Keratoacanthoma or cutaneous squamous cell carcinoma revealing a DNA mismatch repair default (Muir-Torre Syndrome).

Keratoacanthoma (KA) and well-differentiated cutaneous squamous cell carcinoma (cSCC) are hardly distinguishable clinically and histologically. They both can be seen in patients with hereditary non-polyposis colorectal cancer (HNPCC) or Lynch Syndrome, corresponding to DNA microsatellite instability. In our case, a young man had the excision of two rapidly growing skin tumours for which distinction between KA and cSCC was initially clinically and pathologically challenging. The diagnosis of well-differentiated cSCCs was made and the patient was treated with surgery. Ten years after the first cSCC, he was diagnosed with Muir-Torre syndrome, a variant of Lynch syndrome, with an heterozygote mutation of the MSH2 gene. This later diagnosis allowed to screen his family members for the same mutation and to adopt an appropriate follow-up regarding the risk of digestive tumours for him and his family. Furthermore, it is important to know that, in case of non-resectable cSCC occurring in this patient, immunotherapy using anti-PD1 antibody would probably be effective due to the known increased immunogenicity of MMR deficient tumours.

Sentinel lymph node biopsy in cutaneous head and neck melanoma.

PURPOSE: Sentinel lymph node biopsy (SLNB) is now a standard of care for cutaneous melanoma, but it is still controversial for cutaneous head and neck melanoma (CHNM). This study aims to confirm the feasibility, accuracy and low morbidity of SLNB in CHNM and evaluate its prognostic value. METHODS: A monocentric and retrospective study on patients with CHNM treated in our tertiary care center (Gustave Roussy) between January 2008 and December 2012 was performed. The feasibility, morbidity and prognostic value of this technique were analysed. RESULTS: One hundred and twenty-four consecutive patients were included. SLNB was realized in 97.6% of the cases. No significant post-operative morbidity was observed. Nineteen percents of patients had a positive SN while only 14.3% of complete lymph node dissections (CLND) had additional nodal metastasis. The risk of recurrence after positive SN was significantly higher (69.2 vs 30.8%, p = 0.043). The false omission rate was low with 7.1%. Overall survival and disease-free survival were better in the negative SN group (82 vs 49%, p < 0.001 and 69.3 vs 41.8%, p = 0.0131). The risk of recurrence was significantly higher in the positive SN group (p = 0.043) and when primary tumour was ulcerated (p = 0.031). Only the mitotic rate of the primary tumour was associated with SN positivity (p = 0.049). CONCLUSION: As in other sites, SLNB status is a strong prognostic factor with comparable false omission rate and no superior morbidity.

Predictors of responses to immune checkpoint blockade in advanced melanoma.

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

Efficacy of neoadjuvant cetuximab alone or with platinum salt for the treatment of unresectable advanced nonmetastatic cutaneous squamous cell carcinomas.

BACKGROUND: Refractory locally advanced or metastatic nonmelanoma skin cancer (NMSC) is a frequent therapeutic impasse. OBJECTIVES: To address the question of the efficacy of induction therapy with cetuximab as neoadjuvant treatment for locally advanced NMSC. METHODS: From 2008 to 2013, all patients with a diagnosis of unresectable locally advanced skin squamous cell carcinoma were treated with neoadjuvant cetuximab alone (CM) or combined with a platinum salt and 5-fluorouracil (CC). Resectability, and clinical and pathological response, as well as relapse-free and overall survival were evaluated. RESULTS: Thirty-four patients, with a median age of 74·5 years, were evaluated. Twenty-five patients received CC. After three cycles of CC, 23 of 25 patients whose tumours were initially unresectable became amenable to surgery (92%). A complete histological response was observed in 15 (65%) patients. The mean progression-free and mean overall survival in operated patients were 8·5 and 26·0 months, respectively. CONCLUSIONS: There was a good response in terms of resectability and tumour control in the majority of patients, with few relapses, despite the initially poor prognosis of these tumours in this elderly group of patients. However, this therapeutic strategy needs to be validated in a prospective, randomized study.

Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients.

