Time trends in the prevalence of HPV in oropharyngeal squamous cell carcinomas in northern Spain (1990-2009).

Recent studies support an important role for human papillomavirus (HPV) in oropharyngeal squamous cell carcinomas (OPSCC), although the incidence varies widely depending on the geographic location and time period studied. The aim of this study was to determine the proportion of HPV in a large cohort of OPSCC in northern Spain in the years 1990-2009. Clinical records and paraffin embedded tumor specimens of 248 consecutive patients surgically treated for OPSCC (140 tonsillar and 108 base of tongue) between 1990 and 2009 were retrieved. OPSCC cases were histomorphologically evaluated, and protein expression of p16 and p53 was analyzed by immunohistochemistry. Detection of high-risk HPV DNA was performed by GP5+/6+-PCR and in situ hybridization (ISH). Thirty cases (12%) were positive for p16 immunostaining, of which eight (3.2% of the total series) were found positive for HPV type 16 by genotyping of GP5+6+-PCR products. All HPV GP5+/6+-PCR-positive tumors were p53-immunonegative, seven had a basaloid morphology and seven were also positive by HPV ISH. Presence of HPV correlated inversely with tobacco and alcohol consumption (p < 0.001), but not with age of onset of OPSCC. Overall survival was better in the HPV-positive group, although not statistically significant (p = 0.175). OPSCC patients in northern Spain demonstrated a low involvement of HPV, increasing (although not significantly, p = 0.120) from 1.8% in 1990-1999 to 6.1% of cases in 2000-2009.

NFκB expression is a feature of both activated B-cell-like and germinal center B-cell-like subtypes of diffuse large B-cell lymphoma.

The activation of nuclear factor kappa B (NFκB) transcription factor family is considered to have a key role in diffuse large B-cell lymphoma (DLBCL) pathogenesis and is associated with a specific molecular subtype, the activated B-cell-like (ABC) subtype. We evaluated the expression of NFκB by immunohistochemistry in a large series of DLBCL cases. The five different NFκB family members (NFκB1, NFκB2, RELA, RELB, and REL) showed a heterogeneous expression pattern with the vast majority of cases being positive for at least one factor. Two independent series of tumor samples were classified into germinal center B-cell-like (GCB) or ABC subtypes using different approaches, immunohistochemistry, or gene expression profiling, and the expression of NFκB family members was assessed. Notably, no significant differences regarding the expression of the different NFκB members were detected between the two subtypes, suggesting that NFκB signaling is a prominent feature not only in the ABC subtype, but also in the GCB tumors. Of the five transcription factors, only REL expression had a significant clinical impact on R-CHOP-treated diffuse large B-cell lymphoma, identifying a subgroup of patients with superior clinical outcome.

A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma.

Despite improvement in the treatment of advanced classical Hodgkin lymphoma, approximately 30% of patients relapse or die as result of the disease. Current predictive systems, determined by clinical and analytical parameters, fail to identify these high-risk patients accurately. We took a multistep approach to design a quantitative reverse-transcription polymerase chain reaction assay to be applied to routine formalin-fixed paraffin-embedded samples, integrating genes expressed by the tumor cells and their microenvironment. The significance of 30 genes chosen on the basis of previously published data was evaluated in 282 samples (divided into estimation and validation sets) to build a molecular risk score to predict failure. Adequate reverse-transcription polymerase chain reaction profiles were obtained from 262 of 282 cases (92.9%). Best predictor genes were integrated into an 11-gene model, including 4 functional pathways (cell cycle, apoptosis, macrophage activation, and interferon regulatory factor 4) able to identify low- and high-risk patients with different rates of 5-year failure-free survival: 74% versus 44.1% in the estimation set (P < .001) and 67.5% versus 45.0% in the validation set (P = .022). This model can be combined with stage IV into a final predictive model able to identify a group of patients with very bad outcome (5-year failure-free survival probability, 25.2%).

Levels and patterns of expression of hypoxia-inducible factor-1α, vascular endothelial growth factor, glucose transporter-1 and CD105 in adenoid cystic carcinomas with high-grade transformation.

