2. Observer Variation in the Diagnosis of Follicular Variant of Papillary Thyroid Carcinoma Lloyd, Ricardo V MD; Erickson, Lori A MD; Casey, Mary B MD; Lam, King Y MBBS, FRCPA; Lohse, Christine M BS; Asa, Sylvia L MD, PhD; Chan, John K. C MBBS, FRCPA; DeLellis, Ronald A MD; Harach, H Ruben MD, PhD; Kakudo, Kennichi MD, PhD; LiVolsi, Virginia A MD; Rosai, Juan MD; Sebo, Thomas J MD, PhD; Sobrinho-Simoes, Manuel MD, PhD; Wenig, Bruce M MD; Lae, Marick E MD Am J Surg Pathol Vol. 28, No. 10, Oct 2004

3. PROLOGUE Encapsulated tumors with a follicular architecture ?Whether minor nuclear changes of the type seen in typical papillary caricnomas justify a diagnosis of follicular variant of papillary carcinoma (FVPCA) ?Whether minor degrees of capsular penetration justify a diagnosis of malignancy Two proposals regarding the terminology of thyroid tumors. Williams ED. Two proposals regarding the terminology of thyroid tumors. Int J Surg Pathol. 2000;8:181-183

5. MATERIALS 4000 cases from the Mayo Clinic, 1961 - 2000 including all cases diagnosed as FVPCA, follicular adenoma, and follicular carcinoma 105 cases with one or more of the major features of FVPCA 87 cases had sufficient materials 85 cases (97.7%) had been originally diagnosed as FVPCA 2 cases were originally diagnosed as follicular adenoma and were not associated with invasive growth or metastatic disease

6. MATERIALS Cytoplasmic invagination in the nucleus (nuclear pseudoinclusions) Abundant nuclear grooves Enlarged overlapping nuclei Ground glass nuclei Irregularly shaped nuclei Psammoma bodies

7. dark staining colloid in the FVPCA on right

8. nuclear clearing / colloid scalloping / irregularly shaped follicles

9. irregularly shaped, overlapping nuclei with clearing and grooving

10. psammoma bodies / ground glass nuclei / nuclear pseudoinclusion

11. nuclear pseudoinclusion

12. capsular invasion / suspicious vascular invasion

13. METHODS One representative slide from each case was selected The same H&E section was seen by all 10 reviewers The reviewers did not know about follow-up information Statistical analysis: cumulative number and percent of diagnoses by reviewers concordant diagnoses among reviewers criteria for diagnosis

14. RESULTS Capsular invasion: 67% Lymphovascular invasion: 5.7% Metastasis: 24.1% cervical lymph nodes: 18.3% lung: 4.6% others (e.g. bone, brain, etc.): 3.4% Die of disease:2.2 % Mean follow-up duration: 8.4 years

18. Other WDT-UMP WDC-NOS 12.6 10.3 2.3 26.4 25.2 2.3

22. Diagnosis by Reviewers 19 of 21 (90.4%) tumors associated with metastases were clearly invasive with lymphovascular and/or capsular invasion There were no significant morphologic differences between invasive and non-invasive carcinomas.

23. TABLE 4.Most Important (Major) Criteria for the Diagnosis of FVPCA

24. TABLE 4.Less Important Criteria for the Diagnosis of FVPCA

25. DISCUSSION Most reviewers were able to diagnose the FVPCA cases that were capable of metastasizing. (concordant diagnosis: 39%  66.7%) Cases capable of metastasizing were usually associated with lymphovascular and/or capsular invasion Altough the diagnosis of FVPCA is somewhat controversial, most experienced pathologists generally concurred in making this diagnosis in cases with metastatic disease

26. DISCUSSION One case with metastatic disease to a lymph node was diagnosed as an adenoma by the one reviewer The case did not have invasive growth. Three cases with metastatic disease were diagnosed as follicular carcinoma Two other cases were diagnosed as WDT-UMP

