Macrophage subtypes in recurrent nodular basal cell carcinoma after Mohs micrographic surgery Emerson H. Padoveze1, MD, PhD, Nilton Di Chiacchio2, MD, PhD, Jorge Ocampo-Garza3,4, 2 5 6 MD, Selma S. Cernea , MD, Walter Belda , MD, PhD, and Mirian N. Sotto , MD, PhD

1 Department of the Sao Paulo Municipal Public Server Hospital, Department of ~o Paulo Dermatology, University of Sa ~o Paulo, Brazil, Medical School, Sa 2 Department of the Sao Paulo Municipal Public Server Hospital, Hospital do servidor ~o Paulo, Brazil, Publico Municipal, Sa 3 Dermatology Department, University  Eleuterio Gonza lez”, Hospital “Dr. Jose noma de Nuevo Leo n, Universidad Auto xico, 4Dermatology Monterrey, Me Department, Faculty of Medicine of ABC, ~o Paulo, Brazil, 5Department of Sa ~o Paulo Dermatology, University of Sa ~o Paulo, Brazil, and Medical School, Sa 6 Departments of Pathology and ~o Paulo Dermatology, University of Sa ~o Paulo, Brazil Medical School, Sa


Correspondence Emerson H. Padoveze, MD Department of the Sao Paulo Municipal Public Server Hospital Department of Dermatology ~o Paulo Medical School University of Sa MMDC street, 50. Ap. 141 Cambui-Campinas ~o Paulo Sa Brazil E-mail: [email protected]

average percentage of M1 cells, M2 cells, and total cells.

Background The macrophages associated with solid tumors are related to the progression or regression of tumors, depending on the differentiation in M1 or M2. M2 subtype promotes angiogenesis, remodeling, and tissue repair (tumor proliferation). In contrast, M1 produces toxic mediators and presents antigens, destroying microorganisms and tumor cells. The microenvironment of most aggressive forms of basal cell carcinoma (BCC) shows an increase in macrophages due to M2 phenotype compared to noninvasive forms. The treatment of nodular BCC by Mohs micrographic surgery (MMS) provides high cure rates, but relapses can occur. Aims To compare the total population of macrophages and their subpopulations M1 and M2 in cases of recurrent and nonrecurrent nodular BCC after excision by MMS. Materials & Methods Histological sections obtained from paraffin blocks of nine cases of recurrent nodular BCC after MMS and 18 cases of nonrecurrent nodular BCC operated by MMS were immunostained for iNOS, CD204, CD163, and CD68. The expression of these markers was analyzed by image analysis. Results No significant differences were found between the groups in relation to the Discussion and Conclusion A relationship was not seen between tumor-associated macrophages (TAM) and tumor recurrence.

Funding: This work was funded by FUNADERSP Conflict of interest: The authors have no conflicts of interest to declare. The trial was approved by the Medical Ethics and Scientific Committee of the Sao Paulo Municipal Public Server Hospital, Brazil. Number: 12960713.8000.5442 doi: 10.1111/ijd.13790


Among all BCC types, nodular BCC is the most common histological subtype.2 It is clinically characterized by a slow

Basal cell carcinoma (BCC) is the most common type of skin cancer (80%), followed by squamous cell carcinoma (15%) and,

growth which results in high cure rates and low recurrence

more rarely, melanoma (4%).1,2

tumor nests of various sizes surrounded by dense stroma with

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rates. Histopathology shows solid, well-bordered, lobulated

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Macrophage subtypes in basal cell carcinoma

Padoveze et al.

numerous fibroblasts and mucinous material, mostly hyaluronic acid.1

populations based on tumor size and tumor progression time. The knowledge of these factors is extremely important because

Mohs micrographic surgery (MMS) has become an excellent

it gives us information about the immunological behavior of the

therapeutic method for nonmelanoma skin cancers.3 Although

tumor that may allow in the future identifying possible prognos-

MMS allows for the analysis of all margins, relapses may

tic markers or new therapeutics options.

occur.3 Factors such as the presence of dense inflammatory infiltration and cancer cell invasion in the perineural tissue may hinder the visualization of tumor cells on the histologic frozen

Materials and methods

sections, resulting in higher therapeutic failure rates.4 In addition, it has been observed that BCC progression depends on

