Angélique Girod

Progressive Upregulation of PD-1 in Primary and Metastatic Melanomas Associated with Blunted TCR Signaling in Infiltrating T Lymphocytes

Programmed death-1 (PD-1) is involved in T-cell tolerance to self-antigens. For some cancers, it has been suggested that the expression of a ligand of PD-1, namely PD-L1, could contribute to tumor escape from immune destruction. Nevertheless, the relationship between PD-1 expression on tumor-infiltrating T lymphocytes (TILs), disease stage, and TIL responsiveness is still poorly documented. In this study, we show that freshly isolated CD4(+) and CD8(+) TILs express substantial levels of PD-1 in primary melanomas. The expression of PD-1 was further increased at later stages in distant cutaneous metastases, especially on CD8(+) TILs. The expression of PD-1 ligands was frequent only in metastases, on both tumor cells and tumor-derived myeloid cells. TILs isolated from these cutaneous tumors are poorly reactive ex vivo, with blunted calcium response and IFN-γ production after TCR stimulation. Surprisingly, in distinct parts of a primary melanoma, either invasive or regressing, we show that TILs similarly express PD-1 and remain dysfunctional. The expressions of PD-1 and PD-L1 in metastatic melanoma lesions could be considered as witnesses of an unsuccessful anti-tumoral immune response, but the direct involvement of PD-1 in the severity of the disease, and the importance of TILs in tumor regression, remain to be established.

Mature Cytotoxic CD56bright/CD16+ Natural Killer Cells Can Infiltrate Lymph Nodes Adjacent to Metastatic Melanoma

Melanomas are characterized by high metastatic potential, with regional lymph node representing the most frequent site of early dissemination in this disease. These regional lymph nodes also represent the primary site for differentiation of natural killer (NK) cells. Although blood-derived NK cells can efficiently lyse melanoma cells isolated from metastatic lymph node (M-LN), there has been no study of the properties of the most disease-relevant NK cells isolated from M-LN in patients with melanoma. Here, we report that M-LN contains 0.5% to 11% of CD56(bright) NK cells among CD45(+) hematopoietic cells present and that this cell population surrounds tumor cell clusters in M-LN. This NK cell population was characterized by expression of CD62L, chemokine receptors, and high levels of natural cytotoxicity receptors (NCR), NK group 2 D (NKG2D), and DNAX accessory molecule 1 (DNAM-1). Expression of NCR-NKp30 and NKG2D correlated negatively with percentages of tumor cells in M-LN. Interestingly, M-LN contained a unique subset of mature CD56(bright)CD16(+) NK cells displaying coregulated expression of NCR and NKG2D activating receptors. Ex vivo analyses suggested that M-LN-derived NK cells were inactive but could be activated by appropriate cytokine signals [interleukin (IL)-2 or IL-15], and could lyse metastatic melanoma cells in a highly efficient manner compared with blood-derived NK cells. Taken together, the results offer evidence that adjuvant immunotherapy that targets NK cells in M-LN for activation may improve treatment of patients with sentinel lymph node-positive melanoma.

Metallothionein expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patient survival

Theocharis S, Klijanienko J, Giaginis C, Rodriguez J, Jouffroy T, Girod A, Point D, Tsourouflis G & Sastre‐Garau X
(2011) Histopathology59, 514–525

Women and Squamous Cell Carcinomas of the Oral Cavity and Oropharynx: Is There Something New?

PURPOSE Incidence of squamous cell carcinoma (SCC) of the oral cavity and oropharynx is increasing in French female patients. The objective of this study was to study the clinical and demographic characteristics and the prognosis of this female population. Secondary outcomes were to determine if a subgroup of patient had a different prognosis. MATERIALS AND METHODS A prospective study from 1989 to 2002 of all female patients presenting SCC of the upper aerodogestive tract was conducted. Data for 171 women were extracted. Clinical and histological features were analyzed using chi(2) and log-rank tests along with the Kaplan Meier method and multivariate analysis using the Cox regression procedure. RESULTS Mean patient age was 62 years. Of the study population, 48.5% used tobacco and 34.5% used alcohol. The relative risk of death for overall and cancer-specific survival increased for patients below the age of 45 or over the age of 70 (95% Cl; 0.3-1.05; P = .0085). Tobacco consumption decreased cancer-specific and overall survival (P = .0008 and .0001, respectively). The other prognostic factors we found were tumor and nodal status, previous or simultaneous cancer, oral cavity primary site. CONCLUSIONS Prognosis of oropharyngeal and oral squamous cell carcinomas is less favorable in females who smoke as well as in younger and older women. With these patients, the oversight must be closer. Smoking, however, should be stopped.

