CYTOPATHOLOGY OF FOLLICULAR CELL NODULES

Transcription

1 104 th Annual USCAP Meeting Boston, March 21-27, 2015 Endocrine Pathology Society. March 21, 2015 Follicular cell-derived tumors of the thyroid gland, a practical update CYTOPATHOLOGY OF FOLLICULAR CELL NODULES Philippe Vielh MD, PhD, FIAC Gustave Roussy Cancer Campus, Villejuif, France President of the International Academy of Cytology Conflict of interest: no disclosure

2

3 Pierre MASSON ( ) «Of all cancers thyroid carcinomas are those giving to the histopathologists the highest lessons of humility. No classification is more difficult to establish than that of thyroid carcinomas. Their pleomorphism is the rule and very few are adapted to a precise classification» In Tumeurs Humaines. Histologie. Diagnostics et Techniques. 1956, 2 ème édition, page 488.

4 OUTLINE Thyroid fine-needle aspiration (FNA) diagnostic and screening capacities the PSC initiative and the NCI meeting Challenges for morphologists Today & tomorrow Conclusions

5 THYROID FNA Most widely used method for the preoperative diagnosis and screening of thyroid nodules Recommended by national and international societies / associations American Thyroid Association (revised) recommendations Cooper DS, et al. Thyroid 2009;19:

6 THYROID FNA Diagnostic method for tumors with clearly defined cytologic features (benign lesions, classical papillary, medullary, and anaplastic ca ) Screening method for follicular carcinomas and other carcinomas with less distinct nuclear features

7 THYROID FNA Great success the majority of thyroid FNAC can be classified as benign (>450,000 annually in the USA) Big shortcoming 15-30% of FNAC are difficult to be classified and have a variable risk of malignancy, while being mostly benign on histology.

8 THYROID FNA Before 2007 Huge variability in reporting and classifying (4-6tier) as well as in defining some thyroid lesions («grey zone») before the Papanicolaou Society of Cytopathology (PSC) initiative Interobserver variability Stelow EB, et al. Am J Clin Pathol 2005;124: PSC initiative started in 2006 NCI Thyroid Fine-Needle Aspiration State of the Science Conference (2007) The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC): standardization

9 THYROID FNA The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC): terminology and criteria Baloch ZW, et al. Diagn Cytopathol 2008;36(6):

10 THYROID FNA TBSRTC: diagnostic categories Cibas ES & Ali SZ. Am J Clin Pathol 2009;132:

11 THYROID FNA TBSRTC: images

12 THYROID FNA TBSRTC : risk & management Cibas ES & Ali SZ. Am J Clin Pathol 2009;132: Bongiovanni M, et al. Acta Cytol 2012;56(4):

13 THYROID FNA TBSRTC : 28 members from 14 European countries Kocjan G, et al. Cytopathology 2010;21:86-92

14 THYROID FNA Spectrum of follicular nuclear size and amount of colloid in follicular lesions of the thyroid. (modified from Cervino JM, Paseyro P, Grosso O, et al. La exploracion citologica de la glandula tirodes y sus correlaciones anatomoclinicas. In, Thyroid Cytopathology: an atlas and text. Kini SR, 2008.

15 THYROID FNA : benign

16 THYROID FNA : benign Thyroid FNA demonstrating a macrofollicular group of cells in a background of abundant watery colloid. These features are typical of a benign thyroid nodule. (Papanicolaou stain) Faquin WC. Head & Neck Pathol 2009;3:82 5

17 THYROID FNA : malignant

18 CHALLENGES TBSRTC: 3 categories ( grey zone, indeterminate) Atypia/follicular lesion of undetermined significance (AUS/FLUS) Suspicious for a follicular neoplasm/ follicular neoplasm (SFN/FN) Suspicious for malignancy (SM): typically papillary carcinoma

19 CHALLENGES Nondiagnostic/unsatisfactory? Fewer than 6 groups of well-preserved, well-stained follicular cell groups with 10 cells each AUS / FLUS?

