Neovascularization of native cardiac valves, and correlation with histopathologic, clinical, and radiologic features.

Native cardiac valves in the setting of chronic injury undergo remodeling that includes fibrous thickening and dystrophic calcification, as well as neovascularization, that result in abnormal valve function. In order to characterize the presence of neovascularization in valves, a retrospective review of 1246 sequentially reviewed native cardiac valves of all types was performed, with correlation with other histopathologic features, and clinical and echocardiographic findings. Neovascularization was present in 55.5% of cases, with the greatest prevalence amongst aortic valves. While microvasculature (representing capillaries, venules, and/or lymphatics) was at least present in all cases of valves with neovascularization, arterial vessels were never identified in valves without also the finding of concomitant microvasculature present. Patients with neovascularization had a greater mean age and body mass index compared to those without, and the proportions of cases with significant coronary artery disease, dyslipidemia, diabetes mellitus, rheumatic fever, and malignancy were greater in the setting of valves with neovascularization compared to cases without. The rate of neovascularization increased with degree of valve thickening and/or calcification, and stenosis; in contrast, neovascularization was observed at a greater rate with decreasing degrees of regurgitation. The prevalence rates of hemosiderin-laden macrophages, osseous metaplasia, chondromatous metaplasia, smooth muscle, and chronic inflammation were greater in valves with neovascularization compared to valves without. Neovascularization within native cardiac valves is a frequent histopathologic alteration associated with chronic valve disease, likely representing a constituent of structural remodeling that mediates and reflects chronic injury.

Chondromatous metaplasia within native cardiac valves: clinicopathologic characterization with particular focus upon aortic valves.

Native cardiac valves in the setting of chronic injury may become thickened and disrupted by dystrophic calcification, which impede valve structure/function, and there may be evidence of chondromatous (i.e., cartilaginous, CM) metaplasia admixed with dystrophic calcification. In order to characterize the presence of CM in native cardiac valves - with particular focus upon aortic valves - a retrospective review of the histologic features of 46 native aortic valves (identified from 1094 sequentially reviewed native valves of all types) containing CM were focused upon, as well as correlation with other histopathologic features, and clinical and echocardiographic findings. The prevalence rate of CM was low, and greatest among aortic valves, less in mitral valves, and never identified in tricuspid or pulmonic valves. CM in aortic valves was less commonly identified in patients with a history of autoimmune disease. The rate of CM increased with degree of valve thickening and/or calcification. The proportion of aortic valves with CM increased with an increasing degree of stenosis and decreasing degree of regurgitation, and aortic valves with CM were more commonly associated with a smaller aortic valve area, and greater peak and mean gradients. The rate of osseous metaplasia, arterial vessels, capillary bed formation, and chronic inflammation were greater in aortic valves with CM compared to valves without. CM within aortic valves is an infrequent albeit identifiable histopathologic alteration associated with chronic valve disease alongside changes in valve thickening and calcification.

Primary cardiac and pericardial lymphangiomas: clinical, radiologic, and pathologic characterization derived from an institutional series and review of the literature.

Lymphangiomas are comprised of aggregates of lymphatic vessels, considered to represent either aberrant embryogenic remnants or developing secondary to obstruction. Lymphangiomas primary to the heart and pericardial are exceedingly rare, and to date sparingly reported in individual case reports. In this study, the histopathologic, clinical, and radiologic features of 35 cases of cardiac/pericardial lymphangiomas described in the literature to date together with four cases from our own institution (39 cases in total) are examined to provide clinicopathologic characterization. Cardiac/pericardial lymphangiomas were identified in both children and adults, with two cases initially discovered in utero. If presenting with symptoms, patients most commonly exhibited respiratory distress/dyspnea. By X-ray, a widened cardiac silhouette could be noted, and echocardiogram generally showed an echogenic mass with cystic and septal components. On computed tomography (CT) and magnetic resonance imaging (MRI), cystic and septal components were again observed, with CT showing an absence of calcifications or macroscopic fat. Most lymphangiomas were pericardial (specifically visceral) based, and frequently situated in the right atrioventricular groove. A majority of cases proceeded to surgical resection, with no evidence of recurrence post-operatively. Grossly, lesions had a median size of 6 cm and in almost all cases were multicystic/multilocular. Microscopically, the lymphangiomas were composed of lymphatic spaces lined by endothelial cells that specifically express podoplanin (D2-40) with immunoperoxidase staining. Further investigation with a larger and more uniformly organized cohort is required to better characterize the clinicopathologic features of lymphangiomas of this unusual anatomic location.

Osseous metaplasia within native cardiac valves: clinicopathologic characterization of a histologic constituent with particular focus upon aortic valves.

