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Immunohistochemical expression of CD117 and CD34 as stem cell markers in intradermal nevi, dysplastic nevi, and malignant melanomas

Shamloula, Maha M.a; Gheida, Shereen F.b; El-sakka, Ayman M.a

Journal of the Egyptian Women's Dermatologic Society: January 2013 - Volume 10 - Issue 1 - p 10–17
doi: 10.1097/01.EWX.0000419611.97535.5e
Original articles
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Background The potential role of stem cells in neoplasia is a subject of recent interest. Cancer stem cells are able to proliferate and self-renew extensively because of their ability to express antiapoptotic and drug resistant proteins, thus sustaining tumor growth. Therefore, the strategy to eradicate cancer stem cells might have significant clinical implications.

Objective The aim of this study was to assess the immunohistochemical expression of both CD117 and CD34 as stem cell markers in intradermal nevi, dysplastic nevi, and malignant melanoma (MM).

Patients and methods The present study included a total of 38 patients; 11 patients with intradermal nevi, nine patients with dysplastic nevi, and 18 patients with MM (12 primary, four metastatic, and two recurrent). Using immunohistochemistry, we studied CD117 and CD34 in the tissue of all studied patients.

Results Intradermal nevi were all negative for CD117, whereas dysplastic nevi showed 100% positivity and MMs showed 83.3% positivity. There was statistically significant difference between intradermal nevi and both dysplastic nevi and MMs, but no significant difference was found between the last two in CD117 expression. Intradermal nevi were completely negative for CD34 expression, the dysplastic nevi showed positivity in 6/9 (66.7%) patients and MM showed expression in 2/18 (11%). There was a statistically significant difference between intradermal nevi and both dysplastic nevi and MMs and between the last two in terms of CD34 expression.

Conclusion CD117 could be considered as an indicator of malignant proliferative process. It could further be a useful marker to differentiate completely benign nevi from malignant melanocytic lesions. This may have therapeutic implications as a molecular target, which needs further investigations. CD34 neither has a role as a stem cell marker nor is a potential target for clinical trials with monoclonal antibody therapy in MMs.

Departments of aPathology

bDermatology and Venereology, Faculty of Medicine, Tanta University, Tanta, Egypt

Correspondence to Shereen F. Gheida, Department of Dermatology and Venereology, Tanta University, 31527 Tanta, Egypt Tel:+20 122 646 4724; fax:+2 040 2010708; e-mail: gheidas@yahoo.com

Received March 13, 2012

Accepted July 27, 2012

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Introduction

Malignant melanoma (MM) is a malignant tumor arising from melanocytes. Its incidence has been increasing in last decades 1. Despite improvements in overall survival, the prognosis for advanced-stage disease remains poor 2. Newer technologies, such as gene expression profiling and proteomics, are rapidly expanding our knowledge of melanoma cell biology. In addition, this may lead to the identification of new prognostic and therapeutic markers, possibly including stem cell markers 3. The cancer stem cell (CSC) hypothesis suggests that malignant tumors are composed of both CSCs, which have great proliferative potential, and more differentiated cancer cells, with limited proliferative potential 4. The existence of CSC has been established in many different malignancies including acute myeloid leukemia, breast cancer, and glioblastoma 5. Identification of CSC may help refine classification, diagnosis, and treatment of these cancers and potentially others including melanoma 3.

CD117 is a transmembrane receptor tyrosine kinase that binds stem cell factors 6. CD117 is encoded by the kit proto-oncogene, localized to human chromosome 4 and to mouse chromosome 5 7. The CD117/stem cell factor interaction is critical for the survival and development of stem cells involved in hematopoiesis 8, pancreas development 9, and melanogenesis 10. CD117 is a growth factor for melanocyte migration and proliferation 11. Malignant transformation of melanocytes is associated with changes in the expression of the CD117 receptor 12. CD117 is a marker for CSCs 13.

The CD34 antigen is a 110 kDa protein encoded by a gene located on chromosome 1q and expressed on the surface of stem cells in the bone marrow 14. It was first used as a means to isolate stem cells for transplantation and to identify subgroups of acute leukemia. It is also found in vascular and spindle cell tumors, as well as in tumors of neural and myofibroblastic derivations including dermatofibrosarcoma protuberans, solitary fibrous tumors, and pleomorphic fibromas. Melanocytic neoplasms have long been established as being CD34 negative, but there is limited literature on CD34 expression in lesions of melanoma 15. Accordingly, it is worth studying the expression of CD117and CD34 in neoplastic melanocytic lesions.

