case report
Oman Medical Journal [2015], Vol. 30, No. 5: 382–390
A Rare Case of Adrenal Pheochromocytoma with Unusual Clinical and Biochemical Presentation: A Case Report and Literature Review Waad-Allah S. Mula-Abed1*, Riyaz Ahmed2, Fatima A. Ramadhan3, Manal K. Al-Kindi1, Noor B. Al-Busaidi4, Hilal N. Al-Muslahi4 and Mohammad A. Al-Lamki5 Department of Chemical Pathology, Royal Hospital, Muscat, Oman Department of Endocrine Surgery, Royal Hospital, Muscat, Oman 3 Department of Histopathology, Royal Hospital, Muscat, Oman 4 National Diabetes and Endocrine Centre, Royal Hospital, Muscat, Oman 5 Medical Endo-Metabolic Unit, Royal Hospital, Muscat, Oman 1 2
A RT I C L E I N F O
A B S T R AC T
Article history: Received: 27 August 2014 Accepted: 18 January 2015
A 50-year-old Omani woman presented to the Outpatient Clinic, Royal Hospital, Oman with right upper abdominal pain and backache that had lasted 10 days. She had no palpitation, sweating, or hypertension (blood pressure 122/78mmHg). The patient’s history revealed that she had a similar incidence of abdominal pain two months prior, which was a “dull ache” in nature and somewhat associated with headache. The pain was relieved using a mild analgesic drug. Abdominal ultrasonography showed a right adrenal mass, and both computed tomography and magnetic resonance imaging of the adrenal glands confirmed a right adrenal mass consistent with adrenal pheochromocytoma. However, clinical biochemistry tests revealed normal levels of plasma catecholamines (dopamine, norepinephrine, and epinephrine) and metanephrine, which are unusual findings in adrenal pheochromocytoma. Meanwhile, the patient had markedly raised plasma normetanephrine (10-fold) which, together with the normal metanephrine, constitutes a metabolic profile that is compatible with extra-adrenal pheochromocytoma. The patient also had markedly raised chromogranin A (16-fold), consistent with the presence of a neuroendocrine tumor. Laparoscopic right adrenalectomy was done and the adrenal tumor was excised and retrieved in total. Histopathology and immunohistochemistry confirmed the diagnosis of adrenal pheochromocytoma; the tumor cells being positive for chromogranin, synaptophysin, and S-100 protein. Following surgery, the patient did well and showed full recovery at follow-up after three months. Molecular genetic testing showed no pathogenic mutation in pheochromocytoma genes: MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, VHL, and PRKAR1A. A review of the literature was conducted to identify the pathophysiology and any previous reports of such case. To our knowledge, this is the first report in Oman of the extremely rare entity of pheochromocytoma with an unusual clinical and biochemical scenario.
Online: DOI 10.5001/omj.2015.76 Keywords: Adrenal glands; Adrenalectomy; Catecholamines; Chromogranin A; Metanephrine; Normetanephrine; Pheochromocytoma.
