Increased expression of tenascin in pheochromocytomas correlates with malignancy.

Tenascin is a significant extracellular matrix glycoprotein, which is upregulated in various neoplasias and pathologic processes. Pheochromocytomas are rare tumors of the sympathoadrenal system, whose malignancy is almost impossible to predict. There are no histologic or chemical markers available that would define the malignant behavior of these tumors, except the discovery of metastases. In our search for new markers, we investigated the immunohistochemical expression of tenascin in a large number of pheochromocytomas and paragangliomas. Seven tumors were metastasized and were thus considered malignant. Normal adrenal medulla was tenascin negative. A striking difference was seen between malignant and benign pheochromocytomas. All malignant pheochromocytomas expressed stromal tenascin strongly or moderately, whereas most benign pheochromocytomas (28 of 37, 70%) showed no or only weak immunopositivity. The staining was strong or moderate also in 13 of 28 (46%) of the tumors that showed histologically suspicious features, here called borderline tumors. Paragangliomas showed a more heterogeneous staining pattern, and no significant difference was found between benign and malignant paragangliomas. To our knowledge, this is the first study to demonstrate the expression of tenascin in pheochromocytomas and particularly the enhanced expression in malignant pheochromocytomas. We therefore suggest that tenascin may be associated with the malignant transformation and metastasis of pheochromocytomas. It is also a potential marker predicting more aggressive behavior in pheochromocytomas.     

Malignant pheochromocytomas and paragangliomas: a diagnostic challenge

Introduction  

Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare disorders arising from the adrenal gland, from the glomera along parasympathetic nerves or from paraganglia along the sympathetic trunk. According to the WHO classification, malignancy of PCCs and PGLs is defined by the presence of metastases at non-chromaffin sites distant from that of the primary tumor and not by local invasion. The overall prognosis of metastasized PCCs/PGLs is poor. Surgery offers currently the only change of cure. Preferably, the discrimination between malignant and benign PCCs/PGLs should be made preoperatively.     

Malignant pheochromocytoma: A diagnostic and therapeutic dilemma

IntroductionMalignant pheochromocytomas are rare endocrine tumors that develop within chromaffin tissue. The diagnosis of malignancy is based on neoplastic recurrence or the presence of metastasis in organs that lack chromaffin tissue. We report a series of four cases because of their diagnostic and therapeutic particularities.Presentation of casewe describe four clinical cases of patients with malignant pheochromocytoma whose Menard triad “headache-palpitations-sweating” was present in three out of four patients, the methoxylated derivatives were measured in 4 patients, 3 of which had high values, all of our patients carried out a CT scan which objectified signs of malignancy, MRI was performed on a single patient; presenting with a neoplastic recurrence; looking for a locoregional invasion.DiscussionPheochromocytoma (PC) is a rare neuroendocrine tumor derived from the chromaffin cells of the adrenal medulla. Its annual incidence is 2 to 8 per million adults. A peak frequency is observed between 30 and 40 years of age. Approximately 10% of pheochromocytomas are malignant and in 10% of cases, bilateral localization is observed. Criteria for malignancy include the invasion of neighboring organs, a large tumor, the presence of lymphadenopathy on imaging, or fixation on scintigraphy. Surgery for MAP is not always curative. In the case of multiple liver metastases, treatment is based on adrenalectomy, which can be effectively combined with chemoembolization, cryoablation, or radiofrequency techniques.ConclusionThe main prognostic factors of the malignant pheochromocytomas are a large tumor volume, the existence or number of visceral metastases, and the presence of a mutation in the SDHB (Succinate dehydrogenase B) gene.     

