cyclin-d1 and Laryngeal-Diseases

In a previous trial, we found that combined 13-cis-retinoic acid, IFN-alpha, and alpha-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that cyclin D1 (CD1) G/A870 single nucleotide polymorphism correlated with cancer risk. We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1, both genotype and protein expression, in association with cancer risk in this setting. Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined 13-cis-retinoic acid daily, alpha-IFN twice weekly, and alpha-tocopherol daily for 1 year; 14 nonprogressing patients then were randomized to maintenance fenretinide or placebo for 2 years. During induction, two patients had pathologic complete responses, six had partial responses (30% overall response rate), and five developed laryngeal cancer. There were no significant differences between maintenance fenretinide and placebo in response or cancer rates. Ten patients developed cancer overall. Twenty-four patients were evaluated for the CD1 G/A870 genotype, and 23 for pretreatment and posttreatment CD1 protein expression. Consistent with our earlier report, shorter cancer-free survival was associated with the CD1 AA/AG genotype (P = 0.05). Extending our earlier work, high CD1 expression was associated with worse cancer-free survival overall (P = 0.04) and within each CD1 genotype group. These findings support CD1 genotype and protein expression as important risk markers for laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription.

Topics: alpha-Tocopherol; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cyclin D1; Female; Fenretinide; Gene Expression; Genotype; Humans; Immunohistochemistry; Interferon-alpha; Isotretinoin; Laryngeal Diseases; Laryngeal Neoplasms; Male; Polymorphism, Single Nucleotide; Precancerous Conditions

To evaluate CD163+ tumor-associated macrophages (TAMs), Ki-67, and cyclin D1 to differentiate laryngeal dysplasia in the 2017 World Health Organization classification.. Immunohistochemistry for CD163, Ki-67, and cyclin D1 was performed using paraffin-embedded specimens. CD163+ TAMs infiltrating the epithelium were estimated. Ki-67 and cyclin D1 were evaluated in four parts of the epithelium-basal, parabasal, middle third, and upper third layers.. In total, 133 specimens were analyzed, including low-grade dysplasia (n = 31), high-grade dysplasia (n = 49), carcinoma in situ (n = 23), and normal mucosa (n = 30). CD163+ TAMs infiltrating the epithelium were significantly higher in high-grade dysplasia than in low-grade dysplasia. In the basal layer, Ki-67+ and cyclin D1+ cells were overexpressed in high-grade dysplasia (P < .0001). The area under the curve was 0.958 for Ki-67 and 0.909 for CD163+ TAMs (P < .0001).. CD163+ TAMs infiltrating the epithelium and Ki-67 overexpression in the basal layer may serve as biomarkers to differentiate low-grade dysplasia from high-grade dysplasia of the larynx. A symmetric proliferative pattern was observed during laryngeal carcinogenesis following Ki-67 overexpression.

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Carcinoma in Situ; Cyclin D1; Humans; Immunohistochemistry; Ki-67 Antigen; Laryngeal Diseases; Laryngeal Mucosa; Laryngeal Neoplasms; Macrophages; Receptors, Cell Surface

Squamous carcinoma of the larynx arises from pre-existing lesions, the so-called "preneoplastic lesions". Hyperplastic lesions represent a part of their spectrum, from both clinical and biological points of view. On morphologic grounds, the most characteristic feature with prognostic value in the evaluation of preneoplastic lesions is dysplasia. It is not only nuclear alterations that are seen in the process of malignant transformation, the cytoplasmic pattern of cytokeratins changes through neoplastic progression, with a progressive reduction of the molecular weight of the produced species. Dysplasia also associates with gross alterations of the DNA content. This is in agreement with our finding of alterations of genes participating in the control of the cell cycle, p53 and p21(WAF1/cip1). p53 overexpression is detected in non-invasive squamous lesions (even in the absence of obvious dysplasia) and p21(WAF1/cip1) shows a dramatic change in the pattern of expression in dysplastic epithelium compared with the normal. However, not all genes participating in the control of the cell cycle are altered in early lesions. Overexpression of cyclin D1, a common phenomenon in advanced carcinomas, is not likely to participate in the early phases of neoplastic development.

Topics: Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cyclin D1; Cyclin-Dependent Kinases; Cyclins; DNA, Neoplasm; Epithelium; Genes, p53; Humans; Hyperplasia; Keratins; Laryngeal Diseases; Laryngeal Mucosa; Laryngeal Neoplasms; Oncogene Proteins; Precancerous Conditions