Thoracic Aortic Aneurysm and Dissection: Review and Recommendations for Evaluation.

ABSTRACT: Aortic dissection and rupture (collectively termed "sudden aortic death") are commonly encountered by forensic pathologists, with an estimated incidence at autopsy between 0.6% and 7.7%. Despite this, there is no standard of practice for the evaluation of sudden aortic death at autopsy.Recent studies have shown 20% of patients with thoracic aortic aneurysm or dissection (TAAD) have an identifiable genetic syndrome, and 19% will have an affected first-degree relative. The past 2 decades have seen identification of new culprit genes and syndromes, which can have subtle or nonexistent external phenotypes. A high index of suspicion is warranted to identify possible hereditary TAAD (H-TAAD), allowing family members to obtain screening to avoid catastrophic vascular events. Forensic pathologists need broad knowledge of the spectrum of H-TAAD and awareness of the relative significance of hypertension, pregnancy, substance use, and microscopic changes of aortic architecture.This article reviews the common subtypes of H-TAAD, including Marfan syndrome, vascular Ehlers-Danlos, Loeys-Dietz, and familial thoracic aortic aneurysm and dissection. Recommendations for the evaluation of sudden aortic death at autopsy are presented, including (1) performance of a complete autopsy, (2) documentation of aortic circumference and valve morphology, (3) notifying family of the need for screening, and (4) preservation of a sample for potential genetic testing.

Development of sacral/buttock retiform purpura as an ominous presenting sign of COVID-19 and clinical and histopathologic evolution during severe disease course.

Retiform purpura has been described as a relatively frequent cutaneous finding in patients with coronavirus disease 2019 (COVID-19). The etiology is hypothesized to be related to thrombotic vasculopathy based on lesional biopsy specimen findings, but the pathogenesis of the vasculopathy is not completely understood. Here, we present a case of a retiform purpuric patch on the sacrum/buttocks in a hospitalized patient prior to subsequent diagnosis of COVID-19 and an eventual fatal disease course. Two lesional biopsy specimens at different time points in the disease course revealed thrombotic vasculopathy, despite therapeutic anticoagulation. Detailed histopathologic evaluation using immunohistochemical markers suggest the etiology of the vasculopathy involves both persistent complement activation and platelet aggregation, which possibly promote ongoing thrombus formation. This case highlights that sacral/buttock retiform purpuric patches may be a presenting sign of infection with SARS-CoV-2 virus and may represent an ominous sign supporting a future severe disease course. In addition, biopsy specimen findings at separate time points demonstrate that cutaneous vasculopathy may persist despite adequate systemic anticoagulation, possibly due to the combination of persistent complement and platelet activation. Finally, occlusive thrombi in sacral/buttock retiform purpuric patches may contribute to future ulceration and significant cutaneous morbidity in patients who survive COVID-19.

A Clinico-Pathologic Approach to the Differential Diagnosis of Pericardial Tumors.

PURPOSE OF REVIEW: Tumors of the pericardium are rare, but a wide variety of congenital, infectious, inflammatory, and neoplastic processes have been reported. Pericardial tumors can be categorized as non-neoplastic or neoplastic. Neoplastic lesions can be further divided into benign or malignant, with malignancies being either primary or secondary (metastatic). Clinical, radiographic, and pathologic features of the most common entities are discussed. RECENT FINDINGS: Metastatic neoplasms involving the heart and pericardium are far more common than primary pericardial neoplasms. Of primary pericardial malignancies, mesothelioma is the most common; notably, cytology of effusion fluid is relatively insensitive to the diagnosis. The prognosis for most malignancies of the pericardium, primary or secondary, is poor. Increasingly, clinically recognized diseases that involve the pericardium include Erdheim-Chester and IgG4-related disease. This article provides a comprehensive review of the most recent literature to develop a structured framework to the differential diagnosis of pericardial tumors.

Clinical diagnosis and management of large vessel vasculitis: Takayasu arteritis.

