
| A | In adults, approximately 80% of
pheochromocytoma are unilateral and solitary |
| B | Less than 10% of these tumors
are malignant |
| C | Malignancy can be determined
from the histologic appearance |
| D | One fourth of tumors in
children are bilateral and additional one fourth are extradrenal |
| E | Solitary lesions favor the
right side |
5.
(A) |
Which statement about
extraadrenal pheochromocytomas is False? |
| A | Extraadreanal pheochromocytomas
usually are larger than 5 cm |
| B | Most are located within the
abdomen |
| C | The most common regions are
associated with the celiac, superior mesenteric and inferior
mesenteric ganglia |
| D | Approximately 10% are in the
thorax |
| E | About 1% are within the urinary
bladder |
6.
(B) |
What are the most
common catecholamines secreted by the following tumors successively?
(1)benign pheochromocytoma,
(2)extraadrenal
pheochromocytoma,
(3)pheocrhomocytoma associated with multiple
endocrine neoplasia (MEN),
(4)malignant pheochromocytoma |
| A | Norepinephrine, epinephrine,
epinephrine, dopamine |
| B | Norepinephrine, norepinephrine,
epinephrine, dopamine |
| C | Dopamine, norepinephrine,
epinephrine, epinephrine |
| D | Norepinephrine, epinephrine,
dopamine, epinephrine |
| E | Norepinephrine, epinephrine,
norepinephrine, dopamine |
7.
(B) |
About the heritable
type of pheochromocytoma, which of the following is True? |
| A | The MEN 2A and 2B syndromes are
associated with the RET protooncogene located on choromosome 11 |
| B | In the MEN 2A, the patient may
also have a calcitonin-producing carcinoma of the thyroid |
| C | In the MEN 2A, the patient may
also have a parathyroid hormone-producing carcinoma of the
parathyroid |
| D | In the MEN 2A, the patient may
also have mucosal neuromas |
| E | In the MEN 2B, the patient may
also have a parathroid hormone-producing adenoma of the parathyroid |
8.
(C) |
Which statement about
the biochemical diagnosis of pheochromocytoma is False? |
| A | The assays employed include
vanillylmandelic acid (VMA), metanephrine and unconjugated or free
catecholamines |
| B | A full 24-h urine sample with
creatinine determination is feasible, and the urine should be
acidified and refrigirated during and after collection |
| C | The VMA assay is both more
sensitive and more specific than the other two assays |
| D | The collection of urine
specimen should be made when the patient is at rest, on no
medication, and without recent exposure to contrast media |
| E | False-positive results are
related to drugs such as methyldopa, levodopa, labetalol and
sympathomimetic amines which may elevate catecholamine excretion up
to 2 weeks |
9.
(A) |
Which of the followings
should not be included in preoperative managements of
pheochromocytomas? |
| A | Give a short course of medical
treatment and operate the patient as soon as possible if the patient
has recent myocardial infarction |
| B | Treatment directed toward
reduction of symptoms, lowering of BP and amelioration of paroxysms |
| C | Expansion of the vascular bed
and plasma volume with normal saline |
| D | Alpha receptor blockade should
be established before propranolol is given to control marked
tachycardia and arrhythmias |
| E | In patient with persisten
hypertension, phenoxybenzamine, a noncompetitive alpha-adrenergic
antagonist, is indicated |
10.
(E) |
Which statements about
the treatments of pheochromocytoma are True?
