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Objectives Paratesticular rhabdomyosarcoma accounts for 7-10% of genitourinary rhabdomyosarcoma tumors and is the 3rd most common after RMS of the prostate and bladder. Though most (60%–80%) patients with paratesticular rhabdomysarcoma present with localized disease, assessment of systemic disease is vital. The treatment of paratesticular rhabdomyosarcoma has evolved over several decades; the current standard of care is multimodal treatment including surgery, chemotherapy, and radiation. We give insight into the evolution of treatment, present the oncologic outcomes of seminal studies, and summarize the current recommendations for the management of these patients. Methods A comprehensive search of the literature on the electronic databases PubMed was conducted for management of paratesticular rhabdomyosarcoma. Case reports were excluded, clinical trials from all the oncologic society were reviewed and relevant articles are included in the review. Results The treatment regimen is based on following principles: (1) local control of the primary site with radical orchiectomy and (2) assessment of local control and distant sites. Further treatment is directed according to disease stage, histology, and age of the patient. The goal of treatment is to achieve cure or maximum tumor control while minimizing toxicity. Conclusions With the changing landscape in the management of paratesticular rhabomyosarcoma, significant improvement is evident in the oncologic outcomes. Further advance in genomic testing would lead us to tailor treatment based on individual risk factors and minimize long-term side effects.

Familial hyperparathyroid syndromes involving mutations of HRPT2 (also CDC73), a tumor suppressor, are important to identify because the relatively high incidence of parathyroid malignancy associated with such mutations warrants a specific surveillance strategy. However, there is a dearth of reports describing experience with surveillance and early detection informed by genetic insight into this disorder. Introduction: Familial isolated hyperparathyroidism (FIHP) is a rare cause of parathyroid (PT) tumors without other neoplasms or endocrinopathies. Germline mutations in CASR, MEN1, and rarely, HRPT2 have been identified in kindreds with FIHP. HRPT2 mutations may be enriched in FIHP families with PT carcinoma, underscoring the importance of identifying causative mutations. Materials and Methods: A 13-year-old boy, whose father had died of PT carcinoma, developed primary hyperparathyroidism. A left superior PT mass was identified by ultrasonography and removed surgically. Aggressive histological features of the boy's tumor included fibrous trabeculae, mitoses, and microscopic capsular infiltration. Two years later, under close biochemical surveillance, primary hyperparathyroidism recurred 5 months after documentation of normocalcemia and normal parathyroid status. Ultrasound and MRI identified a newly enlarged right superior PT gland but indicated no recurrent disease in the left neck. Histologic features typical of a benign adenoma were evident after surgical extirpation of the gland. Results: Leukocyte DNA analysis revealed a frameshift mutation in exon 2 of HRPT2. The initial tumor manifested the expected germline HRPT2 mutation, plus a distinct somatic frameshift mutation, consistent with the Knudson “two hit” concept of biallelic inactivation of a classic tumor suppressor gene. Genetic screening of the patient's 7 asymptomatic and previously normocalcemic siblings revealed three with the same germline HRPT2 mutation. One of the siblings newly identified as mutation-positive was noted to be hypercalcemic at the time of the genetic screening. He was found to have a PT adenoma with aggressive features. Two of the five children of another mutation-positive sibling also carry the same HRPT2 mutation. Conclusions: Despite the reported rarity of HRPT2 mutations in FIHP, a personal or family history of PT carcinoma in FIHP mandates serious consideration of germline HRPT2 mutation status. This information can be used in diagnostic and management considerations, leading to early detection and removal of potentially malignant parathyroid tumors.

