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Molecular basis of thyroid neoplasm subhasish

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Molecular basis of thyroid neoplasm subhasish

  1. 1. MOLECULAR BASIS OF THYROID NEOPLASMSpeaker- Dr Subhasish SahaModerator- Dr Manisha MahataDepartment of PathologyR G Kar Medical College & Hospital
  2. 2. INTRODUCTIONThyroid cancer is most common endocrine malignancy, incidencegrowing steadily( 0.5-10 cases per 100,000 populations).Women are 3 times more common than male.Benign thyroid neoplasm outnumbers malignancy by a ratio of10:1.More than 95% of thyroid cancers - thyroid follicular cells.2-3% of thyroid tumors (medullary thyroid cancers) - C-cells.Radiation exposure, iodine deficiency are few of the risk factors
  3. 3. WHO HISTOLOGICAL CLASSIFICATION OF THYROID TUMORSThyroid carcinoma-Papillary carcinoma.Follicular carcinoma.Poorly differentiated carcinoma.Undifferentiated (anaplastic) carcinoma.Squamous cell carcinoma.Mucoepidermoid carcinoma.Sclerosing mucoepidermoid carcinoma with eosinophilia.Mucinous carcinoma.Medullary carcinoma.Mixed medullary & follicular carcinoma.Thyroid adenoma & related tumor-Follicular adenoma.Hyalinizing trabecular adenoma.
  4. 4. CONTD….Other thyroid tumor-Teratoma.Thymoma.Primary lymphoma& plasmacytoma.Angiosarcoma.Smooth muscle tumor.Peripheral nerve sheath tumor.Solitary fibrous tumor.Secondary tumors.
  5. 5. CONTD…Papillary carcinoma (approximately 80%).follicular carcinoma (approximately 15%).Poorly differentiated and anaplastic thyroid carcinomas canarise de novo or from the preexisting well differentiatedpapillary or follicular carcinoma.Medullary thyroid carcinoma- 3% of all thyroid cancers.
  6. 6. Rapidly expanding knowledge of molecular genetics of thyroidcancer has started to translate into clinical practice, offeringsignificant improvement in accuracy of the preoperative diagnosisof thyroid cancer and better tumor prognostication.CONTD…
  7. 7.  Gene mutations:-BRAF .RAS point mutations .RET/PTC .PAX8/PPAR rearrangements.CONTD…
  8. 8. AVERAGE PREVALENCE OF MUTATIONS IN VARIOUSTYPES OF THYROID CANCERTumor Type PrevalencePapillary carcinomaBRAF 40-45%RET/PTC 10-12%RAS 10-12%TRK <5%Follicular CarcinomaRAS 40-50%PAX8/PPAR 30-35%PIK3CA <10%PTEN <10%
  9. 9. Tumor Type PrevalencePoorly differentiated carcinomaRAS 25-30%ß catenin 10-20%TP53 20-30%BRAF 10-15%Anaplastic carcinomaTP53 70-80%ß catenin 60-70%RAS 40-50%BRAF 20-30%Medullary CarcinomaFamilial RET >95%Sporadic RET 40%CONTD…
  10. 10. Normal follicular epithelial cellPapillary carcinomaFollicular adenomaPoorly differentiated carcinomaAnaplastic carcinomaFollicular carcinomaBRAF-45%RET/PTC-20%RAS-10-15%RAS-20-40%PAX8/PPAR-10%RAS-40-50%PAX8/PPAR-30-40%RAS,PAX8/PPAR BRAF,RET/PTC,RASMOLECULAR BASIS OF FOLLICULAR CELL DERIVED NEOPLASM
  11. 11. THYROID ADENOMABenign neoplasm derived from follicular epithelium.Usually solitary.Majority of adenomas are nonfunctional, a small proportionproduces thyroid hormones ("toxic adenomas") and causeclinically apparent thyrotoxicosis.Follicular adenoma shared genetic alterations support – possibilitythat at least of subset of follicular carcinoma arise in preexistingfollicular adenoma.
  12. 12. PATHOGENESIS OF FOLLICULAR ADENOMA Thyroid adenoma have mutation of RAS or PIK3CA or bear aPAX8-PPAR fusion gene- genetic alteration are similar to thoseseen in follicular carcinoma.
  13. 13. PAPILLARY CARCINOMAPapillary carcinoma carries point mutations of BRAF ,RAS gene ,RET/PTC and TRK rearrangements.They are able to activate mitogen-activated protein kinase(MAPK) pathway .These mutually exclusive mutations are found in >70% ofpapillary thyroid carcinomas.
