Ependymal and choroid plexus tumors. Cytokeratin and GFAP expression

Twenty-six ependymal and 15 choroid plexus tumors were examined with monoclonal antibody against cytokeratin using the avidin-biotin-peroxidase complex (ABC) technique. Serial sections were examined with antisera to glial fibrillary acidic protein (GFAP). In five ependymal tumors (one ependymoma, two papillary ependymomas, and two primitive neuroectodermal tumors [PNET] with ependymal cells), a variable number of cytokeratin-positive cells were present. Most tumor cells (except two PNET) were positive with GFAP antisera. Many cytokeratin-positive cells were present in all choroid plexus tumors. GFAP-positive cells were present focally in six of 11 papillomas and in one of four carcinomas. Although their staining patterns and distribution were clearly different, focal coexistence of cytokeratin and GFAP was observed in six papillomas and two ependymal tumors. Thus, some ependymal tumors (especially papillary ependymomas and occasional PNET) and many choroid plexus tumors have demonstrable positivity with antibody to cytokeratin, suggesting a transitional cell type with features of both ependyma and choroid plexus.     

Immunohistochemical Markers for Prognosis of Ependymal Neoplasms

Intracranial ependymomas are the third most common primary brain tumor in children. Although clinical and histological criteria for ependymoma prognosis are recognized, studies have reported contradictory results. Prognostic significance based on immunohistochemistry of ependymomas has been reported in a few studies. One-hundred and twelve patients with intracranial ependymomas were examined retrospectively for immuno-expression of various tumor-associated antigens and apoptosis. The results demonstrated significant preponderance of expression of the tenascin, vascular endothelial growth factor protein (VEGF), epidermal growth factor (EGFR) and p53 protein in high-grade tumors. Also high-grade ependymomas revealed more prominent labeling indices (LI) for proliferative marker Ki-S1 and apoptotic index (AI), and lower LI for cyclin-dependent kinase inhibitors p27/Kip1 and p14ARF. For low-grade ependymomas the progression-free survival time (PFS) was found to be significantly shorter for Ki-S1 LI>5%, and for tenascin, VEGF and EGFR positivity. For high-grade ependymomas PFS was found to be significantly reduced for p27 LI<20%, p14ARF LI<10%, for p53 positivity, and for AI<1%. The CART modeling process exhibited five final groups of ependymoma patients (1) low-grade and tenascin-negative; (2) low-grade and tenascin-positive; (3) high-grade and p53-negative with p14 LI>0%; (4) high-grade with combination of either p53 positivity and p14 LI>10% or p53 negativity and p14 LI<10%; (5) high-grade and p53-positive with p14 LI<10%. In summary, some immunohistochemical variables were found to be the strong predictors of ependymoma recurrence and they seem to be useful for assessing individual tumor prognosis in routinely processed biopsy specimens together with tumor grade. For histologically benign ependymomas immunohistochemical study should be focused on Ki-S1, tenascin, EGFR and VEGF evaluation, whereas p53 expression and number of p27, p14 and ISEL-positive nuclei will be of value in determining PFS from high-grade ependymomas.     

Aberrant CpG Island Methylation of Multiple Genes in Ependymal Tumors

Aberrant methylation of promoter CpG islands in human genes represents an alternative mechanism for genetic inactivation, and contributes to the development of human tumors. Nevertheless, thus far, few reports have analyzed methylation in ependymomas. We determined the frequency of aberrant CpG island methylation of several tumor-associated genes: p16(INK4a), RB1, MGMT, DAPK, TIMP3, THBS1, TP73, NF2 and Caspase 8 in a group of 27 ependymomas, consisting of 22 WHO grade II samples and five anaplastic WHO grade III tumors. The respective methylation indices (number of genes methylated/total genes analyzed) for both tumor groups was 0.195 and 0.198. Overall methylation rates greater than 20% were detected in MGMT, TIMP3, THBS1 and TP73. NF2 and Caspase 8 each presented hypermethylation in less than 10% of cases, and the cell-cycle regulators RB1/p16(INK4a) were hypermethylated in 4% and 18% of the samples, respectively, mostly affecting the low-grade forms. Our findings suggest that methylation commonly contributes to the inactivation of cancer-related genes in ependymomas.     

