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Case Study
Pheochromocytoma and tetralogy of Fallot: Coincidence or a rare association?
Asian Cardiovascular & Thoracic Annals 0(0) 1–3 ß The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492314545499 aan.sagepub.com
Gagan Deep Singh1, Subramanian Anuradha1, Prayas Sethi1, Sumeet Singla1, Ravindra Kumar Saran2 and Richa Dewan1
Abstract We report the case of a 25-year-old woman with tetralogy of Fallot who presented with chest pain and hypertension, and on further investigation, was diagnosed with a pheochromocytoma in the right adrenal gland. She underwent surgical excision of the tumor. While the simultaneous occurrence of these two diseases is extremely rare, the suspicion of a possible relationship has been raised in the past.
Keywords Adrenal gland neoplasms, Anoxia, Heart defects, congenital, Pheochromocytoma, Tetralogy of Fallot
Introduction Pheochromocytomas are rare neuroendocrine tumors that originate from neuroectodermal chromaffin cells of the adrenal medulla. One third of neuroendocrine tumors (pheochromocytomas and paragangliomas) are associated with various genetic disorders such as multiple endocrine neoplasia type 2, von HippelLindau syndrome, von Recklinghausen’s fibromatosis, Sturge-Weber’s disease, and Carney’s syndrome. We describe the rare occurrence of pheochromocytoma in a patient with tetralogy of Fallot (TOF). A few cases of congenital heart disease with neuroendocrine tumors have been reported in the United States and Japan.1–4 Only one case of uncorrected TOF with a pheochromocytoma has been reported from India.5 Although the possibility of a relationship between the two diseases has been speculated in the past, definite evidence and etiopathogenesis are elusive.
Case report A 25-year-old woman diagnosed with uncorrected TOF presented to the emergency department with complaints of breathlessness at rest and chest pain for one day. She also complained of 6–8 episodes of vomiting, constipation, and abdominal pain. There was no history of fever, headache, or sweating. Her blood pressure was 150/90 mm Hg and her pulse rate
was 150 beats min 1 and regular. She was cyanotic and had grade III digital clubbing. Cardiovascular examination revealed a loud first heart sound and a single second sound. There were bilateral basilar rales in the chest, but the abdominal examination was unremarkable. An electrocardiogram demonstrated sinus tachycardia, right bundle branch block, and right atrial enlargement with right ventricular hypertrophy. Laboratory investigations showed hemoglobin 17.7 g dL 1 and oxygen saturation 70% with a PaO2 of 24 mm Hg on arterial blood gas analysis. Radiographs of the abdomen (erect and supine) were normal. The patient was initially managed with O2 inhalation, beta blockers, and intravenous furosemide for heart failure, and she improved symptomatically. The abdominal symptoms (distension and pain) also improved when she passed stools 5–6 h after admission. Echocardiography confirmed cyanotic congenital heart disease: TOF with normal biventricular function. A subsequent measurement of blood pressure after 1 Department of Medicine, Maulana Azad Medical College Hospital and Associated Hospitals, New Delhi, India 2 Department of Pathology, GB Pant Hospital, New Delhi, India
Corresponding author: Subramanian Anuradha, Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi 110002, India. Email: [email protected]
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Figure 1. (A) Transverse and (B) coronal computed tomography views of the abdomen, showing a right suprarenal mass (arrows).
Figure 2. (A) Neoplastic cells arranged in nests with thickened fibrovascular cores traversing the tumor cells and the capsule. Hematoxylin and eosin stain, magnification 50. (B) Bizarre tumor cell forms with nuclear pleomorphism and smudging of chromatin. Hematoxylin and eosin stain, magnification 100.
admission, when the patient complained of severe headache, was 210/110 mm Hg. An abdominal ultrasound revealed a right suprarenal mass that was confirmed on contrast-enhanced computed tomography of the abdomen. There was a heterogeneously enhancing soft tissue mass in the right suprarenal region, with areas of necrosis within, and maintained fat planes with adjacent liver, inferior vena cava, and right kidney. A mass effect was evident with a mild indentation on the upper pole of the right kidney (Figures 1A, 1B). The 24-h urine epinephrine and norepinephrine levels, using high-performance liquid chromatography, demonstrated norepinephrine 3188.20 mg/24 h (normal: 20–105 mg/24 h) and epinephrine 76.8 mg/24 h (normal: 4–20 mg/24 h). The patient was prescribed extended-release prazosin 2.5 mg for blood pressure control. Subsequently, she underwent a complete right adrenalectomy. Histopathological examination of the mass revealed an encapsulated tumor composed of neoplastic cells arranged in nests (Zellballen pattern) and smudging of nuclear chromatin which was consistent with a diagnosis of pheochromocytoma (Figure 2A, 2B). Specific staining for neuroendocrine tumors using chromogranin A was confirmatory (Figure 3). The patient is being assessed and worked up for repair of TOF.
