Thyroid tumors for pg activity for presentaion.pptx

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1. Follicular lesions of thyroid

2. OUTLINE OF PRESENTATION Introduction – Normal Thyroid anatomy and histology WHO 2017 classification Thyroid tumors with Follicular pattern Summary

3. The thyroid is an endocrine gland derived from floor of primitive pharynx, as down growth in region of developing tongue. It is placed ant. in lower neck, level with the 5 th cervical to 1 st thoracic vertebrae Normal adult thyroid consists of two lobes connected by an isthmus, weight ranges from 14-18g, each lobe ms 5x2.5x2.5cm. Superior and inferior thyroidal arteries supply the gland. Lymphatics drain into the internal jugular lymph nodes. THYROID: NORMAL ANATOMY

4. Thyroid gland is made up of round or oval follicles that vary considerably in size. Follicles are lined by a single layer of follicular cells that can be flattened, cuboidal or low columnar. The cytoplasm has a pale acidophilic or amphophilic staining quality. Follicular cells with abundant granular eosinophilic cytoplasm are referred to as Hurthle cells , Askanazy cells, oxyphilic cells, or oncocytes. Ultrastructurally , this granularity is due to the accumulation of mitochondria. NORMAL THYROID HISTOLOGY

5. Normal thyroid follicles lined by a single layer of flat to cuboidal follicular epithelial cells. A rich vascular network is observed between the follicles.

6. C cells (parafollicular cells) represent a minor component of the thyroid gland. They are responsible for the production of the peptide hormone calcitonin. C cells are located, individually or in small groups, within thyroid follicles. C cells (parafollicular cells )

7. Immunostain for calcitonin demonstrates C cells Cluster of C cells with pale cytoplasm round to oval nucleus and a centrally placed nucleolus

8. WHO CLASSIFICATION OF TUMORS OF THYROID GLAND (2017)

9. Follicular adenoma Hyalinizing trabecular tumour Other encapsulated follicular-patterned thyroid tumours -Follicular tumour of uncertain malignant potential -Well-differentiated tumour of uncertain malignant potential -Non-invasive follicular thyroid neoplasm with papillary-like nuclear features Papillary thyroid carcinoma (PTC) -Papillary carcinoma -Follicular variant of PTC -Encapsulated variant of PTC -Papillary microcarcinoma -Columnar cell variant of PTC - Oncocytic variant of PTC Follicular thyroid carcinoma (FTC), NOS -FTC, minimally invasive -FTC, encapsulated angioinvasive -FTC, widely invasive Hurthle ( oncocytic ) cell tumours -Hurthle cell adenoma -Hurthle cell carcinoma Poorly differentiated thyroid carcinoma Anaplastic thyroid carcinoma Squamous cell carcinoma

10. Medullary thyroid carcinoma Mixed medullary and follicular thyroid carcinoma Mucoepidermoid carcinoma Sclerosing mucoepidermoid carcinoma with eosinophilia Mucinous carcinoma Ectopic thymoma Spindle epithelial tumour with thymus-like differentiation lntrathyroid thymic carcinoma Paraganglioma and mesenchymal / stromal tumours Paraganglioma Peripheral nerve sheath tumours (PNSTs) -Schwannoma -Malignant PNST Benign vascular tumours -Haemangioma -Cavernous haemangioma -Lymphangioma Angiosarcoma Smooth muscle tumours -Leiomyoma -Leiomyosarcoma -Solitary fibrous tumour

11. Haematolymphoid tumours Langerhans cell histiocytosis Rosai -Dorfman disease Follicular dendritic cell sarcoma Primary thyroid lymphoma Germ cell tumours Benign teratoma (grade O or 1) Immature teratoma (grade 2) Malignant teratoma (grade 3) Secondary tumours

12. FOLLICULAR PATTERN IS SEEN IN….. Benign thyroid parenchyma Nodular goitre/ Adenomatous nodule/hyperplastic nodule Follicular neoplasm (Adenoma and Carcinoma) Follicular variant of papillary carcinoma Diffuse follicular variant of papillary carcinoma Noninvasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP) Hurthle cell adenoma and Hurthle cell carcinoma Medullary carcinoma, follicular/tubular variant Poorly differentiated carcinoma Collison tumors Mixed medullary and follicular cell carcinoma

13. Approach to histologic diagnosis? Assess the growth pattern, quality of the stroma, and background thyroid. Assess whether the nuclear features characteristic of papillary carcinoma are present. Check for any capsular or vascular invasion.