Ependymal differentiation of a glioblastoma multiforme after heterotransplantation into nude mice

A glioblastoma multiforme from a 64-year-old man was heterotransplanted sc into nude mice (nu/nu BALB/c out-bred). The subsequent growth of the transplanted tumor featured the appearance and eventual domination by cells with ependymal characteristics. This finding supports the view that the host's influence on heterotransplants may be substantial and should be considered when extrapolating the results of therapeutic trials on such animal models to the clinical situation. The view that ependymal cells and astrocytes share a common precursor is also partly supported by the observations.     

Colorectal mesenchymal tumors - from smooth muscle tumors to stromal tumors

Colorectal mesenchymal tumors are rare. Therefore, distinguishing between gastrointestinal stromal (GIST) and smooth muscle tumors is important. This study aimed to delineate the immunophenotype and prognostic factors of 75 colorectal mesenchymal tumors. Fifty-three GIST and 22 smooth muscle tumor specimens were included from 1986 to 2007. Forty of 53 GIST were initially diagnosed as smooth muscle tumors and re-diagnosed as CD117 (+) GIST. Immunohistochemical studies were performed with antibodies of CD117, CD34, smooth muscle actin (SMA), desmin, S-100, Ki-67 and PCNA for clinicopathologic and prognostic correlation. In comparison, colorectal GIST exhibited a larger tumor size (P<0.001), higher mitotic count (P<0.001), higher cellularity (P<0.001), less spindle cell type (P=0.004), higher nuclear pleomorphism (P=0.004), and a higher NIH risk (P<0.001) than that of smooth muscle tumors. Positive immunoreactivities of GIST to a panel of antibodies were 88.6% to CD34, 28.3% to SMA, 1.8% to S-100 and 15.1% to desmin. For 75 mesenchymal tumors, survival analyses revealed that older patients (P=0.006), with a large tumor size (P<0.001), high mitotic count (P<0.001), increased NIH risk (P<0.001), non-spindle cell type (P<0.001), high cellularity (P=0.015), high cell pleomorphism (P<0.001), positive Ki-67 (P<0.001), high PCNA (P<0.001) and GIST (P=0.001) had a shorter disease-free survival than that of comparative groups. When the analyses concentrated on 53 GIST, the cell type and cellularity were no longer viable prognostic factors. The tumor mitotic count was the only independent prognostic factor for either mesenchymal tumors or GIST. In conclusion, GIST exhibited heterogeneous characteristics and was significantly larger, more mitotic and a poorer prognostic factor than smooth muscle tumor. The mitotic count is still the most valuable prognostic factor for colorectal mesenchymal tumors after KIT.     

Pineal tumors

From 1972–1985, 30 patients with pineal area tumor have been treated with combinations of surgery and irradiation, no patient receiving chemotherapy as a primary recommendation. Patients ranged between 3 and 69 years of age, 18 were male and 12 female. In 18 patients a tissue diagnosis was made initially, 14 patients required shunts before definitive management and in 8 of the 14 tissue diagnosis was made at the same time. Eight patients had no surgical intervention at any time. Patients who have received irradiation have had whole brain irradiation, local field irradiation, or craniospinal irradiation. Two elderly patients died rapidly of their malignant processes before definitive treatment could be given. Only one patient with a non neoplastic lesion was seen. This was a bleed from an AVM with no underlying tumor. One patient with a pineocytoma was not irradiated. Overall, two-thirds of our patients are alive 5 to 15 years after treatment. There has been no surgical mortality and minimal morbidity from biopsy. Late effects of treatment include one patient with mild hearing loss and three patients with endocrinopathies amenable to medical treatment. We believe that tissue diagnosis allows optimal field design and dose recommendations to be made by the radiotherapist in addition to defining prognosis. In our experience, endodermal sinus tumor and pineoblastoma are highly malignant, and in view of their poor prognosis with conventional management consideration of more radical treatment with a possible role for chemotherapy is suggested.     

