Right atrial myxoma as the first manifestation of granulomatosis with polyangiitis, and a possible association with vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6): a case report and review of the literature.

BACKGROUND: Granulomatosis with polyangiitis and myxomas are rare conditions previously described to co-exist. Cardiac masses are often presumed to be myxomas rather than lesions of granulomatosis with polyangiitis. CASE PRESENTATION: We present a review of the symptoms for the two diagnoses along with the first verified case. CONCLUSIONS: Two possible risk factors for developing myxomas (VEGF and IL-6) are explored and discussed.

Cerebral embolization associated with parenchymal seeding of the left atrial myxoma: Potential role of interleukin-6 and matrix metalloproteinases.

Systemic embolization has been reported in up to 40% of patients with left atrial myxoma, half of them with cerebral involvement. However, development of intracerebral embolization associated with parenchymal seeding of the myxoma emboli is an extremely rare complication, with only 36 histologically diagnosed cases reported in the published literature. We describe a 69-year-old woman who arrived at the emergency service with hemiparesis associated with drug-resistant epilepsy and a medical history of resection of a left atrial myxoma 10 months previously. Cranial computed tomography revealed multiple large lesions of heterogeneous density and cystic components in the occipital lobes and posterior fossa parenchyma. Histopathological analyses after stereotactic biopsy of the occipital lesion revealed infiltrative myxoma cells with benign histological findings and uniform expression of calretinin similar to that of the primary cardiac myxoma. Additional immunohistochemical studies confirmed brain parenchymal seeding of the myxoma cells with strong expression of interleukin-6 (IL-6) and focal expression of matrix metalloproteinases-2 (MMP-2). Here, we discuss the clinicopathological features of intracerebral embolization of left atrial myxomas associated with progressive parenchymal seeding of the tumor emboli and the potential pathogenic role of IL-6 and MMPs.

Sex-dependent expression of prostatic markers and hormone receptors in cystic tumor of the atrioventricular node: A histopathological study of three cases.

We pathologically investigated three autopsy cases of cystic tumor of the atrioventricular node (CTAVN) with sudden death. Case 1 was a 36-year-old woman without any clinical history. Case 2 was a 76-year-old man with an implanted pacemaker for complete atrioventricular block. Case 3 was a 45-year-old man with a history of first-degree AV block and sinus bradycardia. Microscopically, all three cases showed the bilayered structure of tumor glands and corpora amylacea in the glandular lumens. Immunohistochemically, the inner cells of the tumor glands were positive for cytokeratin CAM5.2, CEA, EMA, olfactomedin-4 and alpha-methylacyl-coenzyme A racemase; the outer cells were positive for p63 and cytokeratin high molecular weight. In Case 1, androgen receptor and estrogen receptor were negative; progesterone receptor was focally positive in both the inner and outer cells. In Case 2, androgen receptor showed intermediate positivity in the inner cells; estrogen receptor and progesterone receptor were positive in the outer cells. Positive expression of both prostate-specific antigen and prostate-specific acid phosphate were found in the inner cells of both male cases. Because CTAVN cells exhibit different degrees of the prostatic phenotype depending on the patient's sex, we believe that CTAVN may originate from urogenital sinus tissue in some cases.

The Use of Peptide Receptor Radionuclide Therapy in Patients With Neuroendocrine Tumor Cardiac Metastases.

Cardiac metastases are an infrequent site of metastasis in neuroendocrine tumors, and the treatment implications in the era of peptide receptor radionuclide therapy (PRRT) are unclear. Potential safety concerns exist regarding cardiac integrity and function in response to PRRT. We describe our institutional experience with 4 patients with well-differentiated, midgut neuroendocrine tumors with cardiac involvement detected on Ga-DOTATATE PET/CT scans who were treated with PRRT.

Hypermetabolic Cerebral Metastases of Cardiac Myxoma on FDG PET/CT.

