Reoperation for Hirschsprung Disease: Two cases of Vanishing Ganglion Cells and Review of the Literature.

Hirschsprung disease (HD) is characterized by circumferential aganglionosis of the rectum with variable proximal bowel involvement. The underlying pathogenesis is due to failure of caudal migration of neural crest cells during pre-natal development, causing functional bowel obstruction. Definitive therapy is surgical resection; however, a subset of patients will require reoperation. An important cause of reoperation is the rare but distinct entity described as the ganglion cell "vanishing" phenomenon. In this phenomenon, affected patients have normal circumferential ganglion cells present at the proximal margin during primary resection. They undergo a variable asymptomatic period post-primary resection but ultimately develop recurrent symptoms. Upon reoperation, ganglion cells seemingly vanish and are no longer present in the previously functioning and ganglionated bowel proximal to the initial anastomotic site. To further characterize and investigate this poorly understood pathology, here we present 2 cases of HD patients who required reoperation. Our small series implicates that an immune component may contribute as patient 2 had a brisk neurotrophic eosinophilic infiltrate only present in the reoperation specimen. However, this was not observed in patient 1. Other possible etiologies include post-operative ischemia/hypoxia, visceral neuropathy, or signaling abnormalities within the residual ganglion cells themselves.

Clinico-histopathological correlation of symptomatic left main coronary artery electrocardiographic ischemia pattern in a young child with hypertrophic cardiomyopathy.

The specific electrocardiographic (ECG) pattern of left main coronary artery ischemia is exceptionally rare in children and under recognized. Occasional reports are bereft of a detailed mechanistic ECG description and limited to dissection, spasm, or anomalous origin of the left main coronary artery. An association with pediatric hypertrophic cardiomyopathy (HCM) is hitherto unreported. We furbish a detailed electrocardiographic description of this entity in the unusual setting of a 4-year-old child with HCM with a restrictive phenotype and exertional symptoms consistent with myocardial ischemia. Heart transplant was performed for this rare indication. Histopathology of the explanted heart in particular revealed left main coronary artery narrowing and provided us with a unique window of opportunity to correlate with clinical findings. The pathophysiology was also likely exacerbated by diffuse sub endocardial ischemia in the milieu of left ventricular hypertrophy with elevated end diastolic pressures. We anticipate that this illustrative case will help contextualize this as well as pediatric scenarios in which the 'left main ischemia' ECG pattern can be encountered and foster an accurate electrocardiographic recognition of this entity in children.

Giant Anal Fibroepithelial Polyp in a Healthy Teenage Boy: A Case Report and Literature Review.

Background: Fibroepithelial polyps of the anus have been described as mucosal hypertrophy in response to chronic irritation or tissue damage. Lesions usually remain small and mostly present in elderly adults with local disease. Case Report: An otherwise healthy 15-year-old male presented with a giant pedunculated mass projecting out of the anal verge that enlarged over 2 years, causing discomfort. Results: Upon surgical excision and histologic examination, the mass resembled a fibroepithelial polyp with numerous dilated lymphatics. Conclusions: While literature describes the spectrum of pathology possible in such lesions, often consisting of a mixture of stromal and epithelial components, dilated lymphatics are less common. This giant anal fibroepithelial polyp characterized by edematous stroma and numerous dilated lymphatics is consistent with lymphangioma. To our knowledge, this presentation is novel in this age group with no underlying risk factors.

Urothelial Rests, Incidental Finding in a Patient with Acute Appendicitis: A Case Report and Literature Review.

Background: Urothelial rests, also known as Walthard rests, are benign nests of epithelial cells that most often are found in the female gynecologic tract. Only four of these urothelial rests have been described in the appendix. Case report: A 10-year-old female underwent an appendectomy for appendicitis. Histologically, there was acute appendicitis, and an incidental urothelial rest was identified, confirmed by immunostains positive for p63, CK7, and negative for synaptophysin. CD34 highlighted a rim of endothelial cells. Conclusion: Urothelial rests, which often appear in the female gynecologic tract, can occur in other sites such as the appendix. These benign lesions require differentiation from neuroendocrine lesions. The rim of endothelial cells in our report supports a vascular migrational origin.

Histopathology of the Conduction System in Long QT Syndrome.

Background: While much is known about the channelopathy disorder Long QT Syndrome (LQTS), the histopathological findings and their implications on the disease have remained largely unexplored to date. In this review, we discuss the background of LQTS and highlight the importance of histological findings in the absence of genetic markers or when genetic testing is unavailable.Materials and methods: Three pediatric cases of LQTS were identified, evaluated histologically, and compared to two adult cases.Results: Histological examination of three pediatric LQTS patients demonstrated fibrotic alterations to the cardiac conduction system with markedly decreased conductive tissue density and volume. Both adult cases revealed fibrosis with similar reductions in tissue volume.Conclusion: When diagnostic methods such as genetic testing are unavailable, histopathology offers clinicians an alternative tool for postmortem diagnosis of LQTS when considered alongside clinical presentation. Confirmation of diagnosis in a proband can prevent the death of relatives in hereditary LQTS.

