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1、Vol.:(0123456789)1 3https:/doi.org/10.1007/s12022-022-09707-3Overview ofthe2022 WHO Classification ofThyroid NeoplasmsZubairW.Baloch1 SylviaL.Asa2 JustineA.Barletta3 RonaldA.Ghossein4 C.ChristoferJuhlin5,6 ChanKwonJung7 VirginiaA.LiVolsi1 MauroG.Papotti8 ManuelSobrinhoSimes9 GiovanniTallini10,11 Ozg
2、urMete12 Accepted:27 January 2022 The Author(s),under exclusive licence to Springer Science+Business Media,LLC,part of Springer Nature 2022AbstractThis review summarizes the changes in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the thyroid gland.T
3、he new classification has divided thyroid tumors into several new categories that allow for a clearer understanding of the cell of origin,pathologic features(cytopathology and histopathology),molecular classification,and biological behavior.Follicular cellderived tumors constitute the majority of th
4、yroid neoplasms.In this new classifica-tion,they are divided into benign,low-risk,and malignant neoplasms.Benign tumors include not only follicular adenoma but also variants of adenoma that are of diagnostic and clinical significance,including the ones with papillary architecture,which are often hyp
5、erfunctional and oncocytic adenomas.For the first time,there is a detailed account of the multifocal hyperplastic/neoplastic lesions that commonly occur in the clinical setting of multinodular goiter;the term thyroid follicular nodular disease(FND)achieved consensus as the best to describe this enig
6、matic entity.Low-risk follicular cellderived neoplasms include non-invasive follicular thyroid neoplasm with papillary-like nuclear features(NIFTP),thyroid tumors of uncertain malignant potential,and hyalinizing trabecular tumor.Malignant follicular cellderived neoplasms are stratified based on mole
7、cular profiles and aggressiveness.Papillary thyroid carcinomas(PTCs),with many morphological subtypes,represent the BRAF-like malignancies,whereas invasive encapsulated follicular variant PTC and follicular thyroid carcinoma represent the RAS-like malignancies.This new classification requires detail
8、ed subtyping of papillary microcarcinomas similar to their counterparts that exceed 1.0cm and recommends not designating them as a subtype of PTC.The criteria of the tall cell subtype of PTC have been revisited.Cribriform-morular thyroid carcinoma is no longer classified as a subtype of PTC.The term
9、“Hrthle cell”is discouraged,since it is a misnomer.Oncocytic carcinoma is discussed as a distinct entity with the clear recognition that it refers to oncocytic follicular cellderived neoplasms(composed of 75%oncocytic cells)that lack characteristic nuclear features of PTC(those would be oncocytic PT
10、Cs)and high-grade features(necrosis and 5 mitoses per 2 mm2).High-grade follicular cellderived malignancies now include both the traditional poorly differentiated carcinoma as well as high-grade differentiated thyroid carcinomas,since both are characterized by increased mitotic activity and tumor ne
11、crosis without anaplastic histology and clinically behave in a similar manner.Anaplastic thyroid carcinoma remains the most undifferentiated form;squamous cell carcinoma of the thyroid is now considered as a subtype of anaplastic carcinoma.Medullary thyroid carcinomas derived from thyroid C cells re
12、tain their distinct section,and there is a separate section for mixed tumors composed of both C cells and any follicular cellderived malignancy.A grading system for medullary thyroid carcinomas is also introduced based on mitotic count,tumor necrosis,and Ki67 labeling index.A number of unusual neo-p
13、lasms that occur in the thyroid have been placed into new sections based on their cytogenesis.Mucoepidermoid carcinoma and secretory carcinoma of the salivary gland type are now included in one section classified as“salivary glandtype carcinomas of the thyroid.”Thymomas,thymic carcinomas and spindle
14、 epithelial tumor with thymus-like elements are classified as“thymic tumors within the thyroid.”There remain several tumors whose cell lineage is unclear,and they are listed as such;these include sclerosing mucoepidermoid carcinoma with eosinophilia and cribriform-morular thyroid carcinoma.Another i
15、mportant addition is thyroblastoma,an unusual embryonal tumor associated with DICER1 mutations.As in all the WHO books in the 5th edition,mesenchymal and stromal tumors,hematolymphoid neoplasms,germ cell tumors,and metastatic malignancies are discussed separately.The current classification also emph
16、asizes the value of biomarkers that may aid diagnosis and provide prognostic information.Extended author information available on the last page of the article/Published online:14 March 2022Endocrine Pathology(2022)33:27631 3Keywords WHO classification of thyroid tumors Papillary thyroid carcinoma Fo
17、llicular thyroid carcinoma High-grade thyroid carcinoma Anaplastic thyroid carcinoma Poorly differentiated thyroid carcinoma Medullary thyroid carcinoma Thyroblastoma Cribriform-morular thyroid carcinoma Hyalinizing trabecular tumor Follicular nodular diseaseIntroductionThe thyroid gland gives rise
