Pathology of explanted pediatric hearts: An 11-year study. Population characteristics and implications for outcomes.

BACKGROUND: As more pediatric patients become candidates for heart transplantation (HT), understanding pathological predictors of outcome and the accuracy of the pretransplantation evaluation are important to optimize utilization of scarce donor organs and improve outcomes. The authors aimed to investigate explanted heart specimens to identify pathologic predictors that may affect cardiac allograft survival after HT. METHODS: Explanted pediatric hearts obtained over an 11-year period were analyzed to understand the patient demographics, indications for transplant, and the clinical-pathological factors. RESULTS: In this study, 149 explanted hearts, 46% congenital heart defects (CHD), were studied. CHD patients were younger and mean pulmonary artery pressure and resistance were significantly lower than in cardiomyopathy patients. Twenty-one died or underwent retransplantation (14.1%). Survival was significantly higher in the cardiomyopathy group at all follow-up intervals. There were more deaths and the 1-, 5- and 7-year survival was lower in patients ≤10 years of age at HT. Early rejection was significantly higher in CHD patients exposed to homograft tissue, but not late rejection. Mortality/retransplantation rate was significantly higher and allograft survival lower in CHD hearts with excessive fibrosis of one or both ventricles. Anatomic diagnosis at pathologic examination differed from the clinical diagnosis in eight cases. CONCLUSIONS: Survival was better for the cardiomyopathy group and patients >10 years at HT. Prior homograft use was associated with a higher prevalence of early rejection. Ventricular fibrosis (of explant) was a strong predictor of outcome in the CHD group. We presented several pathologic findings in explanted pediatric hearts.

Rare cardiac inflammatory pseudotumor in a toddler: Complementary roles of cardiac magnetic resonance and positron emission tomography.

We present a rare pediatric case of cardiac inflammatory pseudotumor (IPT) with a unique presentation of fever of unknown origin with markedly elevated inflammatory markers. A right atrial mass was discovered incidentally by echocardiography. The cardiac magnetic resonance (CMR) signal characteristics and mass location were not consistent with any of the common benign cardiac tumors of childhood. The presence of high signal intensity on T2 imaging and late gadolinium enhancement, in conjunction with intense metabolic activity at the mass site on positron emission tomography (PET), raised the possibility of an inflammatory or malignant mass. The diagnosis of IPT was confirmed by biopsy. Our case highlights the utility of PET imaging to confirm the inflammatory nature and extent of an IPT.

Histopathology of resected tissue from repair of anomalous aortic origin of a coronary artery: Potential mechanism of coronary artery compression.

Objective: This study aimed to describe the histomorphologic characteristics of resected (unroofed) common wall tissue from repair of anomalous aortic origin of a coronary artery and to determine whether the histologic features correlate with clinical and imaging findings. Methods: The histology of resected tissue was analyzed and reviewed for the presence of fibrointimal hyperplasia, smooth muscle disarray, mucoid extracellular matrix accumulation, mural fibrosis, and elastic fiber disorganization and fragmentation using hematoxylin and eosin and special stains. Clinical, computed tomography imaging, and surgical data were correlated with the histopathologic findings. Results: Twenty specimens from 20 patients (age range, 7-18 years; 14 males) were analyzed. Anomalous aortic origin of a coronary artery involved the right coronary in 16 (80%), and a slit-like ostium was noted in 18 (90%). By computed tomography imaging, the median proximal coronary artery eccentricity index was 0.4 (range, 0.20-0.90). The median length of intramural course was 8.2 mm (range, 2.6-15.2 mm). The anomalous vessel was determined to be interarterial in 14 patients (93%, 15 had evaluable images). The median distance from a commissure was 2.5 mm above the sinotubular junction (STJ) (range: 2 mm below the STJ-14 mm above the STJ). Prominent histopathologic findings included elastic fiber alterations, mural fibrosis, and smooth muscle disarray. The shared wall of the aorta and intramural coronary artery is more similar to the aorta histologically. Mural fibrosis and elastic fiber abnormalities tended to be more severe in patients >10 years of age at the time of surgery, but this did not reach statistical significance. The extent of vascular changes did not appear to have a clear relationship with the imaging features. Conclusions: The findings confirm the aortic wall-like quality of the intramural segment of the coronary artery and the presence of pathologic alterations in the wall microstructure.