We analyzed all of the patients who were treated with MMS at our hospital between January 1996 and December 2007, and

the host’s immune response and the tumor’s inflammatory infil-

presented with relapsed BCC. We analyzed the patients’ age


and gender, tumor characteristics (i.e., anatomic location, size,

A significant number of solid tumors consist of noncancer

and progression time of the disease), number of Mohs stages

cells, including stromal cells (fibroblasts and endothelial cells)

required for tumor extirpation, time to relapse, and M1 and M2

and leukocytes, particularly macrophages. In the past, tumor-

macrophage levels.

associated macrophages (TAMs) were thought to be related to

During the 11-year study period, a total of 500 MMS

the host’s response to the tumor growth; however, several studies have demonstrated that macrophages only have the poten-

procedures were performed for BCC. Surgeries were performed by several dermatologic surgeons, however the slides from

tial to destroy tumors when they are properly stimulated.6–8

each case were evaluated by a single micrographic surgeon.

Macrophages are classified into two types: M1 and M2.9 The

Twenty-three cases presented with relapse, of which 11 were

exposure of monocytes to microbial products (lipopolysaccha-

nodular and 12 were superficial, morpheaform, or micronodular

ride [LPS]) or interferon-y (IFN-c) leads to M1 polarization. Clas-

(Table 1).

sical macrophage activation (i.e., M1 macrophage activation) is characterized by the ability to present antigens, the increased production of interleukin-12 (IL-12) and IL-23, and the high production of toxic mediators (e.g., nitric oxide [NO] and reactive

Table 1 Tumor recurrences after Mohs micrographic surgery between 1996 and 2007

oxygen intermediates [ROI]). The production of such substances enables M1 macrophages to have a high potential for destroying microorganisms and tumor cells.9,10 In contrast, M2 macrophages promote angiogenesis, remove debris, and remodel and repair tissue. Monocyte differentiation into M2 macrophages is stimulated by macrophage colony-stimulating factor (M-CSF), IL-4, IL-13, IL-10, immune-complex TLR/IL-1R, and glucocorticoids.10,11 In tumors, TAMs generally acquire the M2 phenotype, which plays an important role in many aspects of tumor growth and progression.12 The association of TAM with breast cancer,13 intestinal cancer,14 and melanoma15,16 has been extensively





1 2 3 4

59 71 7 62


5 6 7 8

52 48 74 82


9 10

75 66





12 13 14 15

71 63 79 66


16 17 18 19

64 60 71 64


Nose Temple Canthus Nose Nose Malar Malar Temple Lower eyelid Nose Nose Upper lip Nose Lower eyelid Nose Canthus Upper lip Nose Nose Ear Nose Malar Canthus

studied; however, studies evaluating the presence of the M2 phenotype in BCC are rare.7 Furthermore, no studies have evaluated the presence of these cells in recurrent tumors following the MMS technique. Tiju et al.5 found that the number of TAMs infiltrating the tumor was correlated with the depth of invasion, microvessel density, and cyclooxygenase-2 (COX-2) expression in human BCC cells. They also found that compared to noninvasive BCC, aggressive forms of BCC showed an increase in macrophages.5 Based on the difference in the macrophage populations between the histological subtypes of BCC, only solid tumors were selected, and a study comparing the populations of M2 and M1 macrophages in recurrent solid BCCs after MMS, ver-

Time of appearance of recurrences (months)

Histologic subtype

34 39 44 23 18 26 13 72 47

Nodular Nodular Superficial Nodular Micronodular Nodular Morpheaform Micronodular Nodular

9 13 20 15 26

Micronodular Morpheaform Nodular Nodular Nodular

30 44 18 10 14 24 7 17 84

Nodular Superficial Nodular Morpheaform Morpheaform Nodular Morpheaform Micronodular Morpheaform

sus nonrecurrent cases, was proposed. Additionally, the purpose was to evaluate the differences in the macrophage International Journal of Dermatology 2017

M, male; F, female ª 2017 The International Society of Dermatology

Padoveze et al.

Macrophage subtypes in basal cell carcinoma

Two nodular BCC cases were excluded from the study because of the poor conditions of their conserved paraffin blocks; nine cases remained.


quadrants, and the zones of inflammatory infiltrate were randomly selected around the nests of basaloid cells. M1 macrophages were identified by the expression of

With these data, the study was divided into two groups: (i)

inducible nitric oxide synthase (iNOS; diluted 1 : 1000, 482728,

the study group, which comprised nine recurrent nodular BCC

Merck Millipore), and M2 macrophages were identified by using

cases that occurred between 1996 and 2007; and (ii) the

the CD163 (diluted 1 : 150, clone 10D6, Leica Microsystems)

control group which comprised 18 relapse-free nodular BCC

and CD204 (diluted 1 : 200, SRA-E5, TransGenic) markers.7,13

cases who were randomly selected out of all of the Mohs

The total macrophage population was identified through using

surgeries performed within the same period (Table 2). We only selected cases of nodular BCC to avoid a selection bias in the

the CD68 antibody (diluted 1 : 150, KP1, Cell Select). The developing system LSAB Plus system-HRP,

study. The survey included patients who were followed for

DakoCytomation (Carpinteria, CA, USA; code K0690), and

five years after surgery.

diaminobenzidine chromogen were used to perform the immunohistochemistry.