P
heochromocytoma is a rare but lifethreatening condition that has varied clinical presentations particularly hypertension, headache, palpitation, and 1,2 sweating. Patients with suggestive clinical features are frequently tested for pheochromocytoma. The medical interest in this tumor has increased with the improved availability of diagnostic laboratory tools particularly plasma or urinary fractionated metanephrines (metanephrine and normetanephrine), and other neuroendocrine markers particularly chromogranin A.3,4 The wide universal availability of different imaging facilities,
*Corresponding author: [email protected]
both anatomical and functional, has also improved the detection of pheochromocytoma.5 The growing awareness for implementing different protocols and guidelines that consider pheochromocytoma in the work-up and differential diagnosis has improved diagnosis of the disorder.6 Accurate diagnosis is important because if the tumor is detected early laparoscopic or surgical treatment is usually curative before other changes or complications take place. Catecholamine-producing tumors are neuroendocrine tumors that affect the chromaffin cells of adrenal medulla and postganglionic fibers of
383
Waad -A ll ah S. Mul a-A bed, et.al
CH2 CH NH2 COOH
HO
CH2 CH NH2 COOH
-
Phenylalanine Tetrahydrobiopterin O2
CH2 CH NH2 COOH CH2 CH2 NH2
Dihydrobiopterin
NADPH
Tyrosine *Tyrosine hydroxylase
+ Minor cAMP action
CH CH2 NH2 OH
HO HO
CH OH
+
Minor action
DOPA decarboxylase
Major action
Dopamine (DA) Cortisol
1/2 O2 (Adrenal and extra-adrenal) (Vitamin C) Dopamine β-hydroxylase
HO HO
ACTH
Dihydroxyphenylalanine (DOPA)
(Adrenal and extra-adrenal) CO2
HO HO
Phenylalanine Hydroxylase
(Liver) H2O
(Adrenal and extra-adrenal)
HO HO
NADP+
+
Important action
Norepinephrine (NE)
(SAM) Phenylethanolamine -N(Adrenal) (SAH) methyltransferase (PNMT)
CH2 N
H CH3
*Rate-limiting step
Epinephrine (Epi) Adrenal medulla secret both NE and Epi (with species differences in the proportions of each).
Figure 1: Adrenal medulla catecholamines biosynthesis showing the required enzymes, coenzymes, and the influencing hormonal effect. In extra-adrenal sympathetic fibers the biosynthesis stops at the production of norepinephrine while in the adrenal medulla the end product of catecholamines synthesis is epinephrine. the sympathetic nervous system.1,2 These tumors are characterized by the synthesis, storage, release, and secretion of catecholamines and their metabolites. They include pheochromocytomas in the adrenal medulla and paragangliomas in the extra-adrenal sympathetic ganglions usually below the diaphragm in the retroperitoneum or organ of Zuckerkandl and various sites including the head, neck, thorax, and abdomen. However, although the majority of these tumors are benign and adrenal, investigation workup should consider their tendency for being multiple, malignant, and familial with genetic pathogenesis.7 Epinephrine (and its metabolite metanephrine) is the catecholamine that is produced exclusively by the adrenal medulla and adrenal pheochromocytoma. On the other hand, norepinephrine (and its metabolite normetanephrine) is the catecholamine produced by the adrenal medulla and adrenal pheochromocytoma as well as by the extra-adrenal pheochromocytoma and paraganglioma, which can also produce dopamine and its metabolite methoxytyramine. However, this is rare. 8 The biochemical synthesis of the different catecholamines and their metabolites is shown in Figure 1.
