Primary extrarenal nephroblastoma, or extrarenal Wilms tumor, is an exceptionally rare embryonal tumor outside the kidney. Spinal/lumbosacral involvement is particularly uncommon and may mimic congenital dysraphic lesions. We report a 10-month-old female infant followed since birth for presumed sacral lipoma and operated on for suspected meningomyelocele/lipomeningocele. Imaging demonstrated a solid S1 to S3 lesion adjacent to a thin lipomatous lesion near the conus medullaris. Histopathology unexpectedly showed a blastemal-predominant triphasic nephroblastoma with epithelial differentiation and limited stromal component. Tumor cells were diffusely positive for nuclear WT1 and PAX8. Normal bilateral kidneys, absence of teratomatous component, and negative metastatic work-up supported primary localized extrarenal disease. Complete excision was followed by vincristine/actinomycin-D-based chemotherapy; 6-month imaging showed no residual or recurrent lesion.
AIMS:Supratentorial ependymoma with ZFTA fusion represents a molecularly defined entity with characteristic but heterogeneous histopathological features. In routine diagnostic practice, morphologic diversity and limitations of individual molecular assays may lead to diagnostic uncertainty. This study aimed to systematically characterize the clinicopathological spectrum of pediatric supratentorial ZFTA fusion-positive ependymomas and to highlight potential diagnostic pitfalls. METHODS:Seventeen pediatric cases with confirmed ZFTA fusion were retrospectively analyzed. Clinical, radiological, histopathological, immunohistochemical (including L1CAM, p65/RELA, etc.), and molecular findings (FISH, NGS, DNA methylation profiling), along with follow-up data, were evaluated. RESULTS:The median patient age was 7 years (range, 1-14 years). Non-classical morphologic patterns (embryonal-like, sieve-like, ependymoblastic-like) occurred in 8/17 cases (47.1%), mostly in WHO grade 3 tumors. Crucially, all 8 cases retained focal conventional ependymal features upon thorough sampling and maintained diffuse L1CAM positivity, nuclear p65/RELA, and dot-like EMA positivity in deceptive areas. Molecularly, FISH yielded a 28.6% (4/14) false-negative rate in high-grade cases, and NGS showed 1 false-negative result (7.1%), rescued by DNA methylation profiling. Overall median follow-up was 48 months (range, 6-68). WHO grade 2 tumors had zero recurrence (median follow-up, 60 months), whereas WHO grade 3 tumors showed median time to recurrence of 6 months (range, 3-12). CONCLUSIONS:Pediatric ZFTA fusion-positive ependymomas exhibit morphologic divergence and false-negative molecular risks. Extensive tissue sampling, integrated IHC surrogate panels (p65/L1CAM/GFAP/EMA), and complementary molecular platforms are essential for accurate diagnosis.
Patent omphalomesenteric duct (OMD) with intestinal prolapse coexisting with omphalocele is an exceptional ventral folding anomaly that may be misdiagnosed as gastroschisis. The vitellointestinal duct normally involutes between the seventh and ninth gestational weeks; failure of obliteration produces a spectrum of anomalies including Meckel diverticulum, fibrous bands, umbilico-ileal fistulae, or, rarely, a fully patent duct with bowel prolapse. Fewer than 15 cases of the combined anomaly have been reported since 1967. We describe a preterm neonate (32 + 4 weeks, 2160 g) with an intact omphalocele sac and a separate, widely patent OMD through which both the proximal and distal limbs of the terminal ileum had prolapsed. Histopathological examination of the resected sac and OMD-bearing ileal segment demonstrated the umbilical cutaneous transition with vitelline-derived vascular remnants, preserved intestinal architecture with intact myenteric ganglion cells, and no heterotopic gastric or pancreatic mucosa. These findings indicate persistence of a fully patent vitellointestinal duct at the morphologically simple end of the vitelline duct anomaly spectrum, supporting a developmental rather than an acquired origin. The case illustrates the diagnostic pitfall of misidentification as gastroschisis and the value of clinicopathological correlation in establishing the developmental basis of this rare anomaly.
