Genetic alterations in pulmonary epithelioid hemangioendothelioma and epithelioid angiosarcoma

Epithelioid hemangioendothelioma (EHE) is a low-to-intermediate-grade vascular tumor that occurs in many organs, and epithelioid angiosarcoma (EA) is a subtype of angiosarcoma that is associated with high-grade malignancy. These two types of tumors have different forms of biological behavior. Pulmonary epithelioid hemangioendothelioma (PEH) and epithelioid angiosarcoma (PEA) are both very rare, and genetic studies on them are extremely limited. We examined and compared the cytogenetic characteristics of these two types of lung tumors in two patients utilizing the Array-Comparative Genomic Hybridization (Array-CGH) method. Considerable differences in the cytogenetic characteristics were observed between the two types of tumors. Small fragment gains (<10 MB) were dominant in PEH, whereas large fragment gains and deletions (>10 MB) were dominant in PEA. Some large fragment alterations, such as gains in chromosomes 19q and 19p, and deletions in chromosomes 9p and 13q, involved over half of a chromosome arm. PEH and PEA showed great cytogenetic differences; therefore, further genetic studies on these two types of tumors are warranted.     

Fine needle aspiration cytology of epithelioid angiosarcoma: a case report

BACKGROUND: Malignant vascular tumors are rare. Few studies have described cytomorphologic features of hemangioendothelioma and angiosarcoma on fine needle aspiration cytology (FNAC). Malignant vascular tumor with epithelioid morphology can create diagnostic difficulty, as the cytology may simulate that in other nonvascular malignant tumors. We describe epithelioid angiosarcoma, diagnosed on FNAC, in which a differential diagnosis of histiocytosis and inflammatory granulation tissue was considered. CASE: A 20-year-old man presented with forehead and scalp swellings. The forehead lesion was radiologiocally associated with a lytic lesion in the bone. FNA resulted in high cellular yield, and smears revealed prominent vascular pattern with endothelial cell atypia and histiocytoid/epithelioid neoplastic cells, occasional mitotic figures and a few cells displaying nuclear grooving. Smear background showed a significant number of neutrophils. Epithelioid hemangioendothelioma/angiosarcoma, histiocytosis and inflammatory granulation tissue were considered. A cytologic diagnosis of epithelioid angiosarcoma/epithelioid hemangioendothelioma was suggested and confirmed on histopathologic and immunohistochemical examination. CONCLUSION: Cellular aspirates from malignant epithelioid endothelial tumors involving bone may be cytologically mistaken for histiocytosis and, rarely, inflammatory granulation tissue. However, prominent vascular pattern with striking endothelial cell atypia, presence of mitotic figures and careful search for presence of endothelial differentiation are helpful in accurate cytologic diagnosis.     

Fine needle aspiration of metastatic epithelioid angiosarcoma: a report of 2 cases

BACKGROUND: Epithelioid angiosarcomas (EAs) are uncommon mesenchymal tumors occurring in the thyroid, deep-seated soft tissues, parenchymal organs and, more rarely, superficial soft tissues of the head and neck. Due to their cytologic and immunocytochemical presentation on fine needle aspiration cytology (FNAC) samples, these neoplasms may closely mimic a number of different tumors, potentially causing an erroneous cytopathologic diagnosis unless immunophenotypical markers of vascular differentiation are sought in the cellular material. CASES: A 68-year-old man with a 1-year history of total thyroidectomy for EA presented with a suspicious right neck node and underwent FNA. A 63-year-old woman with a history of recurring multiple scalp nodules diagnosed as EA ultimately developed small multiple, bilateral lymph nodes in the neck and underwent FNA. In both cases a cytopathologic diagnosis of metastatic EA was made. CONCLUSION: The cytopathologic diagnosis of EA is a challenge. Knowledge of the clinical history is of great help in diagnosing metastatic lesions. The cytopathologicpicture of metastases is a useful way for cytopathologists to gain confidence with presentaton of this rare entity in primary sites on FNAC samples. Cytopathologic hints of vascular differentiation should be sought in the cytopathologic material when a diagnosis of EA is entertained.     