ABSTRACT: A 66-year-old woman with a history of surgical resection of left atrial myxoma 6 months ago presented with multiple brain lesions with MRI. An FDG PET/CT was performed for further evaluation. The images showed that cerebral tumors had variable and increased FDG uptake in general, and no other abnormal FDG-avid lesions were noted. The tumor of right occipital lobe was resected and confirmed as metastatic cardiac myxoma on histology.

Cardiac Myxoma: Review and Update of Contemporary Immunohistochemical Markers and Molecular Pathology.

Cardiac myxoma is an uncommon benign mesenchymal neoplasm of the heart. It usually arises in the left atrium, near the valve of the fossa ovalis, and most frequently affects adults in the third through the sixth decades of life. It is hypothesized to arise from subendothelial vasoformative reserve cells or primitive cells that differentiate along the lines of the endothelium, but this remains speculative. Microscopically, the neoplastic cells are arranged individually, and nests, and are oriented in single or multiple layers around vascular channels. The neoplastic cells are immunoreactive for vimentin, calretinin, S100, nonspecific enolase, factor VIII, CD31, and CD34. The tumor can have diverse clinical presentations depending on its location and extent of disease and is predisposed to embolization. The current treatment is prompt surgical excision.

Early and delayed neurological manifestations of cardiac myxomas.

Cardiac myxoma can embolize and cause early and delayed sequelae including stroke, growth into intracranial fusiform aneurysms and cerebral tumors with risk of hemorrhage and mass effect. Here, we report the rare coincidence of all these manifestations in a 63-year-old man who presented with cognitive and behavioral changes, and seizures 9 months after an embolic stroke from the heart tumor. C-reactive protein (CRP) was elevated at the time of stroke and cardiac myxoma diagnosis but was normal at late neurologic manifestation with isolated myxoma-related intracranial tumors and aneurysms. Low-dose whole-brain radiotherapy can be helpful to diminish cerebral myxoma tumors and fusiform aneurysms despite reported increased risk of aneurysm rupture.

Cardiac myxoma and neural crests: a tense relationship.

In cardiac myxomas, the malignant transformation process, selecting incidental gene mutations and leading to loss of proliferation control, has not a so drastic effects in terms of growth rate of tumor mass, but frequently the particular location of lesion engrosses the high risk for health. For accurate cancer cell profiling, it is important to establish the embryologic origin of malignant cells and their initial commitments, above all, in the sight of therapeutic strategies and solutions. Here, we advance, for cardiac myxoma, the hypothesis of an origin from cardiac neural crest cells and we attempt to support it by an integrated discussion of current knowledge about embryological characteristics of neural crest cells and most recent studies focusing cardiac myxomas. We discuss the relationship between the basic plasticity of cardiac neural crest cells and some typical mutations arising in neoplastic lesions as well as the expression of typical cell markers of neural crests derivatives. Dysfunctions in proliferative and migratory programs, focused in other studies, are evaluated in the context of the topological and histopathological characteristics of cardiac myxomas.

POT1 and Damage Response Malfunction Trigger Acquisition of Somatic Activating Mutations in the VEGF Pathway in Cardiac Angiosarcomas.

Background Mutations in the POT1 gene explain abnormally long telomeres and multiple tumors including cardiac angiosarcomas (CAS). However, the link between long telomeres and tumorigenesis is poorly understood. Methods and Results Here, we have studied the somatic landscape of 3 different angiosarcoma patients with mutations in the POT1 gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the POT1 gene has been studied. Patients with CAS and nonfunctional POT1 did not repress ATR (ataxia telangiectasia RAD3-related)-dependent DNA damage signaling and showed a constitutive increase of cell cycle arrest and somatic activating mutations in the VEGF (vascular endothelial growth factor)/angiogenesis pathway (KDR gene). The same observation was made in POT1 mutation carriers with tumors different from CAS and also in CAS patients without mutations in the POT1 gene but with mutations in other genes involved in DNA damage signaling. Conclusions Inhibition of POT1 function and damage-response malfunction activated DNA damage signaling and increased cell cycle arrest as well as interfered with apoptosis, which would permit acquisition of somatic mutations in the VEGF/angiogenesis pathway that drives tumor formation. Therapies based on the inhibition of damage signaling in asymptomatic carriers may diminish defects on cell cycle arrest and thus prevent the apoptosis deregulation that leads to the acquisition of driver mutations.

