Wei-Chou Lin md, Department of Pathology, National Taiwan University Hospital, No. 7, Chung-Shan S. Road, Taipei 100, Taiwan. Email: email@example.com
Background: Malignant pheochromocytomas are rare. Many controversies still exists in clinical practice. We report the clinical and histological data of long-term follow up in 10 patients with malignant pheochromocytoma.
Methods: The clinical charts of 10 patients with malignant pheochromocytoma from a single institute were reviewed. The diagnosis of pheochromocytoma was confirmed at surgery. All patients had metastases in sites where chromaffin tissue was normally absent.
Results: The median follow-up period was 5.5 years (range, 2–20 years). Extra-adrenal tumors occurred in four patients including paraganglioma tumors in three cases and bladder tumor in one case. Regional lymph node metastases were noted in six patients. Distant metastases were located in the lungs of two patients, in the bones of two patients and in the liver of one patient. Histological characteristics were not helpful for diagnosis of malignancy and for prediction of prognosis. Metastases were present in postoperative pathology in seven patients. In another three patients, metastases were discovered 6 months to 10 years after surgery. Three patients received chemotherapy and one patient received combination therapy of high-dose 131I-meta-iodobenzylguanidine (131I-MIBG) therapy and chemotherapy. All patients achieved long-term survival except for two who died of metastasis 1.5 years and 2 years after diagnosis.
Conclusions: Early complete resection and adjunctive lymphadenectomy can cure malignancy. Close long-term follow up for more than 10 years after surgery is necessary in patients with pheochromocytoma. The possibility of malignancy should be kept in mind even though the initial pathology is benign.
Pheochromocytomas are rare tumors arising in chromaffin cells of the adrenal medulla or paraganglia. The annual incidence of pheochromocytoma is not precisely known. Pheochromocytomas are usually benign, but they may also present as, or develop into, a malignancy. The prevalence of malignancy has been reported to be 5–26% of pheochromocytoma.1,2 There are no reliable histological or biochemical markers for distinguishing benign from malignant tumors. The diagnosis of malignancy requires evidence of metastases to the site where chromaffin cells do not exist. Early diagnosis of malignant pheochromocytoma is difficult. Currently, controversies still exist in diagnosis, treatment and prognosis in this rare disease.2 We retrospectively reviewed the medical records of 64 patients with pheochromocytoma in our institution from January 1984 to December 2004. Ten patients (15.6%) were found with malignant pheochromocytoma. We attempt to establish the clinical and pathological characteristics of malignant pheochromocytoma for clinical utility.
Materials and methods
The medical records of 10 patients with malignant metastatic pheochromocytoma treated at our hospital were analyzed. All patients had metastases in sites where chromaffin tissue was normally absent. The diagnosis of pheochromocytoma was confirmed by postoperative pathology in all patients. Factors including age, gender, clinical presentations, catecholamine-associated complications, biochemical profile, treatment, pathological characteristics and prognosis were studied. Long-term follow up was carried out by means of re-examination of the patients in outpatient clinics or by personal contact.
The clinical characteristics of the 10 patients are shown in Table 1. There were seven men and three women. Their ages ranged 14–61 years (mean, 37.5). The median follow-up period was 5.5 years (range, 2–20 years). Hypertension, headache and palpitation were the prominent symptoms. One patient had incidentaloma and was not obviously symptomatic. Two patients presented with cardiogenic shock, which was associated with catecholamine-associated cardiomyopathy. Three patients had hypertensive retinopathy. One patient (case 4) matched the diagnosis of multiple endocrine neoplasia (MEN) type IIA (medullary carcinoma of the thyroid, parathyroid adenoma) and had a family history. Intra-adrenal pheochromocytoma was presented in seven patients including bilateral sides in one patient, the right side in three patients and the left side in three patients. Extra-adrenal pheochromocytoma occurred in the other four patients including paraganglioma tumors in three patients and a urinary bladder tumor in one patient. Synchronous multifocal lesions were noted in one patient (case 10) with a right adrenal tumor and paraganglioma.
Table 1. Characteristics of 10 patients with malignant pheochromocytoma
0 (died of ventricular arrhythmia on 3rd day after operation)
Adrenal: 5 × 4 × 3; paraganglioma: 5 × 5 × 4
Tumor resection, LN dissection
Died of ventricular arrhythmia on post-op 3rd day.