20 CHALLENGES Ali SZ & Cibas ES book

21 CHALLENGES: AUS/FLUS (1) Nondiagnostic/unsatisfactory Fewer than 6 groups of well-preserved, wellstained follicular cell groups with 10 cells each Follicular variant of papillary carcinoma

22 CHALLENGES: AUS/FLUS (1)

23 A case diagnosed as FLUS/AUS on initial FNA due to the presence of focal microfollicle formation A) Diff-Quik stained air-dried smear, X20 B) Papanicolaou stained alcoholfixed smear, X40. A repeat FNA showing monolayer sheet of benign appearing follicular cells and macrophages was diagnosed as hyperplastic nodule C and D) Papanicolaou stained alcohol-fixed smears, X40). Surgical pathology follow-up showing a hyperplastic / adenomatoid nodule E and F) H&E, X40). Faquin WC, et al. Diagn Cytopathol 2010;38:731-9

24 A case diagnosed as FLUS/AUS on initial FNA The majority of the specimen showed features of nodular goiter (A: Pap stained alcohol-fixed smear, X10) However, one group of follicular cells displayed nuclear elongation with chromatin clearing and intranuclear grooves (B: Pap-stained alcohol-fixed smear, X40) Repeat FNA demonstrated monotonous population of follicular cells arranged in cohesive groups (C: Diff-Quik stained air-dried smear, X20) showing diagnostic nuclear features of papillary thyroid carcinoma (D: ThinPrep-Papanicolaou stain, X40. Surgical pathology follow-up showed an encapsulated follicular patterned lesion (E: H&E, X10) exhibiting diagnostic nuclear cytology of papillary carcinoma (F: H&E, X40. Faquin WC, et al. Diagn Cytopathol 2010;38:731-9

25 A case diagnosed as FLUS/AUS due to the presence of oncocytic follicular cells with nuclear pleomorphism Notice the lymphocytic infiltrate indicating an element of chronic lymphocytic thyroiditis A) Papanicolaou stained alcoholfixed smear, X10; B) ThinPrep-Papanicolaou stain, X60; C and D) ThinPrep, Papanicolaou stain, X40). Surgical excision was performed without repeat FNA which showed an oncocytic follicular nodule with marked random nuclear atypia arising in chronic lymphocytic thyroiditis E) H&E, X20; F) H&E, X40). Faquin WC et al. Diagn Cytopathol 2010;38:731-9

26 CHALLENGES : SFN/FN (2) Follicular adenoma Follicular carcinoma

27 CAPSULAR INVASION (CI) Schematic drawing for the interpretation of the presence or absence of CI. The diagram depicts a follicular neoplasm (orange) surrounded by a fibrous capsule (green). a) bosselation on the inner aspect of the capsule does not represent CI; b) sharp tumor bud invades into but not through the capsule suggesting invasion requiring deeper sections to exclude; c) tumor totally transgresses the capsule invading beyond the outer contour of the capsule qualifying as CI; d) tumor clothed by thin (probably new) fibrous capsule but already extending beyond an imaginary (dotted) line drawn through the outer contour of the capsule qualifying as CI; e) satellite tumor nodule with similar features (architecture, cytomorphology) to the main tumor lying outside the capsule qualifying as CI; f) Follicles aligned perpendicular to the capsule suggesting invasion requiring deeper sections to exclude g) follicles aligned parallel to the capsule do not represent CI; h) mushroom-shaped tumor with total transgression of the capsule qualifies as CI; i) mushroom-shaped tumor within but not through the capsule suggests invasion requiring deeper sections to exclude; j) neoplastic follicles in the fibrous capsule with a degenerated appearance accompanied by lymphocytes and siderophages does not represent CI but rather capsular rupture related to prior fine needle aspiration. Ghossein R. Head & Neck Pathol 2009;3:86 93

28 VASCULAR INVASION (VI) Schematic drawing for the interpretation of the presence or absence of VI. The diagram depicts a follicular neoplasm (green) surrounded by a fibrous capsule (blue) a) Bulging of tumor into vessels within the tumor proper does not constitute VI. b) Tumor thrombus covered by endothelial cells in intracapsular vessel qualifies as VI. c) Tumor thrombus in intracapsular vessel considered as VI since it is attached to the vessel wall. d) Although not endothelialized, this tumor thrombus qualifies for VI because it is accompanied by a fibrin thrombus. e) Endothelialized tumor thrombus in vessel outside the tumor capsule represents VI. f) Artefactual dislodgement of tumor manifesting as irregular tumor fragments into vascular lumen unaccompanied by endothelial covering or fibrin thrombus. Ghossein R. Head & Neck Pathol 2009;3:86 93