Fine needle aspiration cytology of epithelioid angiosarcoma. Report of a case with nuclear grooves and indentations

BACKGROUND: Angiosarcoma, because of its rarity and histologic diversity, has been a persistent challenge to cytopathologists. Epithelioid angiosarcomas are often confused with carcinomas, melanomas and other epithelioid sarcomas, both cytologically and histologically. Here we report the cytopathologic features of a case of epithelioid angiosarcoma with prominent nuclear grooves. CASE: A 61-year-old male visited the hospital with a neck mass. On fine needle aspiration the hypercellular smear, with a lymphocytic bloody background, showed variable-sized, round to oval, pleomorphic cells with frequent nuclear grooves, indentations and plump cytoplasm. The cells were diffusely scattered or loosely aggregated, with occasional acinar and cell-in-cell configuration. The case was diagnosed as epithelioid angiosarcoma on excisional biopsy. CONCLUSION: Whenever fine needle aspiration cytology, especially in the head and neck area, suggests malignancy composed predominantly of epithelioid cells, epithelioid angiosarcoma should be considered. The differential diagnosis should include metastatic tumors, such as carcinoma, melanoma and primary sarcoma. Nuclear grooves and indentations are 1 of the important diagnostic features of epithelioid angiosarcoma.     

Pulmonary metastasis of a postradiation breast epithelioid angiosarcoma mimicking adenocarcinoma. A case report

BACKGROUND: Epithelioid angiosarcoma (EAS) is a mesenchymal neoplasm that may appear indistinguishable from carcinoma, melanoma and other tumors with epithelioid/epithelial differentiation. We report a case of metastatic postradiation EAS to the lungs that was mistaken for adenocarcinoma. CASE: A 45-year-old woman who received radiotherapy for ductal carcinoma in situ (DCIS) 5 years previously had a local recurrence a year earlier and recent development of bilateral small pulmonary nodules. Fine needle aspiration biopsy of the lung lesions showed round to oval tumor cells with amphophilic cytoplasm. An interpretation of adenocarcinoma was rendered during assessment for specimen adequacy. The original breast tumor was typical of cribriform DCIS. Review of the recurrent breast tumor (initially reported as DCIS) and a prior wedge resection of the lung nodules (reported as EAS) showed an epithelial-appearing tumor exhibiting an endothelial immunophenotype CONCLUSION: The cytologic features of EAS may resemble those of other neoplasms. In evaluating tumors with epithelioid morphology, mesenchymal tumors should also be considered so that appropriate antibodies can be included in the panel for immunohistochemistry. The importance of reviewing the patient's previous biopsy materials cannot be overemphasized.     

Visceral leishmaniasis with cardiac involvement in a dog: a case report

A dog presented with cutaneous nodules, enlarged lymph nodes and oedema in limbs, face and abdomen. The diagnosis of visceral leishmaniasis was established by identification of Leishmania amastigotes within macrophages from skin and popliteal lymph node biopsies. At necropsy, lesions were found in different organs, but it was particularly striking to observe large areas of pallor in the myocardium. Histological examination revealed an intense chronic inflammatory reaction in many organs, and numerous macrophages were found to contain amastigote forms of Leishmania. The inflammatory reaction was especially severe in the heart, where large areas of the myocardium appeared infiltrated with huge numbers of mononuclear immune cells, causing cardiac muscle atrophy and degeneration. Despite the severe inflammation, the number of parasitized macrophages was low in the myocardium, as revealed by immunohistochemical staining of Leishmania amastigotes. Because cardiac involvement is not usually described in this condition, this dog represents a very rare case of canine visceral leishmaniasis with affection of the myocardium.     

The co-expression of cytokeratin and p63 in epithelioid angiosarcoma of the parotid gland: a diagnostic pitfall

ABSTRACT: SUMMARY: Epithelioid angiosarcoma of the parotid gland is rare, and may pose a great diagnostic challenge. We report a case of primary epithelioid angiosarcoma in a 64-year-old male without history of radiation. The histopathological findings demonstrated a high grade epithelioid neoplasm. Immunostaining showed that the tumor was positive for the pancytokeratin, p63, cytokeratin18, Vimentin and vascular markers CD31, and was negative for CD34, cytokeratin5/6, cytokeratin7, cytokeratin20, CD68, CD30, S-100, HMB45, desmin, alpha- SMA and CD45. The tumor was diagnosed as an epithelioid angiosarcoma. To our knowledge, this is the first reported case of angiosarcoma which showed common positivity for cytokeratin and p63. In addition to cytokeratin, p63 is considered a useful marker for carcinoma. The co-expression of cytokeratin and p63 in epithelioid angiosarcoma represents a diagnostic pitfall. Thus, using a panel of antibodies is essential for distinguishing this tumor from poorly differentiated carcinoma. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6548916707504750.     

