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1.
Molecular pathology of thyroid tumours of follicular cells: a review of genetic alterations and their clinicopathological relevance
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Giorgia Acquaviva Michela Visani Andrea Repaci Kerry J Rhoden Dario de Biase Annalisa Pession Tallini Giovanni 《Histopathology》2018,72(1):6-31
Thyroid cancer is the most common endocrine malignancy. Knowledge of the molecular pathology of thyroid tumours originating from follicular cells has greatly advanced in the past several years. Common molecular alterations, such as BRAF p.V600E, RAS point mutations, and fusion oncogenes (RET–PTC being the prototypical example), have been, respectively, associated with conventional papillary carcinoma, follicular‐patterned tumours (follicular adenoma, follicular carcinoma, and the follicular variant of papillary carcinoma/non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features), and with papillary carcinomas from young patients and arising after exposure to ionising radiation, respectively. The remarkable correlation between genotype and phenotype shows how specific, mutually exclusive molecular changes can promote tumour development and initiate a multistep tumorigenic process that is characterised by aberrant activation of mitogen‐activated protein kinase and phosphoinositide 3‐kinase–PTEN–AKT signalling. Molecular alterations are becoming useful biomarkers for diagnosis and risk stratification, and as potential treatment targets for aggressive forms of thyroid carcinoma. What follows is a review of the principal genetic alterations of thyroid tumours originating from follicular cells and of their clinicopathological relevance. 相似文献
2.
CD57 (leu-7) Expression is helpful in diagnosis of the follicular variant of papillary thyroid carcinoma 总被引:2,自引:0,他引:2
A. Khan S. P. Baker Nilima A. Patwardhan James M. Pullman 《Virchows Archiv : an international journal of pathology》1998,432(5):427-432
CD57 (HNK-1) is a oligosaccharide antigen that is expressed by cells of several lineages. It is present on multipotential
neuroepithelial cells during embryogenesis, and tumours of epithelial, neuroectodermal and nerve sheath origin also express
CD57. Its role in the diagnosis of thyroid tumours is controversial. We have studied CD57 expression by immunohistochemistry
to determine its utility in the classification of thyroid follicular lesions. Study material included 114 normal thyroid sections,
77 benign thyroid lesions (29 colloid nodules, 22 follicular adenomas, 20 cases of Hashimoto’s thyroiditis and 6 of Grave’s
disease) and 83 thyroid carcinomas, including 31 follicular variants of papillary carcinoma. We observed CD57 positivity in
95% of thyroid carcinomas, 27% of follicular adenomas and 10% of colloid nodules. It was not expressed in the normal thyroid.
CD57 expression in thyroid carcinomas was significantly different from that in normal and benign thyroid lesions (P < 0.0001). The follicular variant of papillary thyroid carcinoma also showed significantly higher CD57 expression than colloid
nodules (P < 0.0009) or follicular adenomas (P < 0.0009). No significant difference was seen between colloid nodules and follicular adenomas. We conclude that CD57 immunohistochemistry
is valuable in the classification of thyroid follicular lesions into benign and malignant groups and is also helpful in the
diagnosis of the follicular variant of papillary thyroid carcinoma.
Received: 26 August 1997 / Accepted: 14 October 1997 相似文献
3.
Thyroid cancer is the most common endocrine malignancy, and its incidence is rising in the USA and other countries. Papillary
and follicular thyroid carcinomas are the two most common types of thyroid cancer. Non-overlapping genetic alterations, including
BRAF and RAS point mutations, and RET/PTC and PAX8/PPARγ rearrangements, are found in more than 70% of papillary and follicular thyroid carcinomas. These represent the most common
genetic alterations in thyroid cancer, as well as molecular markers of diagnostic and prognostic significance. The use of
these and other emerging molecular markers will likely improve the diagnosis of malignancy in thyroid nodules as well as facilitate
more individualized operative and postoperative management. Herein, we provide a brief overview of the common genetic alterations
in papillary and follicular thyroid carcinoma and discuss the diagnostic and prognostic significance thereof. 相似文献
4.
Understanding the genotype of follicular thyroid tumors 总被引:1,自引:0,他引:1
Hunt J 《Endocrine pathology》2005,16(4):311-321
Tumors of the thyroid with a follicular growth pattern are controversial and can be diagnostically challenging for the pathologist.
