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北京大学学报（医学版） ›› 2023, Vol. 55 ›› Issue (2): 234-242. doi: 10.19723/j.issn.1671-167X.2023.02.006

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甲状腺粗针穿刺活检病理诊断的准确性评估

熊焰1,*(),李鑫1,梁丽1,李东1,鄢丽敏1,李雪迎2,邸吉廷1,李挺1   

  1. 1. 北京大学第一医院病理科，北京 100034
    2. 北京大学第一医院生物统计学室，北京 100034
  • 收稿日期:2022-10-11 出版日期:2023-04-18 发布日期:2023-04-12
  • 通讯作者: 熊焰 E-mail:yanxiong1109@163.com

Evaluation of accuracy of pathological diagnosis based on thyroid core needle biopsy

Yan XIONG1,*(),Xin LI1,Li LIANG1,Dong LI1,Li-min YAN1,Xue-ying LI2,Ji-ting DI1,Ting LI1   

  1. 1. Department of Pathology, Peking University First Hospital, Beijing 100034, China
    2. Department of Biostatistics, Peking University First Hospital, Beijing 100034, China
  • Received:2022-10-11 Online:2023-04-18 Published:2023-04-12
  • Contact: Yan XIONG E-mail:yanxiong1109@163.com

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摘要：

目的: 探讨甲状腺结节粗针穿刺活检(core needle biopsy, CNB)的病理诊断规范以及生物标记物在辅助良恶性肿瘤鉴别中的应用, 在此基础上分析甲状腺结节CNB的恶性确诊效率和临床价值。方法: 从2015—2020年以甲状腺结节就诊于北京大学第一医院的病例中筛选出既有术前CNB又有匹配的手术标本的病例, 共598例。CNB样本的诊断, 遵循韩国内分泌病理学甲状腺粗针穿刺工作组推荐的甲状腺粗针穿刺活检病理分类标准: Ⅰ级, 不具有诊断价值; Ⅱ级, 良性; Ⅲ级, 不确定; Ⅳ级, 滤泡肿瘤; Ⅴ级, 可疑恶性; Ⅵ级, 恶性。本组中共有40例CNB Ⅲ级的病例, 进一步行免疫组织化学染色(immunohistochemistry, IHC)和二代测序(next-generation sequencing, NGS)。IHC采用抗体CK19、Galectin-3、HBME-1和CD56。NGS采用OncoAim?甲状腺癌多基因检测试剂盒, 共检测26个基因, 覆盖甲状腺癌常见的基因突变。以术后诊断为金标准, 分析CNB术前确诊恶性的效率, 以及生物标记物辅助CNB Ⅲ级病例良恶性鉴别的效率。结果: 598例患者中, Ⅰ级0例, Ⅱ级40例, Ⅲ级40例, Ⅳ级32例, Ⅴ级35例, Ⅵ级451例。CNB Ⅳ级的病例术前确诊滤泡性肿瘤的灵敏度和特异度均为100.00%;CNB Ⅴ~Ⅵ级的病例术前确诊恶性的灵敏度为94.55%, 特异度为100.00%;CNB Ⅱ级的病例术前确诊良性的灵敏度为75.00%, 特异度为99.80%。生物标记物辅助CNB Ⅲ级病例确诊恶性的效率为: 将检测到"致病性"和"可疑致病性"突变定义为NGS阳性, 可获得96.30%的灵敏度和92.31%的特异度; 将CD56阴性或CD56阳性的同时其他三个标记物均阳性定义为IHC阳性, 可获得81.48%的灵敏度和92.30%的特异度。结论: 韩国甲状腺粗针穿刺活检病理分类标准兼顾了CNB样本的组织学特殊性和临床医生的习惯, 具有可操作性强、术前确诊率高、临床参考价值大的优点, 值得推广。遵循该分类标准, Ⅳ级的病例均应进一步手术切除, 鉴别良恶性; Ⅴ~Ⅵ级的病例推荐遵循恶性肿瘤的处理原则; Ⅱ级的病例绝大部分可安心随访, 极个别B超检查高度怀疑恶性者可考虑再次活检; Ⅲ级的病例应用生物标记物可高效辅助良恶性的鉴别诊断。