STK11 Adnexal Tumor in an Adolescent Female: Diagnostic Pitfalls of a Recently Described Entity.

STK11 adnexal tumor is a recently described entity with less than 25 cases reported to date. These aggressive tumors typically occur in paratubal/paraovarian soft tissues, have characteristically striking morphologic and immunohistochemical heterogeneity, and harbor pathognomonic alterations in STK11. These occur almost exclusively in adult patients, with only one reported in a pediatric patient (to our knowledge). A previously healthy 16-year-old female presented with acute abdominal pain. Imaging studies revealed large bilateral solid and cystic adnexal masses, ascites, and peritoneal nodules. Following frozen section evaluation of a left ovarian surface nodule, bilateral salpingo-oophorectomy and tumor debulking were performed. Histologically, the tumor demonstrated distinctively variable cytoarchitecture, myxoid stroma, and mixed immunophenotype. A next generation sequencing-based assay identified a pathogenic STK11 mutation. We report the youngest patient to date with an STK11 adnexal tumor, highlighting key clinicopathologic and molecular features in order to contrast them with those of other pediatric intra-abdominal malignancies. This rare and unfamiliar tumor poses a considerable diagnostic challenge and requires a multidisciplinary integrated approach to diagnosis.

2 Cases of Spontaneous Coronary Artery Dissection in Neonates.

Spontaneous coronary artery dissection in infants is a rare phenomenon. We present 2 neonates with severe ventricular dysfunction due to coronary artery dissection. Neither patient had evidence of extracardiac fibromuscular dysplasia or other comorbidities that would explain the presentation. (Level of Difficulty: Advanced.).

Age-related enhanced degeneration of bioprosthetic valves due to leaflet calcification, tissue crosslinking, and structural changes.

AIMS: Bioprosthetic heart valves (BHVs), made from glutaraldehyde-fixed heterograft materials, are subject to more rapid structural valve degeneration (SVD) in paediatric and young adult patients. Differences in blood biochemistries and propensity for disease accelerate SVD in these patients, which results in multiple re-operations with compounding risks. The goal of this study is to investigate the mechanisms of BHV biomaterial degeneration and present models for studying SVD in young patients and juvenile animal models. METHODS AND RESULTS: We studied SVD in clinical BHV explants from paediatric and young adult patients, juvenile sheep implantation model, rat subcutaneous implants, and an ex vivo serum incubation model. BHV biomaterials were analysed for calcification, collagen microstructure (alignment and crimp), and crosslinking density. Serum markers of calcification and tissue crosslinking were compared between young and adult subjects. We demonstrated that immature subjects were more susceptible to calcification, microstructural changes, and advanced glycation end products formation. In vivo and ex vivo studies comparing immature and mature subjects mirrored SVD in clinical observations. The interaction between host serum and BHV biomaterials leads to significant structural and biochemical changes which impact their functions. CONCLUSIONS: There is an increased risk for accelerated SVD in younger subjects, both experimental animals and patients. Increased calcification, altered collagen microstructure with loss of alignment and increased crimp periods, and increased crosslinking are three main characteristics in BHV explants from young subjects leading to SVD. Together, our studies establish a basis for assessing the increased susceptibility of BHV biomaterials to accelerated SVD in young patients.

Tricuspid Valve Blood Cysts Mimicking Thrombus or Vegetation on Echocardiogram in a Neonate.

A 2-month-old male infant, born premature with a birth weight of 865 g, was found to have a tricuspid valve mass mimicking thrombus and vegetation by echocardiogram on the fourth day of life. The patient was treated with antibiotics and anticoagulation with no change in the size of the mass on serial follow-up echocardiography. The patient died of severe pulmonary vein stenosis and complex neurological disability. Postmortem cardiac examination revealed numerous cardiac blood cysts with two dominant ones (1.6 and 1.5 mm) on the septal leaflet of the tricuspid valve, which based on the location and position corresponded to the suspected vegetation and thrombus on imaging. Cardiac blood cysts on valve leaflets are a common incidental finding during autopsy within the first 6 months of life; however, they are rarely detected on imaging because of their minute size, often < 0.5 mm. In this case, the sizable blood cysts were thought to represent thrombus or vegetation on echocardiogram, which influenced the patient management.