Reduced cardiac output is associated with decreased mitochondrial efficiency in the non-ischemic ventricular wall of the acute myocardial-infarcted dog

Cardiogenic shock is the leading cause of death among patients hospitalized with acute myocardial infarction (MI).Understanding the mechanisms for acute pump failure is therefore important.The aim of this study is to examine in anacute MI dog model whether mitochondrial bio-energetic function within non-ischemic wall regions are associated withpump failure.Anterior MI was produced in dogs via ligation of left anterior descending (LAD) coronary artery,thatresulted in an infract size of about 30% of the left ventricular wall.Measurements of hemodynamic status,mitochondrialfunction,free radical production and mitochondrial uncoupling protein 3 (UCP3) expression were determined over 24h period.Hemodynamic measurements revealed a>50% reduction in cardiac output at 24 h post infarction when com-pared to baseline.Biopsy samples were obtained from the posterior non-ischemic wall during acute infarction.ADP/Oratios for isolated mitochondria from non-ischemic myocardium at 6 h and 24 h were decreased when compared to theADP/O ratios within the same samples with and without palmitic acid (PA).GTP inhibition of (PA)-stimulated state 4respiration in isolated mitochondria from the non-ischemic wall increased by 7% and 33% at 6 h and 24 h post-infarctionrespectively when compared to sham and pre-infarction samples.This would suggest that the mitochondria are uncoupledand this is supported by an associated increase in UCP3 expression observed on western blots from these same biopsysamples.Blood samples from the coronary sinus measured by electron paramagnetic resonance (EPR) methods showedan increase in reactive oxygen species (ROS) over baseline at 6 h and 24 h post-infarction.In conclusion,mitochondrialbio-energetic ADP/O ratios as a result of acute infarction are abnormal within the non-ischemic wall.Mitochondria ap-pear to be energetically uncoupled and this is associated with declining pump function.Free radical production may beassociated with the induction of uncoupling proteins in the mitochondria.     

X-ray diffraction from a left ventricular wall of rat heart

We studied x-ray diffraction from the left ventricular wall of an excised, perfused whole heart of a rat using x rays from the third-generation synchrotron radiation facility, SPring-8. With the beam at right angles to the long axis of the left ventricle, well-oriented, strong equatorial reflections were observed from the epicardium surface. The reflections became vertically split arcs when the beam passed through myocardium deeper in the wall, and rings were observed when the beam passed into the inner myocardium of the wall. These diffraction patterns were explained by employing a layered-spiral model of the arrangement of muscle fibers in the heart. In a quiescent heart with an expanded left ventricle, the muscle fibers at the epicardium surface were found to have a (1,0) lattice spacing smaller than in the rest of the wall. The intensity ratio of the (1,0) and (1,1) equatorial reflections decreased on contraction with a similar time course in all parts of the wall. The results show that it is possible to assign the origin of reflections in a diffraction diagram from a whole heart. This study offers a basis for interpretation of x-ray diffraction from a beating heart under physiologically and pathologically different conditions.     

Widespread association of a Rickettsiales-like bacterium with reef-building corals

White band disease type I (WBD I) has been a major cause of the dramatic decline of Acroporid coral populations throughout the Caribbean during the last two decades, yet the aetiological agent of this disease is unknown. In this study, the bacterial communities associated with both healthy and diseased Acropora species were compared by 16S rDNA analyses. The bacterial communities of both healthy and diseased Acropora spp. were dominated by a single ribotype with 90% identity to a bacterium in the order Rickettsiales. Screening by nested PCR specific to the coral-associated Rickettsiales 1 (CAR1) bacterium showed that this microbe was widespread in both healthy and diseased A. cervicornis and A. palmata corals from 'healthy' (i.e. low WBD I incidence) and 'stressed' reefs (i.e. high WBD I incidence). These results indicate that there were no dramatic changes in the composition of the microbial community associated with WBD I. CAR1 was also associated with non-Acroporid corals of the Caribbean, as well as with two Acroporid corals native to the Pacific. CAR1 was not present in the water column. This bacterium was also absent from preserved Caribbean Acroporid samples collected between 1937 and 1980 before the outbreak of WBD I. These results suggest CAR1 is a relatively new bacterial associate of Acroporids and that a non-bacterial pathogen might be the cause of WBD I.     

