Forest F, David A, Arrufat S, et al.
Conventional chondrosarcoma in a survivor of rhabdoid tumor: enlarging the spectrum of tumors associated with SMARCB1 germline mutations.
Am J Surg Pathol. 2012; 36(12):1892-6 [PubMed]

SMARCB1 germline mutations mainly predispose to rhabdoid tumors. However, less aggressive tumors with a later onset have also been reported in a context of SMARCB1 constitutional mutation-that is, schwannomatosis and meningiomatosis. No other tumor type has formally been observed in such a context thus far. We report on a patient treated for a thoracic malignant rhabdoid tumor at 8 years of age who subsequently developed a mandibular conventional chondrosarcoma at 13 years of age. Both tumors showed a loss of BAF47 expression. The malignant rhabdoid tumor exhibited a large 22q11.2 deletion and an intragenic deletion of SMARCB1 (exons 1 to 3), thus leading to a biallelic inactivation. A 2.8 Mbp deletion encompassing SMARCB1 was found in the germline. This context was a strong incentive to investigate SMARCB1 alterations in the second tumor. As expected, the chondrosarcoma showed the large 22q11.2 deletion but also an additional c.243C>G(p.Tyr18X) premature stop codon in the remaining allele. This report relates for the first time a pediatric conventional chondrosarcoma to the wide family of SMARCB1-deficient tumors. Moreover, we report here the first case of conventional chondrosarcoma arising in a context of constitutional SMARCB1 deletion and, thus, enlarge the spectrum of this tumor predisposition syndrome.

Demir HA, Kaçar A, Emir S, et al.
Multiple axillary-infraclavicular lymph node metastasis from malignant rhabdoid tumor of unknown primary site.
Turk J Pediatr. 2012 May-Jun; 54(3):305-8 [PubMed]

Malignant rhabdoid tumors (MRT) mostly originate from the kidney and central nervous system. However, they may also originate from retroperitoneal and paravertebral regions, mediastinum, liver, chest wall, extremity, and neck, as well as from the soft tissues. The most important method in the differential diagnosis is the analysis of cytogenetic alterations in the INI1 gene. A six-month-old girl presented with multiple conglomerated lymphadenopathies located in the anterior axillary line. MRT diagnosis was confirmed by loss of INI1 expression in the tumor tissue. This is the first case in the literature with unknown primary focus diagnosed from lymph node metastasis.

Kohashi K, Nakatsura T, Kinoshita Y, et al.
Glypican 3 expression in tumors with loss of SMARCB1/INI1 protein expression.
Hum Pathol. 2013; 44(4):526-33 [PubMed]

Glypican 3 (GPC3), a membrane-bound heparin sulfate proteoglycan, is mutated in Simpson-Golabi-Behmel syndrome, characterized by tissue overgrowth and an increased risk of embryonal malignancies such as Wilms tumor. Malignant rhabdoid tumor (MRT), originally described as a rhabdomyosarcomatoid variant of Wilms tumor, is a tumor with loss of SMARCB1/INI1 protein expression. We analyzed the frequency of GPC3 protein expression, GPC3 mRNA, and serum-soluble GPC3 levels in 71 cases of tumors with loss of SMARCB1/INI1 protein expression, including 14 MRTs, 48 epithelioid sarcomas (ES) (proximal-type, 21; distal-type, 27), 4 extraskeletal myxoid chondrosarcomas, and 5 pediatric undifferentiated soft-tissue sarcomas. We found that GPC3 overexpression of more than 10% of the labeling index was recognized in 6 (42.9%) MRTs, 1 (2.1%) proximal-type ES, and 3 (60%) pediatric undifferentiated soft-tissue sarcomas (MRT vs ES, P = .0003). All the remaining cases revealed GPC3-absent expression of less than 1% of the labeling index. The median values of GPC3 mRNA in the GPC3-absent expression group and overexpression group were 10.2 and 309, respectively, with a statistically significant difference between these 2 groups (P = .004). However, there was no statistically significant difference in the prognoses of these 2 groups of MRT (P = .99). In analyzable cases of small-number MRT and pediatric undifferentiated soft-tissue sarcoma, there is no significant correlation between GPC3 immunoreactivity and serum-soluble GPC3 level. Therefore, evaluation of GPC3 immunoexpression may be a useful diagnostic tool to distinguish ES from MRT, especially extrarenal MRT. It was suggested that MRTs with GPC3 overexpression may become a new target of GPC3 immunotherapy.

