The Variable Definition of "Negative Appendicitis" Remains a Surgical Challenge.

AIM: Acute appendicitis (AA) is treated primarily surgically with histopathology being the gold standard for confirmation of appendicitis and reported rates of negative appendicectomies (NA) ranging between 3.2% and 19% worldwide and 15.9-20.6% in the UK. NA rates are frequently used to identify poor performing centers as part of a Model Health System and form an integral part of appendicitis scoring systems. This study aims to evaluate the prevalence of negative appendicectomies within our institution and critically analyze the appropriateness of its use as a quality metric and its impact on clinical practice and research. PATIENTS AND METHODS: Data analysis from a prospective dataset of pediatric appendicitis patients between 2015 and 2021 in a tertiary center in the UK was performed. Detailed analysis of negative appendicectomies was performed and further stratified by two distinct age and gender groups looking at the incidence of NA and the classification of non-histologically normal appendix specimens. RESULTS: In our series, 819 patients met inclusion criteria, 736 (89.9%) had acute appendicitis. Our overall institutional negative appendicectomy rate was 10.1% (83 patients) with the breakdown as follows: 65 histologically normal appendix (7.9%), 10 Enterobius vermicularis, 3 eosinophilic appendicitis, 2 neoplasms, 1 isolated faecolith, 1 fibrous obliteration of the lumen, and 1 peri-appendiceal inflammation. CONCLUSION: Our negative appendicectomy rate is below established UK pediatric NA rates. This rate ranges from 7.9% to 10.1% depending on the definition of NA utilized. A single standard pathological definition for histological acute appendicitis is required when being used as a comparative quality metric. Centers engaged in clinical research should be aware of variations in NA definitions both in scoring systems and individual centers to avoid skewing derived results.

Urorectal Septum Malformation Sequence With Retroperitoneal Neuroblastoma: A Case Report of an Unusual Association.

Urorectal septum malformation sequence (URSMS) is an uncommon disease characterized by a failure of the anorectal septum to divide the cloaca and fuse with the cloacal membrane. Complete URSMS is usually lethal in newborn due to severe renal dysfunction and pulmonary hypoplasia. Partial URSMS is compatible with life with a single perineal opening draining a common cloaca with an imperforate anus which amenable to surgical management. Antenatal diagnosis of URSMS is challenging because of multisystem, complex abnormalities involving gastrointestinal, urogenital tract, cardiovascular, and musculoskeletal systems. In this case report, we describe a 15-week male fetus with partial URSMS having a spectrum of multisystem structural anomalies associated with fetal neuroblastoma in retroperitoneal location and adrenal neuroblastoma in situ.

Mucosal Soft Tissue Lesions.

Mucosal soft tissue lesions are fairly common in the pediatric population. However, the precise prevalence is unknown. This is the result of the limited number of studies, the use of various diagnostic criteria in those studies, and the transient nature of commonly encountered lesions in this population. In this section, we seek to familiarize the pediatric pathologist with a sampling of mucosal soft tissue lesions encountered in pediatric patients, highlight key diagnostic features and correlations with systemic diseases should they exist.

Biliary Atresia in an Infant Presenting With Kabuki Syndrome: An Autopsy Report and Review of the Literature.

Biliary atresia (BA) is an inflammatory obliterative cholangiopathy which is very common during neonatal and infancy period. We present an autopsy report of a BA in an infant suffering from a genetic syndrome.

Tissue Shrinkage of Resected Specimens in Hirschsprung's Disease: Why Pediatric Surgeons Think the Bowel Specimen was Longer Than Indicated in the Pathology Report.