Five New Cases of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS), with One Case Showing a Novel Mutation.

BACKGROUND: Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a lethal congenital disorder characterized by a large, non-obstructed bladder, microcolon, and lack of proper peristalsis. MATERIALS AND METHODS: Five cases of MMIHS were identified, confirmed histologically and were predominantly female (F:M, 4:1). DNA sequencing was also performed. RESULTS: Four cases showed mutations in the α3 and ß4 nicotinic acetylcholine receptor (ηAChR) subunits (CHRNA3 and CHRNB4, respectively) on chromosome 15q24. The 5th case had a delayed clinical presentation of intussusception at 11 months and showed a novel missense mutation in ATP2B4 on Chromosome 1q32. CONCLUSION: The first four patients showed a previously identified mutation. The 5th patient shows a novel mutation in ATP2B4. This novel gene was associated with a less severe presentation and increases success of multiorgan transplant than the other four patients. This highlights how identifying various mutations may impact prognosis and clinical treatment plans for MMIHS patients.

Revisiting the Newly Modified Criteria for Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) and Reporting Newly Identified Genes.

Background: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia is an inherited cardiomyopathy, characterized by replacement of the RV muscle wall with fibrofatty tissue. The diagnosis is challenging, due to the absence of a unique presentation and a lack of specific reproducible diagnostic criteria. Materials and methods: Slides and additional clinical information including follow up from 16 cases were reviewed. Pediatric criteria of >30% of muscle replacement was used, instead of >40% as used in adults. Results: All 16 cases were confirmed by genetic testing and show ARVC/D. Applying the adult criteria, 7 cases would not have been categorized as ARVC/D. Conclusion: The modified pediatric criteria for ARVC/D should be used for pediatric patients. Better detection will aid in genetic counseling in order to identify those additional family members susceptible to sudden cardiac deaths so they can be followed optimally.

Chronic Recurrent Multifocal Osteomyelitis (CRMO): A Study of 12 Cases from One Institution and Literature Review.

BACKGROUND: CRMO is a sterile auto inflammatory bone disease that affects the pediatric population. Recently, single gene mutations in LPIN2, DIRA, and IL1RN have been reported in murine models of CRMO. MATERIALS AND METHODS: The medical records and histopathological slides of twelve patients were reviewed. RESULTS: The diagnosis was determined by multiple lesions, imaging, negative cultures, bone biopsy, and lack of antibiotic response. Biopsy showed early neutrophilic infiltrates, and older lesions showed lymphoplasmacytic infiltrates and fibrosis. Patients were treated with anti-inflammatory medication with some lesions completely resolving. CONCLUSION: Bone biopsy aids the diagnosis of CRMO in correlation with clinical presentation, imaging, and culture findings. Our findings indicate the kinetics of CRMO is not well defined and the fibrosis may be reached after months, in contrast to the previously reported several years. We hope that these genetic mutations can be further studied in human models to describe the genetics behind CRMO.

Correlation Between E6 and E7 Oncogenes and Malignant Transformation of Laryngeal Papillomatosis (LP) with Human Papillomavirus (HPV) in Pediatric Population.

INTRODUCTION: Laryngeal papillomatosis (LP) is the most common benign neoplasm affecting the upper respiratory tract mucosa in children. The most common genotypes of HPV associated with LP are types 6 and 11. Methods: Among 187 patients identified in our institution with LP, four cases showed malignant transformation to invasive squamous carcinoma. Results: These patients had tumors with HPV viruses that showed high expression of oncogene E6 and E7 and low expression of E2. Conclusion: Malignant transformation of LP is associated with oncogenic expression of E6 and E7.

Pediatric Right Ventricular Cardiac Steatosis following Immunosuppressive Treatment.

Background Right ventricular myocardial fatty infiltration has been observed in pediatric cardiac allografts with an associated decrease in graft life expectancy. A possible explanation included an immunosuppressant drug effect which prompted us to examine common factors between non-cardiac transplanted immunosuppressed patients and postmortem hearts of pediatric patients who died of non-cardiac causes.Materials and Methods Sixty-one of 1,030 pediatric autopsies were from immunosuppressed children who were treated with corticosteroids for malignant tumors, non-cardiac transplantations, or other chronic clinical conditions. 62 children who died for non-medical reasons served as controls. Cardiac H&E autopsy slides were examined for right ventricular fatty infiltration.Results There was a significant increase in right ventricular fatty infiltration in patients that were non-cardiac transplanted and immunosuppressed compared to controls. None of the index patients had other features of arrhythmogenic right ventricular dysplasia.Conclusions Immunosuppression may lead to right ventricular fatty infiltration in childhood.

