ORIGINAL STUDY

Immunohistochemical Expression of MCM2 in Nonmelanoma Epithelial Skin Cancers Asmaa Gaber Abdou, MD,* Mohammed Gaber Abd Elwahed, MD,† Marwa Mohammed Serag El-dien, MD,* and Dina Sharaf Eldien, MSC†

Abstract: Cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) represent 45.5% and 37.02%, respectively, of total malignant skin cancer according to the latest registry of Egyptian National Cancer Institute. Minichromosome maintenance (MCM) proteins are essential replication initiation factors. The current study examined the immunohistochemical expression of MCM2 in normal skin (10 cases), some proliferative skin lesions (6 psoriasis, 2 keratoacanthoma, and 2 seborrheic keratosis), and nonmelanoma epithelial skin cancers (20 BCC and 21 SCC). MCM2 was expressed in basal layer of normal epidermis and upregulated in proliferative skin lesions and nonmelanoma epithelial skin cancers without significant differences between the latter groups (P . 0.05). Mean and median values of MCM2 percentage of expression in BCC were higher than that of SCC (P = 0.004). MCM2 promotes proliferative capacity of the cells manifested by its expression in basal layer of epidermis, hyperproliferative skin lesions, and malignant cutaneous tumors. Proliferative capacity of BCC may be higher than SCC and this does not necessarily reflect aggressive behavior. Key Words: MCM2, BCC, SCC, hyperproliferative skin lesions (Am J Dermatopathol 2014;36:959–964)

INTRODUCTION Nonmelanoma skin cancer (NMSC) is the most common skin cancer. It consists mainly of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Its incidence has been rapidly increasing over the past several decades.1 Cutaneous BCC and SCC represent 45.5% and 37.02%, respectively, of total malignant skin cancer according to the latest registry of Egyptian National Cancer Institute.2 This increasing incidence is most likely due to a combination of multiple factors, including increased exposure to ultraviolet light, ozone depletion, and increased surveillance. Long-term exposure to the sun resulting in photodamage is perhaps the biggest risk factor for NMSC. Also, genetic defects, as in basal cell nevus syndrome and xeroderma pigmentosa, are risk factors for the accelerated development of NMSC.3 BCC causes significant local destruction, but it is generally nonmetastatic, whereas SCC is biologically more aggressive and can cause significant mortality.4 From the Departments of *Pathology and †Dermatology and Andrology, Faculty of Medicine, Menofiya University, Shebein Elkom, Egypt. The authors declare no conflicts of interest. Reprints: Asmaa Gaber Abdou, MD, Department of Pathology, Faculty of medicine, Menofiya University, Gamal Abd Elnaser St, Shebein Elkom, 32511, Egypt (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins

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Regulation of the cell cycle is complex and involves a wide variety of genes and proteins, among which are the minichromosome maintenance (MCM) proteins that are essential replication initiation factors.5 They play a vital role in the licensing of the origin of replication. The MCM protein family consists of 6 major isoforms (MCMs 2–7), which have similar biochemical functions.6 They are equally important for continuous chromosome replication after the activation of early origins of DNA replication.7 As cells exit mitosis, these newly synthesized MCM proteins accumulate in the nucleus (early G1 phase) and assemble into prereplicative complexes.7 The nuclear localization of the MCMs 2–7 complex is regulated by the cyclin-dependent kinases (CDKs).8 MCMs 2–7 are imported into the nucleus when CDK activity is low in early G1 and exported from the nucleus during S phase when CDK activity is high.7 Therefore, MCM activity is essential for DNA replication in dividing cells, which is lost in quiescence.9 MCM proteins are obvious markers for proliferation.10 Molecular studies suggested that increased levels of MCM proteins mark not only proliferative malignant cells but also precancerous cells and the potentially recurrent cells.11 The superior sensitivity of the MCM proteins over the standard proliferation markers such as Ki-67 resides in the fact that MCM proteins are expressed throughout the whole cell cycle including cells leaving G0 to enter into the early G1 phase, this characteristic is not found in Ki-67, which identifies cells throughout cell cycle (except for the G0 resting phase).12 Therefore, MCM proteins specifically MCM5 and MCM2 have been proposed as potential prognostic markers in dysplastic lesions and cancer.11,13,14 Little is known about the expression of MCM2 in normal epidermis and NMSC; therefore, in the current study, we examined the expression of MCM2 in normal skin, some proliferative skin lesions, and nonmelanoma epithelial skin cancers (BCC and SCC).