Figure 3. Histopathology of the pheochromocytoma with chromogranin A stain. Magnification 400.
Discussion The incidence of congenital heart disease among all live births in India has been reported to be 0.5%–0.8%. TOF is the second most common congenital heart disease after ventricular septal defect, seen in 17.86% of all congenital heart disease cases. The simultaneous occurrence of pheochromocytoma and TOF is extremely rare and few case reports exist in the global literature.
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Cases of TOF with pheochromocytoma have been reported in the USA since the 1960s.1 A case series of 15 patients described by de la Monte and colleagues1 found a statistically significant correlation between congenital heart disease and neuroendocrine tumors.1 Folger and colleagues2 reported 5 cases of cyanotic malformation of the heart with pheochromocytoma, and 2 cases of TOF with pheochromocytoma were described by Kita and colleagues4 in Japanese patients in their early forties who had undergone surgical repair of TOF in childhood. There is speculation that chronic hypoxia possibly leads to the development of pheochromocytoma. Cheek and colleagues6 found considerably increased plasma levels of epinephrine and norepinephrine in premature infants with placental insufficiency and postmaturity. In a study of two patients who died due to severe hypertension, Bialestock7 reported adrenal medullary hyperplasia in each case, and attributed its occurrence to increased functioning of the adrenal medulla. Sherwin8 also noted a histological relationship between adrenal medullary hyperplasia and neoplasia. In the light of this evidence, it is conceivable that chronic hypoxic states can give rise to adrenal medullary hyperplasia, eventually leading to pheochromocytoma. While this hypothesis has been suggested before, the detailed mechanism of congenital heart disease leading to the production of a pheochromocytoma has yet to be elucidated. There is another point of clinical interest here. When patients with TOF have vasodilation due to numerous aortopulmonary collaterals, excessive sweating and flushing is uncommon (probably masked by the intense cyanosis and vasodilatation of TOF). Episodic hypertension, headaches, and hyperglycemia offer valuable clues and should raise a high degree of suspicion of pheochromocytoma in a patient with cyanotic heart disease. The diagnosis of pheochromocytoma in such patients is of the utmost importance before cardiac catheterization or operative procedures because sudden death has been reported in patients with
pheochromocytoma during such procedures and on induction of anesthesia. Acknowledgement The authors wish to acknowledge Dr. Anil Agarwal, Director Professor and Head of Gastro-Surgery Department, GB Pant Hospital, along with his team, for the surgical expertise and management.
Funding This research received no specific grant from any funding agency in the public, commerical, or not-for-profit sectors.
Conflict of interest statement None declared.
References 1. de la Monte SM, Hutchins GM and Moore GW. Peripheral neuroblastic tumors and congenital heart disease. Possible role of hypoxic states in tumor induction. Am J Pediatr Hematol Oncol 1985; 7: 109–116. 2. Folger GM Jr, Roberts WC, Mehrizi A, et al. Cyanotic malformations of the heart with pheochromocytoma: a report of five cases. Circulation 1964; 29: 750–757. 3. Reynolds JL and Gilchrist TF. Congenital heart disease and pheochromocytoma. Am J Dis Child 1966; 112: 251–255. 4. Kita T, Imamura T, Date H, et al. Two cases of pheochromocytoma associated with tetralogy of Fallot. Hypertens Res 2003; 26: 433–437. 5. Balakrishnan G, Ravikumar R, Rao S and Balakrishnan KR. Tetralogy of Fallot with pheochromocytoma: an unusual therapeutic challenge. Asian Cardiovasc Thorac Ann 2013; 21: 464–466. 6. Cheek DB, Malinek M and Fraillon JM. Plasma adrenaline and noradrenalin in the neonatal period, and infants with respiratory distress syndrome and placental insufficiency. Pediatrics 1963; 31: 374–384. 7. Bialestock D. Hyperplasia of the adrenal medulla in hypertension of children. Arch Dis Child 1961; 36: 465. 8. Sherwin RP. Histopathology of pheochromocytoma. Cancer 1959; 12: 861–877.
Downloaded from aan.sagepub.com at UNIV NEBRASKA LIBRARIES on August 27, 2015
(AAN)
[1–3] [PREPRINTER stage]
Case Study
Pheochromocytoma and tetralogy of Fallot: Coincidence or a rare association?
