非小细胞肺癌NCCN指南2017第4版讨论（病理评估）

Pathologic Evaluation of Lung Cancer 肺癌的病理学评估

Pathologic evaluation is performed to classify the histologic type of the lung cancer, determine the extent of invasion, determine whether it is primary lung cancer or metastatic cancer, establish the cancer involvement status of the surgical margins (ie, positive or negative margins), and do molecular diagnostic studies to determine whether certain gene alterations are present (eg, epidermal growth factor receptor [EGFR] mutations) (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). Data show that targeted therapy is potentially very effective in patients with specific gene mutations or rearrangements (see EGFR Mutations, ALK Gene Rearrangements, and ROS1 Rearrangements in this Discussion). Preoperative evaluations include examination of the following: bronchial brushings, bronchial washings, sputum, FNA biopsy, core needle biopsy, endobronchial biopsy, and transbronchial biopsy. Minimally invasive techniques can be used to obtain specimens in patients with advanced unresectable NSCLC; however, diagnosis may be more difficult when using small biopsies and cytology. The mediastinal lymph nodes are systematically sampled to determine the staging and therapeutic options. Other lung diseases also need to be ruled out (eg, tuberculosis, sarcoidosis). 病理学评估的目的是对肺癌进行组织学分型、确定浸润范围、判断是原发性肺癌还是转移癌、确定手术切缘的癌症累及情况（即阳性或阴性切缘），并进行分子诊断研究以确定是否存在某些基因改变（如，表皮生长因子受体[EGFR]突变）（见非小细胞肺癌NCCN指南中的病理学评估原则）。数据显示，特定基因突变或重排的患者靶向治疗有可能非常有效（见本讨论中的EGFR突变和ALK基因重排）。术前评估包括下列检查：支气管刷检、支气管灌洗、痰液、细针穿刺活检、空心针穿刺活检、支气管内活检和经支气管肺活检。晚期不可切除的非小细胞肺癌患者，可以用微创技术来获取标本；不过，当使用小活检和细胞学时，诊断可能会更困难。对纵隔淋巴结进行系统采样，以确定分期和治疗方案。还需要排除其他肺部疾病（如结核病、结节病）。山东省肿瘤医院呼吸肿瘤内科张品良

Lobectomy or pneumonectomy specimens are evaluated intraoperatively to determine the surgical resection margin status, diagnose incidental nodules discovered at the time of surgery, or evaluate the regional lymph nodes. Postoperative evaluation provides the pathology characteristics necessary for the classification of tumor type, staging, and prognostic factors. The surgical pathology report should include the WHO histologic classification for carcinomas of the lung. In 2011, the classification for lung adenocarcinoma was revised by an international panel, which has been adopted by the WHO (see Adenocarcinoma in this Discussion). The revised classification recommends immunohistochemical (IHC) and molecular studies (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). In addition, the revised classification recommends that use of general categories (eg, NSCLC) should be minimized, because more effective treatment can be selected when the histology is known. 术中评估肺叶或全肺切除标本以确定手术切缘情况、确诊在手术时偶然发现的结节或评估区域淋巴结。术后评估提供必需的肿瘤分型、分期和预后因素病理特征。手术病理报告应采用WHO肺癌组织学分类。国际专家组在2011年修订了肺腺癌的分类并已被WHO采纳（见此讨论中的腺癌）。修订后的分类推荐免疫组织化学（IHC）和分子学研究（见非小细胞肺癌NCCN指南中的病理学评估原则）。此外，修订的分类法推荐应尽量避免使用综合分类（如，非小细胞肺癌），因为当组织学已知时，可以选择更有效的治疗。