Native cardiac valves may undergo calcification in the setting of chronic injury, subsequently impeding normal valve structure and function. In the same setting, there may be evidence of metaplasia-specifically osseous metaplasia-with lamellar bone admixed with dystrophic calcification. In this study, the histologic features of 123 native aortic valves (identified from 1094 sequentially reviewed native valves of all types that included a total of 754 aortic valves) with osseous metaplasia are focused upon, as well as correlation with other histopathologic features, and clinical and echocardiographic findings. Osseous metaplasia was identified in aortic and significantly less frequently in mitral valves, and never in tricuspid or pulmonic valves. Notable observations included that osseous metaplasia in aortic valves were seen in patients with greater body mass index, and less commonly identified in patients with a history of autoimmune disease. Aortic valves with osseous metaplasia were more commonly tricuspid (as opposed to bicuspid), and with smaller aortic valve area and greater peak and mean gradients. The rate of osseous metaplasia in aortic valves increased with increasing degree of stenosis and decreasing degree of regurgitation. The rates of the presence of chondromatous metaplasia, smooth muscle, arterial vessels, capillary bed formation, chronic inflammation, and hemosiderin laden macrophages were greater in aortic valves with osseous metaplasia compared to valves without osseous metaplasia. Further investigation is required to determine potential physiologic and/or pathologic consequence of the presence of valvular osseous metaplasia.

Pericardial lymphangioma: a rare benign albeit variably symptomatic tumefactive lesion.

Primary pericardial-based tumefactive lesions include pericardial cysts, mature teratomas, and lymphangiomas, and while benign they may result in clinical symptomatology that leads to their radiologic detection. We present the case of a 5-year-old boy with a heart murmur who was otherwise healthy and without significant medical history. Transthoracic echocardiogram, computed tomography, and magnetic resonance imaging studies revealed a pericardial multicystic mass imparting compression upon the right atrium and ventricle. The case proceeded to surgery in which complete resection of the mass was performed without complication, and the patient was discharged three days after. Pathology examination of the lesion determined it to be a pericardial lymphangioma with characteristic histologic features of sequestered vascular channels lined by endothelium that specifically expressed lymphatic-specific podoplanin (also known as D2-40), and with associated adipose tissue, smooth muscle bundles, and reactive lymphoid aggregates. Although a rare underlying etiology for mediastinal and specifically pericardial tumors, lymphangiomas should be considered in the differential of tumefactive lesions in this anatomic location.

Case Report: Acute Thrombotic Angiopathy of Atrial Appendage Epicardial Veins: A Seemingly Innocuous Finding Portending a Fatal Outcome.

Thrombotic angiopathy is a pathologic description to describe endothelial injury, and with sufficient and sustained injury can lead to exposure of underlying tissue factor and the deposition of associated fibrin material. We present briefly a case of an 87-year-old woman with mitral valve regurgitation and atrial fibrillation undergoing mitral valve annuloplasty, Cox-maze procedure, and excision of the left atrial appendage. Pathologic examination of the excised atrial appendage revealed commonly encountered cardiomyocyte hypertrophy and endocardial fibroelastosis, however also showed a non-occlusive, acute thrombotic angiopathy involving epicardial veins. The surgical and immediate post-operative course was unremarkable; however, 3 weeks after discharge, the patient would develop a fatal pulmonary embolism. While fibrin thrombosis developing within the atrial appendage chamber is a recognized concern in the setting of atrial fibrillation, the significance of an acute thrombotic angiopathy involving epicardial veins of the atrial appendage is less clear although in the presented case was the sole potential harbinger of a subsequent fatal thrombotic event.

Case Report: Isolated and Focal Non-necrotizing Granulomatous Inflammation of Mitral Valves: A Report of Two Cases.

Cardiac valve inflammation is seen in the setting of autoimmune or infectious processes, and rarely is valvulitis characterized by granulomatous inflammation. We present two patients who underwent surgical repair of prolapsing/regurgitating mitral valves. Excised valve tissue in both cases revealed commonly encountered nodular fibrosis and calcification, however each also revealed an isolated focus of non-necrotizing granulomatous inflammation. Typical implicating etiologies for non-necrotizing granulomatous inflammation were not present for either patient based on clinical history, or radiologic and laboratory data. In a review of 1048 cardiac valves excised at our institution, the finding of non-necrotizing granulomatous inflammation was seen in only the two described cases (prevalence of 0.19%). The description of non-necrotizing granulomatous inflammation within cardiac valves is limited in the literature, and the significance of the detailed isolated and incidental finding is unclear and requiring further investigation.

Adipocytes and membranous fat necrosis within native cardiac valves: Clinicopathologic characterization of histologic constituents.