AIMS: To compare the expression of proteins regulated by hypoxia between adenoid cystic carcinoma (ACC) with and without high-grade transformation (HGT). METHODS AND RESULTS: In eight ACC-HGT and 18 ACC without HGT, expression of hypoxia-inducible factor-1 (HIF-1α), vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT-1) and microvascular density (MVD) by CD105 (a hypoxia-inducible protein expressed in angiogenic endothelial cells) was determined. Expression levels of HIF-1α and VEGF as well as CD105-MVD did not differ significantly between: (i) transformed and conventional areas (TA and CA, respectively) of ACC-HGT, (ii) CA and ordinary ACC. HIF-1α was detected in 100% of cases and presented a diffuse expression pattern. No significant association was found between levels of HIF-1α expression and tumour size, metastasis and recurrence. GLUT-1 showed a prostromal expression pattern and was observed exclusively in TA (three of six cases) and in only three of 14 ACC. CONCLUSIONS: Both the absence of significant alterations in levels of expression of HIF-1α, VEGF and CD105 and the patterns of expression of HIF-1α and GLUT-1 suggest that hypoxia may not play a key role in the process of high-grade transformation of ACC. Although HIF-1α expression is a common finding in ACC, it cannot be used as a marker of tumour aggressiveness.

Expression and clinical significance of the Kv3.4 potassium channel subunit in the development and progression of head and neck squamous cell carcinomas.

The concept of ion channels as membrane therapeutic targets and diagnostic/prognostic biomarkers has attracted growing attention. We therefore investigated the expression pattern and clinical significance of the Kv3.4 potassium channel subunit during the development and progression of head and neck squamous cell carcinomas (HNSCCs). KCNC4 mRNA levels were determined by real-time RT-PCR in both HNSCC tissue specimens and derived cell lines. Kv3.4 protein expression was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 84 patients with laryngeal/pharyngeal squamous cell carcinomas and 67 patients with laryngeal dysplasias. Molecular alterations were correlated with clinicopathological parameters and patient outcome. Increased KCNC4 mRNA levels were found in 15 (54%) of 28 tumours, compared to the corresponding normal epithelia and varied mRNA levels were detected in 12 HNSCC-derived cell lines analysed. Increased Kv3.4 protein expression was observed in 34 (40%) of 84 carcinomas and also at early stages of HNSCC tumourigenesis. Thus, 35 (52%) of 67 laryngeal lesions displayed Kv3.4-positive staining in the dysplastic areas, whereas both stromal cells and normal adjacent epithelia exhibited negligible expression. No significant correlations were found between Kv3.4-positive expression in HNSCC and clinical data; however, Kv3.4 expression tended to diminish in advanced-stage tumours. Interestingly, patients carrying Kv3.4-positive dysplasias experienced a significantly higher laryngeal cancer incidence than did those with negative lesions (p = 0.0209). In addition, functional studies using HNSCC cells revealed that inhibition of Kv3.4 expression by siRNA leads to the inhibition of cell proliferation via selective cell cycle arrest at the G2/M phase without affecting apoptosis. Collectively, these data demonstrate for the first time that Kv3.4 expression is frequently increased during HNSCC tumourigenesis and correlated significantly with a higher cancer risk. Our findings support a role for Kv3.4 in malignant transformation and provide original evidence for the potential clinical utility of Kv3.4 expression as a biomarker for cancer risk assessment.

Podoplanin expression in the development and progression of laryngeal squamous cell carcinomas.

BACKGROUND: Podoplanin expression is attracting interest as a marker for cancer diagnosis and prognosis. We therefore investigated the expression pattern and clinical significance of podoplanin during the development and progression of laryngeal carcinomas. RESULTS: Podoplanin expression was determined by immunohistochemistry in paraffin-embedded tissue specimens from 84 patients with laryngeal premalignancies and 53 patients with laryngeal squamous cell carcinomas. We found podoplanin expression extending from the basal to the suprabasal layer of the epithelium in 37 (44%) of 84 dysplastic lesions, whereas normal epithelium showed negligible expression. Patients carrying podoplanin-positive lesions had a higher laryngeal cancer incidence than those with negative expression reaching borderline statistical significance (51% versus 30%, P = 0.071). Podoplanin expression in laryngeal carcinomas exhibited two distinct patterns. 20 (38%) cases showed diffuse expression in most tumour cells and 33 (62%) focal expression at the proliferating periphery of tumour nests. High podoplanin expression was inversely correlated with T classification (P = 0.033), disease stage (P = 0.006), and pathological grade (P = 0.04). There was a trend, although not significant, towards reduced disease-specific survival for patients with low podoplanin levels (P = 0.31) and diffuse expression pattern (P = 0.08). CONCLUSIONS: Podoplanin expression increases in the early stages of laryngeal tumourigenesis and it seems to be associated with a higher laryngeal cancer risk. Podoplanin expression in laryngeal squamous cell carcinomas, however, diminishes during tumour progression. Taken together, these data support a role for podoplanin expression in the initiation but not in the progression of laryngeal cancers.

