Krohn K, Emmrich P, Ott N, Paschke R
III. Medical Department, University of Leipzig, Germany.
Thyroid. 1999 Mar;9(3):241-6. doi: 10.1089/thy.1999.9.241.
Most toxic thyroid nodules (TTN) result from clonal expansion of a single cell caused by a somatic mutation in the thyrotropin (TSH) receptor, the Gsalpha protein, or yet unknown proteins. Expanding a single cell into a TTN with thousands of cells suggests a prolonged increase in proliferation compared to nonaffected surrounding cells. To test this hypothesis, we evaluated cell proliferation in TTN. Tissue from 20 TTN and their surrounding normal thyroid tissue was studied for the occurrence of the proliferating cell nuclear antigen (PCNA) and Ki-67 epitope as markers for cell proliferation. The labeling index (number of labeled cells versus total cell number) for nodular and surrounding tissue was calculated. Nineteen samples were evaluated for PCNA immunohistochemistry. In 16 TTN, a significant (p< or =0.05%) up to 3-fold increase in the labeling index for PCNA was detectable. In only 3 toxic nodules (2 without a detectable TSH receptor or Gsalpha protein mutation), we found no significant difference in the labeling index compared to the surrounding tissue. Because labeling for KI-67 was much lower, only 16 toxic thyroid nodules were quantified. Twelve of these showed significantly (p< or =0.05%) increased labeling indices. The increase of the labeling index for both markers was similar for histologically defined adenoma versus adenomatous nodule or nodules with or without TSH receptor mutation or clonal versus polyclonal origin of toxic nodules studied. These findings are evidence that an increased thyroid epithelial cell proliferation is a uniform feature common to most TTNs, independent of their histopathological or molecular characteristics. Although increased proliferation in many TTNs is very likely the result of TSH receptor mutations, the cause of increased proliferation in TTN without a mutation is unknown.
大多数毒性甲状腺结节（TTN）是由促甲状腺激素（TSH）受体、Gsα蛋白或其他未知蛋白中的体细胞突变导致的单个细胞克隆性扩增引起的。将单个细胞扩增成含有数千个细胞的TTN，这表明与未受影响的周围细胞相比，其增殖持续增加。为了验证这一假设，我们评估了TTN中的细胞增殖情况。对20个TTN及其周围正常甲状腺组织进行研究，检测增殖细胞核抗原（PCNA）和Ki-67抗原决定簇作为细胞增殖标志物的情况。计算结节组织和周围组织的标记指数（标记细胞数与总细胞数之比）。对19个样本进行了PCNA免疫组织化学评估。在16个TTN中，可检测到PCNA标记指数显著升高（p≤0.05%），最高可达3倍。仅在3个毒性结节中（2个未检测到TSH受体或Gsα蛋白突变），我们发现其标记指数与周围组织相比无显著差异。由于Ki-67的标记率低得多，仅对16个毒性甲状腺结节进行了定量分析。其中12个显示标记指数显著升高（p≤0.05%）。对于组织学定义的腺瘤与腺瘤性结节，或有或无TSH受体突变的结节，以及毒性结节的克隆性与多克隆性起源，两种标志物的标记指数升高情况相似。这些发现证明，甲状腺上皮细胞增殖增加是大多数TTN共有的一个统一特征，与它们的组织病理学或分子特征无关。虽然许多TTN中增殖增加很可能是TSH受体突变所致，但无突变的TTN中增殖增加的原因尚不清楚。