Malignant pheochromocytoma

Background Malignant pheochromocytomas are rare tumors comprising about 15% of all pheochromocytomas. A specific diagnosis of malignancy requires evidence of local invasion or metastases. The purpose of this paper is to review current management of pheochromocytomas proven to be malignant. Methods Both a review of the literature and case studies of more than 100 patients with proven malignant pheochromocytoma seen at the University of Michigan Hospitals from 1980 to 1992 are the basis of management recommendations. Representative individual cases are used to illustrate treatment principles. Results Malignancy as evidence by local invasion, particularly peritumor veins, does not preclude complete resection. Bone is the most common site of distant metastases. The¹³¹I-MIBG scintiscan is the most useful means of identifying occult metastases. Conclusions Aggressive surgical resection of local recurrences and soft tissue metastases can result in excellent palliation. Adrenergic blockade is a cornerstone of treatment, regardless whether surgical resection, triple drug therapy,¹³¹I-MIBG or external radiation therapy is ultimately utilized.      

Malignant catecholamine-secreting carotid body paraganglioma

The second known case of a malignant catecholamine-secreting (DA)-secreting carotid body paraganglioma is presented. Dopamine synthesis and secretion can be increased in malignant tumors derived from neural crest cells. Whether this is true, in addition, for extra-adrenal paragangliomas is not yet clear. Malignant paragangliomas of the carotid body and larynx, although rare, frequently have been accompanied by increased catecholamine secretion. Malignant catecholamine-secreting carotid body paragangliomas are best treated by composite resection (internal carotid artery and neck dissection), with special attention being given to measures preventing severe hypertension and arrhythmias in the perioperative period.     

Functional tumors of the organ of Zuckerkandl.

Chromaffin-reacting pheochromocytomas of the adrenal medulla are the most frequently encountered functional paraganglionic neoplasms. However, extra-adrenal pheochromocytomas as well as non-chromaffin paragangliomas, including those of the carotid body and glomus jugulare, may produce symptoms from catecholamine secretion. One of the extra-adrenal sites from which these tumors arise is from a collection of para-aortic, paraganglion cells around the origin of the inferior mesenteric artery. This collection of paraganglia was described in fetuses by Zuckerkandl in 1901 and has subsequently been referred to as the organ of Zuckerkandl. The diagnosis and management of these neoplasms differ somewhat from that of adrenal pheochromocytomas, but excellent results are often obtained by excision of these lesions. Four patients with functional tumors of the organ of Zuckerkandl are reviewed together with the other reported cases in the literature.     

Pheochromocytomas: can malignant potential be predicted?

OBJECTIVES: The presence of metastatic lesions is the only acceptable fact to confirm malignant pheochromocytoma. Patients with malignant pheochromocytomas, however, have a very poor survival rate. The aim of our study was to postulate predictive values for malignant pheochromocytomas. METHODS: We evaluated symptoms, diagnostic modalities, treatment, and long-term follow-up of 86 patients with 85 benign and 10 malignant pheochromocytomas. Parameters from the benign were compared with those of the malignant pheochromocytomas. RESULTS: Preoperative 24-hour urinary dopamine was in the normal range for benign pheochromocytomas but increased in malignant pheochromocytomas (P<0.0001). Vanillylmandelic acid was elevated in both benign and malignant pheochromocytomas but higher in malignant than in benign tumors (P = 0.01). No differences could be shown in urinary epinephrine and norepinephrine samplings. Tumor location was divided into 77 adrenal (81%) and 18 extra-adrenal (19%) sites. Malignant pheochromocytomas were located more often at extra-adrenal sites (P = 0.03). There was no increased incidence of malignancy in patients with familial bilateral pheochromocytomas or multiple endocrine neoplasia. Tumors greater than 80 g in weight corresponded to malignancy (P<0.0001). Dopamine tumor concentration was higher in malignant than in benign pheochromocytomas (P = 0.01). Persistent arterial hypertension occurred in 9 (13%) of 72 benign and 6 (60%) of 10 malignant pheochromocytomas (P = 0.001). The 10-year survival rate was 94% for benign pheochromocytomas. All patients with malignant pheochromocytomas died within this period (P = 0.0001). CONCLUSIONS: High preoperative 24-hour urinary dopamine levels, extra-adrenal tumor location, high tumor weight, elevated tumor dopamine concentration, and postoperative persistent arterial hypertension are all factors that increase the likelihood of malignant pheochromocytoma. Patients with these characteristics should have more frequent follow-up evaluations to identify malignancy at earlier states.     

