Metastatic peritoneal neurocutaneous melanocytosis.

Neurocutaneous melanosis, better referred to as neurocutaneous melanocytosis (NCM), is a rare congenital disorder occurring in childhood characterized by proliferation of melanocytes in the central nervous system (CNS), associated with large congenital melanocytic nevi. The phenotype of the CNS lesions varies, ranging from that of a benign, nevuslike lesion, to one of an aggressive-looking, atypical cell proliferation; however, specific diagnostic criteria allow the distinction from CNS metastasis of a primary skin melanoma. NCM can present with severe neurologic manifestations, and usually has a relentless clinical progression whence neurologic symptoms appear. Dissemination to the peritoneal surface by ventriculo-peritoneal shunting has been exceptionally observed, and we describe 2 cases of such occurrence, one of which was associated with a "bulky perineal nevocytoma" with complex cytogenetic rearrangements. This "metastatic" spreading supports an aggressive phenotype, able to seed and establish new colonies, although only after facilitated translocation of the proliferating cells through the shunt conduit; the aggressiveness of these lesions in our cases is further supported by the histopathologic features and clinical course. The biologic features of NCM cells merit further exploration, as they may shed light on a much more frequent neoplastic neurocristopathy, namely, malignant melanoma.

Analysis of vanillylmandelic acid and homovanillic acid by UPLC-MS/MS in serum for diagnostic testing for neuroblastoma.

BACKGROUND: Vanillylmandelic acid (VMA) and homovanillic acid (HVA) are typically measured in urine for the diagnosis and monitoring of neuroblastoma, a tumor in children <5 y. A protocol for evaluation of serum VMA and HVA has been utilized at our institution for approximately 25 y, originally validated using high performance liquid chromatography (HPLC) with an electrochemical detector. We recently validated a serum VMA/HVA method by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: After solvent extraction and clean up with Ultrafree centrifugal filters, samples were analyzed by UPLC-MS/MS in multiple reaction monitoring mode. RESULTS: The assay was linear between 2 and 1000 ng/ml for VMA and HVA. Within run and run to run CVs were <5% for VMA at all levels, <10% for HVA at high levels, and <20% at low levels. Correlation with the HPLC method was acceptable with a constant bias. The reference interval for VMA by UPLC-MS/MS was determined to be ≤20 ng/ml, and HVA≤30 ng/ml. Original patient data comparing urine to serum showed diagnostic agreement >80% for both VMA and HVA. CONCLUSION: Correlation of VMA and HVA was acceptable after adjustment of reference intervals. Collection of a single serum sample instead of 24-h urine collection saves time and improves accuracy of measurement due to difficulty of collecting a 24-h urine sample in infants and young children. UPLC-MS/MS also offers improved analyte specificity, improved signal to noise, and rapid analysis time.

J. Bruce Beckwith: physician scientist.

Throughout his career, Dr. J. Bruce Beckwith has set the standard as physician/pathologist. Beginning with formal clinical training in pediatrics, Dr. Beckwith honed his practice of pediatric pathology to meet the needs of patient, family, and practitioner, always using a careful and compassionate blend of diagnostic accuracy and clinical practicability. Dr. Beckwith's scientific contributions are legion and cover the diverse fields of congenital disease, forensic medicine, and neoplasia. Our fundamental understandings of in situ neuroblastoma, Beckwith-Wiedemann syndrome, sudden infant death syndrome, and Wilms tumor are all based on Dr. Beckwith's original observations and interpretations. But equal to his research has been his extraordinary ability to communicate with, console, and inspire people of all walks of life and all disciplines, from patients and their families to students and colleagues. With this passion, Dr. Beckwith has reached far beyond the artificial confines of the laboratory and, in so doing, has earned a rightful place in the annals of pathology, pediatrics, and, indeed, humanity.

Agenesis of the mesencephalon and metencephalon with cerebellar hypoplasia: putative mutation in the EN2 gene--report of 2 cases in early infancy.

Congenital absence of the midbrain and upper pons is a rare human malformation. We describe two unrelated infants with this anomaly and cerebellar hypoplasia who were born at term but died in early infancy from lack of central respiratory drive. MRI in both cases disclosed the lesions during life. Neuropathological examination, performed in one, included immunocytochemical studies of NeuN, synaptophysin, vimentin, and glial fibrillary acidic protein (GFAP). Autopsy revealed a thin midline cord passing through the clivus, in place of the midbrain; it corresponded to hypoplastic and fused corticospinal tracts with ectopic neural tissue in the surrounding leptomeninges. Some ectopia were immunoreactive for synaptophysin and NeuN and others were nonreactive. The neural surfaces facing the subarachnoid fluid-filled space left by the absent midbrain and upper pons were lined by an abnormal villous ependyma. The architecture of the cerebellar cortex was imperfect but generally normal, and Bergmann glial cells had normal radial processes shown by vimentin and GFAP. Structures of the telencephalon, diencephalon, lower brainstem, and spinal cord were generally well formed, but inferior olivary and dentate nuclei were rudimentary and the spinal central canal was dilated at lumbar levels. The cerebral cortex was normally laminated, but pyramidal neurons of layer 5 were sparse in the frontal lobes. The hippocampus, olfactory system, and corpus callosum were formed. An ectopic lingual thyroid was found and had been associated with hypothyroidism during life. A murine model resembling this dysgenesis is demonstrated by homozygous mutations of the organizer genes Wnt1 or En1, also resulting in cerebellar aplasia, and En2, associated with cerebellar hypoplasia. These genes are essential to the formation of the mesencephalic neuromere and rhombomere 1 (metencephalon or upper pons and cerebellum). Pax8 has binding sites in the promoter for En2 and is essential for thyroid development. We speculate that in the human, the failure to form a mesencephalon and metencephalon, with cerebellar hypoplasia, results from a mutation or deletion in the EN2 (Engrailed-2) gene.