18、to the most common endocrine tumors,and therefore,it represents the largest chapter in the new 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors.The approach taken in this edition is somewhat different from its prior iterations;there is a focus on taxonomy following the ap
19、proach of Carl Linnaeus 1,2,and cytogenesis forms the basis of framework for this new classification,with histology and molecular features defining tumor types and subtypes.Over the last 15years,the importance of molecular biol-ogy in thyroid pathology has both revolutionized the dis-cipline and,at
20、the same time,proven the inherent value of classical histopathology.It is a field in which pathologists have long recognized patterns that reflect specific molecu-lar alterations,but the addition of molecular tools to the pathologists armamentarium has enhanced our ability to prognosticate and predi
21、ct the efficacy of targeted therapies.This review will focus on the most important and novel changes in the new WHO thyroid tumor classification scheme(Table1)employing a questionanswer framework.We encourage the reader to use this as a framework to under-stand the new classification,but it is not a
22、 substitute for the actual text that provides detailed descriptions,illustrative figures,and a highly structured approach to assist in identi-fying the complexities of diagnosis and differential diagnosis of thyroid neoplasms.Question 1:What Are theNew Categories ofBenign Follicular Cell Thyroid Les
23、ions andWhy Are They Included intheWHO 5th Edition?The 4th edition of the WHO classification of endocrine tumors 3 included a single benign lesion:follicular ade-noma(FA).While FAs are well-recognized tumors,they occur in many different scenarios with distinct clinical,radiological,biochemical,and m
24、orphological features.In this edition,the important variants are described.The clinical entity known as multinodular goiter has been used for pathology diagnosis but this is inappropri-ate,since many lesions,including thyroiditis,hyperplasias,and neoplasms,can give rise to a clinically enlarged,mul-
25、tinodular thyroid gland.The entity that is most commonly associated with this clinical scenario is a disorder charac-terized by multiple thyroid lesions composed of follicular epithelial cells that have highly variable architecture;they can be very small or very large,they range from colloid-rich ma
26、crofollicular nodules to cellular microfollicular nodules,and they can be poorly delineated or well circum-scribed with absent,well-defined or incomplete capsules(Fig.1).These lesions have not generally been classified as Table 1 WHO classification scheme of thyroid neoplasms,5th edi-tionDevelopment
27、al abnormalities 1.Thyroglossal duct cyst 2.Other congenital thyroid abnormalitiesFollicular cellderived neoplasms 1.Benign tumors a.Thyroid follicular nodular disease b.Follicular adenoma c.Follicular adenoma with papillary architecture d.Oncocytic adenoma of the thyroid 2.Low-risk neoplasms a.Non-
28、invasive follicular thyroid neoplasm with papillary-like nuclear features b.Thyroid tumors of uncertain malignant potential c.Hyalinizing trabecular tumor 3.Malignant neoplasms a.Follicular thyroid carcinoma b.Invasive encapsulated follicular variant papillary carcinoma c.Papillary thyroid carcinoma
29、 d.Oncocytic carcinoma of the thyroid e.Follicular-derived carcinomas,high-grade i.Differentiated high-grade thyroid carcinoma ii.Poorly differentiated thyroid carcinoma f.Anaplastic follicular cellderived thyroid carcinomaThyroid C-cellderived carcinoma 1.Medullary thyroid carcinomaMixed medullary
30、and follicular cellderived carcinomasSalivary glandtype carcinomas of the thyroid 1.Mucoepidermoid carcinoma of the thyroid 2.Secretory carcinoma of salivary gland typeThyroid tumors of uncertain histogenesis 1.Sclerosing mucoepidermoid carcinoma with eosinophilia 2.Cribriform morular thyroid carcin
31、omaThymic tumors within the thyroid 1.Thymoma family 2.Spindle epithelial tumor with thymus-like elements 3.Thymic carcinoma familyEmbryonal thyroid neoplasms 1.Thyroblastoma28Endocrine Pathology(2022)33:27631 3Fig.1 Thyroid follicular nodu-lar disease.Grossly,the thyroid gland is enlarged with vari
32、ably sized multiple nodules(A).By light microscopy,this disorder manifests with a spectrum of morphologies from small col-loidrich nodules with Sander-sons polsters(B)to large poorly defined colloid-rich macrofol-licular nodules(C).They are usually multiple and generally show highly variable deline-
33、ation and encapsulation(D).Some are more well-defined and microfollicular,resembling adenomas(E);however,while clonality studies have shown that some are monoclonal while others are polyclonal,there is no good correlation between clonality and morphology.Large lesions can have central degeneration w
