Cote R J, Rosen P P, Hakes T B, Sedira M, Bazinet M, Kinne D W, Old L J, Osborne M P
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Am J Surg Pathol. 1988 May;12(5):333-40. doi: 10.1097/00000478-198805000-00001.
Thirty-five to 40% of patients with operable breast carcinoma develop metastases after primary therapy. There is a need for more specific prognostic parameters to identify patients who are most likely to benefit from adjuvant therapy. The success of such treatment stems from its ability to eradicate preclinical microscopic metastases. The bone marrow is an accessible and frequent site of breast carcinoma metastases. Following studies of Redding et al. (16), we used monoclonal antibodies that recognize membrane and cytoskeletal antigens expressed by epithelial cells (C26, T16, AE-1) in an immunohistochemical assay to find cancer cells in bone marrow aspirates. The assay can detect one cancer cell among 50,000-100,000 hematopoietic cells. None of the 44 control bone marrows (from normal individuals and patients with leukemias and lymphomas) contained antigen-positive (extrinsic) cells. We found extrinsic cells in the bone marrow of 35% (18 of 51) of patients with operable breast carcinoma; no extrinsic cells were identified by routine bone marrow cytology in these patients. Twenty-seven percent (six of 22) of patients with negative lymph nodes had antigen-positive cells, while 41% (12 of 29) of patients with lymph node metastases had such cells. Similarly, 23% (three of 13) of patients with TNM stage I disease, 38% (13 of 34) of patients with stage II disease, and 50% (two of four) of patients with stage III disease had extrinsic cells. In those cases where extrinsic cells were identified, stage II patients with negative lymph nodes and patients with stage I disease were found to have fewer such cells in their marrow than patients with lymph node metastases and patients with stage II disease. These trends did not reach the level of statistical significance in this small number of patients. The presence of extrinsic cells did not correlate with tumor size of lymphatic invasion around the tumor. We conclude that the epithelial cells detected in the bone marrow of the patients with breast carcinoma were carcinoma cells based on the following criteria: (a) they expressed both membrane and cytoplasmic epithelia-specific antigens, (b) they possessed the cytologic characteristics of malignant epithelial cells, and (c) these cells were not detected in the bone marrow from normal individuals or patients with nonepithelial neoplasms involving the bone marrow. We have shown that the technique described here can detect occult metastases in bone marrow and that the presence of extrinsic cells correlates with some established predictors of prognosis. Long-term clinical correlative follow-up studies are now underway.
35%至40%的可手术乳腺癌患者在接受初始治疗后会发生转移。需要更具特异性的预后参数来识别最有可能从辅助治疗中获益的患者。此类治疗的成功源于其根除临床前微小转移灶的能力。骨髓是乳腺癌转移易于累及且常见的部位。继雷丁等人（参考文献16）的研究之后，我们在免疫组织化学分析中使用了能识别上皮细胞表达的膜抗原和细胞骨架抗原的单克隆抗体（C26、T16、AE - 1），以在骨髓穿刺物中查找癌细胞。该分析可在50000 - 100000个造血细胞中检测到一个癌细胞。44份对照骨髓（来自正常个体以及白血病和淋巴瘤患者）中均未含有抗原阳性（外来）细胞。我们在35%（51例中的18例）可手术乳腺癌患者的骨髓中发现了外来细胞；这些患者的常规骨髓细胞学检查未发现外来细胞。27%（22例中的6例）淋巴结阴性的患者有抗原阳性细胞，而41%（29例中的12例）有淋巴结转移的患者有此类细胞。同样，TNM I期疾病患者中有23%（13例中的3例）、II期疾病患者中有38%（34例中的13例）以及III期疾病患者中有50%（4例中的2例）有外来细胞。在那些发现有外来细胞的病例中，淋巴结阴性的II期患者和I期疾病患者骨髓中的此类细胞数量少于有淋巴结转移的患者和II期疾病患者。在这一小部分患者中，这些趋势未达到统计学显著水平。外来细胞的存在与肿瘤周围淋巴管浸润的肿瘤大小无关。我们基于以下标准得出结论：乳腺癌患者骨髓中检测到的上皮细胞为癌细胞，即（a）它们同时表达膜上皮特异性抗原和细胞质上皮特异性抗原，（b）它们具有恶性上皮细胞的细胞学特征，（c）在正常个体或未累及骨髓的非上皮性肿瘤患者的骨髓中未检测到这些细胞。我们已表明，此处描述的技术可检测骨髓中的隐匿性转移灶，且外来细胞的存在与一些已确立的预后预测指标相关。长期的临床相关性随访研究正在进行中。