Adenocarcinoma 腺癌

In the revised classification for adenocarcinoma, the categories of BAC or mixed subtype adenocarcinoma are no longer used. If necessary, former BAC can be used. The categories for adenocarcinoma include: 1) AIS (formerly BAC), which is a preinvasive lesion; 2) MIA; 3) invasive adenocarcinoma (includes formerly nonmucinous BAC); and 4) variants of invasive adenocarcinoma (includes formerly mucinous BAC). Both AIS and MIA are associated with excellent survival if they are resected. The international panel and NCCN recommend that all patients with adenocarcinoma be tested for EGFR mutations; the NCCN Panel also recommends that these patients be tested for anaplastic lymphoma kinase (ALK) gene rearrangements, ROS1 rearrangements, and programmed death (PD-1) receptor expression levels. The panel also advises testing for other genetic alterations to identify rare driver mutations for which effective therapy may be available such as BRAF V600E. The terms—AIS, MIA, and large cell carcinoma—should not be used for small samples because of challenges with cytology specimens.
在修订的腺癌分类法中，不再使用肺泡细胞癌（BAC）或混合腺癌亚型。如有必要，可以使用以前的肺泡细胞癌（BAC）。腺癌的类型包括：1）AIS（原位腺癌，以前称为肺泡细胞癌），这是一种癌前病变；2）MIA（微浸润腺癌）；3）浸润性腺癌（包括以前的非黏液性肺泡细胞癌）；和4）浸润腺癌的变异型（包括以前的黏液性肺泡细胞癌）。AIS（原位腺癌）和MIA（微小浸润性腺癌）如果切除两者均具有极好的生存。国际性组织和NCCN推荐对所有腺癌患者进行EGFR突变检测；NCCN小组还推荐对这些患者检测间变性淋巴瘤激酶（ALK）基因重排、ROS1重排以及程序性死亡（PD-1）受体表达水平。小组还建议检测其他的遗传学改变以确定罕见的、可获得有效治疗的驱动突变，如BRAF V600E。术语——AIS（原位腺癌）、MIA（微浸润腺癌）和大细胞癌——不应该用于小样本，因为面临细胞学标本的挑战。

Immunohistochemical Staining 免疫组化染色

Immunostains are used to differentiate primary pulmonary adenocarcinoma from metastatic adenocarcinoma to the lung (eg, breast, prostate, colorectal), to distinguish adenocarcinoma from malignant mesothelioma, and to determine the neuroendocrine status of tumors. IHC staining is described in the NSCLC algorithm (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). However, limited use of IHC in small tissue samples is recommended to conserve tumor tissue for molecular studies, especially in patients with advanced disease. The NCCN Panel recommends that IHC should be judiciously used to preserve tissue for molecular testing. Before using IHC, all findings should be assessed including routine H&E histology, clinical findings, imaging studies, and the patient’s history. Although cytology can be used to distinguish adenocarcinomas from squamous cell carcinomas, IHC is also useful for poorly differentiated NSCLC in small biopsy and/or cytology specimens. Squamous cell carcinomas are often TTF-1 negative and p63 positive, whereas adenocarcinomas are usually TTF-1 positive. These 2 markers may be sufficient to distinguish adenocarcinomas from squamous cell carcinomas. Other markers (eg, p40, Napsin A) may also be useful in distinguishing adenocarcinoma from squamous cell carcinoma. 免疫标记用于鉴别原发性肺腺癌和肺转移性腺癌（如乳腺、前列腺、结肠）、区分恶性间皮瘤的腺癌以及确定肿瘤的神经内分泌状态。免疫组化在NSCLC工作步骤中描述（见非小细胞肺癌NCCN指南中的病理学评估原则）。然而，在小组织标本中免疫组化应用受限，建议保存肿瘤组织进行分子研究，尤其是在晚期患者中。NCCN小组推荐对于保存的用于分子检测的组织应审慎使用免疫组化。在使用免疫组化之前，应评估所有的检查结果包括常规H&E组织学、临床表现、影像学检查及患者的病史。虽然细胞学可以用来区分腺癌与鳞癌，但是对于小活检的低分化NSCLC和/或细胞学标本免疫组化也是有用的。鳞癌通常是甲状腺转录因子1（TTF-1）阴性和p63阳性，而腺癌通常是TTF-1阳性。这两个标记可能足以区分腺癌与鳞癌。其他标记（如p40、新天冬氨酸蛋白酶A）在区分腺癌与鳞癌方面可能也是有用的。

An appropriate panel of IHC stains is recommended to rule out metastatic carcinoma to the lung if the primary origin of the carcinoma is uncertain. TTF-1 is very important for distinguishing primary lung adenocarcinoma from metastatic adenocarcinoma, because most primary adenocarcinomas are TTF-1 positive. TTF-1 is typically negative for squamous cell carcinoma. However, TTF-1 is positive in tumors from patients with thyroid cancer. In addition, thyroglobulin is present in tumors from patients with thyroid cancer, while it is negative in lung cancer tumors. Pulmonary adenocarcinoma of the lung is usually CK7+ and CK20-, whereas metastatic adenocarcinoma of the colorectum is usually CK7- and CK20+. CDX2 is a marker for metastatic gastrointestinal malignancies that can be used to differentiate them from primary lung tumors. All typical and atypical carcinoid tumors are positive for chromogranin and synaptophysin, whereas SCLC is negative in 25% of cases. 如果癌的原发灶不确定，推荐使用一组合理的免疫组化染色以排除肺转移性癌。对于识别原发肺腺癌与转移性腺癌，甲状腺转录因子1（TTF-1）是非常重要的，因为大多数原发性腺癌TTF-1阳性。鳞癌甲状腺转录因子1（TTF-1）通常阴性。然而，甲状腺癌患者的肿瘤甲状腺转录因子1（TTF-1）是阳性的。此外，甲状腺球蛋白存在于甲状腺癌患者的肿瘤中，而在肺癌肿瘤中阴性。肺部的肺腺癌通常是CK7+和CK20-，而结直肠的转移性腺癌通常是CK7-和CK20+。肠道特异性转录因子2（CDX2）是转移性胃肠道恶性肿瘤的一个标记物，可用于区分原发性肺肿瘤。所有的典型与不典型类癌，嗜铬粒蛋白和突触素均阳性，而25%的小细胞肺癌病例是阴性的。

