Metastasis Of Pheochromocytoma Research Articles

Comparison of 18 F-FDOPA and 18 F-MFBG PET/CT Images of Metastatic Pheochromocytoma.

A 30-year-old man with pheochromocytoma was hospitalized for hemoptysis without inducement. CT revealed a mass in the left lung, and biopsy pathology under the bronchoscope suggested that it was a pheochromocytoma metastasis. To further identify the location of the metastatic lesions, the patient was enrolled in a clinical trial and underwent 18 F-FDOPA and 18 F-MFBG PET/CT. Images from both examinations showed similar lesions. However, the lesions differed in that the uptake of some lesions was significantly higher with 18 F-FDOPA than with 18 F-MFBG, whereas the para-aortic lesion was active in 18 F-MFBG but not in 18 F-FDOPA.

Locally invasive recurrence or metastasis of pheochromocytoma into the liver?—clinicopathological challenges

Pheochromocytomas (PCC) are rare and functional neuroendocrine tumors developing from adrenal chromaffin cells. Predicting malignant behavior especially in the absence of metastasis can be quite challenging even in the era of improved understanding of the molecular mechanisms involved in PCCs. Currently, two histopathological grading systems Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) score are used in clinical practice, but these are subject to significant interobserver variability. Some of the most useful clinical factors associated with malignancy are large size ([4–5 cm), and genetic features such as presence of SDHB germline mutations. Local invasion is uncommon in PCC and metastasis seen in 10 to 17% but higher in germline mutations and when this occurs management can be challenging. Here, we report on a case with challenges faced by the pathologist and clinicians alike in diagnosis and management of PCC recurrence.

SUN-939 Case Report: Malignant Pheochromocytoma

Introduction: The concept of malignancy for pheochromocytoma is complex and the best definition is the presence of metastases, according to WHO. Anatomopathological scoring systems are not effective in predicting metastases. Malignancy should be considered when tumors larger than 8cm (> 80g), paragangliomas (especially retroperitoneal), dopamine / methoxythyramine increase, Ki67> 6% and SDHB mutation. At 5 years, survival ranges from 50-69%. Metastases may appear 20-40 years after initial treatment of pheochromocytoma. We describe a case that metastasis was identified 33 years after pheochromocytoma excision Case report: A 57-year-old female patient with a postoperative history of 33 years of right adrenal pheochromocytoma was discharged from the endocrinologist after 10 years of follow-up. At diagnosis 33 years ago, she had symptoms of hypertension with paroxysms and weight loss that disappeared after tumor removal. 2 years investigating weight loss with general practitioner without another celebratory. On physical examination, orthostatic hypotension was highlighted. Plasma methanephrine 0.8 nmol / L (VR <0.5) and plasma normetanephrine 1.8 nmol / L (VR <0.9), chromogranin A 5.7 nmol / L (VR <3 nmol / L) and clonidine test with 36.6% suppression of metanephrines, suggesting tumor recurrence. MRI localized recurrence of the adrenals and MIBG scintigraphy with I131 that showed, respectively, in the topography next to the paracaval and retroportal right diaphragmatic crura, isointense T1 and slightly hyperintense T2 at 1.8 cm and radiopharmaceutical hypercaptation in right adrenal topography. Genetic panel by NGS did not identify germline mutation in 22 pheochromocytoma-related genes. FDG PETCT was consistent with MRI and MIBG images. Gallium PETCT68 DOTATOC detected the lesions already described, in addition to a lytic lesion in the left femoral intertrochanteric medulla. Anatomopathological approached abdominal lesion confirming pheochromocytoma metastasis in lymph node conglomerate. Currently has a negative methanephrine plasma, however chromogranin A 142 ng / mL (VR <93), and was chosen by the observant approach. Conclusion: The case of the patient illustrates that pheochromocytoma should be followed indefinitely, as metastases may appear many years later and may present different aggressiveness potentials.

