Oncology/Endocrine
Prognostic Criteria for Squamous Cell Cancer of the Skin

https://doi.org/10.1016/j.jss.2008.12.008Get rights and content

Background

Non-well-differentiated cutaneous squamous cell carcinomas may display a more aggressive behavior. It is important to better define prognostic criteria for these tumors.

Methods

This was a retrospective case-control analysis of a squamous cell carcinoma database. Patients with non-well-differentiated and well-differentiated tumors were matched based on site of tumor, age, and immunocompromised status. Comparisons included demographics, histology, immunohistochemical protein expressions (Ki-67, p53, E-cadherin, cyclin D1), and clinical outcomes.

Results

Demographic features were similar between cases (n = 30) and controls (n = 30). Non-well-differentiated tumors were larger (1.8 cm versus 1.3 cm, P = 0.08), deeper (0.81 cm versus 0.32 cm, P < 0.0001), and had greater recurrence (P = 0.003). Non-well-differentiated tumors showed increased proliferation rate, Ki-67 index (77% versus 61%, P = 0.001); no significant difference in activity of p53, E-cadherin, and cyclin D1 between the two groups.

Conclusions

Tumor differentiation and depth are important pathologic and prognostic criteria for cutaneous squamous cell carcinoma. Immunohistochemistry helps describe patterns of biomarker protein expression and may exemplify aggressive subtypes.

Introduction

Cutaneous squamous cell carcinoma (SCC) is primarily seen in the elderly population and usually occurs in areas of long-term sun exposure [1], with an estimated lifetime risk of 7% to 11% [2]. Most SCCs show relatively benign behavior and can be cured by local surgical and dermatologic methods. However, some of these lesions can have a locally invasive and aggressive course. The rate of metastasis is 0.3% to 3.7%, with a 5-y survival rate of less than 30% [3].

There have been a number of studies that have examined the clinical and tumor factors that correlate with an increased risk of developing metastatic lesions. Tumor-related factors include size, anatomic location, tumor thickness, depth of invasion, tumor grade, histopathologic subtypes, degree of inflammation, and presence of perineural invasion 4, 5. Immunocompromised patients have been found to have a more aggressive course. In addition, there is evidence that age and gender may play a role in survival [6]. Although some of these factors offer insight into the prognosis and metastatic potential of SCC, they are underutilized and have not been developed into staging schemes [3].

Several biomarkers, including E-cadherin, Ki-67, p53, and cyclin D1, have been shown to be abnormal in several types of cancer [7]. Studies suggest that Ki-67 rate and p53 protein expression reflect the degree of malignancy in non-melanoma cutaneous neoplasms [7]. E-cadherin, a calcium dependent intercellular adhesion molecule, is expressed in epithelial tissues in which it contributes to the maintenance of epithelial stability. Down-regulation of E-cadherin is linked to increased potential for tumor invasiveness and distant metastasis. The frequencies of E-cadherin promoter hypermethylation appear to be correlated with more advanced stage of squamous carcinogenesis in skin [8]. The most important gene studied for the damaging effects of ultraviolet radiation is the p53 tumor suppressor gene, which plays an important role in apoptosis, cell proliferation, differentiation, and DNA repair. The p53 tumor suppressor gene mutations result in loss of control of aberrant cell growth, such as cancer cells 9, 10. Ki-67 is a cell proliferative index marker and is typically increased in tumors that are aggressive and show rapid growth and recurrence [11]. Cyclin D1 is a proto-oncogene that is an important regulator in the cell cycle. It has been shown that gain of 11q/cyclin D1 overexpression is an essential early step in skin cancer development and causes abnormal tissue organization and differentiation [12]. Abnormality of the molecules regulating the cell cycle has been shown to lead cells to transformation.

There are very few studies that have correlated clinical and pathological factors with biomarkers. The goals of this study were to examine prognostic significance of non-well-differentiated SCC and to better understand the role of immunohistopathological parameters in determining its malignant behavior.

Section snippets

Tissue

The current analysis is a retrospective case-control study, which was approved by the University of Arizona Human Subjects Committee. There are 165 consecutive patients with documented aggressive cutaneous SCC in the Aggressive Squamous Cell Carcinoma database at the Southern Arizona Veterans Affairs Health Care System from January 29, 2001 to February 10, 2006. Inclusion criteria for the database were at least one pathologically confirmed cutaneous SCC that needed surgical excision due to

Results

Thirty-eight patients were identified with non-well-differentiated SCC, eight of which were not able to match to a control; 30 patients were successfully matched for this analysis. All patients were male. Both groups had similar mean age and Charlson-Deyo Index (Table 1). The time of follow-up was not significantly different between the groups (28.2 versus 22.2 mo, P = 0.18) (Table 2). All patients in the control group had negative margins. Three patients in the non-well-differentiated group

Discussion

Differentiation is an important histologic criterion for cutaneous SCC. Though our study is small with only 30 non-well-differentiated and 30 well-differentiated control patients, our findings concur with other studies that attempt to identify clinicopathologic factors that may predict aggressive SCC behavior, demonstrated by the increased recurrence rate for these patients. In addition, the factors found to have a high risk of development of metastatic disease include location, size, depth,

Acknowledgments

This work originated with the Research Service Line at the Southern Arizona Veterans Affairs Health Care System in Tucson, AZ.

This research was supported by a grant from the Veterans Integrated Service Network (VISN18) Research Office: Patterns of Gene Expression, Clinicopathologic, and Karyometric Features of Aggressive Cutaneous Squamous Cell Carcinomas, and an unrestricted donation from Khronos LLC, New York, NY.

The views expressed in this article are those of the authors and do not

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