BACKGROUND: Hirschsprung disease (HD) is an aganglionosis of variable length starting at the rectosigmoid colon with surgery as sole therapeutic option. The length of the resected bowel segment is a crucial information for the treating surgeons and influences the prognosis of the patient. It is often artificially altered due to post operative tissue shrinkage. The objective of this study is to quantify the extent tissue shrinkage of HD specimens. MATERIAL AND METHODS: Colorectal HD specimens were measured at the time of surgery and at the time of cut-up, either fresh or after formalin fixation and statistically analyzed. RESULTS: Sixteen colorectal specimens were included. Following formalin fixation the specimen length decreased by 22.7% (P < .001). Without formalin fixation the specimens shrank by an average of 24.9% (P = .05). There was no significant difference in the extent of tissue shrinkage with or without formalin fixation (P = .76). CONCLUSION: This study showed that there is significant tissue shrinkage in HD specimens. The 2 different cohorts revealed that tissue shrinkage is mostly caused by tissue retraction/alteration after organ removal but also to a lesser extent by fixation with formalin. Surgeons and (neuro-)pathologists should be aware of the sizeable shrinking artifact to avoid unnecessary confusion.

Acute Interstitial Nephritis in the Pediatric Population: A Review of Etiologic Associations, Histologic Findings, and Clinical Outcome.

BACKGROUND: Acute interstitial nephritis (AIN) is an infrequent cause of acute kidney injury in the pediatric population with a broad range of etiologies. This retrospective review attempts to characterize AIN in the pediatric population, delineate etiologic factors, histologic features, and clinical outcome. MATERIALS AND METHODS: Institutional pathology reports were queried for a diagnosis of AIN between 1/2010 and 10/2021. Archived slides and reports and clinical records were reviewed. RESULTS: Twenty-four patients were identified whose ages ranged from 5 to 20 years. A 8 cases (37.5%) were characterized as tubulointerstitial nephritis and uveitis (TINU), 4 cases (16.7%) were associated with an autoimmune disease, 4 cases (16.7%) were likely drug induced, and 8 cases (37.5%) had unclear etiology. DISCUSSION: Although all cases of drug induced interstitial nephritis contained eosinophils they were not exclusive to drug induced interstitial nephritis. A prominent plasma cell infiltrate was seen in both cases of Sjögren's associated interstitial nephritis. The vast majority (n = 18, 75%) showed an improved serum creatinine (<1 mg/dL) 1 year post diagnosis/at last follow-up. In this pediatric series of AIN, TINU contributed to a large subset of cases with known etiologies. On follow up, majority of the cases demonstrated recovery of renal function.

Medulloblastoma: WHO 2021 and Beyond.

In 2016, medulloblastoma classification was restructured to allow for incorporation of updated data about medulloblastoma biology, genomics, and clinical behavior. For the first time, medulloblastomas were classified according to molecular characteristics ("genetically defined" categories) as well as histologic characteristics ("histologically defined" categories). Current genetically-defined categories include WNT-activated, SHH-activated TP53 wildtype, SHH-activated TP53-mutant, and non-WNT/non-SHH. In this article, we review the most recent update to the classification of medulloblastomas, provide a practical approach to immunohistochemical and molecular testing for these tumors, and demonstrate how to use key molecular genetic findings to develop an integrated diagnosis.

Intraoperative Diagnosis for Pediatric Brain Tumors.

Central nervous system (CNS) tumors are now the most common type of solid tumor in individuals aged 0-19 years, with an incidence rate in the United States around 5 per 100,000, accounting for about 1 out of 4 childhood cancers. Pediatric pathologists encounter brain tumor cases with varying frequency, but many of these encounters begin in the context of intraoperative consultation or "frozen section." This review provides an overview of the technical aspects of intraoperative consultation specific to, or more helpful in, CNS tumors, emphasizing helpful cytologic and histologic features of the more commonly encountered pediatric CNS tumors, and illustrating some common diagnostic pitfalls and how these may be avoided.

Evaluation and Diagnosis of Central Nervous System Embryonal Tumors (Non-Medulloblastoma).

Since the 1990s, the sheer number of defined central nervous system (CNS) embryonal tumor entities has continuously increased, with the trend accelerating in the most recent editions of the World Health Organization (WHO) Classification of Tumours of the CNS. The introduction of increasingly specific tumor groups is an effort to create more internally homogeneous categories, to allow more precise prognostication, and potentially to develop targeted therapies. However, these ever-smaller categories within an already rare group of tumors pose a challenge for pediatric pathologists. In this article we review the current categorization of non-medulloblastoma CNS embryonal tumors (including atypical teratoid/rhabdoid tumor, cribriform neuroepithelial tumor, embryonal tumor with multilayered rosettes, CNS neuroblastoma, FOXR2-activated, and CNS tumor with BCOR internal tandem duplication) and provide an overview of available ancillary techniques to characterize these tumors. We provide a practical approach to workup and development of an integrated diagnosis for CNS embryonal tumors.

