|Year : 2012 | Volume
| Issue : 1 | Page : 188-193
Pheochromocytoma in Indian patients: A retrospective study
R Krishnappa, SB Chikaraddi, HN Arun, V Deshmane
Department of Surgical Oncology, KMIO, Bangalore, India
|Date of Web Publication||25-Jul-2012|
S B Chikaraddi
Department of Surgical Oncology, KMIO, Bangalore
Aim: To review the clinical experience on pheochromocytoma in Indian subset of patients. Materials and Methods: Ten patients diagnosed with pheochromocytoma between 2001 and 2010 at our institute were retrospectively studied for clinical, laboratory, radiological and surgical data. Results: A total of 10 patients (5 females and 5 males) aged between 23 and 64 years diagnosed as pheochromocytoma were managed at our institute. The most frequent symptoms were abdominal pain (90%) and hypertension (50%). The tumor was intra-adrenal in 70% and extra-adrenal in 30%. 20% were on right side and 50% on left side. CT scan of abdomen was the most widely used method for tumor localization. Among laboratory assays, 24-h urinary vanillylmandelic acid (VMA) was the most widely used. None of our patients were found to be associated with hereditary pheochromocytoma syndrome. All hypertensive patients were preoperatively treated with phenoxybenzamine and propranolol. All underwent explorative laparotomy and adrenelectomy. Malignancy was reported in 40% of cases and these received adjuvant radiotherapy. Among hypertensive patients, surgery caused remission of hypertension in 60%. All patients were followed up with 24-h urinary VMA levels and CT scan of abdomen regularly. Survival ranged from 1 to 9 years. Conclusions: The present study confirms that the clinical presentation of pheochromocytoma is variable and non-specific. Often the tumor is discovered incidentally. Though pheochromocytoma is a rare tumor, proper evaluation, preoperative preparation and complete surgical excision are important for its management.
Keywords: Adrenal mass, neuroectodermal tumor, pheochromocytoma
|How to cite this article:|
Krishnappa R, Chikaraddi S B, Arun H N, Deshmane V. Pheochromocytoma in Indian patients: A retrospective study. Indian J Cancer 2012;49:188-93
| » Introduction|| |
Pheochromocytoma is a rare catecholamine-producing tumor of neuroectodermal origin arising from chromaffin cells. Incidence is around 1 to 2 per million population. Poll coined the term pheochromocytoma in 1905 when he described the dusky (Pheo) color (Chromo) of the cut surface of the tumor when exposed to dichromate. , An overwhelming 90% of all cases arise from adrenal medulla where the biggest collection of chromaffin cells is found. Extra-adrenal pheochromocytoma (also called paragangliomas) is usually encountered intra-abdominally along the sympathetic chains or from the organs of Zuckerkandl.  Intra-thoracic pheochromocytoma (<1%) is also related to the sympathetic chain. Other extra-adrenal sites are intrapericardial, , inter-atrial septum,  prostate  and urinary bladder.
The first clinical description of pheochromocytoma was by F. Frankel in 1886 when a young female patient with a history of episodic attacks of headaches, palpitations and anxiety died suddenly. Post-mortem examination showed bilateral adrenal medulla tumors. The first surgical excision of the pheochromocytoma was reported in 1927 by Roux who described removal of a suprarenal tumor in a patient with a two-year history of episodic vertigo and nausea. This feat was soon reported in USA by Mayo. ,
Familial pheochromocytoma in association with medullary carcinoma of the thyroid and parathyroid gland hyperplasia or adenoma have been designated as multiple endocrine neoplasia syndrome type II A (MEN IIA or Sipple's syndrome) .MEN type IIB is the coexistence of pheochromocytoma and medullary thyroid carcinoma with gastrointestinal ganglioneuromatosis (benign mucosal neuromas in lips, tongue, buccal cavity), benign mucosal neuromas in eye lids conjuctiva and cornea, and marfanoid features. Pheochromocytoma is also recorded as a first manifestation of von-Hippel-Lindau disease, an autosomal dominant disorder characterized by the development of hemangioblastomas in the cerebellum, spinal cord and retina, renal cell carcinoma and cysts, pancreatic cysts and pheochromocytoma. There is also an increased prevalence of pheochromocytoma among patients with von-Recklinghausen's disease. 