27. DISCUSSION The most inportiant criteria included nuclear pseudoinclusion nuclear grooving ground glass nuclei

28. DISCUSSION Nuclear pseudoinclusion Close to 50% of all papillary thyroid carcinoma (25.3% in this study) Common in the usual papillary carincoma, in solid variant, and tall cell variant Uncommon in the columnar cell variant Rarely in follicular carcinoma Not in follicular adenoma

29. DISCUSSION Nuclear grooving Papillary carcinoma: 100% Follicular carinoma: 0% Follicular adenoma: 10.8 % 103 consecutive cases of thyroid carcinoma (including 89 cases of papillary carcinoma) 100 consecutive cases of noncancer thyroidectomy specimens 5 cases of Hashimoto’s thyoiditis The grooved nucleus: a useful diagnostic criterion of Chan JK, Saw D. The grooved nucleus: a useful diagnostic criterion of papillary carcinoma of the thyroid. papillary carcinoma of the thyroid. Am J Surg Pathol. 1986;10:672-679

30. DISCUSSION Ground glass nuclei Focally seen in many types of thyroid tumors, including follicular carcinoma Usually diffusely seen only in papillary carcinoma (100% cases in this study, ranged from focal to diffuse)

31. DISCUSSION Major criteria: Nuclei are ovoid rather than round Nuclei are crowded, often manifesting as lack of polarization in the cells that line a follicle Nuclei show a clear or pale chromatin pattern or exhibit prominent grooveing Psammoma bodies

32. DISCUSSION Minor criteria: Presence of abortive papillae Predominant elongated or irregularly shaped follicles Dark-staining colloid Presence of rare nuclear pseudoinclusions Multinucleated histiocytes in lumens of follicles

33. Differential Expression of Cytokeratins in Follicular Variant of Papillary Carcinoma: An Immunohistocehmical Study and Its Diagnostic Utility Zubair W. Baloch, MD, PhD; Susan Abraham, MD; Shelly Roberts, MS; Virginia A. LiVolsi, MD Human Pathology Vol. 30, No. 10, Oct 1999

34. MATERIALS 50 cases with formalin-fixed paraffin-embedded tissue University of Pennsylvania Medical Center Personal consultation files of Virginia A. LiVolsi Classification of cases 26: FVPCA (2 cases with lymphocytic thyroiditis) 10: classic papillary carcinoma (1 case with lymphocytic thyroiditis) 1: Warthin’s-like papillary carcinoma (1 case with lymphocytic thyroiditis) 2: columnar cell carcinoma 2: angioinvasive follicular carcinoma 4: follicular adenoma 5: hyperplastic / adenomatous nodules

36. METHODS 0 : no positive cells + / - : rare scattered cells positie 1+ (weak): 1% to 10% cells positive 2+ (moderate): 10% to 50% cells positive 3+ (strong): more than 50% cells positive

37. RESULTS CK19, CK20, CK7 CKs 5/6/18 (LP34) 1 case of classic papillary carcinoma 1 case of hyperplastic nodule CKs 10/13 (DEK13) 2 cases of classic papillary carcinoma 1 case of follicular adenoma CK18 Strong intense positivity in all cases of carcinoma, adenoma, benign nodules, and normal thyroid parenchyma

40. RESULTS hyperplastic / adenomatous nodules (5), follicular adenoma (4), follicular carcinoma (2) CK19 All negative CK 20 1 case of follicular adenoma showed weak positivity The remaining cases are all negative CKs 17 1 case of hyperplastic nodule showed focal staining The remaining cases are all negative

41. DISCUSSION 116 surgically resected thyroids 31 nodular hyperplasias 18 follicular adenomas 48 papillary carcinomas 19 follicular carcinomas CK-19, HMW-CK, EMA Raphael SJ, MacKeown-Essyen G, Asa SL. High-molecular-weight cytokeratin and CK-19 in the diagnosis of thyroid tumors. Modern Pathology. 7(3):295-300, 1994 Apr.