BACKGROUND: BRAF inhibitors are being developed for the treatment of metastatic melanoma harboring a V600E mutation. The use of vemurafenib significantly increases progression-free survival (PFS) and overall survival (OS) in this population of patients, but is associated with numerous adverse skin reactions. PATIENTS AND METHODS: We carried out a systematic dermatologic study of 42 patients treated with vemurafenib. We collected detailed dermatologic symptoms, photos and biopsy specimens of the skin lesions which enabled us to classify the side-effects. The management and evolution of the skin symptoms are also reported. RESULTS: All patients presented with at least one adverse skin reaction. The most common cutaneous side-effects consisted in verrucous papillomas (79%) and hand-foot skin reaction (60%). Other common cutaneous toxic effects were a diffuse hyperkeratotic perifollicular rash (55%), photosensitivity (52%) and alopecia (45%). Epidermoid cysts (33%) and eruptive nevi (10%) were also observed. Keratoacanthomas (KA) and squamous cell carcinoma (SCC) occurred in 14% and 26% of the patients, respectively. CONCLUSIONS: These cutaneous side-effects are cause of concern due to their intrinsic potential for malignancy or because of their impact on patients' quality of life. Management of this skin toxicity relies on symptomatic measures and sun photoprotection.

Genetic variability and integration of Merkel cell polyomavirus in Merkel cell carcinoma.

Merkel cell polyomavirus (MCPyV) is associated to Merkel cell carcinoma (MCC). We studied 113 MCC tumoral skin lesions originating from 97 patients. MCPyV detection was higher in fresh-frozen (FF) biopsies (94%) than in formalin-fixed paraffin-embedded biopsies (39-47%). Mean viral load in FF tumor was of 7.5 copies per cell with a very wide range (0.01-95.4). Nineteen complete sequences of LTAg were obtained, mainly from FF biopsies when the viral load was high. Seventeen showed stop codons, all localized downstream of the pRb protein binding domain. Sequence comparison and phylogenetic analysis showed that all sequences clustered in the large C clade of MCPyV strains. MCPyV integration was demonstrated in 19 out of 27 FF MCC DNA biopsies without evidence of specific host cellular genome integration site. In 13/19 cases, the viral junction was located within the second exon of the LTAg, after the pRB binding domain.

Association between the nuclear to cytoplasmic ratio of p27 and the efficacy of adjuvant polychemotherapy in early breast cancer.

BACKGROUND: The purpose of this study was to evaluate the prognostic and predictive value of p27 expression in patients with early breast cancer. PATIENTS AND METHODS: Quantitative immunofluorescence assays for p27 were done on a tissue microarray that included 823 samples from patients randomized between anthracycline-based chemotherapy and no chemotherapy. Quantification of p27 was done using the AQUA® system (HistoRx, Inc., Branford, CT). Both p27 nuclear expression and the nuclear to cytoplasmic ratio were assessed. RESULTS: Nuclear p27 expression was not predictive for the efficacy of anthracycline-based chemotherapy [adjusted P=0.18 for disease-free survival (DFS)] nor prognostic [95% confidence interval (CI) 0.99-1.01, P=0.49]. However, p27 nuclear/cytoplasmic ratio was predictive for the efficacy of adjuvant chemotherapy (adjusted P=0.016 DFS). The adjusted hazard ratio (HR) for relapse associated with adjuvant chemotherapy was 0.56 (95% CI 0.37-0.84, P=0.005) and 1.06 (95% CI 0.76-1.47, P=0.74) for patients with high and low nuclear/cytoplasmic ratio, respectively. p27 N/C ratio was prognostic in patients treated with chemotherapy (HR for relapse or death for a 1 unit increase in p27 N/C ratio was 0.30, 95% CI 0.12-0.77) but not in the untreated arm (HR for relapse or death was 1.27, 95% CI 0.58-2.8). CONCLUSIONS: This study did not confirm the role of p27 nuclear expression as a prognostic parameter. However, the p27 nuclear/cytoplasmic ratio was predictive in patients treated with anthracycline-based chemotherapy.

The differential response to chemotherapy of ovarian metastases from colorectal carcinoma.