Armeanu-Ebinger S, Herrmann D, Bonin M, et al.
Differential expression of miRNAs in rhabdomyosarcoma and malignant rhabdoid tumor.
Exp Cell Res. 2012; 318(20):2567-77 [PubMed]

Alveolar rhabdomyosarcoma (RMA) and malignant rhabdoid tumor (MRT) have a frequent metastatic spread and a poor prognosis. Aberrant miRNA expression is often found in metastatic tumors. The aim of this study was to identify specific miRNA expression patterns in these tumors. We analyzed the expression of miRNAs in RMA and MRT in tissue samples and in the rhabdomyosarcoma (RMS) cell lines (Rh30 and RD). Selected target miRNAs were modulated with mimic or inhibitor oligonucleotides. Functional analysis was monitored by flow cytometry and migration assays. A set of 107 differentially expressed miRNAs showed tissue-specific clustering of RMA and MRT. Comparison with the Sarcoma microRNA Expression Database revealed RMA- and MRT-specific miRNAs. Metastatic invasion associated miRNA miR-9 was overexpressed in RMA. miR-200c-inhibiting migration-was lower expressed in RMA than in MRT. Transient transfection of RMS cells with a miR-200c mimic and miR-9( inhibitor did neither increase the expression of the known target E-cadherin nor decrease migration. Expression of E-cadherin could be induced in RD cells using decitabine, but demethylation did not influence cell migration. Despite a comparable high rate of metastatic invasion pediatric RMA and MRT show a different pattern of miRNA expression possibly allowing risk stratification.

Kieran MW, Roberts CW, Chi SN, et al.
Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors.
Pediatr Blood Cancer. 2012; 59(7):1155-7 [PubMed] Article available free on PMC after 15/12/2013

BACKGROUND: Rhabdoid tumors (also called atypical teratoid/rhabdoid tumor (AT/RT) in the brain), are highly malignant, poor prognosis lesions arising in the kidneys, soft tissues, and central nervous system. Targeted therapy in this disease would benefit from advanced technologies detecting relevant actionable mutations.
PROCEDURE: Here we report on the evaluation of 25 tumors, all with known SMARCB1/INI1 alterations, for the presence of 983 different mutations in 115 oncogenes and tumor-suppressor genes using OncoMap, a mass spectrometric method of allele detection.
RESULTS: Other than mutations in SMARCB1, our results identified a single activating mutation in NRAS and complete absence of oncogenic mutations in all other genes tested.
CONCLUSION: The absence of mutations in canonical pathways critical for development and progression of adult cancers suggests that distinct mechanisms drive these highly malignant pediatric tumors. This may limit the therapeutic utility of available targeted therapies and require a refocusing toward developmental and epigenetic pathways.

Iida T, Mihara M, Yoshimatsu H, et al.
Reconstruction of an extensive anterior skull base defect using a muscle-sparing rectus abdominis myocutaneous flap in a 1-year-old infant.
Microsurgery. 2012; 32(8):622-6 [PubMed]

Despite the recent advances in microsurgical techniques, reconstruction of extensive skull base defects using free flaps in pediatric patients presents a surgical challenge, and reports on skull base reconstruction in infants is quite limited. We present a case of reconstruction of an extensive anterior skull base defect using a rectus abdominis (RA) myocutaneous flap in a 1 year-old (14 months) infant. Sufficient coverage of the intracranial contents, good aesthetic results, and minimal growth disturbance at the donor site were achieved by the muscle-sparing RA flap transfer. To the best of our knowledge, this was among the youngest case of skull base reconstruction using a free flap. The feasibility of free flap transfer and flap selection in pediatric skull base reconstruction is discussed.

Chakrapani AL, White CR, Korcheva V, et al.
Congenital extrarenal malignant rhabdoid tumor in an infant with distal 22q11.2 deletion syndrome: the importance of SMARCB1.
Am J Dermatopathol. 2012; 34(6):e77-80 [PubMed]

Extrarenal rhabdoid tumor is a rare malignancy of infants and children, typically presenting in the soft tissue of deep, axial locations. We describe a rare dermal presentation of congenital extrarenal rhabdoid tumor in the left paraspinal region of a 6-month-old girl with germline deletion of chromosome 22q11.21q11.23. This case demonstrates that like other rhabdoid tumors, the SMARCB1 gene is also responsible for cutaneous extrarenal rhabdoid tumor oncogenesis.

Lee RS, Stewart C, Carter SL, et al.
A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers.
J Clin Invest. 2012; 122(8):2983-8 [PubMed] Article available free on PMC after 15/12/2013

Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers and the emergence of mutations in genes that encode chromatin remodelers raise the possibility that perturbation of chromatin structure and epigenetic regulation are capable of driving cancer formation. Here we sequenced the exomes of 35 rhabdoid tumors, highly aggressive cancers of early childhood characterized by biallelic loss of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. We identified an extremely low rate of mutation, with loss of SMARCB1 being essentially the sole recurrent event. Indeed, in 2 of the cancers there were no other identified mutations. Our results demonstrate that high mutation rates are dispensable for the genesis of cancers driven by mutation of a chromatin remodeling complex. Consequently, cancer can be a remarkably genetically simple disease.