Experience gained from operation of 103 adrenal incidentalomas

Background: Adrenal incidentaloma poses a perplexing problem for physicians. The challenge is to identify the rare functioning or malignant adrenal tumor that should be removed. Patients and methods: From 1970 until December 1996, we managed 579 patients with adrenal hyperplasia or neoplasm. Of these, 110 were fol-lowed without any operation and 469 were operated on. The histology from the operated patients revealed 145 pheochromocytomas, 72 Cushing's syndrome, 98 aldosteronomas, 21 virilizing tumors, 3 feminizing tumors, 98 non-functioning adrenalomas, 17 metastases, 7 cysts, and 15 miscellaneous tumors. Results: Among the 98 non-functioning adrenal tumors, 79 were incidentalomas. Histological examination of 103 operated incidentalomas found 55 adenomas (5 functioning=aldosteronomas), 12 benign pheochromocytomas, 3 malignant or suspicious pheochromocytomas, 8 cystic lymphangiomas, 4 metastases, 4 angiomas, 3 ganglioneuromas, 4 myelolipomas, 1 hyperplasia, 2 hematomas, 2 cysts, and 5 adreno-cortical carcinomas. Among the non-operated incidentalomas, the most frequent findings were adenomas, metastases, hematomas, cysts and pseudotumoral hyperplasia; three disappeared spontaneously. No patients died of unrecognized adreno-cortical carcinoma. Conclusion: Our experience confirms that in case of incidentaloma, the first concern is a non-functional pheochromocytoma (15%), and the less common occurrence is adreno-cortical carcinoma (2%). We recommend a restrictive surgical approach in the setting of adrenal incidentalomas. Received: 28 January 1998 / Accepted: 16 June 1998     

Spectrum of catecholamine-secreting tumors of the organ of Zuckerkandl

In a series of 24 pheochromocytomas, four were tumors in the organ of Zuckerkandl. Their presenting symptoms of headache, palpitation, diaphoresis, and anxiety were similar to symptoms of adrenal pheochromocytomas. Two patients had paroxysmal and two patients sustained hypertension. All four had elevated urinary vanillylmandelic acid, metanephrine or catecholamine levels. Two of the tumors were localized with angiography before the availability of computerized tomography. Two patients underwent initial computerized tomography, which was nondiagnostic. Later scans looking specifically for organ of Zuckerkandl tumors were positive. Organ of Zuckerkandl tumors, like other ectopic pheochromocytomas, have a higher rate of malignancy. Two of the four were malignant tumors. One patient died 4 years after operation, but the other patient remains stable despite metastatic disease 8 years after operation. The two patients with benign tumors remain well 2 and 3 years after resection and treatment with alpha-blockade.     

