Scattered Crypt Intestinal Epithelial Cell Apoptosis Induces Necrotizing Enterocolitis Via Intricate Mechanisms.

BACKGROUND & AIMS: Necrotizing enterocolitis (NEC) is a life-threatening disease affecting mostly the ileum of preemies. Intestinal epithelial cell (IEC) apoptosis contributes to NEC pathogenesis. However, how scattered crypt IEC apoptosis leads to NEC with excessive villus epithelial necrosis remains unclear. METHODS: A novel triple-transgenic mouse model, namely, 3xTg-iAPcIEC (inducible apoptosis phenotype in crypt-IEC), was developed to induce IEC-specific overexpression of Fasl transgene using doxycycline (Dox)-inducible tetO-rtTA system and villin-cre technology. The 3-day-old neonatal 3xTg-iAPcIEC mice and their littermate controls were subcutaneously (s.c.) challenged with a single dose of Dox. Intestinal tissues were processed at different time points to examine scattered crypt IEC apoptosis-mediated NEC development. Gene knockout technology, antibody-mediated cell depletion, and antibiotic-facilitated Gram-positive bacteria depletion were used to study mechanisms. RESULTS: Treatment of 3xTg-iAPcIEC mouse pups with Dox induces scattered crypt IEC apoptosis followed by crypt inflammation and excessive villous necrosis resembling NEC. This progression correlated with elevated Ifng, Rip3, CD8+ T cells, and Gram-positive bacteria in the ileum. Mechanistically, IFN-γ and RIP3-activated signals mediate the effect of scattered crypt IEC apoptosis on the induction of intestinal crypt inflammation and villous necrosis. Meanwhile, pathophysiological events of CD8+ T cell infiltration and dysbiosis with Gram-positive bacteria primarily contribute to excessive villous inflammation and necrosis. Notably, blocking any of these events protects against NEC development in 3xTg-iAPcIEC mouse pups, underlining their central roles in NEC pathogenesis. CONCLUSIONS: Scattered crypt IEC apoptosis induces NEC in mouse pups via IFN-g, RIP3, CD8+ T cells, and Gram-positive bacteria-mediated comprehensive pathophysiological events. Our findings may advance knowledge in the prevention and treatment of NEC.

Melanoma in infants, caused by a gene fusion involving the anaplastic lymphoma kinase (ALK).

We describe the first cases of pediatric melanoma with ALK fusion gene arising within giant congenital melanocytic nevi. Two newborn boys presented with large pigmented nodular plaques and numerous smaller satellite nevi. Additional expansile nodules developed within both nevi and invasive melanomas were diagnosed before 10 months of age in both boys. Oncogenic driver mutations in NRAS and BRAF were absent in both cases. Instead, oncogenic ZEB2::ALK fusion genes were identified in both the nevus and melanoma developing within the nevus. In both cases, tumors were noted by ultrasound in utero, demonstrated significant nodularity at birth, and progressed to melanoma in the first year of life suggesting that congenital nevi with ALK fusion genes may behave more aggressively than those with other mutations. As ALK kinase inhibitors are effective against a range of tumors with similar ALK fusion kinases, identifying ALK fusion genes in congenital melanocytic nevi may provide an opportunity for targeted therapy.

Feeding mode influences dynamic gut microbiota signatures and affects susceptibility to anti-CD3 mAb-induced intestinal injury in neonatal mice.