29 CHALLENGES: SFN/FN (2) microfollicles trabeculae Ali SZ & Cibas ES book

30 CHALLENGES : SFN/FN (2)

31 CHALLENGES : SFN/FN (2) Follicular adenoma / carcinoma Follicular variant of papillary carcinoma

32 CHALLENGES: SFN/FN (2)

33 CHALLENGES : SFN/FN (2) Follicular carcinoma Follicular variant of papillary carcinoma Poorly differentiated carcinoma

34 CHALLENGES : SFN/FN (2) Oncocytic (Hürthle) cell neoplasms

35 CHALLENGES: SFN/FN (2) Ali SZ & Cibas ES book

36 CHALLENGES: SFN/FN (2) + Ali SZ & Cibas ES book

37 CHALLENGES : SFN/FN (2) Benign lesion Mix of benign follicular cells + Hürthle cells

38 CHALLENGES : SFN/FN (2) Benign lesion Mix of benign follicular cells + Hürthle cells Hashimoto thyroiditis

39 CHALLENGES : SFN/FN (2)

40 CHALLENGES : SFN/FN (2) Benign lesion Mix of benign follicular cells + Hürthle cells Hashimoto thyroiditis Oncocytic tumor (benign/malignant) Auger M. Cancer (Cancer Cytopathology) 2014;122:

41 CHALLENGES : SFN/FN (2)

42 CHALLENGES: SM (3) Ali SZ & Cibas ES book

43 CHALLENGES: SM (3) Ali SZ & Cibas ES book

44 CHALLENGES: other (4) Acute inflammation vs undifferentiated (anaplastic) carcinoma Papillary thyroid carcinoma + Hashimoto thyroiditis

45 CHALLENGES: other (4)

46 CHALLENGES: general (5) Intra- and interobserver variability in thyroid cyto- and histopathology Stelow EB, et al. Am J Clin Pathol 2005;124: Elsheikh TM, et al. Am J Clin Pathol 2008;130: Cibas ES, et al. Ann Intern Med 2013;159:

47 TODAY & TOMORROW Immunocytochemistry Panel : CK19, HMBE-1, Galectin-3, Ki-67 Anti-BRAF (V600E) monoclonal antibody (VE1) : plump +/- sickle-shaped nuclei Liquid-based cytology Molecular cytopathology BRAF mutation; «rule-in» and/or «rule-out» tests Next generation sequencing (NGS) on cytology specimens

48 TODAY & TOMORROW Integration of cytomorphology & molecular pathology to ascertain the diagnosis of benign lesion to evaluate the behavior of carcinomas

49 TODAY & TOMORROW Some aggressive variants of follicular cellderived thyroid carcinomas: papillary variants : tall-cell, columnar-cell, diffuse sclerosing, solid, hobnail, widely invasive (diffuse) follicular poorly differentiated anaplastic Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathol) 2014;122:

50 TODAY & TOMORROW Primary or secondary detection of radioactive iodine-refractory differentiated thyroid cancer Schlumberger M, et al. Lancet Diabetes Endocrinol 2014;2: Study of pathways (MAPK and PI3K-AKTmTOR) implicating druggable kinases (kinase inhibitors) Xing M, Haugen BR, Schlumberger M. Lancet 2013;381:

51 TODAY & TOMORROW Risk evaluation including imaging findings: Thyroid Imaging and Reporting Database System (TI-RADS) Russ G et al. J Radiol 2011;92: The Bethesda System for reporting Thyroid Cytopathology update? British (Cross 2011) & Italian (Nardi 2013) classifications WHO 2004 update!

52 CONCLUSIONS Grey zone still exists Increased incidence of small low risk thyroid cancer Evolution of terminology (indolent lesion of epithelial origin: IDLE)? Esserman LJ, et al. Lancet Oncol 2014;15:e234-e242

53 Penetration of Thyroid-Cancer Screening ( ) and Incidence of Thyroid Cancer (2009) in the 16 Administrative Regions of South Korea. Data on thyroid-cancer screening are from the Korean Community Health Survey Database, Korea Centers for Disease Control and Prevention; data on incidence are from the Cancer Incidence Database, Korean Central Cancer Registry. Ahn HS, et al. N Engl J Med 2014;371:

54 Thyroid-Cancer Incidence and Related Mortality in South Korea, Data on incidence are from the Cancer Incidence Database, Korean Central Cancer Registry; data on mortality are from the Cause of Death Database, Statistics Korea. All data are age-adjusted to the South Korean standard population. Ahn HS, et al. N Engl J Med 2014;371:

55 CONCLUSIONS Primum non nocere! The origin of this phrase is uncertain. The Hippocratic Oath includes the promise «to abstain from doing harm». Perhaps the closest approximation in the Hippocratic Corpus is in Epidemics: "The physician must... have two special objects in view with regard to disease, namely, to do good or to do no harm" (book I, sect. 11, trans. Adams). According to Gonzalo Herranz, Professor of Medical Ethics at the University of Navarre, this sentence was introduced into American and British medical culture by Worthington Hooker, in his 1847 book Physician and Patient, who attributed it to the French pathologist and clinician Auguste François Chomel ( ). 12th-century Byzantine manuscript of the Hippocratic Oath

56 THANK YOU!

57

58 Cell 2014;159:676 90

59

60

61 Tuttle RM et al. Thyroid 2010:20(12):

62 FOLLICULAR ADENOMA Follicular adenoma with complete capsule. No invasion or irregularity was noted in the entirely submitted tumor (H&E 50) LiVolsi V et al. Endoc Pathol 2011;22:184 9

63 Follicular carcinoma is totally encapsulated but shows at low power a finger-like projection into the capsule (H&E 50) LiVolsi V et al. Endoc Pathol 2011;22:184 9

64 FOLLICULAR NEOPLASM Thyroid FNA showing follicular cells in a predominantly microfollicular arrangement This cytoarchitectural pattern is characteristic of a follicular neoplasm. (Papanicolaou stain) Faquin WC. Head & Neck Pathol 2009;3:82 5

65 FOLLICULAR VARIANT OF PAPILLARY THYROID CARCINOMA Characterized by cells with pale chromatin, somewhat enlarged oval nuclei, and occasional longitudinal nuclear grooves in a background of variable amounts of colloid. (Papanicoloau stain) Faquin WC. Head and Neck Pathol 2009;3:82 5

66 ACUS: ATYPICAL CELLS OF UNDETERMINED SIGNIFICANCE Thyroid FNA demonstrating an indeterminate architectural pattern (Papanicolaou stain) Faquin WC. Head & Neck Pathol 2009;3:82 5

67 ACUS: ATYPICAL CELLS OF UNDETERMINED SIGNIFICANCE Thyroid FNA containing occasional follicular cells with enlarged, pale, grooved nuclei in an otherwise benign aspirate (Papanicoloau stain) Faquin WC. Head & Neck Pathol 2009;3:82 5

68 FOLLICULAR ADENOMA WITH BENIGN BEHAVIOR Chetty R. J Clin Pathol 2011;64:737-41

69 FOLLICULAR ADENOMA WITH UNCERTAIN MALIGNANT POTENTIAL OR BEHAVIOR Chetty R. J Clin Pathol 2011;64:737-41

70 NON-INVASIVE FOLLICULAR VARIANT PAPILLARY THYROID CANCER Chetty R. J Clin Pathol 2011;64:737-41

71 INVASIVE FOLLICULAR VARIANT PAPILLARY THYROID CANCER Chetty R. J Clin Pathol 2011;64:737-41

72 MINIMALLY INVASIVE FOLLICULAR CARCINOMA Chetty R. J Clin Pathol 2011;64:737-41

73 Encapsulated follicular-patterned neoplasm without capsular and/or vascular invasion compatible with follicular adenoma (hematoxylin & eosin stain 20 ) Zubair B. Endocr Pathol 2014;25:12 20

74 Follicular carcinoma showing invasion into the vessels within the tumor capsule (hematoxylin and eosin stain 20 ) Zubair B. Endocr Pathol 2014;25:12 20

75 FOLLICULAR VARIANT OF PAPILLARY THYROID CARCINOMA Follicles with thick luminal colloid, and cells lining these demonstrating nuclear features of papillary thyroid carcinoma (hematoxylin & eosin stain 40 ) Zubair B. Endocr Pathol 2014;25:12 20

76 ENCAPSULATED FOLLICULAR VARIANT OF PAPILLARY THYROID CARCINOMA demonstrating diffuse distribution of nuclear features of papillary thyroid carcinoma (hematoxylin and eosin stain, 10, inset 60 ) Zubair B. Endocr Pathol 2014;25:12 20

77 Tall-cell variant of PTC Figure 1. In a sample of the tall-cell variant of papillary thyroid carcinoma, the tumor cells are 3 times as tall as they are wide and exhibit elongated nuclei (inset). Note the nuclear optical clearing, nuclear grooves, and peripherally placed micronucleoli (H&E stain, original magnification 320; inset, 360). Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

