Merkel cell carcinoma (MCC) is a polyomavirus-associated skin cancer that is frequently lethal and lacks established prognostic biomarkers. This study sought to identify biomarkers that improve ...prognostic accuracy and provide insight into MCC biology.
Gene expression profiles of 35 MCC tumors were clustered based on prognosis. The cluster of genes overexpressed in good-prognosis tumors was tested for biologic process enrichment. Relevant mRNA expression differences were confirmed by quantitative polymerase chain reaction and immunohistochemistry. An independent set of 146 nonoverlapping MCC tumors (median follow-up, 25 months among 116 living patients) was employed for biomarker validation. Univariate and multivariate Cox regression analyses were performed.
Immune response gene signatures were prominent in patients with good prognoses. In particular, genes associated with cytotoxic CD8+ lymphocytes were overexpressed in tumors from patients with favorable prognoses. In the independent validation set, cases with robust intratumoral CD8+ lymphocyte infiltration had improved outcomes (100% MCC-specific survival, n = 26) compared with instances characterized by sparse infiltration (60% survival, n = 120). Only stage and intratumoral CD8 infiltration (but not age, sex, or CD8+ lymphocytes localized to the tumor-stroma interface) were significant in both univariate and multivariate Cox regression analyses. Notably, traditional histologic identification of tumor-infiltrating lymphocytes was not a significant independent predictor of survival.
Intratumoral CD8+ lymphocyte infiltration can be readily assessed on paraffin-embedded tissue, is independently associated with improved MCC-specific survival, and therefore, may provide prognostic information that enhances established MCC staging protocols.
Melanoma is a deadly skin cancer with rapidly increasing incidence worldwide. The discovery of the genetic drivers of melanomagenesis in the last decade has led the World Health Organization to ...reclassify melanoma subtypes by their molecular pathways rather than traditional clinical and histopathologic features. Despite this significant advance, the genomic and transcriptomic drivers of metastatic progression are less well characterized. This review describes the known molecular pathways of cutaneous and uveal melanoma progression, highlights recently identified pathways and mediators of metastasis, and touches on the influence of the tumor microenvironment on metastatic progression and treatment resistance. While targeted therapies and immune checkpoint blockade have significantly aided in the treatment of advanced disease, acquired drug resistance remains an unfortunately common problem, and there is still a great need to identify potential prognostic markers and novel therapeutic targets to aid in such cases.
The presence of certain types of human papillomavirus (HPV) is a known risk factor for the development of anogenital squamous cell carcinomas (SCCs). A similar association has been hypothesized for ...cutaneous SCCs, although, to our knowledge, no studies to date have combined sensitive HPV DNA detection techniques with epidemiologic data controlling for known risk factors to explore the association. We designed a case–control study examining HPV prevalence using highly sensitive PCR-detection assays in tissue samples from 85 immunocompetent patients with histologically confirmed SCCs and 95 age-matched individuals without a prior history of skin cancer. A standardized interview was administered to all study subjects to collect information pertaining to potential confounding variables. The overall detection rate of HPV DNA was high in case lesions (54%) and perilesions (50%) and in both sun-exposed normal tissue (59%) and non-sun-exposed normal tissue (49%) from controls. In comparing case tissue to control tissue, there was no differential detection of HPV DNA across various HPV species. However, HPV DNA from β-papillomavirus species 2 was more likely to be identified in tumors than in adjacent healthy tissue among cases (paired analysis, odds ratio=4.0, confidence interval=1.3–12.0). The high prevalence of HPV DNA detected among controls suggests that HPV DNA is widely distributed among the general population. However, the differential detection of HPV β-papillomavirus species in tumors among cases suggests that certain HPV types may be involved in the progression of cutaneous SCCs.
Non-melanoma skin cancers are one of the most common human malignancies accounting for 2-3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 ...mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas.
We studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism).
We found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R.
These studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations.