Malignant pleural mesothelioma is a rare disease; IHC is valuable for distinguishing between malignant mesothelioma and lung adenocarcinoma. However, the NCCN Panel feels that malignant mesothelioma and lung adenocarcinoma can be distinguished using clinical impression, imaging, and a limited panel of immunomarkers (if needed) to preserve tissue for molecular testing. The stains that are positive for adenocarcinoma include carcinoembryonic antigen (CEA), B72.3, Ber-EP4, MOC-31, CD15, claudin-4, and TTF-1; these stains are negative for mesothelioma. Stains that are sensitive and specific for mesothelioma include WT-1, calretinin, D2-40 (podoplanin antibody), HMBW-1, and cytokeratin 5/6. If needed, a panel of 4 markers can be used to distinguish mesothelioma from adenocarcinoma—2 are positive in mesothelioma and 2 are positive in adenocarcinoma but negative in mesothelioma—including calretinin, cytokeratin 5/6 (or WT-1), CEA, and MOC-31 (or B72.3, Ber-EP4, or BG-8). 恶性胸膜间皮瘤是一种罕见病；对于区分恶性间皮瘤和肺腺癌，免疫组化（IHC）是有价值的。然而，NCCN小组认为恶性间皮瘤和肺腺癌可以用临床印象、影像学以及对保存的用于分子检测的组织用一组有限的免疫标记（如果需要）来区分。对于腺癌，阳性染色包括癌胚抗原（CEA）、CA724（B72.3）、Ep-CAM（上皮特异性抗原，Ber-EP4)、MOC-31、CD15、紧密连接蛋白-4和甲状腺转录因子-1（TTF-1）；对于间皮瘤，这些染色是阴性的。对于间皮瘤，敏感且特异的染色包括WT-1、钙结合蛋白、D2-40（平足蛋白抗体）、HMBW-1和细胞角蛋白5/6。如果需要，一组4个标记可以用来区分间皮瘤与腺癌——两个在间皮瘤中阳性、两个在腺癌中阳性但在间皮瘤中阴性——包括钙结合蛋白、细胞角蛋白5/6（或WT-1）、CEA和MOC-31（或B72.3、Ber-EP4或BG-8）。

Although the cytologic diagnosis of NSCLC is generally reliable, it is more difficult to diagnose SCLC. However, many patients with SCLC have characteristic CT and clinical findings (eg, massive lymphadenopathy, mediastinal invasion). Most SCLCs are immunoreactive for TTF-1; they are typically negative for CK34βE12 and p63. Many SCLCs also stain positively for markers of neuroendocrine differentiation, including chromogranin A, neuron-specific enolase, neural cell adhesion molecule, and synaptophysin. However, these markers alone cannot be used to distinguish SCLC from NSCLC, because approximately 10% of NSCLCs are immunoreactive for at least one of these neuroendocrine markers. Data suggest that microRNA expression can be used to distinguish SCLC from NSCLC. 虽然非小细胞肺癌的细胞学诊断通常是可靠的，但是诊断小细胞肺癌更困难。然而，许多小细胞肺癌患者具有典型的CT和临床表现（如淋巴结肿大、纵隔侵犯）。大多数小细胞肺癌甲状腺转录因子-1（TTF-1）免疫反应阳性；CK34βE12和p63通常是阴性的。神经内分泌分化的标记，包括嗜铬粒蛋白A、神经元特异性烯醇化酶、神经细胞黏附分子和突触素，许多小细胞肺癌染色也是阳性的。不过，这些标记不能用来区分小细胞肺癌和非小细胞肺癌，因为大约10%的非小细胞肺癌这些神经内分泌标记至少有一个阳性。数据表明，微小核糖核酸表达可以用来区分小细胞肺癌和非小细胞肺癌。