This group of tumors includes both follicular-derived lesions (adenomas and carcinomas) and papillary carcinoma (follicular
variant of papillary carcinoma). H&E morphology has classically been the gold standard for diagnosis. In the past several
decades, however, several important molecular markers have been identified that may be unique to different types of thyroid
carcinomas. These include the translocations RET/PTC and PAX8-PPARγ and point mutations in the BRAF and RAS genes. Other molecular events in tumor suppressor genes may be useful for diagnosis of these tumors as well. None of the
mutational markers are very sensitive, and there is some question regarding specificity for malignancy, because mutations
have also been described in histologically benign tumors. However, with increasing availability of molecular testing for the
general pathologist, a molecular testing panel used in conjunction with the H&E morphology and immunohistochemical stains
may become useful in the clinical setting for the diagnosis of thyroid tumors. 相似文献
5.
Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinomas 总被引:5,自引:0,他引:5
Nikiforov YE 《Endocrine pathology》2004,15(4):319-327
Recent molecular studies have provided new insights into thyroid carcinogenesis. In thyroid papillary carcinomas at least
three initiating events may occur, which are point mutations in the BRAF and RAS genes and RET/PTC rearrangements. Tumors harboring mutant BRAF and RAS are prone to progression to poorly differentiated and anaplastic carcinoma, but most likely require additional mutations
to trigger this process. In thyroid follicular carcinomas, two known initiating events are RAS mutations and PAX8-PPARγ rearrangements, and RAS predisposes to dedifferentiation of follicular carcinomas. p53 and β-catenin mutations, found with increasing incidence in poorly differentiated and anaplastic carcinomas but not in well-differentiated
tumors, may serve as a direct molecular trigger of tumor dedifferentiation. Additional evidence for progression from a preexisting
well-differentiated carcinoma to poorly differentiated and anaplastic carcinoma comes from the studies of loss of heterozygosity
and comparative genomic hybridization. Molecular studies, although limited by the lack of uniform histologic criteria for
poorly differentiated carcinomas, revealed no genetic mutations or chromosomal abnormalities that are unique for poorly differentiated
carcinoma and not present in well-differentiated or anaplastic carcinomas. This suggests that poorly differentiated carcinoma,
as a group, represents a distinct step in the evolution from well-differentiated to anaplastic thyroid carcinoma, rather than
an entirely separate type of thyroid malignancy. 相似文献
6.
《Diagnostic Histopathology》2008,14(5):236-246
The traditional classification of thyroid tumours is derived from follicular and ‘C’ cells and based on morphology and clinical features, but molecular studies have shown the involvement of distinct genes in each of these tumours. The high prevalence of papillary microcarcinoma in thyroid glands removed for other reasons underpinned the alteration of the TNM classification of thyroid tumors. Molecular studies showed that the high prevalence of BRAF mutations in papillary carcinomas, reaching ≤70% in some series, contrasts with lower levels of this mutation in cases of follicular variants. Follicular variants of papillary carcinoma share oncogene changes with follicular tumours, making the differential diagnosis of follicular lesions a challenge. Hyalinizing trabecular tumour has the same RET oncogene rearrangement encountered in many papillary carcinomas, raising the possibilty that it is a variant of papillary carcinoma. The ‘mixed medullary-follicular cell carcinoma’ is of uncertain histogenesis and merits separate classification. 相似文献
7.
