Jacques Bosq

Lymph node prognostic factors in head and neck squamous cell carcinomas

BACKGROUND This retrospective study included 914 patients who underwent a lymph node dissection at our institute between 1980 and 1985. The primary tumor sites were oral cavity, 287; hypopharynx, 249; larynx, 247; and oropharynx, 131. PATIENTS AND METHODS On the basis of anatomic considerations, the sentinel nodes for well-lateralized oral cavity tumors were defined as homolateral levels I, II, and III; for oropharyngeal, hypopharyngeal, and laryngeal tumors, the sentinel nodes were defined as levels II and III. We took into account the ipsilateral side of the neck for well-lateralized tumors, and both sides for medium or large tumors. For clinically positive nodes of more than 3 cm, a radical neck dissection was performed. Other patients underwent a selective neck dissection on sentinel nodes, with immediate pathologic evaluation. Modified radical neck dissections with contralateral selective dissection were performed when frozen sections were positive. Patients with positive nodes were given postoperative radiotherapy. RESULTS The prognostic factors studied, using the Cox survival model adjusted on the primary tumor site, surprisingly showed a nonsignificant value for extracapsular spread (P = 0.09), and a significant value for the number of positive nodes (P < 0.001) and for the positive node in or out of the sentinel node sites (P < 0.001). Although the node location factor can be used instead of positive node in or out of the sentinel node site, it has a less significant prognostic value. CONCLUSIONS The most significant prognostic factors are the site of the positive node in or out of the sentinel node and the number of positive nodes; and a more accurate approach can be obtained by combining both factors. Node location in the upper or lower neck remains a substitute prognostic factor for the site of the positive node in or out of the sentinel node.

Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review.

Blastic natural killer (NK) cell lymphoma (also termed CD4+CD56+ hematodermic neoplasm) is a recently described entity, with the first case reported in 1994. It was suggested initially that the disease originates from NK cells. Since 1994, single cases and a few small series have been published. In this review, data from the literature and a series of 30 cases from the French and Dutch study groups on cutaneous lymphomas are discussed. The major clinical, histopathologic, and phenotypic aspects of the disease and diagnostic criteria and data suggesting a plasmacytoid dendritic cell origin for the tumor cells are provided.

Combined-Modality Therapy for Clinical Stage I or II Hodgkin's Lymphoma: Long-Term Results of the European Organisation for Research and Treatment of Cancer H7 Randomized Controlled Trials

PURPOSE In early-stage Hodgkins lymphoma (HL), subtotal nodal irradiation (STNI) and combined chemotherapy/radiotherapy produce high disease control rates but also considerable late toxicity. The aim of this study was to reduce this toxicity using a combination of low-intensity chemotherapy and involved-field radiotherapy (IF-RT) without jeopardizing disease control. PATIENTS AND METHODS Patients with stage I or II HL were stratified into two groups, favorable and unfavorable, based on the following four prognostic factors: age, symptoms, number of involved areas, and mediastinal-thoracic ratio. The experimental therapy consisted of six cycles of epirubicin, bleomycin, vinblastine, and prednisone (EBVP) followed by IF-RT. It was randomly compared, in favorable patients, to STNI and, in unfavorable patients, to six cycles of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV hybrid) and IF-RT. RESULTS Median follow-up time of the 722 patients included was 9 years. In 333 favorable patients, the 10-year event-free survival rates (EFS) were 88% in the EBVP arm and 78% in the STNI arm (P = .0113), with similar 10-year overall survival (OS) rates (92% v 92%, respectively; P = .79). In 389 unfavorable patients, the 10-year EFS rate was 88% in the MOPP/ABV arm compared with 68% in the EBVP arm (P < .001), leading to 10-year OS rates of 87% and 79%, respectively (P = .0175). CONCLUSION A treatment strategy for early-stage HL based on prognostic factors leads to high OS rates in both favorable and unfavorable patients. In favorable patients, the combination of EBVP and IF-RT can replace STNI as standard treatment. In unfavorable patients, EBVP is significantly less efficient than MOPP/ABV.

Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type

Biopsies and cell lines of natural killer/T-cell lymphoma, nasal type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared with peripheral T-cell lymphoma, not otherwise specified, NKTCL had greater transcript levels for NK-cell and cytotoxic molecules, especially granzyme H. Compared with normal NKcells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, Epstein-Barr Virus-induced genes, and PDGFRA. Notably, platelet-derived growth factor receptor alpha and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL cell line was sensitive to imatinib. Deregulation of the AKT, Janus kinase-signal transducers and activators of transcription, and nuclear factor-kappaB pathways was corroborated by nuclear expression of phosphorylated AKT, signal transducers and activators of transcription 3, and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 [1q44], IL6R [1q21.3], CCL2 [17q12], TNFRSF21 [6p12.3]). Several features of NKTCL uncovered by this analysis suggest perturbation of angiogenic pathways. Integrative analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets.

CD4+ CD56+ cutaneous neoplasms : A distinct hematological entity ?

We report seven cases of particular cutaneous tumors selected from the register of the French Study Group on Cutaneous Lymphomas. The patients (three men, four women) were aged 37-86 years. They initially presented with cutaneous nodules or papules. Three cases presented with regional lymph nodes. Stagings were negative, except for one patient with bone marrow involvement. Histological features were relevant with pleomorphic medium T-cell lymphoma, but these cells exhibited a distinguishing phenotype. They were positive for CD4, CD56, and also CD45, CD43, and HLA-DR. All other T-cell and B-cell markers were negative. The myelomonocytic markers (CD13, CD14, CD15, CD33, CD117, myeloperoxidase, and lysozyme) were negative excepted CD68, which was clearly positive in four cases and weakly in two cases. Others natural killer cell markers (CD16, CD57, TiA1, granzyme B), TdT, and CD34 were negative. Polymerase chain reaction studies did not detect any B or T clonal rearrangement. The cytogenetic studies, performed in five cases, showed a del(5q) in two cases. All patients were treated successfully by polychemotherapy, but relapsed quickly in the skin, between 4 and 28 months. Five patients developed bone marrow involvement, with leukemia in three cases, and they died in 5-27 months. One patient died at 17 months with skin progression. The seventh patient is alive at 33 months, with cutaneous progression. The origin of these cells is unclear. Despite expression of CD4 or CD56, we failed to demonstrate a T-cell, natural killer cell origin. However, CD4 and CD56 are not specific for T or natural killer lineages. Although these two markers are also known to be expressed by monocytic cells, classic myeloid antigens were negative. These seven cases, together with other rare similar cases already reported, seem to represent a distinct entity likely developed from hematological precursor cells.

Statistical evaluation of diagnostic and prognostic features of CD30+ cutaneous lymphoproliferative disorders : A clinicopathologic study of 65 cases

Several clinical and histopathologic features of 65 CD30+ cutaneous lymphoproliferations were evaluated for their diagnostic value between CD30+ primary versus secondary cutaneous lymphomas and for their prognostic significance. Primary cutaneous disease, spontaneous regression, and absence of extracutaneous spreading (but not age < or =60 years) were associated with a better prognosis. Epithelial membrane antigen, BNH9, CD15 or CBF.78 antigen were expressed in all types of cutaneous lymphoproliferations. However, epithelial membrane antigen immunoreactivity was more frequently expressed in CD30+ secondary cutaneous large-cell lymphoma. Among CD30+ primary cutaneous large-cell lymphoma, CD15 expression was only seen in localized skin lesions. P53 expression was not associated with spontaneous regression, extracutaneous spreading, or survival. Nested reverse transcriptase-polymerase chain reaction allowed the detection of NPM-ALK transcripts in 10 of 26 CD30+ primary and in 3 of 11 secondary cutaneous large-cell lymphomas. The ALK protein was detected in only 1 of 50 primary and in 4 of 15 secondary cutaneous CD30+ lymphoproliferations. In CD30+ primary cutaneous lymphoproliferation, NPM-ALK transcripts might be expressed by very rare normal or tumoral cells that are undetectable by immunohistochemistry. However, the expression of either NPM-ALK transcripts or ALK-protein was not correlated with prognosis or age in CD30+ cutaneous lymphoproliferations.

