ABSTRACT
A female in her 60's presented with a left-sided breast mass. A core needle biopsy specimen showed diffuse proliferation of a round cell tumor, which was positive for vimentin, NKX2.2, BCOR, and focal CD99 on immunohistochemistry (IHC). No fusion genes of the Ewing family sarcomas were detected. With a tentative diagnosis of primary breast sarcoma (PBS), total mastectomy was performed after chemotherapy. The resected tissues showed proliferation of round or spindle-shaped tumor cells with a high nuclear-to-cytoplasmic ratio, exhibiting solid and fascicular arrangements but no epithelial component or organoid pattern. While IHC indicated no particular histological diagnosis, genomic examination revealed gene alterations in MED12 p.G44D, MLL2 (KMT2D) p.T1496fs*27, and EGFR variant III (vIII). Moreover, a retrospective IHC study showed overexpression of EGFRvIII. A malignant phyllodes tumor (PT) with extensive sarcomatous overgrowth was indicated as an integrative diagnosis. This is a rare case of a malignant PT harboring EGFRvIII. The present case provides an importance of accurate diagnosis and genomic analysis of rare breast tumors, as malignant PT and PBS are different in its treatment strategy and prognosis.
Subject(s)
Biomarkers, Tumor , Breast Neoplasms , ErbB Receptors , Immunohistochemistry , Mutation , Phyllodes Tumor , Humans , Female , Phyllodes Tumor/genetics , Phyllodes Tumor/pathology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Middle Aged , ErbB Receptors/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Homeobox Protein Nkx-2.2 , DNA-Binding Proteins/genetics , Homeodomain Proteins , Nuclear Proteins , Mediator Complex , Transcription Factors , Neoplasm ProteinsABSTRACT
Background: Glioblastoma (GBM) is a malignant brain tumor, with radiological and genetic heterogeneity. We examined the association between radiological characteristics and driver gene alterations. Methods: We analyzed the driver genes of 124 patients with IDH wild-type GBM with contrast enhancement using magnetic resonance imaging. We used a next-generation sequencing panel to identify mutations in driver genes and matched them with radiological information. Contrast-enhancing lesion localization of GBMs was classified into 4 groups based on their relationship with the subventricular zone (SVZ) and cortex (Ctx). Results: The cohort included 69 men (55.6%) and 55 women (44.4%) with a mean age of 66.4â ±â 13.3 years. EGFR and PDGFRA alterations were detected in 28.2% and 22.6% of the patients, respectively. Contrast-enhancing lesion touching both the SVZ and Ctx was excluded because it was difficult to determine whether it originated from the SVZ or Ctx. Contrast-enhancing lesions touching the SVZ but not the Ctx had significantly worse overall survival than non-SVZ lesions (441 days vs. 897 days, Pâ =â .002). GBM touching only the Ctx had a better prognosis (901 days vs. 473 days, Pâ <â .001) than non-Ctx lesions and was associated with EGFR alteration (39.4% vs. 13.2%, Pâ =â .015). Multiple contrast lesions were predominant in PDGFRA alteration and RB1-wild type (Pâ =â .036 and Pâ =â .031, respectively). Conclusions: EGFR alteration was associated with cortical lesions. And PDGFRA alteration correlated with multiple lesions. Our results suggest that clarifying the association between driver genes and tumor localization may be useful in clinical practice, including prognosis prediction.
