Merkel cell carcinoma arising on a pre-existing Bowen's disease: is it just by chance?

Merkel cell carcinoma (MCC) has recently been associated with a novel polyomavirus. This rare but highly aggressive skin malignancy has been increasing in incidence over the past two decades.1 It is most common in elderly Caucasians as well as immunocompromised patients. Feng et al.2 was the first to discover that the Merkel cell polyomavirus (MCPyV) was integrated within the tumor genome, suggesting that it may be a contributing factor in the pathogenesis of MCC. Since then other studies have confirmed that approximately 80% of MCC are associated with MCPyV.3–7 Further studies have demonstrated that MCPyV is clonally integrated at various sites in the genome of MCC tumors, with truncating mutations that interrupt viral replication; therefore, demonstrating that the virus is not a passenger virus that secondarily infects MCC tumors, but is an etiological agent.8,9 This recent discovery has since sparked controversy, as there have been conflicting reports of the virus contributing to other skin cancers. Recent studies have shown a high prevalence of MCPyV DNA in MCC, supporting a role for the virus in tumorigenesis; however, a high prevalence of the virus has also been identified in non-melanoma skin cancers as well as non-lesional skin.10–13 One hypothesis suggests that the polyomavirus is ubiquitous, and when the virus is detected in basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), it represents a coincidental infection rather than an etiological agent. Detection of MCPyV DNA polymerase chain reaction (PCR) positivity in BCC and SCC tumors is likely to represent loss of immune control over viral replication leading to enhanced coincidental detection. Because detecting viral DNA by qualitative PCR cannot differentiate incidental infection from causal infections, more studies are needed to demonstrate active viral protein expression of MCPyV small T antigen. Using a monoclonal antibody to detect MCPyV large T antigen, Reisinger et al.14 demonstrated MCPyV protein expression in 75% of MCC tumors but detected no large T antigen positivity in BCC or SCC from the same patients. In our case, we were able to test several lesions for the presence of MCPyV using both qualitative and quantitative PCR. A 73-year old Caucasian male presented to the skin cancer clinic for a full skin examination. He had a history of multiple actinic keratoses treated with cryotherapy but no history of skin cancer. His past medical history was significant for ulcerative colitis, currently treated with prednisone, mercaptopurine, and mesalamine, coronary artery disease status post bypass grafting, gastroesophageal reflux, deep vein thrombosis following a knee replacement, and osteoarthritis. The patient complained of a recurrent lesion on his left mid-cheek that had been previously treated with cryotherapy. Physical examination revealed Fitzpatrick skin type I with marked dermatoheliosis on sun-exposed areas as well as a 3 mm hyperkeratotic pink papule within a scar on the left mid-cheek and a 12 × 8-mm irregular dark brown patch on the inferior left mid-cheek. Skin biopsies were performed on the two facial lesions, revealing nodular BCC of the left mid-cheek and melanoma in situ of the inferior left mid-cheek, respectively. The lesions were removed with elliptical excision and intermediate linear layered closure four days after the initial visit. Two months after the patient’s skin examination, he developed a new, tender red nodule on his posterior right arm, which did not respond to antibiotic therapy and local heat application. His primary care physician removed the nodule by elliptical excision. The pathology report revealed a 2.2-cm MCC with focal necrosis and positive margins with evidence of vascular invasion. Immunohistochemical studies demonstrated the tumor cells were positive for pankeratin, CK20, chromogranin, and synaptophysin, and negative for LCA, HMB-45, keratin-7, and TTF-1. Due to his new diagnosis of MCC, he returned to the skin cancer clinic. At that time, he had a new pink papule on his nose, which was biopsied and found to be a BCC. There was also a new hyperkeratotic papule on his left antitragus, which was biopsied and found to be an actinic keratosis. He underwent a wide local excision of the MCC and an axillary lymph node dissection, which revealed 1/27 positive lymph nodes. Basic blood work was performed, which showed no evidence of hematological malignancy. A human immunodeficiency virus (HIV) test was negative. Chest x-ray showed stable pulmonary fibrosis with no evidence of metastases. He was started on radiation therapy and is scheduled to receive adjuvant chemotherapy with four cycles of cisplatin and etoposide. All tissue specimens obtained from the patient were tested for the presence of MCPyV DNA. DNA quality assessment was first performed using a beta-globin reference gene PCR of the DNA extracted from the samples. MCPyV detection was performed with PCR utilizing a primer set designed in our lab within the “small T” region of the virus. In four samples, putative MCPyV-PCR products were detected. The MCC, two samples of the Merkel cell-positive lymph node, and the actinic keratosis tested positive for MCPyV DNA. The melanoma in situ and the two BCC were negative for the polyomavirus (Fig. 1). MCPyV copy number determination with real-time PCR technology, designed within the “small T” viral region, was then performed on the samples found positive by the qualitative PCR. MCPyV copy number/nanogram tissue DNA was highest in the primary MCC (769) compared with the two metastatic lymph node samples (20, 81). MCPyV copy number was very low in the actinic keratosis (0.15) compared with the samples from the primary MCC and lymph node metastases. Detection of MCPyV DNA by PCR in different lesions from a patient with MCC. PCR products were analyzed on 2.0% agarose gel electrophoresis and visualized on a UV transilluminator. Lanes, M: φX174RF DNA marker (Promega); 1: BCC; 2: actinic keratosis; 3: primary MCC; 4–6: melanoma in situ and adjacent skin edges; 7 and 8: sentinel lymph nodes with MCC metastases; C+: MCPyV positive control (plasmid with MCPyV DNA insert from the small T viral); C−: MCPyVC negative control DNA extracted from PBMC (Promega); R: reagent control. 150-bp MCPyV PCR products can be seen in lanes 2, 3, 7 and 8, as well as in the positive control Our case further confirms the association of MCPyV and MCC. The virus was detected in the MCC and MCC-positive lymph node but was not detected in the melanoma in situ or the two BCC. Our case, however, also demonstrates the complexity and controversial nature of the issue as the virus was also detected in the actinic keratosis. The copy number determination demonstrated a very low number in the actinic keratosis as compared with the MCC and positive lymph node. This strengthens the hypothesis that the polyomavirus did not have an etiological role in the actinic keratosis but that the lesion was likely coincidentally infected by the ubiquitous virus. There are abundant data providing evidence of an association between MCC and immunosuppression. Patients with HIV have a relative risk of MCC of 13.4 compared with the general population.15 An increased rate of other malignancies in patients with MCC further supports an impaired immune status in the pathogenesis of MCC. An increased risk of MCC as a second primary has been identified in patients with multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin’s lymphoma SCC, and melanoma.16,17 Recognizing this association of MCC with other malignancies may lead to earlier detection of MCC and therefore earlier treatment and improved survival. Our case is also consistent with the fact that immunosuppression is a risk factor for MCC. Although the workup for HIV and hematological malignancies was negative, our patient was iatrogenically immunosuppressed as he had been on 10 mg of prednisone daily for the past four years for ulcerative colitis. While most studies have shown an association with patients receiving post-transplantation immunosuppression or chemotherapy, it may be possible that our patient’s four-year history of prednisone therapy was sufficient enough to contribute to the pathogenesis of his MCC.18–20 The newly discovered virus appears to be widespread, so it is unclear why it only causes MCC in very few people. Other factors such as ultraviolet radiation, immunogenetics, and immunosuppression likely also contribute to carcinogenesis. More studies are needed to determine viral oncoprotein expression to further delineate the ubiquitous virus’ role in MCC tumorigenesis from a possible passenger virus in non-lesional skin and non-melanoma skin cancer. Although the role of this polyomavirus is controversial, the discovery of the virus in association with MCC will hopefully lead to more effective therapy for the highly aggressive tumor.

