ALK Translocation in ALK-Positive Mesenchymal Tumors: Diagnostic and Therapeutic Insights.

CONTEXT.­: A wide spectrum of mesenchymal tumors harboring ALK gene rearrangements has been identified outside the archetypal example of ALK-positive inflammatory myofibroblastic tumors. OBJECTIVE.­: To evaluate the molecular pathology of unusual ALK-positive mesenchymal tumors and their response to ALK-targeted treatments. DESIGN.­: Seven patients with ALK-positive mesenchymal tumors, including inflammatory epithelioid cell sarcoma, undifferentiated sarcoma, histiocytic neoplasm, smooth muscle tumor of uncertain malignant potential (STUMP), and atypical fibrohistiocytic tumor, were included on the basis of aberrant ALK immunoexpression. Patients with inflammatory myofibroblastic tumors were excluded from the study. ALK gene rearrangement was investigated either by fluorescence in situ hybridization or next-generation sequencing. RESULTS.­: ALK was immunolabeled in all patients, diffusely (≥50%) in 6 patients and partially (10%-50%) in 1 patient. ALK gene rearrangement was discovered in 5 of the 6 available patients. The 3'-partners of ALK fusion were identified in 3 of 4 investigated patients as follows: PRKAR1A-ALK (ALK-positive histiocytic neoplasm), TNS1-ALK (STUMP), and KIF5B-ALK (ALK-positive atypical fibrohistiocytic tumor). We failed to discover ALK translocation in 1 patient with ALK-positive inflammatory epithelioid cell sarcoma. However, transcriptomic investigation showed that this tumor was significantly enriched with ALK-related pathways, which suggested activation of ALK through a nontranslocation pathway, as a constitutive oncogenic mark in this tumor. ALK-targeted inhibitors, which were administered to 3 patients with metastatic diseases, achieved partial remission in 1 patient with ALK-positive inflammatory epithelioid cell sarcoma and stable disease in patients with ALK-positive undifferentiated sarcoma and STUMP. CONCLUSIONS.­: Molecular investigation of ALK-positive mesenchymal neoplasms could allow for an accurate diagnosis and personalized treatment.

Revisiting vimentin: a negative surrogate marker of molecularly defined oligodendroglioma in adult type diffuse glioma.

Vimentin is a marker of epithelial-mesenchymal transformation and indicates poor prognosis in various cancers, but its role in diffuse gliomas remains unknown. We investigated the vimentin expression of diffuse gliomas according to the upcoming 2021 WHO classification, its variations due to mutational status, and its prognostic effects. We analyzed vimentin immunohistochemistry in 315 gliomas: a test set (n = 164) and a validation set (n = 151). RNA-seq and mutational information from The Cancer Genome Atlas (TCGA, n = 422) were also used for validation. Vimentin was diffusely positive in astrocytic tumors but negative in oligodendroglial tumors (ODGs) and its expression was significantly higher in isocitrate dehydrogenase (IDH) wild-type tumors. High vimentin expression was correlated with poor prognosis (hazard ratio [HR]: 5.99), but it was dependent on the new WHO grade which reflects both histologic features and genetics (HR: 1.28). Using the significant difference in vimentin expression between ODGs and astrocytic tumors, the positive and negative predictive values of the vimentin-based diagnosis for ODGs were 93.5% and 97.8% in the validation set. Along with additional alpha-thalassemia/mental retardation, X-linked (ATRX) immunohistostaining, the values were 98.3% and 97.8%, respectively. Vimentin is a useful ancillary marker for identifying ODGs when combined with routine histochemistry markers.

The substantial loss of H3K27me3 can stratify risk in grade 2, but not in grade 3 meningioma.

Trimethylation of lysine 27 of histone H3 (H3K27me3) has recently emerged as a crucial epigenetic marker in meningioma. The loss of H3K27me3 expression might predict the early recurrence of grade 1 and 2 meningiomas. However, this is controversial in terms of grade 3 meningioma and the effects of H3K27me3 on the overall survival (OS) of patients with low low-grade meningioma have not been studied. Therefore, we immunohistochemically assessed the prognostic implications of H3K27me3 expression in grade 2 and 3 meningiomas. Whole-slide H3K27me3 immunostaining was evaluated for strict quality control and to confirm a significant correlation (P < .0001) with tissue microarray results. The effects of tissue age on H3K27me3 immunostaining were also evaluated, to select an appropriate cohort for survival analysis. Log-rank tests of 115 grade 2 meningiomas and 26 grade 3 meningiomas showed that the loss of H3K27me3 expression was a prognostic factor for early recurrence (P < .0001) and death (P = .00012) in grade 2, but not in grade 3 meningioma. Multivariate analysis revealed that age, recurrent tumor, and loss of H3K27me3 expression (hazard ratio, 1.264-7.510; P = .0133) were significant for recurrentrecurrence-free survival (RFS), and that recurrent tumor and loss of H3K27me3 expression (hazard ratio, 1.717-120.621; P = .0140) were significant for OS. We concluded that H3K27me3 expression is a significant prognostic factor for the RFS and OS of patients with grade 2 meningioma; it should be considered as an ancillary test for risk stratification of this meningioma.