Carcinoid tumors

The authors carried out a retrospective study of 32 patients (23 M, 9 F) with carcinoid tumors who were diagnosed and treated at Harlem Hospital Center, New York, from 1967 to 1988. All the patients were black and the commonest sites were the ileum (28.1%), rectosigmoid and rectum (21.9%), and the appendix and lung (15.6% each). Metastasis correlated with site, size, and depth of the primary tumor and occurred in 12 patients (38%), most frequently to the regional lymph nodes and liver. Carcinoid syndrome developed in 12.5% (3 F, 1 M). Surgical resection for cure or palliation was the mainstay of treatment. Overall 5 year survival rate was 66%, and for those with metastases was 0%. The poorer survival rates are probably related to the socioeconomic status of our patient population. The only observed racial difference compared to other series is the preponderance of males, and the disproportionately higher ratio of females with the carcinoid syndrome.     

Carcinoid tumors

Carcinoid tumors can present a difficult diagnostic and therapeutic dilemma. Despite their reputation as indolent tumors, they frequently metastasize and can cause significant symptomatology. The only curative therapy remains surgical resection. The prognosis and treatment of carcinoids vary based on location and histology, and therapy must be tailored to each patient.     

Carcinoid tumors

Opinion statement Carcinoids are rare endocrine tumors that can develop in several organs in the body. Clinically, patients can have a wide spectrum of signs and symptoms that range from incidental findings of a polyp during endoscopy to the carcinoid syndrome characterized by severe flushing, diarrhea, abdominal cramping, and life-threatening right-sided heart failure. Most carcinoid tumors are indolent but can metastasize to regional lymph nodes and to other organs, including the liver, bone, and the central nervous system. Treatment is determined by tumor location and by the presence of distant metastasis. Surgical resection of the tumor is advocated in patients with localized disease and can often be curative. Long-acting somatostatin analogs, including octreotide, octreotide long-acting repeatable, and lanreotide prolonged release, are effective in providing symptom relief in patients with the carcinoid syndrome. Patients with metastatic disease to the liver that is refractory to somatostatin treatment should be considered for hepatic artery occlusion. Overall, 5- and 10-year survival rates in patients with metastatic disease are favorable, although tumors can be resistant to most forms of medical or surgical therapy.     

Bugging tumors

The effects of bacteria on patients with cancer have been observed for at least two centuries. Recent studies in animal models of cancer have shown efficacy of both anaerobic bacteria such as Clostridia and Bifidobacteria and facultative anaerobes such as Salmonella. In this issue of Cancer Discovery, Flentie and colleagues have identified five Salmonella promoters that are specifically stimulated by cancer cells as well as by acidic pH, a property of most tumors. One of these promoters (STM1787) was linked to a Shiga toxin gene and inserted in a wild-type Salmonella typhimurium strain, which showed in vivo antitumor efficacy. Approaches to further improving the efficacy of S. typhimurium with the use of tumor-targeting mutations are discussed. Because the barriers to efficacy of standard therapy of cancer appear to be opportunities for bacterial cancer therapy, the future of bacterial therapy of cancer appears bright.     

Hematologic tumors

Development of cytarabine and daunorubicin has made a cure for acute myeloid leukemia (AML) possible. Current first line chemotherapy is a combination of idarubicin plus cytarabine. Acute promyelocytic leukemia has the highest cure rate among AML due to the introduction of ATRA. Current first line chemotherapy for advanced Hodgkin's lymphoma is ABVD, based upon results of a prospective randomized study comparing MOPP, ABVD and MOPP/ABVD. CHOP has been frequently selected as first line chemotherapy for advanced non-Hodgkin's lymphoma, based upon results obtained in a phase III study that compared CHOP versus second and third generation combinations.     

Parathyroid tumors

Opinion statement Parathyroid tumors causing primary hyperparathyroidism are common and often remain undiagnosed, despite that the diagnostic work-up is uncomplicated in most patients. The patients often do not receive the appropriate curative treatment, which is surgical. Recent studies show that surgery is beneficial in patients with mild asymptomatic disease, especially in the reversal of bone disease, neuropsychologic symptoms, and dyslipoproteinemia. All patients with the disease deserve a referral to an endocrine surgeon for discussions regarding surgical intervention. Minimally invasive techniques performed in the ambulatory setting have evolved rapidly and show an extraordinary high success rate, low-morbidity rate, and are likely to become the standard treatment for most patients with primary hyperparathyroidism.     

Neuroendocrine tumors

Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.