Reduction in interaction between cGMP and cAMP in dog ventricular myocytes with hypertrophic failure

Baseline function and signal transduction are depressed in hearts with hypertrophic failure. We tested the hypothesis that the effects of cGMP and its interaction with cAMP would be reduced in cardiac myocytes from hypertrophic failing hearts. Ventricular myocytes were isolated from control dogs, dogs with aortic valve stenosis hypertrophy, and dogs with pacing hypertrophic failure. Myocyte function was measured using a video edge detector. Cell contraction data were obtained at baseline, with 8-bromo-cGMP (10(-7), 10(-6), and 10(-5) M), with erythro-9-(2-hydroxy-3-nonyl)adenine [EHNA; a cAMP phosphodiesterase (PDE(2)) inhibitor] plus 8-bromo-cGMP, or milrinone (a PDE(3) inhibitor) plus 8-bromo-cGMP. Baseline percent shortening and maximal rates of shortening (R(max)) and relaxation were slightly reduced in hypertrophic myocytes and were significantly lower in failing myocytes (R(max): control dogs, 95.3 +/- 17.3; hypertrophy dogs, 88.2 +/- 5.5; failure dogs, 53.2 +/- 6.4 mum/s). 8-Bromo-cGMP dose dependently reduced myocyte function in all groups. However, EHNA (10(-6) M) and milrinone (10(-6) M) significantly reduced the negative effects of cGMP on cell contractility in control and hypertrophy but not in failing myocytes (R(max) for control dogs: cGMP, -46%; +EHNA, -21%; +milrinone, -19%; for hypertrophy dogs: cGMP, -40%; +EHNA, -13%; +milrinone, -20%; for failure dogs: cGMP, -40%; +EHNA, -29%; +milrinone, -32%). Both combinations of EHNA-cGMP and milrinone-cGMP significantly increased intracellular cAMP in control, hypertrophic, and failing myocytes. These data indicated that the cGMP signaling pathway was preserved in hypertrophic failing cardiac myocytes. However, the interaction of cGMP with the cAMP signaling pathway was impaired in these failing myocytes.     

Uterine epithelioid leiomyosarcoma in a pig-tailed macaque

Abstract: During ultrasonographic examination following spontaneous abortion, an approximately 6-cm diameter mass of mixed echogenicity is detected in the uterine wall of a mature pig-tailed macaque (Macaca nemestrina). Grossly, the mass is associated with the uterine fundus, multilobulate and tan with red-black mottled foci on cut surface. Microscopically, the invasive mass is composed of poorly differentiated round cells arranged in sheets and bundles supported by a fine fibrous stroma. On immunohistochemical evaluation, neoplastic cells contain vimentin, desmin, muscle actin, and smooth muscle α-actin antigens and do not react with antibodies to low and high molecular-weight cytokeratins. Cell morphology and immunohistochemical results indicate a diagnosis of epithelioid leiomyosarcoma (clear cell variant).     

Microscopic endometrial perivascular epithelioid cell nodules: a case report with the earliest presentation of a uterine perivascular epithelioid cell tumor

ABSTRACT: Perivascular epithelioid cell (PEC) tumors (PEComas) are a family of related mesenchymal tumors composed of PECs which co-express melanocytic and smooth muscle markers. Although their distinctive histologic, immunohistochemical, ultrastructural, and genetic features have been clearly demonstrated, their histogenesis and normal counterpart remain largely unknown. Precursor lesions of PEComas have rarely been reported. We herein describe a tuberous sclerosis patient with microscopic PEC nodules in the endometrium of adenomyosis, pelvic endometriosis, an ovarian endometriotic cyst, and the endometrium of the uterine cavity. The nodules showed a mixture of spindle-shaped and epithelioid cells concentrically arranged around small arteries. The cells exhibited uniform nuclei, light eosinophilic cytoplasm, and immunoreactivity with HMB-45 and CD10. Some nodules revealed continuity with a PEComa in the myometrium. These findings support microscopic endometrial PEC nodules possibly being precursor lesions of uterine PEComas. The wide distribution of the nodules in the pelvis may be related to the multicentricity of PEComas in tuberous sclerosis patients. Owing to the immunoreactivity with CD10, microscopic endometrial PEC nodules may be misinterpreted as endothelial stromal cells unless melanocytic markers are stained. To the best of our knowledge, this is a case with the earliest manifestation of PEC lesions occurring in the endometrium.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9658280017862643.     

