Observer Variation in the Diagnosis of Observer Variation in the Diagnosis of Follicular Variant of Follicular Variant of

Papillary Thyroid CarcinomaPapillary 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

PROLOGUE

• Encapsulated tumors with a follicular architecture? Whether minor nuclear changes of the type seen in typical papillar

y caricnomas justify a diagnosis of follicular variant of papillary carcinoma (FVPCA)

? Whether minor degrees of capsular penetration justify a diagnosis of malignancy

Williams ED. Two proposals regarding the terminology of thyroid tumors.Two proposals regarding the terminology of thyroid tumors.

Int J Surg Pathol. 2000;8:181-183

MATERIALS

• 4000 cases from the Mayo Clinic, 1961 - 2000 including all cases diagnosed as FVPCA, follicular adenoma, and f

ollicular 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

MATERIALS

• Cytoplasmic invagination in the nucleus (nuclear pseudoinclusions)

• Abundant nuclear grooves

• Enlarged overlapping nuclei

• Ground glass nuclei

• Irregularly shaped nuclei

• Psammoma bodies

dark staining colloid in the FVPCA on rightdark staining colloid in the FVPCA on right

nuclear clearing / colloid scalloping / irregularly shaped folliclesnuclear clearing / colloid scalloping / irregularly shaped follicles

irregularly shaped, overlapping nuclei with clearing and groovingirregularly shaped, overlapping nuclei with clearing and grooving

psammoma bodies / ground glass nuclei / nuclear pseudoinclusionpsammoma bodies / ground glass nuclei / nuclear pseudoinclusion

nuclear pseudoinclusionnuclear pseudoinclusion

capsular invasion / suspicious vascular invasion capsular invasion / suspicious vascular invasion

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

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

Other WDT-UMP WDC-NOSOther WDT-UMP WDC-NOS

12.6 10.3 2.312.6 10.3 2.3

26.4 25.2 2.3 26.4 25.2 2.3

Diagnosis by ReviewersDiagnosis 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.

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

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

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

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

DISCUSSION

• The most inportiant criteria included nuclear pseudoinclusion nuclear grooving ground glass nuclei

DISCUSSION

• Nuclear pseudoinclusion Close to 50% of all papillary thyroid carcinoma (2

5.3% in this study) Common in the usual papillary carincoma, in solid variant, and ta

ll cell variant Uncommon in the columnar cell variant Rarely in follicular carcinoma Not in follicular adenoma

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 specimens5 cases of Hashimoto’s thyoiditis

Chan JK, Saw D. The grooved nucleus: a useful diagnostic criterion of 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

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)

DISCUSSION

• Major criteria:Nuclei are ovoid rather than roundNuclei are crowded, often manifesting as lack of polari

zation in the cells that line a follicle Nuclei show a clear or pale chromatin pattern or exhibit

prominent grooveingPsammoma bodies

DISCUSSION

• Minor criteria:Presence of abortive papillaePredominant elongated or irregularly shaped folliclesDark-staining colloidPresence of rare nuclear pseudoinclusionsMultinucleated histiocytes in lumens of follicles

Differential Expression of Cytokeratins in Differential Expression of Cytokeratins in Follicular Variant of Papillary Carcinoma: Follicular Variant of Papillary Carcinoma: An Immunohistocehmical Study and Its DAn Immunohistocehmical Study and Its D

iagnostic Utilityiagnostic Utility

Zubair W. Baloch, MD, PhD; Susan Abraham, MD; Shelly Roberts, MS; Virginia A. LiVolsi, MD

Human Pathology • Vol. 30, No. 10, Oct 1999

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

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

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, benig

n nodules, and normal thyroid parenchyma

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

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. High-molecular-weight cytokeratin and CK-19 in the diagnosis of thyroid tumors.

Modern Pathology. 7(3):295-300, 1994 Apr.

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 iPattern of expression of intermediate cytokeratin filaments in the thyroid gland: an i

mmunohistochemical study of simple and stratified epithelial-type cytokeratins. mmunohistochemical study of simple and stratified epithelial-type cytokeratins. VVirchows Archiv.irchows Archiv. 430(3):239-45, 1997 Mar. 430(3):239-45, 1997 Mar.

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 analyKeratin subsets in papillary and follicular thyroid lesions. A paraffin section analy

sis with diagnostic implications.sis with diagnostic implications.Virchows Archiv.Virchows Archiv. 431(6):407-13, 1997 Dec. 431(6):407-13, 1997 Dec.

Combined Hepatocellular–Cholangiocarcinoma: Combined Hepatocellular–Cholangiocarcinoma: A Histopathologic, Immunohistochemical, and IA Histopathologic, Immunohistochemical, and I

n Situ Hybridization Studyn 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.; Ja

rnagin, William M.D.; Ladanyi, Marc M.D.; Klimstra, David S. M.D.

Am J Surg Pathol • Vol. 26, No. 8, Aug 2002

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

MATERIALS

• 56 cases from the Memorial Sloan-Kettering Cancer Center, New York, 1978 - 1998

• Diagnosis on a morphologic basis27: CHC (including 3 previous reported as CC) 7: pure peripheral CC12: pure HCC

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 promin

ent nucleoli With or without cytoplasmic bile

• Peripheral CC: Significant desmoplsia Prominent glandular formations lined by cuboidal cells With or without mucin production

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

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

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

  HCC CC CHC

Serum AFP usually very high

  most low

HBV / HCV 50%up to 90%

  15%

Cirrhosis 48%39%-78%

  0

Survivalmean

3 years5 years

 46 m54%37%

 37 m58%35%

 38.4 m38%24%

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 (2

5% to >75% in areas) 4 tumors contains distinct HCC- and CC-like areas None was classified as “collision”-type tumor

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