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Figure 1.
Redness of the face and neck (Brenner sign) in a 58-year-old woman with melanoma.

Redness of the face and neck (Brenner sign) in a 58-year-old woman with melanoma.

Figure 2.
Melanoma tumor cells show strong positive cytoplasmic staining with vascular endothelial growth factor. Bar indicates 200 μm.

Melanoma tumor cells show strong positive cytoplasmic staining with vascular endothelial growth factor. Bar indicates 200 μm.

Figure 3.
Sheets of tumor cells showing strong positive cytoplasmic staining with platelet-derived growth factors. Bar indicates 200 μm.

Sheets of tumor cells showing strong positive cytoplasmic staining with platelet-derived growth factors. Bar indicates 200 μm.

1.
Langley  RGBBarnhill  RLMihm  MC  JrFitzpatrick  TBSober  AJ Neoplasms: cutaneous melanoma. Freedberg  IMEisen  AZWolff  K  et al. eds.Fitzpatrick's Dermatology in General Medicine. 26th ed. New York, NY McGraw-Hill Co2003;917- 955
2.
Lázár-Molnár  EHegyesi  HToth  SFalus  A Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 2000;12 (6) 547- 554
PubMedArticle
3.
Redondo  PSanchez-Carpintero  IBauza  AIdoate  MSolano  TMihm  MC  Jr Immunologic escape and angiogenesis in human malignant melanoma. J Am Acad Dermatol 2003;49 (2) 255- 263
PubMedArticle
4.
Pierard  GEPierard-Franchimont  CLapiere  CM Proliferation and hyperplasia of vascular endothelium in human skin. Am J Dermatopathol 1985;7 (5) 477- 488
PubMedArticle
5.
Hanahan  DFolkman  J Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86 (3) 353- 364
PubMedArticle
6.
Brenner  SWolf  R The “red face”—a warning sign of malignant melanoma [letter]? Acta Derm Venereol 1992;72 (6) 464
PubMed
7.
Tamir  EBrenner  S A case of “red face”: a clue to early detection of malignant melanoma Skinmed 2003;2 (5) 272
PubMedArticle
8.
Mashiah  JBarnea  YWohl  YBrenner  S Redness, a possible signpost for malignant melanoma [letter]. J Eur Acad Dermatol Venereol 2005;19 (4) 514- 515
PubMedArticle
9.
Srivastava  ARalhan  RKaur  J Angiogenesis in cutaneous melanoma: pathogenesis and clinical implications. Microsc Res Tech 2003;60 (2) 208- 224
PubMedArticle
10.
Heldin  CHOstman  ARonnstrand  L Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1998;1378 (1) F79- F113
PubMed
11.
Pietras  KSjoblom  TRubin  KHeldin  CHOstman  A PDGF receptors as cancer drug targets. Cancer Cell 2003;3 (5) 439- 443
PubMedArticle
12.
Furuhashi  MSjoblom  TAbramsson  A  et al.  Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. Cancer Res 2004;64 (8) 2725- 2733
PubMedArticle
13.
Hellström  MKalen  MLindahl  PAbramsson  ABetsholtz  C Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999;126 (14) 3047- 3055
PubMed
14.
Claffey  KPBrown  LFdel Aguila  LF  et al.  Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res 1996;56 (1) 172- 181
PubMed
15.
Govindarajan  BBai  XCohen  C  et al.  Malignant transformation of melanocytes to melanoma by constitutive activation of mitogen-activated protein kinase kinase (MAPKK) signaling [published online ahead of print January 3, 2003]. J Biol Chem 2003;278 (11) 9790- 9795
PubMedArticle
16.
Cohen  CZavala-Pompa  ASequeira  JH  et al.  Mitogen-actived protein kinase activation is an early event in melanoma progression. Clin Cancer Res 2002;8 (12) 3728- 3733
PubMed
Study
August 2007

Immunohistochemical Expression of Platelet Growth Factor and Vascular Endothelial Growth Factor in Patients With Melanoma With and Without Redness (Brenner Sign)

Author Affiliations

Author Affiliations: Departments of Dermatology (Drs Mashiah, Wohl, and Brenner), Plastic Surgery (Dr Barnea), General Surgery A (Dr Schneebaum), and Pathology (Dr Gat and Ms Misonzhnik-Bedny), Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Arch Dermatol. 2007;143(8):1001-1004. doi:10.1001/archderm.143.8.1001
Abstract

Objective  To assess whether an erythematous eruption in the vicinity of or distant from a melanoma lesion might be related to the vascular endothelial growth factor, the platelet-derived endothelial cell growth factor, or both.