关键词: 甲状腺结节, 粗针穿刺活检, 病理诊断

Abstract:

Objective: To explore the protocol for diagnosing thyroid nodules based on core needle biopsy (CNB) and study the biomarkers' application in distinguishing indeterminate samples. Methods: Patients with thyroid nodules treated at Peking University First Hospital from 2015 to 2020 were reviewed. In the study, 598 cases with CNB and matched resected specimens were retrieved. According to "diagnostic categories of thyroid CNB" proposed by the Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group, the CNB samples were diagnosed as follows: Ⅰ, unsatisfactory; Ⅱ, benign; Ⅲ, indeterminate; Ⅳ, follicular neoplasm; Ⅴ, suspicious for malignancy; and Ⅵ, malignant. The samples of CNB Ⅲ were stained by immunohistochemistry (IHC) using antibodies against CK19, Galectin-3, HBME-1, and CD56, and detected by next-generation sequencing (NGS) using an OncoAim? thyroid cancer multigene assay kit (Singlera Genomics) that detected 26 genes. Taking the resected specimens' classification as the gold standard, the predictive value of CNB for determining the malignancy of thyroid nodules and the biomarkers for distinguishing the samples of CNB Ⅲ was calculated. Results: The study included 598 patients, of which none were CNB Ⅰ, 40 cases were CNB Ⅱ, 40 cases were CNB Ⅲ, 32 cases were CNB Ⅳ, 35 cases were CNB Ⅴ, and 451 cases were CNB Ⅵ. The predictive value of CNB Ⅳ for determining follicular neoplasm was sensitivity (Sen) 100.00% and specificity (Sep) 100.00%, CNB Ⅴ-Ⅵ for determining malignancy was Sen 94.55% and Sep 100.00%, CNB Ⅱ for determining benign lesions was Sen 75.00% and Sep 99.80%. The predictive value of biomarkers for determining malignancy in cases of CNB Ⅲ was Sen 96.30% and Sep 92.31% by NGS, and Sen 81.48% and Sep 92.30% by IHC. Conclusion: The Korean "diagnostic categories of thyroid CNB", which considers the histological specificity of CNB samples and the habits of clinicians, have strong operability, high diagnosis rate, and high clinical value. Under this framework, the cases of CNB Ⅵ should be treated with surgical operation, the cases of CNB Ⅴ-Ⅵ are recommended to be treated as malignant neoplasms, and the major cases of CNB Ⅱ could be followed up without worrisome except the one considered malignant by ultrasound. The value of biomarkers in distinguishing the cases of CNB Ⅲ is significant.

Key words: Thyroid nodule, Core needle biopsy, Pathological diagnosis

中图分类号: 

  • R736.1

表1

韩国内分泌病理学甲状腺粗针穿刺工作组推荐的甲状腺粗针穿刺活检病理分类[10]"

Categories Describe
Ⅰ Nondiagnostic or unsatisfactory
    Non-tumor adjacent thyroid tissue only
    Extrathyroid tissue only (e.g., skeletal muscle, mature adipose tissue)
    Acellular specimen (e.g., acellular fibrotic tissue, acellular hyalinized tissue, cystic fluid only)
    Blood clot only
    Other
Ⅱ Benign lesion
    Benign follicular nodule
    Hashimoto's thyroiditis
    Subacute granulomatous thyroiditis
    Nonthyroidal lesion (e.g., parathyroid lesions, benign neurogenic tumors, benign lymph node)
    Other
Ⅲ Indeterminate lesion
    Ⅲa     Indeterminate follicular lesion with nuclear atypia
    Ⅲb     Indeterminate follicular lesion with architectural atypia
    Ⅲc     Indeterminate follicular lesion with nuclear and architectural atypia
    Ⅲd     Indeterminate follicular lesion with Hürthle cell changes
    Ⅲe     Indeterminate lesion, not otherwise specified
Ⅳ Follicular neoplasm
    Ⅳa     Follicular neoplasm, conventional type
    Ⅳb     Follicular neoplasm with nuclear atypia
    Ⅳc     Hürthle cell neoplasm
    Ⅳd     Follicular neoplasm, not otherwise specified
Ⅴ Suspicious for malignancy
    Suspicious for papillary carcinoma, medullary carcinoma, poorly differentiated carcinoma, metastatic carcinoma, lymphoma, etc.
Ⅵ Malignant
    Papillary thyroid carcinoma, poorly differentiated carcinoma, anaplastic thyroid carcinoma, medullary thyroid carcinoma, lymphoma,
metastatic carcinoma, etc.