Procedure The clinical parameters that were included in the study analysis were collected through a review of the medical records of the patients. The histologic sections were stained with hematoxylin and eosin, and they were evaluated by a dermatopathologist to confirm the diagnosis of nodular BCC. Then, sequential sections were cut, and immunohistochemical reactions were performed to assess the M1 and M2 macrophage populations in the peritumoral infiltration. The Mohs sections were cut into

Semiquantitative analysis of M1 and M2 macrophages The percentage of stained area for the CD68, CD204, CD163, and iNOS antibodies was assessed by image analysis and based on color thresholds. The measurements were obtained using IMAGE PRO PLUS Software version 4.1 for Windows (Media Cybernetics, Silver Spring, MD, USA) on a PC that was connected to a digital camera (Zeiss AxioCam MRc, Go¨ttingen, Germany) coupled to an optical microscope (Zeiss, Axiophot, €ttingen, Germany). Go

Table 2 Study and control group comprising 25 solid BCC cases






Time of appearance of recurrences (months)

Histologic subtype

Size (cm)

Mohs stages

1 2 3 4 5


59 71 62 52 66


65 71 64 74 58 70 47


76 59 73 68 62 73 83 66 79 62 71 70 71


Nose Temple Nose Malar Upper lip Nose Lower eyelid Nose Ear Nose Nose Nose Forehead Temple Nasolabial fold Canthus Upper eyelid Chin Forehead Trunk Perioral Canthus Nose Ear Temple Nose Canthus

34 39 23 26 20 15 26 30 24 12 4 3 6 6 12 2 5 6 11 6 12 15 12 120 60 12 5

Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular

1,30 2,30 2,20 1,00 1,20 1,50 3,50 1,10 1,20 1,00 1,50 1,30 1,70 1,40 0,80 1,00 1,00 1,60 1,40 2,80 1,20 1,50 0,70 3,00 2,80 0,50 0,50

4 4 1 1 2 1 4 2 1 1 1 1 2 2 1 1 1 2 2 1 1 1 3 2 2 1 2

6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

M, male; F, female; S, study; C, control ª 2017 The International Society of Dermatology

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Macrophage subtypes in basal cell carcinoma

Padoveze et al.

For each antibody, the cells were counted in at least 15 randomly selected fields, next to tumor nests under 40X

the control group. However, in 33.3% of the cases in the study group, four Mohs phases were necessary for total tumor exci-

magnification. All of the stains on the coded tissue samples

sion. However, in relation to tumor size, there were no major

were digitized as coded images. The image analysis was based

differences observed between the two groups.

on color thresholds; thus, subjectivity was avoided.

Statistical analysis Exploratory data analyses (mean, standard deviation, minimum, median, maximum, frequency, and percentages) were performed, and individual value graphs and bar graphs were created using the means and 95% confidence intervals. The comparative analysis of the control group and the study group was conducted using the nonparametric Mann-Whitney test. Comparative analysis of tumor size and appearance times was conducted using the nonparametric Kruskal-Wallis test.

Results Descriptive analysis/Sample characterization Nine lesions from the study group and 18 lesions from the control group were evaluated; there were eight patients in the study group and 17 patients in the control group. One of the study group patients had two recurrent lesions in different sites, and one control group patient had two tumors that were analyzed. The mean age of the patients in the study group and in the control group was similar (67 and 65 years, respectively). The numbers of male and female patients were identical in the study group and almost identical in the control group. With respect to the neoplasm progression time (or the time to relapse in the case of the study group), most of the relapses occurred within a year of follow-up. In terms of the number of MMS stages, in both groups we had a predominance of one phase of Mohs surgery, 44.4% in the study group and 55% in


Comparisons of groups by cell type (M1 or M2) and overall cell population There were no significant differences between the groups in relation to the average percentages of M1 (iNOS) and M2 cells (CD163 and CD204) or total cells (CD68) (P>0.05) (Fig. 1). Comparison of tumor size When the patients were divided into three groups based on tumor size (≤1 cm, 1-2 cm, and ≥2 cm), there were no significant differences between the groups in terms of the average percentage for any of the variables (Fig. 2). Comparison of time to appearance of tumors All cases were divided into three groups according to the time to appearance (4 years). Each group’s mean and standard deviation were evaluated according to the antibody and then compared (Fig. 3). No significant differences between groups were found in terms of percent average for any of the variables.