Methods  Biopsy specimens from 13 patients with primary melanoma, 6 of whom had erythematous eruptions and 7 who did not, were studied by immunohistochemistry for the expression of vascular endothelial growth factor and platelet-derived endothelial cell growth factor.

Results  Vascular endothelial growth factor was positive in 3 of 6 patients (50%) with melanoma and redness (Brenner sign) and in 4 of 7 patients (57%) with melanoma without redness. Platelet-derived endothelial cell growth factor was positive in all 6 patients (100%) with melanoma and redness and in 4 of 7 patients (57%) with melanoma without redness.

Conclusion  Platelet-derived endothelial cell growth factor may have a part in the pathogenesis of the redness observed in patients with melanoma, called Brenner sign, by affecting vasculature function.

The rise in incidence of malignant melanoma is among the greatest for all kinds of cancer, with an annual rise of 3% to 8% in newly diagnosed melanomas worldwide.1 The increase is especially great in regions of the world where intense sun, especially in the Middle East, and a trend toward more revealing clothing expose people to untoward amounts of UV radiation. Despite efforts to achieve early detection and recognition of the unfavorable prognostic factors and the development of novel treatment modes, progressive disease has a dismal prognosis. Tumor progression and development cannot be attributed to a single process. The escape of the tumor from the regulatory mechanisms includes excessive production of cytokines and autocrine growth factors, substituting for cytokines and exogenous growth factors,2 self-tolerance to melanoma antigens, and down-regulation of class II major histocompatibility complex molecules.3 Neoplasms including melanoma are known to induce angiogenesis, which is believed to have a role in the development and spread of the melanoma.4,5

Previous publications68 described an observation of patients with malignant melanoma who had a particular reddish appearance that could not be attributed to any medical cause including photosensitivity. In one study 8 of 14 patients (57%) with melanoma exhibited an erythematous rash adjacent to and in the general vicinity of the melanoma that was confluent with the surrounding tissue and had no distinguishable borders.8 These authors labeled the rash Brenner sign (Figure 1).

In an effort to identify visible signs that can alert the clinician to the possible presence of melanoma, we investigated the expression of 2 cytokines secreted by melanoma cells—vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PDGF)—and their role in the pathogenesis of the rash.

METHODS
PATIENTS

All biopsy specimens were obtained from the tissue files of 13 patients in the Pathology Department, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel. The study was approved by the hospital ethics committee. The formalin-fixed, paraffin-embedded melanocytic lesions represented 13 primary melanomas. One group of patients with melanoma who had the erythematous rash called Brenner sign included 6 patients (4 men and 2 women), with an age range of 31 to 86 years, and a Breslow level range of 0.1 to 10 mm. The group of patients with melanoma without the Brenner sign consisted of 7 patients (3 men and 4 women), with an age range of 43 to 74 years, and a Breslow level range of 0.9 to 23 mm. There was no difference between the 2 groups in the distribution of subtypes of melanoma or in the outcome.

Immunoreactivity to VEGF and PDGF was evaluated by light microscopy following immunochemical staining. Ten high-power fields were viewed for each sample and graded as follows: negative, no cells stained; low, 1% to 10% cells stained; moderate, 15% to 30% cells stained; and high, 40% or more cells stained.

IMMUNOHISTOCHEMISTRY

Formalin-fixed, paraffin-embedded tissues were stained by an automated immunostainer (Nexes-Immunohistochemistry; Vertana Medical Systems, Tuscon, Arizona), after which they were deparaffinized and subjected to a 3-step indirect process based on the labeled (strept) avidin-biotin (LABORATORY-SA) peroxidase complex method, using the I-VIEW detection kit (Vertana Medical Systems). Sections were pretreated with buffer (pH 6.0, Target Retrieval; Zymed, San Francisco, California) for 12 minutes at 97°C by temperature-controlled microwave treatment using a processor (model H28900; Energy Beam Sciences, Inc, Ayawa, Maine). The Ventana Medical System dispensed the primary antibodies; consecutive sections were incubated for 32 minutes with polyclonal antibodies: 1:90 dilution of VEGF (CT) clone (PAD): Z-CVF3 (Zymed), and 1:50 dilution of PDGF-ά CLONE: C-20 (Santa Cruz, California). 3,3′-Diaminobenzidine tetrahydrochloride, which produces a dark brown precipitate chromogen, was used to localize the immunoreactions. Slides were counterstained with hematoxylin, dehydrated, and coverslipped with a permanent mounting medium for microscopic examination.