PATIENTS AND METHODS This study was carried out on biopsies from 20 BCC patients, 21 SCC patients, and 10 hyperproliferative skin lesions (6 psoriasis, 2 keratoacanthoma, and 2 seborrheic keratosis). Ten age and sex-matched healthy subjects were also included in the study as a control group. Those patients were collected from the outpatient Clinic of Dermatology Department, Faculty of Medicine, Menofiya University, during the period between 2010 and 2013. The patients were subjected to complete history taking, general and local examinations, and skin biopsy. www.amjdermatopathology.com |

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Skin biopsies were taken from all patients by surgeon (excision biopsy of lesions) and control subjects after taking informed consent from both. All biopsies were processed in Pathology Department, Faculty of Medicine, Menofiya University, where they were fixed in 10% neutral buffered formalin, dehydrated in ascending grads of ethanol followed by immersion in xylene then impregnated in paraffin. Several 5-m thick sections were cut from each biopsy; the first ones were stained by hematoxylin and eosin for routine histopathologic examination. The other sections were mounted on superfrost plus slides and stored at room temperature, one to be stained immunohistochemically for MCM2 and the other one to represent negative control of MCM2. Positive control for MCM2 was tonsil.

Examination of the Hematoxylin and Eosin–Stained Section The sections stained with hematoxylin and eosin were examined under the light microscope for assessment of the following: 1. Confirmation of the diagnosis. 2. Determination of the histopathologic pattern of BCC either circumscribed or infiltrating. 3. Determination of the status of the margins either positive or negative in cases of BCC and SCC. 4. Grading of SCC according to Broder classification. 5. Examination of the available lymph nodes in cases of SCC and determination if they are involved or not.

Immunohistochemistry The method used for immunostaining was streptavidin–biotin–amplified system. Paraffin-embedded tissue sections were deparaffinized in xylene, rehydrated in a graded series of ethanol, and then incubated with 3% hydrogen peroxide. Slides were rinsed in phosphate-buffered saline and then exposed to heat-induced epitope retrieval in citrate buffer solution (pH 6) for 20 minutes. After cooling, the slides were incubated overnight at room temperature with mouse monoclonal anti-MCM2 antibody (Clone CRCT2.1; NeoMarkers, LabVision, Fremont, CA) (0.1 mL concentrated and diluted by phosphate-buffered saline in a dilution 1:100). Detection of immunoreactivity was carried out using the ultravision detection system, readyto-use antipolyvalent horseradish peroxidase/diaminobenzidine (NeoMarkers, LabVision). Finally, the reaction was visualized by an appropriate substrate/chromogen (diaminobenzidine) reagent. Counter stain was carried out using Mayer hematoxylin.

Interpretation of Immunohistochemical Staining of MCM2 True nuclear staining is required to assign MCM2positive expression. The extent of MCM2 immunoreactivity was assessed as a percentage of positivity and expressed as a mean, median, and range.

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Statistical Analysis Data were collected, tabulated, and statistically analyzed using a personal computer with Statistical Package for the Social Sciences (SPSS) program, version 16. The x2 and Fisher exact tests were used in comparison between qualitative variables, whereas Mann–Whitney and Kruskal–Wallis tests were used in comparison between quantitative variables. P values of #0.05 were considered statistically significant.

RESULTS Clinicopathologic Data of BCC The age of BCC patients ranged between 29 and 80 years with a mean of 61.3 years and a median of 65 years. The cases were 9 males (45%) and 11 females (55%) with 0.82:1 as a male to female ratio. Face was the site of affection of all investigated BCC. The size of the lesions ranged between 0 and 4 cm with a mean of 1.8 cm and a median of 2 cm. The margins were involved in 12 cases (60%) and were free in 8 cases (40%). Thirteen cases of BCC were circumscribed (65%) and 7 cases (35%) were infiltrative.