ABSTRACT
Background: Telomerase reverse transcriptase promoter (TERTp) mutations are a biological marker of glioblastoma; however, the prognostic significance of TERTp mutational status is controversial. We evaluated this impact by retrospectively analyzing the outcomes of patients with isocitrate dehydrogenase (IDH)- and TERTp-wild-type glioblastomas. Methods: Using custom next-generation sequencing, we analyzed 208 glioblastoma samples harboring wild-type IDH. Results: TERTp mutations were detected in 143 samples (68.8%). The remaining 65 (31.2%) were TERTp-wild-type. Among the TERTp-wild-type glioblastoma samples, we observed a significant difference in median progression-free survival (18.6 and 11.4 months, respectively) and overall survival (not reached and 15.7 months, respectively) in patients with and without phosphatase and tensin homolog (PTEN) loss and/or mutation. Patients with TERTp-wild-type glioblastomas with PTEN loss and/or mutation were younger and had higher Karnofsky Performance Status scores than those without PTEN loss and/or mutation. We divided the patients with TERTp-wild-type into 3 clusters using unsupervised hierarchical clustering: Good (PTEN and TP53 alterations; lack of CDKN2A/B homozygous deletion and platelet-derived growth factor receptor alpha (PDGFRA) alterations), intermediate (PTEN alterations, CDKN2A/B homozygous deletion, lack of PDGFRA, and TP53 alterations), and poor (PDGFRA and TP53 alterations, CDKN2A/B homozygous deletion, and lack of PTEN alterations) outcomes. Kaplan-Meier survival analysis indicated that these clusters significantly correlated with the overall survival of TERTp-wild-type glioblastoma patients. Conclusions: Here, we report that PTEN loss and/or mutation is the most useful marker for predicting favorable outcomes in patients with IDH- and TERTp-wild-type glioblastomas. The combination of 4 genes, PTEN, TP53, CDKN2A/B, and PDGFRA, is important for the molecular classification and individual prognosis of patients with IDH- and TERTp-wild-type glioblastomas.
ABSTRACT
Amplification of the epidermal growth factor receptor gene (EGFR) and its variants are the most commonly detected pathogenic gene alterations in glioblastoma. Herein, we report a case of molecularly defined glioblastoma harboring an EGFR variant III (EGFRvIII) without EGFR amplification. The initial histological diagnosis was isocitrate dehydrogenase (IDH)-wildtype low-grade glioma, due to an absence of anaplasia, necrosis, and microvascular proliferation, and a low Ki-67 labeling index. DNA-based next-generation sequencing (NGS) panel analysis revealed a TERTp promoter mutation but no EGFR mutation or amplification, supporting the diagnosis of "molecular glioblastoma." However, RNA-based NGS panel analysis revealed mRNA expression of EGFRvIII. Therefore, the final integrative diagnosis was glioblastoma with non-amplified EGFRvIII. Our report suggests that non-amplified EGFRvIII might be an early molecular event in glioblastoma tumorigenesis. In addition to the usual DNA-based analysis, RNA-based analysis is required to identify exon-skipping EGFR variants without EGFR amplification.
Subject(s)
Brain Neoplasms , Glioblastoma , Glioma , Humans , Glioblastoma/diagnosis , Glioblastoma/genetics , Glioblastoma/pathology , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Glioma/genetics , Mutation/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolismABSTRACT
BACKGROUND: We aimed to evaluate the mutation profile, transcriptional variants, and prognostic impact of the epidermal growth factor receptor (EGFR) gene in isocitrate dehydrogenase (IDH)-wildtype glioblastomas (GBMs). METHODS: We sequenced EGFR, evaluated the EGFR splicing profile using a next-generation sequencing oncopanel, and analyzed the outcomes in 138 grade IV IDH-wildtype GBM cases. RESULTS: EGFR mutations were observed in 10% of GBMs. A total of 23.9% of the GBMs showed EGFR amplification. Moreover, 25% of the EGFR mutations occurred in the kinase domain. Notably, EGFR alterations were a predictor of good prognosis (p = 0.035). GBM with EGFR alterations was associated with higher Karnofsky Performance Scale scores (p = 0.014) and lower Ki-67 scores (p = 0.005) than GBM without EGFR alterations. EGFRvIII positivity was detected in 21% of EGFR-amplified GBMs. We identified two other EGFR variants in GBM cases with deletions of exons 6-7 (Δe 6-7) and exons 2-14 (Δe 2-14). In one case, the initial EGFRvIII mutation transformed into an EGFR Δe 2-14 mutation during recurrence. CONCLUSIONS: We found that the EGFR gene profiles of GBM differ among cohorts and that EGFR alterations are good prognostic markers of overall survival in patients with IDH-wildtype GBM. Additionally, we identified rare EGFR variants with longitudinal and temporal transformations of EGFRvIII.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/genetics , Prognosis , Isocitrate Dehydrogenase/genetics , Genes, erbB-1 , Brain Neoplasms/genetics , Mutation , ErbB Receptors/genetics , ErbB Receptors/metabolism , GenomicsABSTRACT
