Recommandations suisses pour la prise en charge des cancers cutanés chez les patients transplantés d'organe [Swiss clinical practice guidelines for skin cancer in organ transplant recipients]

Swiss clinical practice guidelines for skin cancer in organ transplant recipients Transplant patients have increased over the last decades. As a consequence of long-term immunosuppression, skin cancer, in particular squamous cell carcinoma (SCC), has become an important problem. Screening and education of potential organ transplant recipients (OTRs) regarding prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, OTRs should be seen yearly by a dermatologist to ensure compliance with sun avoidance as well as for treatment of precancerosis and SCC. Early removal is the best treatment for SCC. Reduction of immunosuppression, switch to mTOR inhibitors and chemoprevention with acitretin may reduce the incidence of SCC. The dermatological follow-up of OTRs should be integrated into a comprehensive post-transplant management strategy.

Helical tomotherapy for the treatment of anal canal cancer: a dosimetric comparison with 3D conformal radiotherapy.

AIMS AND BACKGROUND: The standard treatment of anal canal cancer (ACC) is combined chemotherapy and radiation therapy (RT), which is complex because of the shape of the target volumes and the need to minimize the irradiation of normal pelvic structures. In this study we compared the dosimetric results of helical tomotherapy (HT) plans with traditional 3D conformal RT (3DRT) plans for the treatment of ACC. METHODS AND STUDY DESIGN: Twelve patients (median age 57 years, range 38-83; F/M 8/4) treated with HT and concurrent chemotherapy for locally advanced ACC were selected. All had histologically confirmed squamous-cell carcinoma. A clinical target volume including the tumor and pelvic and inguinal lymph nodes was treated with HT to a total dose of 36 Gy in 1.8-Gy daily fractions. Then a sequential boost of 23.4 Gy in 1.8-Gy daily fractions (total dose 59.4 Gy) was delivered to the tumor and involved nodes. For all 12 patients, 3DRT plans were generated for comparison. Treatment plans were evaluated by means of standard dose-volume histograms. Dose coverage of the planning target volumes (PTVs), homogeneity index (HI), and mean doses to organs at risk (OARs) were compared. RESULTS: The coverage of PTV was comparable between the two treatment plans. HI was better in the HT vs. 3DRT plans (1.25 and 3.57, respectively; p<0.0001). HT plans resulted in better sparing of OARs (p<0.0001). CONCLUSIONS: HT showed superior target dose conformality and significant sparing of pelvic structures compared with 3DRT. Further investigation should determine if these dosimetric improvements will improve clinical outcomes regarding locoregional control, survival, and treatment-related acute and late morbidity.

Nuclear receptor peroxisome proliferator activated receptor (PPAR) beta/delta in skin wound healing and cancer

We review the functions of peroxisome proliferator activated receptor (PPAR) beta/delta in skin wound healing and cancer. In particular, we highlight the roles of PPAR beta/delta in inhibiting keratinocyte apoptosis at wound edges via activation of the PI3K/PKB alpha/Akt1 pathway and its role during re-epithelialization in regulating keratinocyte adhesion and migration. In fibroblasts, PPAR beta/delta controls IL-1 signalling and thereby contributes to the homeostatic control of keratinocyte proliferation. We discuss its therapeutic potential for treating diabetic wounds and inflammatory skin diseases such as psoriasis and acne vulgaris. PPAR beta/delta is classified as a tumour growth modifier; it is activated by chronic low-grade inflammation, which promotes the production of lipids that, in turn, enhance PPAR beta/delta transcription activity. Our earlier,work unveiled a cascade of events triggered by PPAR beta/delta that involve the oncogene Src, which promotes ultraviolet-induced skin cancer in mice via enhanced EGFR/Erk1/2 signalling and the expression of epithelial-to-mesenchymal transition (EMT) markers. Interestingly, PPAR beta/delta expression is correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma. Furthermore, there is a positive interaction between PPAR beta/delta, SRC, and TGF beta 1 at the transcriptional level in various human epithelial cancers. Taken together, these observations suggest the need for evaluating PPAR beta/delta modulators that attenuate or increase its activity, depending on the therapeutic target.