A TaqMan low-density array to predict outcome in advanced Hodgkin's lymphoma using paraffin-embedded samples.

PURPOSE: Despite major advances in the treatment of classic Hodgkin's lymphoma (cHL), approximately 30% of patients in advanced stages may eventually die as result of the disease, and current methods to predict prognosis are rather unreliable. Thus, the application of robust techniques for the identification of biomarkers associated with treatment response is essential if new predictive tools are to be developed. EXPERIMENTAL DESIGN: We used gene expression data from advanced cHL patients to identify transcriptional patterns from the tumoral cells and their nonneoplastic microenvironment, associated with lack of maintained treatment response. Gene-Set Enrichment Analysis was used to identify functional pathways associated with unfavorable outcome that were significantly enriched in either the Hodgkin's and Reed-Sternberg cells (regulation of the G2-M checkpoint, chaperones, histone modification, and signaling pathways) or the reactive cell microenvironment (mainly represented by specific T-cell populations and macrophage activation markers). RESULTS: To explore the pathways identified previously, we used a series of 52 formalin-fixed paraffin-embedded advanced cHL samples and designed a real-time PCR-based low-density array that included the most relevant genes. A large majority of the samples (82.7%) and all selected genes were analyzed successfully with this approach. CONCLUSIONS: The results of this assay can be combined in a single risk score integrating these biological pathways associated with treatment response and eventually used in a larger series to develop a new molecular outcome predictor for advanced cHL.

Primary de novo intraosseous carcinoma: report of a new case.

Primary de novo intraosseous carcinoma of the jaws has been rarely reported. We present a new case of this unusual tumour and discuss its histopathological and clinical aspects. The subject was a 76-year-old man who was seen due to complaints of pain and the presence of gingival changes in the left mandible. A panoramic radiograph and computed tomography revealed a large mandibular radiolucency. A segmentary mandibulectomy was performed and histopathologic examination proved that the tumour was an intraosseous squamous cell carcinoma. Surgeons should appreciate the aggressiveness of this tumour, despite adequate surgical treatment.

Oncogene amplification pattern in adenoid cystic carcinoma of the salivary glands.

The aim of the present study was the search of molecular alterations (oncogene amplification or protein overexpression) that could have an impact on the outcome of ACC patients. For this purpose, paraffin-embedded tissue samples of primary ACC of 24 patients were collected. Oncogenic amplification status of six targets previously described to be involved in human carcinogenesis (ERBB1, KIT, PIK3CA, CCND1, MYC and MDM2) were studied by a PCR-based semiquantitative approach. C-Kit, cyclin D1 and EGFR protein levels were immunohistochemically assessed. ERBB1, CCND1 and PIK3CA were frequent targets of oncogene amplification (67, 46 and 38%, respectively). C-Kit and cyclin D1 were overexpressed in 57 and 82%, respectively. CCND1 amplification was associated with advanced tumour stage and ERBB1 amplification to distant metastasis. ERBB1/CCND1/PIK3CA coamplification was the most consistently observed pattern (29%). The cases with this amplification pattern presented a reduced survival. This study points to the importance of ERBB1, CCND1 and PIK3CA oncogenic amplification status in ACC carcinogenesis.

Chondrosarcoma of the temporomandibular joint. A case report and review of the literature.

Chondrosarcoma is a malignant tumor characterized by the formation of cartilage, but not bone, by tumor cells. Only 5% to 10% of chondrosarcomas occur in the head and neck, representing 0.1% of all head and neck neoplasms, with the larynx and the maxillo-nasal region being the most common sites. This report describes an unusual case of chondrosarcoma in a 54-year-old man who presented with pain and swelling in the left preauricular area. Computed tomography demonstrated a soft tissue mass in the left temporomandibular joint without causing erosion of the adjacent bony structures. The tumor was treated by excision in a single block with perilesional tissues, preserving the facial nerve. Histopathologic examination revealed chondrocytes with irregular nuclei with S-100 immunocytochemical staining positive in 30% of the tumor. The diagnosis was a grade I chondrosarcoma. There was no evidence of disease at the 16-month follow-up. The occurrence of chondrosarcoma in the temporomandibular joint (TMJ) is an exceptional event, with only 16 cases described. We report a case of this unusual entity and review the literature.

