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Tuberous sclerosis (TS) is a relatively common neurocutaneous genetic disorder affecting 1 in 10,000 people and has a spectrum of manifestations due to incomplete penetrance (Crino et al., 2006). Common features include cognitive and behavioral problems, seizures, hypomelanotic “ash-leaf” spots, facial angiofibromas, hamartomatous and choristomatous tumors. Lesions commonly associated with TS include subependymal neural tubers, renal angiomyolipomas (rAMLs) and cardiac rhabdomyomas (Crino et al., 2006).

A 15-year-old male patient developed atypical hemolytic uremic syndrome (aHUS) at 16 months of age leading to end-stage renal disease. The family history was suggestive of autosomal dominant aHUS, and he was more recently found to have a C3 heterozygous gene mutation (1835C>T mutation in exon 14, which determines the amino-acidic substitution R570W) with no other complement abnormalities. He had two renal transplants, the first at 2.5 years, and the second at 8 years of age, but allograft dysfunction developed in both transplants leading to graft failure due to recurrent HUS at 5 years and 18 months post-transplantation respectively. At 15 years of age he received a third transplant from a deceased donor with pre-emptive plasmapheresis. He had immediate graft function and nadir serum creatinine was 1.3–1.4 mg/dl. Severe allograft dysfunction and hypertension developed 2 months after transplantation following influenza infection. Renal allograft biopsy showed thrombotic microangiopathy. He received plasmapheresis followed by eculizumab therapy. Allograft function returned to baseline 3 weeks after starting therapy, and post-treatment allograft biopsies showed improvement in thrombotic microangiopathy. He continues to receive eculizumab every 2 weeks with stable graft function 13 months after transplantation.

Morphologically, the distinction between undifferentiated embryonal sarcoma of the liver (UESL) and biliary tract rhabdomyosarcoma (RMS) can be uncertain because of some shared pathologic similarities. Patients with UESL have been consistently but erroneously enrolled in Children's Oncology Group (COG) treatment protocols because UESL was equated with RMS, despite the differing primary treatment modalities of these entities. Review of COG pathology files yielded 20 cases of UESL that were compared to 25 cases of biliary tract RMS. Clinicopathologic features including immunohistochemical staining were examined. In the UESL cases, the male:female ratio was 1:1 and the median age was 10.5 years. Histologically, hyaline globules and diffuse anaplasia were consistently present. The cases of RMS had a male:female ratio of 1.8:1 with a median age of 3.4 years and routinely lacked diffuse anaplasia and hyaline globules. Polyclonal desmin and muscle-specific actin were variably immunoreactive in UESL and RMS; however, myogenin and myogenic regulatory protein D1 (MyoD1) were uniformly negative in UESL and routinely positive in the majority of biliary tract RMS. Myogenin, in particular, was highly significant ( P = 0.0003) in distinguishing RMS from UESL. With a median follow-up of 8 months, 11 of 18 patients with UESL were still alive. The estimated 5-year survival for biliary tract RMS was 66%. Establishing the correct diagnosis of these distinct clinical and pathologic entities is important, as surgery alone may be curative in UESL, whereas initial chemotherapy is often recommended for the treatment of biliary tract RMS.

A frequently fatal, although rare, side effect of cephalosporin antibiotics is noninfectious myocarditis. We report two cases of hypersensitivity myocarditis secondary to administration of cephalosporin antibiotics. In both cases, acute hypersensitivity myocarditis was not suspected clinically, and the diagnosis was made postmortem. Histology revealed intense eosinophilic infiltration of the endomyocardium with eosinophil degranulation and myocyte damage, Clinically, death in both cases was due to cardiac failure. When suspected early, appropriate management may be lifesaving.

Lymphocytic thyroiditis has been associated with an increase in the incidence of thyroid papillary carcinoma in some reports, mostly series of both adults and children. Relatively little is written about thyroiditis and follicular carcinomas. We have seen several cases of pediatric follicular thyroid carcinomas, that had an associated lymphocytic infiltrate, which led us to examine all primary malignant thyroid neoplasms in our surgical files from 1984 through 2000 to examine this relationship. We also investigated the nature of the lymphocytic infiltrate with routine immunohistochemistry. Ten patients (five male, five female, ages 4.5–21 years of age) had a thyroid carcinoma resection, six (three males and three females) with papillary carcinoma and four patients (two males and two females) with low-grade follicular carcinoma. Seven samples (one male had two cases with tumor) from patients who had a papillary carcinoma resection with tissue blocks available were identified (one patient had slides but no blocks), as were all four patients with a follicular carcinoma. The thyroid of all patients with a follicular carcinoma contained a lymphocytic infiltrate; only four of the seven papillary carcinoma samples had an associated lymphoid infiltrate. In all cases with a lymphoid infiltrate, the infiltrate was present in both lobes (both adjacent and separate from the tumor). B lymphocytes were present in the lymphoid infiltrate of three of four patients with follicular carcinomas and in 1 of 3 cases of papillary carcinomas. T cells were dispersed throughout all the tumors with lymphoid infiltrates. We conclude that pediatric follicular carcinomas have an associated lymphocytic infiltrate in the tumor and/or adjacent thyroid, more commonly than papillary carcinomas.