  14. 14. PATHOGENESIS OF PAPILLARY THYROIDCARCINOMAMAPK pathwayand its activatinggenetic alterationsin PTC
  15. 15. CONTD.....MAPK pathway serves to propagate signals from cell membranereceptor tyrosine kinase (RTK) to the nucleus through a series ofadaptor proteins and intracytoplasmic kinase including RAS,RAF(mainly BRAF in thyroid follicular cells), MEK, and ERK.Activated ERK translocates to the nucleus and regulatestranscription of genes involved in cell differentiation, proliferation,and survival.In thyroid cancer, activation of this pathway occurs owing to pointmutations of RAS and BRAF or as a result of RET/PTC and TRKrearrangements involving the RET and NTRK1 genes,respectively.
  16. 16. FOLLICULAR CARCINOMAFollicular carcinomas -harbor either RAS mutations orPAX8/PPAR rearrangement.These mutations are also mutually exclusive , identified in 70% to75% of cases.Genetic alterations involving the PI3K/AKT signaling pathwayoccur in thyroid tumors, rare in well-differentiated thyroid cancerand have higher prevalence in less differentiated thyroidcarcinomas.
  17. 17. ANAPLASTIC& POORLY DIFFERENTIATED CARCINOMA poorly differentiated and anaplastic carcinomas -RAS.BRAF.TP53
  18. 18. MEDULLARY CARCINOMARET proto oncogene located on chromosome 10q11.2 – key role inpathogenesis of MCT.RET gene consist 21 exons, encoding receptor tyrosine kinaseconsist cystein rich extramembrane domain, transmembranedomain & intracellular tyrosine kinase component.
  19. 19. CONTD….RET Domain Codon Disease MCT RiskExtracellularcysteine rich609, 611, 618, 620 MEN2a, FMTC 2Extracellularcysteine rich634 MEN2a 2Intracellular tyrosinekinase 1768 FMTC 1Intracellular tyrosinekinase 1804 FMTC 1Intracellular tyrosinekinase 2883 MEN2b 3Intracellular tyrosinekinase 2918 MEN2b, SporadicMCT3
  20. 20. RAF MUTATIONThree types of RAF kinase- A RAF, B RAF, C RAF.Most mutations seen in thyroid cancer are point mutationsthat involve nucleotide 1799 and result in a valine-to glutamatesubstitution at residue 600 (BRAFV600E).Mutation in other codon identified- codon 598, 599,601.BRAF V600E mutation most commonly - conventional PTC , tallcell variant of PTC & least commonly - follicular variant of PTC,BRAF mutation – anaplastic & poorly differentiated carcinoma.
  21. 21. CONTD....Point mutations of the BRAF gene are the most commongenetic alteration known to occur in thyroid papillarycarcinomas (40% to 45%)-mutation leads to constitutiveactivation of BRAF kinase and chronic stimulation of the MAPKpathway, tumorigenic for thyroid cells.In 1% to 2% of papillary carcinomas, other BRAF mutations canbe found, including K601E point mutation and small in-frameinsertions or deletions surrounding codon 600, as well asAKAP9/BRAF rearrangement which is more common in papillarycarcinomas associated with radiation exposure.
  22. 22. SIGNIFICANCE OF BRAF MUTATIONBRAF V600E has not been found in follicular carcinomas ,benignthyroid nodules.Specific marker of papillary carcinoma and related tumor types.Got diagnostic & prognostic significance.Molecular testing for BRAF V600E in thyroid fine-needleaspiration (FNA) samples significantly improves the accuracy ofcytologic diagnosis of thyroid nodules-helps in establishingdefinitive diagnosis of cancer in nodules with indeterminatecytology.