The fetal lamb model of congenital diaphragmatic hernia shows altered cerebral perfusion using contrast enhanced ultrasound.

BACKGROUND: Neurodevelopmental impairment is common in survivors of congenital diaphragmatic hernia (CDH). Altered cerebral perfusion in utero may contribute to abnormal brain development in CDH patients. METHODS: 5 fetal lambs with surgical left-CDH and 5 controls underwent transuterine cranial Doppler and contrast enhanced ultrasound (CEUS). Global and regional perfusion metrics were obtained. Biometric and perfusion data were compared between groups via nonparametric Mann Whitney U test and Spearman's rank order correlation. RESULTS: No significant differences in cerebral Doppler measurements were identified between groups. By CEUS, CDH animals demonstrated significantly decreased global brain perfusion and increased transit time. With focal regions-of-interest (ROIs), there was a tendency towards decreased perfusion in the central/thalamic region in CDH but not in the peripheral brain parenchyma. Transit time was significantly increased in both ROIs in CDH, whereas flux rate was decreased in the central/thalamic region but not the peripheral brain parenchyma. Biometric CDH severity was correlated to perfusion deficit. There was no difference in cardiomyocyte histology. CONCLUSION: The fetal lamb model of CDH shows altered cerebral perfusion as measured by CEUS, correlating to disease severity. This suggests a physiological abnormality in fetal cerebrovascular perfusion that may contribute to abnormal brain development and neurodevelopmental impairment in survivors.

Clinical, pathologic, and molecular analyses of superficial low-grade fibromyxoid sarcoma in two young patients: A rare and deceptive mimic of benignancy.

Low-grade fibromyxoid sarcoma (LGFMS) is a histopathologically deceptive soft tissue neoplasm with bland cytology, which is typically encountered in deep soft tissue of adults. We report two cases of superficial LGFMS in young patients (16 and 21 years old, respectively), which were difficult to diagnose on histopathologic and clinical findings alone. LGFMS commonly mimics benign neoplasms such as cellular neurothekeoma, fibromatosis, neurofibroma, and perineurioma. Malignancies included in the differential diagnosis are soft tissue neoplasms such as dermatofibrosarcoma protuberans and myxofibrosarcoma. A high degree of reported variation in pattern and cellularity among LGFMS further complicates the diagnosis. Careful examination and appropriate immunohistochemistry panels including MUC4 are essential for narrowing the differential diagnosis. Molecular studies for possible FUS translocation can confirm the diagnosis of LGFMS. Sufficient sampling and workup of these lesions are critical, especially in younger patients. Young age and superficial presentation can easily sway dermatopathologists/dermatologists toward an incorrect diagnosis of benignancy.

Giant Cell Myocarditis in Children: Elusive Giant Cells Might Not Be the Only Clue.

Giant cell myocarditis (GCM) is a form of fulminant myocarditis that is rapidly progressive and frequently lethal even in children. Over the course of 20 years, a definitive histopathologic diagnosis of GCM has been made at our institution in only two pediatric patients, and in neither instance was the diagnosis of GCM rendered on initial cardiac biopsy. We present the two patients and highlight the similarities in their clinical presentation and their challenging and inconclusive- albeit histologically similar- initial cardiac biopsy findings.

Histopathologic Changes After Pulmonary Artery Banding for Retraining of Subpulmonary Left Ventricle.