Background: Platelet-derived growth factor receptor alpha (PDGFRA) is the second most frequently mutated tyrosine kinase receptor in glioblastoma (GBM). However, the prognostic impact of PDGFRA amplification on GBM patients remains unclear. Herein, we evaluated this impact by retrospectively analyzing outcomes of patients with IDH wild-type GBM. Methods: Using a custom-made oncopanel, we evaluated PDGFRA gain/amplification in 107 GBM samples harboring wild-type IDH, along with MGMT promoter (MGMTp) methylation status. Results: We detected PDGFRA gain/amplification in 31 samples (29.0%). PDGFRA gain/amplification predicted poor prognosis (P = .003). Compared to unamplified PDGFRA, PDGFRA gain/amplification in GBM was associated with higher patient age (P = .031), higher Ki-67 score (P = .019), and lower extent of surgical resection (P = .033). Unmethylated MGMTp also predicted poor prognosis (P = .005). As PDGFRA gain/amplification and unmethylated MGMTp were independent factors for poor prognosis in multivariate analyses, we grouped GBM cases based on PDGFRA and MGMTp status: poor (PDGFRA gain/amplification and unmethylated MGMTp), intermediate (PDGFRA gain/amplification or unmethylated MGMTp), and good (PDGFRA intact and methylated MGMTp) prognosis. The Kaplan-Meier survival analysis indicated that these groups significantly correlated with the OS of GBM patients (P < .001). Conclusions: Here we report that PDGFRA gain/amplification is a predictor of poor prognosis in IDH wild-type GBM. Combining PDGFRA gain/amplification with MGMTp methylation status improves individual prognosis prediction in patients with IDH wild-type GBM.
ABSTRACT
Prediction of tumor consistency is valuable for planning transsphenoidal surgery for pituitary adenoma. A prospective study was conducted involving 49 participants with pituitary adenoma to determine whether quantitative pharmacokinetic analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is useful for predicting consistency of adenomas. Pharmacokinetic parameters in the adenomas including volume of extravascular extracellular space (EES) per unit volume of tissue (ve), blood plasma volume per unit volume of tissue (vp), volume transfer constant between blood plasma and EES (Ktrans), and rate constant between EES and blood plasma (kep) were obtained. The pharmacokinetic parameters and the histologic percentage of collagen content (PCC) were compared between soft and hard adenomas using Mann-Whitney U test. Pearson's correlation coefficient was used to correlate pharmacokinetic parameters with PCC. Hard adenomas showed significantly higher PCC (44.08 ± 15.14% vs. 6.62 ± 3.47%, p < 0.01), ve (0.332 ± 0.124% vs. 0.221 ± 0.104%, p < 0.01), and Ktrans (0.775 ± 0.401/min vs. 0.601 ± 0.612/min, p = 0.02) than soft adenomas. Moreover, a significant positive correlation was found between ve and PCC (r = 0.601, p < 0.01). The ve derived using DCE-MRI may have predictive value for consistency of pituitary adenoma.
ABSTRACT
Adamantinomatous craniopharyngiomas (ACP) are characterized by alterations in the CTNNB1 gene while almost all papillary craniopharyngiomas (PCP) harbor a canonical V600E mutation in the BRAF gene. Although other recurrent driver genes have not been described to date in craniopharyngiomas, the heterogeneous clinical course of these tumors might be associated with the acquisition of further genomic alterations. It is well known that telomerase reverse transcriptase (TERT) promoter (TERTp) alterations, including mutations or methylation, upregulate the expression of TERT and increase telomerase activity, promoting tumorigenesis. We investigated whether TERTp mutations or methylation are associated with tumor relapse in a subset of craniopharyngiomas. Samples from 42 patients with histologically confirmed craniopharyngioma were retrieved. We determined TERTp, BRAF, and CTNNB1 hotspot mutations in all samples using targeted sequencing and the TERTp methylation status by methylation-specific polymerase chain reaction (PCR) in 30 samples. While BRAF V600E mutations and CTNNB1 mutations were detected in 12 (28.6%) and 21 patients (50%) in the initial tumors and subsequent recurrences, respectively, none of the patients in our cohort, including those with multiple relapses, harbored a TERTp mutation. Furthermore, TERTp methylation was detected in 14 out of 24 cases (58.3%) with available primary samples; however, no correlation between TERTp methylation with the pathological subtype, genotype, or tumor aggressiveness was detected. These data suggest that elevated telomerase activity via acquisition of TERTp mutations is an infrequent pathway in the tumorigenesis of craniopharyngiomas, regardless of their clinical course.