Takayasu arteritis (TA) is 1 of the 2 main causes of large vessel vasculitides (LVV), giant cell arteritis being the other. LVV can also develop in various other systemic diseases. In TA, a wide variety of symptoms result from vascular stenoses, occlusions, and dilation. Aneurysms may develop and may occasionally dissect or rupture. Disease activity can sometimes be difficult to assess clinically. Diagnostic modalities also have their shortcomings. Often, acute phase reactants do not accurately detect disease activity. Available vascular imaging modalities may be acceptable in defining vascular anatomy, but are notoriously inaccurate in delineating vascular inflammation. Glucocorticoids remain the cornerstone of therapy in TA, in spite of foreseeable long term side effects. In addition, several steroid-sparing agents are also being used, often based on promising results from small uncontrolled studies. Rarely, endovascular revascularization procedures are necessary. Resection of critical-sized aortic aneurysms and repair of aortic dissections are occasionally warranted as lifesaving procedures. The long term outcome of surgical intervention is often unfavorable and relapses are not uncommon. In addition to TA, other less commonly encountered causes of LVV are also briefly discussed in this review.

Clinical diagnosis and management of large vessel vasculitis: giant cell arteritis.

Large vessel vasculitis (LVV) covers a spectrum of primary vasculitides predominantly affecting the aorta and its major branches. The two main subtypes are giant cell arteritis (GCA) and Takayasu arteritis (TA). Less commonly LVV occurs in various other diseases. Clinical manifestations result from vascular stenosis, occlusion, and dilation, sometimes complicated by aneurysm rupture or dissection. Occasionally LVV is discovered unexpectedly on pathological examination of a resected aortic aneurysm. Clinical evaluation is often unreliable in determining disease activity. Moreover, the diagnostic tools are imperfect. Acute phase reactants can be normal at presentation and available imaging modalities are more reliable in delineating vascular anatomy than in providing reliable information on degree of vascular inflammation. Glucocorticoids are the mainstay of therapy of LVV. Patients may develop predictable adverse effects from long-term glucocorticoid use. Several steroid-sparing agents have also shown some promise and are currently in use. Endovascular revascularization procedures and open surgical treatment for aneurysms and dissections are sometimes necessary, but results are not always favorable and relapses are common. This article, the first in a series of two, will be devoted to GCA and isolated (idiopathic) aortitis, while TA will be covered in detail in the next article.

Arrhythmogenic Left Ventricular Mass as the Initial Presentation of Cardiac Sarcoidosis.

Cardiac tumors of the left ventricle are rare, and cardiac magnetic resonance is the preferred imaging tool for evaluation given superior tissue characterization. We present a case of a patient with arrhythmia and left ventricular mass that was ultimately diagnosed with cardiac sarcoidosis, reminding us that tissue is the issue.

Histologic and Immunohistochemical Features of Antemortem Thrombus Compared to Postmortem Clot: Updating the Definition of Lines of Zahn.

CONTEXT.­: Distinguishing true antemortem thrombus (AMT) from artifactual postmortem clot (PMC) can occasionally be challenging at autopsy. Lines of Zahn are cited as pathognomonic of AMT, but review of literature reveals heterogeneous definitions of the term. Neutrophil karyorrhexis and CD61 immunohistochemistry can also be used to define AMT, but there has been no systematic study determining the specificity of these features. OBJECTIVE.­: To identify features that distinguish AMT from PMC, and to clarify the definition of lines of Zahn. DESIGN.­: PMC from the heart was collected in 50 hospital autopsies. Fifty arterial and 50 venous surgical thrombectomy specimens were reviewed for comparison. The microscopic features with hematoxylin-eosin staining, phosphotungstic acid-hematoxylin (PTAH) staining, and CD61 immunohistochemistry were documented. RESULTS.­: Thin curvilinear strands of fibrin and clumps of fibrin were frequently observed in both AMT and PMC. Thick bands of nested platelets wrapped in fibrin were nearly exclusive to AMT. Neutrophil karyorrhexis was readily apparent on low power in AMT but was seen in 40 of 50 PMCs (80%) only sparsely on high-power examination. Bone marrow elements were identified in 38 of 50 PMCs (76%). CD61 staining showed a geographic pattern in AMT and a speckled pattern in PMC. PTAH staining confirmed features seen with hematoxylin-eosin. CONCLUSIONS.­: Thin curvilinear strands of fibrin are found in both AMT and PMC and can be misinterpreted as lines of Zahn. We define lines of Zahn as thick bands formed by nested platelets wrapped in fibrin. Diffuse neutrophil karyorrhexis is common in AMT; in contrast, bone marrow elements are often seen in PMC.