BACKGROUND: In patients with congenitally corrected transposition of the great arteries (ccTGA) with an intact ventricular septum (IVS) or d-looped transposition of the great arteries (DTGA) with IVS after an atrial switch operation, left ventricular dysfunction often develops after anatomic repair despite previous retraining of the morphologically left ventricle (mLV) by using pulmonary artery banding (PAB). This study examined histopathologic changes in such mLVs. METHODS: Capillary density, myocyte diameter, and interstitial fibrous area in the mLV were retrospectively evaluated in postmortem or explanted heart specimens obtained from patients with ccTGA with IVS or DTGA with IVS after atrial switch operations after PAB for retraining and were compared with those of patients with normal cardiac anatomy, ccTGA with IVS or DTGA with IVS without PAB, and ccTGA or DTGA with high mLV pressure by using generalized estimating equations models. RESULTS: Adjusting for age, capillary density in 4 patients with ccTGA with IVS or DTGA with IVS after PAB was approximately 20% lower than that in 8 patients with normal cardiac anatomy (3149 ± 863/µm2 vs 3978 ± 1206/µm2 [mean, SD]; P = .039), whereas myocyte diameter was approximately 50% larger (16.2 ± 4.0 µm vs 11.7 ± 2.4 µm [mean, SD]; P < .001). The interstitial fibrous area did not differ between the 2 groups (803 ± 422 µm2 vs 789 ± 480 µm2; P = .92). CONCLUSIONS: The study investigators observed significant cardiomyocyte hypertrophy but lower capillary density in patients with ccTGA with IVS or DTGA with IVS after PAB for retraining compared with normal control subjects. This finding suggests that inadequate capillary growth is a potential pathologic basis for mLV dysfunction occurring after retraining or anatomic repair.

Heterotopic Liver Nodule Compressing a Two-Vessel Umbilical Cord: An Unusual Cause of Intrauterine Fetal Demise.

Heterotopic liver tissue in the umbilical cord is rare, and the outcome is quite unpredictable based on the few reported cases. We present a case of heterotopic liver nodule in the umbilical cord of a midtrimester fetus who died in utero. Although such association has only been reported once, heterotopic nodular tissue in the umbilical cord must be regarded as a potential cause of fetal demise by a mechanism analogous to the more common umbilical cord abnormalities resulting in umbilical vessel compromise.

Discovery of inverted discordant p57 expression in random clusters of dysmorphic chorionic villi of third trimester placentas suggests a more common occurrence of such phenomenon than initially described.

INTRODUCTION: Inverted discordant p57 expression in chorionic villi, characterized by a loss of nuclear staining in cytotrophoblast with retained staining in villous stromal cells, is rarely described. Following an incidental finding of such peculiar staining pattern in rare clusters of dysmorphic chorionic villi (DCV) in a perinatal autopsy case, we reviewed our archived cases of third trimester placentas with DCV to systematically analyze these curious foci. METHODS: Histopathological features and p57 expression of 26 placentas with DCV were carefully studied by light microscopy and p57 immunohistochemistry. p57 pattern of expression was correlated with a comprehensive list of maternal, fetal, and placental features to reveal potential associations. RESULTS: Inverted discordant p57 expression was observed in 17/26 (65.4%) cases, encompassing all cases with aberrant p57 immunostaining in this series. Among the many features investigated, only the focality (occurring as a single focus) of DCV (Fisher's exact test, p = 0.008) and small cluster size of ≤30 villi (Fisher's exact test, p = 0.034) correlated significantly with inverted discordant p57 staining. Other common features of DCV with inverted discordant p57 expression include larger villous size compared with surrounding tertiary villi (13/17, 76.4%), prominent but not hyperplastic and focally to moderately hyperplastic syncytiotrophoblast (17/21, 80.9%), abnormal shapes/irregular contours (17/22, 77.3%), and markedly hypovascular villous stroma (11/17, 64.7%). No distinctive maternal or fetal features were observed. DISCUSSION: Inverted discordant p57 expression in DCV of third trimester placentas is likely underreported, and might not be an unusual occurrence outside of suspected molar specimens.

Chondroid and Osseous Metaplasia of the Central Fibrous Body in Adolescent Hearts with Mutations in TNNI3 and TNNT2 genes.

The histological spectrum of the central fibrous body (CFB) of the heart, particularly in humans, is not fully characterized. Herein, we describe the presence of cartilage and bone within the CFB of 2 explanted heart specimens from patients with known mutation-driven cardiomyopathy involving the TNNI3 and TNNT2 genes, review the existing literature on the identified variants particularly TNNI3 (p.Asn185Thrfs*14) and TNNT2 (p.Arg141Trp), and provide insights into the plausible nature of such histopathological observation based on animal studies and the few reported cases in humans.

