The Role of p16, p21, p27, p53 and Ki-67 Expression in the Differential Diagnosis of Cutaneous Squamous Cell Carcinomas and Keratoacanthomas: An Immunohistochemical Study

Abstract

Background: Distinguishing squamous cell carcinoma (SCC) from keratoacanthoma (KA) by histopathological features may not be sufficient for a differential diagnosis, as KAs may, in some cases, imitate well-differentiated SCCs.  Aims: In this study, we investigated whether the expression of the p16, p21, p27, p53 genes and a Ki-67 proliferation index are useful in distinguishing between these two tumors.  Study Design: Cross-sectional study. Methods: Immunohistochemistry was used to investigate the expression of the p16, p21, p27, p53 genes and the Ki-67 proliferation index was investigated in well-differentiated SCC with KA-like features (n=40) and KA (n=30). Results: The results of all of the examined markers, except for p27 (p16, p21, p53, and Ki-67) were found to be significantly different between the SCC and KA samples (p<0.05).  Conclusion: In well-differentiated SCC with KA-like features and KA cases where the differential diagnosis is difficult from a histopathological perspective, the use of p16, p21, p53 expression and a Ki-67 proliferation index can be useful for the differential diagnosis of SCCs and KAs.

Keywords

• Differential diagnosis, immunohistochemistry, keratoacanthoma, skin, squamous cell carcinoma

References

1. 1. Vasiljevic N, Andersson K, Bjelkenkrantz K, Kjellström C, Mansson H, Nilsson E, et al. The Bcl-xL inhibitor of apoptosis is preferentially expressed in cutaneous squamous cell carcinoma compared with that in keratoacanthoma. Int J Cancer 2009; 124:2361-6. [CrossRef]
2. 2. Stern RS. The mysteries of geographic variability in nonmelanoma skin cancer incidence. Arch Dermatol 1999;135:843-4. [CrossRef]
3. 3. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol 1994;30:1-19. [CrossRef]
4. 4. Ko CJ .Keratoacanthoma: facts and controversies. Clin Dermatol 2010;28:254-61. [CrossRef]
5. 5. Kingman J, Callen JP. Keratoacanthoma. A clinical study. Arch Dermatol 1984;120:736-40. [CrossRef]
6. 6. Cain CT, Niemann TH, Argenyi ZB. Keratoacanthoma versus squamous cell carcinoma. An immunohistochemical reappraisal of p53 protein and proliferating cell nuclear antigen expression in keratoacanthoma-like tumors. Am J Dermatopathol 1995;17:324-31.
7. 7. Putti TC, Teh M, Lee YS. Biological behavior of keratoacanthoma and squamous cell carcinoma: telomerase activity and COX2 as potential markers. Mod Pathol 2004;17:468-75. [CrossRef]
8. 8. Ho T, Horn T, Finzi E. Transforming growth factor alpha expression helps to distinguish keratoacanthomas from squamous cell carcinomas. Arch Dermatol 1991;127:1167-71. [CrossRef]

9. 9. Takeda H, Kondo S. Differences between squamous cell carcinoma and keratoacanthoma in angiotensin type-1 receptor expression. Am J Pathol 2001;158:1633-7. [CrossRef]
10. 10. Melendez ND, Smoller BR, Morgan M. VCAM (CD-106) and ICAM (CD-54) adhesion molecules distinguish keratoacanthomas from cutaneous squamous cell carcinomas. Mod Pathol 2003;16:8-13. [CrossRef]
11. 11. Skalova A, Michal M. Patterns of cell proliferation in actinic keratoacanthomas and squamous cell carcinomas of the skin. Immunohistochemical study using the MIB 1 antibody in formalin-fixed paraffin sections. Am J Dermatopathol 1995;17:332-4.
12. 12. Kaabipour E, Haupt HM, Stern JB, Kanetsky PA, Podolski VF, Martin AM. p16 expression in keratoacanthomas and squamous cell carcinomas of the skin: an immunohistochemical study. Arch Pathol Lab Med 2006;130:69-73.
13. 13. Kuivanen TT, Jeskanen L, Kyllönen L, Impola U, SaarialhoKere UK. Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas. Mod Pathol 2006;19:1203-12. [CrossRef]
14. 14. Mukunyadzi P, Sanderson RD, Fan CY, Smoller BR. The level of syndecan-1 expression is a distinguishing feature in behavior between keratoacanthoma and invasive cutaneous squamous cell carcinoma. Mod Pathol 2002;15:45-9. [CrossRef]
15. 15. Batinac T, Zamolo G, Coklo M, Hadzisejdic I, Stemberger C, Zauhar G. Expression of cell cycle and apoptosis regulatory proteins in keratoacanthoma and squamous cell carcinoma. Pathol Res Pract 2006;202:599-607. [CrossRef]
16. 16. Lu S, Tiekso J, Hietanen S, Syrjänen K, Havu VK, Syrjänen S. Expression of cell-cycle proteins p53, p21 (WAF-1), PCNA and Ki-67 in benign, premalignant and malignant skin lesions with implicated HPV involvement. Acta Derm Venereol 1999;79:268-73. [CrossRef]
17. 17. Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res 1994;54:3391-5.
18. 18. Fillies T, Woltering M, Brandt B, Van Diest JP, Werkmeister R, Joos U, et al. Cell cycle regulating proteins p21 and p27 in prognosis of oral squamous cell carcinomas. Oncol Rep 2007;17:355-9. [CrossRef]
19. 19. Batinac T, Zamolo G, Jonjic N, Gruber F, Petrovecki M. p53 protein expression and cell proliferation in non-neoplastic and neoplastic proliferative skin diseases. Tumori 2004;90:120-7.
20. 20. Borkowski A, Bennett WP, Jones RT, Borkowski P, Harris CC, Ferreira LR, et al. Quantitative image analysis of p53 protein accumulation in keratoacanthomas. Am J Dermatopathol 1995;17:335-8.
21. 21. Bordbar A, Dias D, Cabral A, Beck S, Boon ME. Assessment of cell proliferation in benign, premalignant and malignant skin lesions. Appl Immunohistochem Mol Morphol 2007;15:229-35. [CrossRef]
22. 22. Beham A, Regauer S, Soyer HP, Beham-Schmid C. Keratoacanthoma: a clinically distinct variant of well differentiated squamous cell carcinoma. Adv Anat Pathol 1998;5:269-80. [CrossRef]
23. 23. Mandrell JC, Santa Cruz D. Keratoacanthoma: hyperplasia, benign neoplasm, or a type of squamous cell carcinoma? Semin Diagn Pathol 2009;26:150-63. [CrossRef]
24. 24. Tronnier M. [Keratoacanthoma. A variant of highly differentiated squamous cell carcinoma and its differential diagnosis]. Pathologe 2002;23:65-70. [CrossRef]
25. 25. Karaa A, Khachemoune A. Keratoacanthoma: a tumor in search of classification. Int J Dermatol 2007;46:671-8. [CrossRef]
26. 26. Cribier B, Asch P, Grosshans E. Differentiating squamous cell carcinoma from keratoacanthoma using histopathological criteria. Is it possible? A study of 296 cases. Dermatology 1999;199:208-12. [CrossRef]
27. 27. Kikuchi A, Amagai M, Hayakawa K, Ueda M, Hirohashi S, Shimizu N, et al. Association of EGF receptor expression with proliferating cells and of ras p21 expression with differentiating cells in various skin tumours. Br J Dermatol 1990;123:49-58. [CrossRef]
28. 28. Ahmed NU, Ueda M, Ichihashi M. p21WAF1/CIP1 expression in non-melanoma skin tumors. J Cutan Pathol 1997;24:223-7. [CrossRef]
29. 29. Oh CW, Penneys N. P27 and Mib1 expression in actinic keratosis, Bowen disease, and squamous cell carcinoma. Am J Dermatopathol 2004;26:22-6. [CrossRef]
30. 30. Hu W, Cook T, Oh CW, Penneys NS. Expression of the cyclindependent kinase inhibitor p27 in keratoacanthoma. J Am Acad Dermatol 2000;42:473-5. [CrossRef]
31. 31. Connolly M, Narayan S, Oxley J, de Berker DA. Immunohistochemical staining for the differentiation of subungual keratoacanthoma from subungual squamous cell carcinoma. Clin Exp Dermatol 2008;33:625-8. [CrossRef]