NRAS and BRAF mutations occur in congenital melanocytic nevi (CMN), but results are contradictory. Sixty-six prospectively collected CMN patients were analyzed for NRAS Q61 mutations using Sanger sequencing. Negative cases were evaluated for BRAF V600E mutation. NRAS Q61 mutations affected 51 patients (77.3%), and BRAF V600E was found in 5 (7.6%). NRAS Q61 mutation affected 29 (80.6%) of 36 giant, 16 (80.0%) of 20 large, and 5 (62.5%) of 8 medium-size CMN; BRAF mutation affected 1 (5%) of 20 large and 4 (11.4%) of 36 giant CMN. Compared to NRAS, BRAF-mutated nevi show scattered/extensive dermal and subcutaneous nodules (100% BRAF+ vs 34.8% NRAS+) ( P = 0.002). Neurocutaneous melanocytosis (NCM) affected 16 (24.2%) of 66 patients, with NRAS Q61 mutation in 12 (75.0%), and BRAF V600E in 2 (12.5%), P = 0.009. Two patients were negative for both mutations (12.5%). In conclusion, although NRAS Q61 mutations predominate, BRAF V600E mutation also affects patients with large/giant CMN (L/GCMN), and with NCM, a novel finding. BRAF V600E is also associated with increased dermal/subcutaneous nodules. These findings open the possibility of BRAF-targeted therapy in some L/GCMN and NCM cases.

Spindle epithelial tumor with thymus-like elements is a rare thyroid lesion of children and young adults thought to be derived from branchial pouch remnants or foci of ectopic thymus. The lesion is poorly understood, and although it was originally believed to follow an indolent clinical course, its potential for late metastasis is becoming generally acknowledged. We have recently seen a unique case of this rare tumor in an 11-year-old boy, in which an unexpected and salient feature is the presence of a micrometastasis in a single lymph node at presentation. With the exception of 1 case with extensively infiltrative tumor and metastatic disease at the time of onset, in all other cases dissemination occurred years after surgical resection of the primary lesion. We review all previously reported cases and provide a detailed study of the histologic and ultrastructural appearances of this lesion.

We describe a 3-year-old girl with intractable, debilitating pruritus associated with a giant congenital melanocytic nevus, resulting in life-threatening anemia from extensive bleeding skin excoriations. Multiple conventional oral and topical antipruritic medications failed to provide relief, but the patient was successfully treated with the selective serotonin 5-hydroxytryptamine type 3 inhibitor ondansetron, suggesting a serotonin-related mechanism to her pruritus.

Six cases are reported of an osteoclast-rich tumor of the gastrointestinal tract that should be segregated from GIST. Five of the cases were located in the small bowel and one in the stomach. The age of the patients ranged from 13 to 37 years. The tumors behaved aggressively, with metastases to regional lymph nodes, liver, and other intraabdominal sites. Microscopically, the tumor cells were medium-sized, predominantly oval, relatively monomorphic, diffusely immunoreactive for S-100-protein, and negative for CD1 17, CD34, HMB-45, and Mart-i. They were admixed with scattered osteoclast-like, multinucleated giant cells which were S-100-protein negative and KPIpositive. One case studied cytogenetically had the karyotype 46XX t(I2;22)(qI3;q12). The cases here reported are interpreted as examples ofa distinctive type of gastrointestinal neoplasm which shares somefeatures with clear cell sarcoma of soft parts (melanoma of soft parts), including in one case the chromosomal translocation that is characteristically associated with that entity.

