B. Couturaud

Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis†

Merkel cell carcinoma (MCC), a skin tumour with neuroendocrine features, was recently found to be associated with a new type of human polyomavirus, called Merkel cell virus (MCV). We investigated the specificity of this association as well as a causal role of MCV in oncogenesis. DNA and RNA from ten cases of MCC were analysed using PCR and RT‐PCR. DNA from 1241 specimens of a wide range of human tumours was also analysed. The DIPS technique was used to identify the integration locus of viral DNA sequences. Array CGH was performed to analyse structural alterations of the cell genome. MCV DNA sequences were found in all ten cases of MCC and in none of the 1241 specimens of other tumour types. Clonal integration of MCV into the host genome was seen in all MCC cases and was checked by FISH in one case. A recurrent pattern of conserved viral sequences which encompassed the replication origin, the small tumour (ST), and the 5′ part of the large tumour (LT) antigen DNA sequences was observed. Both ST and LT viral sequences were found to be significantly expressed in all MCCs. Neither recurrent site of integration nor alteration of cellular genes located near the viral sequences was observed. The tight association of MCV with MCC, the clonal pattern of MCV integration, and the expression of the viral oncoproteins strongly support a causative role for MCV in the tumour process. This information will help the development of novel approaches for the assessment and therapy of MCC and biologically related tumours. Copyright

Oncoplastic breast surgery for cancer: analysis of 540 consecutive cases [outcomes article].

Background: Synchronous plastic and oncological surgery is undertaken to improve the security of excision margins and yield high-quality aesthetic outcomes when conventional breast-conserving therapy either anticipates poor results or is not possible. Methods: A total of 540 consecutive patients underwent primary oncoplastic breast surgery for cancer with high tumor-to-breast volume ratios and locations precluding a good aesthetic result with simple tumor excision. A variety of techniques were employed at the Institut Curie between 1986 and 2007, and aesthetic outcomes were assessed on a five-point scale from 1 (excellent) to 5 (poor). Results: The median age was 52 years (range, 28 to 90 years), and median follow-up was 49 months (6 to 262 months). Median tumor size was 29.1 mm (range, 4 to 100 mm), with most patients (72.3 percent) having a brassiere cup size of B or C. Close or involved margins occurred in 18.9 percent, with mastectomy being necessary in 9.4 percent. A satisfactory aesthetic outcome (ratings of 1 to 3) at 5 years was obtained in 90.3 percent. Five-year overall and distant disease-free survival rates were 92.9 and 87.9 percent, respectively, with local recurrence in 6.8 percent. Conclusions: With local recurrence and survival rates similar to those for breast-conserving therapy, this series confirms the safety of oncoplastic breast surgery for tumors both high in volume and difficult in location. Highly satisfactory cosmetic outcomes extend the indications for conservative surgery, further reduce the mastectomy rate, and limit adverse aesthetic sequelae.

Distinct Merkel Cell Polyomavirus Molecular Features in Tumour and Non Tumour Specimens from Patients with Merkel Cell Carcinoma

Merkel Cell Polyomavirus (MCPyV) is associated with Merkel Cell carcinoma (MCC), a rare, aggressive skin cancer with neuroendocrine features. The causal role of MCPyV is highly suggested by monoclonal integration of its genome and expression of the viral large T (LT) antigen in MCC cells. We investigated and characterized MCPyV molecular features in MCC, respiratory, urine and blood samples from 33 patients by quantitative PCR, sequencing and detection of integrated viral DNA. We examined associations between either MCPyV viral load in primary MCC or MCPyV DNAemia and survival. Results were interpreted with respect to the viral molecular signature in each compartment. Patients with MCC containing more than 1 viral genome copy per cell had a longer period in complete remission than patients with less than 1 copy per cell (34 vs 10 months, P = 0.037). Peripheral blood mononuclear cells (PBMC) contained MCPyV more frequently in patients sampled with disease than in patients in complete remission (60% vs 11%, P = 0.00083). Moreover, the detection of MCPyV in at least one PBMC sample during follow-up was associated with a shorter overall survival (P = 0.003). Sequencing of viral DNA from MCC and non MCC samples characterized common single nucleotide polymorphisms defining 8 patient specific strains. However, specific molecular signatures truncating MCPyV LT were observed in 8/12 MCC cases but not in respiratory and urinary samples from 15 patients. New integration sites were identified in 4 MCC cases. Finally, mutated-integrated forms of MCPyV were detected in PBMC of two patients with disseminated MCC disease, indicating circulation of metastatic cells. We conclude that MCPyV molecular features in primary MCC tumour and PBMC may help to predict the course of the disease.

Donor site sequelae after autologous breast reconstruction with an extended latissimus dorsi flap.