Merkel Cell Carcinoma (MCC) is an uncommon undifferentiated neuroendocrine tumor, arising in skin mainly on sun-exposed areas. We present an unusual case of primary cutaneous undifferentiated small cell carcinoma that co-existed with six other lesions; 2 actinic keratoses, 3 squamous-cell carcinomas and a basal-cell carcinoma. HE stained sections revealed MCC located in the mid-dermis, co-existing with severe actinic keratosis. Immunohistochemically, the tumor cells reacted to cytokeratin 20, epithelial membrane antigen, chromogranin and neuron specific enolase. This is an unusual case of cutaneous MCC co-existing with six other different lesions. The concurrent development of MCC, squamous-cell and basal-cell carcinoma in the same patient indicates the pluripotent epidermal stem cell origin of these tumors. Further research is needed to enlighten the factors inducing this divergent differentiation.

Mixed Merkel cell carcinoma and squamous cell carcinoma of the skin

Maria Sternemann Thomas Wiegel Christoph C. Geilen Constantin E. Orfanos Wolfgang Hinkelbein Basel S. Karger Controversies in the Treatment of Skin Neoplasias 2006 180 pp. $162 hardcover ISBN: 3-8055-8014-2.

Primary neuroendocrine (Merkel cell) carcinoma of the skin: Morphologic diversity and implications thereof