The diagnosis of malignancy was established in seven patients by identifying metastases by postoperative pathology. Among them, six patients had regional lymph node metastasis and one had concomitant liver and lymph node metastasis. In the other three patients, malignancy was diagnosed by subsequent development of distant metastasis (lungs and bones) 6 months to 10 years after resection of the primary tumor.
Biochemical profiles were helpful in the diagnosis of the primary tumor. Subsequent metastases could be established by measuring 24-h urine catecholamines and their metabolites. Preoperative 24-h urine vanillylmandelic acid (VMA) values were all elevated, varying 9.4–160 mg/24 h (mean, 24.5 mg/24 h) in the nine patients tested. Among them, it is noteworthy that three patients had elevated 24-h urine adrenaline levels (range, 20–101 μg/24 h), four had elevated noradrenaline levels (range, 45.9–603 μg/24 h) and four had elevated dopamine levels (range, 12.3–248 μg/24 h) in six patients tested. The measurement of serum noradrenaline and adrenaline were performed in one patient (case 9) and noradrenaline was found to be elevated (154.5 nmol/L). Surgical excision of the primary tumor was performed in all patients. Their catecholamine-associated symptoms and biochemical data all improved postoperatively. In three patients with subsequent distant metastasis, abnormal 24-h urine VMA values were all detected before the diagnosis of metastasis.
131I-meta-iodobenzylguanidine (131I-MIBG) uptake was found in five patients tested initially. Neither 131I-MIBG nor computed tomography (CT) scan were able to detect the small regional lymph node metastasis in any patient. 131I-MIBG was sensitive towards showing synchronous tumors (right adrenal and paraganglioma) in case 10. For localization of subsequent distant metastasis in three patients (cases 1, 7 and 8), two had an uptake of 131I-MIBG, and one had positive positron emission tomography (PET) imaging with (18F) fluorodeoxyglucose (18F-FDG-PET).
One patient (case 1) with lung and bone metastasis received combined chemotherapy (vincristine, adriamycin, cisplatin) with high-dose 131I-MIBG therapy. He achieved long-term survival for over 20 years. Three patients received chemotherapy. Two patients (case 8 and 11) died of metastatic disease 1.5 and 2 years after diagnosis, respectively. One patient (case 3) with only regional lymph node metastasis achieved recurrence-free survival for 3 years.
Tumor size (maximal diameter) ranged 5–14 cm. Histological findings are listed in Table 2. Some features are regarded as being associated with the increased incidence of malignant behaviors such as tumor necrosis, a mitotic rate greater than 3/30 high-power microscopic field (HPF), capsular invasion, vascular invasion and large nests with central degeneration, a lack of hyaline globules, a high nuclear/cytoplasmic ratio, monotony of cytological pattern, and spindle cell patterns.2–4 The representative microscopic picture of lymph node metastasis and primary adrenal malignant pheochromocytoma are shown in Figures 1 and 2.
In the series of 10 patients with histologically confirmed pheochromocytoma, malignancy was diagnosed by metastases to the site where chromaffin cells do not exist. There are no definitive clinical or biochemical markers for distinguishing benign from malignant tumors.2–4 The measurement of catecholamines and their metabolites in plasma or urine is not useful in differentiating benign from malignant lesions despite various reports that claim dopamine levels are higher in malignant lesions than in benign lesions.2,4,5 Both 131I-MIBG and 18F-FDG-PET are useful for localization of subsequently metastatic lesions. 18F-FDG-PET provides another alternative choice and has yielded encouraging results.6–8 In our series, false-negative findings of 131I-MIBG in preoperative detection of metastatic lymph nodes were noted in all five patients. There are two possible reasons for this high false-negative rate: (i) the low affinity of 131I-MIBG for small lymph nodes; and (ii) the early scanning. Furuta et al. reported the quality of image using 123I-MIBG is better than that obtained using 131I-MIBG because 123I-MIBG generates a higher dose of γ-rays with a higher sensitivity and accuracy than 131I-MIBG.9123I-MIBG can be used as an alternative to 131I-MIBG for accurate preoperative localization of small lymph nodes. Genetic analysis and some molecular markers have been reported to be able to predict clinical tumor behavior.2,10 Human telomerase reverse transcriptase has been reported to be more commonly expressed in malignant pheochromocytoma compared with benign pheochromocytoma.2,11 There are still no available markers for clinical utility.