Relationship between oral cancer and implants: clinical cases and systematic literature review

The use of implants for oral rehabilitation of edentulous spaces has recently been on the increase, which has also led to an increase in complications such as peri-implant inflammation or peri-implantitis. Chronic inflammation is a risk factor for developing oral squamous cell carcinoma (OSCC). Objectives: To review the literature of cases that associate implant placement with the development of oral cancer. Study design: We present two clinical cases and a systematic review of literature published on the relationship between oral cancer and implants. Results: We found 13 articles published between the years 1996 and 2009, referencing 18 cases in which the osseointegrated implants are associated with oral squamous cell carcinoma. Of those, 6 articles were excluded because they did not meet the inclusion criteria. Of the 18 cases reported, only 7 cases did not present a previous history of oral cancer or cancer in other parts of the body. Conclusions: Based on the review of these cases, a clear cause-effect relationship cannot be established, although it can be deduced that there is a possibility that implant treatment may constitute an irritant and/or inflammatory cofactor which contributes to the formation and/or development of OSCC.

Surgery Versus Radiotherapy for Early Oropharyngeal Tumors: a Never-Ending Debate.

OPINION STATEMENT: Therapeutic options for early stage oropharyngeal squamous cell carcinoma (OPSCC) include both surgery and radiotherapy as single treatment modality. Retrospective data reporting on locoregional control and survival rates in early stage OPSCC have shown equivalent efficacy, although no prospective randomized trials are available to confirm these results. Given the assumed comparable oncologic results in both groups, complication rates and functional outcomes associated with each modality play a major role when making treatment decisions. Radiotherapy is used preferentially in many centers because few trials have reported higher complication rates in surgical patients. However, these adverse effects were mainly due to traditional invasive open surgical approaches used for access to the oropharynx. In order to decrease the morbidity of these techniques, transoral surgical (TOS) approaches have been developed progressively. They include transoral laser microsurgery (TLM), transoral robotic surgery (TORS), and conventional transoral techniques. Meta-analysis comparing these new approaches with radiotherapy showed equivalent efficacy in terms of oncologic results. Furthermore, studies reporting on functional outcomes in patients undergoing TOS for OPSCC did not show major long-term functional impairment following treatment. Given the abovementioned statements, it is our practice to treat early stage OPSCC as follows: whenever a single modality treatment seems feasible (T1-2 and N0-1), we advocate TOS resection of the primary tumor associated with selective neck dissection, as indicated. In our opinion, the advantage of this approach relies on the possibility to stratify the risk of disease progression based on the pathological features of the tumor. Depending on the results, adjuvant radiation treatment or chemoradiotherapy can be chosen for high-risk patients. For tumors without adverse features, no adjuvant treatment is given. This approach also allows prevention of potential radiation-induced late complications while keeping radiotherapy as an option for any second primary lesions whenever needed. Definitive radiotherapy is generally reserved for selected patients with specific anatomical location associated with poor functional outcome following surgery, such as tumor of the soft palate, or for patients with severe comorbidities that do not allow surgical treatment.

Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer.

There is growing interest in the association of radiotherapy and immunotherapy for the treatment of solid tumors. Here, we report an extremely effective combination of local irradiation (IR) and Shiga Toxin B (STxB)-based human papillomavirus (HPV) vaccination for the treatment of HPV-associated head and neck squamous cell carcinoma (HNSCC). The efficacy of the irradiation and vaccine association was tested using a model of HNSCC obtained by grafting TC-1/luciferase cells at a submucosal site of the inner lip of immunocompetent mice. Irradiation and the STxB-E7 vaccine acted synergistically with both single and fractionated irradiation schemes, resulting in complete tumor clearance in the majority of the treated mice. A dose threshold of 7.5 Gy was required to elicit the dramatic antitumor response. The combined treatment induced high levels of tumor-infiltrating, antigen-specific CD8(+) T cells, which were required to trigger the antitumor activity. Treatment with STxB-E7 and irradiation induced CD8(+) T-cell memory, which was sufficient to exert complete antitumor responses in both local recurrences and distant metastases. We also report for the first time that a combination therapy based on local irradiation and vaccination induces an increased pericyte coverage (as shown by αSMA and NG2 staining) and ICAM-1 expression on vessels. This was associated with enhanced intratumor vascular permeability that correlated with the antitumor response, suggesting that the combination therapy could also act through an increased accessibility for immune cells. The combination strategy proposed here offers a promising approach that could potentially be transferred into early-phase clinical trials.

Keratoacanthoma: a distinct entity?

Keratoacanthoma (KA) are common but exceptional benign tumors, often appearing on sun-exposed areas of light skinned people and showing spontaneous resolution. The goal of this study was to review existing literature, to point out the etiological complexity of KA biology and to answer the controversial debate if or not KA is a distinct entity or a variant of squamous cell carcinoma (SCC). Relying on recent results, we highlight that KA is an individual lesion with a unique molecular signature caused by alterations in the TGFβ signalling pathway. These recent findings will help to understand the nature of KA and to develop new reliable diagnostic tools, simplifying the discrimination of the histologically similar KA and SCC.

Individual differences in gene expression : insights from transcriptional control of the CSL gene and from human population studies

CSL is a key transcription factor, mostly acting as a repressor, which has been shown to have a highly context-dependent function. While known as the main effector of Notch signaling, it can also exert Notch-independent functions. The downstream effects of the Notch/CSL signaling pathway and its involvement in several biological processes have been intensively studied. We recently showed that CSL is important to maintain skin homeostasis, as its specific deletion in mouse dermal fibroblasts -or downmodulation in human stromal fibroblasts- creates an inducing environment for squamous cell carcinoma (SCC) development, possibly due to the conversion of stromal fibroblasts into cancer associated fibroblasts (CAFs). Despite the wide interest in CSL as a transcriptional regulator, the mechanism of its own regulation has so far been neglected. We show here that CSL expression levels differ between individuals, and correlate among others with genes involved in DNA damage response. Starting from this finding we show that in dermal fibroblasts CSL is under transcriptional control of stress inducers such as UVA irradiation and Reactive Oxygen Species (ROS) induction, and that a main player in CSL transcriptional regulation is the transcription factor p53. In a separate line of work, we focused on individual variability, studying the differences in gene expression between human populations in various cancer types, particularly focusing on the Caucasian and African populations. It is indeed widely known that these populations have different incidences and mortalities for various cancers, and response to cancer treatment may also vary between them. We show here several genes that are differentially expressed and could be of interest in the study of population differences in cancer. -- CSL est un facteur de transcription agissant essentiellement comme répresseur, et qui a une fonction hautement dépendant du contexte. C'est l'effecteur principal de la voie de signalisation de Notch, mais il peut également exercer ses fonctions dans une façon Notch- indépendante. Nous avons récemment montré que CSL est important pour maintenir l'homéostasie de la peau. Sa suppression spécifique dans les fibroblastes dermiques de la souris ou dans les fibroblastes stromales humaines crée un environnement favorable pour le développement du carcinome épidermoïde (SCC), probablement en raison de la conversion des fibroblastes en fibroblastes associé au cancer (CAF). Malgré le grand intérêt de CSL comme régulateur transcriptionnel, le mécanisme de sa propre régulation a été jusqu'ici négligée. Nous montrons ici que dans les fibroblastes dermiques CSL est sous le contrôle transcriptionnel de facteurs de stress tels que l'irradiation UVA et l'induction des ROS dont p53 est l'acteur principal de cette régulation. Nous montrons aussi que les niveaux d'expression de CSL varient selon les individus, en corrélation avec d'autres gènes impliqués dans la réponse aux dommages de l'ADN. Dans une autre axe de recherche, concernant la variabilité individuelle, nous avons étudié les différences dans l'expression des gènes dans différents types de cancer entre les populations humaines, en se concentrant particulièrement sur les populations africaines et caucasiennes. Il est en effet bien connu que ces populations montrent des variations dans l'incidence des cancers, la mortalité, ainsi que pour les réponses au traitement. Nous montrons ici plusieurs gènes qui sont exprimés différemment et pourraient être digne d'intérêt dans l'étude du cancer au sein de différentes populations.

Analysis of TRIP expression in different types of skin tumor

TRAF-interacting protein (TRIP) is a ubiquitously expressed nucleolar E3 ubiquitin ligase. Ubiquitination of proteins is a post-translational modification, which decides on the cellular fate of the protein. TRIP in vivo substrate has not been yet identified. However, TRIP has been shown to play an important role in cellular proliferation, especially in keratinocytes. TRIP was found to be up-regulated in basal cell carcinoma (BCC) at the mRNA level. This prompted us to elucidate its role in skin proliferative diseases such as cancer by analyzing its expression in BCCs at protein level and in squamous cell carcinoma (SCC) at mRNA and protein level. To that purpose, we performed a real-time PCR (qPCR) analysis followed by an immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded (FFPE) biopsies. The real-time PCR was performed on 12 RNA samples of which 6 were extracted from SCC biopsies and 6 from normal human skin. The results were statistically insignificant. Further analyses are needed on new RNA samples. The IHC assay was performed on 20 biopsies from BCCs, 21 biopsies from SCCs and on 5 tissues from normal human skin. The results obtained showed an extensive expression of TRIP in keratinocytes nuclei. Due to various limitations related to the technique and to doubts about preservation of the antigens in the tissues from normal human skin, we could not highlight a clear difference in TRIP expression between the different tissues. In conclusion, further analyses are needed on new RNA samples (qPCR) and on better preserved FFPE tissues from normal skin (IHC) to assess TRIP relative expression in BCCs and SCCs versus normal human skin.

Clinical features of oral lichen planus. A retrospective study of 65 cases

Objectives: To describe the clinical features of patients diagnosed with oral lichen planus (OLP) and to establish the prevalence of its malignant transformation in our setting. Study design: A retrospective study was made of 65 patients clinically and histologically diagnosed with OLP in the Service of Oral Surgery (Dental Clinic of the University of Barcelona, Spain) in the period 1990-2005. A descriptive and bivariate statistical analysis was made. Results: The mean patient age was 59 years (SD ± 14.9). Most of the patients (61%) were women, and the most frequent location of the lesions was the buccal mucosa (90.8%). White forms of OLP were noted in 66% of the cases, and 46.2% of the patients reported symptoms of some kind. The patients diagnosed with diabetes mellitus (20%) showed a larger proportion of red lesions (p=0.088). No statistically significant association was observed between chronic liver disease and the OLP lesion types or symptoms. Two cases of squamous cell carcinoma were identified in two patients previously or simultaneously diagnosed with OLP. A statistically significant correlation was observed between dysplastic changes / malignization of the lesions and smoking habit (p=0.019). An association to alcohol abuse was also noted, though in this case statistical significance was not reached (p=0.085). Conclusions: The clinical features of our study population were similar to those described in other studies. Diabetic patients with OLP were seen to be more susceptible to the development of atrophic-erosive lesions. Smokers and/or patients with alcohol abuse in turn showed a greater tendency to develop dysplastic changes / malignization in the histopathological study of the lesions

HPV & head and neck cancer: a descriptive update

The incidence of head and neck squamous cell carcinoma (HNSCC) has been gradually increasing over the last three decades. Recent data have now attributed a viral aetiology to a subset of head and neck cancers. Several studies indicate that oral human papillomavirus (HPV) infection is likely to be sexually acquired. The dominance of HPV 16 in HPV+ HNSCC is even greater than that seen in cervical carcinoma of total worldwide cases. Strong evidence suggests that HPV+ status is an important prognostic factor associated with a favourable outcome in head and neck cancers. Approximately 30 to 40% of HNSCC patients with present with early stage I/II disease. These patients are treated with curative intent using single modality treatments either radiation or surgery alone. A non-operative approach is favored for patients in which surgery followed by either radiation alone or radiochemotherapy may lead to severe functional impairment. Cetuximab, a humanized mouse anti-EGFR IgG1 monoclonal antibody, improved locoregional control and overall survival in combination with radiotherapy in locally advanced tumours but at the cost of some increased cardiac morbidity and mortality. Finally, the improved prognosis and treatment responses to chemotherapy and radiotherapy by HPV+ tumours may suggest that HPV status detection is required to better plan and individualize patient treatment regimes.

Salivary gland cancer in Finland: Incidence, histological distribution, outcome and prognostic factors

Salivary gland cancer (SGC) is a rare cancer. The histological classification of SGC is complex and its biological behavior highly variable: it may vary from a low-grade tumor to a high-grade and often fatal malignancy. These circumstances make this cancer a diagnostic and therapeutic challenge. Older age and exposure to ionizing radiation are known risk factors. The mainstay of treatment is surgery combined with adjuvant radiation therapy, when appropriate. In addition to the histological type, the only well known prognostic factor is the TNM classification, which describes the tumor size and the amount of metastases. This study was performed using a full population-based nationwide cohort of SGC patients and tumors diagnosed in Finland in 1991-1996. The annual incidence of SGC in the entire population was, on average, 47.7 per year. By histological re-evaluation of 237 specimens the most frequent histological types were the adenoid cystic carcinoma (n=65; 27%), the mucoepidermoid carcinoma (n=45; 19%) and the acinic cell carcinoma (n=41; 17%). The highest 10-year disease-specific survival rate occurred among patients with acinic cell carcinoma (90%), followed by mucoepidermoid carcinoma (81%) and adenoid cystic carcinoma (60%). A high volume-corrected index (VCI) of Ki-67 correlated with worse survival of patients with SGC. Computer-assisted morphometric analyses of CD34-positive vessels indicated an unfavorable prognosis for patients with mucoepidermoid carcinoma and an association with poor survival among patients with acinic cell carcinoma. A high level of expression of matrix metalloproteinase-9 (MMP-9) showed a trend for a poorer prognosis in salivary duct carcinoma, and a high level of MMP-13 and a low level of MMP-1 had a trend for a poorer prognosis of patients with SGC. A low level of MMP-7 was associated with a poor prognosis of patients with acinic cell and mucoepidermoid carcinoma.

Rastreamento de lesões pré-neoplásicas do ânus: citologia anal e anuscopia de alta resolução novas armas para prevenção

Squamous anal cell carcinoma frequency has been changing during the last decades. It was a rare disease in the past with 0.2 cases per 100,000 inhabitants in Denmark before the 60’s and 0.5 per 100,000 in the United States of America (USA) in 1973. Currently these figures have risen to a 1.00 / 100,000 ratio in accordance with the public records in the USA. Although the incidence in the general population can still be considered low, regardless of having doubled during the past 30 years, some specific groups in the population seem to have a higher level of risk, with a ratio of 70 ocurrences per each group of 100,000 individuals. The relationship between infections caused by oncogenic types of human papillomavirus and the similarity with cervical squamous cell carcinoma lead us to believe that screening techniques similar to the ones used as from the 40’s aiming the control of the cervical carcinoma, such as Papanicolaou smear (anal cytology) and colposcopy (high resolution anoscopy), may be effective on anal cancer prevention in those specific groups, or at least, to its early diagnosis. This article presents the techniques for tracking these early anal cancer lesions justifying them as a Public Health point of view.

Prevalence of alterations in chest computerized tomography in patients with head and neck cancer

Objective: to assess the prevalence of abnormalities found by computed tomography (CT) of the chest in patients with squamous cell carcinoma of the head and neck. Methods: we retrospectively analyzed chest CT exams of 209 patients with squamous cell carcinoma of the head and neck. The CT findings were stratified as inflammatory / infectious, parenchymal, nodular uncharacteristic and nodular metastatic / tumoral Results: alterations were diagnosed in 66.6% of patients. Of these, 25.3% represented emphysema; 18.8%, uncharacteristic micronodules; 12.9%, metastases; 11.9%, thoracic lymph node enlargements; and in 6.6% we detected active pulmonary tuberculosis or its sequelae, pneumonia or inflammatory / infectious signs and pleural thickening or effusion. Conclusion: the prevalence of exams with alterations and the considerable rate of detected metastases indicate that chest CT should be required for diagnostic and / or staging in cases of head and neck cancer.

Plastic surgery in chest wall reconstruction: relevant aspects - case series

Objective: to discuss the participation of Plastic Surgery in the reconstruction of the chest wall, highlighting relevant aspects of interdisciplinaryness. Methods: we analyzed charts from 20 patients who underwent extensive resection of the thoracic integument, between 2000 and 2014, recording the indication of resection, the extent and depth of the raw areas, types of reconstructions performed and complications. Results: among the 20 patients, averaging 55 years old, five were males and 15 females. They resections were: one squamous cell carcinoma, two basal cell carcinomas, five chondrosarcomas and 12 breast tumors. The extent of the bloody areas ranged from 4x9 cm to 25x40 cm. In 12 patients the resection included the muscular plane. In the remaining eight, the tumor removal achieved a total wall thickness. For reconstruction we used: one muscular flap associated with skin grafting, nine flaps and ten regional fasciocutaneous flaps. Two patients undergoing reconstruction with fasciocutaneous flaps had partially suffering of the flap, solved with employment of a myocutaneous flap. The other patients displayed no complications with the techniques used, requiring only one surgery. Conclusion: the proper assessment of local tissues and flaps available for reconstruction, in addition to the successful integration of Plastic Surgery with the specialties involved in the treatment, enable extensive resections of the chest wall and reconstructions that provide patient recovery.