Associating liver partition and portal vein ligation for staged hepatectomy as bridging therapy for liver transplantation in an infant with an advanced hepatic rhabdoid tumor.

BACKGROUND: Malignant rhabdoid tumors (MRTs) are rare, aggressive tumors that mainly affect children and currently lack effective chemotherapeutic regimens. Liver MRTs are particularly challenging to manage due to the difficulty of performing one-stage liver resection, and preemptive liver transplantation is associated with high recurrence rates. However, the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) technique offers a promising surgical approach for advanced-stage liver tumors where conventional liver resection is not feasible. CASE REPORT: A patient with a large liver rhabdoid tumor that had invaded the three main hepatic veins underwent four courses of cisplatin-pirarubicin chemotherapy. ALPPS was performed due to insufficient residual liver capacity, with hepatic parenchymal dissection between the anterior and posterior liver zones in the first stage of surgery. After confirming adequate remaining liver volume, the liver was resected except for S1 and S6 on postoperative day 14. LDLT was performed 7 months after ALPPS due to the gradual deterioration of liver function caused by chemotherapy. The patient was recurrence-free 22 and 15 months after ALPPS and LDLT, respectively. CONCLUSIONS: The ALPPS technique is a curative option for advanced-stage liver tumors that cannot be managed with conventional liver resection. In this case, ALPPS was used successfully to manage a large liver rhabdoid tumor. Then, liver transplantation was performed after chemotherapy. The ALPPS technique should be considered a potential treatment strategy for patients with advanced-stage liver tumors, particularly those who can undergo liver transplantation.

SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression.

Atypical Teratoid Rhabdoid Tumor (AT/RT) is a rare pediatric central nervous system cancer often characterized by deletion or mutation of SMARCB1, a tumor suppressor gene. In this study, we found that SMARCB1 regulates Human Endogenous Retrovirus K (HERV-K, subtype HML-2) expression. HML-2 is a repetitive element scattered throughout the human genome, encoding several intact viral proteins that have been associated with stem cell maintenance and tumorigenesis. We found HML-2 env expression in both the intracellular and extracellular compartments in all AT/RT cell lines (n = 4) and in 95% of AT/RT patient tissues (n = 37) evaluated. SMARCB1 knock-down in neural stem cells (NSCs) led to an upregulation of HML-2 transcription. We found that SMARCB1 binds adjacent to the HML-2 promoter, repressing its transcription via chromatin immunoprecipitation; restoration of SMARCB1 expression in AT/RT cell lines significantly downregulated HML-2 expression. Further, targeted downregulation of HML-2 transcription via CRISPR-dCas9 coupled with suppressor proteins led to cellular dispersion, decreased proliferation, and cell death in vitro. HML-2 knock-down with shRNA, siRNA, and CRISPR-dCas9 significantly decreased Ras expression as measured by qRT-PCR, suggesting that HML-2 modulates MAPK/ERK signaling in AT/RT cells. Overexpression of NRAS was sufficient to restore cellular proliferation, and MYC, a transcription factor downstream of NRAS, was bound to the HERV-K LTR significantly more in the absence of SMARCB1 expression in AT/RT cells. We show a mechanism by which these undifferentiated tumors remain pluripotent, and we demonstrate that their formation is aided by aberrant HML-2 activation, which is dependent on SMARCB1 and its interaction with MYC.

Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials.

PURPOSE: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. MATERIALS AND METHODS: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3-21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. RESULTS: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS. CONCLUSIONS: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Atypical Teratoid/Rhabdoid Tumor After In Vitro Fertilization: Illustrative Case Report and Systematic Literature Review.