Asian Cardiovascular & Thoracic Annals 0(0) 1–3 ß The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492314545499 aan.sagepub.com
Gagan Deep Singh1, Subramanian Anuradha1, Prayas Sethi1, Sumeet Singla1, Ravindra Kumar Saran2 and Richa Dewan1
Abstract We report the case of a 25-year-old woman with tetralogy of Fallot who presented with chest pain and hypertension, and on further investigation, was diagnosed with a pheochromocytoma in the right adrenal gland. She underwent surgical excision of the tumor. While the simultaneous occurrence of these two diseases is extremely rare, the suspicion of a possible relationship has been raised in the past.
Keywords Adrenal gland neoplasms, Anoxia, Heart defects, congenital, Pheochromocytoma, Tetralogy of Fallot
Introduction Pheochromocytomas are rare neuroendocrine tumors that originate from neuroectodermal chromaffin cells of the adrenal medulla. One third of neuroendocrine tumors (pheochromocytomas and paragangliomas) are associated with various genetic disorders such as multiple endocrine neoplasia type 2, von HippelLindau syndrome, von Recklinghausen’s fibromatosis, Sturge-Weber’s disease, and Carney’s syndrome. We describe the rare occurrence of pheochromocytoma in a patient with tetralogy of Fallot (TOF). A few cases of congenital heart disease with neuroendocrine tumors have been reported in the United States and Japan.1–4 Only one case of uncorrected TOF with a pheochromocytoma has been reported from India.5 Although the possibility of a relationship between the two diseases has been speculated in the past, definite evidence and etiopathogenesis are elusive.
Case report A 25-year-old woman diagnosed with uncorrected TOF presented to the emergency department with complaints of breathlessness at rest and chest pain for one day. She also complained of 6–8 episodes of vomiting, constipation, and abdominal pain. There was no history of fever, headache, or sweating. Her blood pressure was 150/90 mm Hg and her pulse rate
was 150 beats min 1 and regular. She was cyanotic and had grade III digital clubbing. Cardiovascular examination revealed a loud first heart sound and a single second sound. There were bilateral basilar rales in the chest, but the abdominal examination was unremarkable. An electrocardiogram demonstrated sinus tachycardia, right bundle branch block, and right atrial enlargement with right ventricular hypertrophy. Laboratory investigations showed hemoglobin 17.7 g dL 1 and oxygen saturation 70% with a PaO2 of 24 mm Hg on arterial blood gas analysis. Radiographs of the abdomen (erect and supine) were normal. The patient was initially managed with O2 inhalation, beta blockers, and intravenous furosemide for heart failure, and she improved symptomatically. The abdominal symptoms (distension and pain) also improved when she passed stools 5–6 h after admission. Echocardiography confirmed cyanotic congenital heart disease: TOF with normal biventricular function. A subsequent measurement of blood pressure after 1 Department of Medicine, Maulana Azad Medical College Hospital and Associated Hospitals, New Delhi, India 2 Department of Pathology, GB Pant Hospital, New Delhi, India
Corresponding author: Subramanian Anuradha, Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi 110002, India. Email: [email protected]
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Figure 1. (A) Transverse and (B) coronal computed tomography views of the abdomen, showing a right suprarenal mass (arrows).
Figure 2. (A) Neoplastic cells arranged in nests with thickened fibrovascular cores traversing the tumor cells and the capsule. Hematoxylin and eosin stain, magnification 50. (B) Bizarre tumor cell forms with nuclear pleomorphism and smudging of chromatin. Hematoxylin and eosin stain, magnification 100.
admission, when the patient complained of severe headache, was 210/110 mm Hg. An abdominal ultrasound revealed a right suprarenal mass that was confirmed on contrast-enhanced computed tomography of the abdomen. There was a heterogeneously enhancing soft tissue mass in the right suprarenal region, with areas of necrosis within, and maintained fat planes with adjacent liver, inferior vena cava, and right kidney. A mass effect was evident with a mild indentation on the upper pole of the right kidney (Figures 1A, 1B). The 24-h urine epinephrine and norepinephrine levels, using high-performance liquid chromatography, demonstrated norepinephrine 3188.20 mg/24 h (normal: 20–105 mg/24 h) and epinephrine 76.8 mg/24 h (normal: 4–20 mg/24 h). The patient was prescribed extended-release prazosin 2.5 mg for blood pressure control. Subsequently, she underwent a complete right adrenalectomy. Histopathological examination of the mass revealed an encapsulated tumor composed of neoplastic cells arranged in nests (Zellballen pattern) and smudging of nuclear chromatin which was consistent with a diagnosis of pheochromocytoma (Figure 2A, 2B). Specific staining for neuroendocrine tumors using chromogranin A was confirmatory (Figure 3). The patient is being assessed and worked up for repair of TOF.
