Traumatic ulcerative granuloma with stromal eosinophilia: report of a case and literature review.

Traumatic eosinophilic granuloma with stromal eosinophilia is a rare entity that affects the oral mucosa and has a controversial etiologic pathogenesis. Histologically, these lesions are characterized by a dense and deeply infiltrative lymphoproliferation showing epitheliotropic characteristics and massive eosinophilia. Frequently, a population of mitotically active, atypical mononuclear cells can be noted. This report describes a case of traumatic eosinophilic granuloma with stromal eosinophilia in the floor of the mouth of an 88-year-old man. The phenotypic and genotypic profiles of the inflammatory infiltrate and large atypical mononuclear cells, using immunohistochemical and polymerase chain reaction-based molecular analysis, were analyzed.

Prognostic significance of cyclin A and B1 in pediatric embryonal tumors.

Embryonal tumors constitute the most common malignant brain tumor group in children. Although patient prognosis has been substantially improved over recent decades, identification of prognostic markers would be of obvious significance. In the present study we evaluated the prognostic significance of cyclin A and B1 in correlation with Ki-67 index in pediatric embryonal tumors. We retrospectively evaluated 53 children with embryonic tumors who were treated surgically in our institute. All patients had regular follow-up examinations. The streptavidin-biotin-horseradish peroxidase (HRP) method was performed on paraffin sections for detection of Ki-67/MIB-1, and cyclin A and B1. There were 42 cases of medulloblastoma (MB), 9 cases of atypical teratoid/rhabdoid tumor (AT/RT), and 2 cases of supratentorial primitive neuroectodermal tumor (PNET). In MB patients, Ki-67 index >50% was associated with worse survival (P = 0.003). Cyclin A index >40% was associated with significantly poorer survival (P = 0.023). Patients with cyclin B1 index >15% exhibited a trend towards poorer survival (P = 0.068). On multivariate analysis, only Ki-67 index was identified as a factor with independent prognostic power. In AT/RT and PNET, there was high expression of Ki-67 and variable expression of cyclin A and B1. Apart from Ki-67 index, cyclin A may have a prognostic role. Study of the above indices at diagnosis could alter or intensify treatment methods, so as to improve disease outcome. There is obviously a need for future studies with larger number of patients to confirm our preliminary observations.

Expression of epidermal growth factor receptor and HER-2 in pediatric embryonal brain tumors.

BACKGROUND/AIMS: Medulloblastomas (MBs), atypical teratoid rhabdoid tumors (AT/RTs) and central nervous system primitive neuroectodermal tumors (PNETs) are aggressive embryonal brain neoplasms in children with overlapping histological features but with different pathogenetic pathways. We set out to evaluate the role of epidermal growth factor receptor (EGFR), HER-2, Ki-67 and p53 in embryonal tumors. MATERIAL AND METHODS: We retrospectively evaluated 36 children with embryonic tumors (27 MBs, 7 AT/RTs and 2 supratentorial PNETs). The immunohistochemical expression of EGFR and HER-2 was correlated to histology, expression of the Ki-67/MIB-1 proliferative index, p53 tumor suppressor oncoprotein and prognosis. RESULTS: High expression of Ki-67 was observed in all MBs being particularly increased (> 50%) in 8 cases, while p53 protein was detected in 25/27 MBs showing a high expression in 16 cases. EGFR and HER-2 expression was observed in 10/27 and 17/27 MBs, respectively. High Ki-67/MIB-1 and p53 expression was revealed in all AT/RTs and PNETs, while EGFR and HER-2 were detected in 3/7 and 6/7 AT/RTs, respectively. The 5-year progression-free survival and overall survival were 55.5 and 69.2%, respectively. In MBs, the univariate analysis revealed that the Ki-67 index and male gender were both at a significant level related to the survival of the patient. In multivariate analysis, the Ki-67 index was the only independent predictive variable. CONCLUSIONS: The Ki-67 index was identified as a factor with independent prognostic power. EGFR and HER-2 expression is variable in embryonal tumors. HER-2 expression, in a considerable number of MBs and AT/RTs, suggests that HER-2 may be implicated in their pathogenesis representing a potential target for novel therapies.

Topoisomerase IIalpha expression as an independent prognostic factor in Hodgkin's lymphoma.