Inflammatory Myofibroblastic Tumor of the Retroperitoneum Including Chronic Granulomatous Inflammation Suggesting Tuberculosis: A Case Report.

An inflammatory myofibroblastic tumor (IMT) is a solid tumor of unknown etiology frequently affecting children and young adults and commonly affecting the lung or orbital region. We present a case involving a 41-year-old man who had an IMT combined with Mycobacterium tuberculosis infection in the retroperitoneum. He presented with only pain in the right lower abdomen without accompanying symptoms; a retroperitoneal mass was found on computed tomography. The tumor had invaded the end of the ileum and was attached to the omentum, so mass excision could not be performed. The tumor was completely excised surgically and had histological features diagnostic of an IMT. Histologic findings of the omentum were positive for Ziehl-Nielsen staining for acid-fast bacilli and for a positive polymerase chain reaction for M. tuberculosis. The patient had no apparent immune disorder. These findings made this case exceptional because IMTs, which are mostly due to atypical mycobacteria, have been found mainly in immunocompromised patients.

Intracranial Ewing sarcoma with whole genome study.

INTRODUCTION: Ewing sarcoma (ES) as a primary intracranial tumor is very rare. Recently, CNS embryonal tumors with ES-like genomic change have been reported. Patients and methods We report a case of intracranial Ewing sarcoma in a 13-year-old girl who complained of headache and migraine. The tumor had developed in the right middle cranial fossa with a mass effect on the brain with impending transuncal herniation. RESULTS: Undifferentiated small round cell morphology with completely negative results for friend leukemia integration 1 transcription factor (Fli-1) and a nonspecific cytoplasmic CD99-positive staining pattern mislead the diagnosis as central nervous system (CNS) embryonal tumor, NOS. However, whole genome sequencing (WGS) revealed Ewing sarcoma (EWS)-Fli-1 gene fusion, which was confirmed by fluorescence in situ hybridization study and the diagnosis was revised to ES. CONCLUSIONS: This case is a true intracranial but extra-axial ES confirmed by WGS. We report this case of intracranial ES to demonstrate the importance of marker gene studies using FISH or NGS.

Recent Advancement of the Molecular Diagnosis in Pediatric Brain Tumor.

Recent discoveries of brain tumor-related genes and fast advances in genomic testing technologies have led to the era of molecular diagnosis of brain tumor. Molecular profiling of brain tumor became the significant step in the diagnosis, the prediction of prognosis and the treatment of brain tumor. Because traditional molecular testing methods have limitations in time and cost for multiple gene tests, next-generation sequencing technologies are rapidly introduced into clinical practice. Targeted sequencing panels using these technologies have been developed for brain tumors. In this article, focused on pediatric brain tumor, key discoveries of brain tumor-related genes are reviewed and cancer panels used in the molecular profiling of brain tumor are discussed.

Brunner's gland hamartoma: computed tomographic findings with histopathologic correlation in 9 cases.

OBJECTIVE: To describe the computed tomographic (CT) features of Brunner's gland hamartoma with histopathologic correlation. METHODS: The CT images of 9 patients with pathologically proven Brunner's gland hamartoma were reviewed retrospectively. All patients underwent CT performed on multidetector-row CT scanner with various protocols, all of which included portal venous phase. RESULTS: Brunner's gland hamartomas presented as small (mean, 1.9 cm) Yamada type II or III (67%, 6/9) polyps with frequent internal cyst (33%, 3/9). They were isoattenuated on unenhanced CT (83%, 5/6) and hypoattenuated in portal phase (56%, 5/9) when compared with the pancreas. Peripheral rimlike enhancement in earlier phase was commonly found (67%, 6/9) and most of them enhanced homogeneously in the later phase (100%, 4/4). CONCLUSIONS: In a patient with asymptomatic small submucosal mass in the duodenal first or second portion, hypoattenuated mass with peripheral rimlike enhancement or internal cystic change suggests the possibility of Brunner's gland hamartoma.