Outcomes of Pheochromocytoma Management in the Laparoscopic Era

Background Laparoscopic adrenalectomy (LA) is the preferred surgical approach for pheochromocytomas. We have investigated the changes in diagnosis, management and outcome of pheochromocytomas treated since the widespread advent of LA. Methods Data were collected retrospectively from 96 patients with pheochromocytomas that had been surgically treated at three tertiary referral centers. Results There were 53 females. Mean age was 47 years (10–81). Tumors were found incidentally in 40% of patients. Of the 96 patients, 12 (13%) had familial syndromes. CT or MRI localized the adrenal lesion in all patients. MIBG scans obtained from 32 patients were concordant with the CT/MRI in 19, were false negative in 9 and misleading in 1, and altered management in only 3 patients. Mean tumor size was 5.6 cm (1.8–17). There were 92 adrenal pheochromocytomas and 9 paragangliomas. Laparoscopy was successful in 67 of 74 (91%) patients, with 20 of 67 (30%) having tumors of 6 cm or greater in size. Conversions to open procedures were performed in patients with 4 left, 2 right pheochromocytomas and 1 paraganglioma. Of the patients, 22 had an open procedure due to suspicion of malignancy or large tumors. Malignancy was observed in 4 of 92 (4.3%) pheochromocytomas and 4 of 9 (44%) paragangliomas. Average follow-up was 22 months (1–122). There were seven recurrences. Postoperative biochemical tests available in 64 patients were normal in 90%. Conclusions The diagnosis of pheochromocytoma was made incidentally in 40% of patients. MIBG is not necessary for unilateral non-hereditary pheochromocytomas localized by CT/MRI. LA is possible with excellent results in most patients, including for treatment of lesions 6 cm or greater in size with no signs of invasion. Laparoscopy should be used cautiously for paragangliomas because of a high rate of malignancy.     

Pheochromocytoma associated with neurofibromatosis 1: a report of two cases

Pheochromocytomas may occur as either sporadic or familial tumors. Clinical features of pheochromocytomas in neurofibromatosis 1 (NF1) patients are similar to those in patients with sporadic pheochromocytomas, unlike pheochromocytomas associated with other hereditary syndromes. Here we report two cases of pheochromocytoma associated with NF1. Case 1: A 29-year-old man with previously undiagnosed NF1, was admitted to our hospital for hypertension and a right adrenal tumor. On physical examination, café-au-lait spots and neurofibromas were observed on his body. Serum and urine catecholamine levels were markedly elevated. Case 2: The patient was a 46-year-old man with NF1. The tumor was incidentally detected by ultrasonography. Serum and urine catecholamine levels were similarly elevated. 131I-MIBG scintigraphy showed an abnormal accumulation in the right adrenal gland. After this diagnosis of pheochromocytoma associated with NF1, open adrenalectomy was performed. No evidence of malignancy was seen in either case.     

Sporadic Paraganglioma

Paraganglioma are rare chromaffin cell tumors that develop from the neural crest cells. Parasympathetic ganglia-derived tumors are found almost exclusively in the neck and skull base and typically do not secrete catecholamines. In contrast, most sympathetic ganglia-derived tumors are found in the abdomen and produce an excess of catecholamines. Those grow within the adrenal medulla and are known as pheochromocytoma. Other sympathetic paragangliomas are also known as extra-adrenal pheochromocytomas. They arise outside of the adrenal gland and can be found anywhere along the sympathetic chain from the base of the skull and neck (5% of cases) to the bladder and prostate gland (10%). We use the term paraganglioma to refer to extra-adrenal tumors and pheochromocytoma to refer to intra-adrenal tumors. The majority of sympathetic paragangliomas are familial, commonly associated with the SDHB and SDHD gene mutations. Many are malignant. Medical management of catecholamine-secreting paraganglioma is the same as for pheochromocytoma. Favorably located abdominal paragangliomas can be safely resected laparoscopically, but the operation is technically more challenging than that for adrenalectomy. Presented at the International Association of Endocrine Surgeons (IAES) Symposium: Paraganglioma, extra-adrenal, and malignant pheochromocytoma, 29 August 2007, Montreal, Canada.     

Clinical and pathological data of 10 malignant pheochromocytomas: Long-term follow up in a single institute

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 (131)I-meta-iodobenzylguanidine ((131)I-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.     