OBJECTIVE: In vitro fertilization (IVF) is increasingly used for the treatment of infertile couples worldwide. The association between IVF and cancer risk in offspring is conflicting. We present a case of atypical teratoid/rhabdoid tumor (AT/RT) in a girl conceived by IVF and present results of systematic review of literature of primary intracranial neoplasms diagnosed in children conceived by IVF. METHODS: A systematic review of literature was conducted on April 12, 2017, to identify previously published reports of intracranial brain tumors in patients conceived after IVF. RESULTS: A 21-month-old girl born after IVF and uneventful pregnancy presented with progressive nausea, vomiting, irritability, and right-side weakness. Magnetic resonance imaging demonstrated large heterogeneous contrast enhancing left frontotemporoparietal tumor. The operation was aborted due to asystole after subtotal tumor removal. The patient passed away on postoperative day 3. Histologic examination demonstrated AT/RT. We identified 7 previously published case reports of intracranial neoplasms in children conceived by IVF. Patient age at brain tumor diagnosis ranged from 31st week of gestation to 3 years of age. The most common histological diagnosis was AT/RT (3 cases), followed by glioblastoma multiforme, gliosarcoma, medulloblastoma, craniopharyngioma, and choroid plexus papilloma. Three of five operated patients died during perioperative period. Outcomes were dismal in 7 patients. CONCLUSIONS: IVF-associated brain tumors are usually malignant and associated with high mortality. Future studies investigating possible causal relationship between IVF and brain tumor risk are encouraged.

Atypical teratoid/rhabdoid tumor arising in a malignant glioma.

Atypical teratoid/rhabdoid tumor (AT/RT), a highly malignant brain tumor in young children, usually arises de novo and has only rarely been described as a secondary malignancy. Here, we present a case of a child with glioblastoma, who was treated postoperatively by a combination of temozolomide, irradiation, and bevacizumab. AT/RT was diagnosed as a secondary tumor, 2.5 years following primary diagnosis. The child died 13 months after the diagnosis of AT/RT. This case demonstrates that malignant gliomas may give rise to AT/RT. It also emphasizes the diagnostic value of a repeated tumor biopsy in the recurrence setting.

Radiation-induced primary cerebral atypical teratoid/rhabdoid tumour in an adult.

Atypical teratoid/rhabdoid tumours (ATRT) of the central nervous system are uncommon embryonal carcinomas that predominantly affect infants and young children, and less commonly adults. We report a 58 year old woman who presented with ATRT involving the right parietal lobe which was treated with surgery and adjuvant radiotherapy. Her history was significant for soft tissue sarcoma of the right ear treated with surgery and adjuvant radiotherapy at age 3, thus raising the possibility of radiation-induced aetiology.

Epidemiology of rhabdoid tumors of early childhood.

BACKGROUND: Rhabdoid tumors are a rare and aggressive cancer subtype which is usually diagnosed in early childhood. Little is known about their etiology. The purpose of this study was to describe the epidemiology of rhabdoid tumors and examine their relation to perinatal characteristics. METHODS: We identified 44 atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS) and 61 rhabdoid sarcomas (renal and extra-renal non-CNS tumors) from California Cancer Registry records of diagnoses 1988-2007 among children <6 years of age. We randomly selected 208,178 controls from California birthrolls. Multivariable logistic regression was used to examine associations between rhabdoid tumors and perinatal characteristics. RESULTS: After adjustment for demographic characteristics, low birthweight (<2,500 g) strongly increased risk for developing both rhabdoid sarcomas (OR = 2.43, 95% CI 1.09, 5.41) and AT/RT (OR = 2.99, 95% CI 1.31, 6.84). Both preterm delivery (<37 weeks gestation, OR = 2.63, 95% CI 1.34, 5.17) and late term delivery (>42 weeks, OR = 3.66, 95% CI 1.54, 8.71) also increased risk of rhabdoid sarcomas. Rhabdoid sarcoma cases (OR = 3.08, 95% CI 1.11, 8.55) and AT/RT cases (OR = 3.16, 95% CI 1.23, 8.13) also were more likely to be multiple births. CONCLUSION: The excess of twin pregnancies may suggest an association with infertility treatments. This is the first population-based epidemiologic study to examine these rare tumors.

Neonatal soft tissue sarcomas.

