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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 16  |  Issue : 2  |  Page : 148-155

Clinicopathological and immunohistochemical study of recurrent basal cell carcinoma in Egyptian patients


1 Department of Dermatology for Girls, Al-Azhar University, Cairo, Egypt
2 Department of Dermatology, Al-Azhar University, Cairo, Egypt

Date of Submission06-Sep-2018
Date of Acceptance08-Oct-2018
Date of Web Publication27-Feb-2019

Correspondence Address:
Mohamed El-Khalawany
Department of Dermatology, Al-Azhar University, PO Box: 19511, Madenaty, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_94_18

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  Abstract 

Background Although recurrence of basal cell carcinoma (BCC) is uncommon, it may pose a prognostic problem that cannot be fully predicted.
Aim The aim was to assess the clinical, histologic, and immunohistochemical features of recurrent BCC among Egyptian patients.
Materials and methods A retrospective study that included 18 patients who had recurrent BCC during the period from 2010 to 2015 was carried out. Clinical data and histological features were analyzed, and an immunohistochemical study was carried out for primary and recurrent lesions.
Results The study included 11 (61.1%) women and seven (38.9%) men with a mean age of 53±8.3 years. Most of the lesions were located on the scalp (33.3%) and cheeks (27.8%). The mean duration of the lesions was 4.1±1.7 years and the mean size of the lesions was 10.6±3.4 mm. Recurrence time ranged from 13 to 47 months, with a mean of 25.3±9.9 months. Out of 18 cases, only three (16.7%) were surgically excised, whereas 15 (83.3%) were treated by nonsurgical methods. Histological examination of recurrent lesions showed a change in histological type in 38.9%, whereas in 61.1% of cases, it was similar to the primary lesion. Immunostaining showed significant changes with Ki-67, whereas other markers (p53, bcl-2, CD10, and CD34) showed no significant differences between primary and recurrent lesions.
Conclusions Our results proposed an increased risk of BCC recurrence after nonsurgical treatment and still surgical treatment is the best therapeutic method associated with low recurrence rates. We believe that increased awareness of clinical, histological, and molecular risk factors help in minimizing recurrence of BCC.

Keywords: angiogenesis, basal cell carcinoma, CD34, Ki-67, recurrence


How to cite this article:
Sultan M, Mohamed I, Fawzy S, El-Khalawany M. Clinicopathological and immunohistochemical study of recurrent basal cell carcinoma in Egyptian patients. Al-Azhar Assiut Med J 2018;16:148-55

How to cite this URL:
Sultan M, Mohamed I, Fawzy S, El-Khalawany M. Clinicopathological and immunohistochemical study of recurrent basal cell carcinoma in Egyptian patients. Al-Azhar Assiut Med J [serial online] 2018 [cited 2020 Jul 6];16:148-55. Available from: http://www.azmj.eg.net/text.asp?2018/16/2/148/253096


  Introduction Top


Basal cell carcinoma (BCC) is the most common malignant neoplasm in humans, and it represents up to 80% of skin malignancy. The annual incidence of BCC is increasing worldwide, with more predilection of phenotypically lighter-skinned population [1]. The incidence of BCC increases with age and it occurs more often in the elderly population between 50 and 80 years of age, whereas it is rarely encountered in childhood or youth [2].

The most important constitutional risk factors for the development of BCC include light photo-types (I and II by Fitzpatrick classification); a positive family history of BCC (30–60%); freckles in childhood; and light skin, eyes, or hair. It was reported that fair-skinned individuals are likely to develop BCC more than those with dark skin, even when they live in the same region [3]. Lesions of BCC may range in size from a few millimeters to several centimeters. The common clinical subtypes of BCC include nodular-ulcerative, pigmented, fibrosing, and superficial [4].

The main histologic hallmark of BCC is the presence of basaloid masses, peripherally arranged in palisade, and has a gap between the stroma and the tumor parenchyma. The most common histologic variants include the macronodular form, superficial type, fibroepithelioma of Pinkus, sclerodermiform (morpheic), infiltrative, and metatypical (basosquamous) BCC [5]. The macronodular, superficial, pigmented, and cystic variants are considered non-aggressive with less infiltrative behavior. The morpheic, infiltrative, and micronodular variants are considered to have infiltrative growth, with more aggressive clinical behavior and increased risk of recurrence [6].