Consensus statement on the processing, interpretation and reporting of temporal artery biopsy for arteritis.

Giant cell arteritis (GCA) is the most common systemic vasculitis in adults in Europe and North America, typically involving the extra-cranial branches of the carotid arteries and the thoracic aorta. Despite advances in noninvasive imaging, temporal artery biopsy (TAB) remains the gold standard for establishing a GCA diagnosis. The processing of TAB depends largely on individual institutional protocol, and the interpretation and reporting practices vary among pathologists. To address this lack of uniformity, the Society for Cardiovascular Pathology formed a committee tasked with establishing consensus guidelines for the processing, interpretation, and reporting of TAB specimens, based on the existing literature. This consensus statement includes a discussion of the differential diagnoses including other forms of arteritis and noninflammatory changes of the temporal artery.

Sudden cardiac death in the young: A consensus statement on recommended practices for cardiac examination by pathologists from the Society for Cardiovascular Pathology.

Sudden cardiac death is, by definition, an unexpected, untimely death caused by a cardiac condition in a person with known or unknown heart disease. This major international public health problem accounts for approximately 15-20% of all deaths. Typically more common in older adults with acquired heart disease, SCD also can occur in the young where the cause is more likely to be a genetically transmitted process. As these inherited disease processes can affect multiple family members, it is critical that these deaths are appropriately and thoroughly investigated. Across the United States, SCD cases in those less than 40 years of age will often fall under medical examiner/coroner jurisdiction resulting in scene investigation, review of available medical records and a complete autopsy including toxicological and histological studies. To date, there have not been consistent or uniform guidelines for cardiac examination in these cases. In addition, many medical examiner/coroner offices are understaffed and/or underfunded, both of which may hamper specialized examinations or studies (e.g., molecular testing). Use of such guidelines by pathologists in cases of SCD in decedents aged 1-39 years of age could result in life-saving medical intervention for other family members. These recommendations also may provide support for underfunded offices to argue for the significance of this specialized testing. As cardiac examinations in the setting of SCD in the young fall under ME/C jurisdiction, this consensus paper has been developed with members of the Society of Cardiovascular Pathology working with cardiovascular pathology-trained, practicing forensic pathologists.

Does augmentation with a reinforced fascia patch improve rotator cuff repair outcomes?

BACKGROUND: Scaffold devices are used to augment rotator cuff repairs in humans. While the strength of a novel poly-L-lactic acid-reinforced (human) fascia patch has been documented, it is unclear whether such patches will enhance the strength or likelihood of healing of rotator cuff repairs. QUESTIONS/PURPOSES: In a canine shoulder model, we asked: Do tendon repairs augmented with a reinforced fascia patch have (1) increased biomechanical properties at Time 0 and (2) less tendon retraction and increased cross-sectional area and biomechanical properties after 12 weeks of healing compared to repairs without augmentation? (3) Do the biomechanical properties of tendon repairs reach normal values by 12 weeks of healing? And (4) is the host response associated with use of the reinforced fascia patch biocompatible? METHODS: Eleven dogs underwent bilateral shoulder surgery with partial release and acute repair of the infraspinatus tendon, one shoulder with augmentation and one without augmentation. Repair retraction, cross-sectional area, biomechanical properties, and biocompatibility were assessed at 12 weeks. RESULTS: At Time 0, the mean ± SD ultimate load of augmented repairs was 296 ± 130 N (46% ± 25%) more than nonaugmented repairs, with no difference in stiffness between groups. At 12 weeks, the ultimate load of augmented repairs averaged 192 ± 213 N (15% ± 16%) less than nonaugmented repairs, with no difference in stiffness between groups. At the tendon repair site at 12 weeks, the fascia patch showed a biocompatible host tissue response. CONCLUSIONS: The biomechanical properties of repairs augmented with a reinforced fascia patch demonstrated greater ultimate load at Time 0 than nonaugmented repairs but remained essentially unchanged after 12 weeks of healing, despite improvements in the ultimate load of nonaugmented controls in the same time frame.

Mitral annular calcification and valvular dysfunction: multimodality imaging evaluation, grading, and management.