Schindler K, Schicher N, Kunstfeld R, et al.
A rare case of primary rhabdoid melanoma of the urinary bladder treated with ipilimumab, an anti-CTLA 4 monoclonal antibody.
Melanoma Res. 2012; 22(4):320-5 [PubMed]

Primary melanoma of the urinary bladder is a rare subentity of melanoma. The same applies for melanoma of the rhabdoid histopathologic phenotype. A female patient was initially diagnosed with melanoma of unknown origin caused by macroscopic lymph node metastasis in the left inguinal and parailiacal regions. Because of the extent of the disease, radical surgery could not be performed. The patient underwent systemic chemotherapy with dacarbazine, followed by the experimental compound tasisulam. Upon sudden macrohematuria, cystoscopy showed a large infiltrating tumorous structure located on the left side of the urinary bladder. Clinically, the amelanotic tumor showed endophytic growth into the lumen; on the histopathological specimen, the growth pattern was partially undermining the urothelium, which is commonly observed in primary melanoma of the urinary bladder. Cytologically, the tumor cells were classified as rhabdoid melanoma, a very rare variant of melanoma, which is commonly amelanotic and expresses S100, vimentin and Ncam. Mutational analysis showed positive results for BRAF V600E. After detecting the primary melanoma, the patient received anti-CTLA4 antibody treatment with 3 mg/kg ipilimumab, through which a partial response was achieved. Past computed tomography scans should be re-evaluated for suspicious lesions, and cystoscopy should be included in the clinical workup if the pattern of metastasis is congruent with the drainage sites of the urinary bladder.

Brčić I, Spajić B, Krušlin B
Chromophobe renal cell carcinoma with rhabdoid differentiation in an adult.
Wien Klin Wochenschr. 2012; 124(11-12):419-21 [PubMed]

Cases of adult renal cell carcinoma with rhabdoid features have been reported in the literature, usually in association with conventional clear cell and papillary tumors. Till date, only one report described chromophobe renal cell carcinoma with rhabdoid differentiation. We report a case of a 47-year-old male patient that underwent a routine medical check-up. Computer tomography scan revealed a large heterogeneous mass in the left kidney, multiple nodular changes in the lungs and multiple enlarged lymph nodes. On microscopic examination of the left nephrectomy specimen, 65 % of the kidney tumor was comprised of rhabdoid foci and the rest of the tumor showed eosinophilic areas consistent with chromophobe renal cell carcinoma. Final diagnosis was chromophobe renal cell carcinoma with rhabdoid differentiation. Behavior of these tumors in adults is more aggressive, demands more aggressive treatment and has poor prognosis. Therefore, rhabdoid differentiation should be recognized in this type of carcinoma and mentioned in the pathohistology report.

Rizzo D, Fréneaux P, Brisse H, et al.
SMARCB1 deficiency in tumors from the peripheral nervous system: a link between schwannomas and rhabdoid tumors?
Am J Surg Pathol. 2012; 36(7):964-72 [PubMed]

BACKGROUND: Inactivation of SMARCB1 tumor-suppressor gene was originally described as highly specific for rhabdoid tumors (RTs). Nevertheless, recent reports have illustrated that SMARCB1 alterations also characterize other tumors; in particular, some familial schwannomatosis and epithelioid malignant peripheral nerve sheath tumors, both from peripheral nervous system (PNS) origin, lack BAF47 expression. To document the putative role of SMARCB1 in PNS, we reviewed PNS tumors referred to our institution for a molecular analysis of SMARCB1 because of histologic features compatible with RT.
METHODS: Clinicopathologic, radiologic, and molecular characteristics were detailed for the 12 cases showing loss of expression and/or biallelic inactivation of SMARCB1. The status of the NF2 gene, likely to synergize with SMARCB1 in PNS tumors, was also analyzed.
RESULTS: Patients' age ranged from 0 to 45 years (median age, 6.6 y). Neurological symptoms were observed in 7/12 cases with radiologic features evoking a neuroblastic tumor in 6 cases and a peripheral nerve tumor in 4 cases. The mean delay before diagnosis was 3 months. Histologic examination revealed rhabdoid features in 11/12 tumors. All tumors showed a complete loss of SMARCB1 expression. Interestingly, adjacent nervous proliferation resembling neurofibromas were observed in 3 cases, suggesting a multistep transformation. Three tumors harbored a hemizygous deletion at the NF2 locus, but all NF2 sequences were normal.
CONCLUSIONS: We report the first series of PNS RT. In patients with aggressive PNS tumors, RT should be suspected, and anti-SMARCB1 immunohistochemical analysis should be performed. SMARCB1 inactivation, occasionally associated with NF2 deletion, might have oncogenic effects in peripheral nerves.