Cardiac Magnetic Resonance Imaging Macroscopic Fibro-Fatty Infiltration of the Myocardium in Pediatric Patients with Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia.

Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited, progressive form of cardiomyopathy, which is characterized by fibrofatty replacement of the myocardium. While the gold standard for diagnosis remains pathologic evaluation of biopsy, advances in noninvasive imaging, including cardiac magnetic resonance imaging (CMRI), have led to improved clinical diagnosis.Case report: We report three additional cases of pediatric patients that have pathologically confirmed ARVC/D with CMRI images, demonstrating extensive macroscopic fatty infiltration of the right and left ventricular myocardium. The identification using CMRI allowed timely transplantation and patient survival.Conclusion: Our study is designed to highlight how fibrofatty changes are minimal using CMRI in the pediatric population and how this can be a valuable tool to provide an additional method of diagnosis.

Increased Incidence of Villitis in Placentas Exposed to Chemotherapy During Pregnancy: Is There a Correlation?

We have identified 9 pregnant patients who were diagnosed with malignancy and initiated chemotherapy during their second trimester (cervical cancer [n = 3], leukemia [n = 3], breast cancer [n = 2], and Hodgkin's lymphoma [n = 1]). Five of the patients' placentas were small for gestational age (SGA). Pathologic examination revealed inflammatory changes in 4 of the placentas: 2 from the SGA placentas and 2 from non-SGA placentas. Examination revealed 3 placentas with villitis of unknown etiology (VUE) and 1 with intervillositis; all were negative for bacterial and viral cultures and by immunohistochemical (IHC) stains. In the VUE cases, IHC stains showed positivity of CD25+/FOXP3+ with focal positivity and CD3 and CD4 IHC were focally to strongly positive. Literature suggests that the use of chemotherapy during pregnancy can be detrimental to both the mother and the fetus; however, there has been limited focus on the effects of chemotherapy on the placenta. We suggest that the inflammatory process noted in the placentas is due to chemotherapy-induced toxic effects.

Intravascular Papillary Endothelial Hyperplasia in the Coronary Artery: An Unusual Cause of Massive Myocardial Infarction in Hypoplastic Left Heart Syndrome.

Background: Intravascular papillary endothelial hyperplasia (IPEH) is a benign vascular lesion that usually involves the head and neck or extremities. Involvement of the coronary arterial system is unreported. Case: A 1-month-old patient born with hypoplastic left heart syndrome died from a massive myocardial infarction shortly after first stage palliation with Norwood/Sano. Autopsy demonstrated a massive univentricular hemorrhagic infarction with complete occlusion of the left main coronary artery and its intramural branches by intraluminal papillary endothelial hyperplasia (IPEH). Immunostaining with CD34 and CD31 confirmed the diagnosis. The inferior and superior mesenteric artery branches also had IPEH. Conclusion: IPEH can involve the coronary vasculature, can be multifocal and can occur in the newborn.

Primary Pediatric Breast Lesions: Comparing the Prevalence of Malignancies in the Middle East with North America; Review of 1031 Cases.

Benign breast masses are uncommon but are becoming more recognized among the pediatric population. Malignant breast lesions are very rare. The aim of our study was to review and compare the demographics, clinical presentation, treatment, and outcomes of breast lesions, including primary malignancies, and to discuss theories that may explain why there is an increased rate of breast cancers diagnosed at a younger age in the Egyptian population. A total of 1031 cases were reviewed. Comparisons were made between the Egyptian (n = 846) and US (n = 185) cohorts. There were 30 (3.5%) malignant tumors in the Egyptian group with 17 (2%) deaths versus 3 (1.6%) malignant tumors in the US group with 2 (1%) deaths (p = 0.247). The relative risk of breast cancer in the Egyptian group was 2.16 (95% confidence interval (CI): 0.67-7.01) compared with the US group. The trend for increased risk of breast cancer in Egypt may be due to delayed diagnosis because of decreased awareness.

Imaging mass spectrometry assists in the classification of diagnostically challenging atypical Spitzoid neoplasms.

