TP53 mutational status is a potential marker for risk stratification in Wilms tumour with diffuse anaplasia.

PURPOSE: The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information. PATIENTS AND METHODS: We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling. RESULTS: From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes. CONCLUSION: This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker.

Evaluation of nuclear unrest and p53 immunostaining in Wilms' tumor.

BACKGROUND: Nuclear unrest is a term applied to Wilms' tumors (WT) that show nuclear abnormalities close to anaplasia but without abnormal mitoses. p53 is claimed to be associated with anaplasia and poor prognosis. This study was undertaken to evaluate the clinical significance of nuclear unrest and p53 immunostaining in Wilms' tumor. MATERIAL AND METHODS: This is a retrospective study of 63 patients who presented at NCI with Wilms' tumors, and underwent preoperative chemotherapy followed by nephrectomy. Histopathologic assessment and p53 immunohistochemistry were done. RESULTS: WT with nuclear unrest grade III closely resembled anaplastic tumors and both of them (group 1) constituted 19% of cases. Group 1 constituted 29% of cases showing blastema dominant morphology compared to 9.4% of cases without blastema dominant morphology with significant statistical difference (p=0.047). Almost 83% of cases that achieved 1st complete remission were stages I, II and III, while 17% were stages IV and V with significant statistical difference (p<0.001). Stage affected the 3-year relapse-free-survival (RFS) significantly (p=0.014) as it was more in stages I, II and III than in stages IV and V (75.4% versus 50%). Blastema dominant morphology and high risk state significantly lowered the 3-year overall survival (OS) into 54.8% in comparison to 80.9% for cases with non-blastema dominant morphology (p=0.042). Regarding p53 immunohistochemistry, group 1 tumors showed positive p53 more than group 2 with significant statistical difference (p=0.014). p53 Positive immunostaining was significantly associated with high risk nephroblastoma (p=0.004). CONCLUSION: Tumor stage and blastema dominant morphology are potent prognostic factors. p53 is linked to blastema dominant morphology. WT with nuclear unrest grade III closely resembles anaplastic WT. It may be appropriate to group tumors with nuclear unrest grade III with anaplastic histology regarding treatment stratification.

Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma.

BACKGROUND: Anti-Human Epithelial Receptor Type 2 (HER2) antibodies have the ability to induce in vitro apoptosis of glioblastoma (GBM) cells. This study was designed to evaluate the variability of HER2 expression in GBM and its role as a possible prognosis factor. METHODS: Data of 57 patients with GBM and 16 patients with grade III gliomas were retrospectively analyzed. The expression of HER2 was determined by immunohistochemistry and intensity was noted from 0+ to 3+. We compared the HER2 expression in de novo GBM and in GBM resulting from anaplastic transformation of low-grade glioma ("secondary GBM"). Statistical analysis was performed using univariate analysis and the Kaplan-Meier method. FINDINGS: All GBM expressing highly HER2 (2+ and 3+) were de novo GBM. All secondary GBM expressed HER2 with low intensity (0+ and 1+). Survival time was significantly longer when HER2 expression was low (Log Rank test P = 0.04). The patterns of HER2 expression were similar between grade III gliomas and secondary GBM. CONCLUSIONS: To our best knowledge, our study showed for the first time a significant association between HER2 expression and the type of GBM, with subsequent influence on survival rate. GBM with low-HER2 expression are more likely to be secondary GBM, carrying a better prognosis than de novo GBM.

Diagnosis and treatment of atypical and anaplastic meningiomas: a review.

Atypical and anaplastic meningiomas are uncommon tumors with a poorer prognosis than benign meningiomas. We reviewed the current literature and attempted to integrate and summarize available information to determine a logical approach to these tumors. Both tumors are rare and are often integrated with benign meningiomas when treatments are evaluated. In addition, because there has not been one histopathological classification scheme for atypical and anaplastic meningiomas in the past, there are numerous inconsistencies in the literature. Malignant progression with accumulation of mutations in a benign meningioma can result in an atypical and/or anaplastic meningioma. Both tumors are difficult to manage and have high recurrence and poor survival rates. The extent of tumor resection and histological grade are the key determinants for recurrence. In addition, metastases are unusual, but they do occur. We also review the evidence available that has resulted in the current World Health Organization classification. Radiation therapy can be used as an adjunctive treatment after both total and subtotal resection. In addition, the role of stereotactic radiosurgery is increasing, along with a possible role for brachytherapy. There are no effective chemotherapeutic agents available. A treatment algorithm is suggested.