Overproduction of catecholamines (dopamine [DA], norepinephrine [NE]) and their metabolites (homovanillic [HVA] and vanillylmandelic [VMA] acids) characterizes neuroblastoma (NB). In previous studies, increased urinary DA/NE, and DA/VMA ratios have been associated with poor prognosis, whereas low DA/NE ratios have been associated with longer disease-free survival. Higher urinary VMA, HVA, and NE levels have been found in association with low MYCN amplification, in contrast to cases with high MYCN amplification in which normal levels have been found. It is then believed that an "immature" catecholamine pattern indicates poor prognosis. We correlated urinary DA, NE, VMA, and HVA levels with age, clinical tumor stage, histological features (favorable [FH]/unfavorable [UH]) and MYCN status of 33 patients with NB. DA/VMA and DA/HVA ratios were also calculated. Wilcoxon rank sum and chi-squared tests were performed to determine statistical significance. Eighty-eight percent (15/17) of stage 3-4 cases had DA levels2 times the upper limit of normal, but only 8% (1/12) of stage 1-2 cases had DA levels twice the upper limit of normal. In 61% (11/18) of stage 3-4 cases, the VMA level was10 times the upper limit of normal, in contrast to stage 1-2 cases, in which only one patient (1/15) had a VMA level10 times the upper limit of normal. Similar findings were obtained with urinary HVA and NE. Patients older than 12 months of age at diagnosis also had higher urinary levels of DA, VMA, HVA, and NE than those of patients younger than 12 months of age at diagnosis. Eighty-two percent (14/17) of stage 3-4 cases had DA/VMA ratios0.78, with the other 18% (3/17) showing ratios between 1.4 and 8.82 (all stage 4 and12 months of age). In contrast, all stage 1-2 cases ((12)) had ratios1.4. All (12/12) non- MYCN-amplified cases had DA/VMA ratios1.4 (0.06-0.84), while one MYCN-amplified case (1/3) had a ratio of 8.82; the other two MYCN-amplified cases had DA/VMA ratios of 0.09-0.11. Twenty-nine percent (2/7) of cases with UH had a DA/VMA ratio1.4, but in all FH cases (14/14) the DA/VMA ratio was1.4 (0.08-0.084). Similar to previous studies, we found that aggressive NB is associated with higher urinary levels of DA, VMA, HVA, and NE. We also confirmed the previous observation that there appears to be a subset of NB in which a possible blockade in DA metabolism is associated with poor prognostic features (12 months, stage 4, UH, and MYCN amplification). A seemingly novel observation in our study is that all high DA/HVA and DA/VMA ratios were obtained in stage 4 tumors, suggesting an association between the inability to metabolize DA and the acquisition of metastatic potential. On the basis of our results, we would like to emphasize the importance of determining not only DA, HVA, and VMA urinary levels, to support the diagnosis of NB, but also DA/HVA and DA/VMA ratios as a rapid initial assessment of prognosis in these patients.

Background: Late survival after pediatric heart transplantation (HTx) remains poor. Many late deaths are due to “graft failure,” typically in the presence of vasculopathy and diffuse myocardial fibrosis (DMF) - a process associated with ventricular remodeling and heart failure (HF). Cardiovascular magnetic resonance (CMR)-derived extracellular volume (ECV) is a validated measure of DMF in the absence of edema or infiltrative disease, and predicts outcomes of HF and mortality in adults. We hypothesize that ECV is a meaningful biomarker of graft dysfunction following pediatric HTx. Objective: To test the association of ECV with histologic myocardial fibrosis after pediatric HTx. We also explored associations of ECV with hemodynamic, echocardiographic, and serum measures of graft function. Methods: We prospectively enrolled consecutive HTx recipients who were ≥13 years old and ≥9 months post HTx for ECV quantification at the time of surveillance endomyocardial biopsy (EMB). Fibrosis was quantified on EMB by automated image analysis after picrosirius staining and digital scanning. CMR measures of blood and myocardial T1 from basal and mid short axis slices, along with contemporaneous hematocrit, quantified ECV. Results: Nineteen pts (12 male) underwent CMR at a mean age of 18.4 ± 2.8 yrs (range 14.9 - 24.4 yrs) and a mean time after HTx of 10.4 ± 6.6 yrs (1.0 - 20.7 yrs). Four pts were excluded from analysis due to acute rejection (ISHLT grade ≥2R) on concurrent EMB (n=2) or poor quality imaging (n=2). Mean ECV was 27.1 ± 3.8 (20.9 - 32.1). Late gadolinium enhancement was observed in 1 pt. ECV showed moderate correlations with histologic myocardial fibrosis (r=0.61; p=0.02) and serum b-type natriuretic peptide (r=0.66; p=0.008). There was a trend to correlation with pulmonary capillary wedge pressure (r=0.51; p=0.06). We found no associations of ECV with systolic or diastolic function, time after HTx, or graft age. Conclusions: We demonstrate a novel association of ECV with histologic myocardial fibrosis and serum and hemodynamic markers of HF after pediatric HTx. Given prior observations of myocardial fibrosis in chronic graft failure, these findings suggest that ECV may be a relevant, noninvasive marker of graft dysfunction and a potential therapeutic target.