Discussion Cancer recurrence results from the persistence of the original tumor after incomplete excision.17 The percentage of BCC recurrence varies depending on the treatment. The use of MMS over the 11-year study period resulted in a 5-year recurrence rate of 4.6%. This rate is below the rates of other therapeutic modalities and similar to those found in other European and


P = 0.939



0.8 0.6 0.4 0.2


P = 0.487

2.0 1.0 0.0


2.5 6

P = 0.898

1.5 1.0 0.5 0.0

International Journal of Dermatology 2017






P = 0.738

4 3 2 1 0

Figure 1 Median and 95% confidence intervals for the percentage of cells per group ª 2017 The International Society of Dermatology

Padoveze et al.

Macrophage subtypes in basal cell carcinoma

%CD68 6


P = 0.179

P = 0.179















Figure 2 Mean and standard deviation of the immunohistochemical markers and correlation with tumor size groups

P = 0.875

3 2





%CD68 2










Figure 3 Mean and standard deviation of the immunohistochemical markers and correlation with time to appearance of tumors


P = 0.757

P = 0.123

1 a 2 cm




≤ 1 cm

≥ 2 cm

%CD163 P = 0.396


%CD163 3







P = 0.961

< 1 ano 1 a 2 anos > 4 anos

P = 0.892


North American medical centers, which have reported 5-year

As with other solid tumors, the environment is critical for their

recurrence rates of 1-6.7% using the same surgical techniques

survival, given that tumor cells that are transplanted without

and MMS indications.11,18,19

their stroma die within a few days.23–25

In addition to the therapeutic method, tumor biology and the patient’s immune response are also related to tumor recur-

Incompletely excised BCCs relapse in 19.8-67% of cases.26–28 Nouri et al.29 observed that after BCC treatment

rence.17 Compared to immunocompetent patients, immunosup-

with curettage and electrodessication, the tumors persisted in

pressed patients have more aggressive tumors and higher rates

20-40% of the cases, and the 5-year follow-up showed recur-

of tumor recurrence.20,21

rence in only 8-10% of the cases. The inflammatory factors

In addition, histologic subtypes influence the biological behav-

that are released after local tissue damage may be related to

ior of tumors, with the most aggressive cases associated with

antitumor activity and would eventually destroy the remaining

higher recurrence rates.22 In this study, all of the BCCs were of


the same histologic subtype (nodular), and the mean age of the study group was similar to that of the control group (67 and 65,

Levis et al.30 proposed the hypothesis of a nonspecific immune response that causes discontinuity between the tumor

respectively). Age was not associated as an influential factor in

and the stroma; this would justify the elimination of 23% of BCC

patient immunity. Furthermore, none of the patients had immun-

cases that are treated with the topical application of croton oil, a

odeficiency or used immunosuppressive medication.

primary irritant.

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Macrophage subtypes in basal cell carcinoma

Padoveze et al.

An alternative elimination mechanism for the remaining tumor cells could occur during the operative wound healing process,

suppress hypoxia and the lack of nutrients, thereby enhancing tumor neoangiogenesis.37

more specifically, during the proliferative phase. During this

Because nodular BCCs grow slowly,1 differences in the num-

phase, myofibroblasts would induce scar contracture, reducing

ber of macrophages and their subtypes were not expected

its surface and thereby inhibiting the remaining BCC cells at the

when considering the different sizes and disease progression


times. Differences were also not expected when comparing

It is known that most of the cells that are present in the tumor

aggressive (infiltrative, desmoplastic, morpheaform, or micron-

stroma comprise macrophages, particularly of the M2 pheno-

odular BCCs) and nonaggressive forms because the aggressive

type,31 and this cell population is present in greater quantities in more aggressive histological BCC subtypes (morpheaform and

forms have a higher mitotic index and extensive spread, thus requiring more nutrients7 and oxygen.