Mitral annular calcification (MAC) refers to calcium deposition in the fibrous skeleton of the mitral valve. It has many cardiovascular associations, including mitral valve dysfunction, elevated cardiovascular risk, arrhythmias, and endocarditis. Echocardiography conventionally is the first-line imaging modality for anatomic assessment, and evaluation of mitral valve function. Cardiac computed tomography (CT) has demonstrated importance as an imaging modality for the evaluation and planning of related procedures. It also holds promise in quantitative grading of MAC. Currently, there is no universally accepted definition or classification system of MAC severity. We review the multimodality imaging evaluation of MAC and associated valvular dysfunction and propose a novel classification system based on qualitative and quantitative measurements derived from echocardiography and cardiac CT.

Differences in Aortic Histopathology in Patients Undergoing Valve Reimplantation Surgery for Various Clinical Syndromes.

OBJECTIVES: The study aims to investigate aortic histopathologic differences among patients undergoing aortic valve reimplantation, suggest different mechanisms of aortic root aneurysm pathogenesis, and identify factors associated with long-term success of reimplantation. METHODS: From 2006 to 2017, 568 adults who underwent reimplantation for repair of aortic root aneurysm, including patients with tricuspid aortic valves with no connective tissue disease (TAV/NoCTD, n = 314/568; 55.3%), bicuspid aortic valves (BAVs, n = 86/568; 15.1%), or connective tissue disease (CTD, n = 177/568; 31.2%), were compiled into three comparison groups. Patients with both BAV and CTD (n = 9/568; 1.6%) were omitted to increase study power. Patient records were analyzed retrospectively, focusing on pathology reports, which were available for 98.42% of patients, and were classified based on their descriptions of aortic tissue samples, primarily from the noncoronary sinus. Mean follow-up time available for patients was 2.97 years. RESULTS: Aortitis, medial fibrosis, and smooth muscle loss were more common histopathologic findings in patients with TAV/NoCTD than in patients with BAV and CTD (p < 0.05). Cystic medial degeneration was most often found in patients with CTD, then TAV/NoCTD, and least in BAV (p < 0.01). Increases in mucopolysaccharides were found more often in the BAV group than in the TAV/NoCTD and CTD groups (p < 0.01). There were no differences in the frequency of elastic laminae fragmentation/loss across these three groups. Among all patients, 1.97% (n = 11/559) had an unplanned reintervention on the aortic valve after reimplantation, but no significant demographic or histopathologic differences were identified. CONCLUSION: Despite some common histopathologic features among patients undergoing aortic valve reimplantation, there were enough distinguishing features among aortic tissue samples of TAV/NoCTD, BAV, and CTD patients to suggest that these groups develop root aneurysms by different mechanisms. No histopathologic features were able to predict the need for late reintervention on the aortic valve.

Invasive Aortic Valve Endocarditis: Clinical and Tissue Findings From a Prospective Investigation.

BACKGROUND: Advanced aortic valve infective endocarditis (IE) with progression and destruction beyond the valve cusps-invasive IE-is incompletely characterized. This study aimed to characterize further the invasive disease extent, location, and stage and correlate macroscopic operative findings with microscopic disease patterns and progression. METHODS: A total of 43 patients with invasive aortic valve IE were prospectively enrolled from August 2017 to July 2018. Of these patients, 23 (53%) had prosthetic valve IE, 2 (5%) had allograft IE, and 18 (42%) had native aortic valve IE. Surgical findings and intraoperative photography were analyzed for invasion location, extent, and stage. Surgical samples were formalin fixed and analyzed histologically. The time course of disease and management were evaluated. RESULTS: Pathogens included Staphylococcus aureus in 17 patients (40%). Invasion predominantly affected the non-left coronary commissure (76%) and was circumferential in 15 patients (35%) (14 had prosthetic valves). Extraaortic cellulitis was present in 29 patients (67%), abscess in 13 (30%), abscess cavity in 29 (67%), and pseudoaneurysm in 8 (19%); 7 (16%) had fistulas. Histopathologic examination revealed acute inflammation, abscess formation, and lysis of connective tissue but not of myocardium or elastic tissue. Median time from onset of symptoms to antibiotics was 5 days, invasion confirmation 15 days, and surgery 37 days. Patients with S aureus had a 21-day shorter time course than patients non-S aureus. New or worsening heart block developed in 8 patients. CONCLUSIONS: Advanced invasive aortic valve IE demonstrates consistent gross patterns and stages correlating with histopathologic findings. Invasion results from a confluence of factors, including pathogen, time, and host immune response, and primarily affects the fibrous skeleton of the heart and expands to low-pressure regions.