  23. 23. Prognostic marker for papillary thyroid carcinoma. Associatedwith aggressive tumor - extrathyroidal extension, advanced tumorstage at presentation, lymph node or distant metastases.Independent predictor of- treatment failure and tumor recurrence,even in patients with low-stage disease an in-dependent risk fortumor-related death.SIGNIFICANCE OF BRAF MUTATION
  24. 24. BRAF mutation would be of particular importance in T1 papillarycarcinomas(tumors 2 cm or less in size) and papillarymicrocarcinomas ( incidentally discovered tumors measuring 1 cmor less).Both these categories has been strongly associated- withextrathyroidal extension and lymph node metastases.SIGNIFICANCE OF BRAF MUTATION
  25. 25. It is important to note that the association with tumoraggressiveness is limited to the BRAF V600E mutation and is notfound other rare types of BRAF mutation.Patients with BRAF V600E–positive nodules, detectedpreoperatively in FNA samples, would benefit from more extensiveinitial surgery and from postsurgical radioiodine treatment withhigher dose, and require close follow-up of patient.SIGNIFICANCE OF BRAF MUTATION
  26. 26. patients with BRAF V600E–positive nodules, detectedpreoperatively in FNA samples, would benefit from moreextensive initial surgery and from postsurgicalradioiodine treatment with higher dose, and requireclose follow-up of patient.SIGNIFICANCE OF BRAF MUTATION
  27. 27. RET/PTC REARRANGEMENTSRET proto-oncogene encodes a cell membrane receptor tyrosinekinase. RET is highly expressed in thyroid parafollicular or C cellsbut not in follicular cells.It is activated by chromosomal rearrangement known asRET/PTC rearrangement.In RET/PTC, the portion of RET coding for the tyrosine kinasedomain is fused to various unrelated genes.11 types of RET/PTC rearrangements have been reported- formedby RET fusion to different genetic partners.
  28. 28.  2 most common rearrangement types-RET/PTC1 and RET/PTC3,account for most rearrangements found in thyroid cancer.All fusions contain the intact tyrosine kinase domain of the RETreceptor, which enables the RET/PTC protein to activate theMAPK signaling pathwayRET/PTC REARRANGEMENTS
  29. 29. SIGNIFICANCE OF RET/PTC REARRANGEMENTClonal RET/ PTC - reasonably specific for papillary thyroid carcinoma.Clonal RET/PTC rearrangements are found in 10% -20% of adultsporadic papillary carcinomas.RET/PTC rearrangements occur with higher incidence in patientswith a history of radiation exposure (50%–80%) and in children andyoung adults(40%–70%).RET/PTC1 is typically the most common rearrangement type andcomprises up to 60% to 70% of all positive cases.RET/PTC3 accounts for 20% to 30% cases.RET/PTC2 and other novel rearrangement types are< 5% of all positivecases.
  30. 30. Papillary carcinomas with RET/PTC rearrangementstypically present at younger age and have classicpapillary histology and a high rate of lymph nodemetastases.SIGNIFICANCE OF RET/PTC REARRANGEMENT
  31. 31. Correlation of RET/PTC rearrangement & prognosis of papillarycarcinomas remains unclear.In some study RET/PTC rearrangement is associated with morefavorable behavior, &very low probability of progression to poorlydifferentiated and anaplastic carcinomas. Some study shows- tumors carrying RET/PTC3 rearrangementmay be prone to dedifferentiation and more aggressive behavior.SIGNIFICANCE OF RET/PTC REARRANGEMENT
  32. 32. Testing for RET/PTC rearrangements helpful for - diagnosis ofthyroid cancer.Detection of clonal RET/PTC is a strong indicator of papillarycarcinoma.In thyroid FNA samples, RET/PTC detection can improve thepreoperative diagnosis of thyroid nodules, particularly in samplesthat are indeterminate by cytology or have an insufficient amountof cells for cytologic evaluation.SIGNIFICANCE OF RET/PTC REARRANGEMENT
  33. 33. RAS3 type of RAS genes - HRAS, KRAS, and NRAS genes.They encode highly related G proteins that are located at the innersurface of the cell membrane and propagate signals arising fromcell membrane receptor tyrosine kinase and G-protein–coupledreceptors along the MAPK, PI3K/AKT, and other signalingpathways.Activating point mutations in the discrete domains of the RASgenes (codons 12/13 and 61) are common in different types ofhuman tumors.Thyroid tumors the most frequent mutations involve NRAS codon61 and HRAS codon 61. (other cancer KRAS codon 12/13mutations predominate)
  34. 34. CONTD….RAS mutations are found with variable frequency in all types ofthyroid follicular cell-derived tumors.In papillary thyroid carcinomas, RAS mutations occur in 10% to20% of tumors( Follicular variant of papillary carcinoma )RAS mutations are also found in 40% to 50% of conventional-typefollicular carcinomas and 20% to 40% of conventional-typefollicular adenomas.
  35. 35. SIGNIFICANCE OF RASRAS mutations in thyroid carcinomas correlate with tumordedifferentiation and less favorable prognosis.Strong correlation between RAS mutation and metastatic behaviorof follicular and papillary carcinomas, especially with respect tobone metastases has been found.Detection of RAS mutation in a thyroid nodule providesstrong evidence for neoplasia, although it does not establish thediagnosis of malignancy.