Talimogene laherparepvec (T‐VEC) is a novel intralesional oncolytic genetically modified herpes simplex virus type 1 vector for the treatment of unresectable cutaneous, subcutaneous, and nodal ...melanoma. Although immunological therapies such as T‐VEC offer therapeutic promise, they carry a risk of immune‐related adverse events (irAEs), the full spectrum of which is incompletely understood. We report a 63‐year‐old previously healthy man with cutaneous melanoma of the right ankle and progressive right lower extremity in‐transit metastases despite systemic therapy with immunomodulatory and molecularly targeted treatments. T‐VEC treatment resulted in a complete pathologic response on scouting biopsies. Biopsy of the right lateral calf showed lobular and septal panniculitis with lymphoplasmacytic infiltrate and lipophages. Gomori methenamine silver (GMS) stain and acid‐fast bacilli (AFB) stains were negative, and no polarizable foreign material was noted. T‐VEC was discontinued due to complete pathologic response and, in part, concern for development of irAEs including this panniculitis and an early concomitant autoimmune colitis. This case highlights a previously unreported irAE with this novel treatment for advanced cases of melanoma.
To determine the clinical utility of p63 expression, which has been identified in several cohorts as a predictor of poorer prognosis in Merkel cell carcinoma (MCC).
Immunohistochemistry was used to ...determine p63 expression on MCC tumors from 128 patients.
Of the patients, 33% had detectable p63 expression. p63 Positivity was associated with an increased risk of death from MCC (hazard ratio, 2.05; P = .02) in a multivariate Cox regression model considering stage at presentation, age at diagnosis, and sex. Although p63 expression correlated with diminished survival in this largest cohort reported thus far, the effect was weaker than that observed in prior studies. Indeed, within a given stage, p63 status did not predict survival in a clinically or statistically significant manner.
It remains unclear whether this test should be integrated into routine MCC patient management.
Background: Neurofibroma (NF) is a relatively common cutaneous tumor, which typically presents little diagnostic difficulty. Occasionally, however, pleomorphic cells may be present in NF raising ...consideration of other neoplasms like malignant peripheral nerve sheath tumor (MPNST).
Methods: This study examines the clinicopathologic and immunohistochemical features of 11 dermal and subcutaneous ‘atypical’ NF.
Results: 9/11 (82%) atypical NF were from females, aged 8–70 years. One patient had neurofibromatosis‐1. Most presented on the extremities or trunk. The atypical cells had large hyperchromatic, irregular nuclei, and were arranged in a distinct lamellar or fibrillar pattern. Some tumors were hypercellular, but marked density characteristic of MPNST was not observed. All were nonplexiform. Mitoses were mostly absent. The pleomorphic cells expressed S‐100 protein. All were negative for p53. MIB‐1 was negative in 7/10 (70%) and stained only rare cells in 3 (30%). Epithelial membrane antigen (EMA) and p16 expression were variable. Of six patients with available follow‐up, no tumor recurred and none developed malignancy (range 6–63, mean 33 months).
Conclusions: Superficial atypical NF, while morphologically unusual, has no apparent association with neurofibromatosis‐1 or short‐term risk of recurrence or malignant transformation. Awareness of this variant is important in order to avoid misdiagnosis of a more aggressive neoplasm.
The biological nature of Spitz nevi/tumors and their diagnostic distinction from, or relationship to, melanoma remain unresolved issues. In this report, a series of 30 melanocytic lesions removed ...from 28 patients, including atypical Spitz nevi/tumors and metastasizing Spitzoid tumors/melanomas, were evaluated by a panel of dermatopathologists to evaluate interobserver diagnostic concordance and to assess the prognostic power of histological criteria. For inclusion in the study, each lesion had to display some criteria for the Spitz nevus, and in addition one of the following was required: (1) definitive clinical outcome such as metastasis or death of disease, or (2) long-term follow-up if the patient remained disease free. Each lesion was reviewed independently and blinded as to the clinical data by 10 pathologists, who categorized them as (1) typical Spitz nevus/tumor, (2) atypical Spitz nevus/tumor, (3) melanoma, (4) tumor with unknown biological potential, or (5) other melanocytic lesion. There was limited discussion of criteria before the review. Evaluation of 17 Spitzoid lesions yielded no clear consensus as to diagnosis; in only one case did six or more pathologists agree on a single category, regardless of clinical outcome. Notably, however, some lesions that proved fatal were categorized by most observers as either Spitz nevi or atypical Spitz tumors. Conversely, seven or more pathologists scored 13 lesions as melanoma. These results illustrate (1) substantial diagnostic difficulties posed by many Spitz tumors, especially those with atypical features, even among experts, and (2) the lack of objective criteria for their distinction from melanoma and for gauging their malignant potential. Nevertheless, our observations do suggest that a biological relationship exists between the Spitz nevus/tumor and melanoma.
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