Subject(s)
Craniopharyngioma , Pituitary Neoplasms , Telomerase , Craniopharyngioma/genetics , Humans , Mutation , Neoplasm Recurrence, Local/genetics , Pituitary Neoplasms/genetics , Promoter Regions, Genetic/genetics , Telomerase/geneticsABSTRACT
BACKGROUND: High-grade meningiomas are aggressive tumors with high morbidity and mortality rates that frequently recur even after surgery and adjuvant radiotherapy. However, limited information is currently available on the biology of these tumors, and no alternative adjuvant treatment options exist. Although we previously demonstrated that high-grade meningioma cells were highly sensitive to gemcitabine in vitro and in vivo, the underlying molecular mechanisms remain unknown. METHODS: We examined the roles of hENT1 (human equilibrative nucleoside transporter 1) and dCK (deoxycytidine kinase) in the gemcitabine sensitivity and growth of meningioma cells in vitro. Tissue samples from meningiomas (26 WHO grade I and 21 WHO grade II/III meningiomas) were immunohistochemically analyzed for hENT1 and dCK as well as for Ki-67 as a marker of proliferative activity. RESULTS: hENT1 and dCK, which play critical roles in the intracellular transport and activation of gemcitabine, respectively, were responsible for the high gemcitabine sensitivity of high-grade meningioma cells and were strongly expressed in high-grade meningiomas. hENT1 expression was required for the proliferation and survival of high-grade meningioma cells and dCK expression. Furthermore, high hENT1 and dCK expression levels correlated with stronger tumor cell proliferative activity and shorter survival in meningioma patients. CONCLUSIONS: The present results suggest that hENT1 is a key molecular factor influencing the growth capacity and gemcitabine sensitivity of meningioma cells and also that hENT1, together with dCK, may be a viable prognostic marker for meningioma patients as well as a predictive marker of their responses to gemcitabine.
Subject(s)
Meningeal Neoplasms , Meningioma , Pancreatic Neoplasms , Antimetabolites, Antineoplastic/therapeutic use , Deoxycytidine/analogs & derivatives , Deoxycytidine Kinase/metabolism , Deoxycytidine Kinase/therapeutic use , Equilibrative Nucleoside Transporter 1 , Humans , Meningeal Neoplasms/drug therapy , Meningioma/drug therapy , GemcitabineABSTRACT
Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, including IDH1/2 and H3-K27M mutations, as well as 1p/19q codeletion. Here, we aimed to develop and assess the feasibility of a glioma-tailored 48-gene next-generation sequencing (NGS) panel for integrated glioma diagnosis. We designed a glioma-tailored 48-gene NGS panel for detecting 1p/19q codeletion and mutations in IDH1/2, TP53, PTEN, PDGFRA, NF1, RB1, CDKN2A/B, CDK4, and the TERT promoter (TERTp). We analyzed 106 glioma patients (grade II: 19 cases, grade III: 23 cases, grade IV: 64 cases) using this system. The 1p/19q codeletion was detected precisely in oligodendroglial tumors using our NGS panel. In a cohort of 64 grade â £ gliomas, we identified 56 IDH-wildtype glioblastomas. Within these IDH-wildtype glioblastomas, 33 samples (58.9%) showed a mutation in TERTp. Notably, PDGFRA mutations and their amplification were more commonly seen in TERTp-wildtype glioblastomas (43%) than in TERTp-mutant glioblastomas (6%) (P = .001). Hierarchical molecular classification of IDH-wildtype glioblastomas revealed 3 distinct groups of IDH-wildtype glioblastomas. One major cluster was characterized by mutations in PDGFRA, amplification of CDK4 and PDGFRA, homozygous deletion of CDKN2A/B, and absence of TERTp mutations. This cluster was significantly associated with older age (P = .021), higher Ki-67 score (P = .007), poor prognosis (P = .012), and a periventricular tumor location. We report the development of a glioma-tailored NGS panel for detecting 1p/19q codeletion and driver gene mutations on a single platform. Our panel identified distinct subtypes of IDH- and TERTp-wildtype glioblastomas with frequent PDGFRA alterations.
