Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Am J Surg Pathol. 2011 Mar;35(3):447-54. doi: 10.1097/PAS.0b013e31820a091d.
In recent years, immunohistochemistry has emerged as an efficient tool in the detection of DNA mismatch repair protein abnormality in colorectal cancers. Currently, the immunohistochemical test is mainly applied to cancer resection specimens. Detection of mismatch repair abnormality in biopsies carries obvious clinical importance, as it would allow informed decision about the extent of surgery (segmental resection vs total colectomy, prophylactic hysterectomy or not). Moreover, in the case of treated rectal carcinoma with no residual tumor, it provides a means to evaluate the mismatch repair proteins. However, whether biopsy samples can be reliably used for mismatch repair protein detection remains to be determined.
Paired biopsy and resection specimens of adenocarcinomas of the gastrointestinal tract, enriched for patients at increased risk for Lynch syndrome, were analyzed for immunohistochemical staining patterns for MLH1, MSH2, MSH6, and PMS2. Abnormal staining was defined as total loss of protein in the tumor with appropriate control. Cases with focal and weak staining, defined as staining of no more than moderate intensity present in <10% of the tumor cells, were recorded. Correlation analysis with germline mutation data was in a subset of cases.
Among 70 gastrointestinal tract cancers (3 from the small bowel, 36 from the right colon, 15 from the left colon, and 16 from the anorectum), both the biopsy and resection specimens detected the same 29 cancers as having loss of staining for at least 1 protein, 14 affecting MLH1/PMS2 and 15 affecting MSH2/MSH6. Focal and weak staining was most commonly seen for MLH1 stain in biopsies (4 of 70, 6%), followed by MSH6 stain in biopsies (3 of 70, 4%). Concordant staining patterns between biopsies and resections were reached in all 70 cases for MSH2 and PMS2, whereas discordant patterns were identified in 3 cases (3 of 70, 4%) for MLH1 and in 2 cases (2 of 70, 3%) for MSH6. None of the discordant patterns affected the final interpretation of whether the immunohistochemistry test was normal or abnormal in either the biopsy or the resection. In 13 of the 13 cases that were known to have a pathogenic germline mutation (5 in MLH1 and 8 in MSH2), the stains were abnormal for the corresponding protein and/or its partner protein in both the biopsy and the resection specimens.
This study provides data indicating that biopsy samples are as reliable as resections in the immunohistochemical detection of mismatch repair protein abnormality in intestinal cancers. Our study also shows that various staining variations can occur in both biopsies and resections. Awareness and further understanding of such variations will enhance the use of immunohistochemistry, a commonplace tool that is being increasingly used in the screening workup for Lynch syndrome.
近年来，免疫组织化学已成为检测结直肠癌中 DNA 错配修复蛋白异常的有效工具。目前，免疫组织化学检测主要应用于癌症切除标本。检测活检标本中的错配修复异常具有明显的临床意义，因为它可以帮助做出关于手术范围的明智决策（节段切除与全结肠切除、预防性子宫切除术与否）。此外，对于治疗后无残留肿瘤的直肠癌，它提供了一种评估错配修复蛋白的方法。然而，活检样本是否可以可靠地用于检测错配修复蛋白仍有待确定。
对胃肠道腺癌的配对活检和切除标本进行分析，这些标本富集了 Lynch 综合征风险增加的患者，用于 MLH1、MSH2、MSH6 和 PMS2 的免疫组织化学染色模式分析。异常染色定义为肿瘤中蛋白完全缺失，同时适当对照。记录存在局灶性和弱阳性染色的病例，定义为肿瘤细胞中不超过中等强度的染色，阳性细胞比例<10%。在部分病例中进行了与种系突变数据的相关性分析。
在 70 例胃肠道癌（3 例来自小肠，36 例来自右结肠，15 例来自左结肠，16 例来自直肠肛门）中，活检和切除标本均检测到 29 例至少有 1 种蛋白缺失染色的癌症，其中 14 例影响 MLH1/PMS2，15 例影响 MSH2/MSH6。活检中 MLH1 染色最常见局灶性和弱阳性（70 例中有 4 例，6%），其次是活检中 MSH6 染色（70 例中有 3 例，4%）。所有 70 例 MSH2 和 PMS2 活检和切除标本均达到一致的染色模式，而 MLH1 有 3 例（70 例中有 3 例，4%）和 MSH6 有 2 例（70 例中有 2 例，3%）存在不一致的染色模式。这些不一致的模式都不会影响活检或切除标本中免疫组织化学检测的正常或异常最终解释。在已知存在致病性种系突变的 13 例中（MLH1 中 5 例，MSH2 中 8 例），相应蛋白及其伴侣蛋白在活检和切除标本中的染色均异常。
本研究提供的数据表明，活检样本与切除标本一样可靠，可用于检测肠癌细胞中的错配修复蛋白异常。我们的研究还表明，活检和切除标本中均可出现各种染色变化。了解和进一步认识这些变化将提高免疫组织化学的应用水平，免疫组织化学是一种越来越多地用于 Lynch 综合征筛查的常用工具。