Cardiac tamponade as an initial presentation of papillary carcinoma with psammoma bodies and intranuclear grooves-A diagnostic dilemma.

Involvement of body fluids by adenocarcinoma is a common phenomenon. However, metastasis to the pericardial fluid by adenocarcinoma is a rare occurrence. The most common malignancies associated with malignant pericardial effusion are carcinoma of the lung, breast, esophagus, melanoma, lymphoma, and leukemia. Here, we discuss a case of a 36-year-old female with hemorrhagic pericardial effusion presenting with cardiac tamponade and psammoma bodies which was suspected and reported as metastatic papillary carcinoma of thyroid on cytomorphology; however, the immunocytochemical and radiological features confirmed metastatic papillary adenocarcinoma of lung contrary to the thyroid which is more common and expected.

Late Gadolinium Enhancement Cardiac Magnetic Resonance Tissue Characterization for Cancer-Associated Cardiac Masses: Metabolic and Prognostic Manifestations in Relation to Whole-Body Positron Emission Tomography.

Background Cardiac magnetic resonance ( CMR) differentiates neoplasm from thrombus via contrast enhancement; positron emission tomography ( PET) assesses metabolism. The relationship between CMR contrast enhancement and metabolism on PET is unknown. Methods and Results The population included 121 cancer patients undergoing CMR and 18F-fluorodeoxyglucose (18F- FDG) - PET , including 66 with cardiac masses and cancer-matched controls. Cardiac mass etiology (neoplasm, thrombus) on CMR was defined by late gadolinium enhancement; PET was read blinded to CMR for diagnostic performance, then colocalized to measure FDG avidity. Of CMR -evidenced thrombi (all nonenhancing), none were detected by PET . For neoplasm, PET yielded reasonable sensitivity (70-83%) and specificity (75-88%). Lesions undetected by PET were more likely to be highly mobile ( P=0.001) despite similar size ( P=0.33). Among nonmobile neoplasms, PET sensitivity varied in relation to extent of CMR -evidenced avascularity; detection of diffusely enhancing or mixed lesions was higher versus predominantly avascular neoplasms (87% versus 63%). Colocalized analyses demonstrated 2- to 4-fold higher FDG uptake in neoplasm versus thrombus ( P<0.001); FDG uptake decreased stepwise when neoplasms were partitioned based on extent of avascularity on late gadolinium enhancement CMR ( P≤0.001). Among patients with neoplasm, signal-to-noise ratio on late gadolinium enhancement CMR moderately correlated with standardized uptake values on PET ( r=0.42-0.49, P<0.05). Mortality was higher among patients with CMR -evidenced neoplasm versus controls (hazard ratio: 1.99 [95% CI, 1.1-3.6]; P=0.03) despite nonsignificant differences when partitioned via FDG avidity (hazard ratio: 1.56 [95% CI, 0.85-2.74]; P=0.16). Among FDG-positive neoplasms detected concordantly with CMR , mortality risk versus cancer-matched controls was equivalently increased (hazard ratio: 2.12 [95% CI, 1.01-4.44]; P=0.047). Conclusions CMR contrast enhancement provides a criterion for neoplasm that parallels FDG -evidenced metabolic activity and stratifies prognosis. Extent of tissue avascularity on late gadolinium enhancement CMR affects cardiac mass identification by FDG - PET .

On-Tissue Hydrogel-Mediated Nondestructive Proteomic Characterization: Application to fr/fr and FFPE Tissues and Insights for Quantitative Proteomics Using a Case of Cardiac Myxoma.