OBJECTIVE:Dysmorphic chorionic villi (DCV) are histopathological findings typically associated with chromosomal abnormalities in early pregnancy loss. This study aimed to evaluate the clinical and pathological significance of DCV across all trimesters, particularly investigating their association with fetal vascular malperfusion (FVM) and adverse pregnancy outcomes in late gestation. METHODS:We retrospectively analyzed 100 placental cases with DCV diagnosed between June 2024 and July 2025. Cases were classified by trimester and assessed for maternal characteristics, fetal findings, and placental pathologies using standardized histomorphological criteria. RESULTS:DCV were identified across all trimesters, with highest prevalence in the second trimester (57%). FVM was significantly more common in third-trimester placentas (72.4%) compared to first (7.1%) and second (17.5%) trimesters (P < .001). Adverse fetal outcomes included medical termination (30%) and intrauterine fetal demise (25%), both confined to early trimesters. Chromosomal abnormalities were identified in 19% of cases, with trisomy 21 being most frequent (13%). CONCLUSION:DCV are not exclusive to early pregnancy loss but persist as clinically significant findings throughout gestation. The strong association between third-trimester DCV and FVM suggests these lesions may serve as prognostic histological markers for compromised fetoplacental perfusion. These findings support the need for standardized DCV criteria in placental classification systems and highlight the importance of genetic counseling when DCV are identified.
The LAMB1 gene encodes the laminin β1 chain, an essential component of the pial basement membrane required for neural morphogenesis. While biallelic LAMB1 mutations typically result in cobblestone lissencephaly and brainstem abnormalities, we report an extreme, lethal syndromic phenotype that significantly expands the gene's known clinical spectrum. Through genomic sequencing of a 36-week stillborn male fetus from consanguineous parents, we identified a novel homozygous frameshift variant in LAMB1 (NM_002291.3:c.3330dup, p.Gly1111Argfs*23). This fetus exhibited severe growth restriction and a massive occipital meningoencephalocele, alongside pansutural craniosynostosis and an underdeveloped cranial base. Multi-system anomalies included gallbladder agenesis and abnormal lung lobation, alongside secondary endocrine failure and placental vascular defects. This report includes a systematic review of 23 confirmed cases, proposing a 4-category phenotypic classification that positions this case as a lethal extreme. Mechanistically, we propose that this loss-of-function variant impairs integrin-β1-mediated mechanotransduction during human neural tube closure, thereby disrupting the extracellular matrix-planar cell polarity axis. Under this mechanism, the primary encephalocele drives downstream pansutural craniosynostosis by reducing intracranial pressure, and endocrine failure by disrupting the hypothalamo-hypophyso-adrenal axis. Ultimately, these findings highlight LAMB1 as an essential, non-redundant scaffold required for both neural architecture and systemic visceral morphogenesis.
Background: Artificial intelligence (AI)-based methods have demonstrated considerable promise in identifying histological features in whole slide images (WSIs) and supporting risk classification in tumors. For pediatric cancers such as neuroblastoma, integrating histological findings with molecular data may enhance risk stratification and support clinical management. This study aims to evaluate the performance of a deep learning AI model on WSIs to classify neuroblastoma patients according to risk groups and determine the MYCN amplification status. Methods: Hematoxylin and eosin-stained slides from 10 high-risk MYCN amplified, 10 high risk MYCN non-amplified, 5 intermediate-risk MYCN non-amplified, and 5 low-risk MYCN non-amplified neuroblastoma cases were digitally scanned. WSIs were processed using a deep learning-based segmentation and classification algorithms. Two patch-level datasets were constructed: 1 to predict MYCN amplification status (positive versus negative), and another to classify patients into 4 distinct risk groups (low-risk MYCN-negative, intermediate-risk MYCN-negative, high-risk MYCN-negative, and high-risk MYCN-positive). Results: Our deep learning model achieved 98% accuracy of classifying neuroblastoma patients’ risk groups across validation trials on slide-level classification tasks, reflecting robust performance. The accuracy of distinguishing MYCN amplified tumors from MYCN non-amplified tumors was 99%, and even within high-risk neuroblastoma cases, it was 96%. Conclusion: AI models can facilitate accurate risk classification of neuroblastoma patients and may also predict MYCN amplification status. They represent a promising complementary tool for pathologists working on risk stratification, especially when histological examination is limited or molecular testing for MYCN amplification is unavailable.