Feeding modes influence the gut microbiome, immune system, and intestinal barrier homeostasis in neonates; how feeding modes impact susceptibility to neonatal gastrointestinal (GI) diseases is still uncertain. Here, we investigated the impact of dam feeding (DF) and formula feeding (FF) on features of the gut microbiome and physiological inflammation during the first 2 days of postnatal development and on the susceptibility to intestinal injury related to the inflammatory state in neonatal mouse pups. 16S rRNA sequencing data revealed microbiome changes, lower α-diversity, and a distinct pattern of ß-diversity including expansion of f_Enterobacteriaceae and f_Enterococcaceae in the ileum of FF pups compared with DF pups by postnatal day (P)2. Together with gut dysbiosis, the FF cohort also had greater ileal mucosa physiological inflammatory activity compared with DF pups by P2 but maintained normal histological features. Interestingly, FF but not DF mouse pups developed necrotizing enterocolitis (NEC)-like intestinal injury within 24 h after anti-CD3 mAb treatment, suggesting that FF influences the susceptibility to intestinal injury in neonates. We further found that NEC-like incidence in anti-CD3 mAb-treated FF neonatal pups was attenuated by antibiotic treatment. Collectively, our data suggest that FF predisposes mouse pups to anti-CD3 mAb-induced intestinal injury due to abnormal f_Enterobacteriaceae and f_Enterococcaceae colonization. These findings advance our understanding of FF-associated microbial colonization and intestinal inflammation, which may help inform the development of new therapeutic approaches to GI diseases like NEC in infants.NEW & NOTEWORTHY This report shows that a feeding mode profoundly affects gut colonization in neonatal mice. Furthermore, our results demonstrate that formula feeding predisposes mouse pups to anti-CD3 mAb-induced necrotizing enterocolitis (NEC)-like intestinal injury upon inadequate microbial colonization. The study suggests the role of the combined presence of formula feeding-associated dysbiosis and mucosal inflammation in the pathogenesis of NEC and provides a new mouse model to study this disease.

Cytology-histology correlation of myoepithelial tumors harboring EWSR1-POU5F1 fusions: A report of two cases.

Myoepithelial tumors (MET) constitute a group of neoplasms with a variety of morphologic, immunophenotypic, and molecular features. Approximately half of MET of soft tissue harbor EWSR1 gene rearrangements with a subset showing EWSR1-POU5F1 fusions and demonstrating distinctive tendency towards aggressive behavior in children. Histologically, EWSR1-POU5F1-positive MET typically show clear-cell morphology with malignant features including marked pleomorphism and atypical mitotic figures. The cytomorphology of these tumors has not been well characterized. Reported here are the cytomorphologic features of two cases of EWSR1-POUF1-positive MET with histology correlation.

MFG-E8 Plays an Important Role in Attenuating Cerulein-Induced Acute Pancreatitis in Mice.

Milk fat globule-EGF factor 8 (MFG-E8) is a secreted glycoprotein that regulates tissue homeostasis, possesses potent anti-inflammatory properties, and protects against tissue injury. The human pancreas expresses MFG-E8; however, the role of MFG-E8 in the pancreas remains unclear. We examined the expression of MFG-E8 in the pancreas at baseline and during cerulein-induced acute pancreatitis in mice and determined whether MFG-E8 attenuates the progression of pancreatitis, a serious inflammatory condition that can be life-threatening. We administered cerulein to wild-type (WT) and Mfge8 knockout (KO) mice to induce pancreatitis. Immunoblot analysis showed that MFG-E8 is constitutively expressed in the murine pancreas and is increased in mice with cerulein-induced acute pancreatitis. In situ hybridization revealed that ductal epithelial cells in the mouse pancreas express Mfge8 transcripts at baseline. During pancreatitis, Mfge8 transcripts were abundantly expressed in acinar cells and endothelial cells in addition to ductal epithelial cells. Knocking out Mfge8 in mice exacerbated the severity of cerulein-induced acute pancreatitis and delayed its resolution. In contrast, administration of recombinant MFG-E8 attenuated cerulein-induced acute pancreatitis and promoted repair of pancreatic injury in Mfge8 KO mice. Taken together, our study suggests that MFG-E8 protects the pancreas against inflammatory injury and promotes pancreatic tissue repair. MFG-E8 may represent a novel therapeutic target in acute pancreatitis.

Blocking NF-κB Activation in Ly6c+ Monocytes Attenuates Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating disease affecting premature infants with intestinal inflammation and necrosis. The neonatal intestinal inflammatory response is rich in macrophages, and blood monocyte count is low in human NEC. We previously found that NF-κB mediates the intestinal injury in experimental NEC. However, the role of NF-κB in myeloid cells during NEC remains unclear. Herein, inhibitor of kappaB kinase ß (IKKß), a critical kinase mediating NF-κB activation, was deleted in lysozyme M (Lysm)-expressing cells, which were found to be Cd11b+Ly6c+ monocytes but not Cd11b+Ly6c- macrophages in the dam-fed neonatal mouse intestine. NEC induced differentiation of monocytes into intestinal macrophages and up-regulation of monocyte recruitment genes (eg, L-selectin) in the macrophage compartment in wild-type mice, but not in pups with IKKß deletion in Lysm+ cells. Thus, NF-κB is required for NEC-induced monocyte activation, recruitment, and differentiation in neonatal intestines. Furthermore, pups with Lysm-IKKß deletion had improved survival and decreased incidence of severe NEC compared with littermate controls. Decreased NEC severity was not associated with an improved intestinal barrier. In contrast, NEC was unabated in mice with IKKß deletion in intestinal epithelial cells. Together, these data suggest that recruitment of Ly6c+ monocytes into the intestine, NF-κB activation in these cells, and differentiation of Ly6c+ monocytes into macrophages are critical cellular and molecular events in NEC development to promote disease.

Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB).

Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB.

"Z4" Complex Member Fusions in NUT Carcinoma: Implications for a Novel Oncogenic Mechanism.

Nuclear protein in testis (NUT) carcinoma (NC) is a rare, distinctly aggressive subtype of squamous carcinoma defined by the presence of NUT-fusion oncogenes resulting from chromosomal translocation. In most cases, the NUT gene (NUTM1) is fused to bromodomain containing 4 (BRD4) forming the BRD4-NUT oncogene. Here, a novel fusion partner to NUT was discovered using next-generation sequencing and FISH from a young patient with an undifferentiated malignant round cell tumor. Interestingly, the NUT fusion identified involved ZNF592, a zinc finger containing protein, which was previously identified as a component of the BRD4-NUT complex. In BRD4-NUT-expressing NC cells, wild-type ZNF592 and other associated "Z4" complex proteins, including ZNF532 and ZMYND8, colocalize with BRD4-NUT in characteristic nuclear foci. Furthermore, ectopic expression of BRD4-NUT in a non-NC cell line induces sequestration of Z4 factors to BRD4-NUT foci. Finally, the data demonstrate the specific dependency of NC cells on Z4 modules, ZNF532 and ZNF592. IMPLICATIONS: This study establishes the oncogenic role of Z4 factors in NC, offering potential new targeted therapeutic strategies in this incurable cancer.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/12/1826/F1.large.jpg.

In Inflamed Intestinal Tissues and Epithelial Cells, Interleukin 22 Signaling Increases Expression of H19 Long Noncoding RNA, Which Promotes Mucosal Regeneration.

BACKGROUND & AIMS: Inflammation affects regeneration of the intestinal epithelia; long noncoding RNAs (lncRNAs) regulate cell functions, such as proliferation, differentiation, and migration. We investigated the mechanisms by which the lncRNA H19, imprinted maternally expressed transcript (H19) regulates regeneration of intestinal epithelium using cell cultures and mouse models of inflammation. METHODS: We performed RNA-sequencing transcriptome analyses of intestinal tissues from mice with lipopolysaccharide (LPS)-induced sepsis to identify lncRNAs associated with inflammation; findings were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization analyses of intestinal tissues from mice with sepsis or dextran sulfate sodium (DSS)-induced mucosal wound healing and patients with ulcerative colitis compared to healthy individuals (controls). We screened cytokines for their ability to induce expression of H19 in HT-29 cells and intestinal epithelial cells (IECs), and confirmed findings in crypt epithelial organoids derived from mouse small intestine. IECs were incubated with different signal transduction inhibitors and effects on H19 lncRNA levels were measured. We assessed intestinal epithelial proliferation or regeneration in H19ΔEx1/+ mice given LPS or DSS vs wild-type littermates (control mice). H19 was overexpressed in IECs using lentiviral vectors and cell proliferation was measured. We performed RNA antisense purification, RNA immunoprecipitation, and luciferase reporter assays to study functions of H19 in IECs. RESULTS: In RNA-sequencing transcriptome analysis of lncRNA expression in intestinal tissues from mice, we found that levels of H19 lncRNA changed significantly with LPS exposure. Levels of H19 lncRNA increased in intestinal tissues of patients with ulcerative colitis, mice with LPS-induced and polymicrobial sepsis, or mice with DSS-induced colitis, compared with controls. Increased H19 lncRNA localized to epithelial cells in the intestine, regardless of Lgr5 messenger RNA expression. Exposure of IECs to interleukin 22 (IL22) increased levels of H19 lncRNA with time and dose, which required STAT3 and protein kinase A activity. IL22 induced expression of H19 in mouse intestinal epithelial organoids within 6 hours. Exposure to IL22 increased growth of intestinal epithelial organoids derived from control mice, but not H19ΔEx1/+ mice. Overexpression of H19 in HT-29 cells increased their proliferation. Intestinal mucosa healed more slowly after withdrawal of DSS from H19ΔEx1/+ mice vs control mice. Crypt epithelial cells from H19ΔEx1/+ mice proliferated more slowly than those from control mice after exposure to LPS. H19 lncRNA bound to p53 and microRNAs that inhibit cell proliferation, including microRNA 34a and let-7; H19 lncRNA binding blocked their function, leading to increased expression of genes that promote regeneration of the epithelium. CONCLUSIONS: The level of lncRNA H19 is increased in inflamed intestinal tissues from mice and patients. The inflammatory cytokine IL22 induces expression of H19 in IECs, which is required for intestinal epithelial proliferation and mucosal healing. H19 lncRNA appears to inhibit p53 protein and microRNA 34a and let-7 to promote proliferation of IECs and epithelial regeneration.

