甲状腺粗针穿刺活检病理诊断的准确性评估

doi:10.19723/j.issn.1671-167X.2023.02.006

摘要/Abstract

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

熊焰,李鑫,梁丽,李东,鄢丽敏,李雪迎,邸吉廷,李挺. 甲状腺粗针穿刺活检病理诊断的准确性评估[J]. 北京大学学报（医学版）, 2023, 55(2): 234-242.

Yan XIONG,Xin LI,Li LIANG,Dong LI,Li-min YAN,Xue-ying LI,Ji-ting DI,Ting LI. Evaluation of accuracy of pathological diagnosis based on thyroid core needle biopsy[J]. Journal of Peking University (Health Sciences), 2023, 55(2): 234-242.

图/表 6

表1

表2

图1

表3

表4

表5

参考文献 24

1	Teng WLY , Gao M , Huang G , et al. Guidelines on the diagnosis and treatment of thyroid nodules and differentiated thyroid carcinomas[J]. Chin J Endocrinol Metab, 2012, 28 (10): 779- 797.
2	Pitman MB , Abele J , Ali SZ , et al. Techniques for thyroid FNA: A synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference[J]. Diagn Cytopathol, 2008, 36 (6): 407- 424. doi: 10.1002/dc.20829
3	Suster S . Controversies regarding the interpretation of follicular thyroid nodules[J]. Arch Pathol Lab Med, 2019, 143 (12): 1472- 1476. doi: 10.5858/arpa.2019-0301-RA
4	Ha EJ , Baek JH , Lee JH , et al. Complications following US-guided core-needle biopsy for thyroid lesions: A retrospective study of 6 169 consecutive patients with 6 687 thyroid nodules[J]. Eur Radiol, 2017, 27 (3): 1186- 1194. doi: 10.1007/s00330-016-4461-9
5	Jung CK , Baek JH , Na DG , et al. 2019 Practice guidelines for thyroid core needle biopsy: A report of the Clinical Practice Guidelines Development Committee of the Korean Thyroid Association[J]. J Pathol Transl Med, 2020, 54 (1): 64- 86. doi: 10.4132/jptm.2019.12.04
6	Lloyd RV , Osamura RY , Klöppel G . WHO classification of tumours of endocrine organs[M]. 4th ed Lyon: International Agency for Research on Cancer (IARC), 2017: 65- 142.
7	Dunderovic D , Lipkovski JM , Boricic I , et al. Defining the value of CD56, CK19, Galectin 3 and HBME-1 in diagnosis of follicular cell derived lesions of thyroid with systematic review of literature[J]. Diagn Pathol, 2015, 10, 196. doi: 10.1186/s13000-015-0428-4
8	Gharib H , Papini E , Garber JR , et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: 2016 update[J]. Endocr Pract, 2016, 22 (5): 622- 639.
9	Haugen BR , Alexander EK , Bible KC , et al. 2015 American Thyroid Association Management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer[J]. Thyroid, 2016, 26 (1): 1- 133. doi: 10.1089/thy.2015.0020
10	Na DG , Baek JH , Jung SL , et al. Core needle biopsy of the thyroid: 2016 Consensus Statement and Recommendations from Korean Society of Thyroid Radiology[J]. Korean J Radiol, 2017, 18 (1): 217- 237. doi: 10.3348/kjr.2017.18.1.217
11	Travis WDBE , Burke AP , Marx A , et al. WHO classification of tumurs of the lung, pleura, thymus and hear[M]. 4th ed Lyon: International Agency for Research on Cancer (IARC), 2015: 29- 36.
12	Jung CK , Min HS , Park HJ , et al. Pathology reporting of thyroid core needle biopsy: A proposal of the Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group[J]. J Pathol Transl Med, 2015, 49 (4): 288- 299. doi: 10.4132/jptm.2015.06.04
13	Wolinski K , Stangierski A , Ruchala M . Comparison of diagnostic yield of core-needle and fine-needle aspiration biopsies of thyroid lesions: Systematic review and meta-analysis[J]. Eur Radiol, 2017, 27 (1): 431- 436. doi: 10.1007/s00330-016-4356-9
14	Song S , Kim H , Ahn SH . Role of immunohistochemistry in fine needle aspiration and core needle biopsy of thyroid nodules[J]. Clin Exp Otorhinolaryngol, 2019, 12 (2): 224- 230. doi: 10.21053/ceo.2018.01011
15	Cancer Genome Atlas Research Network . Integrated genomic characterization of papillary thyroid carcinoma[J]. Cell, 2014, 159 (3): 676- 690. doi: 10.1016/j.cell.2014.09.050
16	D'Cruz AK , Vaish R , Vaidya A , et al. Molecular markers in well-differentiated thyroid cancer[J]. Eur Arch Otorhinolaryngol, 2018, 275 (6): 1375- 1384. doi: 10.1007/s00405-018-4944-1
17	Landa I , Ibrahimpasic T , Boucai L , et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers[J]. J Clin Invest, 2016, 126 (3): 1052- 1066. doi: 10.1172/JCI85271
18	Patel KN , Angell TE , Babiarz J , et al. Performance of a genomic sequencing classifier for the preoperative diagnosis of cytologically indeterminate thyroid nodules[J]. JAMA Surg, 2018, 153 (9): 817- 824. doi: 10.1001/jamasurg.2018.1153
19	Sadowski SM , Petrenko V , Meyer P , et al. Validation of molecular biomarkers for preoperative diagnostics of human papillary thyroid carcinoma in fine needle aspirates[J]. Gland Surg, 2019, 8 (Suppl 2): S62- S76.
20	Choi SH , Baek JH , Lee JH , et al. Evaluation of the clinical usefulness of BRAFV600E mutation analysis of core-needle biopsy specimens in thyroid nodules with previous atypia of undetermined significance or follicular lesions of undetermined significance results[J]. Thyroid, 2015, 25 (8): 897- 903. doi: 10.1089/thy.2014.0606
21	Choi SH , Baek JH , Lee JH , et al. Initial clinical experience with BRAF(V600E) mutation analysis of core-needle biopsy specimens from thyroid nodules[J]. Clin Endocrinol, 2016, 84 (4): 607- 613. doi: 10.1111/cen.12866
22	Crescenzi A , Trimboli P , Modica DC , et al. Preoperative assessment of TERT promoter mutation on thyroid core needle biopsies supports diagnosis of malignancy and addresses surgical strategy[J]. Horm Metab Res, 2016, 48 (3): 157- 162.
23	Jang EK , Kim WG , Kim EY , et al. Usefulness of NRAS codon 61 mutation analysis and core needle biopsy for the diagnosis of thyroid nodules previously diagnosed as atypia of undetermined significance[J]. Endocrine, 2016, 52 (2): 305- 312. doi: 10.1007/s12020-015-0773-9
24	Marotta V , Bifulco M , Vitale M . Significance of RAS mutations in thyroid benign nodules and non-medullary thyroid cancer[J]. Cancers (Basel), 2021, 13 (15): 3785. doi: 10.3390/cancers13153785

Metrics

Viewed

Full text

Abstract

Cited

Shared

Discussed

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.

Gene	Transcript	Variation type
Gene	Transcript	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

Items	Matched resected samples, n			Predictive value/%
Items	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

Items	Matched resected samples, n			Predictive value/%
Items	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

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