Interdigitating Myocardial Tongues in Pediatric Cardiac Fibromas: Plausible Substrate for Ventricular Tachycardia and Cardiac Arrest.

OBJECTIVES: This study sought to evaluate for the presence of and characterize the interdigitating and entrapped myocardium within cardiac fibromas (CF) and correlate tissue findings with symptoms and surgical outcomes. BACKGROUND: The mechanism of ventricular tachycardia (VT) in CF is unclear. The authors hypothesized that CF harbor tongues of interdigitating myocardium, which could be a substrate for episodes of arrhythmia analogous to peri-infarct zones. METHODS: A total of 29 patients (14 boys) with CF were identified; all subjects had undergone at least partial tumor resection. A semiquantitative grading system was used to assess the degree of myocardial interdigitation and entrapment, myocyte morphology (hematoxylin and eosin stain and immunohistochemical stain for desmin), tumor collagen density, and cellularity (trichrome stain). The subjects' ages at presentation, types of arrhythmia, and responses to surgery were correlated with histology. RESULTS: CF consistently demonstrated interdigitating and entrapped myocardium, and the extent correlated negatively with age at surgery, as did cellularity, whereas collagen increased with age. Median age at arrhythmia recognition was 8 months. Sustained VT was present in 18 of 29 patients (62%), and 5 of 6 patients with prenatally diagnosed conditions developed VT before 8 months. All 8 patients who experienced cardiac arrest had clinically significant arrhythmia events. Sustained arrhythmia episodes correlated with more diffuse myocyte interdigitation. Ten patients had abnormal karyotype: chromosomes 9 (n = 3) and 3 (n = 1) deletions; isolated translocations: t(4;13), t(5;11) and t(1;9); and undefined aberrations (n = 3). All patients who underwent complete resection were cured of arrhythmias, whereas 2 of 14 patients who had subtotal resections had recurrence, with resolution following re-resection in 1 patient. CONCLUSIONS: Interdigitating myocardium represents a potential histopathologic substrate for VT and cardiac arrest in CF, which may also explain the occasional recurrence of arrhythmia following incomplete resection.

Cystic Crypt Changes in Midgestational Human Vermiform Appendix: An Unrecognized Transient Histologic Feature.

INTRODUCTION: Lewis and Huff briefly described the presence of "microcystic cryptitis" in some of fetal vermiform appendices (VA) at autopsy. We further characterized these crypt changes (CC), their timing of occurrence, and tested their association with infection/inflammatory conditions. METHODS: Hematoxylin and eosin-stained slides of 345 VA were evaluated for the presence or absence of CC and their different morphologies. Autopsy reports were reviewed for evidence of amniotic fluid or fetal systemic infection and placental inflammatory conditions. RESULTS: Crypt dilatation with or without irregularity of the lumen, crypt dilatation with semiattenuated epithelium, intraluminal apoptotic debris and inflammatory cells, especially eosinophils, and foci of swirled spindled cells with calcifications or multinucleated giant cells were observed, either alone or in combination, in at least 58.5% (202/345) of the VA. CC began to appear at 17 weeks, peaked at 20 to 25 weeks (with up to 82% of VA exhibiting CC during this time), and followed by a steady decline beyond 28 weeks gestation. χ2 test of independence showed no significant association (P = .435; >0.05) between the presence and absence of CC and infection status of the fetus or placenta. CONCLUSION: The underrecognized CC of the developing fetal vermiform appendix (VA) showed distinct temporal pattern of occurrence and did not seem to be affected by the presence or absence of infection, which so far favored their being a part of the normal gut developmental process.

