Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis
Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis
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DOI：
10.1016/j.surg.2008.02.007
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发表时间：
2008-06-01
期刊：
影响因子：
3.8
通讯作者：
Ghossein, Ronald A.
中科院分区：
文献类型：
--
作者：
Strong, Vivian E.;Kennedy, Timothy;Ghossein, Ronald A.
背景嗜铬细胞瘤是恶性的，大约有10%的患者。良性和恶性肿瘤的组织学鉴别是困难的，后者通过转移性疾病或复发的存在来诊断。确定使用先前提出的肾上腺嗜铬细胞瘤评分（PASS）和细胞周期/凋亡标志物进行术后组织学评估是否可以预测患者的复发风险。使用纪念斯隆-凯特琳癌症中心肾上腺数据库，我们确定了48例患者51例切除嗜铬细胞瘤（1987-2006年）。一位对临床结果不知情的高级内分泌病理学家使用PASS系统审查了所有病例的组织病理学特征。该嗜铬细胞瘤评分系统基于12种不同的组织学参数，包括肿瘤坏死、有丝分裂率、肿瘤细胞纺锤形和大细胞巢的存在。此外，我们构建了所有5个恶性肿瘤和41个良性肿瘤的组织芯片。通过组织芯片的免疫组化染色，我们评估了7种不同的细胞周期/凋亡相关基因（p53，Ki-67，Bcl-2，mdm-2，cyclin D1，p21和p27）的表达。43例患者有一个良性的临床过程，而5例患者窝藏临床恶性嗜铬细胞瘤。肿瘤坏死（局灶性或融合性）是5例恶性肿瘤患者中4例（80%）出现恶性肿瘤的一个特别有力的指标，但仅在42例良性肿瘤患者中3例（7%）出现（P = 0.0009）。高有丝分裂率（>3/10高倍视野）和肿瘤细胞梭形与恶性程度显著相关（分别为P = 0.026和0.041）。恶性病变中高细胞性更常见（P = 0.050）。良性和恶性病例的PASS评分有非常显著的差异（P = 0.0003）。所有恶性嗜铬细胞瘤的PASS评分>= 6，远高于先前提出的>= 4的临界值。4例Ki-67阳性（核染色>2%）的患者中有2例临床表现为恶性，而41例Ki-67阳性率较低的患者中只有3例（7%）表现为恶性（P =. 001）。055）。Ki-67阳性肿瘤发生肿瘤坏死的机会明显高于Ki-67阴性肿瘤（P <0.01）。p53、Bcl-2、mdm-2、cyclin D1、p21、p27在良恶性嗜铬细胞瘤中的表达无差异。(1)PASS评分= 6，明显高于良性病变。PASS评分>= 4的患者应密切随访复发情况。(3)p53、Bcl-2、mdm-2细胞周期蛋白D1、p21和p27似乎在预测嗜铬细胞瘤的行为方面没有作用。Ki-67可能有助于通过提示病理学家积极寻找不良组织学特征来识别那些有复发风险的肿瘤。
Background. Pheochromocytomas are malignant in similar to 10% of patients. The histologic differentiation between benign and malignant tumors is difficult, the latter diagnosed by the presence of metastatic disease or recurrence.Aim. To determine if postoperative histologic evaluation using the previously proposed Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and cell cycle/apoptosis markers can Predict Patients at risk for recurrence.Methods. Using the Memorial Sloan-Kettering Cancer Center adrenal database, we identified 48 patients with 51 resected pheochromocytomas (1987-2006). A senior endocrine pathologist, blinded to clinical outcome, reviewed the histopathologic characteristics of all cases using the PASS system. This pheochromocytoma scoring system is based on the presence of 12 different histologic parameters, including tumor necrosis, mitotic rate, tumor cell spindling, and the presence of large cell nests. In addition, we constructed a tissue microarray of all 5 malignant tumors and 41 of the benign tumors. By immunostaining of the tissue microarray, we assessed the expression of 7 different cell cycle/apoptosis-related genes (p53, Ki-67, Bcl-2, mdm-2, cyclin D1, p21, and p27).Results. Forty-three patients had a benign clinical course while 5 patients harbored a clinically malignant pheochromocytoma. Tumor necrosis (focal or confluent) was a particularly powerful indicator of malignancy present in 4 of 5 patients (80%) with malignant tumors, but only in 3 of 42 cases (7%) with benign neoplasms (P = .0009). The presence of a high mitotic rate (>3/10 high power fields) and tumor cell spindling significantly correlated with malignancy (P = .026 and .041, respectively). High cellularity was more often present in the malignant lesions (P = .050). There was a highly significant difference in PASS scores between benign and malignant cases (P = .0003). All malignant pheochromocytomas had a PASS score >= 6, well above the previously proposed >= 4 cutoff value. Two of the 4 Patients testing positive for Ki-67 (>2% nuclear staining) had a clinically malignant course while only 3 (7%) of the 41 cases with lower Ki-67 positivity rate behaved in a malignant fashion (P =. 055). Ki-67-positive tumor had a significantly higher chance of harboring tumor necrosis than Ki-67-negative neoplasms (P < .01). There was no difference in staining between benign and malignant pheochromocytomas using p53, Bcl-2, mdm-2, cyclin D1, p21, and p27.Conclusions. (1) A PASS score of = 6, which was significantly higher compared with the benign lesions. Patients with a PASS score >= 4 should be followed closely for recurrence. (3) p53, Bcl-2, mdm-2 cyclin D1, p21, and p27 appear to have no role in predicting the behavior of pheochromocytomas. Ki-67 may help identify those neoplasms at risk for recurrence by prompting the pathologist to look aggressively for adverse histologic features.