78 Tall-cell variant of PTC Figure 2. In a fine-needle aspiration smear from the tall-cell variant of papillary thyroid carcinoma, the tumor cells exhibit abundant cytoplasm, well defined cell borders, and elongated nuclei with prominent nuclear grooves. (Inset) The presence of multiple intranuclear inclusions within 1 nucleus ( soapbubble inclusions ) is a characteristic finding (Papanicolaou stain, original magnification 360; inset, 3100). Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

79 Tall-cell variant of PTC Baloch 2013, Fig 1, p734

80 Tall-cell variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

81 Columnar-cell variant of PTC Figure 3. In a sample of the columnar-cell variant of papillary thyroid carcinoma, the tumor exhibits elongated follicles with nuclei arranged in parallel cords. The nuclei are elongated and hyperchromatic and have occasional micronucleoli. Note the vacuolization, similar to that observed in secretory-type endometrium (H&E stain, original magnification 340). Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

82 Columnar-cell variant of PTC Figure 4. In a fine-needle aspiration smear from the columnar-cell variant of papillary thyroid carcinoma, tumor cells are arranged in cohesive papillary clusters and exhibit poorly defined cell borders and indistinct cytoplasm. The nuclei are oval or elongated with powdery chromatin and inconspicuous nucleoli. Focal nuclear pseudostratification, crowding, and overlapping are common (arrows) (Papanicolaou stain, original magnification 340). Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

83 Columnar-cell variant of PTC Baloch 2013, Fig 2, p735

84 Columnar-cell variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

85 Diffuse sclerosing variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122: Figure 5. In a sample of the diffuse sclerosing variant of papillary thyroid carcinoma, the tumor cells exhibit a papillary and/or follicular arrangement in a background of dense, desmoplastic, sclerotictype fibrosis. Innumerable psammoma bodies are evident (H&E stain, original magnification 320).

86 Diffuse sclerosing variant of PTC Figure 6. In a fine-needle aspiration smear from a diffuse sclerosing variant of papillary thyroid carcinoma, the tumor cells are arranged in papillary fragments and monolayer sheets, and they usually are round, low columnar, or polygonal in shape. The nuclei exhibit coarse chromatin with occasionally evident micronucleoli. (Inset) Note the numerous psammoma bodies in this single tissue fragment (Papanicolaou stain, original magnification 340; inset, 360). Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

87 Diffuse sclerosing variant of PTC Baloch 2013, Fig 3, p736

88 Diffuse sclerosing variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

89 Solid variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122: Figure 7. In a sample of the solid variant of papillary thyroid carcinoma, tumor cells are arranged in solid sheets that are separated by delicate, fibrous bands. (Inset) The nuclei of the tumor exhibit the classic nuclear features of papillary thyroid carcinoma (H&E stain, original magnification 310; inset, 360).

90 Solid variant of PTC Figure 8. In a fine-needle aspiration smear from a solid variant of papillary thyroid carcinoma, tumor cells are arranged in syncytial-type tissue fragments. Overlapping and crowding are usually observed toward the periphery of the groups. (Inset) Focally, a microfollicular pattern with thick colloid can be observed. Note the presence of nuclear elongation, focal nuclear grooves, and peripherally located micronucleoli (Papanicolaou stain, original magnification 360; inset, 360). Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

91 Solid variant of PTC Baloch 2013, Fig 4, p737

92 Solid variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

93 Hobnail variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122: Figure 9. In a sample of the hobnail variant of papillary thyroid carcinoma, tumor cells have nuclei located toward the middle or apical portion of the cell, producing a surface bulge and imparting the so-called hobnail appearance (arrows). Occasionally, the cells can appear tall and columnar. Note the ample, eosinophilic, and slightly granular cytoplasm, which is reminiscent of oncocytic cells (H&E stain, original magnification 360).

94 Hobnail variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122: Figure 10. In a fine-needle aspiration smear from a hobnail variant of papillary thyroid carcinoma, the cells are arranged in papillary and/or micropapillary clusters and have apically located nuclei that bulge the surface of the cell (inset). Note the prominent vessel admixed with the clusters of tumor cells (Papanicolaou stain, original magnification 340; inset, 360).