BACKGROUND Muscular ventricular septal defects (mVSDs) are the most common congenital heart defects. Previous studies have suggested maternal use of acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), and/or fever as risk factors. We evaluated the association between mVSDs and maternal use of acetaminophen or NSAIDs adjusting for fever. METHODS Infants with nonsyndromic mVSDs (cases) and without birth defects (controls), with gestational age ≥37 weeks and their mothers were enrolled in the National Birth Defects Prevention Study. Two exposure periods were defined: the first trimester of pregnancy, and one month before pregnancy through delivery. Mothers reporting fever or medication use at least once during either period were considered exposed. Adjusted odds ratios and 95% confidence intervals were estimated independently for each exposure period. RESULTS The analysis included 168 cases and 692 controls. Two case groups were evaluated: all mVSD infants (n = 168) (including those with associated minor cardiac defects or noncardiac defects), and infants with isolated mVSDs (n = 133). Mothers of cases were less likely to be African-American than Caucasian (OR, 0.36; 95% CI, 0.18, 0.73). Approximately equal numbers of case mothers and control mothers (10.4 versus 9.7%, respectively) reported at least one febrile episode during the first trimester. Neither acetaminophen nor NSAID exposure was significantly associated with mVSDs. This was true for both case groups and both exposure periods. CONCLUSIONS Significant associations were not detected between the occurrence of mVSDs and maternal use of NSAIDs or acetaminophen adjusting for maternal fever, nor were they detected between maternal fever and mVSDs. Birth Defects Research (Part A), 2004. Published 2004 Wiley-Liss, Inc.

Studies in various settings reveal that a significant percentage of autopsies demonstrate findings that were not previously clinically diagnosed. In the pediatric and adolescent age group, forensic examinations comprise a large percentage of total autopsies performed. We hypothesized that a similar number of previously undiagnosed findings would be present in this population and thus reviewed a series of autopsy reports from the Medical Examiners Office in the Arkansas Crime Laboratory. During 1997 through 1999, we performed 439 complete forensic autopsies on children and adolescents (age range 1 day to 19 years; median 18 months). Previously undiagnosed lesions were found in 173 (39%). Of these subjects, 68 (39%) had clinically significant pathology, 60 (35%) had insignificant pathology, and 45 (26%) had pathology of undetermined significance. Thirty-six subjects had lesions expected from a previously diagnosed condition. Of the total number of lesions found, 168 were inflammatory, 58 were congenital anomalies (48 unexpected), and 88 comprised miscellaneous other conditions. Infants < 6 months of age were significantly more likely to have a previously undiagnosed lesion than children > 6 months ( P < 0.0001). Previously undiagnosed findings, mostly inflammatory, occur relatively frequently in pediatric and adolescent forensic autopsies and are more likely to occur in infants.

This article is the offshoot of a Pediatric Oncology Group (POG) seminar presented at the Adams Mark Hotel, Denver, Colorado, Friday, May 21, 1999, titled “The Frozen Section in Pediatric Solid Tumors—Crucial Issues.” There were eight presenters who spoke on a wide range of topics that included historical perspectives of the frozen section and discussion of the following systems: brain, renal, germ cell, bone, soft tissue, and lymph nodes. To complement these presentations, a pediatric surgeon explained his concern and philosophy regarding the use of frozen sections, and a lawyer tackled the issues and risks in rendering a frozen section diagnosis. We think that this review covers all the important aspects of the frozen section in our current practice of pediatric pathology.

In normal somatic cells, the methylation pattern of DNA is stably maintained by DNA (cytosine-5-)-methyltransferase (DNA methyltransferase). Increased expression of DNA methyltransferase has been detected in many types of human cancer and has been thought to play an important role in tumorigenesis. In our study, we developed a standardized reverse transcription-polymerase chain reaction (RT-PCR) assay to determine the mRNA levels of DNA methyltransferase in rhabdomyosarcoma, the most common soft tissue cancer in children. Using this assay, expression of DNA methyltransferase was analyzed for 32 rhabdomyosarcomas and 12 normal skeletal muscle samples. All tumor samples, of which 18 were embryonal and 14 were alveolar subtype, showed increased expression of DNA methyltransferase after normalization to beta-actin. Compared to normal skeletal muscle, the average increase of DNA methyltransferase expression was 6.7-fold (6.7 +/-()0.96) in the embryonal tumors and 3.7-fold (3.7 +/- 0.46) in the alveolar rhabdomyosarcomas. The difference in the average increase of the DNA methyltransferase expression was statistically significant in the 2 rhabdomyosarcoma subtypes, which have distinct etiologies and clinical behaviors. Our results are consistent with previous reports that an increase in DNA methyltransferase activity is associated with neoplastic transformation; however, the role of increased DNA methyltransferase expression in the development and progression of rhabdomyosarcoma needs to be investigated in future studies.