Carcinomas are malignant tumours of epithelial origin. Cutaneous carcinomas are primarily of keratinocytic origin (epidermal or follicular keratinocytes) or of adnexal glandular origin. Keratinocytic carcinomas include basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (SCC). BCC and SCC are by far the most common forms of cancer in humans. Paradoxically, as they are not generally recorded in cancer registers, their importance in terms of public health and their economic impact on healthcare systems are widely underestimated. The relative incidences of BCC and SCC differ according to whether SCC is grouped among lesions with the same oncogenesis or not, namely actinic keratosis (AK) and Bowen's disease (BD) (see below). If AK is included in this group, SCC is the most common form of human cancer. If it is excluded, while being responsible for the majority of deaths attributable to non-melanoma skin cancers (NMSC), SCC is the second most important form of cancer in terms of frequency. Although the majority of SCC cases are not life-threatening, this carcinoma is likely to metastasize, particularly if initial treatment was inadequate. The SFD has drawn up guidelines for the treatment of BCC (2004) and melanoma (2005). The present work is the logical continuation of this initiative. It aims to provide practitioners treating skin cancer patients with a series of recommendations based on scientific evidence or, when this was not available, on expert consensus. Medical textbooks refer to a wide array of clinical and histological forms of SCC. The prognosis for these different forms varies according to whether therapy has been specifically codified or not. In addition, the terminology used to describe these lesions varies, which may lead to confusion and prevent use of a clear decision-making tree. The TNM classification, developed by AJCC/IUAC/UICC, which is used for all skin cancers except melanoma, is not suitable for SCC. It does not take into account the multiple prognostic criteria identified in the literature. Many treatments are currently available, in particular, for SCC precursor lesions, but the criteria of choice and the methods of application are generally far from clear for practitioners. This results in major disparities in terms of therapeutic management. The present guidelines deal with the treatment of SCC and precursor lesions in immunocompetent adults in France, in both ambulatory and hospital settings. The aims are as follows: to clarify the terminology used to describe the different forms of SCC and of their precursors AK and BD; to propose a prognostic classification of SCC that takes into account various clinical and histological factors; to recommend diagnostic and therapeutic measures for SCC based on previously identified prognostic factors; to optimize diagnostic and therapeutic management of AK and BD in accordance with recent data in the literature; to provide an overview of the principles for primary prevention of SCC and precursor lesions (based on the same methods), and for screening of subjects identified as at risk for SCC (other than genodermatosis and immunosuppression). Due consideration has been given to the fact that patients with SCC, AK or BD are generally (very) elderly. This creates problems in terms of screening for lesions, and for amenability to care and treatment (poor compliance to certain treatments, difficulty in carrying out sequential physical treatments, refusal of onerous surgery, or surgery requiring multiple operations). The oncogeriatric dimension of therapy has thus been taken into account. These guidelines do not address the following issues: SCC of the nails or the genital and anal mucosa; SCC in immunosuppressed patients, particularly transplanted patients; SCC in the context of certain genodermatoses. The levels of evidence and grades used are those defined by the HAS [French Health Authority] (Annex 1). The literature on SCC generally carries low levels of evidence and, except where otherwise stated, the recommendations included in these guidelines are of grade C. These guidelines have been created in the form of Recommendations for Clinical Practice in accordance with the ADAPTE method.2 As its name suggests, this method advocates the adaptation to a particular situation – in this case, medical practice in France in 2008 – of one or more guidelines on the same theme, drawn up previously or in other countries. Medical societies concerned with SCC were consulted on the initiative of the French Dermatology Society (SFD), the sponsor, to define the scope of the guidelines, identify work performed on the subject and recommend professional members for the organizing committee (OC), the working group (WG) and the reading group (RG). Mention must be made of the difficulty of recruiting general practitioners to these groups, despite the fact that, in view of the subject, their assistance is vital. In the Spring of 2007, the Dermatology Recommendations Association (aRED), a subgroup of the SFD, created a multidisciplinary OC on behalf of the SFD, comprising doctors in private and public practice, both university and non-university practitioners, from a variety of geographic origins. The OC then set up a WG using the same criteria of professional diversity. Members of the OC and WG were asked to complete a form indicating any conflict of interest regarding management of SCC (Annex 2). The members of the RG were recommended by medical societies, once again with the aim of reflecting the diversity of professional practice. The overall arguments, key points and recommendations were drafted by the WG following the identification and selection of previous guidelines on SCC, contextualization (occasionally critical) of recommendations contained therein and a synthetic update of the literature. Practitioners in the reading group were sent a letter asking for their opinion on the topic, including presentation of the key points and recommendations, in particular, regarding clarity and applicability. The