Subject(s)
Glioblastoma/genetics , Isocitrate Dehydrogenase/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Telomerase/genetics , Adult , Aged , Aged, 80 and over , Female , Glioblastoma/classification , Glioblastoma/pathology , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Neoplasm Proteins/genetics , Promoter Regions, Genetic/geneticsABSTRACT
BACKGROUND: Cases of primary central nervous system lymphoma manifesting with hemorrhage are very rare, with only a few previous studies available. CASE DESCRIPTION: A 49-year-old man presented with occipital headache and visual disturbance for the past 4 months. Computed tomography showed a high-density area involving the left basal ganglia, with surrounding vasogenic edema. Head T2∗-weighted imaging showed a hypointense signaling area. Edematous changes and a midline shift were observed on fluid attenuated inversion recovery magnetic resonance imaging. Radiologic features were highly suggestive of intracerebral hemorrhage. Methylprednisolone pulse therapy improved his symptoms transiently and reduced the size of the lesion. Nonetheless, there was recurrence 1 month later. The patient was referred to our institution; a biopsy was performed, and a diffuse large B-cell lymphoma was diagnosed. After 3 cycles of high-dose methotrexate and whole-brain radiation therapy, his symptoms improved, and there were no signs of recurrence. CONCLUSIONS: We report a very rare case of diffuse large B-cell lymphoma manifested with intratumoral hemorrhage. This case indicates the importance of regular clinical and radiologic follow-up, histopathologic examination, and combined treatment with high-dose methotrexate and whole-brain radiation therapy.
Subject(s)
Brain Neoplasms/pathology , Cerebral Hemorrhage/etiology , Lymphoma, Large B-Cell, Diffuse/pathology , Antimetabolites, Antineoplastic/therapeutic use , Brain Neoplasms/therapy , Chemoradiotherapy/methods , Cranial Irradiation/methods , Humans , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Methotrexate/therapeutic use , Middle AgedABSTRACT
BACKGROUND: Sellar neuroblastoma is a very rare entity. We report a rare case of arginine vasopressin (AVP)- producing sellar neuroblastoma presumed to have originated from the lower part of sellar turcica, which grew very rapidly. CASE DESCRIPTION: A 33-year-old woman was found to have a sellar lesion with a diameter of 18 mm invading into the bilateral cavernous sinus on magnetic resonance imaging (MRI) performed for dizziness. Six years later, when she visited the clinic due to bilateral visual disturbance, MRI showed a rapid growth of the tumor, with a maximal diameter of 56 mm at the current state, strongly compressing the optic nerve and chiasm. Transsphenoidal decompression of the optic chiasm revealed an intact pituitary gland on the top of the tumor. The tumor was composed of neoplastic cells that were immunohistochemically positive for neuronal markers and arginine vasopressin (AVP), but negative for all anterior pituitary hormones, glial fibrillary acidic protein, or thyroid transcription factor-1; these findings were suggestive of sellar neuroblastoma. She underwent 50-Gy radiation therapy, which has controlled the growth for the past 3 years. CONCLUSION: Awareness of rare sellar neuroblastomas will allow the accumulation of clinicopathologic information that may facilitate the understanding of their origin, clinical features, neuroimaging characteristics, and pertinent adjuvant treatment.
ABSTRACT
We treated an extremely rare thyroid-stimulating hormone (TSH)-producing pituitary adenoma in a 63-year-old woman with severe hypothyroidism due to autoimmune thyroiditis. She was presented with dizziness and fatigue. The blood level of TSH, prolactin, and fT4 was 288.2 µIU/mL, 72.9 ng/mL, and 0.24 ng/dL, respectively. Magnetic resonance imaging demonstrated a large pituitary tumor, 31 mm in height, and a normal pituitary gland. Preoperative thyroxine replacement reduced the TSH level to 2.05 µIU/mL and produced a significant reduction in the tumor volume. Histopathologically, the surgically removed tumor was a TSH-producing pituitary adenoma.