Pediatric tumors are heterogenous and can be quite varied in appearance. However, those in the infamous "small round blue-cell tumor" group, with their hyperchromatic nuclei and small amount of cytoplasm can be challenging, and their diagnosis and prognostication require cost-efficient and focused immunohistochemistry and ancillary testing. Ideally, ample material should be obtained for routine histology and ancillary testing, including immunohistochemistry, fluorescent in situ hybridization, fresh tissue for cytogenetic studies, and snap-frozen tumor for DNA/RNA extraction both for routine molecular testing (ie, reverse-transcription PCR studies), as well as future research study protocols (genome wide studies, targeted gene sequencing). This review focuses on the main pediatric tumors with emphasis on immunophenotype, keeping in mind that a directed panel approach yields the highest yield with combination of clinical history, histologic features, and ancillary molecular testing.

Primary skin malignancies are uncommon in children, and both benign and metastatic tumors surpass them in frequency. However, the resulting low index of suspicion may lead to a delay in diagnosis and treatment. Underlying factors associated with skin malignancies in children include giant congenital melanocytic nevi, xeroderma pigmentosum, albinism, Gorlin syndrome, immunodeficiency disorders, radiotherapy, and bone marrow and solid organ transplantation, among others [1–3].

A 14-year-old male with familial hypophosphatemic rickets, being treated with oral phosphate and calcitriol therapy, presented to the Division of Pediatric Dentistry, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pa. A panoramic radiograph showed multifocal, multilocular lesions in the mandible leading to surgical exploration and biopsy. Histopathological evaluation of the largest lesion showed features consistent with central giant cell granuloma. Given the patient's history, hyperparathyroidism was suspected. Laboratory data showed an elevated parathyroid hormone of 152 pg/ml (normal range equals nine to 69). This confirmed the diagnosis of multiple brown tumors in the mandible associated with secondary hyperparathyroidism, which was attributed to high-dose phosphate treatment. After endocrinology consultation, calcitriol therapy was increased. Improvement of the patient's brown tumors is expected with medical therapy. The purpose of this case report was to raise awareness among pediatric dentists about the maxillofacial ramifications of secondary hyperparathyroidism.

Actinomyces is a rare pathogen that can be the cause of infections in the digestive and urinary tracts, skin, genitalia, and lungs, which generally have an indolent clinical course. However, in some cases these can be locally destructive and become generalized infections. Actinomyces has been previously implicated in infections of the middle ear, nasopharynx, and sinuses, occasionally causing complications such as chronic mastoiditis. Here we describe the case of a 10-year-old-male presenting with nausea, vomiting, and headache who developed intracranial complications of actinomycotic mastoiditis.

Perspectives in Pediatric Pathology, Chapter 1. Normal Development of Testicular Structures: From the Bipotential Gonad to the Fetal Testis MANUEL NISTAL, RICARDO PANIAGUA, PILAR GONZALEZ-PERAMATO, AND MIGUEL REYES-MUGICA Pathology, Hospital La Paz, Universidad Autonoma de Madrid, Calle Arzobispo Morcillo #2, Madrid 28029, Spain Department of Cell Biology, Universidad de Alcala, Madrid, Spain Department of Pathology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224

Varicocele is characterized by elongation, dilatation, and tortuosity of the veins draining the testis and its covers, causing circulatory reflux along the inner spermatic vein [ 1 ]. Varicocele results in progressive testicular lesions and, if untreated, can lead to testicular atrophy [ 2 ]. Varicocele is considered the most frequently identified cause of male infertility [ 3 ]. The mechanisms involved in varicocele formation are not well known and probably are multiple, differing from one patient to another.

One of the most challenging areas in pediatric testicular pathology is the appropriate understanding and pathological diagnosis of disorders of sexual development (DSD), and in particular, the issue of gonadal dysgenesis. Here we present the main concepts necessary for their understanding and appropriate classification, with extensive genetic correlations.

Perspectives in Pediatric Pathology, Chapter 3. Testicular Development from Birth to Puberty: Systematic Evaluation of the Prepubertal Testis MANUEL NISTAL, RICARDO PANIAGUA, PILAR GONZALEZ-PERAMATO, AND MIGUEL REYES-MUGICA Department of Pathology, Hospital La Paz, Universidad Autonoma de Madrid, Calle Arzobispo Morcillo #2, Madrid 28029, Spain Department of Cell Biology, Universidad de Alcala, Madrid, Spain Department of Pathology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA

Patients with Fanconi anemia subgroup D1, attributable to biallelic mutations in BRCA2, have an increased risk of solid tumors. Tumors in the kidneys of these patients are almost exclusively Wilms tumor. We report the first recorded case, to our knowledge, of a Clear Cell Sarcoma of the Kidney in a patient with this cancer predisposition syndrome. We review different aspects of the need for careful clinical observation in patients of this complementation group, given their risk for malignancy.

Embryonic signaling pathways, in particular those mediated by Wnt and TGF-β, are known to play key roles in tumor progression through the induction of epithelial–mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-β–associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-β pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-β–mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence. Mol Cancer Ther; 13(6); 1457–67. ©2014 AACR.

Nevocytes (NC) and mastocytes (MC) have different progenitors but share stem cell factor as regulator/activator of NC and for differentiation/proliferation of MC. Both cell types express stem cell factor receptor CD117. We hypothesize that large/giant congenital melanocytic nevi (L/GCMN) may associate with MC hyperplasia. Forty-nine L/GCMN were examined, 12 samples from uninvolved skin of L/GCMN patients and 6 control skin samples studied with Giemsa and immunohistochemistry for CD117 and MC-tryptase. Picrosirius red (PR) was used to assess fibrosis. Digital images were used to count MC/mm2 using ImageJ software. Western blot (WB) for MC-tryptase in 12 GCMN and 12 non-nevus samples was performed. Analysis of variance (Tukey) and Pearson statistical tests were applied. Increased MCs were observed in nevus tissue (75.1 ± 35.3 MCs/mm2) and in uninvolved skin (53.74 ± 27.7 MC/ mm2). P = 0.109 from patients with L/GCMN, compared with controls from individuals without L/GCMN (28.74 ± 8.4 MC/mm2); P = 0.001 supported by results of WB analysis for tryptase. A positive trend toward correlation of MC numbers with fibrosis, assessed by PR staining fell short of statistical significance ( r = 0.245; P = 0.086); no difference in fibrosis was found between nevus and non-nevus skin from patients with L/GCMN ( P = 0.136). We found a higher density of MC, both in normal-appearing skin and nevus areas of L/GCMN patients, compared with control skin samples from individuals without nevi. Given the abnormal wound healing and allergic reactions described in L/GCMN patients, these findings suggest a potential role for MC in the biology of L/GCMN, making them a potential target for therapeutic intervention.

The triad of small body size, immunodeficiency, and sun-sensitive facial erythema characterizes the phenotype Bloom syndrome (BS), a rare autosomal recessive disorder with a striking predisposition to multiple types of cancers that arise earlier than expected in the general population. Here we report two sibs with BS. The older, a 15-year-old-girl, developed a hepatocellular carcinoma, a neoplasm not yet reported in association with BS. Her younger brother developed an anaplastic Wilms tumor (WT) associated with nephrogenic rests at the age of 31/2 years, and this was followed by a myelodysplastic syndrome. Complex cytogenetic abnormalities were identified in all three neoplasms. These examples expand the spectrum of malignancies occurring in BS to include liver cell neoplasms, and confirm the association of nephrogenic rests with WT, even in the setting of BS.

The deleted in colorectal cancer (DCC) protein is important in the pathway guidance of cells and cell processes during neural development, and DCC has also been implicated in the aberrant cellular migrations of neuroblastoma dissemination. We attempted to further define DCC protein function by the overexpression of full-length and truncated DCC constructs in a human neuroblastoma cell line. Overexpression of the truncated DCC protein resulted in a less epithelioid morphology. This was accompanied by decreases in expression of N-cadherin and alpha- and beta-catenin by immunoblot and Northern blot analysis. Levels of desmoglein were relatively less affected, whereas endogenous DCC protein levels were increased in the truncated transfectants. N-cadherin immunofluorescence was consistent with the immunoblot studies and localized the protein to the cytoplasm and sites of cell-cell contact. Cell aggregation studies demonstrated diminished calcium-dependent aggregation in the truncated transfectants. In conclusion, overexpression of a truncated DCC protein in neuroblastoma cells resulted in the loss of an epithelioid morphology, diminished expression of N-cadherin and alpha- and beta-catenin, and diminished calcium-dependent cell adhesion. These studies provide the first evidence of an apparent functional link between DCC and N-cadherin/catenin-dependent cell adhesion.