Novel ophthalmic pathology in an autopsy case of autosomal dominant retinal vasculopathy with cerebral leukodystrophy.

Autosomal dominant retinocerebral vasculopathy with cerebral leukodystrophy (RVCL) is a rare neurovascular syndrome causing retinal and central nervous system vasculopathy often recognized as contrast-enhancing white matter changes or pseudotumors on imaging. Heterozygous frameshift mutations in the 3-prime repair exonuclease 1 gene have been identified in families affected by RVCL. Variable light microscopic findings and a characteristic ultrastructural appearance of the vasculature in the brain have been reported. Description of the ophthalmic histopathology is exceedingly rare. Here, we report previously undescribed bilateral eye findings in a patient diagnosed with RVCL. The ophthalmic pathology includes thickening and reduplication of the retinal capillary basal lamina demonstrated by electron microscopy. These findings expand what is known about this disease and help further delineate its phenotype.

Characterization of and host response to tyramine substituted-hyaluronan enriched fascia extracellular matrix.

Naturally-occurring biomaterial scaffolds derived from extracellular matrix (ECM) have been previously investigated for soft tissue repair. We propose to enrich fascia ECM with high molecular weight tyramine substituted-hyaluronan (TS-HA) to modulate inflammation associated with implantation and enhance fibroblast infiltration. As critical determinants of constructive remodeling, the host inflammatory response and macrophage polarization to TS-HA enriched fascia were characterized in a rat abdominal wall model. TS-HA treated fascia with cross-linking had a similar lymphocyte (P = 0.11) and plasma cell (P = 0.13) densities, greater macrophage (P = 0.001) and giant cell (P < 0.0001) densities, and a lower density of fibroblast-like cells (P < 0.0001) than water treated controls. Treated fascia, with or without cross-linking, exhibited a predominantly M2 pro-remodeling macrophage profile similar to water controls (P = 0.82), which is suggestive of constructive tissue remodeling. Our findings demonstrated that HA augmentation can alter the host response to an ECM, but the appropriate concentration and molecular weight needed to minimize chronic inflammation within the scaffold remains to be determined.

Pulmonary Pathology of COVID-19 Following 8 Weeks to 4 Months of Severe Disease: A Report of Three Cases, Including One With Bilateral Lung Transplantation.

OBJECTIVES: Current knowledge of the pulmonary pathology of coronavirus disease 2019 (COVID-19) is based largely on postmortem studies. In most, the interval between disease onset and death is relatively short (<1 month). Information regarding lung pathology in patients who survive for longer periods is scant. We describe the pathology in three patients with severe COVID-19 who underwent antemortem examination of lung tissue at least 8 weeks after initial diagnosis. METHODS: We conducted a retrospective case series. RESULTS: The first patient developed acute respiratory failure and was started on extracorporeal membrane oxygenation (ECMO) on day 21, with subsequent hemothorax. Debridement (day 38) showed extensive lung infarction with diffuse alveolar damage and Candida overgrowth. The second patient developed acute respiratory failure requiring mechanical ventilation that did not improve despite ECMO. Surgical lung biopsy on day 74 showed diffuse interstitial fibrosis with focal microscopic honeycomb change. The third patient also required ECMO and underwent bilateral lung transplantation on day 126. The explanted lungs showed diffuse interstitial fibrosis with focal microscopic honeycomb change. CONCLUSIONS: This series provides histologic confirmation that complications of COVID-19 after 8 weeks to 4 months of severe disease include lung infarction and diffuse interstitial fibrosis.

Case report of isolated cardiac sarcoidosis presenting as hypertrophic obstructive cardiomyopathy-a clinical picture printed on lenticular paper.

BACKGROUND: Cardiac sarcoidosis (CS) is an inflammatory granulomatous process of the myocardium that can be asymptomatic or have several different clinical phenotypes. One of its rarely described presentations consists of hypertrophy of the septal myocardium, similar to hypertrophic cardiomyopathy (HCM). Isolated cardiac sarcoidosis that haemodynamically mimics hypertrophic obstructive cardiomyopathy (HOCM) has been rarely described in the literature. CASE SUMMARY: A 64-year-old Caucasian female previously diagnosed with non-critical aortic stenosis presented with pre-syncope, and echocardiography showed significant obstruction based on left ventricular outflow tract gradients, confirmed by cardiac magnetic resonance (CMR), concerning for a phenocopy of HCM. Septal myectomy was performed and pathology specimen revealed non-caseating granulomata consistent with cardiac sarcoidosis. She was started on oral corticosteroids and initial cardiac fluorodeoxyglucose positron emission tomography (FDG-PET) done after 1 month of treatment was negative. Repeat FDG-PET 15 months later, in the setting of haemodynamic decompensation, demonstrated diffuse FDG uptake in the myocardium without extra-cardiac involvement. DISCUSSION: Our case brings together two entities: isolated cardiac sarcoidosis and its presentation mimicking HOCM, which has been very rarely described in the literature. And it also shows the scenario of surgical pathology diagnosis of sarcoidosis that was not suspected by initial CMR or FDG-PET, despite adequate preparation, only appearing on repeat FDG-PET done 15 months later. Isolated cardiac sarcoidosis should remain a differential diagnosis for any non-ischaemic cardiomyopathy without a clear cause, despite imaging evidence of HCM.

Novel implantable device to detect cardiac allograft rejection.

BACKGROUND: Allograft rejection remains the nemesis of solid organ transplantation. Soul Mate is a novel implantable wireless data transmission system that analyzes 9 intramyocardial electrogram parameters recorded from 4 or 6 configurations of 2 or 3 epicardial leads to detect allograft rejection. This study determined the ability of the Soul Mate to detect early rejection of transplanted hearts. METHODS AND RESULTS: Five dogs underwent heterotopic cervical heart transplantation and simultaneous implantation of the Soul Mate's Cardiac Rejection Monitoring Device. Dogs were initially immunosuppressed, but subsequent drug discontinuation allowed allograft rejection to appear. Allograft biopsies were performed at regular intervals to determine rejection grade, which was compared to a calculated rejection score determined as percent change from baseline of values for each intramyocardial electrogram. There was significant correlation between the biopsy results and the evolution of 5 parameters. The strongest correlation (r=0.939; P<0.001) was obtained using the "general median" parameter from 4 configurations, assessed 1 day before the biopsy, with a sensitivity of 85.7% and a specificity of 100% compared to the myocardial biopsy results. CONCLUSIONS: The Soul Mate allograft rejection monitoring system accurately detected transplanted heart rejection in a canine model noninvasively with continuous sampling. This proof-of-concept study suggests that the Soul Mate could be used to more intensely and more frequently monitor cardiac allografts for rejection.

Diagnosis of antibody-mediated rejection in cardiac transplantation: a call for standardization.

PURPOSE OF REVIEW: Currently clinical antibody-mediated rejection (AMR) requires demonstration of histopathologic changes, presence of donor-specific allo-antibodies and allograft dysfunction to establish the diagnosis. Pathology practice patterns in the immunopathologic evaluation and interpretation of cardiac transplant biopsies vary. Specific recommendations for post-transplant allo-antibody monitoring are lacking. Recently, the occurrence of surveillance biopsies being positive for immunopathologic markers of AMR without concomitant graft dysfunction is increasingly recognized. This review focuses on issues of standardization in the diagnosis of AMR and the need for updated criteria. RECENT FINDINGS: Concomitant use of C4d and C3d proved to be strongly predictive of the presence of circulating allo-antibodies and allograft dysfunction in heart transplant recipients. Asymptomatic patients with histopathologic evidence of AMR in their biopsies appear to have increased risk for cardiac allograft vasculopathy and cardiovascular mortality. The role of nonhuman leukocyte antigen antibodies in AMR has not been adequately addressed. SUMMARY: A consensus on the frequency of AMR screening, antibody panels, interpretation and reporting of stains will enhance standardization of the diagnosis of AMR. Further studies are needed to define asymptomatic or subclinical AMR and to determine the long-term outcome of pathologic evidence of complement activation without allograft dysfunction.