PLAG1 Immunohistochemical Staining Is a Surrogate Marker for PLAG1 Fusions in Lipoblastomas.

BACKGROUND: The hallmark of lipoblastoma is a PLAG1 fusion. PLAG1 protein overexpression has been reported in sporadic PLAG1-rearranged lipoblastomas. METHODS: We evaluated the utility of PLAG1 immunohistochemical staining (IHC) in 34 pediatric lipomatous tumors, correlating the results with histology and conventional cytogenetics, FISH and/or next generation sequencing (NGS) results. RESULTS: The study included 24 lipoblastomas, divided into 2 groups designated as "Lipoblastoma 1" with both lipoblastoma histology and PLAG1 rearrangement (n = 16) and "Lipoblastoma 2" with lipoblastoma histology but without PLAG1 cytogenetic rearrangement (n = 8), and 10 lipomas with neither lipoblastoma histology nor a PLAG1 rearrangement. Using the presence of a fusion as the "gold standard" for diagnosing lipoblastoma (Lipoblastoma 1), the sensitivity of PLAG1 IHC was 94%. Using histologic features alone (Lipoblastoma 1 + 2), the sensitivity was 96%. Specificity, as defined by the ability to distinguish lipoma from lipoblastoma, was 100%, as there were no false positives in the lipoma group. CONCLUSIONS: Cytogenetics/molecular testing is expensive and may not be ideal for detecting PLAG1 fusions because PLAG1 fusions are often cytogenetically cryptic and NGS panels may not include all partner genes. PLAG1 IHC is an inexpensive surrogate marker of PLAG1 fusions and may be useful in distinguishing lipoblastomas from lipomas.

Pediatric Glial Tumors.

Pediatric glial tumors are unique from their adult counterparts. This important distinction is recognized and incorporated into the World Health Organization classification of central nervous system tumors and applies to both high- and low-grade gliomas, incorporating their specific molecular profiles. Molecular alterations in pediatric high-grade gliomas provide important prognostic information, for example in H3 K27M-mutant tumors. The integration of molecular information is also important for pediatric low-grade gliomas due to their overlapping morphologies and the prognostic and therapeutic implications of these molecular alterations. In this paper, we cover a variety of glial tumors, encompassing neoplasms with predominantly glial histology, astrocytic tumors, oligodendroglial tumors, and mixed glioneuronal tumors. Considering the complexity of this evolving field, the purpose of this article is to offer a practical approach to the diagnosis of pediatric gliomas, including the selection of the most appropriate molecular surrogate immunohistochemical stains, basic molecular studies, and more sophisticated techniques if needed. The goal is to reach a rapid, sound diagnosis, helping guide clinical decision-making regarding prognosis and potential therapies.

Secretory Carcinoma in Children and Young Adults: A Case Series.

Secretory carcinoma (SC), previously known as mammary analogue secretory carcinoma, is a rare salivary gland neoplasm that typically presents as a slow-growing painless lesion in the head and neck. SC occurs mainly in adults but has been described in children with the youngest reported patient diagnosed at five years of age. In children the gender distribution has been reported as female to male ratio of 1:1.2. SC is generally considered a low-grade malignancy with characteristic morphological features and immunological profile. SC also harbors ETV6-NTRK3 fusion (t(12;15)(p13:q25)). Surgical resection with or without lymph node dissection is the standard treatment, with generally favorable clinical outcomes. Here we present a single institution case series of six patients (ages 9-21) with SC and a review of the previously described pediatric cases. Our small series showed male predominance in pediatric patients with predominantly low-grade and stage tumors. All cases underwent complete surgical resections and when follow up is available there was no evidence of recurrences or metastases. To the best of our knowledge, this is the only SC case series comprised exclusively of pediatric and youth patients.

SARS-CoV-2 Related Ischemic Colitis in an Adolescent With Trisomy 21: Diagnostic Pitfalls and Considerations.