Latissimus dorsi free flap reconstruction of anterior skull base defects.

INTRODUCTION Surgery of extensive skull base tumour results of a defect of soft and hard tissue and dura. Free flap reconstruction provides tissue to restore the defect and separate the intracranial content from the bacterial flora of the nasal fossae. Vertical and transverse rectus abdominis myocutaneous free flap are usually used. This study was designed to compare our experience of latissimus dorsi free flap reconstruction of extensive skull base defects after tumour resection with the literature concerning the use of other types of free flaps. MATERIAL AND METHOD All extensive skull base tumour resections with latissimus free flap reconstruction made in the head and neck oncology unit of the Institut Curie, Cancer Centre, between January 2004 and December 2009 were reviewed. RESULTS Two infectious complications were observed (11.7%), two cases of CSF leak (11.7%), one case of wound dehiscence following tumour resection comprising the nasal skin (5.9%) and one case of partial distal necrosis of the flap in a zone of skin resection (5.9%) were observed. No flaps were lost. Two latissimus dorsi donor site haematomas were observed (11.7%). CONCLUSION When reconstruction of extensive skull base defect need free flap, the latissimus dorsi free flap is a reliable solution.

Study of the length of hospital stay for free flap reconstruction of oral and pharyngeal cancer in the context of the new French casemix-based funding

The French national health insurance reimbursement system has recently changed from a global hospital funding system to casemix-based funding. The authors studied the factors likely to influence the length of hospital stay for free flap reconstructions after surgery for cancers of the oral cavity or pharynx. Data concerning 207 oral cavity or pharynx free flap reconstructions were extracted from a prospective registration. Lengths of hospital stay were compared by an analysis of variance F test or a nonparametric Kruskal-Wallis test, and transfusion rates were compared by Chi-square test or Fishers exact test, as appropriate. The median length of hospital stay was 24 days (range: 7-145 days). Length of hospital stay was significantly longer according to the type of flap (p<0.005), in N2-N3 patients (p<0.02), a PINI score more than 10, a 3-4 American Society of Anesthesiologists (ASA) score, the presence of a tracheotomy and in patients requiring transfusion (p<0.0001). As the nodal status, the American Society of Anesthesiologists (ASA) score of the patient, the need of tracheotomy and the type of flap cannot be corrected, the management of preoperative haemoglobin and nutritional status are the sole factors which can improve the length of hospital stay. In the context of the new casemix-based funding, this study raises the problem of harvesting of the fibula flap, management of preoperative haemoglobin and nutritional status.

Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy

BACKGROUND Sentinel lymph-node (LN) biopsy (SLNB) is a valuable tool to assess the regional LN status in Merkel cell carcinoma (MCC). However, its prognostic value is still debated. This study was undertaken to assess SLNB usefulness for MCC management and to determine the impact of SLNB status on disease-free survival (DFS) and overall survival (OS) by comparing SLNB-positive versus -negative patients according to demographic, clinical and treatment characteristics. PATIENTS AND METHODS In this retrospective, multicenter observational study, SLNB was proposed to all patients referred for clinically N0 MCC. Treatment schedule consisted of wide-margin surgical resection of primary MCC followed by adjuvant radiation therapy (aRT) to the primary site and, for SLNB-positive patients, radical LN dissection followed by regional aRT. Univariate and multivariate analyses determined factors associated with DFS and OS. RESULTS Among 87 patients with successful SLNB, 21 (24.1%) were SLNB-positive. Median follow-up for the entire series was 39 months; respective 3-year DFS and OS rates were 73% and 81.4%, respectively. Univariate analysis (all patients) identified SLNB-negativity as being associated with prolonged OS (P = 0.013) and aRT (all sites considered) was associated with longer DFS (P = 0.004) and OS (P = 0.018). Multivariate analysis (all patients) retained SLNB status and aRT (all sites considered) as being associated with improved DFS (P = 0.014 and 0.0008) and OS (P = 0.0020 and 0.0019). Moreover, for SLNB-negative patients, tumor-bed irradiation was also significantly associated with prolonged DFS (P = 0.006) and OS (P = 0.014). CONCLUSIONS The present study demonstrates that SLNB-negativity is a strong predictor of longer DFS and OS in stage I and II MCC patients. The similar benefit for aRT on tumor bed observed in this study has to be confirmed by a prospective study. The results advocate for SLNB being considered to all MCC patients.