Raspollini MR, Li Marzi V, Nicita G, Mikuz G
The challenging diagnosis of the rhabdoid carcinoma of the pelvis: a case report with literature review.
Appl Immunohistochem Mol Morphol. 2012; 20(2):177-83 [PubMed]

Rhabdoid tumor is an uncommon neoplasia characterized by a monotonous population of large, noncohesive cells with vesicular nuclei and large nucleoli. The misleading name was originally suggested because of the striking morphologic resemblance to other skeletal muscle tumors, but neither ultrastructural nor immunohistochemical features support a myogenic origin for this tumor. The rhabdoid tumors of the kidney in pediatric age are characterized by mutation or deletion of 22q11. In adults, tumors with rhabdoid features are uncommon neoplasia reported in different anatomic sites, but their histogenesis is still unclear. We focused on the literature data regarding the rhabdoid features in pelvic and renal tumors, and we describe a carcinoma involving the pelvis and the kidney with exclusive rhabdoid features, which make the anatomical allocation of the tumor difficult. The tumor did not exhibit any similarities to conventional histologic types of renal cell cancer, not even of the sarcomatous type. Tumor cells showed a strong positivity for epithelial markers (AE1/AE3 and CK 8) and for vimentin, whereas they were negative for skeletal and smooth muscle markers. The nuclei of the tumor cells demonstrated a INI1-positive immunohistochemical stain, indicating the lack of mutation or deletion of the 22q11 chromosome. The appropriate diagnosis is that of an extrarenal high-grade rhabdoid carcinoma originating from the urothelium of the renal pelvis. The decision as to whether the tumor arose primarily in the renal parenchyma or in the renal pelvis could be of therapeutic importance. Appropriate immunohistochemical markers can help in the difficult differential diagnosis.

Warmann SW, Nourkami N, Frühwald M, et al.
Primary lung metastases in pediatric malignant non-Wilms renal tumors: data from SIOP 93-01/GPOH and SIOP 2001/GPOH.
Klin Padiatr. 2012; 224(3):148-52 [PubMed]

Malignant non-Wilms renal tumors (NWRT) are a small but relevant subgroup of renal neoplasms in children. In this study we analyzed corresponding data from the trials SIOP 93-01/GPOH and SIOP 2001/GPOH of the Society of Pediatric Oncology and Hematology.Data of 22 patients with NWRT and primary lung metastases were retrospectively reviewed. Analyses included epidemiology, tumor characteristics, chemotherapy, local treatment, and outcome.The following diagnoses were registered: Malignant Rhabdoid tumor of the kidney (MRTK, n=15), Renal-cell carcinoma (RCC, n=3), Clear-cell sarcoma of the kidney (CCSK, n=3), and primitive neuro ectodermal tumor (PNET, n=1). Median age of patients at diagnosis was 14 months. Overall survival was 36.36% (8/22). Of the 15 children with MRTK 3 survived, 3/3 patients with RCC, 1/3 patients with CCSK, and 1/1 patient with PNET survived. Lung metastases disappeared in 6 patients after initial chemotherapy, 6/8 patients undergoing local treatment of lung metastases (surgery, irradiation, or both) achieved complete remission. Only patients with complete clearance of lung lesions, either through neoadjuvant chemotherapy or subsequent local treatment, survived. Mean Follow up was 31 months (1-137).Survival of patients with stage IV NWRT is dismal. Complete removal of lung metastases seems mandatory for survival. An aggressive diagnostic and therapeutic approach seems justified in affected children.

Gimi B, Cederberg K, Derinkuyu B, et al.
Utility of apparent diffusion coefficient ratios in distinguishing common pediatric cerebellar tumors.
Acad Radiol. 2012; 19(7):794-800 [PubMed]

RATIONALE AND OBJECTIVES: The aim of this study was to identify clinically useful tumor/normal brain apparent diffusion coefficient (ADC) ratios for distinguishing common pediatric cerebellar tumors.
MATERIALS AND METHODS: Review of medical records revealed 79 patients with cerebellar tumors who underwent preoperative magnetic resonance imaging, including diffusion-weighted imaging sequences, and surgery. There were 31 pilocytic astrocytomas, 27 medulloblastomas, 14 ependymomas, and seven atypical teratoid/rhabdoid tumors. ADC values were measured by placing regions of interest on the solid tumor and normal brain parenchyma by two reviewers. Tumor/normal brain ADC ratios were calculated.
RESULTS: Mean ADC values of the pilocytic astrocytomas were greater than those of ependymomas, whose mean ADC values were greater than those of medulloblastomas and atypical teratoid/rhabdoid tumors. Using a tumor/normal brain ADC ratio threshold of 1.70 to distinguish pilocytic astrocytomas from ependymomas, sensitivity of 92% and specificity of 79% were achieved. A tumor/normal brain ADC ratio threshold of 1.20 enabled the sorting of ependymomas from medulloblastomas with sensitivity of 93% and specificity of 88%.
CONCLUSIONS: Tumor/normal brain ADC ratios allow the distinguishing of common pediatric cerebellar tumors.