Millions of patients seek medical attention for diarrhea, vomiting, nausea, and abdominal pain. In the current environment, it is important to recognize that these symptoms may be the only manifestation or may precede more serious systemic complications of COVID-19. Herein, we describe the first case of ischemic colitis (IC) in a young adult who presented with diarrhea and highlight the laboratory pitfalls for patients with COVID-19 presenting with gastrointestinal (GI) symptoms.

Supernumerary Remnant Vas Deferens Like Wolffian-Derivatives in a Young Child With Abdominal Cocoon Syndrome-A Clinicopathological Novelty.

The abdominal cocoon syndrome is a rare cause of recurring intestinal obstruction in children. It refers to encasement of the small bowel by a fibrocollagenous membrane forming a cocoon. We report a nine year old male presenting with abdominal pain, distension, bilious vomiting and inability to pass stool and flatus for two days. In view of a persistently increasing bilious nasogastric output, an urgent exploratory laparotomy was performed. The small bowel loops were matted together forming a cocoon densely adherent to the parietal peritoneum with supra-colic fibrous bands. The bands histologically displayed multiple ductal remnants with epithelium resembling that of ductus deferens. These structures showed immunopositivity for pan-cytokeratin and basal CD10.Workup for tuberculosis and other etiological causes was unremarkable. This is the first documented case of abdominal cocoon in a pediatric subject associated with supernumerary wolffian remnants.

A History of Board Certification in Pediatric Pathology on Its 30th Anniversary.

In 1983 under the leadership of Dr. Daria Haust, the Pediatric Pathology Club (PPC; forerunner of the Society for Pediatric Pathology [SPP]), promulgated bylaws that included recognition of the special expertise required in pediatric pathology. This standard followed formal discussion that began as early as 1970, suggesting that special certification should be pursued, and the idea was vetted by the PPC in 1980 following a special report by Dr. Benjamin Landing and a letter to PPC members. Under the leadership of Dr. William Donnelly in 1984, a relationship between the SPP and the American Board of Pathology (ABPath) began in order to receive recognition of pediatric pathology as a special discipline. As a result, a test committee chaired by Dr. Jerald Schenken began preparing question categories and examples for ABPath examination. These efforts culminated in the first pediatric pathology subspecialty examination, held in Atlanta, Georgia on November 20, 1990. With this article we wish to detail the history of ABPath pediatric pathology board certification from its beginnings to the current time.

An Unusual Lung Mass of Heterotopic Pancreatic Tissue in a Neonate With an Elevated Immunoreactive Trypsinogen on Newborn Screen.

We present a case of a neonate with tracheoesophageal fistula and esophageal atresia along with a suspicious lung mass who had a false-positive newborn screen for cystic fibrosis due to an elevated serum immunoreactive trypsinogen with an additionally elevated serum lipase. The infant's lung mass was found to contain heterotopic pancreatic tissue consisting of acini, ducts, and islet cells, without an associated gastrointestinal duplication cyst. This constellation of congenital abnormalities has not been described in previous literature. Also, this is the first reported case of a neonate with elevated serum pancreatic enzymes in which the underlying etiology was discovered to be heterotopic pancreas.

Absence of Distinct Immunohistochemical Distribution of Annexin A5, C3b, C4d, and C5b-9 in Placentas From Patients With Antiphospholipid Antibodies, Preeclampsia, and Systemic Lupus Erythematosus.