Hemodynamic instability during percutaneous ablation of extra-adrenal metastases of pheochromocytoma and paragangliomas: a case series

BackgroundSurgical manipulation of pheochromocytomas and paragangliomas (PPGLs) may induce large hemodynamic oscillations due to catecholamine release. Little is known regarding hemodynamic instability during percutaneous ablation of PPGLs. We examined intraprocedural hemodynamic variability and postoperative complications related to percutaneous ablation of extra-adrenal metastases of PPGL.MethodsFrom institutional PPGL registry we identified patients undergoing ablation of extra-adrenal PPGL metastases from January 1, 2000, through December 31, 2016. We reviewed medical records for clinical characteristics and hospital outcomes. Tumors were categorized as functional or nonfunctional based on preprocedural fractionated catecholamine and metanephrine profiles.ResultsTwenty-one patients (14 female [67%]) underwent 38 ablations. Twenty-four ablations were performed in patients with functional metastatic lesions, and 14 were in nonfunctional lesions. Intraprocedural use of potent vasodilators for hypertension was higher for patients with functional tumors (P = 0.02); use of vasopressors for hypotension was similar for functional and nonfunctional tumors (P = 0.74). Mean (±SD) intraprocedural blood pressure range (maximum–minimum blood pressure) during 38 procedures was greater for functional than nonfunctional tumors [systolic: 106 (±48) vs 64 (±30) mm Hg, P = 0.005; diastolic: 58 (±22) vs 35 (±14) mm Hg, P = 0.002; mean arterial: 84 (±43) vs 47 (±29) mm Hg, P = 0.007]. Complications included 5 unplanned intensive care unit admissions (3 for precautionary monitoring, 1 for recalcitrant hypotension, and 1 for hypertensive crisis), 1 case of postoperative bleeding, and 1 death.ConclusionsSubstantial hemodynamic instability may develop during ablation of functional and nonfunctional PPGL metastases. When anesthesia is provided for ablation of metastatic PPGLs in radiology suites, preparation for hemodynamic management should match standards used for surgical resection.

Recurrent malignant pheochromocytoma with unusual omental metastasis: (68)Ga-DOTANOC PET/CT and (131)I-MIBG SPECT/CT scintigraphy findings.

Pheochromocytomas are rare catecholamine-secreting tumors derived from the sympathetic nervous system. The most common sites of metastasis for pheochromocytoma or extra-adrenal paraganglioma are lymph nodes, bones, lungs, and liver. Patients with known or suspected malignancy should undergo staging with computed tomography (CT) or magnetic resonance imaging as well as functional imaging (e.g. with 123I/131I-MIBG (131I-metaiodobenzylguanidine) and 68Ga-DOTANOC (68Ga-labeled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI3-octreotide) positron emission tomography (PET)/CT) to determine the extent and location of disease. We present a case of recurrent malignant pheochromocytoma with unusual site of metastasis in omentum, which was positive on 68Ga-DOTANOC PET/CT and 131I-MIBG single-photon emission computed tomography (SPECT/)/CT scintigraphy.

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.

Hürthle Cell Neoplasms: A New Differential Diagnosis for 18F-FDOPA-avid Thyroid Nodules?

We report the case of a 54-year-old woman who presented with a 33-mm left adrenal mass on surveillance 7 years after a primary breast cancer. She had no symptoms of catecholamine excess, but the comprehensive hormonal testing identified an elevation of the 24-hour urinary normetanephrine (4950 mmol, upper reference limit [URL], 2200) and metaphrine (7462 mmol, URL 1500) levels as well as serum chromogranin A (120 g/L, URL 100). Serum calcitonin and other parameters were all in the normal range. The computed tomography (CT)/magnetic resonance imaging scans were consistent with a pheochromocytoma. F-Fluorodihydroxyphenylalanine (F-FDOPA) positronemission tomography/CT identifieda typicalhighly avid pheochromocytoma (maximum standardized uptake value [SUVmax], 9.4) but also an additional F-FDOPAavid thyroid nodule (SUVmax, 3.9) (Figure 1, A, B, and E). F-Fluorodeoxyglucose positron emission tomography/CT showed the pheochromocytoma (SUVmax, 4.2) but failed to detect the thyroid lesion, which was therefore not consistent with the diagnosis of a paraganglioma or pheochromocytoma metastasis (Figure 1, C and F). Thyroid color Doppler ultrasound showed a 22-mm left thyroid lobe nodule with central/ peripheralhypervascularity (Figure1D).Fine-needleaspiration cytology of the left thyroid nodule revealed a macrofollicular nodule (Bethesda class II), which ruled out nonsecreting medullary thyroid carcinoma despite F-FDOPA uptake (1). The serum TSH level was normal, and serum thyroid autoantibodies were undetectable. An uneventful left laparoscopic adrenalectomy was performed, and histology confirmed a pheochromocytoma (Pheochromocytoma of the Adrenal gland Scaled Score, PASS 0). A diagnostic left thyroid lobectomy was performed separately, and pathological examination found a Hurthle cell adenoma (Figure 1G). It has been previously documented that Hurthle cell neoplasms may be detected by various other radiopharmaceuticals (2–4). This episode suggests that Hurthle cell lesions need to be included in the differential diagnosis of F-FDOPA-avid thyroid nodules. The uptake of F-FDOPA remains currently unexplained. It may be related to an overexpression of L-type amino acid transporter 1, which may potentially play a role in the development of tumors (5).

Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

Genetic changes in the tumorigenesis of sporadic pheochromocytomas are poorly understood, and there are no good markers to discriminate benign from malignant pheochromocytomas. p53 is a tumor suppressor gene and aberrations in this gene are frequently found in many tumor types. The role of p53 in pheochromocytoma tumorigenesis is unclear, with some studies suggesting that p53 mutations can be used to discriminate benign from malignant pheochromocytomas while other studies do not find such an association. Because most of these investigations were hampered by small series of tumors and the use of varying methods, we have performed a comprehensive analysis of p53 aberrations in a large series of pheochromocytomas. Comparative genomic hybridization analysis of 31 benign and 20 malignant tumors showed loss of the p53 locus at chromosome 17p13.1 in 2 3/51 (45%) cases, and most of these results were confirmed by fluorescence in situ hybridization. Forty-three tumors, including the malignant tumors and the tumors with loss of the p53 locus, were analyzed for p53 mutations in exons 5–8, but none were found. Furthermore, p53 immunohistochemistry on 35 cases revealed strong nuclear p53 expression in only two pheochromocytoma metastases, all other tumors being negative. We conclude that, although there is frequent loss of the p53 locus on 17p, the p53 gene does not appear to play a major role in pheochromocytoma tumorigenesis.

Perioperative management of late metastasis of pheochromocytoma in clavicle

Perioperative management of late metastasis of pheochromocytoma in clavicle

Metastasis‐associated gene expression profile of liver and subcutaneous lesions derived from mouse pheochromocytoma cells

The development of metastatic cancer is associated with overexpression or downregulation of specific genes and cell regulatory pathways. Some of these genes and pathways may be involved in invasion and dissemination of tumor cells, while others may promote seeding, survival or growth of cells at specific distant sites. In this investigation, gene expression profiles of nonmetastasizing tumors generated by injecting mouse pheochromocytoma cells (MPCs) subcutaneously were compared to those of liver tumors generated by injecting the cells intravenously. Both were compared to the cultured parental cell line. Tumors in the liver have a route of spread, anatomical distribution, and growth environment similar to naturally metastasizing pheochromocytomas, while intravenous injection of cells bypasses the initial steps of metastasis occurring spontaneously from a primary tumor. Eight genes were upregulated in liver tumors, 15 in subcutaneous tumors and seven in both compared to the cultured cells. Using quantitative real-time PCR, expression of five genes (Metap2, Reck, S100a4, Timp2, and Timp3) was verified as significantly lower in liver tumors than in subcutaneous tumors. Downregulation of these genes has been previously been associated with malignancy of pheochromocytomas. These findings indicate that different microenvironments can differentially affect the expression of metastasis-related genes in pheochromocytomas, and that overexpression or underexpression of these genes need not be present when the tumor cells are initially disseminated. The hepatic localization of tumors formed by intravenously injected MPC cells and the tumors' gene expression profile resembling that of naturally occurring pheochromocytoma metastases support the use of this model to study pheochromocytoma metastasis.

Cutaneous metastasis of pheochromocytoma in multiple endocrine neoplasia IIB

Pheochromocytoma is a rare tumor originating from neuroectodermic cells. Only 10% of these tumors are malignant. There are many familial forms of this tumor, including multiple endocrine neoplasia type II, Von Hippel-Lindau syndrome, and neurofibromatosis type I. Skin manifestations of pheochromocytoma are rare, and cutaneous metastasis in patients with multiple endocrine neoplasia IIB has never been described. The case of a patient with multiple endocrine neoplasia IIB who presented malignant pheochromocytoma with multiple cutaneous metastasis is described.