Soft tissue tumors in very young children pose diagnostic and therapeutic challenges. Vascular tumors are the most prevalent soft tissue neoplasms in the neonatal period. They are generally benign tumors, but may exhibit aggressive behaviour and cause life-threatening complications. Fibroblastic tumors of intermediate prognosis, more prevalent in very young children (especially infantile fibrosarcoma), are locally aggressive. Since metastases are unusual in this group of tumors, complete surgical resection is generally curative. However, these tumors often present a therapeutic challenge because of the location which makes complete surgical resection difficult. Among the malignant soft tissue tumors, rhabdomyosarcoma is most frequent. It is an aggressive high-grade tumor, with local invasiveness and a propensity to metastasize. These tumors respond to chemotherapy and radiotherapy. Neonates with rhabdomyosarcoma seem to have a worse prognosis than in older age groups. This may be a result of inappropriate dosing of chemotherapeutic agents and decreased use of radiation therapy among other factors.

Atypical teratoid rhabdoid tumor located in the pineal region following prophylactic irradiation for acute lymphoblastic leukemia.

Atypical teratoid rhabdoid tumor (AT/RT) is a rare entity. In the central nervous system, AT/RT generally arises from the posterior fossa of infants and behaves aggressively. AT/RT is reported to arise from the infratentorial region (63%) and other sites, such as the suprasellar region, cerebellopontine angle, and spinal cord. The pineal region is rare (6%) as a site of origin. Radiation-induced brain tumors are well known. In this report, we present a case of a pineal region tumor causing acute hydrocephalus that could be pathologically diagnosed as AT/RT following prophylactic cranial irradiation for acute lymphoblastic leukemia.

Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors.

BACKGROUND: Germline mutations and deletions of SMARCB1/INI1 in chromosome band 22q11.2 predispose patients to rhabdoid tumor and schwannomatosis. Previous estimates suggested that 15-20% of rhabdoid tumors were caused by an underlying germline abnormality of SMARCB1. However, these studies were limited by case selection and an inability to detect intragenic deletions and duplications. PROCEDURE: One hundred matched tumor and blood samples from patients with rhabdoid tumors of the brain, kidney, or soft tissues were analyzed for mutations and deletions of SMARCB1 by FISH, multiplex ligation-dependent probe amplification (MLPA), sequence analysis and high resolution Illumina 610K SNP-based oligonucleotide array studies. RESULTS: Thirty-five of 100 patients were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions including regions both proximal and distal to SMARCB1. There were nine cases that demonstrated parent to child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma, and two of the eight families presented with multiple affected children in a manner consistent with gonadal mosaicism. CONCLUSIONS: Approximately one-third of newly diagnosed patients with rhabdoid tumor have an underlying genetic predisposition to tumors due to a germline SMARCB1 alteration. Families may demonstrate incomplete penetrance and gonadal mosaicism, which must be considered when counseling families of patients with rhabdoid tumor.

Atypical teratoid/rhabdoid tumor in an infant conceived by in vitro fertilization.

BACKGROUND: Atypical teratoid/rhabdoid tumor (ATsRT) is a rare tumor and extremely aggressive embryonal neoplasm of the central nervous system. Brain tumors in infant are suggestive of some oncogenic prenatal factors. CASE PRESENTATION: We report on a case of ATRT in a 4-month-old infant conceived by in vitro fertilization (IVF). Some previous reports have raised a question about the possible relation between IVF and childhood cancer, particularly embryonal tumors. CONCLUSION: Report of such cases may provide some evidence to identify if there is a real association between congenital tumors and IVF.

Collecting duct carcinoma exhibiting diastase-resistant PAS-positive globular cytoplasmic inclusions and rhabdoid features arising in adult polycystic kidney disease: a case report.