Encapsulated anaplastic thyroid carcinoma without invasive phenotype with favorable prognosis: report of a case.

We herein report a case of anaplastic thyroid carcinoma in a 77-year-old woman with long-term disease-free survival. The tumor measured 7.5 x 6.0 cm in size and was diagnosed to be anaplastic carcinoma. We investigated the biological aggressiveness of this carcinoma by means of immunohistochemistry and found it have a high cell-proliferating activity, a disruption in the mechanism of apoptosis, and a high potential of cell spreading, similar to that observed in usual anaplastic carcinomas. The only unique point was that this tumor was encapsulated and no invasion of carcinoma cells beyond the capsule was microscopically observed. To avoid an obstruction of the trachea, a lobectomy without lymph node dissection was performed as a "palliative operation." Although neither adjuvant chemotherapy nor radiotherapy was carried out due to her age, she has nevertheless survived with no evidence of recurrence for 57 months after surgery. The presence of such a type of anaplastic carcinoma should thus be noted by surgeons and pathologists, even though the occurrence of such cases seems to be very rare.

Gangliogliomas: an intriguing tumor entity associated with focal epilepsies.

Gangliogliomas represent the most frequent tumor entity in young patients suffering from chronic focal epilepsies. In a series of 326 gangliogliomas collected from the University of Bonn Epilepsy Surgery Program and other departments of neuropathology in Germany, Austria, and Switzerland, epidemiological findings and histopathological hallmarks of gangliogliomas are systematically reviewed. The majority of these tumors occur within the temporal lobe and reveal a biphasic histological architecture characterized by a combination of dysplastic neurons and neoplastic glial cell elements. However, gangliogliomas exhibit a considerable variability in their histopathological appearance. Immunohistochemical studies are an important tool to discriminate these neoplasms from other tumor entities. Almost 80% of gangliogliomas reveal immunoreactivity for CD34, a stem cell epitope not expressed in normal brain. Immunohistochemical reactions for MAP2 or NeuN can be employed to characterize the dysplastic nature of neurons in those areas difficult to discriminate from pre-existing brain parenchyma. Less than 50% of the cases display binucleated neurons. With the frequent finding of "satellite" tumor clusters in adjacent brain regions, gangliogliomas are microscopically less circumscribed than previously assumed. The distinction from diffusely infiltrating gliomas is of considerable importance since tumor recurrence or malignant progression are rare events in gangliogliomas. Only little is known about the molecular pathogenesis of these glioneuronal tumors. Our findings support a dysontogenic origin from a glioneuronal precursor lesion with neoplastic, clonal proliferation of the glial cell population. Candidate genes appear to associate with neurodevelopmental signaling cascades rather than cell cycle control or DNA repair mechanisms. The reelin signaling and tuberin/insulin growth receptor pathways have recently been implicated in ganglioglioma development. Powerful new molecular genetic and biological tools can now be employed to unravel the pathogenesis of these intriguing lesions.

Association of expression of CD44v6 with systemic anaplastic large cell lymphoma: comparison with primary cutaneous anaplastic large cell lymphoma.

CD44 is a ubiquitous multifunctional cell surface adhesion molecule family. High expression of the standard form, CD44s (CD44), and its variant form, CD44v6, has been reported to be associated with tumor dissemination in non-Hodgkin lymphoma. To evaluate the potential role of CD44 and/or CD44v6 in different entities of anaplastic large cell lymphoma (ALCL), 30 cases of systemic ALCL (sALCL; 20 cases) and primary cutaneous ALCL (cALCL; 10 cases) were compared for expression of CD44 and CD44v6 by immunohistochemical staining. Expression of CD44v6 also was analyzed with respect to expression of anaplastic lymphoma kinase (ALK) in sALCL. No difference of CD44 expression was noted between sALCL and cALCL In contrast, expression of CD44v6 was found in 18 (90%) of sALCL cases and in 5 (50%) of cALCL cases. There was no correlation between expression of CD44v6 and expression of ALK in sALCL. These results indicate that expression of CD44v6 rather than CD44 correlates with sALCL. Furthermore, these results suggest that CD44v6 and ALK may be independent predictors of risk for the systemic phenotype of ALCL.

Anaplastic pleomorphic xanthoastrocytoma.