Annexin A2 localizes to the basal epithelial layer and is down-regulated in dysplasia and head and neck squamous cell carcinoma.

Annexin A2 is a highly expressed gene with important roles in cell membrane physiology and is frequently dysregulated in cancer. The objective of this study was to determine the pattern of expression and prognostic significance of annexin A2 protein in head and neck squamous cell carcinoma. We assessed both quantitative changes and qualitative distribution of annexin A2 mRNA and protein expression in normal and diseased tissues by immunohistochemistry, immunofluorescence and in situ hybridization. Annexin A2 expression was confined to the basal and suprabasal cells of normal epithelium and the protein cellular location was consistently observed at the cell membrane. Expression levels correlated with histopathological grade, showing significant suppression in moderately and poorly differentiated tumours. We conclude that annexin A2 exhibits a characteristic pattern of expression, distinct from other annexins and suggestive of a cell-specific functional role. The marked reduction of annexin A2 in poorly differentiated tumours and dysplastic tissue is expected to result in a loss of function aimed at the coordination of membrane signalling enzyme complexes, actin polymerization and extracellular matrix proteolysis. The phenotypic consequences may become manifest in an alteration of epithelial tissue growth and remodelling with secondary influence on tumour development, progression and metastasis.

BRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma.

PURPOSE: BRAF(V600E) mutation represents the most common oncogenic event in sporadic papillary thyroid cancer (PTC). There are, however, significant discrepancies regarding the overall frequency, its prevalence in PTC-variants, and its relationship with clinico-pathological parameters of poor outcome. Moreover, the impact of BRAF(V600E) mutants on tumour-related patient's death has not been evaluated. DESIGN: We analysed, by PCR-SSCP and/or PCR-direct sequencing, exons 8, 10, 11 and 15 of BRAF in 113 tumour samples from 49 PTC-patients. Matched lymph node metastases and/or distant metastases (DMs) were screened in 35 patients. Focal changes in the growth pattern or microscopic grade within the primary tumour (Pt) or the metastases were separately genotyped. Mutations at H-, K-, N-ras and PIK3CA exons 9 and 20 were also investigated. For comparison with PTC cases, the BRAF and Ras mutational status was evaluated in 89 specimens obtained from 24 poorly differentiated thyroid carcinomas (PDCs) and 36 anaplastic thyroid carcinomas (ATCs). RESULTS: BRAF(V600E) was found in 13/16 classical PTCs (CL-PTCs), 6/17 follicular variant PTCs (FV-PTCs) and 8/16 mixed (papillary/follicular) PTCs (Mx-PTCs), being significantly associated with CL-PTCs (P = 0.015). BRAF(V600E) segregated with metastatic PTC-cells in 43% of the patients, but only one DM disclosed the mutation. PTC-tumours featuring concurrent less-differentiated foci were BRAF wild-type in both components. Noteworthy, the frequency of BRAF mutations among PDCs and ATCs resulted considerably lower (16.6% and 25%, respectively) than in PTCs (55%). The prevalence of Ras mutations among PDCs and ATCs (46% and 36%, respectively) was, however, much higher than in PTCs (14%). Five (71%) of the patients who died of PTC displayed somatic mutations. Four of them had other gene alteration associated with BRAF(V600E) and the only one that did not, BRAF(V600E) was restricted to the Pt. The occurrence of BRAF(V600E) associated with other genetic events was an independent predictor of DMs during follow-up, recurrence and tumour-related death. Remarkably, two PDCs (8.3%) and five ATCs (14%) revealed concurrent BRAF and Ras mutations. CONCLUSION: BRAF(V600E)'alone' does not represent a marker for poor outcome, however, when associated with alterations in other genes identifies a subset of PTCs with increased risk of recurrence and decreased survival.

Papillary cystadenoma and cystadenocarcinoma of salivary glands: two unusual entities.