95 Hobnail variant of PTC Baloch 2013, Fig 5, p737

96 Hobnail variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

97 Widely invasive (diffuse) follicular variant of PTC Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

98 Widely invasive (diffuse) follicular variant of PTC Baloch 2013, Fig 6, p738

99 Poorly differentiated thyroid carcinoma Figure 11. In a fine-needle aspiration smear from a poorly differentiated thyroid carcinoma, the aspirate is highly cellular, with a uniformappearing cell population that overlaps significantly at lowpower magnification. (Inset) At higher magnification, small to medium-sized tumor cells are revealed with scant cytoplasm, a high nuclear/cytoplasmic ratio, and noticeable pleomorphism (Diff-Quik stain, original magnification 340; inset, 360). Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

100 Poorly differentiated thyroid carcinoma Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

101 Poorly differentiated thyroid carcinoma Baloch 2013, Fig 7, p739

102 Anaplastic thyroid carcinoma Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122: Figure 12. In a sample of anaplastic thyroid carcinoma, the tumor is composed of markedly atypical cells with significant nuclear pleomorphism and prominent nucleoli replacing the thyroid parenchyma (H&E stain, original magnification 320).

103 Anaplastic thyroid carcinoma Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122: Figure 13. This fine-needle aspiration smear from an anaplastic thyroid carcinoma reveals a highly cellular specimen composed of atypical cells with significant overlapping and necrosis. (Inset) At higher magnification, the nuclei exhibit marked pleomorphism. Note the presence of abundant neutrophils in the background (Papanicolaou stain, original magnification 360; inset, 3100).

104 Anaplastic thyroid carcinoma Baloch 2013, Fig 8, p740

105 Anaplastic thyroid carcinoma Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

106 Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathology) 2014;122:

107 TALL CELL VARIANT OF PTC Papillary formations are lined by tumor cells with eosinophilic cytoplasm and cell height 2 3 times the width A H&E stain, 60 Fine needle aspiration of tall cell variant of papillary thyroid carcinoma demonstrating soap bubble intranuclearinclusions (arrow) B Papanicolaou stain, 100 Baloch Z et al. J Clin Pathol 2013;66:733 43

108 COLUMNAR CELL VARIANT OF PTC Papillary formation, hyperchromatic elongated nuclei and prominent nuclear pseudostratification (H&E stain, 60 ) Baloch Z et al. J Clin Pathol 2013;66:733 43

109 DIFFUSE SCLEROSIS VARIANT OF PTC Low power showing an infiltrating tumour containing numerous psammoma bodies (arrows) (A H&E stain, 40 ). Fine needle aspiration showing a nest of tumour cells containing a psammoma body (arrow) (B Papanicolaou stain, 100 ). Baloch Z et al. J Clin Pathol 2013;66:733 43

110 SOLID VARIANT OF PTC Solid nests of tumor cells showing nuclear features of papillary thyroid carcinoma (H&E stain, 40 ) Baloch Z et al. J Clin Pathol 2013;66:733 43

111 HOBNAIL VARIANT OF PTC Tumor with papillary growth pattern; the inset shows some of the tumor cell nuclei are eccentrically placed causing bulging of the nuclei at the tip of the cell imparting the so-called hobnail appearance to the cells (H&E Stain, 20 and 60 ) Baloch Z et al. J Clin Pathol 2013;66:733 43

112 DIFFUSE FOLLICULAR VARIANT OF PTC A solid and follicular growth pattern tumor demonstrating widespread invasion. The inset highlights the nuclear features of papillary thyroid carcinoma (H&E Stain, 20 and 60 ) Baloch Z et al. J Clin Pathol 2013;66:733 43

113 POORLY DIFFERENTIATED CARCINOMA Pleomorphic tumor cells demonstrating solid and invasive growth (H&E stain, 40 ) Baloch Z et al. J Clin Pathol 2013;66:733 43

114 ANAPLASTIC CARCINOMA Round to spindle shaped tumor cells with marked nuclear pleomorphism (arrows) arranged in solid growth pattern A H&E stain, 40 Fine needle aspiration demonstrating pleomorphic tumor cells (long arrow) in a background of inflammatory cells; mostly neutrophils (short arrow) B Papanicolaou stain, 60 Baloch Z et al. J Clin Pathol 2013;66:733 43

115

116

117 Italian consensus for the classification and reporting of thyroid cytology. Nardi F, Basolo F, Crescenzi A, Fadda G, et al. J Endocrinol Invest 2014;37: