Search

Cutaneous squamous cell carcinoma (SCC) is a malignancy that arises from epidermal keratinocytes. Although the majority of cutaneous SCC cases are easily treated without further complication, some behave more aggressively and carry a poor prognosis. These "high-risk" cutaneous SCCs commonly originate in the head and neck and have an increased tendency toward recurrence, local invasion, and distant metastasis. Factors for high-risk cutaneous SCC include large size (>2 cm), a deeply invasive lesion (>2 mm), incomplete excision, high-grade/desmoplastic lesions, perineural invasion (PNI), lymphovascular invasion, immunosuppression, and high-risk anatomic locations. Both the National Comprehensive Cancer Network ® (NCCN ® ) and the American Joint Committee on Cancer (AJCC) identify several of these high-risk features of cutaneous SCC. The purpose of this article was to review the high-risk features included in these guidelines, as well as their notable discrepancies and omissions. We also provide a brief overview of current prophylactic measures, surgical options, and adjuvant therapies for high-risk cutaneous SCC. © 2016 Wiley Periodicals, Inc. Head Neck 39: 578-594, 2017., (© 2016 Wiley Periodicals, Inc.)

This study aims to determine the survival impact of patient characteristics and treatment options associated with the early stage oral cavity squamous cell carcinoma, OCSCC. The methods are analysis of Irish cancer database examining T1/2, N0, and M0 cases of OCSCC from 1997 to 2007 inclusive. In total, 397 cases were identified. Anterolateral tongue accounted for 52.9 % of cases. Increased age at diagnosis and smoking are independent prognostic survival indicators associated with poorer outcomes. Surgery as the initial intervention was associated with significantly better survival outcomes, while surgery and adjuvant radiotherapy significantly worse outcomes. Surgical intervention is recommended as the first-line treatment in the early stage OCSCC in combination with elective neck dissection.

Background: The adenomatous polyposis coli (APC) gene is a tumor suppressor gene which is mutated in the hereditary disease, familial adenomatous polyposis (FAP). Somatic mutations of the APC gene have also been identified in the majority of sporadic colorectal carcinomas, and mutation of the APC gene appears to be an early step in the initiation of colon cancer. Loss of heterozygosity (LOH) of APC has been described in a variety of other cancer types, including renal cell carcinoma, gastric cancer, non-small cell lung cancer, endometrial cancer and oral squamous cell carcinomas (SCC)., Aim: To determine the role played by APC gene in the genesis of cutaneous SCC., Materials and Methods: Allelic imbalance/loss of heterozygosity (AI/LOH) was examined in twenty-two histologically confirmed cutaneous squamous cell carcinomas (SCC) using microsatellite markers, proximal to the APC gene. Immunohistochemical analysis of APC protein expression was also examined in the cutaneous SCC., Results: AI/LOH was detected in 60% of the SCC samples using D5S346 marker (proximal to the APC gene). Ninty-five percent of the SCC samples showed positive reduced APC expression, however the localization of the APC protein was abnormal., Conclusion: The abnormal expression of APC suggests that APC gene may play a role in cutaneous SCC development.

Aberrations of the tumor suppressor gene, the fragile histidine triad gene (FHIT), have been reported in a wide variety of human cancers including cervical carcinoma, oral squamous cell carcinoma (SCC) and oesophageal SCC. This study aimed to examine the integrity of the FHIT gene in cutaneous SCC. Allelic imbalance/loss of heterozygosity (AI/LOH) was examined in 21 histologically confirmed cutaneous SCC at two microsatellite markers, D3S1300 and D3S4103, both of which are located within intron 5 of the FHIT gene. Immunohistochemical analysis of FHIT protein expression was also examined in the cutaneous SCC. Ten of the 16 informative cutaneous SCC samples (63%) displayed AI/LOH at the D3S1300 locus, and 13 of the 17 informative cutaneous SCC samples (76%) displayed AI/LOH at the D3S4103 locus. Nine of the 21 SCC samples were found to be positive for FHIT protein expression, however, a further nine SCC samples showed reduced FHIT expression, and three SCC samples did not express the FHIT protein. No correlation between AI/LOH of the FHIT gene and reduced/absent FHIT expression was detected in the cutaneous SCC samples. Further investigation into the role of the FHIT protein in the epidermis is warranted to determine if the reduced/lost expression of FHIT observed in a subset of the cutaneous SCC is contributing to tumorigenesis.

Renal transplant recipients incur markedly higher rates of nonmelanoma skin cancer, including both basal and squamous cell carcinoma, by unknown mechanisms that are thought to be activated by long-term immunosuppression. These tumors typically arise in sun-exposed areas of the skin and are biologically more aggressive in renal transplant recipients compared with nontransplant patients. Interestingly also, the incidence of squamous cell carcinoma is generally 2- to 3-fold higher than that of basal cell carcinoma in renal transplant recipients, which is a reversal of the trend in the nontransplant population. We have shown in a previous report that the increased incidence of squamous cell carcinoma in renal transplant patients is characterized by increased telomere lengths when compared with the same tumors in the nontransplant population. This suggests a possible role of telomere lengthening via telomerase in the etiology of these lesions. In our current study, we performed a similar analysis of a cohort of 35 basal cell carcinoma samples from both the renal transplant and nontransplant patient groups. We find that, in contrast to the situation in squamous cell carcinoma, the telomeres of the basal cell carcinomas in renal transplant recipients are in fact shorter than their counterparts in the nontransplant population, but also that these lengths are considerably longer in both cases than their squamous cell counterparts. This is the first report to comprehensively show that the telomere lengths significantly differ between basal and squamous cell carcinomas. This may underlie not only the incidence of these tumors in solid organ transplant recipients, but may also reflect their differing biology that remains poorly understood. These data also suggest that future treatment strategies for nonmelanoma skin cancers that are based upon telomerase inhibition, including those arising in transplant patients, may require different approaches for these two different skin lesions.

Background: Germ line mutations of the BRCA2 tumor suppressor gene with subsequent loss of the remaining wild-type BRCA2 allele have been identified in up to 35% of familial breast cancer cases. A high frequency of allelic loss at the BRCA2 gene locus has also been reported in a variety of sporadic epithelial tumors including oesophageal squamous cell carcinomas (SCC), and sporadic head and neck SCC., Aim: The present study aimed to examine the integrity of the BRCA2 gene in cutaneous SCC., Materials and Methods: Allelic imbalance/loss of heterozygosity (AI/LOH) was examined in 22 histologically confirmed cutaneous SCC at two microsatellite markers, D13S260 (centromeric to the BRCA2 gene) and D13S267 (telomeric to the BRCA2 gene). Immunohistochemical analysis of BRCA2 protein expression was also examined in the cutaneous SCC., Results: AI/LOH at the D13S260 locus was found in eight of the 19 informative SCC, and AI/LOH at the D13S267 locus was found in 12 of the 18 informative SCC. Seven SCC showed allelic loss at both markers, and six SCC showed retention of heterozygosity at both markers. Expression of BRCA2 protein was only detected in six of the normal epidermises and three of the 21 SCC examined., Conclusion: AI/LOH of the BRCA2 gene region was found to be common in the cutaneous SCC.

The incidence and aggressiveness of nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma (SCC), in immunocompromised renal transplant recipients (RTRs) is dramatically higher (up to 100-fold) compared with the normal population. SCC lesions are also predominant in RTRs, in contrast to the normal population where basal cell carcinoma is more common. The mechanisms underlying this phenomenon are unknown, but effective treatments for these skin tumors would have a significant impact upon morbidity in this group of patients. The fundamental role of telomeres and telomerase in the development of most human cancers, including melanoma, is well established, but very few reports have assessed their function during the onset of nonmelanoma skin cancer. To assess whether telomere maintenance plays any role in the increased incidence of SCC in renal transplant patients, we analyzed both the telomere lengths and telomerase expression levels in 44 SCCs and 22 Bowen's disease (BD) samples (carcinoma in situ) from RTRs and nontransplant patients. Our findings provide statistically significant evidence that the telomeres are consistently longer in both BD RTR and SCC RTR lesions compared with their nontransplant counterparts. We also show by immunohistochemistry that there is a trend toward higher telomerase levels in both the BD RTR and SCC RTR lesions, although this was not statistically significant. Our data thus suggest that telomere lengthening may possibly be an early event in the development of SCC in renal transplant patients and demonstrate that telomere maintenance mechanisms should be further evaluated with respect to developing a future therapeutic strategy for these cancers.

Deletions of the short arm of chromosome 9 have been reported in different types of malignancies. This chromosomal region contains a number of known tumour suppressor genes, including the p16INK4A (CDKN2A), p15INK4B and MTAP tumour suppressor genes located at 9p21. In this study twenty-two paraffin embedded invasive cutaneous SCC were examined for allelic imbalance/ loss of heterozygosity (AI/LOH) of the 9p region (in particular 9p21), and for p16 protein expression. DNA was isolated from microdissected sections of normal and tumour cells and analysed for AI/LOH by using six fluorescently labelled microsatellite markers that map to the 9p region. P16 protein expression was examined by immunohistochemistry. At each of the six microsatellite markers the majority of SCC analysed showed AI/LOH. Overall both AI/LOH within the CDKN2A locus and absence of p16 protein expression were frequent among the cutaneous SCC analysed, suggesting that p16 inactivation may play a role in cutaneous SCC development. The majority of the SCC analysed also had AI/LOH of the marker within the MTAP gene, and at markers flanking the CDKN2A gene; thus further investigation as to a possible role for these genes in the development of cutaneous SCC is warranted.

Background: Microsatellite instability (MSI) is a phenotypic characteristic of tumors with biallelic inactivation of mismatch repair genes, such as MSH2 or MLH1, and contributes to malignant transformation., Aims: The aim of this study was to examine the prevalence of MSI in cutaneous squamous cell carcinoma (SCC) using a PCR and fluorescent-based detection system. These methods of analysis offer several advantages over the use of silver staining and autoradiographic techniques. We also aimed to determine if MSI status correlated with expression of the MSH2 and MLH1 mismatch repair proteins in these cutaneous SCC samples., Methods: The MSI status of 22 histologically confirmed invasive cutaneous SCC samples were analyzed at five microsatellite markers (the National Cancer Institute's Bethesda panel of two mononucleotide and three dinucleotide markers) using a PCR and fluorescent-based detection system. Immunohistochemical analysis of MSH2 and MLH1 protein expression was also carried out on the SCC samples., Results: Only one case of cutaneous SCC displayed MSI. This was found at just one of five markers, and thus was low frequency MSI. All 22 cutaneous SCC cases strongly expressed MSH2 protein. Eighteen (82%) of the cutaneous SCC cases showed moderate to strong expression of MLH1 protein. The remaining four cases of cutaneous SCC were negative for MLH1 protein. Therefore, the majority of the SCC patients analyzed showed a correlation between absence of MSI and expression of MSH2 and MLH1 proteins., Conclusions: MSI is uncommon in cutaneous SCC. In addition, MSH2 was strongly expressed in all SCC samples analyzed and appeared to be upregulated when compared with the corresponding normal tissue. MLH1 protein was not detected in 4 of 22 SCC cases, although it was expressed in the corresponding normal tissue, suggesting that inactivation of MLH1 may be a late event in a subset of invasive SCC cases.

Renal transplant recipients are prone to numerous benign and malignant skin lesions. Previous work in the authors' laboratory has determined that the human papillomavirus may be the viral aetiology of these skin lesions. The p53 tumor-suppressor gene is the most frequently mutated gene in a wide range of human cancers. Here the authors describe an immunohistochemical study to evaluate the expression of p53 in benign and malignant skin lesions from renal transplant recipients and immunocompetent patients with skin cancer. The effect of p53 mutations on the expression patterns observed were examined by polymerase chain reaction-single strand conformation polymorphism analysis and direct cycle sequencing. The expression of the p53-regulated cyclin-dependant kinase inhibitor p21Waf1/Cip1 and Mdm2 was also examined in p53-positive cells. The expression of p53 in benign and malignant lesions was found to be markedly different. p53 was expressed in only 40% (6/15) of viral warts analyzed. The expression was confined to the basal layer both in the lesion and in adjacent normal skin, and the level of expression was low and only in a small number of cells (<10%). Of the cutaneous squamous cell carcinomas analyzed, 60% (9/15) showed p53 expression. Two different patterns of expression were observed. Basal layer expression in both the invasive tumor and adjacent normal skin was observed in 50% of the p53-positive squamous cell carcinomas; in the remaining 50%, p53 was expressed diffusely throughout the invasive tumor and in the basal layer of adjacent normal skin. The level of expression was high and in a large number of cells. Polymerase chain reaction-single strand conformation polymorphism analysis revealed that only one of the squamous cell carcinomas expressing p53 harbored a p53 mutation and that the accumulated p53 in the remaining tumors was wild type. No Mdm2 or p21Waf1/Cip1 expression was detected in the p53-positive squamous cell carcinomas, indicating that although the accumulated p53 is stable, it does not function effectively as a transcriptional activator. This represents a novel p53 phenotype in cutaneous squamous cell carcinoma. In addition, no correlation was seen between the presence and absence of human papillomavirus and p53 expression.

Background/aims: Non-melanoma skin cancers frequently harbour multiple human papillomavirus (HPV) types. A recent report suggests that a polymorphism of the p53 tumour suppressor gene that results in the substitution of a proline residue with an arginine residue at position 72 of the p53 protein might act as a risk factor in HPV associated malignancies. This study aimed to determine the following: (1) the relation between HPV infection and the development of cutaneous squamous cell carcinoma (SCC), and (2) whether there is a correlation between p53 codon 72 polymorphism and the development of SCC., Methods: Blood samples were taken from 55 patients with skin cancer (both renal transplant recipients and immunocompetent patients with skin cancer) and 115 ethnically matched volunteers. A polymerase chain reaction based assay was used to determine p53 codon 72 genotypes. In addition, 49 benign and malignant lesions from 34 of the patients with skin cancer and 20 normal human skin samples from 20 of the control volunteers were examined for HPV., Results: The proportions of p53 codon 72 genotypes found were 78% arginine homozygous, 2% proline homozygous, and 20% heterozygous among patients with skin cancer and 79% arginine homozygous, 3.5% proline homozygous, and 17.5% heterozygous among the control population. Statistical analysis showed no significant differences in the distribution of the two p53 isoforms between the patients with skin cancer and the control population. The predominant viral types detected in both the patients and the control group were EV associated HPVs, although the incidence was lower in normal skin samples than in malignant lesions or viral warts., Conclusions: These results suggest that in a Celtic population there is no correlation between the presence of HPV, the p53 codon 72 arginine polymorphism, and the development of skin cancer.

Background/aims: Loss of function of the retinoblastoma (Rb) tumour suppressor gene, located on chromosome 13, is common in many inherited and sporadic forms of cancer. Inactivation of its gene product by oncogenic human papillomaviruses (HPV) plays a key role in the genesis of cervical cancer. It has been shown previously that non-melanoma skin cancers of renal transplant recipients and immunocompetent patients with skin cancer also frequently harbour potentially oncogenic HPV types. This study aimed to examine the integrity of the Rb gene in histologically confirmed squamous cell carcinomas (SCCs) from renal transplant recipients and immunocompetent patients with skin cancer., Methods: Loss of heterozygosity (LOH) at the Rb locus was examined in 13 histologically confirmed SCCs using the D13S153 microsatellite marker, which is located in exon 2 of the Rb gene. Loss of a second marker, D13S118, distal telomerically to the Rb gene at 13q14.3 was also analysed., Results: Of the 13 HPV associated SCCs examined 11 were informative (two SCCs were homozygous for both microsatellite markers). LOH at the D13S153 locus was found in four of the 10 informative SCCs and LOH at the D13S118 locus was found in five of the 11 informative cases. Overall, seven of the 11 informative cases showed LOH at one or other locus. This represents a high degree of chromosomal instability in these tumours. The expression of the Rb gene product in the 11 informative cases was analysed immunohistochemically. Expression of Rb was detected in 10 of the 11 SCCs examined. No correlation between the HPV status of the tumours and the expression of Rb was found. Although the only SCC not to express Rb also demonstrated LOH at the D13S153 locus, the remaining SCCs that had LOH at 13q14 were able to express RB:, Conclusion: Another tumour suppressor gene located at 13q14 might be responsible for the genesis of these tumours.

Objective: CD44, an integral membrane glycoprotein, may have an important role in early tumorigenesis, specifically, facilitating early tumor progression. Reports of the expression of CD44 in early uterine cervical squamous carcinogenesis are conflicting. We examined the expression of CD44 in microinvasive carcinoma of the cervix (MIC), as yet unreported, and compared it to that in cervical intraepithelial neoplasia (CIN) 1 and CIN 3 to further elucidate its role in early squamous carcinogenesis., Methods: Seventeen cases of CIN 1, 24 cases of CIN 3, and 20 cases of MIC were stained with antibodies to CD44s, CD44v5, and CD44v6. Only membranous staining was considered positive., Results: Positive membranous staining (>50% cells) was observed in 97% of cases of CIN 1 using all three antibodies. In CIN 3, positive staining was seen more often with CD44v6 (18/24) and CD44v5 (19/24) than with CD44s (6/24). Expression of CD44v6 was retained more often in MIC (16/20) compared with CD44s (3/20) and CD44v5 (9/20). Those cases of CIN 3 and MIC that failed to meet our criteria for positive staining showed either heterogeneous or absent staining., Conclusion: There is a qualitative and quantitative reduction in expression of CD44 in MIC and CIN 3 compared with CIN 1. Down-regulation of CD44 variants may occur later in neoplastic progression than CD44s. This pattern may reflect their important biological function in early progression by cervical cancer cells. Patchy and heterogeneous staining in more advanced lesions limits the usefulness of CD44 and its variants in the assessment of microinvasion., (Copyright 2000 Academic Press.)

Aims: To compare differences in cell proliferation indexes and apoptotic indexes between cutaneous basal and squamous cell carcinomas, in an attempt to suggest an explanation for the differences in their biological behaviour., Methods: Forty cases of cutaneous basal cell carcinoma (BCC) and 40 cases of moderately and well differentiated squamous cell carcinoma (SCC) were retrieved from the archives. Sections, 4 microns thick, were cut from formalin fixed, paraffin wax embedded tissue in each case and stained with haematoxylin and eosin. These were then examined for mitotic and apoptotic figures per 1000 cells. Sections from the same cases were also immunostained with the mouse monoclonal antibody Ki67 (MIB1); positive nuclear staining was counted per 1000 cells., Results: No significant differences were found between the mitotic indexes and apoptotic indexes in these tumours. There was, however, a significant difference in Ki67 (MIB1) staining, with greater staining in the squamous cell carcinomas., Conclusion: Estimation of the mitotic and apoptotic indexes did not reveal any differences between these two tumour types. The proliferation indexes, assessed by Ki67 immunostaining, did differ. This may be one of the factors underlying the more aggressive behaviour of SCC.

The significant changes over the last decade in the CIN/cervical carcinoma area have involved the increasing recognition of many cervical carcinomas as adenocarcinomas, rather than squamous cell type, and their propensity for arising in young women. Another area of interest is the deployment of new molecular techniques that are unveiling the role of oncogene co-factors (e.g. HPV, p53) in the biologic evolution of CIN and hopefully glandular dysplasia.

An 82-year-old male presented with a two-month history of hoarseness. A 2 cm pedunculated lesion was removed from the base of his epiglottis. Microscopy showed a polypoid atypical spindle cell lesion. Multiple levels failed to reveal an invasive squamous cell carcinoma. On the basis of haematoxylin and eosin stained sections the main differential diagnosis was a pseudosarcoma with an overlying dysplastic squamous mucosa or infiltrating spindle cell carcinoma. Immunohistochemistry showed positive staining for vimentin but no convincing staining with antibodies to cytokeratin and EMA. Ultrastructural analysis also failed to reveal epithelial characteristics. Ploidy analysis by static cytophotometry of the spindle cell proliferation revealed an aneuploid stem line with a DNA index of 1.67. On the basis of this the process was felt unlikely to be reactive and a diagnosis of a spindle cell squamous carcinoma was made. This diagnosis was subsequently supported by a clinical recurrence of the nodule at a six-month follow-up.