Dettmer M, Hench J, Pang B, et al.
Rhabdoid large cell carcinoma of lung, with illustrative immunohistochemical and molecular findings.
Appl Immunohistochem Mol Morphol. 2012; 20(3):208-13 [PubMed]

Large cell carcinomas with rhabdoid phenotype (LCC-RP) account for <1% of pulmonary large cell carcinomas and are associated with extremely poor prognosis. We report a case of a 64-year-old male patient who presented at an advanced stage with a LCC-RP, arising from a poorly differentiated adenocarcinoma of the lung. Ninety percent of the tumor consisted of large pleomorphic rhabdoid tumor cells that showed eosinophilic cytoplasmic inclusions and the remaining 10% showed evidence of adenomatous differentiation. Rhabdoid areas were immunohistochemically positive for pan-cytokeratin AE1/3, epithelial membrane antigen, vimentin, thyroid transcription factor-1, integrase interactor-1, and negative for desmin. Nuclear positivity was absent for Myo-D1. The parent adenocarcinoma was positive for thyroid transcription factor-1 and cytokeratins 7. Epidermal growth factor receptor mutation analysis revealed the same mutation (p.delL747-T751) in both areas, suggesting that the malignant rhabdoid phenotype represents a dedifferentiation phenomenon of the adenocarcinoma. This is the first reported case of an Exon 19 deletion in epidermal growth factor receptor of the activating type detected in a LCC-RP associated with a poorly differentiated pulmonary adenocarcinoma.

Yin WH, Li J, Chan JK
Sporadic haemangioblastoma of the kidney with rhabdoid features and focal CD10 expression: report of a case and literature review.
Diagn Pathol. 2012; 7:39 [PubMed] Article available free on PMC after 15/12/2013

We present here an intriguing case of sporadic renal haemangioblastoma occurring in a 61-year-old male. The tumor consisted of nests of polygonal cells and abundant capillary networks. The neoplastic cells generally showed abundant eosinophilic cytoplasm and prominent eccentric nuclei, resembling the rhabdoid cells. Pronounced intranuclear cytoplasmic pseudoinclusions were another significant feature seen. NSE, a-inhibin and S100 were positive in tumor cells and particularly, focal CD10 expressions were observed. This is possibly the first reported case of a haemangioblastoma showing a rhabdoid phenotype and CD10 immunopositivity. Malignant rhabdoid tumor and renal cell carcinoma with rhabdoid features were probably the most challenging mimics need to be differentiated. The result of focal CD10 staining in our case may further lead to confusion with renal cell carcinoma. To avoid misdiagnosis, more considerations should be attached to the rare neoplasm. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1068858553657049.

Takahashi-Fujigasaki J, Matumoto M, Kan I, et al.
Atypical teratoid/rhabdoid tumor with 26-year overall survival: case report.
J Neurosurg Pediatr. 2012; 9(4):400-5 [PubMed]

Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive embryonic brain tumor predominantly seen in young children. The authors report an unusual case of a fourth ventricle AT/RT in an infant who survived for 26 years. The tumor was resected when the patient was 6 months of age, and radiation therapy (40-Gy total dose) was performed thereafter. The patient was free from the disease for 26 years until a recurrent tumor was found in the spinal cord. The spinal cord neoplasm was a "collision tumor" with 2 components: benign schwannoma and recurrent AT/RT. The patient died of dissemination of the recurrent tumor 5 months after it was excised. This is the longest survival of a patient with AT/RT ever reported and indicates that long-term survival, more than 20 years, can be achieved in infantile-onset AT/RT. Despite intensive treatment, the prognosis for AT/RT is very poor, especially in children younger than 3 years of age. The benefits of upfront radiation therapy for AT/RT should be carefully assessed with respect to its inevitable toxicity in very young children. However, early upfront radiation therapy may be of therapeutic interest to prevent aggressive progression of the disease.

