Extra-adrenal Localization Research Articles

Наблюдение и лечение пациентки с гормонально-активной опухолью надпочечника

In spite of all existing achievements, modern endocrinology comes across a rather complex issue such as treatment of patients with catecholamine secreting tumors. True prevalence of pheochromocytoma is not known, as data obtained during the research depend on criteria of patients’ selection and can vary significantly. The tumors have numerous pathophysiological mechanisms of disease development due to a wide variability of symptoms and complex diagnostics. Meanwhile, timely diagnosis produces a direct effect on prognosis and quality of life. Catecholamine secreting tumors are commonly not detected. In such cases, there is a high risk of severe cardiovascular complications up to a lethal outcome. Complex diagnostics of this pathology also means that the tumors can have adrenal and extraadrenal localization and that the disease is hereditary. This makes diagnostics and treatment of pheochromocytoma even more complex. Timely detection of concomitant tumor and hormonal manifestations belongs to an important factor of management of patients with genetically determined pheochromocytomas. Thus, examination of pheochromocytoma is a pressing issue of modern endocrinology.

Management and outcome of metastatic pheochromocytomas/paragangliomas: a monocentric experience

BackgroundPheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors releasing catecholamines. Metastatic pheochromocytomas/paragangliomas (PPGLs) occur in about 5–26% of cases. To date, the management of patients affected by metastatic disease is a challenge in the absence of guidelines.AimThe aim of this study was to evaluate the overall survival (OS) and the progression-free survival (PFS) in metastatic PPGLs.MethodsClinical data of 20 patients referred to the Careggi University Hospital (Florence, Italy) were retrospectively collected. Follow-up ranged from 1989 to 2019. Site and size of primary tumor, biochemical activity, genetic analysis and employed therapies were considered. Data were analyzed with SPSS version 27.ResultsNine PHEOs (45%) and 11 PGLs (55%) were enrolled. Median age at diagnosis was 43.5 years [30–55]. Mean follow-up was 104.6 ± 89.3 months. Catecholamines were released in 70% of cases. An inherited disease was reported in 50% of patients. OS from the initial diagnosis (OSpt) and from the metastatic appearance (OSmtx) were lower in older patients (OSpt p = 0.028; OSmtx p < 0.001), abdominal PGLs (OSpt p = 0.007; OSmtx p = 0.041), larger tumors (OSpt p = 0.008; OSmtx p = 0.025) and sporadic disease (OSpt p = 0.013; OSmtx p = 0.008).ConclusionOur data showed that older age at the initial diagnosis, sympathetic extra-adrenal localization, larger tumors and wild-type neoplasms are related to worse prognosis. Notably, the employed therapies do not seem to influence the survival of our patients. At present, effective treatments for metastatic PPGLs are missing and a multidisciplinary approach is indispensably required.

A rare mesentric tumor “paraganglioma” – a case report

Paraganglioma are rare type of neuroendocrine tumors that arise from embryonal neural crest. Paraganglioma of adrenal medulla is known as Pheochromocytoma. Extra adrenal localization has incidence of 2-8 per million people per year, which can extend from upper cervical region to pelvis related to autonomic nervous system. Even rarer is occurrence of paragangliomas outside the usual distribution of paraganglionic tissue. Mesenteric paragangliomas are extremely rare. The present case was of a non-functional extra adrenal paraganglioma occurring in a 43-year-old male presented with complain of pain in abdomen and mild discomfort. Abdominal CECT revealed well defined enhancing solid mass with central necrosis in right side of mesentry. Explorative laparotomy and surgical excision were done, on histology typical “zellballen” pattern was found. Paragangliomas are rare neuroendocrine tumor known to store and secrete catecholamines and hence are known as functional paragangliomas and may present with symptoms like headache, sweating, palpitations and hypertension. On other hand, they may remain silent and non-functional and present with vague symptoms like pain abdomen due to episodic release of catecholamines. Surgical excision is treatment of choice. Long term follow up is mandatory as tumor is prone to recur and metastasize.

Genetics of pheochromocytoma and the relevance in surgery

Chromaffin tumors, e.g. pheochromocytomas and paragangliomas are caused by germline mutations of several susceptibility genes in 30-40% of the patients. The corresponding syndromes are multiple endocrine neoplasia type2 (MEN2, RET gene), von Hippel-Lindau disease (VHL), neurofibromatosis type1 (NF1), paraganglioma syndrome types1-5 (PGL1-5, SDHx gene) and familial pheochromocytoma due to mutations in the MAX and TMEM127 genes. Clinically, screening for such diseases should be carried out by clinical symptoms and mutation analyses. Important indications can be found in the history of patients and their families, young age of manifestation (<30years), extra-adrenal localization and the presence of metastatic pheochromocytomas. Organ-preserving endoscopic adrenal operations are nowadays standard for hereditary pheochromocytomas. Previous studies have shown that the reoccurrence of tumors in residual tissue is rare and can occur many years later and that metastatic tumors arising from such recurrences are very rare. When a mutation is detected in a susceptibility gene, a multidisciplinary follow-up care tailored to each individual syndrome is essential.