Recurrence of BCC may pose a prognostic problem and to date, all of the traditional diagnostic criteria have failed to definitively predict which BCC patients should be considered at high risk of recurrence. Moreover, limited demographic, clinical, and histological predictors for BCC recurrence have been identified [7]. In this study, we assessed the clinical characteristics, histological features, and immunohistochemical profile of recurrent BCC aiming to identify the possible risk factors for recurrence of BCC in the Egyptian population.


  Materials and methods Top


During the period from 2010 to 2015, eighteen patients with recurrent BCC were recruited from the Departments of Dermatology, Al-Azhar University hospitals, Cairo, Egypt. The study was approved by the local ethical committee and institutional review board. Informed consent was obtained from some patients for medical photography. Clinical data were recorded including sex and age at time of the diagnosis in addition to the duration, size, morphology, and location of the lesion. Treatment method of the primary lesion was recorded and all lesions were proven to have a complete clinical improvement after treatment. Recurrence time was estimated for each case. Histopathologic examination and immunohistochemistry for Ki-67, p53, bcl-2, CD10, and CD34 were performed.

The specimens of primary lesions were retrieved and histological subtyping as well as immunohistochemical staining were performed and compared with those of recurrent lesions. Histologic subtyping was performed according to the classification mentioned by Weedon as follows: the nodular (solid) type is composed of islands of cells with peripheral palisading and a haphazard arrangement of the more central cells. The micronodular type resembles the solid type, but the nests are much smaller and the peripheral palisading is not always as well developed. The superficial (multifocal) type is composed of multiple small islands of basaloid cells attached to the undersurface of the epidermis, and usually confined to the papillary dermis. The infiltrating type shows elongated strands of basaloid cells, 4–8 cells thick, infiltrating between collagen bundles. The metatypical type is composed of nests and strands of cells maturing into larger and paler cells with common loss of peripheral palisading [8].

Immunohistochemical staining was performed using the avidin–biotin complex method on formalin-fixed, paraffin-embedded tissue sections [9]. Briefly, tissue sections were mounted on 3-aminopropyl-triethoxysilane-coated slides and dried overnight at room temperature. Subsequently, they were dewaxed in xylene and rehydrated in graded alcohol. After rinsing with phosphate-buffered saline, they were immersed in 0.01 mol/l citric acid titrated to pH 6.0 and heated twice for 10 min in a microwave oven. The primary antibodies were then incubated on the sections for 30 min. Diaminobenzidine was used as a chromagen, and the slides were counterstained with Mayer’s hematoxylin. The primary antibodies included Ki-67, p53, bcl-2, CD10, and CD34 (monoclonal mouse antihuman, dilution 1 : 100; Dako, Glostrup, Denmark).

Cytoplasmic positivity for bcl-2 and CD10 and nuclear positivity for Ki-67 and p53 were evaluated. For each case, six fields (×400) with the highest density of stained cells were selected and the percentage of positive cells was scored in relation to the total tumor cell population: 0 (≤10% positive cells), 1+ (11–25%), 2+ (26–50%), 3+ (>50% positive cells). Positive labeling encompassed 2+ and 3+. Microvessels were defined as any brown-stained endothelial cells or cell clusters clearly separated from adjacent microvessels, tumor cells, and other connective tissue elements. Each group of stained endothelial cells or cell clusters was counted as one microvessel. In each case, on a ×200 field, three areas showing the highest vascularization were selected, and the microvessel count was defined as the average of these three counts.

The SPSS software version 13 was used for statistical analysis (SPSS Inc., Chicago, Illinois, USA). The statistical significance of the results was analyzed using the chi-square test for nominal variables and Student’s t-test for ordinal variables. A level of P less than 0.05 was considered significant.


  Results Top


The study included 11 (61.1%) women and seven (38.9%) men, with a male to female ratio of 0.63. The age of the patients ranged from 39 to 70 years, with a mean of 53±8.3 years. The lesions were mostly located on the scalp (33.3%) and cheeks (27.8%). Three lesions (16.7%) were located on the nose, two (11.1%) lesions on the infraorbital region, and one (5.5%) lesion on the ear and neck ([Figure 1]). The duration of the lesions ranged from 1 to 7 years, with a mean of 4.1±1.7 years. The size of lesions ranged from 6 to 17 mm, with a mean of 10.6±3.4 mm. Recurrence time ranged from 13 to 47 months, with a mean of 25.3±9.9 months.
Figure 1 Clinical variants of recurrent basal cell carcinoma in the infraorbital area (a), nose(b), cheek (c), and scalp (d).

