A comparative analysis of RAS variants in patients with disorders of somatic mosaicism.

PURPOSE: RAS genes (HRAS, KRAS, and NRAS) are commonly found to be mutated in cancers, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the mutational spectrum of RAS variants in DoSM has not been performed. METHODS: A total of 938 individuals with suspected DoSM underwent high-sensitivity clinical next-generation sequencing-based testing. We investigated the mutational spectrum and genotype-phenotype associations of mosaic RAS variants. RESULTS: In this article, we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority of RAS variants observed in DoSM. Furthermore, we present 12 individuals with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain. Among the 18.3% individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular malformations. Hotspots were associated with a broad phenotypic spectrum, including vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth, digital anomalies, and combinations of these. The median age at testing was higher and the variant allelic fraction was lower in individuals with in-frame dup/ins variants than those in individuals with mosaic RAS hotspots. CONCLUSION: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.

Facial Nerve Meningioma: A Cause of Pediatric Facial Weakness.

OBJECTIVE: To present an unusual case of a temporal bone meningioma with intrafascicular spread throughout the temporal facial nerve from cerebellopontine angle (CPA) to stylomastoid foramen. PATIENT: Four-year-old female with progressive facial weakness and normal hearing. MAIN OUTCOME MEASURE: Clinical, radiological, and histopathological findings of temporal bone meningiomas. RESULTS: A patient presented with progressive facial weakness and normal hearing. Imaging demonstrated a mass within the left internal auditory canal radiologically consistent with a schwannoma. Asymmetric enlargement with enhancement of the left facial nerve from CPA to the stylomastoid foramen suggested facial schwannoma. At surgery, gross tumor was noted in the internal auditory canal, the fallopian canal seemed expanded and the facial nerve was enlarged and had an irregular contour. Resection of the facial nerve from the CPA to just proximal to its exit at the stylomastoid foramen was necessary to achieve negative margins. Cable grafting was performed. The histopathologic diagnosis was transitional meningioma with intraneural growth throughout the length of the resected facial nerve segment. CONCLUSION: Meningiomas involving the temporal bone are exceedingly rare. We report a rare case of a child presenting with progressive facial weakness due to a presumed facial schwannoma spreading along the facial nerve throughout its intratemporal course that at surgery was found to be an intrafascicular CN VII meningioma.

Ectomesenchymoma with embryonal rhabdomyosarcoma and ganglioneuroma, arising in association with benign triton tumor of the tongue.

Soft-tissue tumors known as "triton" tumors are rare lesions containing neural tissue and skeletal muscle at varying levels of maturity and malignant potential. Benign triton tumors, also called "neuromuscular choristomas" or "neuromuscular hamartomas," consist of neural tissue containing mature skeletal muscle in intimate relationship with peripheral nerve. These tumors are rare in the head and neck in children. Ectomesenchymomas are similar tumors consisting of a malignant mesenchymal component, usually embryonal rhabdomyosarcoma, and a neuroectodermal component represented by mature ganglion cells or primitive neuroblastic/neuroectodermal foci (primitive ectomesenchymoma). Benign triton tumors have been regarded as benign, whereas ectomesenchymomas have been operationally considered to be variants of rhabdomyosarcoma. We present here a unique case that combines features of these 2 entities in a recurrent lesion on the tongue of a 35-month-old girl. This lesion raises questions about the "benign" nature of benign triton tumor and its possible relationship to ectomesenchymoma.

Intestinal spirochetosis in children: five new cases and a 20-year review of the literature.

Intestinal spirochetosis (IS) is an unusual infection in children, one with no standard therapeutic options. This article reports the findings on 5 new cases in conjunction with a 20-year review of the pediatric literature. The diagnosis of IS in children requires a high degree of suspicion by the physician, as many cases present with abdominal pain, chronic diarrhea, and/or hematochezia associated with a normal endoscopic examination. Silver stains (Dieterle or Whartin-Starry) are the preferred confirmatory stains on tissue sections. Giemsa (Diff-Quik) and periodic acid-Schiff stains may also be of value. Current literature favors the use of metronidazole in adult patients with IS, yet little information is available regarding treatment options in pediatric cases. This review indicates that a macrolide antibiotic with or without metronidazole may represent the best therapeutic choice for children. Further investigations are needed to determine the correlation between IS and coexisting gastrointestinal diseases and/or immunodeficiencies.

The value of positron emission tomography and proliferation index in predicting progression in low-grade astrocytomas of childhood.

Astrocytomas are the most common brain tumors of childhood and adolescence. Low-grade astrocytomas (LGAs), in general, have favorable prognosis, but recurrence or progressive disease with dissemination, malignant transformation, and death occur in some cases. Current clinical and pathological measures including age, sex, imaging characteristics, location and size of the tumor, histopathology, and degree of resection cannot predict with certainty which tumors will demonstrate aggressive behavior. The objective of the study is to determine the predictive value of positron emission tomography (PET) and a proliferation index (PI) in identifying high risk LGAs. We reviewed 46 cases ages 5 months to 17 years with low-grade (WHO I-II) astrocytomas. All patients had PET scans utilizing [(18)F] fluorodeoxyglucose (FDG) and 24 cases had measurements with Ki-67/MIB-1 immunohistochemistry. Review of our data confirmed progressive disease (PD) in 18/46 (39%) of cases with 9/21 (42%) occurring after subtotal resection and 9/25 (36%) after gross total resection. The mortality rate was 5/46 (10.8%). Tumors with FDG hypermetabolism were significantly more likely to demonstrate aggressive behavior and PD. Increased PI values also suggested PD. Progression-free survival and time to progression were significantly longer for patients with hypometabolic scans. Time to progression was significantly longer with lower PI values. Results demonstrate that PET and PI are useful measures in the identification and stratification of high risk LGAs. The ability to identify a subset of progressive LGAs earlier may suggest the need for second-look neurosurgical procedures or more intensified adjuvant treatment that may ultimately improve outcome and survival.