表2

OncoAim?甲状腺癌多基因检测试剂盒检测基因"

Gene Transcript Variation type
Mutation Fusion
BRAF NM_004333 Exon 15 Intron 7-10
RET NM_020975 Exon 7-16 Intron 10-11
NRAS NM_002524 Exon 2-3
KRAS NM_033360 Exon 2-4
HRAS NM_176795 Exon 2-3
AKT1 NM_005163 Exon 2-7, exon 9-12
ATM NM_000051 All exon
CNNB1 NM_001904 All exon
TSHR NM_000369 All exon
APC NM_000038 All exon
TTN NM_001256850 All exon
TG NM_003235 All exon
RB1 NM_000321 All exon
MEN1 NM_000244 All exon
PDGFRA NM_006206 All exon
PIK3CA NM_006218 All exon
CDKN2A NM_000077 All exon
EIF1AX NM_001412 All exon
PTEN NM_000314 Exon 5-8
GNAS NM_000516 Exon 8-9
TP53 NM_000546 Exon 5-9
TERT NM_198253 Promoter (chr5: 1 295 183-1 295 302)
PPARG NM_005037 Intron 1
NTRK1 NM_002529 Intron 9, exon 12
NTRK3 NM_002530 Intron 13
ALK NM_004304 Intron 16, intron 19

图1

粗针穿刺活检诊断为CNB Ⅲ级的病例匹配的手术切除标本诊断为乳头状癌的滤泡变型"

表3

CNB Ⅴ~Ⅵ级的恶性确诊效率"

Items Matched resected samples, n Predictive value/%
Malignant Benign Total Sen Sep PPV NPV AC
CNB Ⅴ-Ⅵ 486 0 486 94.55 100.00 100.00 65.00 95.05
Others 28 52 80
Total 514 52 566

表4

CNB Ⅱ级的良性确诊效率"

Items Matched resected samples, n Predictive value/%
Malignant Benign Total Sen Sep PPV NPV AC
CNB Ⅱ 39 1 40 75.00 99.80 97.50 97.53 97.53
Others 13 513 526
Total 52 514 566

表5

生物标记物辅助CNB Ⅲ级病例的恶性确诊效率"

Items Matched resected samples, n Predictive value/%
Malignant Benign Total Sen Spe PPV NPV AC
CK19 Positive 25 6 31 92.60 53.85 80.65 77.78 80.00
Negative 2 7 9
Galectin-3 Positive 25 8 33 92.60 38.46 75.76 71.42 75.00
Negative 2 5 7
HBME-1 Positive 21 3 24 77.78 76.92 87.50 62.50 77.50
Negative 6 10 16
CD56 Negative 17 0 17 62.96 100.00 100.00 56.52 75.00
Positive 10 13 23
IHC-COMB1 Positive 22 1 23 81.48 92.30 95.65 70.59 85.00
Negative 5 12 17
IHC-COMB2 Positive 27 5 32 100.00 61.54 84.38 100.00 87.50
Negative 0 8 8
IHC-COMB3 Positive 27 11 38 100.00 15.38 71.05 100.00 72.50
Negative 0 2 2
OncoAim? -NGS Positive 26 1 27 96.30 92.31 96.30 92.31 95.00
Negative 1 12 13
Total 27 13 40
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