BACKGROUND:Chronic histiocytic intervillositis (CHI) and villitis of unknown etiology (VUE) are immune-mediated placental disorders leading to adverse pregnancy outcomes. This study investigated whether first-trimester pan-immune-inflammation value (PIV), a novel systemic inflammation marker, is associated with these conditions. METHODS:This retrospective case-control study (October 2022-August 2025) included 163 placentas (25 controls, 63 CHI, 75 VUE). First-trimester complete blood counts (<14 weeks) were used to calculate PIV = (neutrophil × platelet × monocyte)/lymphocyte. Histopathological examination followed Amsterdam criteria. Multivariable logistic regression and ROC analyses were performed. RESULTS:PIV was significantly higher in cases versus controls (503.1 vs 381.3, P = .048). Across groups, PIV was highest in CHI (661.6), intermediate in VUE (446.4), and lowest in controls (P < .001). CHI showed the worst perinatal outcomes: lowest gestational age (30.5 weeks), birth weight, and Apgar scores, and highest intrauterine fetal death (41.3%). After multivariable adjustment, first-trimester PIV remained independently associated with CHI (aOR 1.87, 95% CI 1.19-4.27, P = .005) but not with VUE (aOR 0.74, P = 0.103). Discriminatory performance was modest for CHI (AUC 0.677) and poor for VUE (AUC 0.434). CONCLUSION:Elevated first-trimester PIV is independently associated with CHI but not VUE, suggesting that systemic maternal inflammation may be detectable early in gestation, particularly in more severe placental immune pathology. PIV is not a standalone diagnostic test but may contribute to risk assessment when combined with clinical findings.
A 19-month-old patient died suddenly and unexpectedly ~11 months after hematopoietic stem cell transplantation (HSCT) for Hurler syndrome. Post-mortem examination revealed pulmonary air emboli that were attributed to extensive colonic pneumatosis intestinalis, an uncommon but reported complication of HSCT. Gas emboli are not just the result of trauma or decompression sickness but are more commonly iatrogenic in origin, resulting from the procedural-related introduction of air into the vascular system; pneumatosis intestinalis has rarely been associated with air emboli. Pathologists should be cognizant of unusual complications of HSCT and maintain a high index of suspicion for air embolization, even in a medically complex patient, to ensure optimal autopsy examination.
Hirschsprung-associated enterocolitis (HAEC) is a severe complication of Hirschsprung's disease (HSCR), but its pathogenesis remains unclear. Gut-associated lymphoid tissue (GALT), including isolated lymphoid follicles (ILFs), plays a key role in mucosal immunity. This study investigated the presence, distribution, and phenotype of ILFs in colonic tissue from 35 HSCR patients and 12 controls. Histological and immunohistochemical analyses revealed mature ILFs in both ganglionic and aganglionic bowel, with no significant differences in densities between HSCR patients with and without HAEC. However, patients that developed HAEC showed signs of enhanced B-cell activation in ILFs. Patients with a stoma had significantly increased ILF density, suggesting that luminal content may influence ILF development. Despite the absence of enteric neurons, ILFs were structurally similar to those described in adults, indicating that ILF formation occurs independently of a functional enteric nervous system. These findings provide new insights into mucosal immunity in HSCR and suggest a role for activation of the mucosal B-cell compartment in HAEC pathogenesis.
Purpose: This article describes how techniques such as advanced imaging, nucleic acid evaluation, integrated approaches, and data collection systems can facilitate the examination of a stillbirth or newborn, particularly when an autopsy is not possible.Content: The traditional autopsy remains the gold standard for investigating stillbirth and neonatal death. However, declining rates due to parental refusal, financial constraints, and cultural barriers highlight the need to widely adopt modern alternatives. This review examines emerging ancillary and advanced diagnostic techniques necessary to maximize diagnostic yield and ensure equitable access to comprehensive postmortem evaluations. Since imaging alone often misses critical microscopic pathologies, hybrid methods like Minimally Invasive Autopsy with Laparoscopically Assisted Sampling (MinImAL) are essential. MinImAL combines Postmortem Magnetic Resonance Imaging (PMMR) with image-guided tissue sampling to acquire specimens for histological and microbiological analysis. Complementary molecular techniques aid in identifying underlying genetic causes and informing recurrence risk. The success of these tests relies on optimized tissue selection. Systemic improvements include adopting standardized protocols, establishing Stillbirth Centers of Excellence, and using Artificial Intelligence (AI) for risk prediction. Importantly, integrating these advanced, less invasive methods is vital for addressing financial and racial health disparities, especially given the lack of Medicaid coverage for autopsy, thereby ensuring all bereaved families receive accurate and necessary diagnostic information.