PURPOSE: To correlate the immunohistochemical expression of topoisomerase IIalpha (topoIIalpha) in Hodgkin's lymphoma (HL) with clinicopathological parameters, the expression of Ki-67 and the outcome of patients, who had been homogenously treated with ABVD or equivalent regimens. EXPERIMENTAL DESIGN: Immunohistochemistry using the monoclonal antibody Ki-S1 (topoIIalpha) was performed in 238 HL patients. MiB1 (Ki-67) expression was evaluated in 211/238. RESULTS: The mean +/- SD percentage of topoIIalpha- and Ki-67-positive Hodgkin-Reed-Sternberg (HRS) cells was 63 +/- 19% (5%-98%) and 73 +/- 19% (8%-99%), respectively. The median percentage of topoIIalpha-positive HRS cells was 64% (interquartile range, 51-78%). There was no correlation between topoIIalpha expression and patient characteristics. TopoIIalpha and Ki-67 expression were correlated (Spearman's Rho 0.255, P < 0.001). TopoIlalpha expression within the highest quartile of this patient population was predictive of failure free survival (FFS) (10-year rates 82 +/- 3% vs 68 +/- 7%, P = 0.02 for patients falling into the quartiles 1-3 and 4 respectively). In multivariate analysis topoIIalpha expression was independently predictive of FFS. CONCLUSION: TopoIIalpha was expressed in all cases of HL showing a correlation with Ki-67 expression. Under current standard therapy including drugs inhibiting its activity, topoIIalpha was an independent adverse predictor of FFS with no statistically significant correlation with other established prognostic factors.

Ontogeny of intrinsic innervation in the human thymus and spleen.

The ontogeny of the innervation of human lymphoid organs has not been studied in detail. Our aim was to assess the nature and distribution of parenchymal nerves in human fetal thymus and spleen. We used the peroxidase immunohistochemical technique with antibodies specific to neuron-specific enolase (NSE), neurofilaments (NF), PGP9.5, S100 protein, and tyrosine hydroxylase (TH) and evaluated our results with image analysis. In human fetal thymus, NSE-, NF-, S100-, PGP9.5-, and TH-positive nerves were identified associated with large blood vessels from 18 gestational weeks (gw) onwards, increasing in density during development. Their branches penetrated the septal areas at 20 gw, reaching the cortex and the corticomedullary junction between 20 and 23 gw. Few nerve fibers were seen in the medulla in close association with Hassall's corpuscles. In human fetal spleen, NSE-, NF-, S100-, PGP9.5-, and TH-positive nerve fibers were localized in the connective tissue surrounding the splenic artery at 18 gw. Perivascular NSE-, NF-, S100-, PGP9.5-, and TH-positive nerve fibers were seen extending into the white pulp, mainly in association with the central artery and its branches, increasing in density during gestation. Scattered NSE-, NF-, S100-, PGP9.5-, and TH-positive nerve fibers and endings were localized in the red pulp from 18 gw onward. The predominant perivascular distribution of most parenchymal nerves implies that thymic and splenic innervation may play an important functional role during intrauterine life.

Functional p53 can modulate the relationship between E2F-1 expression and tumor kinetics in Hodgkin lymphoma.

E2F-1 is the best-described member of the E2F family of transcriptional factors and is particularly interesting in view of its often opposing roles. Our purpose was to examine the immunohistochemical expression of E2F-1 in Hodgkin lymphoma (HL) and to correlate it with proliferation and apoptosis of the tumor, clinicopathological parameters and patient outcome, as well as with expression of the downstream molecules p53 and p21. The median percentage of E2F-1-expressing Hodgkin Reed-Sternberg (HRS) cells was 80.2%. A significant positive correlation was found between expression of E2F-1 and p53 (p = 0.034). Following stratification of our cases, within the group harboring functional p53, a statistically significant inverse correlation was identified between E2F-1 and Topo IIa (p = 0.019). E2F-1 is up-regulated in the context of HL and its expression is inversely associated with proliferation. It seems that functional p53 can modulate the relationship between E2F-1 expression and tumor kinetics in HL.

Prognostic significance of immunohistochemical expression of the angiogenic molecules vascular endothelial growth factor-A, vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2 in patients with classical Hodgkin lymphoma.

Angiogenesis leads to new blood vessel formation and is implicated in both physiological and pathological situations. The vascular endothelial growth factor (VEGF) family is the major mediator of this process. The aim of our study was to evaluate the expression of VEGF-A, vascular endothelial growth factor receptor-1 (VEGFR-1) and VEGFR-2 and their correlation with clinicopathological parameters and prognosis in patients with classical Hodgkin lymphoma (cHL), since the role of angiogenesis in this tumor still remains unclear. The immunohistochemical expression of VEGF-A, VEGFR-1 and VEGFR-2 was examined in 194 patients with cHL. The neoplastic Hodgkin Reed-Sternberg (HRS) cells expressed VEGF-A, VEGFR-1 and VEGFR-2 in 90.3%, 97.2% and 94.1% of cases, respectively. Only the expression of VEGFR-2 was positively correlated with serum albumin levels ≥ 4 g/dL. No correlation with patient outcome was observed. All three molecules were statistically correlated with ramifications of blood vessels. Summarizing, our results are not sufficient to consider VEGF-A and/or VEGF receptors as prognosticators in cHL.