The aim of this study was to assess the immunohistochemical expression of both CD117 and CD34 as stem cell markers in intradermal nevi, dysplastic nevi, and MMs.

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Patients and methods

This study was carried out on 38 patients with cutaneous melanocytic lesions. They were recruited for the study during the period from 2007 to 2011. They included 11 patients with intradermal nevi, nine patients with dysplastic nevi, and 18 patients with MM (12 primary, four metastatic, and two recurrent). All patients with benign nevi and two with dysplastic nevi were recruited from the Outpatient-clinic of the Dermatology Department, Faculty of Medicine, Tanta University Hospital. The rest of the patients were recruited from the archives of the Pathology Department, Faculty of Medicine, Tanta University Hospital. Patients’ clinical data were collected with emphasis on age, sex, and site. After informed consent was obtained, excision biopsy was carried out and the sample was formalin fixed and paraffin embedded. For all specimens, hematoxylin and eosin (H & E)-stained preparations were examined for re-evaluation and confirmation of clinical diagnosis. Dysplastic nevi were defined histologically as showing distinct cytological and architectural atypia with elongation of the rete ridges and a host response in the dermis. Atypia was graded as mild, moderate, or severe on the basis of a published scoring system by Black and Hunt 16. Melanomas were allocated into the radial or vertical growth phase according to criteria published by Guerry et al.17.

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Immunohistochemical staining

Sections from formalin-fixed, paraffin-embedded tissue blocks were cut at 5 µm thickness, deparaffinized in xylene and decreasing grades of ethanol, and incubated with PBS containing 5% normal goat serum. Microwave antigen retrieval was performed in citrate buffer twice for 20 min. Background staining was performed using normal serum, and hydrogen peroxide was used for blocking endogenous peroxidase. The detection system was avidin biotin. Subsequently, immunostaining with anti-CD-117 rabbit polyclonal antibodies (Catalog #RB-9038-P; Labvision, Fremont, California, USA) and anti-CD34 (Catalog #MS-363-R7, Labvision) mouse monoclonal antibodies, available as primary ready-to-use antibodies, was carried out overnight. Color development was carried out using DAB and Mayer’s hematoxylin as counter stains. The negative control experiment involved omitting the primary antibody, and the positive control experiment involved using sections of gastrointestinal stromal tumor for CD117 and angiosarcoma for CD34. Membranous and/or cytoplasmic expression was considered a positive reaction for both markers.

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Scoring of CD117 immunoreactivity

The scoring system for the CD117 expression level is as follows: score 0, no staining was observed or staining was observed in less than 10% of cells; score 1+, the cytoplasm was discretely and weakly–moderately stained in 10% or more of the melanocytes; score 2+, the cytoplasm was strongly stained with or without membrane staining in 10% or more of the melanocytes. Patients with a score of 1+ or 2+ were considered positive 18.

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Scoring of CD34 immunoreactivity

Immunohistochemistry for CD34 was scored according to a semiquantitative scale: 0 (negative staining), 1+(<25% staining), 2+ (25–50% staining), 3+ (>50% staining) 19.

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Statistical analysis

Data were collected, tabulated, and statistically analyzed using SPSS version 16 (SPSS Inc., Chicago, Illinois, USA). Data were summarized using mean and SD (mean±SD) for quantitative variables and frequency and percentage for qualitative variables. Comparisons between groups were made using the χ2-test and Fisher’s exact test for qualitative variables. Statistical significance was determined at a level of P less than 0.05.

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Results

Clinical results

The clinical criteria are summarized in Table 1.

Table 1

Table 1

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Histopathology results

There were 11 intradermal nevi showing nevoid oval cells with melanin and unapparent mitosis, completely found intradermally without junctional activity with apparent maturation in the lower dermis, resembling Schwann cells (Fig. 1). There were nine dysplastic nevi with marked cellularity, cellular atypia (moderate to severe), junctional activity, some mitotic figures, and elongation of epidermal ridges with bridging of some of them (Fig. 2). There were 18 melanoma cases, 12 of which were of the nodular type and six were superficial spreading MMs. Of the primary melanomas (12), there was one case showing the radial growth phase – that is a microinvasive melanoma infiltrating the papillary dermis – and the remaining 11 cases showed the vertical growth phase – that is invasive melanomas of Clark level IV/V. The four metastatic cases as well as the two recurrent melanoma cases showed the vertical growth phase. The histological features showed highly malignant melanocytes with intracellular and extracellular coarse melanin granules, marked cytologic atypia, frequent mitotic figures, large nucleoli, and epithelioid or sarcomatoid features with pagetoid spread (Fig. 3). One case only showed clear cell features (Fig. 4).