Analysis of p53 Serum Antibodies in Patients With Head and Neck Squamous Cell Carcinoma

BACKGROUND Mutation of the p53 tumor suppressor gene (also known as TP53) often leads to the synthesis of p53 protein that has a longer than normal half-life. Mutant p53 protein that accumulates in tumor cell nuclei can be detected by means of immunohistochemical staining techniques. Serum antibodies directed against p53 protein (p53-Abs) have been detected in some cancer patients. PURPOSE We assayed serum samples from 80 patients with head and neck squamous cell carcinoma (HNSCC) for the presence of p53-Abs, and we evaluated potential associations between the presence of these antibodies and other histopathologic and clinical features. METHODS Serum was collected from each patient at the time of diagnosis. In addition, tumor biopsy specimens were obtained before the initiation of treatment. An enzyme-linked immunosorbent assay was used to detect p53-Abs. The accumulation of p53 protein in tumor cell nuclei was assessed immunohistochemically by use of the anti-p53 monoclonal antibody DO7. Patient treatment consisted of radiotherapy alone, primary chemotherapy followed by radiotherapy, or surgery and postoperative radiotherapy. Relapse-free and overall survival from the beginning of treatment were estimated by use of the Kaplan-Meier method; survival comparisons were made by use of the logrank statistic. Univariate and multivariate analyses were conducted to identify factors associated with survival. Reported P values are two-sided. RESULTS Fifteen (18.8%) of the 80 patients had p53-Abs. Tumor cell nuclei in 43 (58.9%) of 73 assessable biopsy specimens exhibited strong p53 immunostaining. Patient treatment method and the accumulation of p53 protein in tumor cell nuclei were not associated with increased risks of relapse or death. In univariate analyses, advanced tumor stage (> T1 [TNM classification]) and the presence of p53-Abs were significantly associated with an increased risk of death (P for trend = .007 and P = .002, respectively), whereas advanced tumor stage, substantial regional lymph node involvement (> N1), and the presence of p53-Abs were associated with an increased risk of relapse (P for trend = .002, P = .02, and P < .0001, respectively). In multivariate analyses, advanced tumor stage and the presence of p53-Abs were significantly associated with increased risks of relapse (p for trend = .04 and P = .003, respectively) and death (P for trend = .04 and P = .03, respectively). At 2 years of follow-up, the overall survival proportion was 63% (95% confidence interval [CI] = 47%-80%) when no p53-Abs were detected compared with 29% (95% CI = 4%-54%) when p53-Abs were detected. Relapse-free survival at 2 years was 62% (95% CI = 49%-76%) if no p53-Abs were detected compared with 13% (95% CI = 0%-31%) if p53-Abs were detected. CONCLUSIONS AND IMPLICATIONS The proportion of patients with HNSCC who have serum p53-Abs is smaller than that of patients exhibiting tumor cell accumulation of p53 protein. The presence of p53-Abs is significantly associated with increased risks of relapse and death.

Phase II trial of fludarabine monophosphate in patients with mantle-cell lymphomas.

PURPOSE The aim of this phase II trial was to assess the efficacy of fludarabine monophosphate in untreated and pretreated mantle-cell lymphomas (MCL). PATIENTS AND METHODS Fifteen patients with MCL were included in the study. In two cases, fludarabine was the first-line therapy, the second in four cases, the third in five cases, and the fourth in four cases. The diagnosis of MCL was based on the criteria of the European Lymphoma Task Force (ELTF), with morphologic, immunologic, and cytogenetic data. Patients were treated with intravenous fludarabine 25 mg/m2/d for 5 days every 4 weeks. RESULTS Toxicity of fludarabine was mild: World Health Organization (WHO) grade 3 and 4 granulocytopenia occurred in 15 of 56 assessable cycles (cy) (27%), there was no grade 3 or 4 thrombocytopenia, one grade 3 bacterial lung infection, and no treatment-related death. There were five partial responses (33%) but no complete response. The duration of these responses was short and ranged from 4 to 8 months. CONCLUSION These results suggest that fludarabine can be moderately effective in the treatment of MCL. Fludarabine appears to be far less effective than in chronic lymphocytic leukemia (CLL) and follicular non-Hodgkins lymphoma (NHL). Therefore, fludarabine should be evaluated in association with other chemotherapeutic agents in MCL.

Potential doubling time and clinical outcome in head and neck squamous cell carcinoma treated with 70 GY in 7 weeks

PURPOSE To study the predictive value of pretreatment potential doubling time and labeling index, as measured by flow cytometry in patients with head and neck squamous cell carcinoma treated with conventional radiotherapy. METHODS AND MATERIALS 70 patients with a squamous cell carcinoma of the oropharynx and 4 patients with another involved head and neck site were entered in this prospective study. The duration of the S phase (TS), the labeling index (LI), and the potential doubling time (Tpot) were obtained by flow cytometry measurements of a tumor biopsy obtained after i.v. injection of 200 mg bromodeoxyuridine to the patient. The treatment consisted of 70 Gy in 7 weeks, 2 Gy per fraction and five fractions per week. RESULTS The mean and median LI were 7.7% (standard deviation, SD: 5.0) and 6.3%, respectively. The mean and median TS were 9.3 h (SD: 3.6) and 8.3 h, respectively. The mean and median Tpot were 5.6 days (SD: 5.4) and 4.6 days, respectively. No significant relationship was found between the Tpot or LI and the tumor stage (T), nodal status (N), histological grade, and the site of the primary within the oropharynx. The only parameter significantly associated with an increased risk of local relapse was the tumor stage (p < 0.001). The mean Tpot for the group of tumors that relapsed locally was 5.3 days (SD: 3.3), compared to 6.1 days (SD: 4.08) for those who did not relapse locally (NS). Two parameters were significantly associated with a decrease in disease-free (DFS) and overall survival, namely the tumor stage (p < 0.005, and p < 0.001, respectively, for DFS and overall survival) and nodal involvement (p = 0.02 and (p < 0.005, respectively, for DFS and overall survival). The TS, LI, DNA index, and Tpot were not significantly associated with local relapse, DFS, and survival, either in the univariate or in the multivariate analysis. CONCLUSIONS The method used to evaluate tumor cell kinetics did not provide clinically relevant kinetic parameters for this type of cancer. The classic prognostic factors (tumor stage and nodal status) were strongly associated with clinical outcome.

High Resolution Genome-Wide Analysis of Chromosomal Alterations in Burkitt's Lymphoma

Additional chromosomal abnormalities are currently detected in Burkitts lymphoma. They play major roles in the progression of BL and in prognosis. The genes involved remain elusive. A whole-genome oligonucleotide array CGH analysis correlated with karyotype and FISH was performed in a set of 27 Burkitts lymphoma-derived cell lines and primary tumors. More than half of the 145 CNAs<2 Mb were mapped to Mendelian CNVs, including GSTT1, glutathione s-transferase and BIRC6, an anti-apoptotic protein, possibly predisposing to some cancers. Somatic cell line-specific CNVs localized to the IG locus were consistently observed with the 244 K aCGH platform. Among 136 CNAs >2 Mb, gains were found in 1q (12/27), 13q (7/27), 7q (6/27), 8q(4/27), 2p (3/27), 11q (2/27) and 15q (2/27). Losses were found in 3p (5/27), 4p (4/27), 4q (4/27), 9p (4/27), 13q (4/27), 6p (3/27), 17p (3/27), 6q (2/27),11pterp13 (2/27) and 14q12q21.3 (2/27). Twenty one minimal critical regions (MCR), (range 0.04–71.36 Mb), were delineated in tumors and cell lines. Three MCRs were localized to 1q. The proximal one was mapped to 1q21.1q25.2 with a 6.3 Mb amplicon (1q21.1q21.3) harboring BCA2 and PIAS3. In the other 2 MCRs, 1q32.1 and 1q44, MDM4 and AKT3 appeared as possible drivers of these gains respectively. The 13q31.3q32.1 <89.58–96.81> MCR contained an amplicon and ABCC4 might be the driver of this amplicon. The 40 Kb 2p16.1 <60.96–61> MCR was the smallest gained MCR and specifically encompassed the REL oncogene which is already implicated in B cell lymphomas. The most frequently deleted MCR was 3p14.1 <60.43–60.53> that removed the fifth exon of FHIT. Further investigations which combined gene expression and functional studies are essential to understand the lymphomagenesis mechanism and for the development of more effective, targeted therapeutic strategies.