Purpose: A retrospective study was conducted to investigate the relationship between CD44 expression in neuroblastoma and related tumors and other known prognostic indicators. Materials and Methods: Immunostaining of CD44 was done on surgical specimens of 55 cases (42 patients) of neuroblastoma (NB) and ganglioneuroblastoma (GNB) and nine cases of ganglioneuroma. The percentage of positive tumor cells was scored semiquantitatively (0-4+) by two observers. CD44 expression was then correlated with survival, age, stage, and N-myc amplification. Results: Fifty-seven percent of the patients with NB or GNB had heterogeneous positive staining (2-4+) on their diagnostic specimens. Twenty-four percent of the patients had no staining for CD44, and 19% had 1+ staining. In the 17 cases with N-myc analysis, an inverse relationship was demonstrated between N-myc and CD44 expression by univariate analysis. Lack of expression of CD44 was highly associated with pool survival (p = 0.0002). When assessing the joint effects of age, stage, and CD44 in multivariate analysis, the effect of CD44 remains significant (p = 0,028) and appears to be independent of age and stage. Conclusion: Our data suggest a relationship between CD44 and N-myc amplification. Absence or low expression of CD44 correlates with poor survival and may be a biologic marker of tumor aggressiveness. CD44 appears to be an independent prognostic marker and deserves continued investigation in prospective studies of neuroblastoma.

Cryptosporidium parvum intestinal infection in immunodeficient patients can cause severe intestinal fluid losses with severe dehydration or chronic diarrhea with malnutrition. Therapies tried in human beings and animals include paromomycin, clarithromycin, azithromycin, octreotide, hyperimmune bovine colostrum, and bovine transfer factor. No specific therapy has been found to be consistently beneficial to children. We report azithromycin treatment of four children with acquired immunodeficiency syndrome who had severe diarrheal illnesses in which Cryptosporidium parvum was the sole pathogen detected. Three of these children had a marked decrease in stool volume and frequency within 36 hours of initiating therapy and resolution of diarrhea within 5 days; Cryptosporidium organisms became undetectable on examination of stool or colonic biopsy or by both after therapy was discontinued. A fourth patient required prolonged therapy with azithromycin to achieve clearance. Azithromycin therapy should be considered for immunocompromised patients with intestinal Cryptosporidium infection.

Reye's syndrome presents as acute central nervous system and liver dysfunction in children. Its incidence has seen a sharp decline in parallel with the decline in the use of aspirin in the pediatric age group. This report describes a patient with Reye's syndrome and serves as a reminder for health professionals to continue to discourage the use of aspirin for the treatment of viral infections.

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.

Langerhans' cell histiocytosis (LCH) is an abnormal accumulation of dendritic histiocytes of unknown pathogenesis. It has recently been shown to be a clonal process. Bcl-2 is a proto-oncogene whose protein product is known to inhibit apoptosis. The overexpression of bcl-2 has been demonstrated in a number of neoplasms, presumably prolonging the survival of the neoplastic cells. We examined the expression of bcl-2 in normal Langerhans' cells in the skin and in LCH by immunohistochemistry for protein and in situ hybridization for mRNA to see if it could be implicated in the pathogenesis of this disorder. Additionally, we performed Southern analysis to determine if genomic rearrangement of the bcl-2 gene occurs in cases of LCH. Bcl-2 was not detected in normal skin Langerhans' cells. Eleven of thirteen cases of LCH demonstrated bcl-2 protein expression in the cytoplasm of the Langerhans' cells by immunohistochemistry, while 12 of 13 cases had evidence of bcl-2 mRNA by in situ hybridization. Southern analysis revealed a germ-line configuration of the bcl-2 gene in the five cases studied. These findings suggest that bcl-2 expression is present and up-regulated in pathologic Langerhans' cells, however, this overexpression does not appear to be due to genomic rearrangement.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon malignant mesenchymal tumor characterized by local invasion and recurrence. Fewer than 50 cases have been reported in the pediatric population. We reviewed our experience in the treatment of children with DFSP to define clinical and pathological characteristics. Seven pediatric patients were included in the study (mean age, 11.7 yr). Clinically, the tumors were described as firm nodules fixed to the skin but mobile over the deep fascia, with slow, progressive growth. Diagnosis was made by excisional biopsy in 6 patients and punch biopsy in 1 patient. Six of 7 patients had positive margins after the diagnostic procedure. Pathologically, diagnosis was based on histology, with confirmation by CD34 staining. Definitive surgical therapy consisted of wide local excision (1-3 cm margins) in 5 patients and Moh's micrographic resection in 2 patients. There have been no local recurrences or distant metastases, with a mean follow-up of 15.1 months. Pathological and clinical diagnostic criteria for the pediatric population are reviewed, and treatment options are discussed.

Chen, B., Liu, X., Savell, V.H., Dilday, B.R., Johnson, M.W., Jenkins, J.J., and Parham, D.M., Increased DNA methyltransferase expression in rhabdomyosarcomas. Int. J. Cancer,83, 10–14 (1999). Due to a printer's error, the bottom of Figure 3 was cut off after the proofs had been approved by the author. The correct figure and legend is reprinted below. The publisher regrets this error.