&NA; The indications for autologous reconstruction are increasing. The standard procedure is the transverse rectus abdominis muscle flap; however, this flap has contraindications and drawbacks. The latissimus dorsi muscle flap is simple and reliable. Hokin et al. demonstrated in 1983 that this flap can be extended and used for breast reconstruction without an implant. Since then, it has been widely studied in this setting and is known to provide good aesthetic results. Dorsal sequelae, conversely, were not appraised. The aim of this study was to assess objective and subjective dorsal sequelae after the harvest of an extended flap. Forty‐three consecutive patients who had had breast reconstruction with an autologous latissimus dorsi flap were assessed by a surgeon and a physiotherapist for muscular strength and shoulder mobility. Patient opinion was studied through a questionnaire. Mean delay between the operation and the evaluation was 19 months. Early complications, mainly dorsal seromas, were frequent after the harvest of an extended flap (72 percent). There was no late morbidity and, especially, no flap loss or partial necrosis. As for functional results, 37 percent of the patients had complete adjustment and 70 to 87 percent demonstrated no change in shoulder strength. Sixty percent of the patients experienced no limitation in everyday life, and 90 percent said they would undergo this procedure again. The authors show that dorsal sequelae after an extended latissimus dorsi flap are minimal and that this technique compares favorably with the transverse rectus abdominis muscle flap. (Plast. Reconstr. Surg. 109: 1904, 2002.)

The role of nipple-sparing mastectomy in breast cancer: a comprehensive review of the literature.

Background: The role of nipple-sparing mastectomy for breast cancer is controversial, as there is concern regarding its oncologic safety and complication rate. The authors reviewed the literature to quantify the incidence of occult nipple malignancy in breast cancer, identify the factors influencing occult nipple malignancy, quantify locoregional recurrence rates, and quantify nipple-sparing mastectomy complication rates. Methods: A search of the literature was performed using PubMed. Key words used were “mastectomy,” “nipple involvement,” “nipple-sparing mastectomy,” “skin-sparing mastectomy,” “occult nipple malignancy,” “occult nipple disease,” and “breast cancer recurrence.” Articles were analyzed regarding incidence of occult nipple malignancy, potential factors influencing the incidence of occult malignancy, and recurrence/complications following nipple-sparing mastectomy. The incidence of occult nipple disease was compared between groups using chi-square or Fisher’s exact tests for categorical variables and t tests for continuous variables. Values of p < 0.05 were considered significant. Results: The overall rate of occult nipple malignancy was 11.5 percent. Primary tumor characteristics influencing occult nipple malignancy were tumor-nipple distance less than 2 cm, grade, lymph node metastasis, lymphovascular invasion, human epidermal growth factor receptor-2–positive, estrogen receptor/progesterone receptor–negative, tumor size greater than 5 cm, retroareolar/central location, and multicentric tumors. The overall nipple recurrence rate considered significant was 0.9 percent, and the skin flap recurrence rate was 4.2 percent. Full- and partial-thickness nipple necrosis rates were 2.9 and 6.3 percent, respectively. Conclusions: Nipple-sparing mastectomy for primary breast cancer is appropriate in carefully selected patients. All patients should have retroareolar sampling. There is strong evidence to suggest that suitable cases are well circumscribed single or multifocal lesions that have a tumor-to-nipple distance greater than 2 cm. Tumors should be grade 1 to 2 and not have lymphovascular invasion, axillary node metastasis, or human epidermal growth factor receptor-2 positivity.

Management of Phyllodes Breast Tumors

Abstract:  Phyllodes tumors are a rare distinctive fibroepithelial tumors of the breast and their management continues to be questioned. The aim of our study was to examine the treatment and outcome of 165 patients with phyllodes tumors and to review the options for surgical management. This is a retrospective study of 165 patients who presented to the Institut Curie between January 1994 and November 2008 for benign, borderline or malignant phyllodes tumors. The median follow‐up was 12.65 months [range 0–149.8]. The median age at diagnosis was 44 years [range 17–79]. One hundred and sixty patients (97%) had breast‐conserving treatment, of whom 3 patients (1.8%) had oncoplastic breast surgery. Younger women had a significantly higher chance of having a benign phyllodes tumor (p = 0.0001) or a tumor of small size (p < 0.0001). Histologic examination showed 114 benign (69%), 37 borderline (22%) and 14 malignant tumors (9%). The median tumor size was 30 mm [range 5–150]. The tumor margins were considered incomplete (<10 mm) in 46 out of 165 cases (28%) with 52% revision surgery. Only the tumor grade was a significant risk factor for incomplete tumor margins (p = 0.005). Fifteen patients developed local recurrence (10%) and two, metastases. In univariate analysis, the histologic grade (p = 0.008), and tumor size (p = 0.02) were significative risk factors for local recurrence with an accentuated risk for “borderline” tumors and tumors of large size.).Similar results were obtained using multivariate analysis (p = 0.07). The mainstay of treatment for phyllodes tumors remains excision with a safe surgical margin, taking advantage breast conserving surgery where amenable. For borderline or malignant phyllodes tumors or in cases of local tumor recurrence, mastectomy, and immediate breast reconstruction may become the preferred option. Genetic analysis will potentially supplement classical histologic examination in order to improve our management of these tumors. The role of adjuvant treatments is unproven and must be considered on a case‐by‐case basis.