We report a 19-year-old man with pulmonary squamous cell carcinoma (SCC) who had a history of vertebral, anal, cardiac, tracheal, esophageal, renal, and radial limb defects (VACTERL) association and tracheoesophageal fistula (TEF) + esophageal atresia (EA) repair as an infant. Children that undergo TEF + EA repair may have an increased risk for developing cancer as they reach adulthood.

How radiologists meet and care for neonates with mass lesions of the chest has changed. Formerly, infants with respiratory distress and no diagnosis presented for emergent imaging for the clinician to make a diagnosis and formulate a treatment plan. Widespread use of prenatal ultrasound (US) screening has resulted in the identification of many of these infants in utero with a prenatally determined presumptive diagnosis and a perinatal care strategy. Depending on the style and system of prenatal and perinatal care, imaging may be performed by obstetricians, general radiologists, or pediatric radiologists in women's and infant's institutions. The mainstay of prenatal imaging remains US, but research continues into the use of MR imaging in certain circumstances. Without imaging, some of the fetuses have no clinical signs to lead to their diagnoses. Others may show maternal polyhydramnios as evidence of their masses by creating esophageal impairment to normal amniotic fluid pathways. Once diagnosed, the coexisting finding of a mediastinal shift serves as a warning to pay very close attention in follow-up, because all authorities currently seem to agree that once the mediastinum is so shifted as to impair venous return to the fetal chest, to create a state of low cardiac output, and to result in a hydropic fetus, viability is severely threatened. 1 Some mothers become ill in association with their threatened fetuses, a preeclamptic state referred to as the maternal mirror syndrome . 8 Despite even heroic and curative fetal surgery, maternal symptoms may inexorably progress, mandating that the child be emergently delivered. Some researchers believe that the placenta may release a causative factor responsible for the mirror syndrome. 20

The gross and microscopic findings from 2 fatal cases of plastic bronchitis (PB) in children, a rare entity characterized by the formation of large mucous casts in the bronchial tree, are presented. These casts differ from ordinary mucus because of their increased cohesiveness and consistency, resulting in solid structures that model the respiratory airway tree. PB usually presents as a complication of underlying diseases, which determine the prognosis of the afflicted patients. Conditions commonly associated with PB include congenital cardiopathies, lymph vessel malformations, asthma, and sickle cell disease. The first case is a typical example of PB following surgical treatment of a cyanotic cardiopathy, with very characteristic and illustrative morphology. The second case describes the fatal course of PB in a patient with sickle cell disease, which has never been reported to the best of the authors' knowledge; in this case, an overlooked association with asthma could have contributed to the fatal outcome.

We report on three brothers with renal tubular dysgenesis and absent nipples, each also had other malformations including pre-auricular pits and a preauricular tag, branchial clefts, choanal atresia, pulmonary lobation anomaly, ventricular septal defect, type IIB interrupted aortic arch, absent gallbladder, absent thymus, parathyroid gland, accessory spleen, imperforate anus, clinodactyly, and broad digits and small nails. All three infants died neonatally. This pattern of clinical malformations appears to be a previously unreported syndrome.

Objective: Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration. Study design: We analyzed 27 cases representing five FAO disorders and compared the results with those obtained in a retrospective blinded analysis of 418 cases of sudden infant death (313 SIDS, 45 infections, and 34 accidents and abuse). Results: All cases of accidents and abuse correctly tested negative. Among the others, 25 (6%) showed at least two abnormal findings. Of these, 14 closely matched the biochemical profiles seen in specific FAO disorders. These included 2 cases with medium-chain acyl-CoA dehydrogenase deficiency, 4 cases consistent with glutaric acidemia type 2, 4 cases with either very long-chain acyl-coenzyme A dehydrogenase deficiency or long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency, and 4 cases predicted to be affected with carnitine uptake defect. Conclusion: The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an FAO disorder. (J Pediatr 1998;132:924-33.)

A girl 5 years 11 months of age, belonging to an extensive kindred with multiple endocrine neoplasia, type IIA (MEN IIA), was found to have multifocal medullary thyroid carcinoma with metastasis in one paraglandular lymph node after positive findings on a calcium-pentagastrin stimulation test. Her sister, 3 years 8 months of age, also had an elevated calcitonin level, and thyroidectomy revealed C-cell hyperplasia and a focus of medullary thyroid carcinoma. These two cases underscore the need for prophylactic thyroidectomies in MEN IIA patients as young as 5 years of age and strict yearly provocative screening beginning at age 1 year.