PATIENTS AND METHODS: All patients with metastatic (ovarian and extraovarian) CRC who underwent resection of ovarian metastases in our institution from April 1988 to August 2006 were analyzed and the response to preoperative chemotherapy was evaluated according to the RECIST criteria, and analyzed with respect to the sites of metastases (ovarian and extraovarian). RESULTS: The studied population consisted of 23 women. At presentation, 20 patients had symptoms. Preoperative chemotherapy resulted in tumor control of measurable extraovarian metastases in 65% of cases. In contrast, no objective tumor response of ovarian metastases was observed, disease stabilization was obtained in only 3 patients (13%), and progression or occurrence of new ovarian metastases were observed in 20 patients (87%) (p=0.0005). With a median follow-up of 54 months [15-229], median overall survival was 30 months, and 3-year overall survival was 18%. CONCLUSION: Ovarian metastases are less responsive to chemotherapy compared to other sites. As these "metastatic sanctuaries" often cause symptoms, surgical resection should always be considered for ovarian metastases, even in the case of associated extraovarian metastases.

Comparison between the minimum margin defined on preoperative imaging and the final surgical margin after hepatectomy for cancer: how to manage it?

BACKGROUND: The liver surgeon's decision to operate is based on imaging studies. However, no clear practical guidelines are available enabling surgeons to safely predict tumor-free margins after a partial hepatectomy. The aim of this retrospective study is to provide surgeons with simple and easily applicable practical guidelines. METHODS: We retrospectively stringently selected 42 anatomical right or left hepatectomies whose main characteristic was to pass along the median hepatic vein, which was preserved. This vein is an easily visualized anatomical landmark on preoperative imaging and is never transgressed by the surgeon. We compared the minimum distance between the tumor and this vein measured on preoperative imaging, and the minimum tumor-free excision margin measured on the specimen by the pathologist. RESULTS: The median tumor-free excision margin was 5 mm at pathological analysis, significantly different (P < .0001) from the tumor-free margin measured on preoperative imaging (15 mm). The mean difference between these two measurements was 10 +/- 4 mm (median, 9 mm). This difference was partly the result of the transection and partly the result of technical deviations in relation to the ideal resection line. CONCLUSIONS: The liver surgeon must consider that roughly a 5 to 8 mm tumor-free margin will disappear during hepatectomy when comparing measurements on the basis of preoperative imaging versus tumor-free specimen margins. If the histologically assessed minimum 2-mm tumor-free margin is added, the surgeon must plan to have a 7 to 10 mm tumor-free margin on preoperative imaging. However, few technical solutions exist that would enable the surgeon to increase the safety margin in borderline cases.

Expression patterns and predictive value of phosphorylated AKT in early-stage breast cancer.

BACKGROUND: AKT phosphorylation is a critical step in the activation of growth factor receptors and can mediate tumor resistance to anthracyclines. We evaluated the expression patterns and predictive value of phosphorylated AKT (pAKT) in breast cancer tissues. PATIENTS AND METHODS: pAKT expression was assessed by immunohistochemistry in 823 tumors from patients with early breast cancer enrolled in two randomized trials. The distribution of pAKT expression was correlated with HER2 and epidermal growth factor receptor (EGFR) expression. The predictive value of pAKT for the efficacy of adjuvant chemotherapy was determined by test for interaction. RESULTS: pAKT, EGFR, and HER2 were expressed in 119 of 781 (15%), 118 of 758 (16%), and 99 of 775 (13%) assessable tumors. Staining was positive for pAKT in 28 of 99 (28%) and 90 of 676 (13%) HER2+ and HER2- tumors (P < 0.001). pAKT was expressed in 15 of 94 (16%) and 75 of 563 (13%) HER2-/EGFR+ and HER2-/EGFR- tumors, respectively (P = 0.49). A positive staining for pAKT did not correlate with prognosis (P = 0.94), and did not predict the resistance to anthracyclines (test for interaction, P = 0.70). CONCLUSIONS: AKT phosphorylation is associated with HER2 expression but not EGFR expression in patients with early breast cancer. pAKT is not predictive for the efficacy of anthracycline-based adjuvant chemotherapy.

Efficacy of adjuvant chemotherapy according to Prion protein expression in patients with estrogen receptor-negative breast cancer.