micronodular).5 Thus, we only selected cases of nodular BCC

The recurrence of the tumors studied was not demonstrated

to avoid a selection bias in the study. This restriction in the

to occur under the influence of TAM, and there was no signifi-

selection of only one histological subtype led to a limitation in

cant difference in the macrophage subpopulations according to

our work with a small study sample, since nodular BCC recur-

tumor progression and tumor size. Few studies on BCC and the

rence after MMS is rare.

immune system have been published, and further research is

In the study sample, there was no significant relationship between the percentage of M2 macrophages and the tumors in either the study group or the control group; this contradicts the

needed to better understand the behavior of BCC among tumor subtypes (histological types) and patient’s characteristics.

theory that there is an increase of M2 macrophages that is favorable to lesion growth in cases with any remaining cancer cells. Likewise, the comparative analysis of total macrophages (represented by the CD68 marker) did not show significant differences between the groups. Perhaps TAM is more related to BCC aggressiveness (i.e., the degree of invasion and tissue destruction) than to its ability to relapse. There are many speculations about the roles of the specific and nonspecific immune responses in residual tumor eradication. However, to our knowledge, no scientific evidence has explained these mechanisms. We know that macrophages go through







response to specific environmental signals,32 and they may go through polarization from an M2 macrophage cell to an antitumor phenotype (M1) and vice versa.33 Perhaps factors other than the TAM and M2 phenotypes are involved in the proliferation of the remaining tumor cells, as observed in this study. No significant difference was observed in macrophage subtypes according to tumor progression. The recent (less than 1 year) and late (over 4 years) tumors were similar in terms of the number of macrophages and population subtypes. Tumor infiltration is believed to initially consist of M1 macrophages;34 over time, a polarization to the M2 phenotype occurs.35 The cause of this polarization is unknown; however, hypoxic areas in the tumor have been proposed as a probable cause of phenotypic shifts. Sites with oxygen deficiency in endometrial, breast, prostate, and ovarian cancers have been shown to have high concentrations of M2 macrophages.34 In the analysis of the nodular BCC cases according to the tumor size (2 cm), no significant difference was observed in the macrophage subpopulations. According to the literature, solid tumors do not grow to be larger than 3 mm3 because of hypoxia.36 To continue growing and to survive in a hostile environment, rapidly growing tumors must International Journal of Dermatology 2017

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 A, et al. Incomplete excision of 26 Farhi D, Dupin N, Palangie basal cell carcinoma: rate and associated factors among 362 consecutive cases. Dermatol Surg 2007; 33: 1207–1214. 27 Staub G, Revol M, May P, et al. Excision skin margin and recurrence rate of skin cancer: a prospective study of 844 cases. Ann Chir Plast Esthet 2008; 53: 389–398. 28 Rosso S, Zanetti R, Martinez C, et al. The multicentre south European study ‘Helios’. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin. Br J Cancer 1996; 73: 1447–1454. 29 Nouri K, Spencer JM, Taylor JR, et al. Does wound healing contribute to eradication of basal cell carcinoma following curettage and electrodessication? Dermatol Surg 1999; 25: 183–188. 30 Levis WR, Kraemer KH, Klingler WC, et al. Topical immunotherapy of basal cell carcinoma with dinitrochlorobenzene. Cancer Res 1973; 33: 3036–3042. 31 Singh A, Talekar M, Raikar A, et al. Macrophage-targeted delivery systems for nucleic acid therapy of inflammatory diseases. J Control Release 2014; 28: 515–530. 32 Zhou D, Huang C, Lin Z, et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell Signal 2014; 26: 192–197. 33 He M, Xu Z, Ding T, et al. MicroRNA-155 regulates inflammatory cytokine production in tumor-associated macrophages via targeting C/EBPbeta. Cell Mol Immunol 2009; 6: 343–352. 34 Tripathi C, Tewari BN, Kanchan RK, et al. Macrophages are recruited to hypoxic tumor areas and acquire a Pro-Angiogenic M2-Polarized phenotype via hypoxic cancer cell derived cytokines Oncostatin M and Eotaxin. Oncotarget. 2014; 5: 5350–5368. 35 Biswas SK, Sica A, Lewis CE. Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J. Immunol 2008; 180: 2011–2017. 36 Lewis CE, Leek R, Harris A, et al. Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J Leukoc Biol 1995; 57: 747–751. 37 Park JE, Tan HS, Datta A, et al. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics 2010; 9: 1085–1099.

International Journal of Dermatology 2017


Macrophage subtypes in recurrent nodular basal cell carcinoma after Mohs micrographic surgery.

The macrophages associated with solid tumors are related to the progression or regression of tumors, depending on the differentiation in M1 or M2. M2 ...
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