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

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Immunohistochemical results

Positive expression for CD117 and CD34 was detected as cytoplasmic and/or membranous accentuation.

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Intradermal nevi

All 11 intradermal nevi were negative for CD117 and CD34 expression in the nevus cells. Positive expression for CD34 was detected in the blood vessels and was used as an internal control (Table 2; Fig. 5).

Table 2

Table 2

Figure 5

Figure 5

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Dysplastic nevi

CD117 was positive in all nine patients (100%), with score 1 in two patients and score 2 in seven patients (Figs 6 and 7). The dysplastic nevi showed positive expression for CD34 in 6/9 (66.7%) patients, with score 1 in four patients and score 2 in two patients, and negative expression in 3/9 (33.3%) patients, with positive reaction in the walls of the blood vessels and sweat glands. Two patients showed positive expression only in the nevus cells located superficially in the papillary dermis and negative expression in the deeply located cells in the reticular dermis (Table 2).

Figure 6

Figure 6

Figure 7

Figure 7

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Malignant melanomas

CD117 was positive in the melanoma cells in 15/18 (83.3%) patients, with score 1 in three patients, one of whom had clear cell melanoma, and score 2 in 12 patients (Figs 8 and 9), and it was negative in 3/18 (16.7%) patients. The three negative cases were primary MMs, the metastatic and recurrent melanomas were all positive for CD117. Two of 18 (11%) patients with melanoma showed positive expression for CD34 in the malignant cells, one had spindle cell melanoma (Fig. 10) with score 2 positivity and the other had epithelioid melanoma with score 1 in which the pagetoid spread of malignant melanocytes, as well as the rest of the tumor, showed positive expression (Figs 11 and 12); 16/18 (89%) patients showed negative expression for CD34 (Table 2).

Figure 8

Figure 8

Figure 9

Figure 9

Figure 10

Figure 10

Figure 11

Figure 11

Figure 12

Figure 12

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Statistical analysis of immunohistochemical results

There was a significant difference in the expression of CD117 and CD34 between intradermal nevi and dysplastic nevi (P-value=0.001 and 0.002, respectively). There was also a significant difference in the expression of CD117 and CD34 between intradermal nevi and MM (P-value=0.001 and 0.025, respectively). There was no significant difference between dysplastic nevi and MM in the expression of CD117 (P-value=0.193). There was a significant difference between dysplastic nevi and MM in the expression of CD34 (P-value=0.003; Table 3).

Table 3

Table 3

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Discussion

Stem cells are initial cells that have the ability of self-renewal, infinite multiplication, as well as multidirectional differentiation. Many studies 4,13,20 have indicated that bone marrow, the nervous system, and prostate glands have stem cells. CSCs have the ability of infinite self-renewal, high multiplication, as well as multidirectional differentiation. They can produce cancer cells of different phenotypes that form the new tumor. In the past 10 years, both the incidence and mortality rate from MM have significantly increased worldwide. The main goal of the traditional treatment modalities is to eradicate tumor cells; however, recurrence, metastasis, therapy resistance, and treatment toxicities are still the main obstacles. To cure MM, we must identify the source of the tumor and eradicate it. The theory of CSCs makes the targeting of anti-CSCs and eradication the tumor possible. So far, there have been no local reports on MM stem cells; however a few studies in the literature have reported on MM stem cells 20. For this reason, the current work studied CD117 and CD34 expression in different melanocytic lesions. Intradermal nevi were all negative for CD117, whereas dysplastic nevi showed 100% positivity, MMs showed 83.3% positivity, and the three negative cases, primary, metastatic, and recurrent melanomas, were all positive for CD117. There was a statistically significant difference between intradermal nevi and both dysplastic nevi and MMs, but no significant difference was found between the last two in CD117 expression. These results agree with those of Alexis et al.21 who, in their study, found that 35/40 (87.5%) patients with MM were positive for CD117. Pilloni et al.11, in their study on melanocytic lesions including blue nevi, intradermal nevi, junctional nevi, compound nevi, Spitz nevi, and MMs, found that the vast majority of nevi and melanomas were positive for CD117 with minimal difference between benign and malignant lesions; however, the percentage of CD117-positive intradermal nevus cells was significantly increased in MM compared with benign lesions. They also mentioned that the MM cells on top of a pre-existing nevus showed strong positivity for CD117, whereas the intradermal nevus cells were negative for CD117. In their study, all the metastatic melanoma cases were negative for CD117. In our study, CD117 can differentiate between completely benign lesions and dysplastic and malignant lesions. Comparatively, in the study by Isabel and Fitzpatrick 22, there was no significant difference in CD117 staining in either the epidermis or dermis between Spitz nevi and primary melanomas. However, staining in metastatic melanomas is less compared with dermal staining of primary MMs and Spitz nevus. Several studies 12,22,23 have demonstrated that progression of human melanoma is associated with loss of expression of the CD117 proto-oncogene. These results disagree with our results, which may be because of the small number of metastatic melanomas in this study. The percentage of positivity of CD117 in dysplastic nevi was more than that in MMs; one explanation of this result is that all dysplastic nevi were of the same type but MMs were of different types with different origins, or the malignant potential of MMs was more than that of dysplastic nevi, which were associated with loss of expression of CD117. Dysplastic nevi have variably demonstrated an increased risk for evolving into melanoma 24. This may represent a causal relationship between both or may be because of a common origin. There is a continuum of the histological pattern that spans from dysplastic nevi to melanoma 25. The immunohistochemical study is not useful in the differentiation of dysplastic nevi from melanomas 26. Potti et al.27 added that the identification of CD117 in a significant proportion of their patients could possibly have important therapeutic implications for future clinical trials evaluating the role of site-specific therapy in melanomas. This is in agreement with the findings of Alexis et al.21, who stated that imatinib mesylate (Gleevec), a selective tyrosine kinase inhibitor that binds the CD117 receptor, has proven to be an effective therapeutic agent in the treatment of MM.

In this study, intradermal nevi were completely negative for CD34 expression; the dysplastic nevi showed positivity in 6/9 (66.7%) patients, whereas MM showed expression in 2/18 (11%) patients. There was a statistically significant difference between intradermal nevi and both dysplastic nevi and MMs and between the last two in terms of CD34 expression. In a reported case study, Hoang et al.28 described an MM resembling dermatofibrosarcoma protuberans, with short fascicles of spindle cells expressing CD34. In this study, there were two patients with MMs expressing CD34, one of them had spindle cell melanoma. In another study CD34 was found positive in a patient with nodular melanoma 29. In the study by Pisacane et al.30, no cases of common melanocytic nevi immunoreacted with CD34. CD34 was also negative in melanomas of Clark’s level I/II; however, 20 and 55% of level III and IV/V melanomas, respectively, were positive for CD34. CD34 expression was never found in metastatic melanomas in their study, and this is comparable with the findings of our study. Comparatively, CD34 expression has also been described in a cellular blue nevus 31. A report on a series of cutaneous melanomas showing CD34 expression in one-third of the 30 patients with invasive melanoma studied has been published 32.In this study, because of the low percentage of positivity of CD34 expression in MMs, we cannot state the difference between primary, recurrent, and metastatic melanomas. The expression of CD34 in melanoma may be explained by genetic dysregulation. It has been shown that aggressive melanoma cells express inappropriate markers, which would not be expected of normal melanocytes 33. Nevi may also be precursors of melanoma; however, most nevi are stable and will not progress to malignancy. Nevi are vastly more common than melanomas, and the rate of progression of individual lesions is very low. Therefore, nevi are not, as a rule, managed by wholesale excision to prevent melanoma. Nevi are also important as risk markers, identifying individuals at a greater risk of developing melanoma in the future 34. Many studies have been conducted to identify molecular markers that might distinguish benign lesions from malignant melanocytic ones and also the various stages of progression in primary MMs of the skin 35.

The CSC hypothesis suggests that mutated melanocyte stem cells are present in skin as precursors of melanoma cells 36. In our study, CD117 is highly expressed in MMs, but is absent in intradermal nevus, suggesting that tumor stem cells might exist in MM tissue.

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Conclusion

On the basis of present data, CD117 should be considered as an indicator of the malignant proliferative process. It could further be a useful marker to differentiate primary melanoma from intradermal nevi, although not entirely useful in differentiating primary melanoma from dysplastic nevi. CD34 is not a diagnostic or prognostic marker and may have no role in neoplastic melanocytic lesions. Further, large-scale studies on patients with MM in various stages of progression are still required in order to identify the origin of the tumor and find methods to eradicate it.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

CD117; CD34; dysplastic nevi; malignant melanoma; melanocytic nevi; stem cell

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