M. Miettinen Albert J. Kovatich Päivi Kärkkäinen 《Virchows Archiv : an international journal of pathology》1997,431(6):407-413
Previous studies indicate that keratins 7, 8 and 18 are present in all thyroid papillary and follicular lesions, but the
distribution of other keratins has been incompletely characterized. The profile of individual keratin (K) polypeptides was
evaluated immunohistochemically in over 200 non-neoplastic and neoplastic thyroid papillary and follicular lesions. Monoclonal
antibodies to K19, K17, K16, K5/6 and K10 were applied in paraffin sections of formaldehyde-fixed tissue. K19 was present
variably, often only focally in goitres, and was present only sporadically in papillary hyperplasia. However, K19 was strongly
and uniformly expressed in virtually all papillary carcinomas, indicating differential diagnostic usefulness in differentiating
papillary hyperplasia and papillary carcinoma. About half of the follicular carcinomas (defined as tumours strictly excluding
the follicular variant of papillary carcinoma) were also strongly K19-positive, suggesting that K19 patterns are not reliable
in differentiating papillary and follicular carcinoma. K17 and K5/6 were present in cysts and squamous metaplasia of goitres,
and focally in papillary but only exceptionally in follicular carcinoma in areas of squamous differentiation and tumour cells
in desmoplastic stroma. K16 in turn was present only focally in well-developed squamous metaplasia in goitres but was not
found in differentiated thyroid carcinomas. K10, a high-molecular-weight keratin typical of epidermal differentiation, was
identified neither in non-neoplastic nor in neoplastic differentiated thyroid lesions, including squamous metaplasia. These
results indicate that papillary carcinomas differ from other differentiated thyroid tumours in their varying, usually focal,
expression of stratified epithelial keratins that are partly but not exclusively related to squamous differentiation in such
lesions. However, papillary carcinomas do not express truly epidermally restricted keratins; their previously described reactivity
with polyclonal ”epidermal keratin” antibodies most probably results from the reactivity of such antibodies with K19.
Received: 14 April 1997 / Accepted: 28 May 1997 相似文献
8.
Sobrinho-Simões M Preto A Rocha AS Castro P Máximo V Fonseca E Soares P 《Virchows Archiv : an international journal of pathology》2005,447(5):787-793
The newly discovered molecular features of well-differentiated thyroid carcinomas derived from follicular cells are reviewed,
within the frame of the 2004 WHO classification of thyroid tumours, under the following headings: “Follicular carcinoma”,
“Papillary carcinoma”, “Follicular variant of papillary carcinoma” and “Hürthle cell tumours”. A particular emphasis is put
on the meaning of PAX8–PPARγ rearrangements, RAS and BRAF mutations, and deletions and mutations of mitochondrial genes and of nuclear genes encoding for mitochondrial enzymes, for
thyroid tumorigenesis. 相似文献
9.
Hyalinizing trabecular tumours of the thyroid represent a rare entity of follicular cell derived tumours and are characterized by a marked intratrabecular hyalinisation. These tumours share architectural similarities with medullary thyroid carcinomas and exhibit nuclear features such as nuclear pseudoinclusions resembling papillary thyroid carcinoma. However, the clinical behaviour remains unclear. On the basis of their inconspicuous appearance and absence of invasion or recurrence during follow-up, the tumour was initially classified as an adenoma. Subsequently, molecular findings such as the detection of RET?/?PTC rearrangements in some hyalinizing trabecular tumours favoured the designation as a variant of papillary thyroid carcinoma. However, miRNA profiling of hyalinizing trabecular tumours compared with benign thyroid lesions and papillary thyroid carcinoma failed to demonstrate the characteristic up-regulation found in papillary thyroid carcinoma. This article summarizes conventional diagnostic criteria with supplementary information regarding molecular pathogenesis of hyalinizing trabecular tumours of the thyroid. 相似文献
10.
Komminoth P 《Endocrine pathology》1997,8(3):235-239
TheRET proto-oncogene has not only conclusively been identified as responsible for the three subtypes of the inherited cancer syndrome
multiple endocrine neoplasia type 2 (MEN-2) but also shown to be involved in the molecular evolution of sporadic medullary
and papillary thyroid carcinoma as well as Hirschsprung’s disease. A variety of recent studies have elucidated the pathophysiological
mechanisms leading to neoplastic disease and we now understand that dominant activating germline mutations lead to MEN-2A,
MEN-2B, and familial MTC; somatic mutations to sporadic medullary thyroid carcinoma;RET rearrangements to papillary thyroid carcinoma; and inactivating alterations to Hirschsprung's disease. The clinical significance,
however, ofRET alterations especially in sporadic thyroid tumors is still controversial and therapeutic concepts in MEN-2 gene carriers
only start to emerge. This article is a short summary of the recent findings on the structure and physiology of theRET proto-oncogene and its role in familial and sporadic thyroid cancer.