Distinct Histopathological Features at Diagnosis of Very Early Onset Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Children with very early onset inflammatory bowel disease [VEO-IBD] represent a unique cohort, often with a severe phenotype that is refractory to conventional medications, and some cases have underlying primary immunodeficiencies. Previous work has identified distinct histopathological patterns in the gastrointestinal tract in patients with primary immunodeficiencies. The aim of this study is to characterise the diagnostic histological findings in patients with VEO-IBD as compared with older onset paediatric IBD, and determine if there are unique pathological changes that can shed light on the driving forces of the disease, particularly immunodeficiencies. METHODS: Clinical retrospective chart review, including disease characteristics and endoscopic findings, was performed on all included subjects. Two paediatric pathologists reviewed biopsies from diagnostic upper endoscopies and colonoscopies of subjects with very early onset inflammatory bowel disease and older onset inflammatory bowel disease, to evaluate for the presence of 11 histological features previously associated with inflammatory bowel disease and primary immunodeficiencies. RESULTS: The diagnostic gastrointestinal biopsies of subjects with very early onset inflammatory bowel disease differed from those in older onset paediatric IBD, demonstrated by increased frequency of apoptosis, severe chronic architectural changes, small intestine villous blunting, and eosinophils in the crypts, lamina propria, and surface epithelium. CONCLUSIONS: The diagnostic biopsies of children with very early onset inflammatory bowel disease can identify characteristic features that may be important in guiding the diagnostic work-up in this population.

Pathology of valved venous homografts used as right ventricle-to-pulmonary artery conduits in congenital heart disease surgery.

OBJECTIVES: Although valved venous homografts (VVHs) are used for establishing right ventricle-to-pulmonary artery continuity in some complex heart defects, the tissue changes that occur in situ have not been described. We review the gross and microscopic changes observed in explanted VVH conduits and their effects on functionality. METHODS: In total, 20 explanted VVH conduits were evaluated for valve integrity, presence of thrombus, and stenosis. Hematoxylin and eosin- and trichrome-stained sections were reviewed for neointima formation, wall remodeling, inflammation, and calcification. Regurgitation and narrowing were assessed on pre-explant echocardiogram, and angiographic video clips were correlated with tissue findings. The source of the proliferating cells within the conduits was investigated by fluorescent in situ hybridization. RESULTS: Thirteen male and 7 female infants underwent VVH implantation either as part of a composite Sano shunt (65%) or to establish right ventricle-to-pulmonary artery continuity in biventricular hearts (35%). The median duration of conduits in situ was 140 days (range: 98-340 days). Conduits were predominantly explanted for staged conversion to bidirectional Glenn (60%) and conduit upsizing (20%). The valves remained intact and functional in 75% of cases. Occlusive thrombosis was absent in all. Wall thickening due to neointima formation and wall remodeling was uniformly present and appeared to be driven by smooth muscle actin-expressing cells, which by fluorescent in situ hybridization are predominantly of recipient origin. Minimal calcification and mild adventitial chronic inflammation were present. CONCLUSIONS: Vein wall thickening is a uniform finding and can cause stenosis. The valves remain functional in most, and vein walls undergo remodeling with only minimal inflammation and calcification.

CD5-Positive Intravascular Large B-Cell Lymphoma in a Patient with Wilson's Disease: Case Report and Review of the Literature.

Intravascular large B-cell lymphoma (IVLBCL) is a rare extra-nodal B-cell lymphoma that proliferates within small/intermediate blood vessels and capillaries while sparing large blood vessels and organ parenchyma. Clinical presentation is highly variable and may include B symptoms, neurological deficits, and/or cutaneous findings. The diagnosis of IVLBCL is difficult due to multiorgan involvement and nonspecific symptoms. We describe the case of a 68-year-old male who presented with progressive weakness, confusion, and falls. He had a past medical history of liver cirrhosis secondary to Wilson's disease. Physical exam and laboratory results revealed a lethargic man with jaundice, hepatic encephalopathy, and abnormal liver/kidney function tests. He expired after a short hospital course in the setting of hepatic and renal failure. Postmortem examination revealed large neoplastic lymphoid cells involving multiple organ blood vessels; however skin and neurologic involvement was absent. The neoplastic cells demonstrated B-cells positive for CD5, rendering a diagnosis of IVLBCL. Our case represents the occurrence of IVLBCL with CD5-positivity in a patient with Wilson's disease, diagnosed at autopsy demonstrating the challenging nature of diagnosing IVLBCL.