Endolymphatic sac tumor in a 4-year-old boy.

INTRODUCTION: Endolymphatic sac tumors (ELST) are rare, low-grade, locally aggressive papillary neoplasms. We present a case of a 4-year-old boy with an ELST, the youngest described in the literature. CASE: A boy presented with a right-sided serous otitis media and sudden-onset right facial nerve palsy. An audiogram revealed right-sided profound sensorineural hearing loss. Radiographic imaging demonstrated a 3-cm expansile lytic lesion along the posterior face of the petrous bone. INTERVENTION/RESULTS: The patient initially underwent a right transmastoid-infralabyrinthine biopsy. Pathologic examination revealed a papillary lesion suspicious for an ELST. Subsequently, a transtemporal-transcochlear approach with intra-and extradural resection of the tumor was performed. The facial nerve was dissected and transposed anteriorly and preserved. Histopathologic and immunohistochemical studies confirmed the ELST. At his 6-month follow up, there is no evidence of recurrence and the facial nerve function has returned to Grade II palsy. CONCLUSION: ELST are rare tumors of the temporal bone. This is the youngest case of ELST reported. Presentation, evaluation, and management of ELST is discussed.

Langerhans cell histiocytosis: a primary viral infection of bone? Human herpes virus 6 latent protein detected in lymphocytes from tissue of children.

To better understand the etiology of Langerhans cell histiocytosis (LCH), the authors analyzed tissue from 35 children diagnosed with LCH for the presence of viral proteins and DNA by immunohistochemistry (IHC) and in situ hybridization (ISH). Eighteen control biopsies were obtained from patients without LCH. Confirmatory ISH was randomly performed on four positive and two negative cases determined by IHC. Twenty-five (71.4%) tissue samples with LCH involvement stained by IHC with the 101-kDa antibody against human herpesvirus-6 (HHV-6). None were positive with antibodies against the p41/38 or gp110 viral proteins. Five (27.7%) positive control tissues demonstrated presence of the 101-kDa viral protein in a similar fashion. The difference in the prevalence of HHV-6 in LCH-positive tissues (25/35) when compared with control tissues from patients without LCH involvement (5/18) was statistically significant. ISH confirmed the IHC in all six tissues tested. These findings demonstrate an association between HHV-6 and LCH, suggesting a role for the HHV-6B in the etiology of this disease.

Coincident expression of the chemokine receptors CCR6 and CCR7 by pathologic Langerhans cells in Langerhans cell histiocytosis.

It has been suggested that a switch in chemokine receptor expression underlies Langerhans cell migration from skin to lymphoid tissue. Activated cells are thought to down-regulate CCR6, whose ligand macrophage inflammatory protein-3 alpha (MIP-3 alpha)/CCL20 is expressed in skin, and up-regulate CCR7, whose ligands are in lymphoid tissues. In Langerhans cell histiocytosis (LCH), pathologic Langerhans cells (LCs) accumulate in several tissues, including skin, bone, and lymphoid organs. We have examined 24 LCH cases and find that pathologic LCs expressed CCR6 and CCR7 coincidentally in all cases. Furthermore, MIP-3 alpha/CCL20 is expressed by keratinocytes in involved skin and by macrophages and osteoblasts in involved bone. Expression of CCR6 by pathologic LCs may contribute to their accumulation in nonlymphoid organs such as skin and bone, whereas CCR7 expression may direct them to lymphoid tissue. Histiocytes in Rosai-Dorfman disease and hemophagocytic syndrome also coexpressed CCR6 and CCR7, suggesting that this may be a general attribute of abnormal histiocytes.

Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma.

Accumulating evidence indicates that expression of anaplastic lymphoma kinase (ALK), typically due to t(2;5) translocation, defines a distinct type of T/null-cell lymphoma (TCL). The resulting nucleophosmin (NPM) /ALK chimeric kinase is constitutively active and oncogenic. Downstream effector molecules triggered by NPM/ALK remain, however, largely unidentified. Here we report that NPM/ALK induces continuous activation of STAT3. STAT3 displayed tyrosine phosphorylation and DNA binding in all (four of four) ALK+ TCL cell lines tested. The activation of STAT3 was selective because none of the other known STATs was consistently tyrosine phosphorylated in these cell lines. In addition, malignant cells in tissue sections from all (10 of 10) ALK+ TCL patients expressed tyrosine-phosphorylated STAT3. Transfection of BaF3 cells with NPM/ALK resulted in tyrosine phosphorylation of STAT3. Furthermore, STAT3 was constitutively associated with NPM/ALK in the ALK+ TCL cell lines. Additional studies into the mechanisms of STAT3 activation revealed that the ALK+ TCL cells expressed a positive regulator of STAT3 activation, protein phosphatase 2A (PP2A), which was constitutively associated with STAT3. Treatment with the PP2A inhibitor calyculin A abrogated tyrosine phosphorylation of STAT3. Finally, ALK+ T cells failed to express a negative regulator of activated STAT3, protein inhibitor of activated STAT3. These data indicate that NPM/ALK activates STAT3 and that PP2A and lack of protein inhibitor of activated STAT3 may be important in maintaining STAT3 in the activated state in the ALK+ TCL cells. These results also suggest that activated STAT3, which is known to display oncogenic properties, as well as its regulatory molecules may represent attractive targets for novel therapies in ALK+ TCL.