Thiemann M, Oertel S, Ehemann V, et al.
In vivo efficacy of the histone deacetylase inhibitor suberoylanilide hydroxamic acid in combination with radiotherapy in a malignant rhabdoid tumor mouse model.
Radiat Oncol. 2012; 7:52 [PubMed] Article available free on PMC after 15/12/2013

PURPOSE: Histone deacetylase inhibitors are promising new substances in cancer therapy and have also been shown to sensitize different tumor cells to irradiation (XRT). We explored the effect as well as the radiosensitizing properties of suberoylanilide hydroxamic acid (SAHA) in vivo in a malignant rhabdoid tumor (MRT) mouse model.
METHODS AND MATERIAL: Potential radiosensitization by SAHA was assessed in MRT xenografts by analysis of tumor growth delay, necrosis (HE), apoptosis (TUNEL), proliferation (ki-67) and γH2AX expression as well as dynamic 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG -PET) after treatment with either SAHA alone, single-dose (10 Gy) or fractionated XRT (3 × 3Gy) solely as well as in combination with SAHA compared to controls.
RESULTS: SAHA only had no significant effect on tumor growth. Combination of SAHA for 8 days with single-dose XRT resulted in a higher number of complete remissions, but failed to prove a significant growth delay compared to XRT only. In contrast fractionated XRT plus SAHA for 3 weeks did induce significant tumor growth delay in MRT-xenografts. The histological examination showed a significant effect of XRT in tumor necrosis, expression of Ki-67, γH2AX and apoptosis. SAHA only had no significant effect in the histological examination. Comparison of xenografts treated with XRT and XRT plus SAHA revealed a significantly increased γH2AX expression and apoptosis induction in the mice tumors after combination treatment with single-dose as well as fractionated XRT. The combination of SAHA with XRT showed a tendency to increased necrosis and decrease of proliferation compared to XRT only, which, however, was not significant. The 18F-FDG-PET results showed no significant differences in the standard uptake value or glucose transport kinetics after either treatment.
CONCLUSION: SAHA did not have a significant effect alone, but proved to enhance the effect of XRT in our MRT in vivo model.

Heck JE, Lombardi CA, Cockburn M, et al.
Epidemiology of rhabdoid tumors of early childhood.
Pediatr Blood Cancer. 2013; 60(1):77-81 [PubMed] Article available free on PMC after 01/01/2014

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.

Gauvain KM, Durham BH, McHugh M, Geller TJ
Rapidly progressive primary leptomeningeal atypical teratoid/rhabdoid tumor: a report of 2 cases.
J Child Neurol. 2012; 27(12):1597-601 [PubMed]

Atypical teratoid/rhabdoid tumor is a rare, highly malignant central nervous system tumor most commonly occurring in very young children. Atypical teratoid/rhabdoid tumor most often presents as an expanding mass with symptoms consistent with the location of the tumor and may present with metastatic leptomeningeal disease. The authors describe 2 cases of rapidly progressive, diffuse leptomeningeal atypical teratoid/rhabdoid tumor without a solid primary mass. These cases demonstrate a clinical picture that can easily be confused with a basilar meningitis, encephalomyelitis, or vasculitis.

Motegi H, Kobayashi H, Terasaka S, et al.
Hemorrhagic onset of rhabdoid meningioma after initiating treatment for infertility.
Brain Tumor Pathol. 2012; 29(4):240-4 [PubMed]

Rhabdoid meningioma (RM) is a rare aggressive phenotype and is classified as a grade III neoplasm by the World Health Organization. A 29-year-old woman initiated treatment with clomiphene citrate for infertility. Two weeks later, she presented with acute headache and nausea. Brain computed tomography and magnetic resonance imaging demonstrated a tumor with hematoma in the left frontoparietal region. Surgical resection was performed, and the tumor was subtotally removed. The tumor was diagnosed as a rhabdoid meningioma (RM). Despite radiation and chemotherapy, she experienced regrowth and dissemination to the spinal cord. She died 11 months after onset of symptoms. Spontaneous hemorrhage is an unusual presentation of RM. In our case, infertility treatment may have triggered progression and bleeding because of an imbalance of sex hormones.

Park ES, Sung KW, Baek HJ, et al.
Tandem high-dose chemotherapy and autologous stem cell transplantation in young children with atypical teratoid/rhabdoid tumor of the central nervous system.
J Korean Med Sci. 2012; 27(2):135-40 [PubMed] Article available free on PMC after 01/01/2014