BACKGROUND: Previously, using imaging mass spectrometry (IMS), we discovered proteomic differences between Spitz nevi and Spitzoid melanomas. OBJECTIVE: We sought to determine whether IMS can assist in the classification of diagnostically challenging atypical Spitzoid neoplasms (ASN), to compare and correlate the IMS and histopathological diagnoses with clinical behavior. METHODS: We conducted a retrospective collaborative study involving centers from 11 countries and 11 US institutions analyzing 102 ASNs by IMS. Patients were divided into clinical groups 1 to 4 representing best to worst clinical behavior. The association among IMS findings, histopathological diagnoses, and clinical groups was assessed. RESULTS: There was a strong association between a diagnosis of Spitzoid melanoma by IMS and lesions categorized as clinical groups 2, 3, and 4 (recurrence of disease, metastases, or death) compared with clinical group 1 (no recurrence or metastasis beyond a sentinel node) (P < .0001). Older age and greater tumor thickness were strongly associated with poorer outcome (P = .01). CONCLUSIONS: IMS diagnosis of ASN better predicted clinical outcome than histopathology. Diagnosis of Spitzoid melanoma by IMS was strongly associated with aggressive clinical behavior. IMS analysis using a proteomic signature may improve the diagnosis and prediction of outcome/risk stratification for patients with ASN.

Late primary transplantation in complex congenital heart disease.

Heart transplantation is a viable option for patients with congenital heart disease who manifest heart failure, predominantly post-surgical palliation. We present a case of complex congenital heart disease, where surgical palliation was considered not to be an option. Considerate medical management with close follow-up allowed for a nine-yr delay until eventual successful heart transplantation. The case also highlights the natural history over nine yr of the effects of right ventricular outflow tract obstruction on the left ventricular remodeling which is analogous to a PA banding in patients with dilated cardiomyopathy.

Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D): Review of 16 Pediatric Cases and a Proposal of Modified Pediatric Criteria.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heritable cardiomyopathy characterized by fibro-fatty replacement of right ventricular myocardium. Diagnostic criteria, established in 1994 and modified in 2010, are based on predominately adult manifestations of ARVC/D. The goal of this paper is to review a single-center experience with pediatric ARVC/D and propose modifications of current diagnostic criteria to appropriately include pediatric ARVC/D. We identified 16 pediatric cases of ARVC/D from our tertiary care center. Patient demographics, presentation, course, genetic testing, and family history were reviewed. Sixteen patients were diagnosed with ARVC/D through the modified diagnostic criteria, genetic testing, and pathology. Five patients had positive family histories. Five patients presented with cardiac arrest, and six were found to have ventricular tachycardia. Two patients presented with heart failure. Six autopsies, six explanted hearts, and three biopsies found massive fibro-fatty infiltration of the right ventricular wall. Six patients underwent heart transplantation, and two have received automatic implantable cardioverter defibrillator. Two patients had identifiable genetic mutations previously noted in the literature. One patient had a novel mutation of a known ARVC/D gene. Many pediatric patients do not meet the current ARVC/D diagnostic criteria, resulting in delays in diagnosis and treatment. The current criteria need further revision to encompass pediatric manifestations of ARVC/D. In our opinion, pathological and clinical findings alone are sufficient for accurate diagnosis of pediatric ARVC/D. Creating modified pediatric criteria would facilitate prompt diagnosis and management of ARVC/D and facilitate structured research with the goal of improving outcomes.

Pediatric Meckel's Diverticulum: Report of 208 Cases and Review of the Literature.

We report a review of 208 cases of Meckel's diverticulum among pediatric patients from one single institution. One of the aims of this report is to highlight the different diagnostic modalities of Meckel's diverticulum since a majority of cases is undiagnosed prior to surgery. Our review shows 58 cases containing gastric and/or pancreatic heterotopic tissue, including two unique cases. The first case reported is a desmoid tumor arising at the tip of diverticulum, a case that, to our knowledge, has not been previously reported. The second case involves a female patient appearing with an acute abdomen thought to be appendicitis, instead surgery revealed a diverticulum arising from the ileum. The cause of acute abdomen was due to gonococcal infection. In conclusion, we hope that this large series of Meckel's cases will enrich our readers on the differential diagnosis and preoperative diagnostic techniques of Meckels' diverticulum.

Modified Rapid AChE Method (MRAM) for Hirschsprung Disease Diagnosis: A Journey from Meier-Ruge Until Now.

Hirschsprung disease (HSCR) can be diagnosed using a variety of histological and immunohistochemical methods and stains. Because of the nature of the condition and the need for a rapid diagnostic confirmation, those methods with high accuracy and fast turnaround times are preferred. The authors of this paper have used rapid acetylcholinesterase (AChE) immunohistochemistry in conjunction with standard H&E in order to optimize diagnostic accuracy, and present a modified rapid AChE method (MRAM) that has been successfully utilized for over 20 years. The authors also present a list of over 30 different methods and stains that have been proposed for Hirschsprung disease diagnosis.