BACKGROUND: Prion protein (PrPc) has been previously reported to be associated with resistance to proapoptotic stimuli. We evaluated whether the expression of PrPc was associated with the resistance to adjuvant chemotherapy in patients with estrogen receptor (ER) -negative breast cancer. PATIENTS AND METHODS: The expression of PrPc by primary tumors was assessed by immunohistochemistry in a series of 756 patients included in two randomized trials that compared anthracycline-based chemotherapy to no chemotherapy. The PrPc expression was correlated with ER expression and the benefit of adjuvant chemotherapy was assessed according to PrPc expression in patients with ER-negative tumors. RESULTS: Immunostaining analysis showed that PrPc was mainly expressed by myoepithelial cells in normal breast tissue. Tissue microarray analysis from 756 breast tumors showed that PrPc was associated with ER-negative breast cancer subsets (P < 0.001). Adjuvant chemotherapy was not associated with a significant risk reduction for death in patients with ER-negative/PrPc-positive disease [adjusted hazard ratio (HR) for death = 0.98, 95% confidence interval (CI) 0.45-2.1, P = 0.95], while it decreased the risk for death (HR = 0.39, 95% CI 0.2-0.74, P = 0.004) in patients with ER-negative/PrPc-negative tumors. CONCLUSION: These data indicate that ER-negative/PrPc-negative phenotype is associated with a high sensitivity to adjuvant chemotherapy.

Breast cancer molecular subclassification and estrogen receptor expression to predict efficacy of adjuvant anthracyclines-based chemotherapy: a biomarker study from two randomized trials.

BACKGROUND: The purpose of this study was to determine the predictive value of breast cancer molecular subclassification regarding the benefit of adjuvant anthracycline-based chemotherapy. PATIENTS AND METHODS: Tumor samples from 823 patients included in two randomized trials that compared an anthracycline-based chemotherapy with no treatment were used to construct a tissue array. Estrogen receptor (ER), Her2, epidermal growth factor receptor, cytokeratine 5/6 expressions were determined by immunohistochemistry (IHC). The potential predictive factors of treatment effect on disease-free survival (DFS) were assessed by interaction tests and multivariate analysis. RESULTS: Sixty-four (8%), 98 (12%), 109 (14%) and 527 (66%) patients presented a Her2+/ER-, basal-like, Her2-/ER-/nonbasal and luminal-like breast cancer. ER expression, when assessed by IHC, was an independent predictive factor for the benefit of chemotherapy on DFS (test for interaction, P = 0.0015). The molecular subclassification significantly predicted the efficacy of chemotherapy (test for interaction, P = 0.01), but had no significant added value (P = 0.32) as compared to the ER by treatment interaction. Adjuvant chemotherapy was associated with an adjusted hazard ratio for relapse or death of 0.42 [95% confidence interval (CI): 0.17-1.05], 0.54 (95% CI: 0.27-1.08), 0.35 (95% CI: 0.18-0.68), 1.07 (95% CI: 0.81-1.41) for patients with Her2+/ER-, basal-like, Her2-/ER-/nonbasal and luminal-like tumors, respectively. CONCLUSION: The breast cancer molecular subclassification was predictive for chemotherapy efficacy in adjuvant setting, but did not provide significant additional information to ER.

Contribution of vascular endothelial growth factor to the Nottingham prognostic index in node-negative breast cancer.

The prognostic contribution of intratumour VEGF, the most important factor in tumour-induced angiogenesis, to NPI was evaluated by using flexible modelling in a series of 226 N-primary breast cancer patients in which steroid receptors and cell proliferation were also accounted for. VEGF provided an additional prognostic contribution to NPI mainly within ER-poor tumours.

Adenocarcinoma of the lower third of the rectum surgically treated with a <10-MM distal clearance: preliminary results in 35 N0 patients.

BACKGROUND: Recent reports suggest that a distal clearance (DC) of 10 mm at the lower surgical margin may be considered adequate in the surgical treatment of rectal cancer, but there are no data on the possible adequacy of a < 10-mm DC in N0 patients in whom a good prognosis can otherwise be expected, that is, those with negative surgical margins and negative lymph nodes. METHODS: Between November 1991 and December 1998, 154 consecutive patients with adenocarcinoma of the lower third of the rectum had a total rectal resection with total mesorectal excision and coloendoanal anastomosis. Among 76 N0 patients, there were 35 with <10-mm DC and 41 with > or =10-mm DC. Each group was divided into two subgroups depending on whether the surgical margins were involved or not, and the rate of local recurrence in the various categories was compared. All B2 Astler-Coller stage patients in the series received postsurgical chemoradiotherapy. RESULTS: The local recurrence rate in the 35 patients with DC < 10 mm was 11.4% and that of the 41 patients with DC > or =10 mm was 7.3%. When only patients with negative surgical margins were considered, the local recurrence rate was 3.4% for those with < 10-mm DC and 5.1% for those with > or =10-mm DC. CONCLUSIONS: Our results suggest that a radical surgery with <10-mm DC followed by chemoradiotherapy may be adequate in N0 patients, provided that a careful pathologic examination of the surgical specimen excludes the presence of lymph node metastases and that the distal rectal and mesorectal resection margins fall in healthy tissue.

Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables.

PURPOSE: There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. PATIENTS AND METHODS: Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgroups defined by HER2 and the status of other variables using a Bayesian approach. The end points considered were relapse-free survival (RFS) and cause-specific survival (CSS). RESULTS: Bayesian analysis of the treatment effect for HER2 and other variables indicated a clinical benefit from CMF treatment in all subgroups defined according to variables status. In particular regarding HER2 status, Bayesian estimates of RFS hazard ratios were equal to 0.484 and 0.641 and estimates of CSS hazard ratios were equal to 0.495 and 0.730 for HER2-positive and -negative tumors, respectively. CONCLUSION: CMF treatment showed a clinical benefit in the considered subgroups, defined according to HER2 and other tumor variables status. Patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, and the poor prognosis associated with the HER2 overexpression in the untreated group could be completely overcome by the chemotherapy treatment.

Conservative surgery in breast cancer. Significance of resection margins.

We approached the issue of surgical margins in the conservative treatment of breast cancer by examining the literature germane to four precise questions: At what distance from the macroscopic margin of the tumour should the resection margin be? To what extent do histologically clear resection margins indicate complete local control of the disease? To what extent do histologically involved margins indicate persistence of disease? and Does the local recurrence rate correlate with the status of the resection margin? We propose categorizing margin involvement into five groups (absent, focal, minimal, moderate and extensive involvement) according to strict histological criteria, and assigning increasingly aggressive subsequent treatments according to the extent of any margin involvement.

Gene product immunophenotyping of neuroendocrine lung tumors. No linking evidence between carcinoids and small-cell lung carcinomas suggested by multivariate statistical analysis.

Fifty-three neuroendocrine lung tumors (24 carcinoids, one atypical carcinoid, five large-cell neuroendocrine carcinomas, and 23 small-cell lung carcinomas) were investigated for immunocytochemical expression of several gene products, i.e., p53, Rb, bcl-2, c-kit, mdm-2, cdk-4, p21 proteins, and proliferation index as assessed by MIB-1. The goal of the study was to explore the relationships between histotypes in light of their own gene product-based immunophenotypical profiles. To this aim we applied the multiple correspondence analysis, which is an exploratory statistical multivariate technique that converts a data matrix into a particular type of graphic display in which the rows and columns are depicted as points. Such statistical analysis displayed that some categories of the gene product-based immunophenotyping variables are grouped in the plot identifying three groups: the first group related to carcinoids, the second to small-cell carcinomas, and the third to large-cell neuroendocrine carcinomas. These data support the evidence that carcinoids and small-cell carcinomas are two distinct, apparently immunogenotypically unrelated entities among neuroendocrine lung tumors and that atypical carcinoids and large-cell neuroendocrine carcinomas seem not to represent intermediate steps between them.

Time-dependent relevance of steroid receptors in breast cancer.

PURPOSE: To analyze the time-dependent prognostic role of the investigated variables, considered, when appropriate, on a continuous scale, for the purpose of evaluating and describing the interrelationships between clinically relevant patient and tumor characteristics (age, size and histology, and estrogen receptor [ER] and progesterone receptor content) and the risk of new disease manifestation. PATIENTS AND METHODS: We applied a flexible statistical model to a case series of 1,793 patients with axillary lymph node-negative breast cancer with a minimal potential follow-up of 10 years. To avoid a potential confounding effect of adjuvant treatment, only patients given local-regional therapy until relapse were considered. RESULTS: ER content and tumor size (adjusted for all the other covariates) showed a time-dependent relationship with the risk of new disease manifestations. In particular, ER content failed to show a prognostic effect within the first years of follow-up; thereafter, a positive association with risk of relapse was observed. For tumor size, within the first years of follow-up, the risk of relapse was directly related to size for only tumors up to 2.5 cm in diameter; thereafter, the impact on prognosis progressively decreased. CONCLUSION: The availability of a long follow-up on a large breast cancer series, as well as the use of innovative statistical approaches, allowed us to explore the functional relation between steroid receptors and clinical outcome and to generate a hypothesis on the involvement of ER in favoring long-term metastasis development.