Coexistence of head and face Merkel cell and squamous cell carcinomas in the elderly population - acase report and literature review.

Beta Human Papillomavirus and Merkel Cell Polyomavirus in Skin Neoplasms

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

Mixed Merkel cell carcinoma and squamous cell carcinoma of the skin

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

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer, frequently infected with Merkel cell polyomavirus (MCPyV). H3K27me3 acts as a repressive histone modification that epigenetically controls gene transcription. The aim of this study was to examine H3K27me3 expression in MCC. H3K27me3 expression levels were immunohistochemically analyzed in 20 MCPyV-positive MCCs, 15 MCPyV-negative MCCs with squamous cell carcinoma (SCC) (combined MCCs), and six MCPyV-negative pure MCCs. Reduced H3K27me3 expression was variously observed in MCCs. H3K27me3 H-score was significantly lower in MCPyV-negative MCCs than in MCPyV-positive MCCs (p=0.002). H3K27me3 expression was significantly lower in MCPyV-negative combined MCC component than in MCPyV-positive MCCs (p<0.001), MCPyV-negative pure MCCs (p=0.036), or pure MCC histology (p<0.001). Kaplan-Meier analysis showed no association of H3K27me3 with outcome. Differential reduction in H3K27me3 expression was observed based on MCPyV status and morphological type. These results implicate H3K27me3-mediated epigenetic changes in tumorigenesis of MCC, especially in MCPyV-negative MCC combined with SCC.

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.

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.

Progress in Dermatology: Cutaneous Oncology in Organ Transplant Recipients: Meeting the Challenge of Squamous Cell Carcinoma

Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma

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

Merkel cell carcinoma (MCC) is a highly aggressive, primary neuroendocrine cancer of the skin. The majority of MCC cases are associated with the recently discovered Merkel cell polyomavirus (MCPyV), while the remaining are caused by ultraviolet (UV) light-induced mutations from excessive sunlight exposure. The risk of developing MCC is much higher in the white population relative to all other races. Approximately 10% of all patients with MCC have some form of immunosuppression including HIV-1/AIDS, chronic inflammatory conditions, solid organ transplantation, or hematological malignancies. The age of onset of MCC is lower and the mortality is higher in immunosuppressed individuals than in immune-competent patients. It is plausible that HIV-1/AIDS predisposes to virus-positive MCC, but it should be noted that HIV-1/AIDS increases the risk for developing of UV-induced skin cancers such as cutaneous squamous cell carcinoma and basal cell carcinoma and therefore may also increase the risk for virus-negative MCC. Surgical management is considered standard of care for localized Merkel cell carcinoma with current recommendations advising a wide local excision of the lesion. Most international guidelines support the use of local adjuvant radiotherapy coupled with tumor staging to improve the frequency of cure. For advanced, metastatic, and recurrent MCC, checkpoint blockade inhibitors targeting PD-1 and PD-L1 have shown remarkable activity including durable long-term. MCC in patients living with HIV-1/AIDS are treated with similar modalities as HIV-1 uninfected individuals with MCC.

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.

The main objective of this paper is to establish the predictive value of a dynamic assessment (DA) device on the school performance and progress achieved by a group of subjects with special learning difficulties. We also analyse to what extent the results obtained offer additional information to the one provided by static assessment tests on reading comprehension, personal-social adjustment or cognitive performance. With this aim, we used two external criteria: (a) the assessment of academic performance and progress, and (b) the subjects’ marks in the area of Language. The participating teachers had to evaluate each of the seven proposed assessment criteria using a four-level qualitative scale. In addition, they had to assess whether, for each of those criteria, the subject had made some progress or not during the experimental phase. The sample consisted of 60 subjects (experimental group) with learning disabilities (LD), on whom the DA device was implemented, and 73 subjects (control group) also having LD. The dynamics scores obtained from the application of the EDPL device (dynamic assessment of processes involved in reading tasks) indicated predictive values on school performance and progress that were significantly higher than those shown by various static evaluation approaches to reading and the evaluation of the IQ.

Recently, a new human polyoma virus has been identified in Merkel cell carcinomas (MCC). MCC is a highly aggressive neuroendocrine nonmelanoma skin cancer (NMSC) associated with immunosuppression. Clonal integration of this virus which was termed Merkel cell polyoma virus (MCPyV) was reported in a number of MCC. Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are also NMSC and are the most frequent cancers in the setting of immunosuppression. A unique group of 56 NMSC from 11 immunosuppressed patients and 147 NMSC of 125 immunocompetent patients was tested for MCPyV by DNA PCR, targeting the Large T Antigen and the structural Viral Protein 1. NMSC included SCC, BCC and Bowen's disease (BD). In addition, normal skin and 89 colorectal cancers were tested. MCPyV specific sequences were significantly more frequently found in NMSC of immunosuppressed patients compared to immunocompetent patients (p < 0.001). In particular BD and BCC revealed a significant increased association of MCPyV of immunosuppressed patients (p = 0.002 and p = 0.006). Forty-seven of 147 (32%) sporadic NMSC were MCPyV positive. Interestingly, 37.5% (36/96) of sporadic BCC of immunocompetent patients were MCPyV positive. No MCPyV was detected within normal skin and only 3 out of 89 of additionally tested colorectal cancers were MCPyV positive. Our data show that MCPyV is a frequently reactivated virus in immunocompromized patients. How MCPyV contributes to the pathogenesis of NMSC, i.e., BD, SCC and BCC, in immunosuppressed patients and in addition, potentially to the pathogenesis of a subset of sporadic BCC needs further investigations.