title: Immunohistochemical study of apoptosis markers and involvement of chemokine CXCR4 in skin Merkel cell carcinoma.
abstract: BACKGROUND
  Merkel cell carcinoma (MCC) is a rare, aggressive cancer of the skin that mainly affects elderly patients. Because of its rarity, there is no established treatment or proven markers to guide therapy or prognosis. Immunohistochemical expression of apoptosis proteins is considered a useful marker of both malignancy and tumour progression. Apoptosis plays a fundamental role in skin homeostasis, and apoptotic cells have been detected in normal and diseased skin. Chemokines possess a wide range of biological activities and CXCR4 is expressed in some cancer cells, where it plays an efficient role in metastasis formation.
  
  
  OBJECTIVE
  To identify immunohistochemical parameters that can help clinicians select the most suitable therapy for skin MCC.
  
  
  METHODS
  Antibodies against ki67, bcl-2, p53, survivin, p16 and CXCR4 were tested to assess the usefulness of these antigens as indices of proliferation potential and predictors of prognosis.
  
  
  METHODS
  Immunohistochemical detection of apoptosis inhibitors and CXCR4 was performed on tissue from 12 patients with primary MCC. After excision of the primary lesion, five survived and had no metastases, and seven experienced local recurrence or lymph node metastases.
  
  
  RESULTS
  Expression of ki67 and survivin was increased in patients with local recurrence or metastasis (retrospectively classified as 'poor prognosis') compared with those with a 'good prognosis', and bcl-2 expression was significantly greater (P=0.003). P53 and p16 immunostaining was moderate in both groups. A positive correlation was observed between survivin and mutant p53 in the poor prognosis group (r=0.593, P=0.033; regression coefficient). High values of p53 were measured in patients with high levels of survivin and vice versa. CXCR4 was not detected at all.
  
  
  CONCLUSIONS
  Our results show strong MCC cell apoptosis inhibition and a high cell proliferation capacity. The positive correlation between survivin and p53 may be a predictor of MCC spread via the lymphatic network. Absent CXCR4 expression may reflect a less aggressive form, with less efficient development of distant and non-organ-selective metastasis formation.
authors.affiliation: U.O. Dermatologia, INRCA-IRCCS, Ancona, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Tucci
authors.forename: G
authors.initials: G
authors.lastname: Lucarini
authors.forename: M
authors.initials: M
authors.lastname: Giangiacomi
authors.forename: A
authors.initials: A
authors.lastname: Zizzi
authors.forename: P
authors.initials: P
authors.lastname: Criante
authors.forename: G
authors.initials: G
authors.lastname: Ricotti
authors.forename: G
authors.initials: G
authors.lastname: Biagini
mesh_terms: D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D015266:Carcinoma, Merkel Cell / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D015415:Biomarkers; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019718:Receptors, CXCR4; D000077022:Survivin; D016159:Tumor Suppressor Protein p53