Pathology of Melanotic Schwannoma.

CONTEXT.­: Melanotic schwannoma (MS) is a nerve sheath tumor with a uniform composition of variably melanin-producing Schwann cells and metastatic potential. The MS is an uncommon neoplasm, accounting for less than 1% of all nerve sheath tumors, with a predilection for spinal nerve involvement. Microscopically, the tumors are characterized by spindle and epithelioid cells arranged in interlacing fascicles, with marked accumulation of melanin in neoplastic cells and associated melanophages. The MSs are frequently associated with Carney complex, showing features of psammoma bodies and adipose-like cells. Strict criteria of malignancy in MS are not well developed, although a combination of worrisome histologic features (large, vesicular nuclei, with macronucleoli, brisk mitotic activity, and necrosis) raises concern for aggressive behavior. OBJECTIVE.­: To review the current status of the MS literature, discussing putative etiology, histopathology, current genetics, and differential diagnoses, including overlap with other pigmented tumors. DATA SOURCES.­: Search of PubMed (National Center for Biotechnology Information, Bethesda, Maryland) and the authors' own experiences. CONCLUSIONS.­: The occurrence of MS at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its high tendency to recur locally and to metastasize, which highlights the importance of diagnostic recognition, ancillary molecular genetic testing, and close clinical follow-up of patients with MS.

Malignant Ectomesenchymoma: Series Analysis of a Histologically and Genetically Heterogeneous Tumor.

AIMS: Malignant ectomesenchymoma is a rare pediatric neoplasm with dual mesenchymal and neuroectodermal elements. Mesenchymal component is usually rhabdomyosarcoma, particularly embryonal subtype, whereas neuroectodermal derivatives are frequently a neuroblastic tumor. Ectomesenchymoma manifests in various sites given the wide migration of neural crest cells during development, though the pelvis/perineum is most often involved. Moreover, no unique unifying molecular abnormality has been determined. METHODS: We conducted a retrospective study to analyze the spectrum of ectomesenchymal tumors encountered in our pediatric population. Six patients were identified and data pertaining to patients' demographic, tumor size and site, histologic components with immunophenotypic profile, molecular alterations, treatment, and outcome were collected. RESULTS: Mesenchymal elements, represented by rhabdomyosarcoma in all instances, were the dominant component in the majority of cases (5/6). Embryonal and alveolar morphology had similar distribution (3/6) and all patients with alveolar subtype harbored the characteristic translocations of this entity. The neuroectodermal component was most often a neuroblastic-like neoplasm (4/6); however, 2/6 cases demonstrated primitive neuroectodermal tumor-like morphology. No unifying alterations were found on molecular studies. CONCLUSIONS: Our analysis extends the histologic and molecular spectrum of these tumors and highlights their heterogeneity. The percentage of cases with alveolar rhabdomyosarcoma or primitive neuroectodermal-like tumor components suggests that these types of elements might be underreported. This study is also the first to demonstrate FOXO1 gene rearrangements in malignant ectomesenchymoma with alveolar rhabdomyosarcoma subtype.

Serous Carcinoma of the Testicle and the Paratesticular Tissue: Case Report and Literature Review.