Cystadenoma and cystadenocarcinoma are rare salivary gland tumours histologically characterized by prominent cystic and frequently papillary growth. We present two cases of cystadenoma of a minor salivary gland (upper lip) and parotid cystadenocarcinoma respectively, captured between 834 salivary gland tumors studied in our hospital from 1980 to 2004. The authors review the clinical, histological, and biological features of these two unusual tumours, and differential diagnosis with other salivary glands neoplasms. Both entities usually reveal papillary proliferation of the epithelial lining and are composed of cells that possess bland cytomorphologic features. Differentiation of tumour types depends largely on the identification of actual infiltration of salivary gland parenchyma or surrounding connective tissue by either cystic or solid epithelium in cystadenocarcinomas. Step sections of a borderline tumour may yield unequivocal evidence of invasion. The authors discuss the problematic diagnosis between these rare neoplasms and with other tumours and compare histological findings of these two entities.

Is there an epidemiological link between human papillomavirus DNA and basaloid squamous cell carcinoma of the pharynx?

The epidemiological link between human papillomavirus (HPV) DNA and basaloid squamous cell carcinoma (BSCC) of the pharynx was studied. The expression of p53 protein was evaluated by immunohistochemical analysis. The presence of HPV DNA was evaluated by polymerase chain reaction amplification and "in situ" hybridization. The tobacco and alcohol consumption and the clinical outcomes of nine patients with BSCC of the pharynx are compared with site and stage matched 109 conventional squamous cell carcinoma (SCC) patients. The BSCC specimens were analyzed for the presence of HPV DNA and p53 expression. We did not find any significant differences in tobacco and alcohol consumption between patients with BSCC and patients with SCC. No HPV DNA was detected in BSCC, and p53 overexpression was found in five (55%) of the cases. Our results do not support an etiological link between HPV DNA and BSCC.

Mismatch repair protein MSH2, cytokeratin 18 and cytokeratin 20 expression: clinicopathological correlation and prognostic value in colorectal cancer patients.

BACKGROUND/AIMS: The survival of patients with colorectal cancer has not varied appreciably in recent years. The knowledge that genetic factors and disruption in apoptosis could play a role in the etiology and prognosis of patients with sporadic colorectal cancer has opened up new lines of research. We have studied a group of patients with colorectal cancer and the possible influence on the prognosis of immunohistochemical MSH2, M30 cytodeath and cytokeratin 20 expression. METHODOLOGY: Forty-nine consecutive patients with unselected colorectal cancer treated by resection and with a minimum follow-up period of 5 years. Tumor specimens were evaluated by an inmunohistochemical method for MSH2, cytokeratin 18 (M30 cytodeath) and cytokeratin 20 expression and correlated with epidemiological, clinicopathological and survival data. RESULTS: Thirty-four patients were resected with curative intention. At the end of the follow-up period, 25 (51%) had died, the majority (21) in relation to tumor progression, the overall median survival period being 47.9 months (95% CI = 27-86.6). Only vascular invasion, (lower median values), (p = 0.04) was related to MSH2 expression and tumor stage (p = 0.02) with cytokeratin 20. Patients' survival was related to tumoral stage (p = 0.04) and vascular invasion (p = 0.002). MSH2 expression, apoptosis (M30 cytodeath) and cytokeratin 20 staining did not influence the prognosis of patients. CONCLUSIONS: A change in the percentage of tumoral staining cells for MSH2, M30 cytodeath and cytokeratin 20 is frequent in patients with colorectal cancer. Only vascular invasion was correlated with MSH2 expression and stage of disease with cytokeratyn 20. Survival was related to TNM stage and vascular invasion, but not to MSH2, M30 cytodeath or cytokeratin 20 expressions.

Variability in the degree of expression of phosphorylated IkappaBalpha in chronic lymphocytic leukemia cases with nodal involvement.