The constituents of normal cardiac valves as well as those involved by active and/or chronic processes have been detailed previously, however minor attention has been provided toward mature adipocytes within valves and correlation with other histologic, clinical, and echocardiographic data. The literature also contains a paucity of investigations examining the presence of a particular form of degenerative change of mature adipocytes termed membranous fat necrosis. We retrospectively reviewed the histologic findings of 1042 native cardiac valves which included identification of the presence of adipocytes and membranous fat necrosis within them, as well as correlation with other histopathologic features, and clinical and echocardiographic findings. Notable observations included that membranous fat necrosis was only present in valves with adipocytes, adipocytes and membranous fat necrosis were seen in older patients, and that Caucasians made up a greater proportion of patients while African Americans made up a lower proportion of patients when valves were found with adipocytes and membranous fat necrosis. Aortic valves contained adipocytes and membranous fat necrosis at a greater rate than compared to other valves, and aortic valves with adipocytes and membranous fat necrosis were more commonly tricuspid (as opposed to bicuspid) and with larger aortic valve area and lower peak and mean gradients. Further investigation is required to determine potential physiologic and/or pathologic consequence of their presence.

Concomitant monoclonal immunoglobulin deposition disease and crystalglobulin-induced nephropathy with a membranoproliferative pattern of glomerular injury
.

Monoclonal immunoglobulin paraproteins can deposit in the kidney in variable forms and eliciting differing patterns of injury. Crystalglobulin-induced nephropathy is a rare form of monoclonal immunoglobulin deposition in the kidney, characterized by glomerular capillary endoluminal crystalline material evident by light and electron microscopy that exhibits immunoglobulin restriction via immunofluorescence studies. We present a case of a patient with acute kidney injury, and a subsequent kidney biopsy notably revealed concurrent monoclonal immunoglobulin deposition disease (MIDD) and crystalglobulin-induced nephropathy secondary to an IgM/κ monoclonal protein that resulted in a membranoproliferative pattern of glomerular injury. The two process were distinctly evident by ultrastructural crystalline and non-crystalline (as seen with cases of more conventional MIDD) deposits in the glomeruli. The paraprotein constituency is novel (IgM/κ) for crystalglobulin-induced nephropathy (prior cases exhibited IgG/κ restriction) as was the finding of the two monoclonal immunoglobulin deposition processes contributing to development of an active glomerulitis characterized by a membranoproliferative pattern of glomerular injury (crystalglobulin-induced nephropathy has not been associated with an active glomerulitis before).

Heavy and light chain (AHL)-type cardiac amyloidosis: first histopathologic-proven case illustrating involvement of the heart.

Cardiac amyloidosis is most commonly comprised of either a monoclonal immunoglobulin or transthyretin; however, in practice, detailing of the former beyond light chain restriction is not typically performed. We present briefly the case of an 80-year-old man with concern for cardiac amyloidosis and a subsequent endomyocardial biopsy revealing significant deposition of amorphous Congo red-positive material. By immunofluorescence microscopy, the amyloidogenic material showed positive expression for IgG heavy chain and kappa light chain, with negative staining for IgM and IgA heavy chains and lambda light chain supporting a diagnosis of heavy and light chain (AHL)-type amyloidosis. Immunofluorescence staining for the IgG heavy chain subclasses supported and further classified the patient's AHL-type cardiac amyloidosis as being IgG4/kappa restricted. The presented case is the first to illustrate AHL-type cardiac amyloidosis via sampling of heart tissue.

Cardiac varix: an example via a case report of a radiological mimicker of cardiac myxoma.

Cardiac myxoma is the most frequently encountered primary neoplasm of the heart; however, other tumefactive lesions can share similar radiologic features. We present briefly the case of a 69-year-old man incidentally found to have a mobile right atrial mass that based on initial radiologic findings was considered to represent a myxoma. After pathologic examination, the lesion was determined instead to be a cardiac varix: an endocardial, blood filled cystic space lined by endothelium and considered to represent a dilated vein.

Synchronous Low-grade Appendiceal Mucinous Neoplasm and Primary Peritoneal Low-grade Serous Carcinoma: A First Description of These 2 Neoplasms Presenting Together as Suspected Peritoneal Carcinomatosis.

