Marco Pagano

Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus: a follow-up study in an Italian population

The most important complication of oral lichen planus (OLP) is the development of oral squamous cell carcinoma (OSCC) but this is a very controversial matter. The aim of the study was to estimate in a Northern Italian cohort of OLP patients the risk for OSCC. Four hundred and two patients with histologically confirmed OLP diagnosed from January 1988 to July 1999, were followed-up to the end of February 2001. The standardized incidence ratio (SIR) of OSCC was calculated for the entire cohort and specific for gender, type of OLP, therapy for OLP and hepatitis C virus (HCV) infection. The relative risk (RR) of OSCC according to HCV infection was also estimated in the cohort. During the follow-up period, two men (1.3%) and seven women (2.9%) developed an OSCC. The SIR was 44.9 (95% CI: 20.5-85.2), being higher among women, but statistically significant in both genders. The RR of OSCC for patients with HCV as compared with those without HCV infection was 3.16 (0.8-12.5). Patients with OLP had a significantly increased risk of OSCC, irrespective of the clinical type of OLP and therapy. HCV infection apparently increased the risk for OSCC although this result could reflect the role of confounders, such as liver cirrhosis.

Vascular Endothelial Growth Factor-C Stimulates the Migration and Proliferation of Kaposi’s Sarcoma Cells

Recent evidence suggesting vascular endothelial growth factor-C (VEGF-C), which is a regulator of lymphatic and vascular endothelial development, raised the question whether this molecule could be involved in Kaposi’s sarcoma (KS), a strongly angiogenic and inflammatory tumor often associated with infection by human immunodeficiency virus-1. This disease is characterized by the presence of a core constituted of three main populations of “spindle” cells, having the features of lymphatic/vascular endothelial cells, macrophagic/dendritic cells, and of a mixed macrophage-endothelial phenotype. In this study we evaluated the biological response of KS cells to VEGF-C, using an immortal cell line derived from a KS lesion (KS IMM), which retains most features of the parental tumor and can induce KS-like sarcomas when injected subcutaneously in nude mice. We show that VEGFR-3, the specific receptor for VEGF-C, is expressed by KS IMM cells grown in vitro and in vivo. In vitro, VEGF-C induces the tyrosine phosphorylation of VEGFR-2, a receptor also for VEGF-A, as well as that of VEGFR-3. The activation of these two receptors in KS IMM cells is followed by a dose-responsive mitogenic and motogenic response. The stimulation of KS IMM cells with a mutant VEGF-C unable to bind and activate VEFGR-2 resulted in no proliferative response and in a weak motogenic stimulation, suggesting that VEGFR-2 is essential in transducing a proliferative signal and cooperates with VEGFR-3 in inducing cell migration. Our data add new insights on the pathogenesis of KS, suggesting that the involvement of endothelial growth factors may not only determine KS-associated angiogenesis, but also play a critical role in controlling KS cell growth and/or migration and invasion.

Prognostic impact of HER-2/neu expression on squamous head and neck carcinomas.

HER‐2/neu gene amplification and protein overexpression have been identified in various solid tumors, but its prognostic relevance in head and neck squamous cell carcinoma (HNSCC) is still controversial.

Immunohistochemical Expression Analysis of the Human Interferon-Inducible Gene IFI16, a Member of the HIN200 Family, Not Restricted to Hematopoietic Cells

This is the first description of an extensive immunohistochemical analysis of interferon (IFN)-inducible gene IFI16 expression in normal tissues. Immunohistochemical detection of IFI16 in paraffin-embedded tissues is achieved by using a polyclonal antibody raised against its C-terminal fragment that recognizes its three closely migrating isoforms in Western blotting. The results clearly indicate that IFI16 expression is not restricted to the hematopoietic compartment. In normal adult human tissues, it is prominent in stratified squamous epithelia and particularly intense in parabasal cells in the proliferating compartments, but it gradually decreases in the more differentiated suprabasal layers. Understanding of IFI16 expression in vivo is essential for interpretation of the results obtained from in vitro studies and elucidation of its physiologic role. The constitutive expression and wider distribution of IFI16 in normal human tissues, not restricted to the hematopoietic compartment, strongly support the possibility of an important role in cell differentiation that can be further modulated by other stimuli, such as IFN.

Gorham-Stout Syndrome: A Monocyte-Mediated Cytokine Propelled Disease†

We studied the biological features and the immunophenotype of a cell culture established from the lesion of soft tissues of a woman affected by Gorham‐Stout syndrome. We found that these cells belonged to a monocytic lineage with some characteristics of immature osteoclasts and were able to release large amounts of osteoclastogenic and angiogenic molecules that may contribute to disease progression.