42. DISCUSSION 87 cases 41 papillary carcinomas 10 follicular carcinomas 2 poorly differentiated carcinomas 34 normal thyroid parenchyma and lymphocytic thyroiditis CK 7, CK 18, CK 8, CK 19, CK 5/6, CK 13 Fonseca E, Nesland JM, Hoie J, Sobrinho-Simoes M. Pattern of expression of intermediate cytokeratin filaments in the thyroid gland: an immunohistochemical study of simple and stratified epithelial-type cytokeratins. Virchows Archiv. 430(3):239-45, 1997 Mar.

43. DISCUSSION > 200 non-neoplastic and neoplastic thyroid papillary and follicular lesions CK19 was strongly and uniformly expressed in virtually all papillary carcinomas About half of the follicular carcinomas were also strongly CK19-positive Miettinen M, Kovatich AJ, Karkkainen P. Keratin subsets in papillary and follicular thyroid lesions. A paraffin section analysis with diagnostic implications. Virchows Archiv. 431(6):407-13, 1997 Dec.

45. Combined Hepatocellular–Cholangiocarcinoma: A Histopathologic, Immunohistochemical, and In Situ Hybridization Study Tickoo, Satish K. M.D.; Zee, Sui Y. M.D.; Obiekwe, Sam M.D.; Xiao, Hong B.S.; Koea, Jonathan M.D.; Robiou, Christian M.D.; Blumgart, Leslie H. M.D., F.A.C.S.; Jarnagin, William M.D.; Ladanyi, Marc M.D.; Klimstra, David S. M.D. Am J Surg Pathol Vol. 26, No. 8, Aug 2002

46. INTRODUCTION A rare tumor (< 1% of all liver carcinoma) containing unequivocal elements of both hepatocellular and cholangiocarcinoma that are intimately admixed This tumor should be distinguished from separate hepatocellular carcinoma and cholangiocarcinoma arising in the same liver. Such tumor may be widely separated or close to each other (“collision tumor”) The category should not be used for tumors in which either form of growth is insufficiently differentiated for positive identification

47. MATERIALS 56 cases from the Memorial Sloan-Kettering Cancer Center, New York, 1978 - 1998 Diagnosis on a morphologic basis 27: CHC (including 3 previous reported as CC) 7: pure peripheral CC 12: pure HCC

48. MATERIALS Goodman et el.: tumors with intermediate differentiation and identifiable transition between HCC and CC, or with the presence of discrete and separate nodules of HCC and CC HCC: Trabecular growth pattern Without significant desmoplasia Bearing cells with eosinophilic cytoplasm, large vesicular nuclei containing prominent nucleoli With or without cytoplasmic bile Peripheral CC: Significant desmoplsia Prominent glandular formations lined by cuboidal cells With or without mucin production

49. MATERIALS Scoring (CK & EMA): 0: no staining 1+:  5% positive cells 2+: 6-25% positive cells 3+: 26-50% positive cells 4+: > 50% positive cells pCEA: canalicular staining AFP: any cytoplasmic staining

51. In Situ Hybridation for Albumin mRNA Albumin is a ubiquitous protein that is synthesized only by hepatocytes 69 hepatic tumors 29 extrahepatic tumors 50 non-neoplastic, noncirrhotic liver Krishna, M. M.D.; Lloyd, R. V. M.D.; Batts, K. P. M.D. Detection of Albumin Messenger RNA in Hepatic and Extrahepatic Neoplasms: A Marker of Hepatocellular Differentiation Am J Surg Pathol. 1997;21:147-152

53. Statistical Analysis Fisher exact test: relationship between the IHC/ISH profile and different morphologic phenotypes in the tumors Kaplan-Meier method: survival analyses Long –rank test: differences in survival between different clinical groups

55. HCCCCCHC Serum AFPusually very high most low HBV / HCV50% up to 90% 15% Cirrhosis48% 39%-78% 0 Survival mean 3 years 5 years 46 m 54% 37% 37 m 58% 35% 38.4 m 38% 24%

56. Pathologic Features of CHC 9 single; 12 mutiple Gross features: HCC vs. CC Histologic features: All (27 cases) show intermediate features between HCC and CC (25% to >75% in areas) 4 tumors contains distinct HCC- and CC-like areas None was classified as “collision”-type tumor

59. Thank you