Pediatric and Developmental Pathology

Gastrointestinal polyps and certain extraintestinal lesions in children may herald a hereditary polyposis syndrome, with an increased risk of neoplasia and other health problems for both children and their relatives. The availability of molecular/genetic screening tests has increased early diagnosis of younger members of known polyposis families. This article reviews the gross and microscopic features of polyposis syndromes of childhood and summarizes the molecular/genetic advances in this field. Clinical management is also briefly discussed.

Islet cell apoptosis plays a role in both normal development of the endocrine pancreas and in the pathogenesis of Type I and Type II diabetes. The molecular mechanisms regulating islet cell death and survival in both normal and pathological situations are still not completely elucidated. The inhibitor of apoptosis protein (IAP) Survivin has an anti-apoptotic function mediated by several mechanisms; these include inhibiting caspase 3 and caspase 7. Survivin expression has been reported in human fetal islets and it may play a role in pancreatic remodeling and islet homeostasis. However, there are no data concerning either its expression in neonate or adult islets or its expression in any specific subtype of islet cells. We identified Survivin expression by immunohistochemistry in alpha cells and beta islet cells of 5/5 fetal pancreases. In contrast, fetal delta cells failed to demonstrate any detectable level of Survivin expression. Survivin expression was subsequently lost in the beta cells but not the alpha cells of 5/5 newborns and 5/5 adult subjects. Neonatal and adult delta cells maintained the lack of Survivin expression seen in fetal islets. These data show that different subtypes of islet cells differ in their pattern of Survivin expression. Furthermore, expression of Survivin in the beta cells is developmentally regulated.

The molecular characterization of human mammary myoepithelial cells is incomplete, hindering our understanding of its importance in breast physiology and pathology. Because data on the precursors of this cell lineage remain scarce and often contradictory, basal epithelial cells of second trimester fetal breasts were studied by light microscopy (LM) and immunohistochemistry (IHC). Up to 20 wk of gestational age, the mammary rudiments only comprised roundish primary outgrowths, “primary buds,” more likely to represent immature nipples than true mammary tissue. At 21 wk secondary outgrowths, “projections,” extended from enlarged primary buds into well-vascularized layers of dense mesenchyme. Basal projection cells had a partial myoepithelial-like phenotype: they reacted with CD29, CD49f, CD104, keratin 14, vimentin, S100β protein, and p63; furthermore, many became positive for keratin 17, α-smooth muscle actin, and CD10 (but not for keratin 19) between wk 21 and 25. The continuous basement membrane associated with the fetal mammary rudiments was strongly positive for collagens type IV and VII, and for laminin 5. Consistently strong and basally polarized staining for hemidesmosomal components suggested that although incompletely differentiated, most second trimester myoepithelial precursors might already mediate local epithelial-mesenchymal interactions, i.e., complex signaling pathways which are crucial for both orderly growth during development and maintenance of homeostasis during adult life. Because they are likely implicated in the phenomenon of menstrual cycle-related growth spurts in the adult resting breast, the strategically positioned cells of the myoepithelial lineage might constitute critical protagonists in defective epithelial-mesenchymal signaling associated with cancer progression.

Parvovirus infection during pregnancy is an important cause of hydrops fetalis. It is attributed to anemia caused by viral-induced destruction of red blood cells. Infection of other organs has been reported including the heart, liver, and lungs. Few of these reports, however, convincingly demonstrate virions within the functional parenchyma of the tissue. This is of particular concern regarding myocardium in the context of hydrops fetalis which is, in part, due to cardiac failure. The problem in routine pathology practice is that most fetuses with the infection are macerated. This, in part, probably explains the paucity of published information on cardiac involvement. This study examined five cases of fatal hydrops fetalis with variable maceration with serologically proven parvovirus B19 infection. Transmission electron microscopy of cardiac tissue demonstrated intranuclear virions in both erythroid precursor cells and in cardiac myocytes in three of these cases. In each of these, immunogold electron microscopy provided confirmatory evidence of parvovirus infection. Virions were not identifiable where maceration had caused disintegration of nuclei in the myocytes. In addition, virions were absent in the three negative control cases where retroplacental hemorrhage was confirmed as the cause of death. This study suggests that parvovirus infection of cardiac myocytes may play a more important role in causing hydrops fetalis than previously realized. It also demonstrates that maceration should not discourage the use of electron microscopy.

From 1995–2002, 14 patients with predominantly prehepatic, noncirrhotic portal hypertension were evaluated. At presentation, the eight females and six males had a mean age of 9 years (range 2–18). Seven were admitted with gastrointestinal, mostly esophageal bleeding, three with splenomegaly, three with hepato-pulmonary syndrome, and one with hyperammonemia. Imaging studies showed portal vein obstruction in six patients and non-obstructed but frequently anomalous vascular patterns, including hypoplasia of the portal vein, in the remaining eight patients. At the onset, liver function was marginally abnormal in all patients, but thrombocytopenia of approximately 100 × 10⁹/L was consistently observed, probably reflecting chronic mild consumption coagulopathy and hypersplenism. The most striking and frequent histopathologic finding in 25 liver samples, was the presence of hypoplastic portal triads with collapsed portal vein radicles. In contrast, other triads showed markedly distended and misshapen portal vein radicles and likely lymphatics. These two patterns of collapse and distention presumably reflect areas of impaired versus overloaded intrahepatic portal venous flow. Some of the biopsies showed variable portal/sinusoidal fibrosis. Four patients (two with intestinal bleeding, two with hepatopulmonary syndrome) required liver transplants and are doing well. Eight patients are doing well clinically after surgical or spontaneous vascular shunting. Two patients with intestinal bleeding and hepato-pulmonary syndrome, respectively) who had congenital dyskeratosis, underwent bone marrow transplantation and died of nonhepatic-related complications. It is possible to suggest prehepatic causes of portal hypertension even in needle biopsies when collapsed portal vein radicles are present in portal triads, but more than one biopsy sample with larger bore bioptomes may be required to see the changes. Conversely, identifying these changes may suggest to the clinicians the need to work-up a patient for portal hypertension.