(1) CT or MRI is
useful in intraadrenal tumors
(2) Percutaneous fine-needle
aspiration of chromffin tumors is indicated if the tumors are
visible by adrenal ultrasound
(3) Surgical mortality is 2~3%
(4) In early pregnancy, the tumor should be not be removed until
the second trimester
(5) Malignant pheochromocytoma metastasizes
most commonly to liver
(6) The recurrence rate of benign
pheochromocyroma is less than 10%
(7) Complete removal cures the
hypertension in about 3/4 of patients |
| A | (1)(2)(3)(4)(5)(6)(7) |
| B | (1)(3)(4)(5)(6)(7) |
| C | (1)(3)(5)(6)(7) |
| D | (1)(3)(4)(6)(7) |
| E | (1)(3)(6)(7) |
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(C) 在一般人口中, essential
hypertension約佔92~94%, renal parenchymal hypertension 2~3%,
renovascular hypertension 1~2%, primary aldosteronism 0.3%,
Cushing's syndrome與 pheochromocytoma各約佔0.1%,
口服避孕藥引起者約佔0.5~1%。其中仍以renal parenchymal disease佔最大宗,
而常見的原因包含chronic pyelonephritis, acute and chronic
glomerulonephritis, polycystic renal disease, 以及大部分secere
renal disease (如: arteriolar nephrosclerosis, diabetic
nephropathy等等)。
-
(D) 在臨床病史的詢問上,
若有很強的hypertension家族史, 且病人過去即常有紀錄到血壓較為偏高的情況,
診斷上比較傾向為essential hypertension。但若病人在35歲以前或55歲以後才發病, 沒有顯著家族史,
以一般降血壓藥物不太容易控制其高血壓時, 則必須考慮到secondary hypertension
的可能性。若病人有長期使用estrogen 或adrenal steroids時, 須考慮藥物引起之高血壓;
若有反覆泌尿系統感染之病史、夜尿或多尿的情況, 需考慮renal 或endocrine diseases;
若有顯著體重增加的病史, 需考慮Cushing's syndrome的可能; 相反的,
體重減輕有可能是pheochromocytoma所造成。
-
(E) 高血壓的患者,
在初次診斷之後有幾項檢查是例行而且必需做的, 包括尿液分析protein, blood 與glucose,
microscopic urinalysis, hematocrit, BUN
及creatinine來評估病人的renal status, 血清中的potassium
濃度主要用來篩檢mineralocorticoid所引起的hypertension, 並可提供diuretics治療前,
基礎potassium 濃度的參考。至於血糖的測定, 主要是因為糖尿病常會伴隨高血壓一起發生,
且會加重高血壓引起的動脈硬化等併發症。另外, 許多secondary hypertension也會同時引起高血糖的表現,
加上利尿劑之類的降血壓藥物, 有時也會引其血糖上升, 故而了解病人的blood glucose
level是相當重要的。心電圖檢查對偵測病人是否已。有left ventricular hypertrophy
也是很重要的基本檢查。至於血清calcium與phosphate, 在考慮cost與benefit後,
若覺得有必要且cost上許可, 也可列入檢查項目, 但比較不具迫切性。
-
(C) 成年人約有80%
的pheochromocytoma為單側且為單一腫瘤, 10%為雙側, 另10%
發生在腎上腺以外的部位。在小孩則約有1/4是雙側發生,
另外有1/4是位於腎上腺以外的部位。單一的病灶常出現在右側的腎上腺, 大部分大小是直徑小於10公分,
重量小於100公克, 少數會重達3公斤以上。另有小於10%的患者為惡性腫瘤，跟其他endocrine tumors一樣,
要從histology診斷pheochromocytoma為malignant是不可能的,
必須根據腫瘤對周邊組織的侵犯度, 以及是否有遠處轉移, 來判斷是否為惡性。 另外, flow
cytometry若有aneuploid 或tetraploid cells,
也表示病人將來較容易會有recurrence。
-
(A)
超過95%的pheochromocytoma發生於腹腔內,
其中有85%位於腎上腺。而在腎上腺以外的部位的pheochromocytoma幾乎均小於5公分,
重量則在20~40公克之間, 大部分仍是位於腹腔內。常見相關位置包括: celiac ganglia, superior
and inferior mesenteric ganglia附近。另有10%左右位於胸腔, 1%位於urinary
bladder, 小於3%位於頸部, 常在sympathetic ganglia或第9第10對腦神經附近。
-
(B)
大部分的pheochromocytoma同時分泌norepinephrine 與epinephrine,