Prognostic significance of tumor shape and stromal chronic inflammatory infiltration in squamous cell carcinomas of the oral tongue

BACKGROUND Squamous cell carcinoma (SCC) of the oral tongue is well known to be an aggressive disease with early metastatic spread in early stage tumors. It is also established that locoregional recurrences are the main causes of treatment failure. Thus, the identification of histopathological factors possessing a predictive value remains important for the management of the disease. The aim of the present study was to define histopathological parameters of the tumor and to compare with the follow-up and status in primary SCCs of the mobile tongue. METHODS Histopathological parameters such as mitotic index, the presence of vascular emboli or perineural invasion, the thickness of the tumor, the histological grade, the tumor shape as well as chronic stromal inflammatory infiltration were assessed in 52 patients with SCC of the mobile tongue and compared with the follow-up and status in patients treated initially by surgery. RESULTS Tumor shape was significantly associated with the presence of perineural invasion. Well-defined shaped tumors displayed almost half the incidence of perineural invasion when compared with ill-defined shaped tumors. In addition, the high density of the chronic inflammatory infiltration of the stroma exhibited significant correlation with the survival of the patients. Finally, the intense chronic inflammatory infiltration of the stroma was associated with well-defined shaped tumors. CONCLUSION Tumor shape and stromal chronic inflammatory infiltration should be considered in the planning of the management of patients with SCC of the mobile tongue.

Giant basal cell carcinoma with regional lymph node and distant lung metastasis

The prevalence of metastatic basal cell carcinoma (MBCC) varies between 0.0028% and 0.55% of all cases. In total, more than 300 MBCC have been reported in the literature. We report the case of a 72 year old lady, who presented in September 2009 with a 10-year history of a progressively growing, giant, facial basal cell carcinoma (BCC). Clinical and imaging evaluations identified large local invasion with bone and meningeal involvement. Treatment consisted of an extensive surgery including left eye exenteration and meningeal resection followed by radiotherapy. A solitary lung metastasis was identified five months after the primary tumor resection. As the lesion remained solitary but had increased in size five months later, the patient finally accepted a surgical resection. A right upper-lobe pneumonectomy was performed and pathologic examination confirmed the metastasis as a MBCC.

RCAS1 expression in mobile tongue squamous cell carcinoma: An immunohistochemical study

Summary Background The receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that has been considered to play a crucial role in tumor progression by enabling cancer cells to evade immune surveillance. The present study aimed to evaluate the clinical significance of RCAS1 expression in mobile tongue squamous cell carcinoma (SCC). Material/Methods RCAS1 protein expression was assessed immunohistochemically on 49 mobile tongue SCC tissue samples obtained from an equal number of patients and was statistically analyzed with clinicopathological characteristics and overall and disease-free patients’ survival. Results Enhanced RCAS1 expression was significantly associated with reduced depth of invasion (p=0.0069), low mitotic index (p=0.0251) and no evidence of muscular invasion (p=0.0098). A borderline association between RCAS1 expression and stromal inflammatory reaction was also noted (p=0.0660). RCAS1 expression was not associated with overall and disease-free survival. Conclusions Our data support evidence for possible implication of RCAS1 at the early stage of tumor progression in mobile tongue SCC, whereas the survival prediction using RCAS1 expression as a clinical marker seems uncertain for this type of malignancy.