Pheochromocytomas can affect individuals of all ages. They are common in people aged between 40 and 50 years, and relatively more common among females. Adrenal pheochromocytomas constitute nearly 85% of cases of pheochromocytomas, with 15% being extra-adrenal paragangliomas that affect the sympathetic ganglions anywhere from the base of the brain to the urinary bladder.1,2 Laboratory diagnosis is usually achieved by measuring the catecholamines, or more importantly their metabolites in plasma or urine. Although different markers, including catecholamines and vanillylmandelic acid, are utilized as diagnostic tests, total and fractionated metanephrines in plasma or urine provide the best valid laboratory test for excluding or confirming pheochromocytoma. 2,9 In addition, chromogranin A is another reliable marker for neuroendocrine tumors, including pheochromocytoma and is increasingly used in the diagnostic workup and follow-up of patients with these tumors.4 Following diagnosis, removal of the adrenal gland or the tumor is done by open surgery or by the laparoscopic technique, which is considered the ‘gold standard’ treatment choice since 1992.10-12
O M A N M E D J, V O L 3 0 , N O 5 , S E P T E M B E R 2015
384
Waad -A ll ah S. Mul a-A bed, et.al
Table 1: Plasma levels of catecholamines (and their metabolites), renin, aldosterone, cortisol, and chromogranin A compared to the recommended adult’s reference ranges in the preoperative week. One- week post-operative levels are provided for plasma metanephrine, normetanephrine and 24-hour urine cortisol. Laboratory test
Preoperative result
Postoperative result
Reference range
Dopamine (pmol/L)
Oman Medical Journal [2015], Vol. 30, No. 5: 382–390
A Rare Case of Adrenal Pheochromocytoma with Unusual Clinical and Biochemical Presentation: A Case Report and Literature Review Waad-Allah S. Mula-Abed1*, Riyaz Ahmed2, Fatima A. Ramadhan3, Manal K. Al-Kindi1, Noor B. Al-Busaidi4, Hilal N. Al-Muslahi4 and Mohammad A. Al-Lamki5 Department of Chemical Pathology, Royal Hospital, Muscat, Oman Department of Endocrine Surgery, Royal Hospital, Muscat, Oman 3 Department of Histopathology, Royal Hospital, Muscat, Oman 4 National Diabetes and Endocrine Centre, Royal Hospital, Muscat, Oman 5 Medical Endo-Metabolic Unit, Royal Hospital, Muscat, Oman 1 2
A RT I C L E I N F O
A B S T R AC T
Article history: Received: 27 August 2014 Accepted: 18 January 2015
A 50-year-old Omani woman presented to the Outpatient Clinic, Royal Hospital, Oman with right upper abdominal pain and backache that had lasted 10 days. She had no palpitation, sweating, or hypertension (blood pressure 122/78mmHg). The patient’s history revealed that she had a similar incidence of abdominal pain two months prior, which was a “dull ache” in nature and somewhat associated with headache. The pain was relieved using a mild analgesic drug. Abdominal ultrasonography showed a right adrenal mass, and both computed tomography and magnetic resonance imaging of the adrenal glands confirmed a right adrenal mass consistent with adrenal pheochromocytoma. However, clinical biochemistry tests revealed normal levels of plasma catecholamines (dopamine, norepinephrine, and epinephrine) and metanephrine, which are unusual findings in adrenal pheochromocytoma. Meanwhile, the patient had markedly raised plasma normetanephrine (10-fold) which, together with the normal metanephrine, constitutes a metabolic profile that is compatible with extra-adrenal pheochromocytoma. The patient also had markedly raised chromogranin A (16-fold), consistent with the presence of a neuroendocrine tumor. Laparoscopic right adrenalectomy was done and the adrenal tumor was excised and retrieved in total. Histopathology and immunohistochemistry confirmed the diagnosis of adrenal pheochromocytoma; the tumor cells being positive for chromogranin, synaptophysin, and S-100 protein. Following surgery, the patient did well and showed full recovery at follow-up after three months. Molecular genetic testing showed no pathogenic mutation in pheochromocytoma genes: MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, VHL, and PRKAR1A. A review of the literature was conducted to identify the pathophysiology and any previous reports of such case. To our knowledge, this is the first report in Oman of the extremely rare entity of pheochromocytoma with an unusual clinical and biochemical scenario.
Online: DOI 10.5001/omj.2015.76 Keywords: Adrenal glands; Adrenalectomy; Catecholamines; Chromogranin A; Metanephrine; Normetanephrine; Pheochromocytoma.
