Departments of *Pathology †Surgery, Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA.
Am J Surg Pathol. 2014 May;38(5):583-92. doi: 10.1097/PAS.0000000000000194.
The distinction between low-grade and high-grade disseminated appendiceal mucinous neoplasms is of critical importance in assessing prognosis and guiding patient therapy. SMAD4 encodes a protein that is a central component of the TGFβ signal transduction pathway, and loss of SMAD4 expression has been associated with poor prognosis in carcinomas of the gastrointestinal tract. We reviewed the clinicopathologic and molecular features of 109 disseminated appendiceal mucinous neoplasms identified over an 8-year period at our institution in an attempt to: (1) correlate SMAD4 immunohistochemical expression with tumor grade; and (2) assess the prognostic significance of SMAD4 expression in predicting overall survival. Compared with tumors demonstrating preserved SMAD4 expression, tumors with loss of SMAD4 expression more frequently exhibited high cytologic grade (85% vs. 50%, P=0.035), high cellularity (100% vs. 45%, P<0.001), and destructive invasion (100% vs. 55%, P=0.001). SMAD4 expression significantly correlated with overall tumor grade (P=0.003): all 13 tumors with loss of SMAD4 expression were high grade, whereas all 42 low-grade tumors displayed preserved SMAD4 expression. A significantly higher proportion of tumors with loss of SMAD4 immunohistochemical expression demonstrated loss of heterozygosity at chromosome 18q (38%) compared with tumors with preserved SMAD4 expression (11%) (P=0.049), suggesting that loss of SMAD4 expression is due to genomic deletion in a high proportion of cases. Patients with SMAD4-negative tumors had significantly worse overall survival in comparison with patients with preserved SMAD4 expression (log rank P=0.023). However, our multivariable analysis found that SMAD4 expression was not independent of overall tumor grade in predicting overall survival. Our results indicate that loss of SMAD4 immunohistochemical expression is associated with loss of heterozygosity at chromosome 18q and is always associated with aggressive histologic features in disseminated appendiceal mucinous neoplasms. SMAD4 immunohistochemistry may be a useful ancillary study in select cases of disseminated appendiceal neoplasia, in which the distinction between low-grade and high-grade tumors is difficult.
低级别和高级别播散性阑尾黏液性肿瘤的区分对评估预后和指导患者治疗至关重要。SMAD4 编码一种蛋白，是 TGFβ 信号转导途径的核心组成部分，SMAD4 表达缺失与胃肠道癌的预后不良相关。我们回顾了 8 年来在我们机构中发现的 109 例播散性阑尾黏液性肿瘤的临床病理和分子特征，试图：(1) 将 SMAD4 免疫组织化学表达与肿瘤分级相关联；(2) 评估 SMAD4 表达在预测总生存率方面的预后意义。与保留 SMAD4 表达的肿瘤相比，SMAD4 表达缺失的肿瘤更常表现出高细胞学分级(85%比 50%，P=0.035)、高细胞密度(100%比 45%，P<0.001)和破坏性浸润(100%比 55%，P=0.001)。SMAD4 表达与总肿瘤分级显著相关(P=0.003)：SMAD4 表达缺失的 13 例肿瘤均为高级别，而所有 42 例低级别肿瘤均显示保留 SMAD4 表达。SMAD4 免疫组织化学表达缺失的肿瘤中，染色体 18q 杂合性缺失的比例明显高于保留 SMAD4 表达的肿瘤(38%比 11%，P=0.049)，提示在大多数情况下，SMAD4 表达缺失是由于基因组缺失所致。与保留 SMAD4 表达的患者相比，SMAD4 阴性肿瘤患者的总生存率明显较差(对数秩检验，P=0.023)。然而，我们的多变量分析发现，SMAD4 表达在预测总生存率方面并非独立于总肿瘤分级。我们的结果表明，SMAD4 免疫组织化学表达缺失与染色体 18q 杂合性缺失相关，并且总是与播散性阑尾黏液性肿瘤中侵袭性组织学特征相关。SMAD4 免疫组织化学检查可能是在某些播散性阑尾肿瘤中有用的辅助研究，在这些肿瘤中，低级别和高级别肿瘤的区分很困难。