comments made by the RG were analysed by the WG and, whenever possible, taken into consideration in the final draft. Lastly, on the 11 December 2008, the main recommendations were presented and discussed publicly in the presence of practitioners to whom the guidelines were addressed during the Journées Dermatologiques de Paris, the main French national dermatology congress. The low level of evidence in the existing literature underscores the continuing lack of knowledge about optimal management of patients with SCC. These areas represent subjects for future work by the OC and WG (see Perspectives section). I.2.1. ADAPTE method This rigorous and explicit method, recently described and published by an international group,2,3 is designed to enable the adaptation of existing guidelines, and to reduce the time, effort and cost required to create a fresh set of guidelines. Methodological guidelines concerning the use of this method were published online by HAS in March 2007.3 I.2.2. Choice of method for drafting guidelines In the spring of 2007, the SFD Bureau and the aRED decided that the ADAPTE method could be used to draft French guidelines for the management of SCC. Foreign guidelines on this topic, some of them fairly old, were already known, and ADAPTE contextualization was entirely possible, as these guidelines had been published by agencies or medical societies for populations and levels of health infrastructure and organization comparable with those in France. However, as the literature used for the drafting of these guidelines was deemed to be of mediocre quality, the ADAPTE method presented a number of limitations. In addition to this, several questions that have subsequently come to the fore (e.g. the nature of AK or the place of new medical treatments) occupied little or no place in the existing guidelines. Therefore, in addition to adaptation, updating of the literature proved necessary. I.2.3. Definition of the scope of the guidelines The limits of the SCC topic were discussed in conference calls between members of the OC in July 2007. The PIPOH checklist3 used to define the scope and target audience of the guidelines was as follows: P (patient population) = French population of both sexes; I (interventions) = prevention, screening, diagnosis, treatment and monitoring; P (professionals) = specialists responsible for diagnostic and therapeutic management of SCC, general practitioners (GPs), occupational therapists as well as specialists involved in the screening and follow-up; O (outcomes, the evaluation criteria used for the recommendations) = levels of treatment response in terms of remission, local relapse, remote metastasis and mortality, when these parameters were available; H (healthcare setting) = ambulatory or hospital. In addition to diagnosis and curative treatment of SCC, it was decided to include: screening of subjects identified as at risk for SCC (excluding genodermatosis and immunodepression); cutaneous or cutaneous-mucosal sites on the borderline of dermatology: eyelids and vermilion border of the lips; lesions considered precancerous and keratoacanthoma. These lesions are histogenetically related to SCC and have been dealt with in several recent studies of medical and surgical therapies. However, genital and anal sites in both genders were ruled out as these are normally dealt with by gynaecological surgeons, urologists, gastroenterologists or digestive surgeons. Ungual sites were similarly ruled out. In addition, it was decided not to include SCC observed in immunosuppressed organ transplant recipients, as guidelines for the management of these patients were being drawn up under the auspices of the HAS.4 I.2.4. Documentary research In late June to early July 2007, Mrs J. Brugneaux performed a literature search for practical guidelines on SCC and precursor lesions using systematic surveys of medical bibliography databanks (Annex 3) and looking out for guidelines, consensus conferences, articles on decision-making process, systematic reviews, meta-analyses and other national and international evaluation studies. Relevant websites (government agencies, medical societies, etc.) were also explored. Documents not accessible by the standard diffusion circuits ('grey literature') were consulted using every available means. Legal and regulatory texts on this subject were also consulted. Only English- and French-language articles were considered eligible. Initially, the selected references were screened by L. Martin and J.-J. Bonerandi to eliminate all texts unrelated to the subject on the basis of their titles, (e.g. non-cutaneous CE of the head and neck; genital CE) and irrelevant literature (guidelines currently at project level, etc.). The remaining texts (n = 58) were submitted to all CO members in July 2007 to ensure that they were authentic guidelines, didactic articles or authors' opinions. I.2.5. Determination of questions to be covered in the guidelines At a plenary session of the OC held on 19 September 2007, the scope of the guidelines was definitively agreed upon, as were the various topics to be covered therein: clinical, pathological and epidemiological forms of SCC and precursor lesions; prognostic factors for SCC; treatment methods for SCC and precursor lesions; patient management. At 19 September 2007 meeting, a list with the following documents, theoretically amenable to adaptation, was established: Non-melanoma skin cancer: guidelines for treatment and management in Australia. National Health and Medical Research Council. 2002 (NHMRC, Australia). Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. British Association of Dermatologists/British Association of Plastic Surgeons. 2002 (BAD/BAPS, UK) Guidelines for management of Bowen's disease: 2006 update. British Association of Dermatologists. 2006 (BAD, UK). Guidelines for the management of actinic keratosis. British Association of Dermatologists. 2007 (BAD, UK). Basal cell and squamous cell skin cancers. National Comprehensive Cancer Network. 