Ovarian-type epithelial lesions of the testicle and the paratesticular tissue are uncommon, especially invasive serous adenocarcinoma with only 18 cases reported in the literature. Although the majority of these tumors occur in adults with an age range from 16 to 87 years, only 1 patient was less than 10 years old. Herein, we report only the second case of invasive serous adenocarcinoma occurring in the first decade of life, that of a 7-year-old boy. Additionally, clinical presentation, imaging, histopathology, immunohistochemistry, and clinical follow-up of invasive serous adenocarcinoma of the testicle are discussed, along with a review of the literature.

Ossifying parosteal lipoma of the thoracic spine: a case report and review of literature.

INTRODUCTION: Lipomas are derived from the mesodermal germ layer and are frequently encountered in adults, and account for almost 50% of all soft tissue tumors. Lipomas are classified based on their component tissues and location. A rare subtype, ossifying parosteal lipoma, accounts for 0.3% of all lipomas and occurs with intimate association with the underlying periosteum of the adjacent bone. Though lipomas are considered to be benign tumors, ossifying parosteal lipomas can manifest symptoms due to their location and relationship to nearby skeletal tissues. We herewith report the first known case of ossifying parosteal lipoma presenting in the region of the thoracic spine. CASE PRESENTATION: An otherwise healthy adolescent boy presented with a 3-year history of a slowly enlarging painless thoracic mass. A general physical examination was normal, aside from a painless 10 cm mobile, hard mass along the posterior spine in the region of T4 through T6. Musculoskeletal and neurovascular examinations were normal. An ultrasound suggested a solid, cylindrically shaped mass with diffuse ossification. The mass was resected, and the pathology revealed ossifying parosteal lipoma without evidence of malignancy. CONCLUSION: Ossifying parosteal lipomas are rare, benign soft tissue tumors that should be added to the differential diagnosis of thoracic masses.

Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis.

BACKGROUND: Decreased intestinal perfusion may contribute to the development of necrotizing enterocolitis (NEC). Vascular endothelial growth factor (VEGF) is an angiogenic protein necessary for the development and maintenance of capillary networks. Whether VEGF is dysregulated in NEC remains unknown. OBJECTIVES: The objective of this study was to determine whether intestinal VEGF expression is altered in a neonatal mouse model of NEC and in human NEC patients. METHODS: We first assessed changes of intestinal VEGF mRNA and protein in a neonatal mouse NEC model before significant injury occurs. We then examined whether exposure to formula feeding, bacterial inoculation, cold stress and/or intermittent hypoxia affected intestinal VEGF expression. Last, we visualized VEGF protein in intestinal tissues of murine and human NEC and control cases by immunohistochemistry. RESULTS: Intestinal VEGF protein and mRNA were significantly decreased in pups exposed to the NEC protocol compared to controls. Hypoxia, cold stress and commensal bacteria, when administered together, significantly downregulated intestinal VEGF expression, while they had no significant effect when given alone. VEGF was localized to a few single intestinal epithelial cells and some cells of the lamina propria and myenteric plexus. VEGF staining was decreased in murine and human NEC intestines when compared to control tissues. CONCLUSION: Intestinal VEGF protein is reduced in human and experimental NEC. Decreased VEGF production might contribute to NEC pathogenesis.

Anaplastic thyroid carcinoma with rhabdoid features.

Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive neoplasm, characterized by complete or partial composition by undifferentiated cells. We report a case of ATC with rhabdoid features in a 68-year-old male, who presented with a rapidly enlarging neck mass. Fine-needle aspiration (FNA) of the thyroid mass showed discohesive, pleomorphic round to polygonal rhabdoid cells with one to multiple eccentric, large, rounded nuclei with a prominent nucleolus, moderate to abundant, globoid cytoplasm which oftentimes harbor a pale para-nuclear inclusion. The cytoplasm of some cells contained variously sized, eosinophilic granules. Rare cells contained neutrophils in their cytoplasm. Mitoses including atypical mitotic figures and necrosis were readily seen. Histologic examination of needle core biopsy (NCB) revealed individual dispersed and sheets of pleomorphic neoplastic cells with similar cytomorphologic features as described above. The tumor extensively infiltrated a myxocollagenous stroma containing lymphocytes and neutrophils, and demonstrated foci of necrosis. Tumor cells were immunoreactive for keratins AE1/AE3, CAM5.2, and CK19; PAX-8, and p63, but negative for S-100, HMB-45, calcitonin, TTF-1, thyroglobulin, CD56, HBME-1, glypican-3, PAX-5, myogenin, CD31, and INI-1. The differential diagnosis of this malignant rhabdoid tumor is discussed.