Pheochromocytomas account for 0.1% of all patients with hypertension and can present with a highly variable clinical picture. These two characteristics (rarity and variability) render these tumors very difficult to diagnose so that many of them are discovered incidentally during radiological examinations (especially of the abdomen) or at autopsy. A better understanding of the pathophysiology of this disease would result in an improvement in the outcome. Advances have also been made in recent years in regards to preoperative radiological and biochemical evaluation to localize these tumors. 
Studies evaluating the clinical presentations of pheochromocytoma in Indian population have not been done. This study describes the first 10 year experience with respect to the diagnosis and management of pheochromocytoma in Indian patients.
| » Materials and Methods|| |
We retrospectively evaluated the data of ten patients diagnosed of pheochromocytoma between 2001 and 2010 at our institute. Demographic data, clinical symptoms, familial disease, pre- or post-operative urinary concentrations of VMA, localization procedures, preoperative pharmacological treatment, surgical findings, and follow up status were recorded and analyzed.
| » Results|| |
In our hospital, 10 patients underwent resection of pheochromocytoma over the 10-year period from 2001 to 2010. At presentation, their ages ranged from 23 to 64 (mean, 39) years. Age distribution is shown in [Table 1]. Five patients were males and five were females. None of our patients were associated with the familial form of pheochromocytoma.
The frequency of different clinical features is detailed in [Table 2]. Abdominal pain was the most common presentation (90%), followed by hypertension (50%). Chest pain and nausea (30%) and sweating, palpitation, constipation, giddiness, menorrhagia(20%) accounted for the rest of the symptoms. None of our patients were incidentally detected to have the tumor.
Biochemical and pathological evaluation
All patients had 24-h urinary VMA levels measured, of whom 3 (30%) had elevated urinary VMA levels. VMA levels ranged from 2.8 mg to 36.5 mg (Normal -- <13.5 mg for 24 h). Plasma-free metanephrines and plasma catecholamines were not measured in our patients.
Computed tomographic scan of abdomen and pelvis was used to localize the tumor in all our patients. CT scan localized the tumor in all ten patients and thus yielded 100% sensitivity.
Metaiodobenzylguanidine (MIBG) was done in one patient with positive result.Tc-99 octreotide scan was done in one patient. In our study 7 (70%) were intra-adrenal and 3 (30%) extra-adrenal. All extra adrenal tumors were located in para aortic region. Among intra-adrenal, 5 (71%) tumors were located on left side and 2 (29%) on right side. The size of the tumor was taken as its largest dimension as determined by CT scan of abdomen. Size of tumors ranged from 3.5 to 16 cm. None showed evidence of malignancy as judged by local infiltration or presence of metastasis [Figure 1], [Figure 2].
|Figure 2: Contrast enhanced CT scan of abdomen showing right pheochromocytoma|
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All hypertensive patients received phenoxybenzamine and propranolol before the operation.
Arterial line placement and preoperative correction of intravascular volume was done in all patients.
Intraoperative events and adjuvant therapy
All our patients underwent open laparotomy. Midline incision with lateral extension was used in all cases. Adrenal vein was ligated first and minimal handling of tumor was done in all cases. In four of our patients infiltration into gerota's fascia was present. One patient developed hypertensive crisis (BP-270/200mm Hg) and cardiac arrest during the procedure. Patient was successfully resuscitated and procedure abandoned. Later second laparotomy was planned and tumor excision done. Malignancy was reported in 40% of cases. All malignant patients received adjuvant radiotherapy [Figure 3], [Figure 4].
|Figure 3: Intraoperative photograph showing left adrenal pheochromocytoma|
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Blood pressure changes after surgery
Five (50%) patients were taking antihypertensive drugs before the surgery, and out of these after surgery two (40%) continued to have hypertension. Surgery cured hypertension in three (60%) patients.
All patients were followed up regularly with 24-h urinary VMA and CT scan of abdomen. Survival is shown in [Table 3]. Survival ranged from 1 to 9 years. There was no evidence of local recurrence in any of our patients. During follow up period, two patients developed liver metastasis and one patient pleural effusion. These patients were treated with palliative care.
Summary of demographic and clinical data is shown in [Table 4].
| » Discussion|| |
Most of the patients in our study belonged to younger age group with mean age being 39 years. Pheochromocytoma was equally found in both males and females in our study. The present study showed wide variability in symptoms as in previous studies.  The presence of a paroxysmal event which, although aspecific, has always been considered as a hallmark, has been reported by only 2 out of 10 patients in our study. In contrast to previous studies,  the most frequent symptoms were abdominal pain and hypertension while frequency of other symptoms was rather low. Therefore, in view of the very low sensitivity of any symptom or of any association of them, the clinical suspicion is often extremely difficult. This difficulty can explain the long mean time lag between initial symptoms and diagnosis and why, quite often, pheochromocytoma is discovered as an incidental adrenal mass or at autopsy. Therefore, the most frequent reason for suspecting pheochromocytoma is hypertension, especially if paroxysmal or resistant, especially if accompanied by an adrenal mass.