Large and giant congenital melanocytic nevi (CMN) are the rarest types of a proliferative malformation affecting the pigment cells of the skin. The phenotypic presentation is highly variable, and few reports of familial transmission exist. Current models favor a somatic mutational event occurring during at or after the end of the first trimester of gestation, within the melanocyte precursor lineage, in a predisposing genetic background. The effect of potentially implicated signaling molecules on progenitor neural crest and derivative melanocyte development is discussed. Candidates include effectors such as NRAS and BRAF of the MAP kinase pathway but also other pathways that converge on transcription factors critical for either multipotent precursor maintenance or melanocyte differentiation and which may predispose cells to inappropriate proliferation in the central nervous system or at other sites. These associated proliferations can lead in a patient-dependent manner to a clinically favorable or fatal outcome. Continued exploration of the molecular bases of large and giant CMN development will lead to new tools for more accurate prognoses in both isolated and syndromic forms.

A retrospective analysis of the medical records of 234 children with renal tumors managed over a 25-year period at the Children's Memorial Medical Center was undertaken to evaluate long-term morbidity and mortality. There was a significant increase in survival over the years of the study. The 5-year survival for patients treated during the period 1985 to 1989 was 94% versus 68% for the period 1965 to 1969. Thirty-three children have died, 15 with known disease progression. Long-term morbidity included scoliosis (39), cardiorespiratory insufficiency (13), hypertension (7), renal insufficiency (7), small bowel obstruction (10), chest wall deformity (3), amenorrhea (1), leg length discrepancy (1), and 1 patient with an esophageal stricture. One patient with cardiomyopathy secondary to adriamycin has recently undergone cardiac transplantation. Five patients with renal insufficiency have required dialysis. Of these five, one patient has had two renal transplants. The presence of distant metastases and positive hilar or regional lymph nodes were the only findings at operation that were associated with an increased mortality (P = .005). There was a significantly increased mortality in those children operated on by general surgeons or urologists at other hospitals (11/43) versus those operated upon at our hospital (22/191) (P = .033). There was no statistical difference in the staging or histology among these children. We feel that the careful and systematic approach of a radical nephrectomy assures accurate staging of the tumor removing gross and microscopic disease in the abdomen.

BACKGROUND: Although the literature reports a low incidence of Burkitt lymphoma (BL) as a post-transplant lymphoproliferative disorder (PTLD), this entity appears to be different from other monomorphic PTLDs (M-PTLDs), both in its aggressive clinical presentation and its distinct pathologic profile. METHODS: Patients with BL, diagnosed in the post-transplant setting, (patients aged ≤18 years) were retrieved from the pathology archives at Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center from 1982 to 2010. Clinical outcomes were obtained along with pathologic review. RESULTS: Twelve patients with pediatric BL in the post-transplant setting (9 boys, 3 girls) were retrieved. The patients displayed a monomorphic population of small to intermediate-sized, noncleaved, lymphoid elements with a “starry-sky” pattern. The immunophenotype for patients available to the study was CD20+ (n = 9/10), CD10+ (n = 8/8), bcl-6+ (n = 11/11), with a near 100% Ki-67/MIB-1 proliferation index (n = 7/7), and negative for TdT (n = 7/7). Most pretransplant Epstein-Barr virus titers were negative (n = 8/10), with post-transplant titers positive in all tested patients (n = 11), and with positive Epstein-Barr–encoded RNA in situ hybridization in most cases (n = 9/11). The median time from transplantation to diagnosis was 52 months (range, 6-107 months). Nine patients were currently alive after immediate antineoplastic chemotherapy, with median disease-free time of 93 months from diagnosis (range, 2-199 months). CONCLUSIONS: BL-PTLD had a higher Epstein-Barr virus incidence compared with sporadic and immunodeficiency-associated BL and represented a distinct monomorphic PTLD. Although some M-PTLDs can be managed less aggressively with decreased immunosuppression alone, immediate lymphoma-specific chemotherapy was associated with a favorable outcome and was strongly recommended. Cancer 2011;. © 2011 American Cancer Society.