  36. 36. The importance of RAS mutation detection - it represents amarker of the follicular variant of papillary carcinoma, which ismost difficult to diagnose, especially by FNA cytology.RAS mutation apparently predisposes the well-differentiatedcancer to dedifferentiation and more aggressive behavior.Therefore, surgical removal of follicular adenomas that carry thisoncogenic mutation is justified to prevent progression.SIGNIFICANCE OF RAS
  37. 37. PAX8/PPARPAX8/PPAR rearrangement is a result of t(2;3)(q13;p25)translocation that leads to the fusion between the PAX8 gene,which encodes a paired domain transcription factor and theperoxisome proliferator–activated receptor (PPAR) gene.PAX8/PPAR is found in 30% to 40% of conventional-typefollicular carcinomas and with lower prevalence in oncocyticcarcinomas.This rearrangement is also found in the follicular variant ofpapillary carcinoma, (5-38%) follicular adenomas(2-13%)
  38. 38. Tumors harboring PAX8/PPAR tend to present- Younger age. Smaller in size. Vascular invasion. PAX8/PPAR rearrangements and RAS point mutations rarelyoverlap in the same tumor suggesting that follicular carcinomasmay develop via at least 2 distinct molecular pathways- eitherPAX8/PPAR or RAS mutation.SIGNIFICANCE OF PAX8/PPAR
  39. 39. Detection of PAX8/PPAR rearrangement in a follicular lesion isnot fully diagnostic for malignancy by itself, but it should promptthe pathologist to perform an exhaustive search for vascular orcapsular invasion.PAX8/PPAR rearrangement can be detected in thyroid FNAsamples, and this typically correlates with the presence ofmalignancy.SIGNIFICANCE OF PAX8/PPAR
  40. 40. OTHER GENETIC ALTERATIONSRare types of somatic mutations found in thyroid papillarycarcinoma include TRK rearrangement. It is found in < 5% ofpapillary carcinoma.At least 3 types of the rearrangement exist, formed by fusion of theNTRK1 gene to different partners. The diagnostic utility of testingfor TRK rearrangement is limited.
  41. 41. Expression of various microRNAs (miRNAs) appears to differbetween papillary carcinomas and benign thyroid lesions .Used diagnostically in thyroid surgical and FNA samples.Several miRNAs, including miR-146b, miR-221, miR-222, miR-181b, miR- 155, and miR-224, have been found to be significantlyupregulated in papillary carcinomas .Several upregulated miRNAs have been reported in thyroidfollicular carcinoma.OTHER GENETIC ALTERATIONS
  42. 42. GENETIC ALTERATION IN FOLLICULAR CELL DERIVEDMALIGNACIES OF THYROIDPapillarycarcinoma(Translocation/inversion)RASGTPBRAFPapillarycarcinoma(point mutation)MEKERKPI3KFCT&AnaplasticCA ( Pointmutation)PDK1PTENAKTPAX8/PPARCell growth,proliferation,differentiationFollicularcarcinoma(Translocation)RET/PTC
  43. 43. SUMMARYMany genetic mutations and other molecular alterations occurringin thyroid carcinomas has been discovered .These alterations, particularly specific mutations, can be reliablydetected by molecular techniques in thyroid can be usedsuccessfully to improve cancer diagnosis and management ofpatients with thyroid nodules.Diagnostic use of BRAF mutation, which is highly specific formalignancy when detected using well-validated techniques hasbeen established.
  44. 44. Biggest diagnostic impact can be achieved by testing FNA samplesfor a panel of mutations that typically includes BRAF, RAS,RET/PTC, and PAX8/PPAR.Finding any of these mutations in a thyroid nodule provides strongindication for malignancy and helps to refine clinical managementfor a significant proportion of patients with indeterminatecytology.The use of these and other emerging molecular markers isexpected to improve significantly the accuracy of cancer diagnosisin thyroid nodules and allow more individualized surgical andpostsurgical management of patients with thyroid cancer.SUMMARY
  45. 45. REFERENCES….Rosai & Ackerman’s Surgical Pathology- 10th edition , Volume1.Christopher D.M. Fletcher Diagnostic histopathology of tumors- 3rdedition, volume 2.Robbins & Cotran Pathological basis of Diseases – 8th edition.Mingzhao Xing-BRAF Mutation in Papillary Thyroid Cancer:Pathogenic Role, Molecular Bases, and Clinical ImplicationsDivision of Endocrinology and Metabolism, the Johns HopkinsUniversity School of Medicine .28(7):742–762JAMES A. FAGIN-Genetics of papillary thyroid cancerinitiation:Implications for therapy. The American Clinical andClimatological Association, Vol. 116, 2005.
  46. 46. Thank you

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