Downregulation of p27KIP1 and Ki67/Mib1 Labeling Index Support the Classification of Thyroid Carcinoma Into Prognostically Relevant Categories

Abstract

The cyclin-dependent kinase inhibitor p27KIP1 has been proposed as a valuable prognostic indicator for a variety of human neoplasms. Immunohistochemical reactivity for p27KIP1 and the proliferation marker Ki67/Mib1 were investigated in 90 thyroid carcinomas of follicular cell origin. The neoplasms were divided into three prognostic groups on the basis of their morphologic features: group 1, well-differentiated papillary or follicular carcinomas with favorable pathologic features (43 papillary carcinomas and 4 minimally invasive follicular carcinomas); group 2, papillary or follicular carcinomas with unfavorable pathologic features (21 poorly differentiated carcinomas and 2 papillary carcinomas, tall cell variant); and group 3, undifferentiated, or anaplastic, carcinomas. p27KIP1 expression (p = 0.007) and Ki67/Mib1 labeling index (p = 0.02) showed a strong correlation with the subdivision of the thyroid carcinomas in the three prognostic groups with a significant linear trend for tumors with low p27KIP1 (p = 0.002) and high Ki67/Mib1 labeling index (p = 0.005) to segregate into the unfavorable categories (groups 2 and 3). Low p27KIP1 expression, but not cellular proliferation, was related to adverse prognostic factors, such as large tumor size (p = 0.03) and extrathyroidal extension (p = 0.01), but the correlation was not independent of the subdivision in the three groups. Low p27KIP1 expression (p = 0.03) and high proliferative rate (p = 0.02) were associated with poor survival, reflecting the close association between patient morbidity and mortality rates and tumor differentiation. No significant association could be seen between p27KIP1 or cellular proliferation and clinicopathologic parameters (e.g., age, sex, tumor size, extrathyroidal extension, vascular invasion, lymph node metastases, distant metastases, tumor stage, and survival rate) within any of the groups, or the histologic diagnosis of papillary versus follicular carcinoma irrespective of their degree of differentiation. Modulation of p27KIP1 and cellular proliferation patterns in thyroid carcinoma correlate with tumor differentiation and support the morphologic classification of thyroid carcinoma into prognostically relevant categories.

Poorly differentiated carcinoma of the thyroid: validation of the Turin proposal and analysis of IMP3 expression

“…Thus, the usefulness of these markers in poorly differentiated carcinoma diagnosis is very limited. Similarly, an increase of proliferation index is associated with decrease of differentiation in thyroid tumors, 29 and Martyniak et al 30 suggested that p53 and Ki67 stains can assist in cases where diagnosis of poorly differentiated carcinoma is suspected on the basis of growth pattern, but lacking convoluted nuclei, increased mitotic count, or necrosis. In our experience, Ki67 might thus replace mitotic count as a more objective means of evaluating cell proliferation, but in well-preserved tissues, only.…”

Clinicopathological and molecular characterization of nine cases of columnar cell variant of papillary thyroid carcinoma

“…11,27 Mutations of candidate genes such as TP53 and CTNNB1, the gene encoding b-catenin, and abnormal cell cycle regulation, proliferation, and apoptosis are associated with aggressive neoplasms and have been suggested as markers of thyroid tumor progression. [28][29][30][31][32] Columnar cell carcinoma is a recognized variant of well-differentiated papillary thyroid carcinoma that is associated with an uncertain clinical course. Small size, encapsulation, and tumor circumscription are associated with a more favorable prognosis, whereas large size, extrathyroidal extension, and metastasis confer a worse prognosis.…”

“…57,58 A positive correlation between the nuclear overexpression of cyclin D1, cellular proliferation, and the proliferation marker, Ki-67, with tumor stage and aggressive biological behavior was reported previously. 31,32,39,[59][60][61][62][63][64] An alteration in the gene encoding cyclin D1 has not been reported in thyroid neoplasia, but a link between aberrant b-catenin expression and upregulation of cyclin D1 has been shown in a variety of neoplasms. [65][66][67] In this study, the nuclear expression of cyclin D1 was markedly increased in the vast majority of indolent and aggressive neoplasms.…”

Potent Mitogenicity of the RET/PTC3 Oncogene Correlates with Its Prevalence in Tall-Cell Variant of Papillary Thyroid Carcinoma

“…They have a greater tendency to local recurrences and are associated with a higher mortality (20 to 25%) than the classic PTC variant. 4 -6 Furthermore, DNA topoisomerase II 7 and p53 8 expression is higher, p27KIP1 expression lower, 9 and the frequency of trisomy of chromosome 2 higher 10 in the TCV than in classic PTC. Somatic rearrangements of the RET proto-oncogene are the most frequent genetic lesion found in PTC (from 2.5% to 40% depending on the series).…”