We report a 19-year-old man with pulmonary squamous cell carcinoma (SCC) who had a history of vertebral, anal, cardiac, tracheal, esophageal, renal, and radial limb defects (VACTERL) association and tracheoesophageal fistula (TEF) + esophageal atresia (EA) repair as an infant. Children that undergo TEF + EA repair may have an increased risk for developing cancer as they reach adulthood.

We describe two instances of a previously unrecognized variant of congenital giant pigmented naevus (GPN), presenting as a bulky naevocytic tumour in the perineal region. In both cases the lesion was present at birth and attained massive dimensions. In addition to the characteristic histological patterns found in GPN, which included extensive areas with a neural appearance, these tumours presented an uncommon tendency to form pseudo-follicular structures lined by naevus cells. No features suggestive of malignant transformation were found. Because GPN may associate with an underlying malignancy, accurate diagnosis of this lesion is important in clinical practice.

✓ A case of meningeal fibroma in a 5-year-old girl is described. The lesion presented as a benign intracranial tumor, eroding the frontal bone and protruding under the skin. It was composed of fibroblasts and collagen, embedded in a loose background with focal myxoid changes. The authors describe the patient's clinical presentation and the tumor's histological, immunohistochemical, and ultrastructural features, and discuss its differential diagnosis. It is concluded that fibromas of the meninges should be distinguished from fibroblastic meningiomas.

Fatty liver is increasingly common in obese adolescents. We determined its association with glucose dysregulation in 118 (37M/81F) obese adolescents of similar age and percent total fat. Fast-magnetic resonance imaging (MRI) and simple MRI were used to quantify hepatic fat content and abdominal fat distribution. All subjects had a standard oral glucose tolerance test. Insulin sensitivity was estimated by the Matsuda Index and homeostasis model assessment of insulin resistance. Baseline total and high molecular weight (HMW)-adiponectin and interleukin (IL)-6 levels were measured. The cohort was stratified according to tertiles of hepatic fat content. Whereas age and %fat were comparable across tertiles, ethnicity differed in that fewer Blacks and more Whites and Hispanics were in the moderate and high category of hepatic fat fraction (HFF). Visceral and the visceral-to-subcutaneous fat ratio increased and insulin sensitivity decreased across tertiles. Two-hour plasma glucose rose with increasing hepatic steatosis (P < 0.008). 73.7% of the subjects in the high HFF had the metabolic syndrome compared to 19.5% and 30.6%, respectively, in the low and moderate categories. Both total and HMW-adiponectin decreased, and IL-6 increased with increasing hepatic steatosis. Conclusion: In obese adolescents, independent of total fat, increasing severity of fatty liver is associated with glucose dysregulation, metabolic syndrome, and with a proinflammatory milieu. (HEPATOLOGY 2009.)

Sclerosing stromal tumors are an uncommon type of benign ovarian sex cord-stromal tumor. Histologically, they are characterized by a cellular pseudolobular pattern, composed of fibroblasts and round cells separated by densely collagenous or markedly edematous hypocellular tissue and prominent vascularity. Although the usual age of presentation is in the 2nd and 3rd decades, sclerosing stromal tumor can occur in adolescence or premenarchal girls. Clinical symptoms include premature menarche, menstrual irregularities, abdominal discomfort, and rarely, ascites. Imaging studies frequently reveal solid or complex cystic adnexal masses with marked vascularity raising concern for germ cell tumors and, especially in the absence of elevated tumor markers, surface epithelial neoplasms. The differential diagnosis of a benign sclerosing stromal tumor is seldom entertained. We present the clinicopathological findings in 4 adolescent patients, presenting with unilateral adnexal masses, in which the preoperative clinical suspicion for malignancy was very high. We stress the importance of being familiar with sclerosing stromal tumors when evaluating ovarian neoplasms in children and adolescents in order to contribute to the appropriate clinical management preventing extensive and unnecessary surgery, and preserving fertility.

A term infant was born with respiratory distress, and subsequent imaging, histopathologic, and hormonal studies confirmed congenital hypothyroidism. This report is intended to alert pediatricians to the possibility of congenital hypothyroidism as a cause of respiratory symptoms of unknown cause in neonates with respiratory distress.