Clinicopathologic Data of SCC The age of SCC patients ranged between 12 and 80 years with a mean of 48.3 years and a median of 52 years. The cases were 14 males (66.7%) and 7 females (33.3%) with a 2:1 as a male to female ratio. Ten cases were located in sunexposed sites (47.6%) (facial location) and 11 cases were in nonsun–exposed sites (52.4%) (tongue, leg, foot, and vulva). The cases varied in size, ranging between 0.5 and 11 cm with a mean of 6.4 cm and a median of 3 cm. Eight cases (38.1%) showed involved margins and 13 cases (61.9%) were of free surgical margins. Seven cases (33.3%) showed well differentiation (grade I), 12 cases (57.1%) showed moderate differentiation (grade II), and 2 cases (9.5%) showed poor differentiation (grade III). According to the size of the tumor, TNM staging system15 was applied and the cases were divided into 7 cases (33.3%) belonged to stage I and 3 cases (14.3%) belonged to stage II, whereas 7 and 4 cases belonged to stages III and IV, respectively. By lumping stages I and II, 10 cases belonged to this early stage grouping (57.1%), whereas the remaining 11 cases belonged to the advanced stage grouping (lumping stages III and IV) (42.9%).

MCM2 Expression in Normal Skin All 10 normal skin biopsies included in the current study showed positive nuclear MCM2 expression confined to the basal layer of epidermis (Fig. 1A).

MCM2 Expression in Hyperprproliferative Skin Lesions MCM2 was expressed in the 6 psoriasis cases with a percentage ranged between 10% and 30% (Fig. 1C). MCM2 was expressed in the 2 seborrheic keratosis cases with a percentage ranged between 15% and 50% (Fig. 1B). Fifty percent of keratoacanthoma cases showed MCM2 expression with a percentage ranged between 0% and 20% (Fig. 1D). There was no significant difference between the studied  2014 Lippincott Williams & Wilkins

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FIGURE 1. MCM2 expression in basal layer of normal epidermis (A), seborrheic keratosis (B), psoriasis (C), and keratoacanthoma (D) (immunohistochemical staining ·400 for A and ·200 for B, C, and D).

hyperproliferative skin lesions with regard to MCM2 expression (P . 0.0 5) (Table 1).

MCM2 Expression in BCC Sixteen cases were positive for MCM2 (80%) (Fig. 2A) with a percentage ranged between 0% and 90%, with a mean of 24.4% and a median of 7.5%. The nuclear expression usually stained the malignant basaloid nests diffusely.

MCM2 Expression in SCC Fourteen cases showed positive MCM2 (Fig. 2B) expression (66.7%) with a percentage ranged between 0% and 40%, with a mean of 9.8% and a median of 10%. The expression was localized mainly to the periphery of malignant nests.

Differences in MCM2 Expression Between Hyperproliferative Skin Lesions and Malignant Epithelial Skin Tumors (BCC and SCC)

skin lesions regarding MCM2 positivity and percentage of expression (P . 0.05) (Table 2). Although there was a significant difference between BCC and SCC regarding the percentage of MCM2 expression where mean and median values of MCM2 expression in BCC were higher than that of SCC (P = 0.004) (Table 2).

Correlation Between MCM2 Expression and the Studied Clinicopathologic Parameters in BCC and SCC Cases There was no significant association between MCM2 percentage of expression and the studied parameters in BCC. However, negative MCM2 expression was significantly associated with cases showing free surgical margin involvement (P = 0.006) (Table 3). There was no significant association between MCM2 expression (positivity and percentage) in SCC and the studied parameters.

DISCUSSION

There was no significant difference between malignant cases represented by SCC and BCC versus hyperproliferative

In our study, all normal specimens showed positive nuclear staining for MCM2 confined to the basal cell layer of

TABLE 1. MCM2 Expression in Different Types of Hyperproliferative Skin Lesions MCM2 Positivity Percentage

+ve 2ve X 6 SD Median Range

6 0

Psoriasis

Seborrheic keratosis

66.7% 0% 20 6 8.4 17.5 10–30

2 0

22.2% 0% 23.5 6 24.7 32.5% 15–50

Keratoacanthoma 1 1

11.1% 100% 10 6 14.1 10 0–20

Test of Sig 0.44*

P 0.108

1.5** 0.208

*Chi square test. **Kruskal–Wallis test.