Oral acanthosis nigricans, tripe palms and sign of leser-trélat in a patient with gastric adenocarcinoma

Acanthosis nigricans (AN), tripe palms (TP) and the sign of Leser‐Trélat (LT) may be seen with the presence of malignancy. Acanthosis nigricans may have a mucocutaneous localization involving the oral mucosa with papillomatous and verrucous lesions usually on the lips and buccal mucosa. These paraneoplastic dermatoses are generally linked with intra‐abdominal malignancy, most often gastric adenocarcinoma. Improvement of the associated dermatoses after the treatment of the malignancy has been frequently observed. We report the case of a 53‐year‐old man suffering from advanced gastric adenocarcinoma, in which metastases seemed to sustain all three paraneoplastic dermatoses. To the best of our knowledge this is the first case of a patient showing manifestations of all three paraneoplastic dermatoses. Patients presenting with this set of dermatoses should be suspected to harbor an occult malignancy, or have persistence of a known malignancy.

Altered patterns of the interferon-inducible gene IFI16 expression in head and neck squamous cell carcinoma: immunohistochemical study including correlation with retinoblastoma protein, human papillomavirus infection and proliferation index.

Aims:  To investigate whether the expression of interferon (IFN)‐inducible gene IFI16 is inversely related to proliferative activity in vivo, we compared immunohistochemical reactivity of IFI16 in a series of head and neck squamous cell carcinomas (HNSCCs) with their proliferation index and the cell cycle regulator pRb. As human papillomavirus (HPV) infection is manifested by changes in the function or expression level of host genes such as IFN‐inducible genes, we also investigated the presence of HPV DNA to determine whether head and neck cancers associated with HPV DNA can be distinguished from tumours that are presumably transformed by other mechanisms.

Vasculogenic potential of long term repopulating cord blood progenitors.

In the adult, involvement of bone marrow‐derived circulating endothelial progenitor cells (EPCs) in tissue revascularization (vasculogenesis) and the cooperation of hematopoietic cell subsets in supporting this process have been described in different experimental animal models. However, the effective contribution of such cells in restoring organ vascularization in a clinical setting needs to be clarified. In this study, a mouse transplantation model was engrafted by human cord blood hematopoietic stem and progenitor cells to follow the behavior of donor‐derived endothelial and hematopoietic cells in the presence of a localized source of an angiogenic inducer. Human endothelial markers (CD31+/CD45–, VE‐cadherin+) were always detectable in the bone marrow of transplanted mice, while they were only randomly detectable in peripheral neovascularization sites. To investigate the ability of human transplanted hematopoietic stem cells to support new vessel formation in response to altered homeostatic conditions, chimeric mice were further treated by systemic injection of human mononuclear cells (MNCs). Our data indicate that MNC administration in transplanted mice enhances vasculogenesis in the newly formed vessels. Taken together these results suggest that human‐derived EPCs, long‐term engrafting a xenotransplantation model, have hematopoietic and endothelial developmental potential, which can be modulated by altering the physiological conditions of host microenvironment.

Immunohistochemical expression of basement membrane proteins of verrucous carcinoma of the oral mucosa

Squamous cell carcinoma (SCC) of the oral cavity is an extremely invasive tumour of stratified squamous epithelium that spreads throughout degradation of the basement membrane (BM) and extra-cellular matrix. Oral verrucous carcinoma (VC) is a rare low-grade variant of oral SCC that penetrates into the subepithelial connective tissue. It also has a different clinical behaviour from classical oral SCC. We investigated the immunohistochemical expression of laminin, laminin-5, collagen IV and fibronectin in VC, severe epithelial dysplasia (SED) and SCC in order to analyse if the patter of these molecules expression contributes to the differences in the biological behaviour of these diseases. The staining pattern of laminin was less intensive in SCC compared with SED and VC, and collagen IV expression was increased in VC compared with SED. Discontinuities of laminin, collagen IV and fibronectin were more evident in SED than in VC. This study indicates that VC has a biological behaviour different from SED or SCC, observable by immunohistochemistry in the BM zone.

Follicular Origin of a Subset of CD5+ Diffuse Large B-Cell Lymphomas

Most follicular lymphomas (FLs) have a phenotype consistent with the origin from CD5-, CD10+, bcl-6+ follicular center cells and can progress to diffuse large B-cell lymphoma (DLBCL). CD5 is expressed in about 10% of DLBCLs, showing prognostic value, whereas expression is rare in FL. We present 6 cases with coexisting features of CD5+ FL and CD5+ DLBCL, supporting a follicular origin for some CD5+ DLBCLs. The follicular areas showed a meshwork of CD21+ follicular dendritic cells that were lacking in the DLBCL areas. All cases showed a clonal CD19+, CD20+, CD5+, and CD10+ population in both follicular and diffuse areas. Molecularly, 4 of 6 cases demonstrated immunoglobulin heavy chain rearrangements and 1 case, a bcl-2/immunoglobulin heavy chain gene rearrangement. Somatic hypermutations were high in all 4 cases, in keeping with their germinal center origin. Four of five patients died of disease within 42 months, consistent with the proposed prognostic value of CD5 expression in DLBCL. Our data describe an aggressive variant of CD5+ FL suggesting the follicular origin of some CD5+ DLBCLs.