Left ventricular catecholamines during acute myocardial infarction in the dog

To determine whether changes in left ventricular catecholamine content occur during the first 30 to 90 min of acute myocardial infarction, myocardial catecholamine (radioenzymatic assay) over the interval was studied in the dog. In nine pentobarbital-anesthetized opened-chest dogs without coronary ligation, myocardial catecholamine at 2.5 h after pentobarbital (i) consisted mainly of norepinephrine (87% total catecholamine), (ii) showed a base to apex gradient in norepinephrine (1.44 +/- 0.10 vs. 1.03 +/- 0.10 micrograms/g, p less than 0.05) and dopamine (0.20 +/- 0.03 vs. 0.12 +/- 0.02 micrograms/g, p less than 0.05) but not epinephrine (0.017 vs. 0.016 micrograms/g), and (iii) showed no difference in norepinephrine, dopamine, or epinephrine across basal, mid, and apical left ventricular transverse planes spanning the vascular territories of the two coronary arteries. In 18 pentobarbital-anesthetized dogs with coronary ligation, (i) norepinephrine, measured in 14 regions across the mid left ventricle after 90 min ischemia in four dogs, was less in the ischemic center of the occluded bed than normal myocardium (1.01 +/- 0.04 vs. 1.29 +/- 0.04 micrograms/g, p less than 0.05), and (ii) norepinephrine was unchanged in normal myocardium of 14 dogs at 30, 60, 90 min, and 48 h but decreased in ischemic myocardium by 31% at 60 min (0.89 +/- 0.10 vs. 1.29 +/- 0.08 micrograms/g, p less than 0.025) and 79% at 48 h (0.27 +/- 0.04 vs. 1.26 +/- 0.08 micrograms/g, p less than 0.001). Thus, norepinephrine depletion from ischemic but not normal myocardium is detectable by 60 min during acute myocardial infarction.     

Calcium in isolated mitochondria from the left ventricular wall

The content of calcium per mg mitochondrial protein has been measured by conventional biochemical methods in myocardial tissue of some mammalian species. In addition, a method is presented for (1) the analysis of mitochondrial volumes in the same tissues and (2) calculating the amount of calcium in units of 10(6) mitochondria. It appears that a highly significant correlation exists between the calcium content and the number of mitochondria, with a positive correlation coefficient of 0.92. The mean mitochondrial volume in fractions of the rabbit myocardium was found to be 1.3386 micron3. Electron microscopic studies demonstrate pure mitochondrial fractions and only moderate structural alterations. The method described may represent a useful supplement for the estimation of calcium fluxes in mitochondria and of alterations in their volume, number and structure under conditions of myocardial ischemia.     

Calcium in isolated mitochondria from the left ventricular wall

Summary The content of calcium per mg mitochondrial protein has been measured by conventional biochemical methods in myocardial tissue of some mammalian species. In addition, a method is presented for (1) the analysis of mitochondrial volumes in the same tissues and (2) calculating the amount of calcium in units of 10⁶ mitochondria.It appears that a highly significant correlation exists between the calcium content and the number of mitochondria, with a positive correlation coefficient of 0.92. The mean mitochondrial volume in fractions of the rabbit myocardium was found to be 1.3386 m³. Electron microscopic studies demonstrate pure mitochondrial fractions and only moderate structural alterations. The method described may represent a useful supplement for the estimation of calcium fluxes in mitochondria and of alterations in their volume, number and structure under conditions of myocardial ischemia.This work was supported by grants from the Norwegian Council on Cardiovascular Disease and from The Norwegian Research Council for Science and the Humanities     

Changes in ventricular fibrillation threshold with stimulation of cardiac sympathetic nerves of the developing dog

The effect of stimulation of the developing cardiac sympathetic nerves on the vulnerability to ventricular fibrillation was investigated in 50 puppies 1 to 6 weeks of age. Ventricular fibrillation thresholds were obtained before and during sympathetic nerve stimulation. Stimulation of either stellate ganglion increased ventricular fibrillation threshold, possibly due to diffuse functional innervation in pups. The effect of the left stellate increased progressively with age, whereas the effect of the right, although initially greater than that of the left, did not increase further with age. In contrast, stimulation of the left ventrolateral cardiac nerve, which is locally distributed, resulted in decreased ventricular fibrillation threshold. This decrease was progressively greater with age. The fact that activation of the left stellate ganglion and the left ventrolateral cardiac nerve affects ventricular fibrillation threshold in opposite directions suggests different sympathetically mediated changes on ventricular vulnerability in early life. The differing temporal patterns of maturation and the localized nature of the major distal branch distributions could provide a mechanism for promotion of arrhythmiogenesis under some conditions in early life.