PURPOSE: Based on previous preliminary observations, we hypothesize that the molecular and clinical variability of chronic lymphocytic leukemia (CLL) reflects differences in the degree of nuclear factor (NF)-kappaB activation, as determined by the expression of phosphorylated IkappaBalpha (p-IkappaBalpha). EXPERIMENTAL DESIGN: The expression profile (mRNA and protein expression) was analyzed with the Centro Nacional de Investigaciones Oncologicas Oncochip, a cDNA microarray containing 6386 cancer-related genes, and a tissue microarray (TMA). The results were correlated with the IgV(H) mutational status, ZAP-70 expression, cytogenetic alterations, and clinical outcome. RESULTS: We found correlations between the presence of p-IkappaBalpha, a surrogate marker of NF-kappaB activation, and changes in the expression profile (mRNA and protein expression) and clinical outcome in a series of CLL cases with lymph node involvement. Activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, was associated with the expression of a set of genes comprising key genes involved in the control of B-cell receptor signaling, signal transduction, and apoptosis, including SYK, LYN, BCL2, CCR7, BTK, PIK3CD, and others. Cases with increased expression of p-IkappaBalpha showed longer overall survival than cases with lower expression. A Cox regression model was derived to estimate some parameters of prognostic interest: IgV(H) mutational status, ZAP-70, and p-IkappaBalpha expression. The multivariate analysis disclosed p-IkappaBalpha and ZAP-70 expression as independent prognostic factors of survival. CONCLUSIONS: A variable degree of activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, is an identifiable event in CLL, and is correlated with changes in the expression profile and overall survival.

Complete spontaneous regression of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a very aggressive primary cutaneous neoplasm most often occurring on the head and neck of the elderly. Spontaneous regression of MCC was first described in 1986. A 79-year-old woman with MCC on the right cheek underwent spontaneous regression of the malignancy, documented by photographic follow-up, computed tomography, and histologic studies. A review of the literature is presented. Complete clinical and histologic regression of MCC was observed in the present case. Although the literature documents 11 similar cases, only 6 can be regarded as complete spontaneous regressions following exclusive performance of a biopsy (primary complete spontaneous regression). Primary complete spontaneous regression of MCC is infrequent, and most case reports describe this phenomenon in women with MCC on the cheek. The reasons underlying regression are unknown.

Prevalence of human papillomavirus in laryngeal and hypopharyngeal squamous cell carcinomas in northern Spain.

BACKGROUND: Recent studies support a role for human papillomavirus (HPV) in oropharyngeal squamous cell carcinomas (SCCs); however, the significance of HPV in non-oropharyngeal head and neck cancers is uncertain. The aim of this study was to determine the prevalence of HPV in a large cohort of laryngeal and hypopharyngeal SCCs in northern Spain. MATERIALS AND METHODS: Clinical records and paraffin-embedded tumor specimens of 124 consecutive patients surgically treated for laryngeal (62 cases) and hypopharyngeal (62 cases) SCCs between 2002 and 2007 were retrieved. All cases were histologically evaluated, and presence of HPV was assessed by p16-immunohistochemistry followed by GP5+/6+-PCR-based DNA detection. Samples positive in both assays were subjected to HPV genotyping and HPV E6 transcript analysis. RESULTS: Seventeen cases (14%) were positive for p16 immunostaining, of which 2 (1 larynx, 1 hypopharynx, 1.6% of total series) were found positive for HPV DNA by subsequent GP5+6+-PCR. Both SCCs contained HPV type 16 and showed HPV16 E6 mRNA expression. CONCLUSIONS: HPV is only occasionally involved in laryngeal and hypopharyngeal SCC patients in northern Spain.

Large B-cell lymphoma presenting in the spleen: identification of different clinicopathologic conditions.

Only a few series of splenic large B-cell lymphoma have been previously reported, including limited immunophenotypic studies and clinical data. Here we review the clinical data, morphology, and immunophenotype of series of 33 cases of large B-cell lymphoma presenting in the spleen. Three main groups of tumors are identified. Group A was characterized by macronodular tumors (20 cases), with predominantly stage I disease and a favorable clinical outcome. All cases were bcl6 positive. Group B was characterized by a micronodular pattern (nine cases), including a subset with T-cell-rich B-cell lymphoma features. Most of the patients in this group were diagnosed at advanced clinical stages and died of the disease. All cases were bcl6 positive. Group C was characterized by diffuse red pulp infiltration (four cases) and advanced clinical stages and showed an aggressive behavior. All but one case were bcl6 positive. The results of this series define a characteristic type of large B-cell lymphoma presenting in the spleen as a tumoral mass, associated with a relatively favorable clinical course. Additionally, they provide evidence that clinical presentation as a tumor confined to the spleen and the hilar lymph nodes is associated with lower aggressivity.