Pheochromocytoma/paraganglioma: clinical and genetic aspects

The present retrospective descriptive and analytical study included 167 patients divided into three groups. Two groups were comprised of the patients with genetically predetermined pheochromocytoma (type 2 MEN syndrome and von Hippel-Lindau disease respectively), the third croup consisted of the patients presenting with sporadic pheochromocytoma. The median age at which pheochromocytoma was diagnosed was 25 years in group 1, 18 years in group 2, and 47 years in group 3. Adrenalin-type secretion was predominated in group 1 in contrast to the noradrenalin-type and mixed-type secretion in the patients of groups 2 and 3 respectively. The patients of group 1 showed positive correlation between the tumour size and excretion of methylated catecholamines. 82% of these patients exhibited bilateral adrenal lesions and 58% suffered multifocal lesions; no cases of extra-adrenal localization of the tumour were documented. The extra-adrenal localization of pheochromocytomas was observed in 16.4% of the patients in group 2, where 6.6% of the patients had metastases. No metastases of pheochromocytoma were found in the patients of groups 1 and 3. It is concluded that the patients under the age of 40 presenting with bilateral and multicentral pheochromocytoma with the aggravated familial history need the genetic predetermination of the disease to be excluded taking into account syndromal symptoms. Examination for the detection of type 2 MEN is not required in the patients showing isolated normetanephrin excretion. Nor is the search for metastases of pheochromocytoma and its extra-adrenal localization is necessary in the patients presenting with type 2 MEN syndrome and/or exhibiting isolated metanephrin excretion.

MAGNETIC RESONANCE IMAGING IN DYNAMIC EXAMINATION OF PATIENTS WITH ADRENAL TUMORS AND ARTERIAL HYPERTENSION: PP.18.193

Objectives: To evaluate MRI diagnostic possibilities dynamic examination of patients (pts) with adrenal tumors and arterial hypertension. Methods: Study included 291 pts (106 pts with aldosteroma, 95 pts with pheochromocytoma, 71 pts with corticosteroma, 19 pts with incidentaloma). MRI was performed with Magnetom Avanto, Siemens, 1.5T. Standard MRI included T1-, T2-weighted, fat saturation sequence; 137 pts underwent MRI with contrast enhancement (Gd-DTPA-BMA 0.2 mgkg). Duration of arterial hypertension before treatment was 1–6 years. Period after surgical treatment of adrenal tumors was 0.5–4 years. Control group included 25 healthy volunteers. Results: In 52% pts after surgical treatment of aldosteroma some enlargement of contra- lateral adrenal was found as a result of vicar hypertrophy; in 28% pts we determined inhomogeneity of adrenal structure, possibly because the small nodes or areas of dysplasia present in adrenal gland. In all pts after surgical treatment of pheochromocytoma we marked enlargement of contra- lateral adrenal gland. In 19% pts after 1–2 year new tumors (size less than 3 cm) of the second adrenal gland was found. Majority of pts did not show any changes in renals in comparison with first examination, but in 20% pts we determined pyelectasis. MRI after surgical treatment of corticosteroma showed no changes in the contra- lateral adrenal gland in 30% of pts, in 15% - reduction in size and 40% - enlargement compared with the data obtained before treatment. In 12 pts on the basis of clinical status and laboratory data presence another adrenal tumor data was suspected, which was confirmed by MRI. In pts with incidentaloma were present the same date. In all cases MRI allowed to estimate structure, shape, and size of contra- lateral adrenal gland, find tumor of adrenal or extra adrenal localization. Conclusion: MRI is method of high effectiveness dynamic examination of pts after surgical treatment of adrenal tumors and arterial hypertension. MRI with contrast enhancement gives the important additional information.