Figure 3. Histopathology of the pheochromocytoma with chromogranin A stain. Magnification 400.
Discussion The incidence of congenital heart disease among all live births in India has been reported to be 0.5%–0.8%. TOF is the second most common congenital heart disease after ventricular septal defect, seen in 17.86% of all congenital heart disease cases. The simultaneous occurrence of pheochromocytoma and TOF is extremely rare and few case reports exist in the global literature.
Downloaded from aan.sagepub.com at UNIV NEBRASKA LIBRARIES on August 27, 2015
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Cases of TOF with pheochromocytoma have been reported in the USA since the 1960s.1 A case series of 15 patients described by de la Monte and colleagues1 found a statistically significant correlation between congenital heart disease and neuroendocrine tumors.1 Folger and colleagues2 reported 5 cases of cyanotic malformation of the heart with pheochromocytoma, and 2 cases of TOF with pheochromocytoma were described by Kita and colleagues4 in Japanese patients in their early forties who had undergone surgical repair of TOF in childhood. There is speculation that chronic hypoxia possibly leads to the development of pheochromocytoma. Cheek and colleagues6 found considerably increased plasma levels of epinephrine and norepinephrine in premature infants with placental insufficiency and postmaturity. In a study of two patients who died due to severe hypertension, Bialestock7 reported adrenal medullary hyperplasia in each case, and attributed its occurrence to increased functioning of the adrenal medulla. Sherwin8 also noted a histological relationship between adrenal medullary hyperplasia and neoplasia. In the light of this evidence, it is conceivable that chronic hypoxic states can give rise to adrenal medullary hyperplasia, eventually leading to pheochromocytoma. While this hypothesis has been suggested before, the detailed mechanism of congenital heart disease leading to the production of a pheochromocytoma has yet to be elucidated. There is another point of clinical interest here. When patients with TOF have vasodilation due to numerous aortopulmonary collaterals, excessive sweating and flushing is uncommon (probably masked by the intense cyanosis and vasodilatation of TOF). Episodic hypertension, headaches, and hyperglycemia offer valuable clues and should raise a high degree of suspicion of pheochromocytoma in a patient with cyanotic heart disease. The diagnosis of pheochromocytoma in such patients is of the utmost importance before cardiac catheterization or operative procedures because sudden death has been reported in patients with
pheochromocytoma during such procedures and on induction of anesthesia. Acknowledgement The authors wish to acknowledge Dr. Anil Agarwal, Director Professor and Head of Gastro-Surgery Department, GB Pant Hospital, along with his team, for the surgical expertise and management.
Funding This research received no specific grant from any funding agency in the public, commerical, or not-for-profit sectors.
Conflict of interest statement None declared.
References 1. de la Monte SM, Hutchins GM and Moore GW. Peripheral neuroblastic tumors and congenital heart disease. Possible role of hypoxic states in tumor induction. Am J Pediatr Hematol Oncol 1985; 7: 109–116. 2. Folger GM Jr, Roberts WC, Mehrizi A, et al. Cyanotic malformations of the heart with pheochromocytoma: a report of five cases. Circulation 1964; 29: 750–757. 3. Reynolds JL and Gilchrist TF. Congenital heart disease and pheochromocytoma. Am J Dis Child 1966; 112: 251–255. 4. Kita T, Imamura T, Date H, et al. Two cases of pheochromocytoma associated with tetralogy of Fallot. Hypertens Res 2003; 26: 433–437. 5. Balakrishnan G, Ravikumar R, Rao S and Balakrishnan KR. Tetralogy of Fallot with pheochromocytoma: an unusual therapeutic challenge. Asian Cardiovasc Thorac Ann 2013; 21: 464–466. 6. Cheek DB, Malinek M and Fraillon JM. Plasma adrenaline and noradrenalin in the neonatal period, and infants with respiratory distress syndrome and placental insufficiency. Pediatrics 1963; 31: 374–384. 7. Bialestock D. Hyperplasia of the adrenal medulla in hypertension of children. Arch Dis Child 1961; 36: 465. 8. Sherwin RP. Histopathology of pheochromocytoma. Cancer 1959; 12: 861–877.
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