Sixty Adrenal Masses of Large Dimensions: Hormonal and Morphologic Evaluation

Objectives. To evaluate the nature and function of adrenal masses of large dimensions (macrotumors).Methods. Sixty consecutive patients (31 women, 29 men, age range 15 to 84 years) with adrenal masses 4.0 cm in diameter or larger (range 4.0 to 15.0 cm) underwent morphologic study by computed tomography (CT); the majority also underwent 131-I-6beta-norcholesterol (131I-NC) or 131I-MIBG scintigraphy. Basal evaluation of glucocorticoids, mineralcorticoids, and catecholamines was performed in all patients, and in 38 cases determination of androgens was also made. In addition, on the basis of various clinical suspicions, a dynamic hormonal study was performed.Results. Macrotumors were benign in 78.3% of cases and included pheochromocytomas (n = 17), nonfunctioning cortical adenomas (n = 12), and cortisol-secreting tumors (n = 7, Cushing’s syndrome). Malignant forms were 21.7% of the total, including pheochromocytomas (n = 3), cortical carcinomas (n = 6), and metastases (n = 4). On CT, malignant masses were larger (8.4 ± 0.9 cm) than benign ones (5.7 ± 0.3 cm) (P < 0.0001) and the mass size was strictly related to malignancy (P < 0.03). CT did not offer other diagnostic criteria for malignancy, except irregular margins and regional lymph node enlargement, which were more frequently (P < 0.0001) found in malignant forms. 131I-MIBG scintigraphy showed tracer uptake in all pheochromocytomas, both benign and malignant. By contrast, on 131I-NC scintigraphy, cortical malignancies never accumulated the radiotracer, whereas uptake was observed in all cases of solid cortical benign adenomas. Patients with cortical carcinomas showed plasma sex steroids above the normal range, pheochromocytomas were asymptomatic in 15% of cases, and almost half of the patients with Cushing’s syndrome did not show clinical features of the disease (pre-Cushing’s syndrome).Conclusions. Adrenal macrotumors frequently show endocrine activity and the medulla seems to be involved more than the cortex. Pheochromocytomas and cortisol-secreting adenomas are sometimes asymptomatic. Malignancy is often found in macromasses and, at least for the cortical forms, size of the tumor on CT, 131I-NC uptake on scintigraphy, and determination of levels of sex steroids seem to be useful criteria for predicting the nature of the mass.     

Malignant giant pheochromocytoma: a case report and review of the literature

Malignant pheochromocytoma is a rare disease and surgical resection is the only curative treatment. There are no definitive histological or cytological criteria of malignancy, as it is impossible to determine this condition in the absence of advanced locoregional disease or metastases. We report a case of a patient with a giant retroperitoneal tumour, the second largest to be published, which was diagnosed as a malignant pheochromocytoma; it was treated with surgery. The literature is reviewed to evaluate tumour features and criteria to distinguish between benign and malignant pheochromocytomas.     

Paragangliomas of the urinary bladder: A report of 6 cases and review of the literature

ObjectiveExtra-adrenal pheochromocytomas are known as paragangliomas. The majority of extra-adrenal tumors occur intra-abdominally along the sympathetic chain. However, they may also occur in the urinary tract, including the urinary bladder.Materials and methodsIn this study, we report a clinical series of six patients diagnosed with bladder paragangliomas in our hospital over the past two decades, and review the literature regarding this unusual disease.ResultsAmong the six cases, two were male and four were female. The most common presentation was painless gross hematuria, with five of the six patients (83.3%) having this chief complaint. Two patients presented with hypertension and one with palpitations. Two had malignant bladder paragangliomas, and one died within one year after the diagnosis. Four patients received transurethral resection of the bladder tumors, and one patient developed tumor recurrence within one year of follow-up.ConclusionBladder paraganglioma is an extremely rare tumor with a high recurrence rate, and the most common presenting symptom in our series was painless gross hematuria. Large, polypoid, and multiple tumors indicate malignancy.     

