Ambros R A, Kallakury B V, Malfetano J H, Mihm M C
Department of Pathology, Albany Medical College, NY 12208, USA.
Int J Gynecol Pathol. 1996 Oct;15(4):320-5. doi: 10.1097/00004347-199610000-00004.
In a previous report, we observed by light microscopy the extracellular matrix in 51 vulvar squamous carcinomas and found that some tumors has a prominent stromal response in the form of a regional or diffuse zone of extracellular myxoid matrix containing immature collagen and fibroblasts at the tumor-stromal junction. These tumors were associated with clitoral involvement, ulcerative nonexophytic growth pattern, older age groups, poorer survival rate, and more extensive lymph node metastases than when prominent fibromyxoid stromal response (PFSR) was absent. This behavior was demonstrated despite the fact that these tumors were not larger, more deeply invasive, or of higher grade than when PFSR was absent. In the current immunohistochemical study, we examined cytokine, cell adhesion receptor, and tumor suppressor gene expression in 50 vulvar squamous carcinomas using a panel of antibodies to identify any potential role of these proteins in the development of a PFSR. Semiquantification of expression into none, focal (< 25% of cells showing expression), regional (25-50%), and diffuse (> 50%) patterns revealed PFSR to be statistically associated with high CD44, transforming growth factor (TGF) beta 3, and p53 protein expression, but not with fibroblast growth factor, epidermal growth factor, epidermal growth factor receptor, or E-cadherin expression. When expression of CD44 and either stromal or tumor TGF-beta 3 expression was high, i.e., regional or diffuse in distribution, 15 (50%) of 30 cases were associated with PFSR. In contrast, only 1 (7%) of 14 cases was associated with PFSR when expression was high for only one of these two proteins and none of 3 cases was associated with response when expression was low for both proteins (p = 0.005). Furthermore, in cases showing high expression for both TGF-beta 3 and CD44, PFSR was found in 13 (72%) of 18 cases when p53 expression was diffuse compared with 2 (17%) of 12 cases when expression was less (p = 0.01). Since TGF-beta acts mitogenically for fibroblasts and has been shown to be an inhibitor of epithelial cell growth, its high expression in a carcinoma with PFSR would suggest loss of effect on the epithelial component but an intact effect on the stroma. Since CD44 is known to act as a receptor for hyaluronic acid, which is a prominent stromal component and known to play an important role in cell mobility and tumor aggressiveness, its high expression in association with PFSR would suggest a role of CD44 overexpression in altered hyaluronate metabolism with accelerated tumor cell migration and subsequent distal spread. The current study demonstrates that alterations in cytokine and cell adhesion receptor status variably occur in vulvar squamous carcinoma and that such alterations may affect tumor morphology and behavior.
在之前的一份报告中，我们通过光学显微镜观察了51例外阴鳞状细胞癌中的细胞外基质，发现一些肿瘤在肿瘤-基质交界处有显著的基质反应，表现为局部或弥漫性的细胞外黏液样基质区，其中含有未成熟的胶原蛋白和成纤维细胞。与无显著纤维黏液样基质反应（PFSR）的肿瘤相比，这些肿瘤与阴蒂受累、溃疡型非外生性生长模式、老年人群、较差的生存率以及更广泛的淋巴结转移相关。尽管这些肿瘤在大小、浸润深度或分级方面并不比无PFSR时更大、更深或更高，但仍表现出这种行为。在当前的免疫组织化学研究中，我们使用一组抗体检测了50例外阴鳞状细胞癌中细胞因子、细胞黏附受体和肿瘤抑制基因的表达，以确定这些蛋白质在PFSR发生过程中的任何潜在作用。将表达半定量为无、局灶性（<25%的细胞显示表达）、区域性（25-50%）和弥漫性（>50%）模式，结果显示PFSR与高CD44、转化生长因子（TGF）β3和p53蛋白表达在统计学上相关，但与成纤维细胞生长因子、表皮生长因子、表皮生长因子受体或E-钙黏蛋白表达无关。当CD44表达以及基质或肿瘤TGF-β3表达较高，即分布为区域性或弥漫性时，30例中有15例（50%）与PFSR相关。相比之下，当这两种蛋白中只有一种表达较高时，14例中只有1例（7%）与PFSR相关，而当两种蛋白表达均较低时，3例中无一例与反应相关（p=0.005）。此外，在TGF-β3和CD44均高表达的病例中，当p53表达为弥漫性时，18例中有13例（72%）出现PFSR，而当表达较少时，12例中有2例（17%）出现PFSR（p=0.01）。由于TGF-β对成纤维细胞有促有丝分裂作用，并且已被证明是上皮细胞生长的抑制剂，其在伴有PFSR的癌中的高表达表明对上皮成分的作用丧失，但对基质的作用完整。由于已知CD44作为透明质酸的受体，透明质酸是一种突出的基质成分，并且已知在细胞迁移和肿瘤侵袭性中起重要作用，其与PFSR相关的高表达表明CD44过表达在改变透明质酸代谢、加速肿瘤细胞迁移及随后的远处扩散中发挥作用。当前研究表明，外阴鳞状细胞癌中细胞因子和细胞黏附受体状态的改变各不相同地发生，并且这种改变可能影响肿瘤形态和行为。