Development and validation of a clinical prediction rule for bone marrow involvement in patients with Hodgkin lymphoma.

We developed a clinical prediction rule for bone marrow involvement (BMI) in Hodgkin lymphoma based on 826 patients and validated it in 654 additional patients. Independent prognostic factors for BMI were x1, B symptoms; x2, stage III/IV prior to bone marrow biopsy; x3, anemia; x4, leukocytes fewer than 6 x 10(9)/L; x5, age 35 years or older; and x6, iliac/inguinal involvement. Each factor was graded as x(i)=1, if present, or x(i)=0, if absent. A simplified score Zs=8x1+6x2+5x3+5x4+3x5+3x6-8 was assigned to each patient. The sensitivity, specificity, and positive and negative predictive value of this prediction rule was 97.8%, 51.5%, 10.6%, and 99.8%, respectively. In the validation group, they were 98.1%, 40.3%, 12.7%, and 99.6%. According to Zs value, 3 risk groups for BMI were defined: low risk (Zs<0, 44% of patients, 0.3% risk), standard risk (Zs, 0-9; 37% of patients; 4.2% risk), and high risk (Zs>or=10, 20% of patients, 25.5% risk). Patients with low risk (stage IA/IIA without anemia and leukopenia; stage IA/IIA, younger than 35 years, with either anemia or leukopenia but no inguinal/iliac involvement; and stage IIIA/IVA without any of these 4 risk factors) do not need bone marrow (BM) biopsy. Patients with standard risk should be staged with unilateral biopsy, but patients with high risk may benefit from bilateral biopsy.

Genetic and molecular coordinates of neuroendocrine lung tumors, with emphasis on small-cell lung carcinomas.

The aim of this review is to present the advances in our understanding of the progression of tumorigenesis in neuroendocrine lung tumors. Current information on established and putative diagnostic and prognostic markers of neuroendocrine tumors are evaluated, with a special reference to small-cell lung carcinoma, due to its higher incidence and aggressive behavior. The genetic and molecular changes that accompany these neoplasms are highlighted, and factors that influence cell-cycle progression, apoptosis, drug resistance, and escape from immune surveillance are critically assessed.

Vascular endothelial growth factor (VEGF) is expressed by neoplastic Hodgkin-Reed-Sternberg cells in Hodgkin's disease.

Vascular endothelial growth factor (VEGF) is involved in tumour angiogenesis, an important process for the growth and metastatic potential of solid tumours. Numerous studies have demonstrated up-regulation of VEGF at both mRNA and protein level in various tumours and a correlation with advanced stage and prognosis has been demonstrated in some cases. Limited information exists about its role in lymphoid malignancies and in particular, Hodgkin's disease. The present study examined the immunohistochemical expression of VEGF using the monoclonal antibody VG1 in a series of 61 cases of Hodgkin's disease, including both classical Hodgkin's disease and the nodular lymphocyte predominance variant, and correlated these results with microvessel density, using an anti-CD31 monoclonal antibody. In 41 cases (70.6%) of classical Hodgkin's disease and one of the three cases of nodular lymphocyte predominance Hodgkin's disease, the neoplastic Reed-Sternberg and Hodgkin cells expressed VEGF. The staining observed was cytoplasmic, either diffuse or with a focal paranuclear distribution. Macrophages were always positive, while reactive lymphocytes showed occasional positivity. A variable amount of strong extracellular staining was also observed in the tissue stroma and intravascular plasma staining was prominent. There was no statistically significant relationship between VEGF expression and the subtype of Hodgkin's disease or microvessel density. In vitro studies using the Reed-Sternberg cell lines L428 and KM-H2 were also performed in both normoxia and hypoxia and VEGF protein production was assessed by flow cytometry (FACS), immunoassay of cell culture supernatant, and RT-PCR. Analysis by FACS demonstrated a subset of cells in both cell lines reacting with VG1 and analysis of secreted VEGF (pg/ml per 1x10(6) cells) in cell culture supernatant confirmed the normoxic production in both cell lines and significant hypoxic induction (p<0.005). Additionally, both cell lines expressed VEGF mRNA, as demonstrated using the RT-PCR method. In conclusion, neoplastic cells express VEGF in Hodgkin's disease, as is the case in solid tumours, and this expression may be induced by hypoxia. The presence of VEGF in reactive macrophages and in the extracellular matrix might facilitate tumour progression.