PURPOSE: The application of a methodology for quantitative protein analysis from formalin-fixed and paraffin-embedded (FFPE) tissue by using hydrogels. Miniaturized polymeric gels are placed onto histologically defined tissue regions in order to perform localized digestion for bottom-up proteomics. Hydrogel-extracted peptides are then labeled with tandem mass tags (TMT) reagents for relative protein quantification. A cardiac myxoma biopsy is used. EXPERIMENTAL DESIGN: Multiple hydrogels, incorporating the proteolytic enzyme trypsin, are placed on serial tissue sections, and processed for digestion and TMT derivatization. SCX fractionation before LC-MS/MS analysis and bioinformatics analysis are carried out. RESULTS: Two histologically different areas on both FFPE and frozen sections of the same cardiac myxoma biopsy are compared. In total, 1949 (FFPE) and 2491 (frozen) proteins are identified, with a total overlap of 56%. The quantitative comparison highlighted 15 (FFPE) and 138 (frozen) differentially expressed proteins between myxoma regions. CONCLUSION: The methodology successfully detects numerous protein signals from FFPE and frozen specimens and is able to differentiate between tissue regions. A fast and reliable tissue preparation for quantitative protein analysis by minimum sample manipulation is developed. This offers an option for on-tissue proteomics analysis while preserving the inherent spatial information on the tissue.

Giant cardiac tumours in the newborn: an unusual image.

Primary heart tumours in the paediatric population are very rare and they range from 0.01% to 0.04%. Most are benign lesions of which about half are rhabdomyomas. Rhabdomyoma tumour diagnosis is associated with a 75-80% risk of tuberous sclerosis complex (TSC). TSC are characterised with numerous changes of hamartoma-type located in the brain, kidneys, skin and other organs including the heart. More than two-thirds of newborns with TSC present rhabdomyomas in the heart. These changes may be asymptomatic, but in some cases they may cause heart failure, arrhythmias and death. We present a case report of an infant with giant rhabdomyoma tumours in the course of TSC.

Nephronectin is Decreased in Metastatic Breast Carcinoma and Related to Metastatic Organs.

Breast cancer causes death mostly due to distant metastasis. During metastasis, cancer cells create new conditions in which normal tissue structure can be disturbed. Nephronectin, which is the primary ligand for α8ß1 integrin, plays an important role in kidney development. There are conflicting findings regarding its role in cancer progression and metastasis, especially in breast carcinoma. The aim of this study was to determine changes in nephronectin expression in primary tumor tissues and metastatic visceral organs, using metastatic and non-metastatic cell lines in a mouse model of breast cancer. In our study, 4T1-Liver Metastatic and 4T1-Heart Metastatic cells, originally derived from 4T1-murine breast carcinoma, and non-metastatic 67NR carcinoma cells were used. Cancer cells were injected orthotopically into the mammary gland of 8-10 week-old Balb-c mice. Primary tumors, lung, liver tissues were collected on 12th and 25th days after the tumor injection. Immunohistochemistry was used to determine expression of nephronectin in tissues. We also investigated the expression levels of the protein by using western blot technique. We found that lung and liver tissue of control animals (not-injected with tumor cells) expressed nephronectin which was lost in animals bearing metastatic tumor for 25 days. In accordance, nephronectin staining of lung and liver was preserved in animals injected with non-metastatic 67NR tumors. These results demonstrate that loss of nephronectin may play an important role in formation metastatic milieu for cancer cells. This is the first study demonstrating that tumor-induced loss of nephronectin expression in visceral organs in which metastatic growth takes place.

Intracardiac Metastases Detected by 18F-FSPG PET/CT.

PET/CT imaging is frequently used for cancer diagnosis and restaging as metabolically active cells, including cancer, utilize glucose for proliferation. F-FDG is the most commonly utilized radiopharmaceutical in PET/CT imaging. Limitations of F-FDG imaging include intense physiologic uptake in benign tissues such as the brain and myocardium. We present a case of non-small cell lung cancer with myocardial and pericardial metastases obscured by physiologic F-FDG cardiac uptake but detected with the investigational PET radiotracer (4S)-4-(3-F-fluoropropyl)-L-glutamate (F-FSPG), which targets a pathway associated with glutathione biosynthesis. This case demonstrates the added value of F-FSPG PET/CT imaging.