Metachronous pheochromocytoma metastasis to the upper dorsal spine—6-year survival

BACKGROUND CONTEXT: Malignant pheochromocytoma is a rare neoplasm of chromaffin tissue. Very few cases of malignant adrenal pheochromocytoma metastatic to vertebrae exist. PURPOSE: To determine the prognosis of a patient with an excised adrenal pheochromocytoma and a single metachronous metastasis to the upper dorsal spine. STUDY DESIGN: Case report METHODS: The authors report a patient who underwent total excision of an adrenal pheochromocytoma of the left adrenal gland in 2000 who developed a single metastasis to the second dorsal vertebra in 2002 with no evidence of abdominal recurrence. RESULTS: Four-year survival is documented after the spinal metastasis was first detected after two attempts at excision and radiotherapy. CONCLUSIONS: Patients with adrenal pheochromocytomas must be screened periodically with whole body imaging despite normal abdominal imaging as there is a definite risk of metachronous metastasis. Aggressive therapy may result in improving survival significantly in a subset of patients with isolated spinal metastases.     

Surgery of retroperitoneal pheochromocytoma

Retroperitoneal pheochromocytomas are very uncommon tumors. During the last 10 years only 3 cases have been operated on in our clinic. Two of them were primary retroperitoneal paragangliomas. These two patients are now well and without recurrence 1 and 10 years respectively after operation. The third patient had retroperitoneal metastases of an adrenal pheochromocytoma. Now, after 1 year he has disseminated metastases without response to therapy with (131I)metaiodobenzylguanidine (MIBG). The surgical procedure includes often extended resection and replacement of retroperitoneal blood vessels and requires therefore an experienced surgical team and optimal anesthetic management (Swan-Ganz-katheter). In two cases the aorta was resected and replaced with a Dacron-graft. Reimplantation of both renal arteries into the graft was necessary in one case. Further interventions were: nephrectomy (2x), resection and ligation of the inferior vena cava (1x), resection and replacement of the left renal vein (1x).     

Remarkably Suppressed Manganese Superoxide Dismutase Activity in Malignant Pheochromocytoma

There are almost no special histopathological characteristics or criteria that exactly define a malignant pheochromocytoma. Tissue concentrations of catecholamine metabolites and superoxide dismutase activity have been proposed as possible candidates for discriminating between benign and malignant pheochromocytomas. Tissue concentrations of dihydroxyphenylalanine, metanephrine, normetanephrine, vanillylmandelic acid, and 3-methoxy-4-hydroxyphenylethylglycol were determined in 29 normal adrenal medullas, 13 benign pheochromocytomas and 6 malignant pheochromocytomas, respectively. The copper-zinc superoxide dismutase and manganese superoxide dismutase activities in remnants of these tissues were determined by interruption of nitric formation from hydroxylamines. Catecholamine metabolites and copper-zinc superoxide dismutase activity in benign and malignant pheochromocytomas were identical. Manganese superoxide dismutase activity in malignant pheochromocytoma was the lowest among the groups examined.

These data suggest that the assay of catecholamine metabolites in removed specimens is not a reliable method for making a differential diagnosis of benign or malignant pheochromocytoma. However, a low level of manganese superoxide dismutase activity in malignant pheochromocytoma may be a marker for malignancy of this neoplasm.     

肾上腺肿瘤自发性破裂出血5例报告

目的 提高对肾上腺肿瘤自发性破裂出血的认识及诊治水平.方法 回顾性分析2004年1月到2009年3月,共收治5例肾上腺肿瘤白发性破裂出血患者的诊治资料,并进行总结.所有患者均以突发患侧剧烈腰痛急诊,行B超、CT检查发现肾上腺肿块较大,直径4.5cm～12cm不等,平均8.5cm,肿瘤性质均有病理明确.结果 5例自发性破裂出血的肾上腺肿瘤中,3例为嗜铬细胞瘤(其中1例失随访),1例肺癌肾上腺转移,1例肾上腺皮质癌.结论 肾上腺肿瘤自发出血较为少见,临床表现以突发性患侧腰痛、胸闷、心悸为主.B超、CT是有效的诊断方法.肾上腺肿瘤白发性破裂出血多见于较大功能性肿瘤和恶性肿瘤破裂出血.应在稳定生命体征的情况下,积极手术.