Oncoplastic breast surgery: A review and systematic approach

Oncoplastic breast surgery (OBS) is relatively new, but has made rapid progress from its tentative steps of infancy in the 1990s. The recent Milanese Consensus Conference on Breast Conservation concluded that, firstly, oncoplastic techniques are warranted to allow wide excision and clear margins without compromising cosmesis. Secondly, such surgery is ideally performed at the same time as oncological excision. Whilst technically more challenging than standard breast conserving therapy (BCT), OBS is well proven, if not yet widely practised, both oncologically and aesthetically and a review of the available techniques is perhaps timely. The roots of breast conserving therapy can be traced to the 1930s, actually due to advances made in radiotherapy, and the last 20 years have seen it become firmly established. This review aims to summarise the key historical developments and latest innovations in OBS. Not only are our patients, who expect not only safe cancer treatment but a satisfactory aesthetic outcome, increasingly informed and demanding, but longer follow up has stimulated surgeons to improve outcomes. In many cases, particularly with ptosis and macromastia, the cancer can be treated, usually with wider excision margins, simultaneously improving the aesthetic appearance. Present at the birth of OBS, the Institut Curie has continued to introduce innovative techniques over the last two decades and a systematic approach, comprising nine basic techniques, has evolved to allow high quality treatment of any and all breast cancers suitable for OBS.

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.

Management of exposed, infected implant-based breast reconstruction and strategies for salvage.

INTRODUCTION Complications of implant-based breast reconstruction are rare but mastectomy flap necrosis and peri-implant infection are the most frequent and remain an important cause of early implant failure. This study aimed to compare the results of three different management strategies employed to deal with these complications at our institution. PATIENTS AND METHODS A consecutive series of 71 infected/exposed prostheses in 68 patients over a 20-year period were analysed. Management strategies included explantation and delayed reconstruction, implant salvage and explantation and immediate autologous reconstruction. RESULTS Only 19 of 45 (42%), managed with implant removal, went on to delayed reconstruction. Methods of delayed reconstruction were distributed equally between implant-only, implant and autologous tissue and autologous-only reconstructions. The implant was successfully salvaged in nine cases, but reducing the implant size or introducing new tissue as a flap increased the success from 45% to 53%. Three patients with infected implant-only breast reconstruction underwent explantation and immediate conversion to autologous-only reconstructions. CONCLUSIONS All the three interventions reviewed here have their place in the management of infected implant-based breast reconstructions. It is noteworthy that following implant removal, the likelihood of the patient proceeding to delayed reconstruction of any kind is similar to the likelihood of successful salvage (42% vs. 45%). This study population had high numbers of exposed implants in irradiated fields. Reducing implant size or introducing new tissue in the form of a flap increases the chances of successful implant salvage. In the presence of mild infection, removal of exposed/infected implants and immediate conversion to an autologous-only reconstruction can prove to be successful.

Reasons of not having breast reconstruction: a historical cohort of 1937 breast cancer patients undergoing mastectomy.

BackgroundThe aims of the study were to investigate the factors associated with not having breast reconstruction following mastectomy and to assess patient satisfaction with information on reconstruction.Patients and methodsWe analysed a historical cohort of 1937 consecutive patients who underwent mastectomy at Institut Curie between January 2004 and February 2007. Their sociodemographic and clinicobiological characteristics were recorded in a prospective database. A questionnaire was sent to 10% of nonreconstructed patients.ResultsThe proportion of patients with invasive cancer was 82.7%. The rate of nonreconstruction in patients with in situ and invasive cancer was 34.6% and 74.9%, respectively. On multivariate analysis, only employment outside the home was associated with reconstruction in patients with in situ cancer (p < 0.001). In patients with invasive cancer, employment status (p < 0.001) and smoking (p = 0.045) were associated with reconstruction, while age > 50, ASA score >1, radiotherapy (p < 0.0001) and metastatic status (p = 0.018) were associated with nonreconstruction. For 80% of questionnaire responders, nonreconstruction was a personal choice, mainly for the following reasons: refusal of further surgery, acceptance of body asymmetry, risk of complications and advanced age. Information on reconstruction was entirely unsatisfactory or inadequate for 62% of patients.ConclusionBetter understanding the factors that influence decision of nonreconstruction can help us adapt the information to serve the patient’s personal needs.