This article was presented in part at the Endocrine Pathology Society Companion Meeting of the USCAP in Orlando, FL, March
1, 1997. 相似文献
11.
Hyalinizing trabecular tumor (HTT) is a rare thyroid tumor of follicular cell origin with a trabecular pattern of growth and
marked intratrabecular hyalinization. This tumor is known to share morphological and architectural similarities with paraganglioma
and medullary thyroid carcinoma, as well as the nuclear features and RET/PTC1 translocations of papillary thyroid carcinoma.
These tumors are not associated with RAS or BRAF mutations. Whether the presence of RET alterations in HTT are sufficient molecular proof of its relationship with papillary
thyroid carcinoma (PTC) is still to be defined. Of great interest is the characteristic strong peripheral cytoplasmic and
membranous staining of the tumor cells with MIB1 immunostain, not seen in any other thyroid neoplasm. Although cases of malignant
HTT have been recorded, HTT should be considered a benign neoplasm or, at most, a neoplasm of extremely low malignant potential. 相似文献
12.
BRAF belongs to the RAF family of protein kinases that are important components of the MAPK signaling pathway mediating cell
growth, differentiation and survival. Activating point mutation of the BRAF gene resulting in V600E (previously designated as V599E) is a common event in thyroid papillary carcinoma, being found in
approx 40% of this tumor. It has strong association with classical papillary carcinoma and tall cell and possibly Warthin-like
variants. This mutation also occurs in thyroid poorly differentiated and anaplastic carcinomas, usually those containing areas
of papillary carcinoma. Alterations in the BRAF gene do not overlap with RAS mutations and RET/PTC rearrangement, indicating that activation of one of the effectors of the MAPK pathway is sufficient for papillary thyroid
carcinogenesis. Recently, another mechanism of BRAF activation has been identified, which involves chromosome 7q inversion
that results in the AKAP9-BRAF fusion. It is rare in sporadic papillary carcinomas and is more common in tumors associated with radiation exposure. Yet
another mechanism of BRAF activation may involve copy number gain, which is seen in a significant portion of thyroid follicular
tumors of both conventional and oncocytic (Hürthle cell) types. 相似文献
13.
A. Frilling W. Höppner C. Eng L. Mulligan F. Raue C. E. Broelsch 《Journal of molecular medicine (Berlin, Germany)》1995,73(5):229-233
Medullary thyroid carcinoma occurs sporadically or as a part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. The MEN 2 gene has been identified as the RET proto-oncogene on chromosome 10. In MEN 2A, RET mutations are detectable in one of five cysteine codons within exons 10 and 11 and in MEN 2B in codon 918 (exon 16). Direct DNA testing for RET proto-oncogene mutations is the method of first choice in presymptomatic screening of MEN 2 families. Gene carriers should be offered prophylactic thyroidectomy. The process of DNA analysis for RET proto-oncogene mutations is demonstrated in one family with hereditary medullary thyroid carcinoma. RET mutations were detectable in five of the nine family members at risk.Abbreviations
MEN
Multiple endocrine neoplasia
-
MTC
Medullary thyroid carcinoma
-
FMTC
Familial medullary thyroid carcinoma
-
PCR
Polymerase chain reaction
-
C-cells
Calcitonin-producing parafollicular cells 相似文献
14.
Struma ovarii is an ovarian mature teratoma composed exclusively or predominantly of thyroid tissue. Malignant transformation
of struma ovarii is rare and poorly understood, although this process is thought to be similar to carcinogenesis in malignant
tumors of differentiated thyroid tissue originating in the thyroid gland. Genetic alterations in the mitogen-activated protein
kinase pathway, including mutations of BRAF, RAS, and RET genes, have been implicated in the development of differentiated thyroid carcinoma arising in the thyroid gland. We report
here a case with RAS mutation detected in a malignant struma ovarii. The patient is a 38-year-old female who had a 2.4 cm ovarian cyst noted incidentally
on a first trimester ultrasound. She proceeded to ovarian cystectomy post-delivery, with pathologic examination detecting
a papillary thyroid carcinoma, follicular variant, arising in a cystic teratoma. The tumor was tested for BRAF, RAS, and RET/PTC mutations. HRAS codon 61 mutation was identified. This is the first report of RAS mutation detected in the follicular variant of papillary carcinoma arising in a struma ovarii. It provides evidence that
tumors developing in this setting involve molecular mechanisms similar to those implicated in tumors developing in the thyroid
gland. 相似文献
15.