ABSTRACT
Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by rapid proliferation, aggressive migration, and invasion into normal brain tissue. Formin proteins have been implicated in these processes. However, the role of formin-like 1 (FMNL1) in cancer remains unclear. We studied FMNL1 expression in glioblastoma samples using immunohistochemistry. We sought to analyze the correlation between FMNL1 expression, clinicopathologic variables, and patient survival. Migration and invasion assays were used to verify the effect of FMNL1 on glioblastoma cell lines. Microarray data were downloaded from The Cancer Genome Atlas and analyzed using gene set enrichment analysis (GSEA). FMNL1 was an independent predictor of poor prognosis in a cohort of 217 glioblastoma multiforme cases (p < 0.001). FMNL1 expression was significantly higher in the mesenchymal subtype. FMNL1 upregulation and downregulation were associated with mesenchymal and proneural markers in the GSEA, respectively. These data highlight the important role of FMNL1 in the neural-to-mesenchymal transition. Conversely, FMNL1 downregulation suppressed glioblastoma multiforme cell migration and invasion via DIAPH1 and GOLGA2, respectively. FMNL1 downregulation also suppressed actin fiber assembly, induced morphological changes, and diminished filamentous actin. FMNL1 is a promising therapeutic target and a useful biomarker for GBM progression.
Subject(s)
Brain Neoplasms/metabolism , Formins/metabolism , Glioblastoma/metabolism , Mesoderm/metabolism , Autoantigens/genetics , Autoantigens/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Female , Formins/genetics , Gene Expression Regulation, Neoplastic , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mesoderm/pathology , Prognosis , RNA Interference , Survival AnalysisABSTRACT
BACKGROUND: Intracranial schwannomas are rarely confined to the skull. We here report a large schwannoma localized in the petrous apex that presented with intratumoral hemorrhage. CASE DESCRIPTION: A 35-year-old woman with mild hearing disturbance and ear fullness underwent computed tomography scan and magnetic resonance imaging, which demonstrated a tumor accompanied with intratumoral hematoma in the right petrous apex. Bone marrow was totally destroyed, but the bone cortex was relatively preserved. Pathologic specimen showed that the tumor was composed of proliferation of elongated neoplastic cells and positive for S-100 protein. It showed a nuclear palisading pattern, compatible with schwannoma. The lack of any cranial nerve signs and relative preservation of canals through which cranial nerves pass suggested the neurilemma cells surrounded vessels or mismigrated fetal neurilemma cells in the petrous apex as origin of the tumor. Benign nature of the tumor and total disappearance of the symptoms, supposedly due to the spontaneous absorption of the hematoma, made the patient choose a wait-and-watch approach. Magnetic resonance imaging studied 7 years after the diagnosis showed significant decrease of the tumor volume and disappearance of the hematoma. CONCLUSIONS: Although it is a large intraosseous schwannoma in the petrous apex, it has a benign nature, its size is reduced due to the hematoma absorption, and the patient is asymptomatic. We observed the patients for 7 years after the diagnosis.
Subject(s)
Intracranial Hemorrhages/diagnostic imaging , Neurilemmoma/diagnostic imaging , Petrous Bone/diagnostic imaging , Adult , Biopsy , Female , Hearing Loss, Conductive/etiology , Humans , Intracranial Hemorrhages/complications , Magnetic Resonance Imaging , Neurilemmoma/blood supply , Neurilemmoma/complications , Neurilemmoma/pathology , Tumor BurdenABSTRACT
BACKGROUND: Xanthogranuloma is a chronic inflammatory mass characterized by cholesterol crystal deposition, which is rarely seen in the sellar region. The objective of this study is to identify the clinical features and cause of sellar xanthogranulomas. METHODS: We retrospectively analyzed manifestation, radiographic, and endocrinologic presentation in 9 patients (7 women and 2 men) whom we had previously treated. RESULTS: The patients were between 26 and 73 years of age (median, 56 years). The chief symptoms were visual symptoms in 3, polyuria in 3, headache in 4, and tiredness in 4 patients. Perimetry found visual field deficit in 6 patients. Anterior pituitary provocation tests disclosed impairment of ≥1 hormone in all patients: growth hormone in 8 patients and adrenocorticotropic hormone-cortisol axis in 8 patients. The lesions were suprasellar in 2 patients, intrasellar in 2 patients, and intrasuprasellar region in 5 patients. Three of the lesions were solid and 6 were single cystic to multicystic. Very low intensity area on T2-weighted magnetic resonance imaging was observed in 4 lesions. Postcontrast study performed in 7 lesions showed enhancement in solid parts or cyst walls. Surgical decompression improved visual disturbance in half of the patients but rarely improved hormonal deficits. Follow-up (median, 47 months) found no recurrence of the lesion. In addition to these 9 cases, we found 2 xanthogranulomatous lesions pathologically associated with ciliated epithelia, which also presented with severe hypopituitarism. CONCLUSIONS: Xanthogranuloma seems to be the last stage of the chronic inflammation affecting Rathke cleft cyst or craniopharyngioma presenting with severe anterior pituitary insufficiency.