A 76-year-old man complained of lumbago, and a subsequent detailed examination revealed a mass in the left kidney. Macroscopically, multiple cysts were recognized in the bilateral kidney; the tumor proliferated predominantly in the renal medulla and showed a whitish color with focal necrosis and hemorrhage. A histologic examination of the surgically resected tumor showed various growth patterns, such as solid, tubular, and papillary, by tumor cells. The diagnosis of collecting duct carcinoma (CDC) was made. Furthermore, tumor cells contained globular inclusions resembling hyaline globules and large eosinophilic inclusions, resulting in rhabdoid features, in the cytoplasm. Histochemically, globular inclusions were positive for periodic acid-Schiff (PAS) with diastase pretreatment. Immunohistochemically, large esosinophilic inclusions were reactive for vimentin. Although these findings are rare in CDCs, they should be recognized in the pathologic spectrum of CDCs. Int J Surg Pathol 12(2):171-177, 2004

Molecular analysis of the rhabdoid predisposition syndrome in a child: a novel germline hSNF5/INI1 mutation and absence of c-myc amplification.

The authors report a case of the rhabdoid predisposition syndrome (RPS) secondary to a germline hSNF5/INI1 mutation, whose brain tumor was originally unclassified but finally diagnosed as an atypical teratoid/rhabdoid tumor (AT/RT) by molecular analysis. A 7-month-old infant presented with hydrocephalus secondary to a huge pineal tumor and subsequently developed a renal rhabdoid tumor. The histology of the brain tumor was initially undetermined; however, an AT/RT was strongly suspected because of her clinical course. Mutational screening of the hSNF5/INI1 gene by heteroduplex and direct sequence analysis detected a missense mutation at codon 53 (CGA --> TGA, arginine --> stop) in both tumors, as well as in normal tissue of the kidney. Polymerase chain reaction (PCR)-based microsatellite analysis showed in both tumors allelic loss on chromosome arm 22q to which the hSNF5/INI1 gene maps. c-myc amplification was examined by differential PCR but not detected. Histologic review of the brain tumor by immunohistochemistry confirmed focal expression of epithelial membrane antigen and smooth muscle actin. These findings suggest that the brain tumor was really an AT/RT as a component of RPS secondary to a germline hSNF5/INI1 mutation. The present mutation has never been reported in the literature.

A masked NES in INI1/hSNF5 mediates hCRM1-dependent nuclear export: implications for tumorigenesis.

INI1 (integrase interactor 1)/hSNF5 is a component of the mammalian SWI/SNF complex and a tumor suppressor mutated in malignant rhabdoid tumors (MRT). We have identified a nuclear export signal (NES) in the highly conserved repeat 2 domain of INI1 that is unmasked upon deletion of a downstream sequence. Mutation of conserved hydrophobic residues within the NES, as well as leptomycin B treatment abrogated the nuclear export. Full-length INI1 specifically associated with hCRM1/exportin1 in vivo and in vitro. A mutant INI1 [INI1(1-319) delG950] found in MRT lacking the 66 C-terminal amino acids mislocalized to the cytoplasm. Full-length INI1 but not the INI1(1-319 delG950) mutant caused flat cell formation and cell cycle arrest in cell lines derived from MRT. Disruption of the NES in the delG950 mutant caused nuclear localization of the protein and restored its ability to cause cell cycle arrest. These observations demonstrate that INI1 has a masked NES that mediates regulated hCRM1/exportin1-dependent nuclear export and we propose that mutations that cause deregulated nuclear export of the protein could lead to tumorigenesis.

Long-term survival in an adolescent with widely metastatic renal cell carcinoma with rhabdoid features.

Renal cell carcinoma is rarely seen in children and adolescents. Patients with widespread disease at diagnosis have a particularly poor survival rate. Currently, all known chemotherapy has been ineffective in improving the median survival in patients with advanced disease. A 13-year-old black boy with stage IV renal cell carcinoma with rhabdoid features is a long-term disease-free survivor after aggressive multiagent chemotherapy. After the initial evaluation and histologic diagnosis of renal cell carcinoma, the patient received three courses of an aggressive chemotherapy regimen consisting of vincristine, doxorubicin, cyclophosphamide with mesna uroprotection, granulocyte colony-stimulating factor and erythropoietin (Epogen). After an almost complete response, a radical nephrectomy was performed and results demonstrated a solitary small nodule with viable tumor. After surgery, he received floxuridine infusion for 14 days by circadian schedule at 28-day intervals for a total of 1 year. The patient is well and free of disease 5 years after initial presentation. The dramatic response to treatment and long-term disease-free survival of this patient suggest this chemotherapeutic approach warrants additional investigation.