2007 (NCCN, US). Multiprofessional guidelines for the management of the patient with primary squamous cell carcinoma. National Guideline Clearinghouse. 2007 (NGC, US). Green A, Marks R. Squamous cell carcinoma of the skin (non-metastatic). Clin Evid 2005; 4: 2086–2090. I.2.6. Selection of guidelines for adaptation The suitability of these seven guidelines for adaptation in different areas of practice was assessed by five WG, using the simplified AGREE appraisal instrument5 (Annex 4). The NGC guidelines and the Clinical Evidence article were not used, as the former is a retranscription of the BAD 2002 guidelines, whereas the latter gives no indication of the method used for the bibliography search, and was thus deemed inconsistent with the scope of the present guidelines. The following three SCC guidelines were ultimately selected: Basal cell and squamous cell skin cancers, 2007 (NCCN); Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma, 2002 (BAD 2002); Non-melanoma skin cancer: guidelines for treatment and management in Australia, 2002 (NHMRC), together with Guidelines for the management of actinic keratoses, 2007 (BAD 2007) and Guidelines for management of Bowen's disease: 2006 (BAD 2006). I.2.7. Layout of the guidelines, key points and recommendations Each section was divided into 'items', some of which contained one or more 'key points' or 'recommendations'. An item was comprised of a topic concerning epidemiology, diagnosis or treatment amenable to targeted documentary research (e.g. prevalence of SCC among the French population; use of imiquimod in the treatment of AK). Each item was assigned to a group comprising two or three WG members, based on their experience or interest in the topic. Individual items were either identified as existing in one or more adapted guidelines, or were created anew by the WG. Items are summarized at the end of this section in a summary table showing the adapted guideline(s), where they are also discussed (Table 1). Key points comprise information items of cultural relevance which are possibly not directly related to day-to-day practice. Recommendations refer to the diagnostic or therapeutic management of patients. Key points and, wherever possible, recommendations were graded using the HAS method (Annex 1). In accordance with the ADAPTE method,6 items identified in previous guidelines were evaluated by WG members to determine the degree of concordance between the data analysed and the conclusions set out in the arguments, and between these conclusions and the recommendations proposed. Any divergence with regard to prior guidelines is indicated at the start of the paragraph. In most cases, updating of bibliographical references proved necessary, and this was carried out by Mrs J. Brugneaux (January 2008) (Annex 3). Finally, actual adaptation (drafting of the arguments, key points and recommendations) involved summarizing the proposals set out in the various guidelines and drafting the arguments suitable for medical practice in France in 2008. An initial version of the arguments and the proposed recommendations was reread and discussed in plenary sessions by the WG on 11 March 2008 and by the OC on 25 March 2008. Updating of the bibliography was suspended at this point. Opinions differed within the WG regarding a number of relevant items (prognostic classification of primary SCC, value of routine histological analysis of excision margins and hierarchical classification of therapeutic choices for precancerous lesions). In the absence of consensus within the adapted guidelines and of literature providing an adequate level of evidence, these divergent opinions gave rise to numerous e-mail exchanges and meetings until a pragmatic consensus was reached within the WG and the CO. The successive versions of the arguments attest to changes in viewpoints regarding these items. The WG stressed the need for clinical trials designed to obtain factual information which would settle these divergences. A complete argumentation framework and an initial version of the short text comprising the key points and recommendations were sent to readers during summer 2008. Final versions of the documents and of a highly synthetic pocket-sized flyer were prepared in autumn 2008. The CO and the WG are well aware that their editorial choices simply reflect medical and scientific knowledge concerning SCC and precursor lesions up to spring 2008. Follow-up on bibliography data and annual meetings of the WG are scheduled to ensure prompt modification of the guidelines following the publication of relevant diagnostic, prognostic or therapeutic information regarding SCC and precursor lesions (see Perspectives). The term squamous cell carcinoma encompasses all malignant epithelial tumours with predominantly malpighian differentiation. SCCs include primary malignant skin tumours with malpighian differentiation, and are distinct from other primary epithelial skin tumours such as BCC. The term thus covers a number of different clinico-anatomical entities, some of which only differ in terms of clinical presentation or degree of aggressiveness. The inclusion of AK and keratoacanthoma under SCC by some authors and in certain reference works is currently disputed.6 The adapted guidelines, i.e. the three guidelines dedicated to SCC (NHMRC,7 NCCN8 and BAD9) and those specifically focused on AK and BD,10,11 restrict themselves to a summary description of these entities without discussing clinico-anatomical forms and nomenclature. The WG felt it was necessary to adopt a position on this subject and therefore, the ADAPTE method was not used in drafting this chapter, for which a specific bibliographical analysis was performed. This chapter contains epidemiological overviews and proposals with regard to terminology and classification. It also describes the populations targeted by these guidelines. II.1.1. Environmental factors Exposure to sun Sunlight is the principal environmental factor, and evidence for its role in SCC relies on the appearance of