Eli Rosenbaum Gregory Hosler Marianna Zahurak Yoram Cohen David Sidransky William H Westra 《Modern pathology》2005,18(7):898-902
Papillary thyroid carcinoma may encompass a mixed group of neoplasms where divergence in clinical behavior may reflect distinct genetic alterations. For example, young patients with papillary thyroid carcinoma have a better prognosis than affected adults, and their carcinomas are much more likely to harbor chromosomal rearrangements involving the RET proto-oncogene. Mutational activation of the BRAF oncogene has recently been identified as the most common genetic alteration in papillary thyroid carcinoma, but little is known about its frequency as a function of patient age. We tested 20 papillary thyroid carcinomas from young patients ranging from 10 to 17 years of age for the thymine (T) --> adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector assay). The prevalence of BRAF mutation was compared with a larger group of papillary thyroid carcinomas from previously tested adult patients (>20 years). BRAF mutations were not common in papillary thyroid carcinomas from young patients compared to their counterparts in adults (20 vs 77%; OR=13.3, 95% confidence interval (CI)=3.4-56.5; P<0.0001), but they become increasingly prevalent with advancing patient age (OR as a function of age at 10-year intervals=1.80 CI=1.33-2.44; P<0.001). Unlike papillary thyroid carcinomas that arise in adults, mutational activation of BRAF is not a major genetic alteration in papillary thyroid carcinomas that arise in young patients. The increasing frequency of BRAF mutations as a function of age could help account for the well documented but poorly understood observation that age is a relevant prognostic indicator for patients with papillary thyroid carcinoma. 相似文献
16.
Gül?in?Yegen Mehmet?Akif?Demir Ye?im?Ertan Olcay?Ak?Nalbant Müge?Tun?yürek 《Virchows Archiv : an international journal of pathology》2009,454(1):101-105
CD10–common acute lymphoblastic leukemia antigen is a membrane-bound zinc metalloproteinase that is expressed by different
hematopoietic cell types at unique stages of lymphoid and myeloid differentiation. It was reported to be expressed in various
nonlymphoid cells and tissue, as well as in various types of neoplasms. Recently, it has been found to be useful in the differential
diagnosis of benign and malignant follicular-patterned lesions of the thyroid. In the present study, we evaluated the staining
pattern of CD10 in various thyroid lesions, including 14 benign and 61 malignant cases, as well as in adjacent thyroid tissue.
CD10 was negative in normal thyroid tissue, adenomatous nodules, minimally invasive follicular carcinoma, and well-differentiated
carcinoma. It was expressed in nine of 14 (64.2%) conventional papillary carcinomas, four of 24 (16.6%) follicular variant
of papillary carcinomas, three of six (50%) papillary microcarcinomas, one of nine (11.1%) widely invasive follicular carcinomas,
and three of ten (30%) follicular adenomas. In contrast to results of previous studies, CD10 is not useful in the classification
of thyroid follicular lesions as benign or malignant, but it shows strong positivity in conventional papillary carcinoma. 相似文献
17.
French CA Fletcher JA Cibas ES Caulfield C Allard P Kroll TG 《Endocrine pathology》2008,19(3):166-174
The pathologic diagnosis of thyroid follicular tumors is difficult, particularly in preoperative fine-needle aspiration biopsies.