Purpose: This manuscript examines the role of postmortem conference in supporting families in their grief and enhancing care following perinatal loss. It synthesizes current knowledge, highlights challenges in recognition and support, and recommends evidence-based approaches for healthcare professionals to better address the needs of grieving families.Content: Perinatal loss, encompassing miscarriage, stillbirth, and neonatal death, is profoundly distressing, affecting individuals, couples, and families. This manuscript explores the complex nature of grief following perinatal loss, emphasizing the psychological, emotional, and social challenges bereaved parents may face. It synthesizes recent literature focused on grief and bereavement. The disenfranchised nature of perinatal grief, the insufficient recognition and support from social networks and healthcare providers, and implications for long-term mental health are discussed. Evidence-based interventions and supportive approaches include compassionate communication, memory-making practices, and psychological therapies tailored for perinatal loss. Best practices for healthcare professionals and recommendations for institutional policies that foster a supportive environment for grieving families are highlighted. The manuscript addresses the need for increased education, resources, and research to improve care outcomes. By recognizing the legitimacy and depth of perinatal grief, and addressing it through holistic, responsive care, both immediate suffering and long-term complications for parents and families can be mitigated.
PURPOSE:To explain which growth and development parameters are most useful when faced with a perinatal autopsy and identify factors complicating the use of these parameters. BACKGROUND:Growth and development charts seem to be straightforward, but when faced with a perinatal autopsy, they may be confusing or misleading. Autopsy weight and measurement charts are based on much smaller groups of individuals than clinical charts. Perinatal postmortem growth charts are confounded by maceration, the small numbers of subjects to define normal, and population differences. Interpretation of growth and development parameters when performing a perinatal autopsy is complicated by the interpretation of deviations from expected or "normal" as defined by the charts. RESULTS:This article provides an analysis of growth and development charts used in perinatal examinations and gives guidance about which charts are the most robust. Weights, measurements, and aspects of development will be described and distilled into those most relevant to the general pathologist. CONCLUSION:Growth and development charts are important when performing a perinatal autopsy to define what is normal versus pathologic, and a distillation of the key points with review of the literature is central to using them.
Words are our primary means of communication as practitioners of perinatal pathology and so we must focus on detail, accuracy, and clarity. This aim of this article is to provide a glossary of common terms in order to improve clarity when writing or speaking about the infant, fetus, pregnancy, and the placenta. We address terminology used in perinatal pathology when performing an autopsy or examining products of conception or a placenta that can be confusing or unclear. The purpose is to convey meanings of commonly used terms, keeping to the subject of the normal, uncomplicated examination as much as possible. Additional articles in this Perspectives issue focused on fetal growth and development as well as the perinatal autopsy expand on many of the definitions below.
PURPOSE:The purpose of this article is to highlight the unique aspects of the perinatal autopsy, compared to the autopsy of patients outside the perinatal period. This article focuses on what would be useful to general pathologists who perform autopsies as a small portion of their practice. We will also discuss in some detail the autopsy of the macerated fetus and determining time of death prior to delivery. BACKGROUND:General pathologists performing perinatal autopsies commonly lack specific training in perinatal autopsy techniques, where interpretation of detailed measurements and dissections are essential. Macerated fetuses provide an additional challenge, as planes of dissection are hard to see and microscopic examinations require interpretation of degenerated tissue. CONTENT:This article describes the basic steps to perform a perinatal autopsy including tips to streamline dissections, which are useful for the general pathologist. It includes how to recognize features of maceration to provide an accurate time of death prior to delivery and information about the classification of the cause of death in stillbirth.
PURPOSE:This review is intended to provide practical guidance to those who examine the tissues of fetuses and infants under the microscope. We focus on what is normal at various stages of development, and try to point out when caution should be used in interpreting histologic findings. CONTENT:We present descriptions and images of normal developmental histology and its variations in the major human organs during fetal and neonatal life. The organs reviewed include the cardiovascular system, lungs, liver, pancreas, tubular gastrointestinal tract, kidneys, thymus, adrenal glands, gonads, thyroid gland, spleen, brain, bone, and skeletal muscle.