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Histological assessment of primary lesions showed the nodular type in 38.9%, superficial in 16.7%, infiltrative in 22.2%, micronodular in 11.1%, and morpheic in 11.1% ([Figure 2]). Out of 18 cases, only three (16.7%) were surgically excised, whereas 15 (83.3%) cases were treated by nonsurgical methods. Histological examination of recurrent lesions showed a change in histological type in 38.9%, whereas in 61.1% of cases, the histologic type was the same as the primary lesion.
Figure 2 Common histologic variants of recurrent basal cell carcinoma including nodular (a, HE ×20), infiltrative (b, HE ×200), superficial (c, HE ×100), and micronodular (d, HE ×400). HE, hematoxylin and eosin.

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In primary lesions, aggressive types (n=8) constituted 44.4%, whereas in recurrent lesions, they constituted 33.3%. Among all the primary lesions, only one (5.5%) case showed transformation from a nonaggressive form into an aggressive type after treatment with topical 5-Fluorouracil, whereas two (11.1%) aggressive types showed transformation into nonaggressive types ([Table 1]).
Table 1 Clinical and histologic characteristics of 18 patients with recurrent basal cell carcinoma

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Immunohistochemical staining showed positive labeling (2+ and 3+) in primary lesions for Ki-67, p53, bcl-2, and CD10 in eight (44.4%), eight (44.4%), seven (38.9%), and one (5.6%) cases, respectively. In recurrent tumors, Ki-67, p53, bcl-2, and CD10 were found in 15 (83.3%), 10 (55.6%), six (33.3%), and two (11.1%) cases, respectively ([Figure 3]). The average microvessel counts as determined by CD34 for the primary and recurrent tumors were 20.4±3.9 (range: 16–23) and 22.2±4.2 (range: 18–25), respectively. Significant changes (P<0.05) were only observed with Ki-67, whereas other markers showed no significant differences between primary and recurrent lesions ([Table 2]).
Figure 3 Immunohistochemical reactivity of recurrent basal cell carcinoma with strong positive immunostain for Ki-67 (a, ×100), strong focal immunostain for p53 (b, ×200), strong peripheral immunostain for bcl-2 (c, ×200), and weak peripheral immunostain for CD10 (d, ×400).

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Table 2 Comparison between immunohistochemical staining of primary and recurrent basal cell carcinoma

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  Discussion Top


BCC is mostly a locally malignant skin tumor that rarely metastasizes or shows recurrence. In some instances, BCC recurrences may represent a major therapeutic problem. Although there are several risk factors that could predict the increased incidence of BCC recurrence, none of them can be assessed individually and overall assessment should be considered in all cases. Clinically, it was suggested that male sex, topographic localization in the central region of the face, the increased tumor size, sun-sensitive skin, and older age group are the most important risk factors that increase the liability for BCC recurrence [10]. Relapsing may clinically manifest as areas of erythema, induration, ulceration, or bleeding at a previous site of BCC [11].

The average time of BCC recurrence after surgical excision was estimated in most cases by 3 years, but in ∼20% of cases, recurrence occurs between 6 and 10 years [12]. In our study, the average duration of recurrence was 2 years, which was shorter than that reported in most previous reports. The main explanation for this short duration could be the different therapeutic modalities. In previous reports, the duration was estimated after surgical treatment while in this study, the majority of cases were treated by nonsurgical methods. The estimation of the recurrence rate after nonsurgical methods was reported rarely in the literature and we believe that this study may prove the superiority of surgical management over nonsurgical methods in decreasing the incidence of BCC recurrence.

The location of BCC is an important clinical risk factor in recurrence. Most of the cases arise on high-risk areas of the body such as the nose, paranasal regions, ears, chin, mandibular area, perioral, and periocular region, and are associated with high recurrence rates and worse prognosis. Also, in intermediate-risk areas, such as the scalp, forehead, malar areas, preauricular, and postauricular areas, the prognosis of BCC may also be worse [13]. This could be because of the difficulty of complete excision of the lesion partly caused by extensive subclinical spread of the tumor [14]. In this study, all lesions were located in these risk areas, with predominance of scalp lesions. It is believed that the presence of hair follicles makes the tumor less amenable to complete excision, thus increasing the likelihood for recurrence [15]. We also observed that most of the scalp lesions recurred after nonsurgical treatment and this may indicate that Mohs micrographic surgery is the best treatment modality for such lesions if possible [11]. Conversely, relapses become much less frequent on the low-risk anatomical areas (neck, trunk, and extremities) of the body. These data are in agreement with our results, which showed 94% of cases on the head and only one case on the neck that recurred after CO2 laser therapy.

The size of BCC is important in the assessment of the treatment method. It is generally accepted that large-sized lesions are more difficult to remove and it could be associated with a higher risk of recurrence. It has been reported that large-sized tumors (>2 cm) have a twofold or threefold increased relapse rate than small-sized tumors (<2 cm) [16]. However, the evaluation of this relationship is usually restricted for clinical practice because of the major difficulty in removal and staging assessment of large lesions. Our results suggested that nonsurgical methods, even for small-sized BCC in anatomical risk areas, are associated with a high relapse rate. However, the absence of full data on the total number of cases registered during the same period and the outcome of surgical and nonsurgical method is one of the limitations, which does not enable a better evaluation of the relationship between the size of the lesion and the relapse rate.

The correlation between histological types and recurrence rate is more evident with aggressive variants, with a higher incidence in infiltrative types (≥27%), and less commonly the nodular (≥8%) type, whereas superficial types showed variable results, ranging from 3 to 26% [12],[17]. Therefore, no definitive correlation could be established between the BCC subtype and recurrence, and the histopathological criteria for prognosis are limited. Moreover, a better understanding of the pathogenesis and histological evolution of BCC recurrence is required for determination of the histomorphological changes between primary and recurrent lesions. Microscopic evaluation of relapsing BCC is very difficult for the pathologist because the tumor structure is significantly modified by scar formation and overproduction of fibrous tissue, which alters the original morphology as well as the nature of tissue infiltration [11].

In our study, it was observed that histomorphological changes accounted for up to 39%. However, the changes from the nonaggressive to the aggressive type were only recorded in one (5.5%) case. The incidence of histomorphological changes between primary and recurrent lesions was variable in the literature, with an overall increase in our study. Boulinguez et al. [18] reported that 24% recurrent BCC became histologically more aggressive. In an earlier study, it was reported that 65% of all primary tumors were aggressive and in recurrent lesions, 13.7% became more indolent, whereas 23.5% developed more aggressive features [19]. These results prove that primary and recurrent lesions may not always manifest the same histomorphology, and can also show different biological behavior and clinical outcomes [11].

The immunohistochemical profile of our cases showed a significant difference in the proliferative activity of tumor cells, estimated by the Ki-67 marker, whereas other markers indicating angiogenesis (CD34), tumor suppressor gene (p53), antiapoptosis or oncogenesis (bcl-2), and others (CD10) showed nonsignificant differences between primary and recurrent tumors. These results suggested the significant role of the proliferative activity of the tumor cells in the other pathogenic mechanisms in relation to recurrence.

However, in other previous studies, variable results were obtained as reported by Yerebakan et al. [20], who found that the expression of Ki-67 and CD31 was significantly higher in recurrent (i.e. more aggressive) tumors compared with primary tumors. Conversely, Ionesco et al. [21] reported that the expressions of the antigens Ki-67, p53, and bcl-2 showed no significant differences between aggressive (metastatic) BCC tumors and BCC with a benign course.

In agreement with our study, Healy et al. [22] also reported a significant difference in Ki-67 expression between primary and relapsed BCC, whereas p53 showed similar expressions in both groups. These results, in addition to those of other studies [23],[24], suggest the significant role of cellular proliferation in BCC, and its significant pathogenic role in BCC recurrence.

Currently, surgical treatment is considered the most optimal therapy for BCC and it shows a low recurrence rate (2–5%) when complete excision is achieved [25]. In this study, there was a predominance of BCC recurrences after nonsurgical treatment. The overall assessment of surgical treatment for BCC is still controversial. It is well known that Mohs surgery is the best treatment for BCC, especially in high-risk areas and aggressive variants [26].

The main drawback of conventional surgery is the risk of reactivation of tumor cells at the margins of the lesion, whereas in nonsurgical methods, the presence of residual tumor cells may lead to an increased risk of spontaneous relapse of the tumor.


  Conclusion Top


Our results proposed an increased risk of BCC recurrence after nonsurgical treatment and still surgical treatment is the best method associated with the low recurrence rate of BCC. We recommend that careful monitoring, especially after nonsurgical treatment, be performed as early as possible without much consideration of the histologic type.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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