Well-documented cases of malignant degeneration in pleomorphic xanthoastrocytoma and of anaplastic pleomorphic xanthoastrocytoma are rare in the literature. We report 2 cases of pleomorphic xanthoastrocytoma, 1 of which demonstrated clear evidence of malignant degeneration in the absence of prior radiation therapy over an 18-year period. Both anaplastic tumors were characterized by foci of necrosis and increased mitotic activity (3 and 2 mitotic figures/10 high-power fields). Both tumors demonstrated focal positive staining for glial fibrillary acidic protein and showed marked reticulin deposition. An MIB-1 labeling index (marker of cell proliferation) in the initial low-grade-appearing tumor in case 1 was 0.1%. The recurrent tumor in case 1 had an MIB-1 labeling index of 4.9%, and the anaplastic tumor in case 2 had an MIB-1 labeling index of 5.4%. Significant cyclin D1 immunoreactivity was not observed in either anaplastic tumor. Two percent to 3% of tumor cells stained positive with p53 protein antibody in the recurrent anaplastic tumor in case 1. Although histology may not reliably predict aggressive behavior in pleomorphic xanthoastrocytomas, the presence of increased mitosis, necrosis, and increased cell proliferation labeling indices may be indicative of a higher grade tumor.

A high ratio of insulin-like growth factor II/insulin-like growth factor binding protein 2 messenger RNA as a marker for anaplasia in meningiomas.

Insulin-like growth factors (IGFs) I and II have been implicated as autocrine or paracrine growth promoters. These growth factors bind to specific receptors, and the response is modulated by interaction with IGF-binding proteins (IGFBPs). We observed a strong correlation between anaplastic/atypical histopathology and a high IGF-II/IGFBP-2 mRNA ratio in a set of 68 sporadic meningiomas. A strong correlation was also found between clinical outcome and IGF-II/IGFBP-2 ratio, whereas previously used histochemical markers were less correlated to outcome. We suggest that a high IGF-II/IGFBP-2 mRNA ratio may be a sign of biologically aggressive behavior in meningiomas that can influence treatment strategies. We propose that low IGFBP-2 levels in combination with increased levels of IGF-II would result in more free IGF-II and consequently greater stimulation of proliferation.

Dedifferentiated chondrosarcoma with muscle and cytokeratin differentiation in the anaplastic component.

Dedifferentiated chondrosarcoma is a biphasic tumour, comprising well-differentiated chondrosarcoma and an anaplastic non-cartilaginous sarcoma juxtaposed but distinct from each other. Two cases of dedifferentiated chondrosarcoma, one primary and one recurrent, demonstrated muscle differentiation when studied with monoclonal antibodies to muscle specific actin, desmin and myoglobin. One of the tumours was also positive for cytokeratin, identified by AE1/AE3 and CAM 5.2 antibodies. Our findings are consistent with the concept that these tumours are capable of diverse patterns of morphological and immunophenotypic differentiation.

Intermediate filaments and anaplastic change of ENU-induced gliomass: immunohistochemical study with vimentin and astroprotein (GFAP).

To study the expression of two different subclasses of intermediate filaments in ethylnitrosourea-induced rat cerebral gliomas, the number of cells immunopositive for each subunit protein, vimentin and astroprotein (GFAP), was quantitatively analyzed. Vimentin is a subunit protein of non-specific intermediate filaments which appear transiently in immature glial cells, while astroprotein (GFAP) is a subunit protein of glial filaments, normally expressed in mature astrocytes. Although most normal astrocytes were negative for vimentin, many tumor cells showed weak to strong immunoreaction for vimentin. The expression of vimentin was more frequent and intense in anaplastic forms of gliomas than in benign forms. Accordingly, the vimentin/GFAP ratio [the number of vimentin-positive cells divided by the number of astroprotein (GFAP)-positive cells] was increased from 0.23 to 1.86, and from 0.26 to 1.85, respectively, as oligodendrogliomas and mixed gliomas become anaplastic. The present study demonstrated that the immunohistochemical study for those two subclasses of intermediate filaments can provide important informations on the cell biological nature of glial tumors.

[Interstitial substance of a chondrosarcoma (a histochemical study]. / Mezhutochnoe veshchestvo khondrosarkomy (gistokhimicheskoe issledovanie).

The content of acid mucopolysaccharides of the interstitial matrix of various structural variants of chondrosarcoma was studied in the operation material of 28 chondrosarcomas. The chondrosarcoma tissue contained a large amount of sulphated mucopolysacharides and a low amount of hialuronic acid. The quantity and quality of mucopolysaccharides directly depended on the degree of maturity of the tumour tissue which was reflected morphologically in the scarcity of intercellular substance in the tissue.