The role of DNA ploidy in the management of oesophageal carcinoma is unclear. Most studies have employed flow cytometry (FC) for DNA analysis but some have used image analysis (IA) of tissue sections. In this study aneuploidy rates in stage IIa squamous tumours were determined by both FC and IA of cell suspensions and results were compared with outcome in two patient subgroups. Group 1 (n = 15) were patients who died from tumour recurrence within 1 year of surgery while Group 2 (n = 21) were patients who survived tumour free for at least 1 year. Aneuploidy rates differed significantly between techniques; 29 of 36 tumours (81%) were aneuploid by IA compared with 19 of 34 (56%) by FC (P < 0.05). Aneuploidy rates differed significantly between groups 1 and 2 as determined by FC (79%) versus 40%) (P < 0.05) but not by IA (93% versus 71%) (P = ns). Euploid status was a good prognostic indicator; 6 of 7 (86%) patients with euploid tumours by IA and 12 of 15 (80%) by FC (P < 0.05) survived more than 1 year. The sensitivity and specificity of euploidy was 93% and 28.6% for IA compared with 78.6% and 60% for FC. Since 33 (92%) of these tumours exhibited a marked peritumoral desmoplastic or chronic inflammatory reaction IA, being more sensitive to subtle nuclear change, may be a more appropriate technique than FC for evaluation of the role of ploidy in such tumours.

This is the first comparative study of DNA quantification of oesophageal squamous cell carcinoma by flow cytometry (FCM) and image cytometry (ICM) using formalin fixed paraffin embedded tissue. The potential advantages of ICM include the identification of a reliable control cell population; avoidance of non-tumour stromal and inflammatory cell nuclei, nuclear fragments, degenerate cell nuclei and doublets, triplets etc., which are not possible with FCM using archival tissue. Twenty-eight cases, all of the same stage (stage 2a) and similar grade (well or moderately differentiated) were analysed. The cases were separated into two groups, those that had succumbed to tumour in less than 18 months (group A) and those that were tumour free at least 18 months post-resection (group B). Using ICM all 28 tumours yielded interpretable histograms by comparison to 25 of 28 using FCM. Aneuploidy was identified in 100% of cases in group A using ICM (in comparison to 73% by FCM) and in 73% of group B using ICM (in comparison to 44% by FCM). Any tumour aneuploid by FCM was also aneuploid by ICM. Nine cases aneuploid by ICM were euploid by FCM. The mean 5C exceeding rate (% of cells whose nuclei contain a DNA mass equivalent to > 5 sets of 23 chromosomes) was 21% in group A and 14% in group B (P < 0.01). Euploidy was confined to tumours of those patients disease free for more than 18 months. The conclusions of this study are that: firstly, ICM is superior in its yield of interpretable histograms to FCM using formalin fixed paraffin embedded tissue; secondly, ICM is more sensitive in the identification of aneuploid stemlines than FCM; and thirdly, euploid tumours (as detected by ICM) appear to have a better prognosis than aneuploid tumours of similar stage and grade.

Mixed types of carcinoma of the prostate are rare. The majority of those described (22 cases) are examples of mixed adenocarcinoma and transitional cell carcinoma. Much more unusual is the mixed adenosquamous carcinoma, of which only three cases have been described. This report presents an additional case of the rare adenosquamous carcinoma of the prostate. It discusses the clinicopathologic features and the possible histogenesis of this tumor and suggests a role for stilbestrol in its development.

This case report demonstrates the origin of a primary squamous cell carcinoma of the parotid gland in squamous metaplasia of the parotid ducts. Comparison is made between parotid ductal intraepithelial neoplasia and cervical intraepithelial neoplasia. The clinical importance of establishing the primary origin of these tumours and the need for extensive tissue sampling is emphasized.