The feasibility and effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) were evaluated in children younger than 3 yr of age with atypical teratoid/rhabdoid tumors (ATRT). Tandem HDCT/autoSCT was administered following six cycles of induction chemotherapy. Radiotherapy (RT) was administered if the tumor relapsed or progressed, otherwise, it was administered after 3 yr of age. Tumors relapsed or progressed during induction chemotherapy in 5 of 9 patients enrolled; 3 of these 5 received tandem HDCT/autoSCT as a salvage treatment. One patient died from sepsis during induction chemotherapy. The remaining 3 patients proceeded to tandem HDCT/autoSCT; however, 2 of these patients showed tumor relapse/progression after tandem HDCT/autoSCT. All 7 relapses/progressions occurred at primary sites even in patients with leptomeningeal seeding. Toxicities during tandem HDCT/autoSCT were manageable. A total of 5 patients were alive with a median follow-up of 20 (range 16-70) months from diagnosis. Four of 5 patients who received RT after relapse/progression are alive. The probability of overall survival at 3 yr from diagnosis was 53.3% ± 17.3%. Our tandem HDCT/autoSCT is feasible; however, early administration of RT prior to tandem HDCT/autoSCT should be considered to improve the outcome after tandem HDCT/autoSCT.

Moschovi M, Koultouki E, Stefanaki K, et al.
Prognostic significance of angiogenesis in relation to Ki-67, p-53, p-27, and bcl-2 expression in embryonal tumors.
Pediatr Neurosurg. 2011; 47(4):241-7 [PubMed]

AIM: We investigated the angiogenesis and density of newly formed blood vessels in embryonal tumors in relation to Ki-67, bcl-2, p-53 and p-27 expression.
METHODS: Forty-five children with embryonal tumors were enrolled in the study. Forty patients had a medulloblastoma (MB) and 5 patients had atypical teratoid/rhabdoid tumor (AT/RT).
RESULTS: In MB, the 5-year PFS and OS was 62.5 and 70%, respectively. Patients with Ki-67 index >50%, bcl-2 index >30% and higher density of new vessels were associated with worse survival. In the multivariate analysis, Ki-67 index was identified as a factor with independent prognostic power. In AT/RTs, high density of new vessels (>25 HRF) was observed in 3 patients and Ki-67 index over 25% was found in 4 patients.
CONCLUSION: Increased Ki-67, bcl-2 and density of new vessels are of prognostic value for the disease outcome in MB.

Khatua S, Sadighi ZS, Pearlman ML, et al.
Brain tumors in children--current therapies and newer directions.
Indian J Pediatr. 2012; 79(7):922-7 [PubMed]

Brain tumors are the second most common malignancy and the major cause of cancer related mortality in children. Though significant advances in neuroimaging, neurosurgery, radiation therapy and chemotherapy have evolved over the years, overall survival rate remains less than 75%. Malignant gliomas, high risk medulloblastoma with recurrence and infant brain tumors continue to be a major cause of therapeutic frustration. Even today diffuse pontine gliomas are universally fatal. Though tumors like low grade glioma have an overall excellent survival, recurrences and progression in eloquent areas pose therapeutic challenges. As research continues to unravel the biology including key molecules and signaling pathways responsible for the oncogenesis of different childhood brain tumors, novel targeted therapies are profiled. Identification of major targets like the Epidermal Growth factor Receptor (EGFR), Platelet Derived Growth Factor Receptor (PDGFR), Vascular Endothelial Growth factor (VEGF) and key signaling pathways like the MAPK and PI3K/Akt/mTOR has enabled us over the recent years to better understand tumor behavior and design tailored therapy. These efforts have improved overall survival of children with brain tumors. This review article discusses the current status of common brain tumors in children and the newer therapeutic approaches.

Venkataraman S, Alimova I, Tello T, et al.
Targeting Aurora Kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells.
J Neurooncol. 2012; 107(3):517-26 [PubMed]

Atypical teratoid/rhabdoid tumors (ATRT) are rare, highly malignant, embryonal CNS tumors with a poor prognosis. Therapy relies on highly toxic chemotherapy and radiotherapy. To improve outcomes and decrease morbidity, more targeted therapy is required. Gene expression analysis revealed elevated expression of multiple kinases in ATRT tissues. Aurora Kinase A was one of the candidate kinases. The objective of this study was to evaluate the impact of Aurora Kinase A inhibition in ATRT cell lines. Our analysis revealed that inhibition of Aurora Kinase A induces cell death in ATRT cells and the small molecule inhibitor MLN 8237 sensitizes these cells to radiation. Furthermore, inhibition of Aurora Kinase A resulted in decreased activity of pro-proliferative signaling pathways. These data indicate that inhibition of Aurora Kinase A is a promising small molecule target for ATRT therapy.

Nageswara Rao AA, Packer RJ
Impact of molecular biology studies on the understanding of brain tumors in childhood.
Curr Oncol Rep. 2012; 14(2):206-12 [PubMed]

Pediatric brain tumors are the second most common form of childhood malignancy. Brain tumors are a very heterogenous group of tumors and the pathogenesis of many of these tumors is yet to be clearly elucidated. Current diagnostic tools include histopathology and immunohistochemistry, but classification based on these means has significant limitations. As our understanding of the molecular biology of individual tumors continues to increase it has led to the identification of reliable and increasingly available molecular biomarkers. Molecular techniques are likely to complement current standard means of investigation and help not only overcome diagnostic challenges but may also result in better disease classification and risk stratification, leading to more personalized therapeutic approaches.