Expression of Wilms tumor gene in high risk neuroblastoma: complementary marker to tyrosine hydroxylase for detection of minimal residual disease.

BACKGROUND: Neuroblastoma (NB) is an enigmatic tumor that often presents with metastatic disease at diagnosis and it is this aggressive propensity which places it among the deadliest pediatric tumors despite intensive multimodal therapy including hematopoietic stem cell transplantation (HSCT). We have previously demonstrated that Wilms tumor 1 gene (WT1) is a surrogate marker of proliferation in leukemia. To determine the potential association between WT1 and a known marker of NB, tyrosine hydroxylase (TH) in this high risk group of patients. METHODS: A total of 141 random samples from 34 patients were obtained, at diagnosis (n=27), during therapy (n=95), in clinical remission (n=13), and at the time of relapse (n=6). Quantitative RT-PCR was used for the evaluation of the level of gene expression using specific primers. RESULTS: Although similar gene expressions were demonstrated in both controls when evaluating both genes, significant difference was found at each clinical time point. Furthermore, when comparing patient samples from diagnosis to clinical remission and diagnosis to clinical relapse, individual gene expression varied. WT1 demonstrated significance (P=0.0002) and insignificance (P=0.06) whereas TH remained non-significant (P=0.2, P=0.09) respectively. CONCLUSIONS: WT1 gene is indicative of cellular proliferation in NB and for this reason it can be adjuvant to TH for the detection minimal residual disease (MRD).

Rhabdoid carcinoma of anal canal: role of electron microscopy and immunohistochemistry in establishing lineage.

ABSTRACT Rhabdoid carcinoma is a high-grade carcinoma with rhabdoid features and it is different from rhabdoid tumors that are broadly defined as malignant neoplasms with rhabdoid cellular appearance found primarily in the pediatric population, but adult cases have been reported in many anatomic locations. To date, no cases of anal canal rhabdoid carcinoma have been reported in the adult or pediatric population. We are reporting the first case of anal canal rhabdoid carcinoma, found in a 75-year-old male. We utilized ultrastructural as well as immunohistochemical studies to arrive at our diagnosis. Ultrastructural studies demonstrated the intermediate filament congregating to impart a rhabdoid appearance to tumor cells, and cytokeratin intermediate filaments and short microvilli indicating nature of tumor as carcinoma. Immunohistochemical phenotype showed neoplastic cells were positive for vimentin, pan-cytokeratin AE1/3, p63 and D2-40, which supports the genesis of tumor from skin adnexa. Even in the modern era of surgical pathology that routinely utilizes immunohistochemistry and molecular studies, adequate use of electron microscopy to help pinpoint the diagnosis in challenging cases is important.

A gene signature for a long-term survivor of an atypical teratoid/rhabdoid tumor.

Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors that are commonly associated with a dismal prognosis. However, there have been isolated reports of long-term survival that was not necessarily correlated with other prognostic factors such as age, clinical stage, or extent of surgical resection. Here, we report the case of a 6-year-old boy with AT/RT who remained disease-free for 8 years after undergoing subtotal surgical resection followed only by radiation therapy. On recurrence, the tumor rapidly progressed, leading to the patient's death a short time later. To further characterize this case and learn more about the tumor biology of long-term survivors, we compared the gene expression (GE) profiles from representative samples obtained from primary, recurrent, and progressive disease tumors of the above-mentioned patient along with a cohort of primary untreated AT/RT samples using cDNA microarrays. Global GE analysis and unsupervised hierarchical clustering showed the three events clustered together and distinctly apart from the rest of the samples. This indicates a GE background that is maintained throughout the course of the disease. This unique case suggests that there may be specific clinical characteristics associated with distinctive molecular subtypes of AT/RT. The identification and characterization of AT/RT subtypes could lead to advances in both prognosis and treatment of these tumors.