RESULTS

Immunoreactivity for VEGF was positive (moderate and high staining grades) (Figure 2) in tissue specimens of 3 of 6 patients (50%) with melanoma and redness and in 4 of 7 patients (57%) with melanoma without redness. No VEGF was detected in any of the melanomas with a Breslow depth of 1 mm or less.

In contrast, immunoreactivity for PDGF was positive (moderate and high staining grades) (Figure 3) in tissue specimens of 6 of 6 patients (100%) with melanoma and redness and in 4 of 7 patients (57%) with melanoma without redness. There was no difference between the 2 groups in Breslow depth.

COMMENT

An erythematous rash accompanying malignant melanoma lesions, confined mainly to the face, was first described by Brenner and Wolf6 and Tamir and Brenner.7 Another study8 confirmed this observation, reporting the rash in 57% of patients with melanoma classified as stages I through III, and in none of the keratinocyte-derived tumor group or healthy individuals. Subject to further investigation and confirmation of the significance of this phenomenon, the rash could serve as an additional tool for the diagnosis of melanoma (asymmetry, border, color variegated, and diameter >6 mm) as well as a measure of progression or regression of the disease. Explanation of this phenomenon probably lies in the pathogenesis of malignant melanoma. Melanoma cells can express cytokines and growth factors, having autocrine, paracrine, or both effects that permit autonomous growth of cells, including tumor cells as well as fibroblasts, monocytes, lymphocytes and granulocytes, keratinocytes, and endothelial cells.2

Angiogenesis is a crucial component of growth, invasive progression, and metastatic spread of solid tumors, including melanoma. The interaction and reciprocal signaling between melanoma cells and endothelial cells are thought to guide the progression and growth of tumor cells. Melanoma cells produce a plethora of angiogenic cytokines, including VEGF, PDGF, and others. These cytokines are in constantly changing equilibrium with antiangiogenic agents.9

Platelet-derived growth factors are a family of dimeric disulfide-bonded growth factors that activate tyrosine kinase receptors that are expressed on mesenchymal origin cells such as pericytes, fibroblasts, glial cells, and smooth muscle cells.10 Platelet-derived growth factors participate in the process of solid tumor development in several ways, including recruitment of tumor stroma fibroblasts, stimulation of tumor angiogenesis, autocrine stimulation of tumor cell growth,11 and paracrine stimulation of vascularized stroma growth.12

Pericytes are formed in the connective tissue and remain there. These smooth muscle–like cells, smaller than fibroblasts, are located mainly along the blood capillaries and stabilize the capillary wall. Platelet-derived growth factors regulate embryonic pericyte recruitment.13 Neovessels in melanoma show perivascular PDGF-receptor staining of pericytes and possibly perivascular fibroblasts. Melanoma-derived PDGF is associated with enhanced tumor growth rate and increased coverage of tumor vessels with pericytes (not at late tumor growth phase), but with no increase in vessel density. This may reflect a pericyte-mediated protection from regression of immature vessels, because pericyte deficiency in mice causes endothelial hyperplasia, vessel dilation, vessel leakage, and rupture. The effect of PDGF on tumor vasculature is functional; it increases functionality of tumor vessels, decreases the fraction of nonperfused vessels, and promotes endothelial cell maturation through pericyte-derived signals.11Our findings of positive PDGF immunoreactivity in tissue specimens of all 6 patients (100%) with melanoma and redness and in 4 of 7 patients (57%) without redness are in accord with the known activity of PDGF in melanoma. The erythema observed in cases of melanoma may reflect the higher percentage of mature endothelial cells and functional and perfused vessels.

Vascular endothelial growth factor is a glycosylated dimeric polypeptide that comprises a multifunctional cytokine expressed by most tumors. It acts on endothelial cells through tyrosine kinase receptors by being a selective endothelial cell mitogen and by causing an increase in microvessel permeability.14Melanocytic tumors but not benign melanocytic proliferations display strong VEGF expression. Vascular endothelial growth factor is expressed in thicker melanoma, appears later in melanoma development, and correlates with the presence of metastases. It is also associated with an increase in vascular density.3 In our study the immunoreactivity for VEGF did not differ statistically between patients with melanoma with (50%) and without (57%) redness, indicating that the Brenner sign cannot be attributed to VEGF. Because VEGF is expressed in thick melanoma, no melanoma with a Breslow depth 1 mm or less was found to express VEGF.