34、ith fibrosis and calcification(F)29Endocrine Pathology(2022)33:27631 3neoplasms.Pathologists have used many different names for this enigmatic entity;they have been called“colloid nod-ules,”but most common diagnostic verbiages include the term“hyperplasia”as well as“adenomatous”and“adeno-matoid,”ref
35、lecting the fact that the nodules in this disorder may morphologically mimic adenomas.Interestingly,mul-tiple studies have shown that these nodules are frequently but not always clonal 48;therefore,some are indeed adenomas,while others are hyperplastic.The clonality of these lesions explains why foc
36、i of malignant transformation can occur within the nodules of multinodular goiter.An alternative terminology proposed to address this enigma is“thyroid follicular nodular disease,”a term that avoids defining a lesion as hyperplastic,neoplastic,or the contradictory“adenomatous hyperplasia”9.This term
37、 achieved consensus support from the WHO editorial board.An unusual but clinically important tumor is follicular adenoma with papillary architecture.This is a benign non-invasive encapsulated follicular cellderived neoplasm characterized by a distinct“centripetal”intrafollicular papillary architectu
38、re that is more organized than papil-lary thyroid carcinoma(PTC),lacks nuclear features of PTC,and is often associated with autonomous hyperfunc-tion(Fig.2).Unlike follicular adenomas that harbor RAS mutations,these tumors are often associated with activating TSHR mutations(in up to 70%of cases)or G
39、NAS mutations(in a small subset)1012 and/or EZH1 mutations 13,14.These molecular alterations result in activation of adenylyl cyclase,increased intracellular cyclic AMP,and unrestrained stimulation of function and proliferation 15.These tumors are features of McCune-Albright syndrome due to germline
40、 mosaic GNAS mutations,and Carney com-plex,due to germline inactivating mutations in PRKAR1A that also cause constitutive activation of the cAMP-protein kinase A(PKA)pathway 16.These clinical associations as well as the more common sporadic tumors that cause clinical or subclinical hyperthyroidism a
41、re important for clinic-pathological correlation,recognizing the radiological correlates of hot nodules.The importance of oncocytic change in the thyroid cannot be overemphasized therefore oncocytic follicular adenomas now hold their own special place in the clas-sification.The term“Hrthle cell”is d
42、iscouraged;it is actually a misnomer since Hrthle described the C cells of the thyroid gland.These tumors have distinct genomic alterations in the mitochondrial genome(mtDNA)1720 or in the related GRIM19(NDUFA13)gene 21,and more than one-third have copy number variations 22.It is well known that fol
43、licular adenomas can have focal oncocytic change;the definition of 75%oncocytic cytology is used in this classification,but this remains to be proven as a valid criterion.Fig.2 Papillary adenoma non-invasive encapsulated neoplasm characterized by a distinct“centripetal”intrafollicular papillary arch
44、itecture lacking nuclear features of PTC30Endocrine Pathology(2022)33:27631 3Question 2:What Distinguishes theVarious LowRisk Follicular Thyroid Neoplasms?The 2022 WHO classification of endocrine tumors has organized follicular cellderived neoplasms into three cat-egories:benign neoplasms,low-risk n
45、eoplasms,and malig-nant neoplasms.The low-risk neoplasms are borderline tumors that are morphologically and clinically intermedi-ate between benign and malignant tumors(Table2).These neoplasms have the potential to develop metastasis,but the incidence of metastasis is extremely low.Histologically,th
46、ey are classified into three types including non-invasive folli-cular thyroid neoplasm with papillary-like nuclear features(NIFTP),thyroid tumors of uncertain malignant potential(UMP),and hyalinizing trabecular tumor(HTT).The term“tumor”was intended to reduce the risk of overtreatment for these low-
47、risk neoplasms.These terms are the same as those in the previous edition.In the 2017 WHO classifica-tion,HTT was described in a different chapter from that of NIFTP and UMP tumors,but in the new edition,they were all combined into one category of low-risk follicular cellderived neoplasms 3.The diagn
48、osis of NIFTP requires assessment of strict diagnostic criteria in a surgical resection specimen and requires meticulous microscopic examination of the entire tumor capsule/periphery to rule out invasive growth(Fig.3A,B).The NIFTP terminology was pro-posed in 2016 and included as a new entity in the
49、 2017 WHO classification 3.Since then,there has been debate about the criterion allowing less than 1%of true papillae because some studies reported BRAF V600E and lymph node metastasis in a subset of NIFTPs with 1%papillae 2325.To avoid misdiagnosing these malignant tumors as NIFTP,the NIFTP consens
50、us group changed the diag-nostic criterion of 1%papillae to no well-formed papil-lae in 2018 26.However,in subsequent studies using the original criteria of 1%true papillae,no adverse events were found in NIFTP patients 2733.In a study performed at Memorial Sloan Kettering Cancer Center,lymph node m