The distinction between benign and malignant pheochromocytoma has long been problematic, with the only widely accepted and definitive proof of malignancy being metastasis to other organs. Tumors with benign histological features may metastasize, while tumors with some histological bizarre pleomorphism may have a benign course. Some features have been regarded to be associated with an increased incidence of malignant behaviors such as tumor necrosis, a mitotic rate of greater than 3/30 HPF, capsular invasion, vascular invasion, large nests with central degeneration, a lack of hyaline globules, a high nuclear/cytoplasmic ratio, monotony of a cytological pattern and spindle cell patterns.2–4 In our series, there still exists some exceptions to each feature, and no single criterion has proven entirely reliable. However, the tumor size gives us some hints. All the tumors had a maximal diameter in excess of 5 cm. When the diameter of the tumor is over 5 cm, the possibility of malignancy should be kept in mind.
Pheochromocytoma occurs in approximately 50% of patients with MEN-IIA. Compared with sporadic cases of pheochromocytoma, the familial variety within MEN-IIA syndrome has bilateral pheochromocytoma in over 50% of cases. The pheochromocytomas in MEN-IIA usually produce adrenaline as is presented in our case 9. Pheochromocytomas are benign in most patients with MEN-IIA; however, malignant pheochromocytoma with regional lymph node metastasis was identified in our case.4,10,12,13
Complete surgical removal of the tumor is the treatment of choice. Minimally invasive techniques with laparoscopic adrenalectomy have been the gold standard in the treatment of adrenal tumors. In the absence of apparent invasion or metastatic disease, the laparoscopic approach can be safely proposed for pheochromocytoma. However, if the adrenal pheochromocytoma is suspected as malignant, laparoscopic surgery may not be indicated. Open conversion with regional lymph node dissection is necessary in the presence of larger tumor sizes over 5 cm in diameter, local invasion or difficult dissection that could result in inadequate resection of malignant disease. Surgical mortalities range 0–3.3%, depending on the center.1,4,10,12–14 In our series, one patient developed ventricular arrhythmia postoperatively despite administration of phenoxybenzamine and propranolol before the operation. Locally aggressive tumors with invasion of adjacent tissues or regional lymph node metastases may be adequately treated by radical surgery.4,7,13–15 We recommend regional lymphadenectomy for all patients with suspicious or apparent lymph node enlargement noted preoperatively or intraoperatively. It is especially important in patients whose tumor size is over 5 cm in diameter.
Without treatment, 5-year survival is generally less than 50%. The course, however, can be highly variable. Some patients die with a rapidly progressive course. Some patients may follow a prolonged and indolent course. However, the usual prognosis is reported to be poor because of dissemination to various organs along with heart failure associated with hypercatecholaminemia.2,4,7,13–16 Our series had a long-term follow up during with a median period of 5.5 years. Our data demonstrates that complete excision of the primary tumor with lymphadenectomy can achieve an excellent prognosis. Even if distant metastasis occurs, survival for more than 20 years is possible (case 1). Follow up of serum and urinary catecholamines and their metabolites is a useful tool for monitoring patients with recurrent or metastatic disease.
The effect of radiotherapy and chemotherapy is not good in metastatic malignant pheochromocytomas. High-dose 131I-MIBG radionuclide therapy helps in relief of symptoms, hormonal response and tumor burden.8,17 Some reports have shown that a combination of 131I-MIBG and cytotoxic chemotherapy produces additive effects in reducing tumor volume and function.4,13,18–20 In our series, a combination of chemotherapy and a high dose of 131I-MIBG therapy achieved palliation of the symptoms of catecholamine hyperproduction along with prolonged survival.
Metastases may be microscopic at the time of initial surgery. In our series, metastasis may have been present at initial diagnosis or may have become evident 10 years after surgical removal of the primary tumor. Long-term biochemical screening should continue at yearly intervals. Long-term follow up for over 10 years is necessary for patients with benign pheochromocytoma, especially for those whose tumors are judged by existing risk for malignancy such as having a large tumor diameter over 5 cm or histopathological criteria for malignancies.
Malignant pheochromocytoma remains a challenging entity in diagnosis and treatment. Because the diagnosis of malignancy may rely upon subsequent clinical behavior, close long-term follow up of patients with pheochromocytoma is needed. We should keep in mind that metastatic disease in pheochromocytoma may be present at the time of initial diagnosis or may only become evident 10 or more years later after surgical removal of the primary tumor. Radical surgery with adjunctive lymphadenectomy is feasible for patients with tumors of more than 5 cm and is especially important for patients with suspicious or apparent lymphadenopathy.