且norepinephrine所佔的比例常高過正常adrenal gland的分泌情況。
而絕大多數的extraadrenal pheochromocytoma, 就如同ganglia或nerve
endings一般, 只分泌norepinephrine。少數情況下,
特別是與MEN有關的pheochromocytoma,
會只單獨分泌epinephrine。雖然epinephrine可能引起較偏重beta-receptor的effect,
病人的臨床表現並無法用來預測腫瘤的分泌情況。Dopamine在benign lesions很少分泌,
但在malignant pheochromocytoma時, 可能會有dopamine與homovanilllic
acid (HVA)分泌增多的現象。
-
(B)
MEN2A與2B是chromosome10上pericentromeric region的RET
protooncogene異常所導致的疾病。 這些突變, 導致所謂的receptor tyrosine kinase
的活化, 使adrenal medullary chromaffin cells 及parafollicular C
cells 產生hyperplasia, 並使之易於發生惡性變化。在MEN 2A,
此突變發生在receptor的extracellular domain; 而在MEN 2B,
則發生於intracellular domain。此外, 由疾病的phenotypes表現,
就可以知道病人屬於哪一類突變。MEN 2A主要表現為medullar carcinoma of thyroid,
parathyroid adenoma及pheochromocytoma; MEN 2B則為medullary
carcinoma of thyroid, pheochromocytoma, 以及口腔與腸道的mucosal
neuromas。
-
(C) 24-h urine
VMA在診斷pheochromocytoma的sensitivity 與specificity, 各約只有70%左右;
而24-h urine metanephrine與normetanephrine,
或epinephrine與norepinephrine,
這兩種組合的sensitivity與specifity均可達將近100%。在收集24-h urine時,
為了確認收集的完整度, 必須同時檢查creatinine的含量作為參考。此外,
最好是在病人有paroxysms發作期間或之後, 在休息狀態下,
並且至少兩星期以內沒有服用任何藥物的情況下收集urine; 收集好的檢體必須酸化並且冰存起來,
以避免catecholamine的decay。
-
(A)
雖然大多數患者在給予短期的alpha-adrenergic blocking agents後,
就可以接受手術治療移除腫瘤, 但在最近剛發生過心肌梗塞的患者, 或是懷孕而在第3個trimester的患者,
最好在藥物治療較久之後, 再接受手術治療。 藥物治療的原則在於盡量將病人的症狀及血壓控制在正常範圍, 且補充水分,
擴充病人的血漿容積(可用hematocrit來作監測), 以避免手術移除腫瘤後,
病人會有血壓急速降低及休克的危險。當病人有tachycardia或arrhythmia時, 在充分給予alpha
blockade之後, 可使用低劑量的propranolol來控制心跳。 若先給propranolol,
而未給alpha-blocker, 可能會拮抗skeletal muscle中的beta-mediated
vasodilatation, 而導致血壓的paradoxical increase。 此外,
若病人仍持續有hypertension, 可使用非競爭性的alpha-blocker:
phenoxybenzamine, 來控制血壓。劑量由口服20~40 mg/d開始, 每一到兩天可增加10~20 mg,
直到血壓控至下來為止, 一般約60~80 mg/d即已足夠。
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(E) 一般而言, CT或MRI均可有效找到位於adrenal
gland內的pheochromocytoma; MRI對腹腔內adrenal以外的tumors效果與131I-MIBG
scan 是相似的。 胸腔內腫瘤, 則以CT scan 效果較佳。 至於percutaneous fine-needle
aspiration cytology, 對於chromaffin tumors是contraindication,
可能會引起高血壓危症的發生。 手術切除pheochromocytoma的死亡率, 約只有2%; 手術過程,
必須嚴格監控心電圖、血壓及中心靜脈壓力, 此外, 充分的補充體液是非常重要的。 懷孕早期,
若病人發現有pheochromocytoma, 在給予phenoxybenzamine後, 腫瘤必須盡速移除,
以免危及胎兒性命。 若懷孕第3個trimester才診斷出有pheochromocytoma,
則可先用alpha-blocker治療, 等胎兒足夠大之後, 再做cesarean section,
並同時將tumor切除。 Pheochromocytoma的手術後5年存活率高達95%, 復發率小於10%。
若手術成功, catecholamine的分泌往往在兩星期內就可回復正常。 若病人為惡性腫瘤, 5年存活率小於50%。
腫瘤完全切除後, 約有3/4的病人其高血壓可以完全治癒, 不需依賴任何降血壓藥物; 剩下1/4的病人,
只要用一般標準的高血壓藥, 即可將血壓控制的不錯。 而其持續高血壓的原因, 可能是本身有essential
hypertension, 或是之前的pheochromocytoma引起的高catecholamine狀態,
已經造成不可逆的血管病變。
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