Low-grade appendiceal mucinous neoplasm is a neoplasm typically of appendiceal origin, which is characterized by diffuse peritoneal involvement by pools of mucin with mucinous epithelium lacking high-grade cytologic atypia, and clinically presents as suspected peritoneal carcinomatosis. A similar clinical presentation can sometimes be seen with disseminated low-grade serous carcinomas of the peritoneum, fallopian tubes, or ovaries; however, this neoplasm is histologically characterized by tubal-type epithelium and invasive or confluent growth. In this case report, we describe a patient presenting with a clinical examination and radiologic features suggestive of peritoneal carcinomatosis and a prominent pelvic mass; however, after pathologic review, the patient was proven to have peritoneal involvement by both low-grade appendiceal mucinous neoplasm of appendiceal origin and a low-grade peritoneal primary serous carcinoma. In short, we present the first description of low-grade appendiceal mucinous neoplasm and serous carcinoma of the peritoneum presenting synchronously, providing morphologic characterization and immunohistochemical studies supporting the diagnosis, and illustrating a rare instance in which 2 neoplastic processes are underlying clinically suspected peritoneal carcinomatosis.

IgG4-related Disease of the Ovary: A First Description.

IgG4-related disease has been previously described to involve numerous organs and anatomic sites, however, involvement of the ovary has not yet been reported in the literature. In this case report we describe an ovary involved with an inflammatory process with histopathologic features supportive of involvement by IgG4-related disease: a dense lymphoplasmacytic infiltrate with an eosinophilic component, obliterative phlebitis, and a prominent proportion of IgG-positive cells with IgG4 expression by immunohistochemistry (40%-50%). The differential diagnosis for this case would include eosinophilic perifolliculitis involving the ovary, another rare entity that shares the eosinophilic component of IgG4-related disease. In short, we present the first description of IgG4-related disease of the ovary providing morphologic characterization and immunohistochemical studies supporting the diagnosis.

Nodular fasciitis of the vulva: a challenging histopathologic diagnosis supported by the detection of USP6 gene rearrangement.

Nodular fasciitis involving the vulva on physical examination can mimic a Bartholin gland lesion, and histologically can have overlapping features with more ominous mesenchymal pathologies. We describe a case in which a 52-year-old perimenopausal woman presents with a vulvar mass. After an initial biopsy and later excision, the myofibroblastic lesion was noted to have areas of differing cellularity, with compact nodule formations at the periphery. Immunohistochemical staining showed lesional cells to be positive for desmin, estrogen receptor, progesterone receptor, and smooth muscle actin, and negative for CD34, ALK-1, myogenin, caldesmon, S100, and wide spectrum (Oscar) cytokeratin. Desmin is generally negative in this lesion type, but the positivity in this case was considered to be secondary to the origin of the myofibroblastic cells of the vulva. The morphologic pattern and immunophenotype favored a diagnosis of nodular fasciitis, however, the degree of hypercellularity and desmin positivity warranted further analysis. The diagnosis was supported with fluorescence in situ hybridization that demonstrated USP6 gene rearrangement. This highlights the necessity in certain challenging cases for ancillary molecular and/or cytogenetic analysis.

Rheological influence upon the glomerular podocyte and resultant mechanotransduction.

The glomerular podocyte is exposed to numerous mechanical forces as a constituent of the glomerular filtration apparatus. This includes fluid shear stress (FSS) displaced upon the podocytic foot process's apical, lateral, and basal surfaces. Even in the face of continuous flow the podocyte is capable of contributing to physiologic filtration, however with pathologic levels of hyperfiltration there is increased FSS placed upon the cell. The mechanisms by which the podocyte detects and responds to FSS are topics of recent investigations, with the aim to clarify the way these cells are injured and/or adapt in times of hyperfiltration and disease states. As the pathogenesis of numerous glomerulopathies is contingent on the status of the podocyte, understanding the manner that these cells can be modified by FSS is essential. Likewise, determination of the effect of such mechanical forces upon other resident cells of the renal corpuscle would reveal the contribution of FSS in the progression of glomerular diseases. The biochemical manner in which podocytes sense and respond to FSS, that is mechanotransduction, will be discussed.

A compendium of urinary biomarkers indicative of glomerular podocytopathy.

It is well known that glomerular podocyte injury and loss are present in numerous nephropathies and that the pathophysiologic consecution of disease hinges upon the fate of the podocyte. While multiple factors play a hand in glomerulopathy progression, basic logic lends that if one monitors the podocyte's status, that may reflect the status of disease. Recent investigations have focused on what one can elucidate from the noninvasive collection of urine, and have proven that certain, specific biomarkers of podocytes can be readily identified via varying techniques. This paper has brought together all described urinary biomarkers of podocyte injury and is made to provide a concise summary of their utility and testing in laboratory and clinical theatres. While promising in the potential that they hold as tools for clinicians and investigators, the described biomarkers require further comprehensive vetting in the form of larger clinical trials and studies that would give their value true weight. These urinary biomarkers are put forth as novel indicators of glomerular disease presence, disease progression, and therapeutic efficacy that in some cases may be more advantageous than the established parameters/measures currently used in practice.