lesions on the areas of skin most exposed to sun, a greater prevalence of lesions among fair-skinned subjects, a latitude gradient for populations with the same skin phototype and a higher incidence of the disease among patients working outdoors.12 The occurrence of SCC is associated with total cumulative lifetime UV dose. The most commonly affected sites include the face, back of the hands and forearms. In a Spanish study, more than 92% of SCC cases occurred in these areas.13 UVB (290–320 nm) and UVA (320–400 nm) play a role in carcinogenesis. For most SCC, UV-induced mutations are observed in the P53 gene.14 Artificial sources of UV have also been incriminated.15 PUVA therapy in excess of 200 sessions is associated with the onset of SCC. Sources of this type of radiation in tanning salons are not harmless and must be added to other risk factors.16 According to the 2005 report by the French Environmental Health Safety Agency (AFSSE), 'Evaluation of risks associated with exposure to UV radiation', the risk of skin cancer (carcinoma or melanoma) is increased by a factor 1.10 with 30 sessions per year over a 10-year period and by 1.39 with 100 sessions. Other exogenous risk factors include arsenic, pesticides, hydrocarbons, tobacco (lower lip), ionizing radiation, local factors The main factor is the skin which is The risk is higher in patients with a for In a a in that to is associated with a risk of SCC, AK and keratoacanthoma. Other risk factors The following factors are involved in than of and have been particularly in the genital and anal but also in in the of in areas that are both exposed and to and in and immunocompetent patients However, the presence of is to risk factors are in organ sun and Squamous cell carcinoma a number of malignant primary epithelial skin tumours with malpighian differentiation, and is distinct from BCC. The key factor onset of SCC, Bowen's disease (BD) or actinic keratosis (AK) is the total lifetime of UV whether or The risk of BD or SCC is affected by skin which is A number of which may be specific to particular have been such as tobacco for actinic and SCC of the as well as for genital or anal SCC. medical also to and keratosis of common lesions, particularly among subjects, in areas exposed to the sun such as the face, the back of the hands and the in subjects, and is associated with other of (e.g. etc.). is based on the clinical and is by lesions of more to the than to the with a of or with of and or In practice, AK or of AK are from multiple which come together to form the actinic is the of This particular is by the presence of tobacco as a second factor and by the of SCC in this is no histological of may be or of the The is to and is or An on with the and is a is based on the presence of various keratinocytic of by changes in the or In these in and do not the or the skin The term carcinoma in is only used when these together in a and the reference works of and The WG that these are simply of the same and, as do not classification as distinct These are not for France. The published prevalence for adults over between and in populations of the but between and in populations of the In of between and and of patients over have at one If AK may or to SCC. The of of such lesions over a period has been to be between and of A in this particular that a patient with AK has a risk of one of these AK into SCC within According to several from to of AK to SCC within of the genital form a group of AK to their and the role of in their A of gynaecological literature has the of subsequently and as well as cases observed are under the term or or according to whether they the or more than of the epithelial the is the term SCC or Bowen's disease is the between AK and lesions and that the of lesions and be in the same as their in the genital or using the term keratinocytic The WG felt that was little value in to criteria for entities with divergent and clinical It considered that were no for the clinical name of by the medical with a name that is clear to practitioners. may to grade the level of epithelial in their This to be were it not for its impact in terms of treatment and health etc.). of a that all forms of AK are in fact SCC, together with carcinoma, keratoacanthoma and other these entities are by the of mutations in However, a number of epidemiological studies have that the of AK may take three different or to SCC. The for AK is In the by Marks in the the over a period was than per The guidelines AK as precancerous However, the and BAD guidelines do not adopt a position concerning the nature of simply that most SCC to but that the risk of of AK to SCC is thus the choice of therapy for most AK described in to carcinomas of the a a and and mutations the of new primary tumours and of local the it has been that UV radiation is associated with the and of carcinogenesis. have been to be more common in areas than in have been at AK excision These clinical namely the of SCC and and only on and the of of AK in certain areas (e.g. In practice, these could treatment of the of the affected than treatment of However, no studies as the value of such an Bowen's disease Bowen's disease is an SCC. The prevalence and incidence of this disease in France and are most affected by the disease in published cases are in the of and are predominantly of the cutaneous as a which is generally or with a It is generally in areas of covered lesions In the and BD may be or and of the or forms are associated with The is with a and of and present at all by they do not the basal of BD with or have been and may be required to determine whether they are In the diagnosis with 3) is based primarily on of clinical medical presence of histological of and, in certain cases, identification of any associated This risk of has been in a and based on several studies. The risk to be between and for cutaneous and for and clinical presentation the appearance on the of an The risk to be greater than that of the common SCC AK is an of AK is associated with exposure to