[Studies of the origin of malignant rhabdoid tumor(MRT)--experimental researches on the MRT evolving in nude mice inoculated with violently variable HeLa cells].

Under the prerequisite that the incidence of cancer or tumor in negatively-controlled nude mice inoculated subcutaneously with feline or canine kidney cell cultures purified in vitro at passage 3 or higher (the modal chromosome number of FKC on passage 3 was 38 of diploid at the rate of 80%) was 0%(0/22) and 0%(0/10) respectively, and the incidence of progressively negative growing tumor in controlled nude mice inoculated subcutaneously with repeatedly-frozen- and thawed-HeLa cell cultures of X strain was 20%(1/5), the negative growing malignant tumor (MT) was found in half of the nude mice inoculated subcutaneously with HeLa cell cultures of H strain(with modal chromosome number of 78 +/- 2 of sub-tetraploid at the rate of 40%), the progressively-growing malignant tumor was found in all the other 40 nude mice inoculated subcutaneously with HeLa cell cultures of other strains, with the incidence of MT in nude mice with KB strain (with modal chromosome number of 60 +/- 3 of hyperdiploid at the rate of 72%-76%) 10/10, the incidence of poorly-differentiated MT originated from epithelia in nude mice with X strain (with modal chromosomal number of 62 +/- 3 of hyperdiploid at the rate of 69%) 25/25, and the incidence of MRT in nude mice with in vitro cultured tumor cell NM20/X strain (with modal chromosome number of 68 +/- 3 of both hyperdiploid and subtetraploid at the rate of 52%) 5/5. After being continuously cultivated for 20 passages in vitro, HeLa cell of X strain was subcutaneously inoculated into nude mice and cultivated for 1 passage in vivo within 15 days, and then the developed growing MT was collected as HeLa cell of NM20/X strain on passage 0 and continuously cultivated for 11 passages to prepare for transplanting into nude mice again. Therefore, the highly variable strain of HeLa cells can be successfully selected by alternate cultivation in vitro and in vivo. Occasionally in another experiment, the progressively-growing MRT was found in all the 4 nude mice of one test group inoculated subcutaneously with 0.17 ml cell-cultures of super-high density containing 12.75 x 10(7) HeLa cells of KB strain on passages 10-11(with the rate of chromosome aberration high to 20% on passages 10-11 including 18% dicentric chromosome and 2% breakage chromosome). Although the incidence of MRT in nude mice inoculated subcutaneously with violently variable HeLa cells of NM20/X strain on passage 11, HeLa cells of KB strain on passages 10-11 reaches 100%(5/5) & 100%(4/4) respectively, yet it is requested that the inoculated live cell number is huge (5-12 x 10(7) cells per nude mouse), the tumor emerges immediately, develops violently, grows very fast, and has an extremely aggressive malignancy, the tumor is rich in the blood vessel giving a full supply of blood for it, and the mean value of major diameter X minor diameter of the tumor is essentially up to the standard of 30 mm x 20 mm in 16-22 days after the inoculation of the cells into the nude mice. The first finding of MRT in model animals provides an opportunity for answering the origin problem of MRT. Based on this reason, human uterus vertical epithelium may be an original tissue of MRT, thus opening up a new era for the research of MRT origin. It is also concluded as follows: 1. Cellular tumorigenicity is different among differently-karyotypic cells. 2. Highly variable strain of tumor cell line can be selected quickly and successfully in nude mouse. 3. Cellular tumorigenicity may be increased if chromosome aberration is very high. 4. The genetic characteristics of chromosomes of HeLa cells determines their tumorigenicity, chromosome number variation of HeLa cells has positive relationship with their carcinogenesis or tumorigenicity, and the turn of HeLa cells concerning their tumorigenicity from weak to strong is KB, X and NM20/X strains (excluding H strain, in which tumorigenicity remains to be determined by further experiments) respectively.