PURPOSE:To provide information for the general pathologist about what is considered normal in the placenta and to differentiate findings that are abnormal or pathologic. BACKGROUND:The literature about the placenta is confusing. It can be opinionated, and terminology varies among authors. Even what is expected to be seen, which we refer to as normal, is not consistent among experts. RESULTS:This article focuses on what the general pathologist should know about normal macroscopic and histologic features of the placenta throughout gestation, as well as alterations that are controversial related to whether they are normal or not. Normal findings are differentiated from pathology when the morphology is confusing or overlaps. We further guide the reader to selected literature that describes pathology in clear, understandable terms. This is not a consensus document but does represent agreement among the authors and, when agreement isn't reached, differing opinions are noted. CONCLUSION:This article is a report of normal features in the placenta based on distillation of evidence from the literature and personal experience in areas where the literature fails to provide clarity.
BACKGROUND:Erythropoietic Protoporphyria (EPP) is a rare inherited disorder of heme biosynthesis caused by pathogenic variants in FECH. Although most patients present with cutaneous photosensitivity in childhood, clinically significant liver disease is uncommon, and severe fibrosis in early childhood is rarely reported. CASE:A 2-year-old girl presented with recurrent photosensitivity and erythematous swelling after sun exposure. Laboratory evaluation revealed markedly elevated erythrocyte protoporphyrin (2406 µg/dL) and elevated plasma protoporphyrin. Genetic testing identified compound heterozygous FECH variants: c.901_902del (p.Trp301Alafs*23) and c.801G>A (p.Met267Ile). Liver enzymes were significantly elevated. Following liver biopsy demonstrated stage 3 bridging fibrosis with crystalline deposits in hepatocytes consistent with protoporphyric hepatopathy. The patient subsequently underwent hematopoietic stem cell transplantation with improvement of protoporphyrin levels and liver enzymes. However, the post-transplant course was complicated by severe infections, acute respiratory distress syndrome, and multiorgan failure, resulting in death. CONCLUSION:This case highlights rapidly progressive liver fibrosis in a toddler with EPP and emphasizes the importance of early hepatic monitoring in pediatric patients with markedly elevated protoporphyrin levels and rare FECH variants.
Fetiform teratoma (FT) and fetus-in-fetu (FIF) represent a spectrum of rare retroperitoneal masses containing organoid structures. While FIF is classically defined by the presence of a vertebral axis, FT lacks this organized skeletal development. Distinguishing between these entities is critical given the malignant potential associated with FT, estimated at approximately 10%. We report a case of a 5-month-old male presenting with a large (12 cm) retroperitoneal mass and elevated alpha-fetoprotein (AFP 56.8 IU/mL; age-matched reference <7 IU/mL). Macroscopically, the resected tumor featured a distinct rudimentary digitiform projection with a nail bed. Histopathology demonstrated extensive organoid differentiation, including gastrointestinal loops with muscular layers, respiratory epithelium, and well-formed pancreatic parenchyma and adrenal cortex. Despite the complex organogenesis and limb-like morphology, the absence of a vertebral column or ossified long bones supported a diagnosis of mature cystic teratoma with fetiform features (FT) over FIF. This report highlights the diagnostic ambiguity within the “gray zone” of these lesions and emphasizes the role of axial skeletal organization and serum AFP levels as complementary tools for classification and oncologic surveillance.
BACKGROUND:Fetal hemorrhage (FH) is an important and difficult cause of death to recognize at perinatal autopsy. Existing literature is restricted to case reports and small case series, and none comprehensively describe both placental and autopsy findings. We sought to characterize fetal and placenta findings where the ultimate cause of death was determined to be FH to aid in the identification of these cases. MATERIALS AND METHODS:This is an autopsy series of perinatal deaths with fetomaternal hemorrhage (FMH) and FH into the amnionic sac. We included singleton pregnancies with Kleihauer Betke (KB) testing, and divided cases into 3 groups: FMH with ≥40% of fetal blood volume, FMH ≤39%, and suspected FH into the amnionic sac with negative KB test. RESULTS:We identified 20 cases from 691 perinatal autopsies, 10 with FMH ≥40%, 5 with FMH ≤39%, and 5 suspected FH into the amnionic sac. Cases with FMH≥40% were likely to have a normal placental weight, villous edema, and fetal hydrops. While FH into the amnionic sac was more likely to have a small placenta with disruption/defect of fetal vessels, and less likely to have fetal hydrops. CONCLUSION:This study describes the differences and similarities between cases with FMH and FH in to the amnionic sac, and highlights the need for careful placenta and fetal autopsy examinations.