Jain M, Harbhajanka A, Choudhary SR
Cytomorphology and immunohistochemistry of extrarenal rhabdoid tumor: a case report with review of literature.
Indian J Pathol Microbiol. 2011 Oct-Dec; 54(4):819-21 [PubMed]

Extrarenal rhabdoid tumor (ERRT) is a rare, aggressive tumor with extremely poor prognosis. We report a case of ERRT with intraspinal extension in a 1.5-year-old child diagnosed by fine needle aspiration cytology (FNAC) and immunohistochemistry. The child presented with a right lumbar region lump of two months duration. Ultrasound guided FNAC was performed and cell block was prepared. Smears were highly cellular and showed a dispersed population of large round cells having abundant pale eosinophilic cytoplasm, centrally to eccentrically placed nucleus with large prominent nucleoli. Immunohistochemistry was carried out on cell block which was positive for epithelial membrane antigen EMA and Vimentin. It was negative for leucocyte common antigen [LCA], wilms tumor 1, WT1, desmin and neuron specific enolase NSE, thus ruling out other tumors like lymphoma, Wilms tumor, rhabdomyosarcoma, and neuroblastoma. A final diagnosis of ERRT was given. ERRT is an extremely rare tumor of retroperitoneal area; it should be included in the differential diagnosis of malignant round cell tumor in children. Cell block in this case is mandatory for putting up the panel of immunohistochemistry which can clinch the diagnosis of rhabdoid tumor and treatment can be started as early as possible.

Mestre-Fusco A, Trampal C, Intriago B, et al.
Assessment of rhabdoid brain tumor by F-18 FDG PET, C-11 methionine PET and MRI.
Clin Nucl Med. 2012; 37(2):e33-5 [PubMed]

A 28-year-old man with headache, nausea, and decreased vision had a left parieto-occipital tumor demonstrated by MRI. Postradical resection and histology showed a solid mass containing rhabdoid cells, 10% positive for Ki-67. After completing chemotherapy and radiotherapy treatment, follow-up MRI revealed possible tumoral recurrence. Cerebral F-18 FDG PET revealed no pathologic uptake, and C-11 methionine PET showed a pathologic low uptake. These findings suggested recurrence of a mild-grade aggressiveness tumor, which was confirmed by a second neurosurgical resection.

Kuge A, Sato S, Sakurada K, et al.
Atypical teratoid rhabdoid tumor located in the pineal region following prophylactic irradiation for acute lymphoblastic leukemia.
Brain Tumor Pathol. 2012; 29(3):177-81 [PubMed]

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.

Buscariollo DL, Park HS, Roberts KB, Yu JB
Survival outcomes in atypical teratoid rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epidemiology, and End Results analysis.
Cancer. 2012; 118(17):4212-9 [PubMed]

BACKGROUND: Atypical teratoid rhabdoid tumor (ATRT) is a rare central nervous system malignancy with a poor prognosis that affects mostly young children. Although radiotherapy (RT) historically has been delayed in patients aged <3 years, emerging evidence suggests a role for RT to achieve long-term survivorship. Clinical features and age-dependent trends of RT use were evaluated for patients with ATRT.
METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify 144 patients with ATRT from 1973 to 2008. The primary endpoint was median overall survival (OS). Clinical and treatment variables were assessed for an association with OS using Cox proportional hazards models. Landmark analysis was used to correct for immortal time bias of adjuvant RT.
RESULTS: The median age at diagnosis was 1 year (range, 0-67 years). Gross total resection of the primary tumor was achieved in 39% of patients, and 33% of patients received RT. From 1992 to 2008, RT use increased 2.4-fold in patients aged ≤3 years. The median OS for was 10 months. In multivariate analyses, metastatic disease (hazard ratio, 2.83; 95% confidence interval, 1.53-5.23; P = .001) and RT (hazard ratio, 0.10; 95% confidence interval, 0.01-0.73; P = .02) were identified as independent predictors of survival. Landmark analysis confirmed a robust association between RT use and survival, which was attenuated in patients ages 4 to 17 years compared with younger patients.
CONCLUSIONS: The current results indicated that RT may offer a significant survival benefit for patients with ATRT and that patients aged ≤3 years may derive more benefit from initial RT compared with older children. The authors concluded that prospective clinical trials are needed to examine the role of RT in the initial management of ATRT in patients aged <3 years.