This study provides new standards for some fetal dimensions frequently concerned with dysmorphological syndromes. Seven dimensions were included: the outer and inner canthal distances (OCD and ICD), the anteroposterior and transversal ocular diameters, the biparietal diameter and head circumference, and the inter-nipple distance. Subjects came from a large data set including more than 4000 fetuses autopsied in fetopathology units of pediatric hospitals in Paris between 1986 and 2001. From this data set, 673 subjects were carefully selected by exclusion of multiple pregnancies, macerated and malformed fetuses, and subjects with abnormal karyotypes and severe infections. Fetal ages ranged from 11 to 42 gestational wk, with a very large sample of fetuses in the first half of gestation. The standards of each dimension were computed in relation to age, as well as the ratio ICD/OCD. The mathematical models used to fit the percentile growth curves were carefully selected for each variable. This study supplies a set of accurate standards of specific dimensions useful for dysmorphological diagnosis in fetuses.

Clinically responsive placental examination seeks to provide useful information regarding the etiology, prognosis, and recurrence risk of pregnancy disorders. The purpose of this study was to assemble and validate a complete set of the placental reaction patterns seen with amniotic fluid infection in the hope that this might provide a standardized diagnostic framework useful for practicing pathologists. Study cases (14 with amniotic fluid infection, 6 controls) were reviewed blindly by six pathologists after agreement on a standard set of diagnostic criteria. After analysis of initial results, criteria were refined and a second, overlapping set of cases were reviewed. Majority vote served as the gold standard. Grading and staging of maternal and fetal inflammatory responses was found to be more reproducible using a two- versus three-tiered grading system than a three-versus five-tiered staging system (overall agreement 81% vs. 71%). Sensitivity, specificity, and efficiency for individual observations ranged from 67–100% (24/30 > 90%). Reproducibility was measured by unweighted kappa values and interpreted as follows: < 0.2, poor; 0.2–0.6, fair/moderate; > 0.6, substantial. Kappa values for the 12 lesions evaluated in 20 cases by the six pathologists were: acute chorioamnionitis/maternal inflammatory response (any, 0.93; severe 0.76; advanced stage, 0.49); chronic (subacute) chorioamnionitis (0.25); acute chorioamnionitis/fetal inflammatory response (any, 0.90; severe, 0.55; advanced stage, 0.52); chorionic vessel thrombi (0.37); peripheral funisitis (0.84); acute villitis (0.90); acute intervillositis/intervillous abscesses (0.65), and decidual plasma cells (0.30). Adoption of this clearly defined, clinically relevant, and pathologically reproducible terminology could enhance clinicopathologic correlation and provide a framework for future clinical research.

The occurrence of smooth muscle neoplasms and lymphoproliferative disorders in immunocompromised patients is well recognized. We report the case of an 8-year-old girl with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) status post-bone marrow transplant (BMT), in whom Epstein-Barr virus (EBV) was detected in innumerable leiomyomas involving the gallbladder (leiomyomatosis), and multifocal leiomyomas in liver, spleen, pancreas, intestinal tract, and lung. The leiomyomas of the gallbladder, liver, spleen, and lung were asymptomatic, while those located in the colon became clinically manifest by recurrent lower intestinal hemorrhage. The patient also developed extensive EBV-associated polymorphic lymphoproliferative disorder (PTLD) in nodal and extranodal sites. In addition, there were pulmonary and gastric adenovirus and small and large intestine cryptosporidum infections. Our case appears to be the first example of leiomyomatosis of the gallbladder coexisting with multifocal leiomyomas of the liver, spleen, pancreas, intestinal tract, and lung, as well as EBV-derived lymphoproliferative disorder in a young girl with ADA-deficient SCID. Awareness of the pattern of involvement and of the coexistence of benign leiomyomatous proliferations with lymphoproliferative disorder is of value when gallbladder, pancreatic, biliary tree, lung, and intestinal lesions become clinically manifest in these patients. The demonstration of EBV infection in both leiomyomata and the PTLD suggests a common pathogenesis that may have therapeutic and prognostic implications.

Primary ocular adnexal lymphoma (POAL) is a rare extranodal lymphoma. The mucosa-associated lymphoid tissue (MALT) subtype predominates and primarily occurs after the sixth decade of life. Most studies of ocular adnexal lymphoma are from the adult population. The data and experience in pediatric patients with POAL are limited to a few cases reported in the literature. Here we describe two pediatric cases of POAL and review the literature to further help characterize the clinical features and histopathologic appearance of this uncommon lymphoma.