Przyzwojaki szyi w materiale Kliniki Otolaryngologii Warszawskiego Uniwersytetu Medycznego w latach 2001–2010

Paragangliomas are rare neoplasms of neurological origin and account for 0.012% of all tumors. Only 10% of them have extraadrenal localization. Head and neck paragangliomas account for 0.33% neoplasms of that localization. Typically paragangliomas are benign tumors, but even 19% cases may have malignant potential. On the neck they are located typically closely to carotid artery bifurcation, jugular bulb and along the course of vagus nerve. Laryngeal localization is very rare. Nonspecific manifestation and wide spectrum of symptoms cause difficulty in diagnosis of paragangliomas. Presentation of the diagnostic process, performed treatment and obtained results of neck paragangliomas in the material of the Department of Otolaryngology of Warsaw Medical University in years 2001-2010. There was performed retrospective analysis, based on the medical documentation of 14 patients with neck paragangliomas (9 women and 5 men), age range 25-62 years, hospitalized in the Department of Otolaryngology of Warsaw Medical University during the last 10 years. The date from the history, physical examination, radiological evaluation and the method of performed treatment and post-treatment complications were studied. Out of 14 patients with neck paragangliomas, there were 9 cases of isolated tumors and 5 cases of synchronic, multicentric neoplasms. The most common and single symptom was nonspecific neck mass. Doppler ultrasonography was adequate diagnostic tool in carotid artery paragangliomas. To diagnose mulicentric paraganglioma, vagal or laryngeal paraganglioma more thorough radiological examination was necessary, including computed tomography, magnetic resonance and angiography. All patients had performed surgical treatment. There were observed very good results in patients with isolated paragangiomas of carotid artery or larynx. Surgical management of multicentric and vagal paragangliomas was exposed to higher risk of cranial nerve paresis. (1) Paragangliomas are rare tumors of nonspecific clinical manifestation, making the early diagnosis very difficult. (2) Precise radiological evaluation is necessary taking into consideration quite high incidence of multicentric paragangliomas. (3) There is higher risk of cranial nerve paresis after surgical treatment of multicentric paragangliomas, neoplasms larger then 5 centimeters in diameter and vagal paragangliomas then in isolated carotid artery paragangliomas.

Embolização pré operatória no tratamento de paraganglioma abdominal: relato de caso

Paragangliomas is a pheochromocytoma of extra adrenal localization. The case report is a male, 55 years old who presented symptoms of adrenergic hyperstimulation associated to an abdominal mass diagnosed as paraganglioma by a biopsy. Because of its size, localization and vascularization, an aortography with embolization of the nutrient branches of the tumor was done pre-operatively. Four days later, a surgical ressection was performed, and the tumor was adhered to the duodenum, infra-renal aorta and inferior vena cava. We believe that an angiographic study pre-operatively with embolization makes possible an analysis of the anastomosis and arterial supplement, making the ressecability of the tumor safer, although it seems the surgical intervention should have been done earlier.

A Rare Cause of Complicated Hypertension: Urinary Bladder Paraganglioma

After a subarachnoid hemorrhage, a 35-year-old patient developed paroxystic hypertension accompanied by typical symptoms. These symptoms occurred exclusively after urination. A urinary bladder paraganglioma was discovered using iodine-123 metaiodobenzylguanidine (I-123 MIBG) scintigraphy and magnetic resonance imaging (MRI) after the detection of an abnormally elevated plasma metanephrine measurement. A partial cystectomy was performed which cured the symptoms. Paragangliomas, defined by their extra-adrenal localization, have slightly different characteristics than pheochromocytomas, leading to specific care and follow up.

Familial isolated pheochromocytoma presenting a new mutation in the von Hippel-Lindau gene

We report a novel germ-line point mutation in the von Hippel-Lindau (vhl) gene in a family with childhood occurrence of isolated pheochromocytoma. Two members of this family (the father and his son) were affected. The son had bilateral adrenal pheochromocytoma and the father had one adrenal and one extra-adrenal localization. Both patients presented cardiac arrest while exposed to surgical stress and severe hypoglycemia was registered in the son. The outcome was uneventful. A DNA sequence analysis of vhl tumor suppressor gene revealed the L163R mutation. This new mutation may be specifically associated with the von Hippel-Lindau type 2C disease phenotype. Whether this mutation is linked to the metabolic alterations developed by these patients remains to be determined.

Clinical differences between benign and malignant pheochromocytomas.

Most pheochromocytomas can be cured by resection. In view of the unfavourable prognosis for surgical therapy in cases of late tumour detection and malignant tumours, the aim of the present study is to differentiate between typical signs and symptoms of malignant versus benign pheochromocytomas. We investigated the records of 133 patients retrospectively (1967-1998). In cases of benign tumours (104 of 133, mean age 42+/-15.8 years) tumour size was 5.9+/-3.4 cm, and history was 47.4+/-75.4 months. 7.7% of the tumours were extraadrenal, and 77% had paroxysmal manifestations. The other 29 patients (mean age: 39.2+/-21.9 years) had malignant lesions (tumour size: 9.4+/-5.9 cm (p=0.0022); history: 7.4+/-5.6 months (p=0.0137); extraadrenal: 24.1% (p=0.0219); paroxysmal: 37.9% (p=0.0012)). Symptoms of patients with benign tumours were hypertension (80%), headaches (42.3%), sweating (30.8%), tachycardia (26%) and pallor (24%) (Malignant: Hypertension 46%, p=0.0873; headaches 11%, p=0.0008; sweating 11%, p=0.0196; tachycardia 14%, p=0.1961 and pallor 0%, p=0.0010). Abdominal pain and dorsalgia occurred more frequently in malignant pheochromocytomas (26% versus 7%, p=0.0014). Unusually short histories and extraadrenal localization appear to be suspicious for malignancy. The "typical" clinical signs and symptoms occur more frequently in patients with benign tumours and can therefore be regarded as typical signs of benign pheochromocytomas.