Merkel cell carcinoma (MCC) is a rare skin cancer that was recently found to be associated with a polyomavirus and with immunosuppression, provoking new interest in its epidemiology. We conducted a nationwide study in Denmark to describe MCC incidence and mortality and the association between MCC and other cancers. We used data from Danish national health and population registers on MCC diagnoses, deaths, and population counts during the study period (1978-2006) to calculate MCC incidence rates, cumulative risks of MCC at age 100 years, and MCC mortality rates by tumor stage. We used Poisson regression to estimate the excess mortality rate ratio attributable to MCC and examined associations between MCC and other cancers diagnosed before and after the MCC diagnosis using standardized incidence rate ratios (SIRs). All statistical tests were two-sided. Between January 1, 1978, and December 31, 2006, 185 persons were diagnosed with MCC in Denmark. MCC incidence between 1995 and 2006 was 2.2 cases per million person-years. In the first year after MCC diagnosis, 22% of persons with localized disease died compared with 54% of patients with nonlocalized disease; by 5 years after diagnosis, the proportions of MCC patients who had died increased to 55% and 84%, respectively. MCC incidence was statistically significantly increased more than 1 year after a diagnosis of squamous cell carcinoma of the skin (SIR = 14.6, 95% confidence interval [CI] = 8.4 to 25.6), basal cell carcinoma (SIR = 4.3, 95% CI = 2.7 to 6.6), malignant melanoma (SIR = 3.3, 95% CI = 1.1 to 10.3), chronic lymphocytic leukemia (SIR = 12.0, 95% CI = 3.8 to 37.8), Hodgkin lymphoma (SIR = 17.6, 95% CI = 2.5 to 126), and non-Hodgkin lymphoma (SIR = 5.6, 95% CI = 1.4 to 22.4). Squamous cell carcinoma (SIR = 12.1, 95% CI = 5.1 to 29.1) and chronic lymphocytic leukemia (SIR = 14.7, 95% CI = 3.7 to 58.8) occurred in statistically significant excess more than 1 year after MCC diagnosis. These results support the existence of shared risk factors for MCC and other cancers. Heightened awareness of the association between MCC and other cancers, particularly squamous cell carcinoma and chronic lymphocytic leukemia, may facilitate earlier clinical detection and treatment of MCC, thereby improving patient survival.