Subject(s)
Granuloma/complications , Granuloma/pathology , Hypopituitarism/complications , Pituitary Neoplasms/complications , Sella Turcica/pathology , Xanthomatosis/complications , Xanthomatosis/pathology , Adult , Aged , Female , Granuloma/diagnostic imaging , Humans , Hypopituitarism/diagnosis , Hypopituitarism/pathology , Male , Middle Aged , Pituitary Gland, Anterior/diagnostic imaging , Pituitary Gland, Anterior/pathology , Pituitary Neoplasms/diagnostic imaging , Pituitary Neoplasms/pathology , Retrospective Studies , Sella Turcica/diagnostic imaging , Xanthomatosis/diagnostic imagingABSTRACT
BACKGROUND: Glioblastoma multiforme (GBM), the most common brain malignancy in adults, is generally aggressive and incurable, even with multiple treatment modalities and agents. Filamins (FLNs) are a group of actin-binding proteins that regulate the actin cytoskeleton in cells. However, the role of FLNs in malignancies-particularly in GBM-is unclear. METHODS: The relation between FLNC expression and overall survival in GBM was evaluated by the Kaplan-Meier analysis using GBM patients from the Kagoshima University Hospital (n = 90) and data from the Cancer Genome Atlas (TCGA) (n = 153). To assess FLNC function in GBM, cell migration and invasion were examined with Transwell and Matrigel invasion assays using FLNC-overexpressing U251MG and LN299 GBM cells, and ShRNA-mediated FLNC knocked-down KNS81 and U87MG cells. The gelatin zymography assay was used to estimate matrix metalloproteinase (MMP) 2 activity. RESULTS: In silico analysis of GBM patient data from TCGA and immunohistochemical analyses of clinical GBM specimens revealed that increased FLNC expression was associated with poor patient prognosis. FLNC overexpression in GBM cell lines was positively correlated with enhanced invasiveness, but not migration, and was accompanied by upregulation of MMP2. CONCLUSIONS: FLNC is a potential therapeutic target and biomarker for GBM progression.
Subject(s)
Biomarkers, Tumor/genetics , Filamins/genetics , Glioblastoma/genetics , Neoplasm Invasiveness/genetics , Actin Cytoskeleton/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Female , Gene Expression Regulation, Neoplastic/genetics , Glioblastoma/epidemiology , Glioblastoma/pathology , Humans , Kaplan-Meier Estimate , Male , Matrix Metalloproteinase 2/genetics , Neoplasm Invasiveness/pathologyABSTRACT
BACKGROUND: Papillary craniopharyngiomas are characterized by BRAFV600E mutations. Targeted therapy can elicit a dramatic radiographic regression of these tumors. Therefore, prediction of BRAF mutation status before definitive surgery could enable neoadjuvant treatment strategies. OBJECTIVE: To establish preoperative prediction criteria to identify patients with a BRAF mutant craniopharyngioma. METHODS: Sixty-four patients with craniopharyngioma were included in this study. We determined BRAF mutation status by targeted sequencing. After scoring interobserver variability between presurgical clinical data and radiographic features, we established a diagnostic rule for BRAF mutation in our discovery cohort. We then validated the rule in an independent cohort. RESULTS: The BRAFV600E mutation was detected in 12 of 42 patients in the discovery cohort. There were no patients under age 18 with BRAF mutation. Calcification was rare in tumors with BRAF mutation (P < .001), and 92% of them were supradiaphragmatic in location. Combining these 3 features-older than 18 years, absence of calcification, and supradiaphragmatic tumor location-we established a rule for predicting BRAF mutation. In cases where all 3 criteria were fulfilled, the sensitivity and specificity for the presence of BRAF mutation were 83% and 93%, respectively. In the validation cohort (n = 22), the sensitivity was 100% and specificity was 89%. CONCLUSION: We propose predictive criteria for a BRAF mutation in craniopharyngioma using preoperative clinical and radiographic data. This rule may be useful in identifying patients who could potentially benefit from neoadjuvant BRAFV600E-targeted systemic therapies.