Regulation of catecholamine synthesizing enzyme gene expression in human pheochromocytoma.

This issue of the European Journal of Endocrinology contains an important report investigating the expression of the mRNAs coding for catecholamine synthesizing enzymes in human pheochromocytomas (1). Despite all efforts to characterize these tumors by molecular biological techniques and to study the expression of various growth factors and their receptors, investigations into the genuine enzymes have so far been surprisingly scarce. This and other studies clearly suggest that this methodological approach cannot only be used to further characterize the genomic properties with regard to the expression of the various enzymes in these tumors, but also to yield prognostic criteria in terms of benign versus malignant pheochromocytoma. In order to fully appreciate the pathophysiological relevance and implications of this approach, it is mandatory to characterize the nature of this tumor and basic mechanisms of catecholamine biosynthesis. I shall thus use this editorial to briefly review the clinical genetics and aspects of pheochromocytoma, followed by novel general aspects of catecholamine enzyme regulation, as well as synthesis, storage and secretion of these hormones, and finally discuss some of the data available on catecholamine synthesizing enzyme mRNA expression in human pheochromocytomas and their possible clinical relevance. The pheochromocytoma represents a catecholamine secreting tumor that can arise both from intraand extraadrenal chromaffin cells. The term paraganglioma describes a subgroup of those tumors which originate in extraadrenal chromaffin cells. These cells are of neuroectodermal origin and thus part of the so-called diffuse neuroendocrine system. This embryogenetic basis also explains the association of a pheochromocytoma with other disorders sharing this origin. There are few data on the incidence and prevalence of this tumor; a prevalence between 0.2 and 0.4% in patients with diastolic hypertension is suggested. A pheochromocytoma can be classified according to various categories. A major criterion is the sporadic versus familial appearance; another is represented by localization (intraversus extraadrenal). Finally, benign and malignant pheochromocytomas have to be differentiated. Approximately 10% of all pheochromocytomas of the adult reveal an extraadrenal localization, while this number appears to be higher in children, with approximately 35%. The majority of pheochromocytomas (approximately 90%) are of sporadic nature; familiarity has in particular been observed when the following diseases are either underlying or coexisting: multiple endocrine neoplasia (MEN) type 2 a/b, von Hippel–Lindau syndrome (vHLS) and neurofibromatosis type I (NFI). In addition to NFI, tuberosis sclerosis and Sturge–Weber disease are of neuroectodermal origin and associated with pheochromocytoma. As mentioned, the potential malignancy of these tumors represents a major clinical problem. Approximately 20% of all pheochromocytomas will eventually be malignant. The most strict criterion for malignancy is the appearance of metastases in organs that otherwise do not contain chromaffin cells (2). The pathogenesis of pheochromocytoma is still unclear. It is only the pheochromocytoma within the context of MEN, vHLS or NF that possesses a characterized molecular genetic background. In MEN 2a/b, mutations of the RET proto-oncogene and chromosome 10 have been very well described. This oncogene belongs to the group of tyrosine kinase receptor coding oncogenes, which can be activated by DNA rearrangement (3). The tyrosine kinase then functions as a receptor for the glial cell-derived neurotrophic factor (GDNF) and GDNF–receptor complex. The vHLS also represents a hereditary disease, which is characterized by the appearance of a number of benign and malignant tumors. The leading clinical characteristics are angioblastomas, retinal angiomas, renal cell tumors and pheochromocytomas, the last of these occurring with a frequency of 15 to 25%. The vHLS is further differentiated into type 1, type 2a and type 2b, where pheochromocytoma is associated with types 2a and b. The vHLS suppressor gene is located on chromosome 3p 25–26. In NFI, a pheochromocytoma is observed in approximately 5% of cases; vice versa in 1 to 2% of all cases diagnosis of a pheochromocytoma will eventually also lead to the diagnosis of NFI. The NFI gene codes for the protein neurofibromin, which stimulates the GTPase activity of p21 ras in vitro. It is thus conceivable that signal transduction will be induced via this protein. The NFI gene also most likely represents a tumor suppressor gene with the mutated gene located on chromosome 17. European Journal of Endocrinology (1998) 138 363–367 ISSN 0804-4643