To investigate whether the molecular diagnosis of PPARγ rearrangements can detect thyroid carcinomas in fine-needle aspiration biopsies, we performed interphase fluorescence in
situ hybridization on 24 thyroid fine-needle aspiration and 17 follow-up thyroidectomy specimens. Two of the 24 fine-needle
aspiration biopsies contained PPARγ rearrangements, and both were diagnosed suggestive of a thyroid follicular neoplasm by cytology. The two corresponding thyroidectomies
each contained PPARγ rearrangements in all tumor cells and, both were diagnosed follicular-patterned thyroid carcinomas—one a follicular carcinoma
and the other a follicular variant of papillary carcinoma, the latter by majority of expert endocrine pathologists. Our experiments
demonstrate that PPARγ rearrangements can detect a subset of follicular-patterned thyroid carcinomas in preoperative thyroid fine-needle aspiration
biopsies. The ultimate utility of mutations such as PPARγ rearrangements in diagnosis of thyroid carcinoma must be proven by direct correlation of mutation status with thyroid tumor
biology and not just with thyroid tumor morphology, a subjective and imprecise marker of clinical behavior. The application
of specific mutations to preoperative diagnosis of thyroid carcinoma is predicted to improve the accuracy and reduce the costs
of treating patients with thyroid tumors.
An erratum to this article can be found at 相似文献
18.
Ricardo Celestino Eva Sigstad Marthe Løvf Gard O. S. Thomassen Krystyna K. Grøholt Lars H. Jørgensen Aasmund Berner Patrícia Castro Ragnhild A. Lothe Trine Bjøro Manuel Sobrinho‐Simões Paula Soares Rolf I. Skotheim 《Genes, chromosomes & cancer》2012,51(12):1154-1164
Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein. In the thyroid, the PAX8‐PPARG fusion is present in the neoplastic lesions that have a follicular architecture—follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA), while the presence of RET/PTC fusions are largely restricted to papillary thyroid carcinoma (PTC). The ability to detect fusion genes is relevant for a correct diagnosis and for therapy. We have developed a new fusion gene microarray‐based approach for simultaneous analysis of all known and predicted fusion gene variants. We did a comprehensive screen for 548 known and putative fusion genes in 27 samples of thyroid tumors and three positive controls—one thyroid cancer cell line (TPC‐1) and two PTCs with known CCDC6‐RET (alias RET/PTC1) fusion gene, using this microarray. Within the thyroid tumors tested, only well known, previously reported fusion genes in thyroid oncology were identified. Our results reinforce the pathogenic role played by RET/PTC1, RET/PTC3, and PAX8‐PPARG fusion genes in thyroid tumorigenesis. © 2012 Wiley Periodicals, Inc. 相似文献
19.
The rearranged during transfection (RET) proto-oncogene encodes a receptor tyrosine kinase that is implicated in the development of endocrine tumors of the thyroid
and adrenal glands. In humans, activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia 2 and in sporadic medullary and papillary
thyroid carcinomas. The specific type and location of RET mutations are strongly correlated with the disease phenotype and
have both diagnostic and prognostic value. Recent advances in the molecular characterization of the RET receptor and its mutants
have begun to define the mechanisms underlying the transforming ability of the different RET mutant forms. This information
has revealed key functional features of these mutant proteins that distinguish the different clinically recognized mutations
and provide clues as to the functional origins of the phenotypes associated with specific RET mutations. The elucidation of
molecular mechanisms involved in RET-mediated transformation is a key step in the development of much needed therapeutics
that target RET’s oncogenic properties. Recent advances have begun to provide a deeper understanding of the receptor’s function,
and dysfunction, in human tumors that may guide this process. 相似文献
20.
Point mutation of the BRAF gene is a common genetic event in papillary thyroid carcinomas. More recently, it has been found that BRAF can also participate in chromosomal rearrangement. In this study, we explore yet another possible mechanism of BRAF alteration, which involves copy number gain. Using fluorescence in situ hybridization with BRAF specific and chromosome 7 centromeric probes, we studied 62 follicular thyroid tumors and 32 papillary carcinomas. We found
that numerical changes in BRAF copy number were rare in papillary thyroid carcinomas, while they occurred in 16–45% of follicular tumors of conventional
and oncocytic (Hürthle cell) types. They were due to amplification of the gene or gain of one or more copies of chromosome
7. Tetrasomy for chromosome 7 was overall the most common finding. The changes in BRAF copy number did not overlap with RAS mutations in follicular tumors. In a group of follicular carcinomas, tumors with BRAF copy number gain were significantly more often widely invasive (67%) compared to tumors with no copy number change (18%).
By Western blotting, the tumors carrying four copies of the gene revealed higher expression of BRAF protein, suggesting that
copy number gain may represent another mechanism of BRAF activation in thyroid tumors. 相似文献