None of our patients were associated with the familial form of pheochromocytoma. Though none of our patients were incidentally discovered, data from previous studies confirm that pheochromocytomas have to be taken into account in the differential diagnosis of adrenal incidentalomas and that the absence of hypertension does not rule out the presence of a pheochromocytoma.  In our study, 50% of patients were hypertensive both in the supine and upright positions. One patient developed hypertensive crisis (BP-270/200mm Hg) and cardiac arrest intraoperatively.
Studies have shown that aneuploid or tetraploid DNA occurred more frequently in malignant tumors and that diploid DNA did not develop metastasis.  Malignant pheochromocytomas may express more c-myc oncogene.  Levels of neuropeptideY and enolase are slightly higher in malignant pheochromocytomas when compared with benign pheochromocytomas.  Genetic testing was not used in our study.
The biochemical method used for the diagnosis of pheochromocytoma in our study was 24-h urinary VMA levels. This finding is in agreement with the data reported in the literature, ,, but use of more sensitive assays such as urinary and plasma free metanephrines should be considered for better sensitivity and specificity. Results indicate similarly high sensitivity of plasma total or free or urinary metanephrines for the diagnosis of pheochromocytoma. All three measurements provide clearly better clues to detect this tumor compared with the classical determination of plasma catecholamines.  To date, none of these tests appear to be able to detect pheochromocytoma before the others at an earlier time of tumor development.  A normal value of any of these does not exclude the presence of a pheochromocytoma. Recent studies indicate plasma free metanephrines as the most sensitive diagnostic index. 
Localization of the tumor relies mainly on CT scan of abdomen.  Nevertheless, due to the frequency of incidental adrenal masses, MIBG scintigraphy should also be performed before surgery. In the present study, CT scan of abdomen was used in all cases for localization with 100% sensitivity while MIBG scan was used in one patient. In contrast to other studies, the left adrenal gland was more commonly affected than the right one. In our study, 3 out of 10 tumors were extra-adrenal, which is in line with most recent studies in which ectopic tumors comprise 10 to 29% of the adult pheochromocytomas. The 10% rule is no longer applied;  the higher rate may well reflect increased disease awareness and improved tumor localizing facility since the last century. None of Our tumors showed evidence of malignancy as judged by local infiltration or presence of metastasis.
As in previous studies,  preoperative preparation formed an important part of management in our study. All hypertensive patients received phenoxybenzamine and propranolol before the operation. Arterial line placement and preoperative correction of intravascular volume was done in all patients. In the present study, surgical findings are in close agreement with those reported in the literature. One patient developed hypertensive crisis (BP-270/200mm Hg) and cardiac arrest during the procedure. Patient was successfully resuscitated and procedure abandoned. Later second laparotomy was planned and tumor excision done. Malignancy was reported in 40% of cases. All malignant patients received adjuvant radiotherapy and one received combination chemotherapy.
The effects of surgery on BP were documented in our study by the disappearance of hypertension in about 60% of patients. BP did not change significantly after surgery in 40% of our patients with hypertension indicating, as suggested by others, the presence of other causes of hypertension or nonreversible catecholamine-induced structural changes in the cardiovascular system or delay in diagnosis. 
As mentioned earlier, all patients were followed up regularly with 24-h urinary VMA and CT scan of abdomen. Survival ranged from 1 to 9 years. In contrast to other studies, there was no evidence local recurrence in any of our patients while two patients developed liver metastasis and one patient pleural effusion during follow up.
| » Conclusion|| |
Though the pheochromocytoma is a rare tumor, proper evaluation, preoperative preparation and complete surgical excision can cure the patient. The present study confirms that the clinical presentation of pheochromocytoma is variable and aspecific. Hypertension is present in half of the cases and often the tumor may be discovered incidentally. CT-scans are almost always successful in localizing the tumor. Surgery cures or ameliorates hypertension in most of the patients. Delay in the diagnosis seems to be responsible for the irreversibility of hypertension after surgery.
| » Acknowledgment|| |
Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore. Department of Anaesthesia, Kidwai Memorial Institute of Oncology, Bangalore.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]