Platelet-derived growth factors may have a role in the pathogenesis of the redness by affecting the function of the vasculature rather than its abundance. The number of patients is too small to draw definitive conclusions about these differences, but there seems to be a pattern that warrants further study. We continue to investigate other cytokines, angiogenic growth factors, and their promoters such as mitogen-activated protein kinase,15,16 and vascular leak promoters such as angiopoietin 2. We are also examining the red area for increased vascular density. While our search for the pathogenesis of Brenner sign continues, there is evidence that it could possibly serve as a red flag to primary care physicians, as another prognostic factor, or as a marker of the efficacy of treatment.

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Article Information

Correspondence: Sarah Brenner, MD, Department of Dermatology, Tel Aviv Sourasky Medical Center, 6 Weizman St, 64239 Tel Aviv, Israel (derma@tasmc.health.gov.il).

Financial Disclosure: None reported.

Accepted for Publication: February 14, 2007.

Author Contributions:Study concept and design: Mashiah and Brenner. Acquisition of data: Mashiah, Wohl, Gat, and Brenner. Analysis and interpretation of data: Mashiah, Wohl, Gat, Misonzhnik-Bedny, and Brenner. Drafting of the manuscript: Mashiah. Critical revision of the manuscript for important intellectual content: Mashiah, Wohl, Barnea, Schneebaum, Gat, Misonzhnik-Bedny, and Brenner. Administrative, technical, and material support: Brenner. Study supervision: Brenner. Performed the surgery: Barnea and Schneebaum. Pathological interpretation: Gat. Immunohistochemistry sample analysis: Misonzhnik-Bedny.

Additional Contributions: The manuscript was read and corrected by an English-speaking editor.

References
1.
Langley  RGBBarnhill  RLMihm  MC  JrFitzpatrick  TBSober  AJ Neoplasms: cutaneous melanoma. Freedberg  IMEisen  AZWolff  K  et al. eds.Fitzpatrick's Dermatology in General Medicine. 26th ed. New York, NY McGraw-Hill Co2003;917- 955
2.
Lázár-Molnár  EHegyesi  HToth  SFalus  A Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 2000;12 (6) 547- 554
PubMedArticle
3.
Redondo  PSanchez-Carpintero  IBauza  AIdoate  MSolano  TMihm  MC  Jr Immunologic escape and angiogenesis in human malignant melanoma. J Am Acad Dermatol 2003;49 (2) 255- 263
PubMedArticle
4.
Pierard  GEPierard-Franchimont  CLapiere  CM Proliferation and hyperplasia of vascular endothelium in human skin. Am J Dermatopathol 1985;7 (5) 477- 488
PubMedArticle
5.
Hanahan  DFolkman  J Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86 (3) 353- 364
PubMedArticle
6.
Brenner  SWolf  R The “red face”—a warning sign of malignant melanoma [letter]? Acta Derm Venereol 1992;72 (6) 464
PubMed
7.
Tamir  EBrenner  S A case of “red face”: a clue to early detection of malignant melanoma Skinmed 2003;2 (5) 272
PubMedArticle
8.
Mashiah  JBarnea  YWohl  YBrenner  S Redness, a possible signpost for malignant melanoma [letter]. J Eur Acad Dermatol Venereol 2005;19 (4) 514- 515
PubMedArticle
9.
Srivastava  ARalhan  RKaur  J Angiogenesis in cutaneous melanoma: pathogenesis and clinical implications. Microsc Res Tech 2003;60 (2) 208- 224
PubMedArticle
10.
Heldin  CHOstman  ARonnstrand  L Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1998;1378 (1) F79- F113
PubMed
11.
Pietras  KSjoblom  TRubin  KHeldin  CHOstman  A PDGF receptors as cancer drug targets. Cancer Cell 2003;3 (5) 439- 443
PubMedArticle
12.
Furuhashi  MSjoblom  TAbramsson  A  et al.  Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. Cancer Res 2004;64 (8) 2725- 2733
PubMedArticle
13.
Hellström  MKalen  MLindahl  PAbramsson  ABetsholtz  C Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999;126 (14) 3047- 3055
PubMed
14.
Claffey  KPBrown  LFdel Aguila  LF  et al.  Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res 1996;56 (1) 172- 181
PubMed
15.
Govindarajan  BBai  XCohen  C  et al.  Malignant transformation of melanocytes to melanoma by constitutive activation of mitogen-activated protein kinase kinase (MAPKK) signaling [published online ahead of print January 3, 2003]. J Biol Chem 2003;278 (11) 9790- 9795
PubMedArticle
16.
Cohen  CZavala-Pompa  ASequeira  JH  et al.  Mitogen-actived protein kinase activation is an early event in melanoma progression. Clin Cancer Res 2002;8 (12) 3728- 3733
PubMed
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