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FIGURE 2. MCM2 expression in the all layers of malignant nests of BCC (A) and mainly in periphery in malignant SCC nests (B) (immunohistochemical staining ·400).

epidermis and this result agreed with Xiao-guang et al (2008)16 study who showed MCM2 expression in basal cell layer in 10 cases of normal skin. Furthermore, MCM5 (another member of MCM proteins) was also expressed in the nuclei of basal and suprabasal layer of epidermis according to Freeman et al. (1999)13 and Liu et al. (2007)17 studies. Absence of MCM2 expression in the superficial differentiated cells of epidermis and its confinement to the basal layer confirm its promoting proliferative role in the proliferative component of normal epidermis. Similarly, other proliferative markers such as ki-67 and PCNA were also localized to the proliferative component of normal epidermis.17–19

In contrast, Torres-Rendon et al (2009)20 found that MCM2 protein was located mainly in the suprabasal compartment in oral mucosal specimen. The latter study explained absence of MCM2 expression in a significant proportion of basal cells by assuming that these cells are in a temporary G0 state as a part of a self-defense mechanism to maintain a controlled cell proliferation of the oral mucosa. In the present study, MCM2 was upregulated in psoriatic specimens because it was expressed in 100% of them in the basal and suprabasal layers of epidermis. Similarly, Freeman et al (1999)13 and Liu et al (2007)17 have found MCM5 expression in lower epidermal layers of psoriasis, not reaching superficial layers. Therefore, psoriasis as a benign proliferative skin lesion showed MCM2 staining in the lower layers of epidermis, suggesting that the proliferating keratinocyte fraction is still limited to the basal and suprabasal layers in such disease.17 Regarding seborrheic keratosis, another hyperproliferative skin lesion, it showed MCM2 expression in the 2 specimens investigated in the current study. This agreed with Xiaoguang et al (2008) study16 who showed MCM2 expression in the 5 investigated cases of seborrheic keratosis. We agreed with Xiao-guang et al (2008)16 in absence of statistical significance between different hyperproliferative skin lesions (psoriasis, keratoacanthoma, and seborrheic keratosis) with regard to MCM2 expression. While these lesions were 4 cases of chromomycosis, 2 cases of sporotrichosis, 5 cases of seborrheic keratosis, 4 cases of verruca vulgaris, and 4 cases of cutaneous fibroma in the latter study.16 Our study could not demonstrate any significant difference between hyperproliferative skin lesions (psoriasis, seborrheic keratosis, and keratoacanthoma) and malignant cases (BCC and SCC) regarding MCM2 expression. This agreed with Liaw and Boyd (2009)21 who failed to find any differences between BCC and its mimicker (trichoepithelioma) regarding MCM2 expression. In the current study, MCM2 was expressed in 16 of 20 (80%) of BCC where the expression was seen staining the whole malignant basaloid nests. On the other hand, Liu et al (2007)17 have found MCM5-positive cells confined to the periphery of basaloid nests in BCC. This difference may be related to use of different types of MCM proteins. Our study demonstrated that MCM2 expression in BCC was associated with involved surgical margins. The malignant invasive front of any neoplasm usually carries more aggressive features than the remaining neoplasm. One of these features is acquiring more proliferative capacity. This may explain why BCC cases

TABLE 2. Comparison Between Malignant Cases and Hyperproliferative Skin Lesions Regarding MCM2 Expression MCM2 Positivity Percentage

Hyperproliferative Skin Lesions +ve 2ve X 6 SD Median Range

9 1

23.1% 8.3% 20.5 6 3.6 17.5 0–50

BCC

SCC

SCC and BCC

P1

P2

16 80% 4 20% 27 6 25.6 20 0–9

14 66.7% 7 33.3% 9.8 6 10.7 10 0–40

30 76.9% 11 91.7% 18.2 6 21.1 10 0–90

0.261*

0.33*

0.742†

0.004†

P1 compare hyperproliferative skin lesions versus malignant cases; P2 compare between SCC and BCC. *Fisher exact test. †Mann–Whitney test.

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TABLE 3. The Association Between MCM2 Expression and the Clinicopathologic Features in BCC P

Test of Sig. Age/y

Sex Male Female Size/cm

Margins +ve 2ve Type Circumscribed Infiltrative

2ve (4) 58.5 6 13.6 57 45–75

+ve (16) 62 6 14.2 66 29–80 8 8

88.9% 72.7% 1.9 6 0.9 2 0–4

1 3

11.1% 27.3% 1.3 6 1.5 1 0–3

61.3 6 16.8 29–80 65 9 11

45% 55% 1.8 6 1.1 0–4 2

+ve (16) 0.443†

2ve (4) 0.663

0.8081*

0.369

1.176†

0.255

4 0

50% 0%

4 12

50% 0%

8 12

40% 60%

7.5*

0.006S

11 5

84.6% 71.4%

2 2

15.4% 28.6%

13 7

65% 35%

0.495*

0.482

S, significant. *Fisher exact test. †Mann–Whitney test.

with positive surgical margins showed more MCM2 expression than negative one. However, the involvement of surgical margins may be due to incomplete excision because of cosmetic considerations, lack of enough skin, large lesions, repair by grafting, and surgeon’s experience rather than true behavior of the neoplasm.22 In contrast to most other carcinomas, BCC of the skin is characterized by a relatively high percentage of proliferating active tumor cells.23 Mean BCC growth fraction detected immunohistochemically by antibodies against Ki-67 antigen ranged between 20% and 41%.24–31 It is worth noting, however, some of the most serious and aggressive human malignances, such as glioblastoma multiforme, malignant melanoma, or soft tissue sarcomas display a mean Ki-67 expression about 25%,32 27%,33 and 18%,34 respectively. Thus, a proliferative activity of cutaneous BCCs in general reaches or even exceeds the prognostically most serious cancers. This observation raises the possibility that it may have partly different impact on evolution and biologic behavior of this neoplasia. The fact that BCC of the skin shows relatively high percentage of proliferating cells deserves a special attention. It is not in line with the clinical finding that it is usually a slowgrowing and indolent neoplasia with minimal metastatic potential.23 Our study demonstrated MCM2 expression in 14 of 21(66.7%) of cutaneous SCC cases compared with 81.16% of oral squamous cell carcinoma according to Torres-Randon et al (2009).20 In the current study, MCM2 was expressed mainly in the periphery of malignant SCC nests while the central cores of the malignant nests were mostly negative for MCM2. This pattern of expression agreed with Torres-Randon et al (2009),20 who did not find significant correlation between MCM2 expression and the grade of oral SCC. Although other studies demonstrated the association between MCM2 expression and the grade in oral SCC35 and cutaneous SCC.13 The confined nuclear  2014 Lippincott Williams & Wilkins

expression of MCM2 to the periphery of the malignant SCC nests may refer to its expression in the undifferentiated cells. This may indicate that MCM2 protein undergoes gradual loss in differentiated cells. The association between MCM2 expression and higher tumor grades might be explained by the fact that in cancer, differentiated neoplastic cells tend to grow and spread at a slower rate than undifferentiated or poorly differentiated cells, which lack the structure and function of normal cells and grow uncontrollably.36 Therefore, the withdrawal of cells from the cell cycle into differentiated state is coupled with downregulation of MCM2 expression.37 However, these findings are in contrast of those of Ahn and Chan (2010)38 who noted no significant relationship between MCM7 expression and the histological grade of esophageal SCC. In our study, there was significant difference between BCC and SCC regarding the percentage of MCM2 expression where mean and median values of MCM2 expression in BCC were higher than that of SCC (P = 0.004). This may agree with the Egyptian study performed on BCC, verrocus, and nasopharyngeal (NPC) carcinomas in which the authors found that nodular BCC and undifferentiated nonkeratinizing NPC showed the most intense telomerase immunopositivity followed by well-differentiated type of NPC.39 Most of the investigated SCC cases of the present study showed well to moderate differentiation and only 2 cases were of poorly differentiated category. Agreeing with the same concept telomerase activity was lower in cutaneous SCC than BCC.40 Acquiring telomerase activity in any neoplasm helps to maintain continuous tumor growth and proliferation. But in another study done by al-Sader et al (1996)24 to compare proliferative index between SCC and BCC, they found no significant differences between the mitotic indexes and apoptotic indexes in these tumors. There was, however, a significant difference in Ki-67 staining, with greater staining in the SCCs.24 www.amjdermatopathology.com |

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MCM2 was reported to be upregulated in different cancers such as ovarian,41 prostate,42 urothelial,43 and renal carcinomas.44 In summary, MCM2 is a proliferation marker manifested by its expression in proliferative compartment of normal skin and its upregulation in proliferative skin lesions and malignant tumors. Proliferative capacity of BCC may be higher than SCC and this does not necessarily reflect aggressive behavior. REFERENCES 1. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146:283–287. 2. Mokhtar N, Gouda I, Adel I. Cancer Pathology Regestry (2003-2004): and time trend analysis. In: Mokhtar N, Gouda I, Adel I, eds. Malignant Skin Tumors. Cairo, Egypt: Elsheraa Press; 2007; Chapter 9:83–86. 3. Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA. 2005;294:681–690. 4. Bale AE, Yu KP. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet. 2001;10:757–762. 5. Yang J, Ramnath N, Moysich KB, et al. Prognostic significance of MCM2, Ki-67 and gelsolin in non-small lung cancer. BMC Cancer. 2006;6:203. 6. Tye BK. MCM proteins in DNA replication. Ann Rev Biochem. 1999;68: 649–686. 7. Labib K, Tercero JA, Diffley JF. Uninterrupted MCM2-7 function required for DNA replication fork progression. Science. 2000;288:1643–1647. 8. Sclafani RA, Holzen TM. Cell cycle regulation of DNA replication. Ann Rev Genet. 2007;41:237–280. 9. Madine MA, Swietlik M, Pelizon C, et al. The roles of the MCM, ORC and Cdc6 proteins in determining the replication competence of chromatin in quiescent cells. J Struct Biol. 2000;129:198–210. 10. Forsburg S. Eukaryotic MCM proteins: beyond replication initiation. Microbiol Mol Biol Rev. 2004;68:109–131. 11. Going JJ, Keith WN, Neilson L, et al. Aberrant expression of minichromosome maintenance proteins 2 and 5, and Ki-67 in dysplastic squamous oesophageal epithelium and Barret’s mucosa. Gut. 2002;50:373–377. 12. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311–322. 13. Freeman A, Morris LS, Mills AD, et al. Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res. 1999;5:2121–2132. 14. Alison MR, Hunt T, Forbes SJ. Minichromosome maintenance (MCM) proteins may be pre-cancer markers. Gut. 2002;50:290–291. 15. Sobin LH, Wittekind C, eds. TNM Classification of Malignant Tumor. International union against caner (UICC). 6th ed. New York, NY: Wiley-Liss; 2002. 16. Xiao-guang Z, Yan-ling L, Sheng W, et al. Expression of minichromosome maintenance 2 protein in normal skin as well as lesions of malignant hyperplasia and non-malignant hyperplasia. Chinese J Dermatol. 2008; 10:663–665. 17. Liu H, Takeuchi S, Moroi Y, et al. Expression of minichromosome maintenance 5 protein in proliferative and malignant skin diseases. Int J Dermatol. 2007;46:1171–1176. 18. Heenen M, Thiriar S, Noel JC. Ki-67 immunostaining of normal human epidermis: comparison with 3Hthymidine labelling and PCNA immunostaining. Dermatology. 1998;197:123–126. 19. Feng CJ, Li HJ, Li JN, et al. Expression of Mcm7 and Cdc6 in oral squamous cell carcinoma and precancerous lesions. Anticancer Res. 2008;28:3763–3769. 20. Torres-Rendon A, Roy S, Craig GT, et al. Expression of Mcm2, geminin and Ki67 in normal oral mucosa, oral epithelial dysplasias and their corresponding squamous-cell carcinomas. Br J Cancer. 2009;100:1128–1134. 21. Liaw K, Boyd AS. MCM2 expression in basal cell carcinomas and trichoepitheliomas. J Cutan Pathol. 2009;36:1121–1122.

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22. Shanehsaz SM, Ishkhanian S. Incomplete excision of basal cell carcinoma: incidence and demographic evaluation among 30 Syrian case series. Egypt Dermatol Online J. 2013;9:1–8. 23. Tilli CM, Van Steensel MA, Krekels GA, et al. Molecular aetiology and pathogenesis of basal cell carcinoma. Br J Dermatol. 2005;152:1108–1124. 24. al-Sader MH, Doyle E, Kay EW, et al. Proliferation indexes—a comparison between cutaneous basal and squamous cell carcinomas. J Clin Pathol. 1996;49:549–551. 25. Matsuta M, Kimura S, Koseqawa G, et al. Immunohistochemical detection of Ki-67 in epithelial skin tumors in formalin-fixed paraffin-embedded tissue sections using a new monoclonal antibody (MIB-1). J Dermatol. 1996;23:147–152. 26. Horlock NM, Wilson GD, Dalye FM, et al. Cellular proliferation characteristics of basal cell carcinoma: relationship to clinical subtype and histopathology. Eur J Surg Oncol. 1997;23:247–252. 27. Tilli CM, Stavast-Koey AJ, Ramaekers FC, et al. Bax expression and growth behavior of basal cell carcinomas. J Cutan Pathol. 2002;29:79–87. 28. Mazzarelli P, Rabitti C, Parrella P, et al. Differential modulation of Ku70/80 DNA-binding activity in a patient with multiple basal cell carcinomas. J Invest Dermatol. 2003;121:628–633. 29. Ionescu DN, Arida M, Jukic DM. Metastatic basal cell carcinoma. Four cases report, review of literature, and immunohistochemical evaluation. Arch Pathol Lab Med. 2006;130:45–51. 30. Crowson AN. Basal cell carcinoma: biology, morphology and clinical implications. Mod Pathol. 2006;19(suppl 2):S127–S147. 31. Bartos V, Adamicová K, Kullová M, et al. Basal cell carcinoma of the skin—biological behaviour of the tumor and a review of the most important molecular predictors of disease progression in pathological practice. Klin Onkol. 2011;24:8–17. 32. Mahvash M, Hugo HH, Maslehaty H, et al. Glioblastoma multiforme in children: report of 13 cases and review of the literature. Pediatr Neurol. 2011;45:178–180. 33. Nasr MR, El-Zammar O. Comparison of pHH3, Ki-67, and survivin immunoreactivity in benign and malignant melanocytic lesions. Am J Dermatopathol. 2008;30:117–122. 34. Kazanowska B, Reich A, Jelen M, et al. Ki-67 expression in soft tissue sarcomas in children. Nowotwory J Oncol. 2004;54:347–353. 35. Kodani I, Osaki M, Shomori K, et al. Minichromosome maintenance 2 is correlated with mode of invasion and prognosis in oral squamous carcinoma. J Oral Pathol Med. 2003;32:468–474. 36. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;17:342–348. 37. Shetty A, Loddo M, Fanshawe T, et al. DNA replication licensing and cell cycle kinetics of normal and neoplastic breast. Br J Cancer. 2005;93: 1295–1300. 38. Ahn JH, Chan HK. Expression of minichromosome maintenance protein 7 and Smad 4 in squamous cell carcinoma of the esophagus. Korean J Pathol. 2010;44:346–353. 39. El-Sheikh SM, Riad SE. Biological behavior of verrocus, basal and nasopharyngeal carcinoma: telomerase activity as a potential marker. Egypt Dent Assoc J. 2011;3.2:2057. 40. Parris CN, Jezzard S, Silver A, et al. Telomerase activity in melanoma and non-melanoma skin cancer. Br J Cancer. 1999;79:47–53. 41. Gakiopoulou H, Korkolopoulou P, Levidou G, et al. Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications. Br J Cancer. 2007;97:1124–1134. 42. Meng MV, Grossfeld GD, Williams GH, et al. Minichromosome maintenance protein 2 expression in prostate: characterizationand association with outcome after therapy for cancer. Clin Cancer Res. 2001;7:2712–2718. 43. Korkolopoulou P, Givalos N, Saetta A, et al. Minichromosome maintenance proteins 2 and 5 expression in muscle-invasive urothelial cancer: A multivariate survival study including proliferation markers and cell cycle regulators. Hum Pathol. 2005;36:899–907. 44. Rodins K, Cheale M, Coleman N, et al. Minichromosome maintenance protein 2 expression in normal kidney and renal cell carcinomas: relationship to tumor dormancy and potential clinical utility. Clin Cancer Res. 2002;8:1075–1108.

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Immunohistochemical expression of MCM2 in nonmelanoma epithelial skin cancers.

Cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) represent 45.5% and 37.02%, respectively, of total malignant skin cancer accord...
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