Malignant pheochromocytoma with progressive paraparesis in �von Hippel-Lindau disease

Pheochromocytomas are a feature of the von Hippel-Lindau disease spectrum, a multisystem disorder of autosomal dominant inheritance. Pheochromocytomas are, however, observed during life with a lower frequency than other features of this disease, such as retinal angiomas, haemangioblastomas of the CNS, and renal carcinomas. We present the highly unusual case of a patient who required an emergency operation for an intradural extramedullary thoracic tumour which was clinically suggestive initially of neurinoma. We present evidence from NMR, histological and isotope scan investigations of this being a pheochromocytoma metastasis and of an additional right-sided paraganglioma at the same height. A detailed history revealed that this patient had suffered from four other pheochromocytomas and two other paragangliomas, in addition to retinal angiomatosis of von Hippel-Lindau disease. This case is extraordinary due to (i) the unusual site of the metastasis, (ii) the neurological requirement for an emergency operation of pheochromocytoma, (iii) metastasis of pheochromocytoma in von Hippel-Lindau disease (only eight previous cases), and (iv) the number of recurrent pheochromocytomas. It clearly demonstrates the necessity for frequent and life-long follow-up in von Hippel-Lindau disease.

Simultaneously Occurring Liver Metastases of Pheochromocytoma and Medullary Thyroid Carcinoma - A Diagnostic Pitfall with Clinical Implications for Patients with Multiple Endocrine Neoplasia Type 2a

Malignant pheochromocytoma is an exceptional complication in patients with Multiple Endocrine Neoplasia Type 2a (MEN2a). In this paper, we report on a 53-year-old male patient with an evident RET gene germline mutation, who simultaneously developed hepatic metastases of medullary thyroid carcinoma (MTC) and pheochromocytoma. Comprehensive immunohistochemical investigations were performed to elaborate markers which could be useful for differentiating between MTC metastases and pheochromocytoma, respectively. Calcitonin and CEA, in particular cytokeratins and trefoil factor family 1 (TFF1), were detectable exclusively in MTC, whereas all the other markers revealed a comparable expression in both MTC and pheochromocytoma. The only clues that could indicate a potential malignant course were size, a lack of sustentacular cells and hyaline globules, and a focal spindle cell pattern in pheochromocytoma. Owing to a wide agreement in cellular differentiation and a lack of specific, routinely applicable markers for pheochromocytomas, a comprehensive and goal-directed immunohistochemistry is required to rule out pheochromocytoma metastasis in patients with MEN2a. A misinterpretation could lead to harmful clinical complications, as shown in the present case.

A unique allogenic model of metastatic pheochromocytoma: PC12 rat pheochromocytoma xenografts to nude mice and establishment of metastases-derived PC12 variants.

Local invasion and metastatic spread to distant sites are major causes of death in patients with malignant pheochromocytoma. Since appropriate in vivo models do not exist, little is known about the underlying mechanisms of tumor growth and invasion. We, therefore, developed an animal model of malignant pheochromocytoma and established organotropic metastatic variants of PC12 rat pheochromocytoma cells. PC12 cells were established as xenografts to BALB/c NCR-NU mice. Subsequent to development of tumors or metastases, primary cultures from local tumors, metastases to lymph nodes, lungs and liver were established. These were subcultured in vitro and reinjected for up to five successive in vivo/in vitro cycles. Xenografted PC12 cells grew tumors with a doubling time of 6.78 +/- 0.58 days during log phase of tumor growth, killing hosts within 5-12 weeks depending on the experimental conditions. Tumors reproducibly metastasized to lymph nodes and the lung. Spontaneous metastases to the liver were not observed, but were achieved by intrasplenic injection of parent PC12 cells. In vitro, the metastatic cell lines displayed striking differences in morphology, overall growth patterns and nutritional requirements as well as binding to purified extracellular matrix proteins compared to the parent cell line. In vivo, the metastatic variants showed marked enhancement of metastatic ability. This is the first report of PC12 rat pheochromocytoma cells to exhibit the malignant phenotype in vivo. We also established variant PC12 cell lines that preferentially metastasized to specific sites and that had acquired different in vitro behavior and ability to metastasize. This unique model system should be useful for further studies relating to the invasion and metastases of pheochromocytoma and may prove valuable for investigations of novel antineoplastic therapies in vitro and in vivo.

Bronchial Tumorous Invation Caused by Exrathoracic Malignant Growth

The clinical and pathological observations of the two cases with bronchoscopically visible tumors caused by exrathoracic primary malignant growths were reported. In one of them, tumor was located at the carina and developed from parabronchial lymphnode metastasis of gastric adenocarcinoma. In another, tumor was found as a polypous mass in the orifice of the right upper lobe bronchus and developed from the right pulmonary metastasis of pheochromocytoma of the adrenal. The pathological findings of the both malignancies were confirmed on the necropsies. Finally, the differential diagnosis of the primary bronchial malignancy was discussed.