Merkel cell polyomavirus in naevoid basal cell carcinoma syndrome-associated basal cell carcinomas and sporadic trichoblastomas

Lack of evidence for basal or squamous cell carcinoma infection with Merkel cell polyomavirus in immunocompetent patients with Merkel cell carcinoma

Two developmentally highly divergent nonmelanoma skin cancers, the epidermal squamous cell carcinomas (SCC) and the neuroendocrine Merkel cell carcinomas (MCC), occur late in life at sun-exposed body sites. To determine whether these similarities may indicate common genetic alterations, we studied the genetic profile of 10 MCCs and analyzed 6 derived cell lines and 5 skin SCC lines by comparative genomic hybridization (CGH) and molecular genetic analyses. Although the MCCs were highly divergent-only 3 of the 10 tumors exhibited common gains and losses-they shared gain of 8q21-q22 and loss of 4p15-pter with the genetically much more homogeneous SCC lines. In addition, 2 of 5 SCC and 2 of 6 MCC lines exhibited UV-B-type-specific mutations in the p53 tumor-suppressor gene and a high frequency (9/11) of CC-->TT double base changes in codon 27 of the Harvey (Ha)-ras gene. Since 45% of the tumor lines were homozygous for this nucleotide substitution compared to 14% of the controls and in 1 MCC patient the wild-type allele was lost in the tumor, this novel polymorphism may contribute to tumor development. On the other hand, loss of 3p, characteristic for SCCs, was rare in MCCs. Although in 2 of 3 SCC lines 3p loss was correlated with reduced expression of the FHIT (fragile histidine triad) gene, the potential tumor suppressor mapped to 3p14.2 and 2 MCC lines with normal 3p showed aberrant or no FHIT transcripts. Taken together, in addition to the common UV-B-specific mutations in the p53 and Ha-ras gene, MCCs and SCCs also share chromosomal imbalances that may point to a common environmental-derived (e.g., UV-A) oxidative damage.

Seventy-five skin tumours were studied to investigate the value of immunohistochemistry in differentiating basal cell, squamous cell and basosquamous carcinomas of the skin. Archived paraffin-embedded tissue samples of basal cell carcinomas (n = 39), squamous cell carcinomas (n = 23) and basosquamous carcinomas (n = 13) were stained immunohistochemically using a panel of antibodies. All of the basal cell carcinomas stained positively for Ber EP4, in contrast to the group of squamous cell carcinomas, that showed no staining. Basosquamous carcinomas all showed at least some areas of Ber EP4 positivity. None of the basal cell carcinomas, but most of the squamous cell carcinomas (22 of 23) expressed epithelial membrane antigen (EMA). Only one of the basosquamous carcinomas expressed EMA positivity focally. CAM 5.2, carcinoembryonic antigen (CEA) and 34betaE12 antibodies lacked specificity in relation to the different tumour types. Distinction of basal and squamous cell carcinomas of the skin can be readily achieved with routine immunohistochemistry using Ber EP4 and EMA. Identification of basosquamous carcinoma is also facilitated with this method.

Merkel cell carcinoma and chronic arsenicism

Merkel cell carcinoma in a patient with noninvasive vulvar Paget's disease

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine cancer type that predominantly impacts sun-exposed skin areas in the elderly, particularly the head and neck (41-50%), followed by the limbs (32-38%). There is likely an association between MCC and other cutaneous malignancies, such as cutaneous squamous cell carcinoma (CSCC), Bowen's disease, and basal cell carcinoma. Cutaneous squamous cell carcinoma is the most common concurrent tumor with MCC, especially in sun-exposed regions of the skin. Herein, we present a case of coexistence of MCC and CSCC in the craniofacial region, accompanied by an extensive review of relevant literature on this topic.

Basal and squamous cell carcinomas of the skin are the most commonly diagnosed malignancies in the USA. Basal cell carcinoma accounts for approximately 80% and squamous cell carcinoma for 20% of all nonmelanoma skin cancers. Exposure to sunlight is the most common cause of skin cancer. Patients with nonmelanoma skin cancer have a 30–50% risk of developing additional skin cancers. Poor prognostic factors in squamous cell carcinoma of the skin are tumor size of at least 4 cm, perineural invasion, and invasion beyond the subcutis. Basal cell carcinoma of the skin rarely metastasizes but has a predilection for local invasion. Squamous and basal cell carcinomas are most commonly treated with surgery, radiation therapy, or a combination of both. Selection of therapy is based on preservation of function and cosmesis, and patient preference. T-classification at diagnosis correlates with local control in irradiated basal and squamous cell carcinoma of the skin. For T1, T2 and T3 tumors, local control rates are 95, 80, and 53%, respectively. Local control rates of irradiated basal and squamous cell carcinomas of the skin smaller than 1 cm are 97 and 91%, respectively. For tumors between 1 and 5 cm, local control rates are 87 and 76%, respectively.