P
heochromocytoma is a rare but lifethreatening condition that has varied clinical presentations particularly hypertension, headache, palpitation, and 1,2 sweating. Patients with suggestive clinical features are frequently tested for pheochromocytoma. The medical interest in this tumor has increased with the improved availability of diagnostic laboratory tools particularly plasma or urinary fractionated metanephrines (metanephrine and normetanephrine), and other neuroendocrine markers particularly chromogranin A.3,4 The wide universal availability of different imaging facilities,
*Corresponding author: [email protected]
both anatomical and functional, has also improved the detection of pheochromocytoma.5 The growing awareness for implementing different protocols and guidelines that consider pheochromocytoma in the work-up and differential diagnosis has improved diagnosis of the disorder.6 Accurate diagnosis is important because if the tumor is detected early laparoscopic or surgical treatment is usually curative before other changes or complications take place. Catecholamine-producing tumors are neuroendocrine tumors that affect the chromaffin cells of adrenal medulla and postganglionic fibers of
383
Waad -A ll ah S. Mul a-A bed, et.al
CH2 CH NH2 COOH
HO
CH2 CH NH2 COOH
-
Phenylalanine Tetrahydrobiopterin O2
CH2 CH NH2 COOH CH2 CH2 NH2
Dihydrobiopterin
NADPH
Tyrosine *Tyrosine hydroxylase
+ Minor cAMP action
CH CH2 NH2 OH
HO HO
CH OH
+
Minor action
DOPA decarboxylase
Major action
Dopamine (DA) Cortisol
1/2 O2 (Adrenal and extra-adrenal) (Vitamin C) Dopamine β-hydroxylase
HO HO
ACTH
Dihydroxyphenylalanine (DOPA)
(Adrenal and extra-adrenal) CO2
HO HO
Phenylalanine Hydroxylase
(Liver) H2O
(Adrenal and extra-adrenal)
HO HO
NADP+
+
Important action
Norepinephrine (NE)
(SAM) Phenylethanolamine -N(Adrenal) (SAH) methyltransferase (PNMT)
CH2 N
H CH3
*Rate-limiting step
Epinephrine (Epi) Adrenal medulla secret both NE and Epi (with species differences in the proportions of each).
Figure 1: Adrenal medulla catecholamines biosynthesis showing the required enzymes, coenzymes, and the influencing hormonal effect. In extra-adrenal sympathetic fibers the biosynthesis stops at the production of norepinephrine while in the adrenal medulla the end product of catecholamines synthesis is epinephrine. the sympathetic nervous system.1,2 These tumors are characterized by the synthesis, storage, release, and secretion of catecholamines and their metabolites. They include pheochromocytomas in the adrenal medulla and paragangliomas in the extra-adrenal sympathetic ganglions usually below the diaphragm in the retroperitoneum or organ of Zuckerkandl and various sites including the head, neck, thorax, and abdomen. However, although the majority of these tumors are benign and adrenal, investigation workup should consider their tendency for being multiple, malignant, and familial with genetic pathogenesis.7 Epinephrine (and its metabolite metanephrine) is the catecholamine that is produced exclusively by the adrenal medulla and adrenal pheochromocytoma. On the other hand, norepinephrine (and its metabolite normetanephrine) is the catecholamine produced by the adrenal medulla and adrenal pheochromocytoma as well as by the extra-adrenal pheochromocytoma and paraganglioma, which can also produce dopamine and its metabolite methoxytyramine. However, this is rare. 8 The biochemical synthesis of the different catecholamines and their metabolites is shown in Figure 1.
Pheochromocytomas can affect individuals of all ages. They are common in people aged between 40 and 50 years, and relatively more common among females. Adrenal pheochromocytomas constitute nearly 85% of cases of pheochromocytomas, with 15% being extra-adrenal paragangliomas that affect the sympathetic ganglions anywhere from the base of the brain to the urinary bladder.1,2 Laboratory diagnosis is usually achieved by measuring the catecholamines, or more importantly their metabolites in plasma or urine. Although different markers, including catecholamines and vanillylmandelic acid, are utilized as diagnostic tests, total and fractionated metanephrines in plasma or urine provide the best valid laboratory test for excluding or confirming pheochromocytoma. 2,9 In addition, chromogranin A is another reliable marker for neuroendocrine tumors, including pheochromocytoma and is increasingly used in the diagnostic workup and follow-up of patients with these tumors.4 Following diagnosis, removal of the adrenal gland or the tumor is done by open surgery or by the laparoscopic technique, which is considered the ‘gold standard’ treatment choice since 1992.10-12
O M A N M E D J, V O L 3 0 , N O 5 , S E P T E M B E R 2015
384
Waad -A ll ah S. Mul a-A bed, et.al
Table 1: Plasma levels of catecholamines (and their metabolites), renin, aldosterone, cortisol, and chromogranin A compared to the recommended adult’s reference ranges in the preoperative week. One- week post-operative levels are provided for plasma metanephrine, normetanephrine and 24-hour urine cortisol. Laboratory test
Preoperative result
Postoperative result
Reference range
Dopamine (pmol/L)