INTRODUCTION: In pregnancy, the presence of preeclampsia (PEC), systemic lupus erythematosus (SLE), and/or antiphospholipid antibody syndrome (APLS) is characterized by poor obstetric outcomes, with potential adverse effects for both mother and fetus. Although the histopathologic changes observed in these entities have been well established, the pathogenic mediators associated with tissue injury are poorly understood. METHODS: Forty placentas were evaluated, including 10 patients with preeclampsia, 9 with SLE, 11 with APLS, and 10 disease-free controls. Each case was subjected to a panel of immunohistochemical markers including C3b, C4d, Annexin A5, and C5b-9. Staining was graded on intensity and distribution. RESULTS: C4d staining was distinctly different among disease groups and controls. Moreover, 6/10 PEC cases, 3/9 SLE cases, and 4/11 APLS cases showed at least focal staining for C4d. All controls were negative. Annexin A5 (AnxA5) staining showed intrinsic variability in all disease groups, while 10/10 controls showed diffuse, strong staining (2+ or 3+). C3b staining was heterogeneous among groups. DISCUSSION: Previously, antiphospholipid antibody (aPLA)-associated pregnancy complications have been thought to be a consequence of a unique aPLA-mediated pathogenic mechanism. However, the immunohistochemical similarity (increased complement and decreased AnxA5 staining) observed in placentas from patients with APLS, PEC, and SLE suggests that aPLA-associated pregnancy complications may reflect a more general autoimmune mechanism.

Focal Chorangiosis: Does It Have Clinical and Pathologic Significance?

INTRODUCTION: Chorangiosis is a proliferation of capillaries in terminal chorionic villi and is considered to be a marker for hypoxia and poor clinical outcome. Not all cases with hypervascular villi meet the generally accepted diagnostic criteria as reported by Altshuler. Our aim was to evaluate cases with villous hypervascularity that do not meet the diagnosis of chorangiosis, in which increased vascularity was present in a significant portion of the villous tissue but was not a diffuse process, which we call focal chorangiosis, to ascertain whether there were clinical or pathologic associations. MATERIALS AND METHODS: A total of 175 placentas with the finding of focal chorangiosis and 176 maternal age- and gestational age-matched controls were evaluated retrospectively. We defined focal chorangiosis as villous hypervascularity that did not meet criteria for a diagnosis of chorangiosis, but in which there was involvement of at least 50% of villi on at least 2 of 3 slides of placental tissue or involvement of all the villi on 1 slide. In these focal areas, the criteria of 10 capillaries in each of 10 villi in ten 10× microscopic fields were required. RESULTS: We found that focal chorangiosis is associated with a decrease in Apgar scores, increased placental weight, fetal vascular thrombosis (fetal vascular malperfusion), umbilical cord abnormalities, increased fetal nucleated red blood cells, villous dysmaturity, and increased rate of vaginal delivery. DISCUSSION: Many of these associations are shared with chorangiosis as traditionally defined, suggesting that focal chorangiosis is a significant finding that should be reported.

Neuroblastoma of the Bone and Bone Marrow Without an Apparent Primary Site: Report of 4 Cases With Long-term Follow-up.

Children with neuroblastoma rarely present with metastatic disease without identifiable primary tumors. We describe the clinical and histopathologic characteristics of 4 patients aged 1, 7, 7, and 11 years with neuroblastoma involving bone or bone marrow without an apparent primary site. One patient presented with a periorbital bone lesion, 1 presented with a distal femoral lesion, and 2 presented with diffuse bone marrow involvement. All tumors were negative for MYCN amplification. All patients were alive without evidence of disease 5 years after completion of multimodality therapy. Patients with neuroblastoma of the bone and bone marrow without an apparent primary site may constitute a unique group characterized by older age at diagnosis, nonamplified MYCN tumors, and good response to treatment.

Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor With SDHC Germline Mutation and Bilateral Renal and Neck Cysts.

Gastrointestinal stromal tumors (GISTs) are rare in children. Succinate dehydrogenase (SDH)-deficient GISTs are wild type and lack KIT proto-oncogene receptor tyrosine kinase and platelet-derived growth factor receptor A ( KIT or PDGFRA) mutations. These tumors result from germline SDH mutations, somatic SDH mutations, or SDH epimutants. Germline mutations in SDH genes ( SDHA, SDHB, SDHC, or SDHD) suggest Carney-Stratakis syndrome, a paraganglioma syndrome with predisposition for GIST. Negative immunohistochemistry for SDHB indicates dysfunction of the mitochondrial complex regardless of the subunit affected. We present an adolescent male with an SDH-deficient GIST and SDHC germline mutation who developed bilateral renal cysts and neck cysts, not previously described in children with this mutation. Germline testing is critical when SDH mutations are discovered due to treatment and surveillance implications. Further investigations are necessary to fully define the phenotypic expression of this mutation.