14. FOLLICULAR NEOPLASM

15. A benign, encapsulated, non-invasive neoplasm showing evidence of thyroid follicular cell differentiation, without nuclear features of papillary thyroid carcinoma. Frequently affect females. Occur in all age groups, but most patients present during their fifth or sixth decades of life. Most follicular adenomas are sporadic. Radiation exposure and iodine deficiency are known risk factors. Usually asymptomatic or presents as a painless nodule Follicular Adenoma

16. Gross:- Very thin fibrous capsule, well-circumscribed. The cut surface shows homogeneous greyish-white, tan, or brown fleshy tumour with areas of haemorrhage.

17. Microscopic Examination :- Follicular adenoma is enclosed by fibrous capsule Architectural growth patterns may be normofollicular , macrofollicular, microfollicular, solid, and trabecular. The tumour cells are cuboidal or polygonal with moderately abundant and pale eosinophilic to amphophilic or clear cytoplasm. The nuclei are round and located basally , with smooth contours and uniform chromatin distribution.

18. Capsular and vascular invasion is absent FNA cannot distinguish between follicular adenoma & follicular carcinoma Mitotic figures are rare Stromal component is scant Secondary changes such as stromal fibrosis, hyalinization, haemorrhage, oedema, cystic degeneration, calcification, and osseous or cartilaginous metaplasia may be seen. IHC: Immunoreactive for cytokeratins , thyroglobulin, TTF1, and PAX8, but not for calcitonin, CEA, or neuroendocrine markers.

19. Follicular adenoma. (A) Tumor is surrounded by a very thin capsule and comprises small follicles, which are architecturally different from those of the surrounding thyroid. (B) The small follicles are lined by cells with uniform round nuclei, which are often hyperchromatic

20. Thyroid malignancy arising from follicular cells in which the diagnostic nuclear features of papillary thyroid carcinoma (PTC) are absent. Accounts for 6-10% of thyroid carcinomas. Seen in adults and very rare in children. Risk factors include iodine deficiency, older age, female gender, and radiation exposure. Clinically, follicular carcinoma usually presents as a solitary mass in the thyroid. Follicular Thyroid carcinoma

21. Traditional AFIP (2014) WHO (2017) Minimally invasive Minimally invasive With capsular invasion Minimally invasive With limited vascular invasion ( < 4 vessels) Encapsulated angioinvasive With extensive vascular invasion (≥ 4 vessels) Widely invasive Widely invasive Widely invasive Classification of Follicular Carcinoma

22. Vascular invasion To qualify for vascular invasion, the involved blood vessels have to be located within or outside the fibrous capsule And the intravascular polypoid tumor growth must be covered by endothelium The only situation whereby the requirement for endothelialization of the tumor island can be waived is when the intravascular tumor cluster is attached to the wall and associated with thrombus formation.

23. Drawing to illustrate interpretation of presence or absence of vascular invasion Scenario A : Bulging of tumor into blood vessels within the tumor proper does not constitute vascular invasion. Scenario B : This satisfies the criterion for vascular invasion because the tumor plug occurs within a capsular blood vessel and is covered by endothelium Scenario C : Sometimes a tumor bud pushes through the fibrous capsule and then protrudes into the lumen of a capsular blood vessel. This bud is also endothelialized in the intravascular portion, satisfying the criterion for vascular invasion. Scenario D : Although the intravascular tumor island is not endothelialized , it is accompanied by fibrin thrombus and thus qualifies for vascular invasion.

24. Scenario E : Presence of endothelialized tumor island within blood vessel outside the tumor capsule qualifies for vascular invasion. Scenario F : Artifactual dislodgement of tumor into blood vessel, manifesting as irregular-contoured fragments of tumor in vascular lumens, unaccompanied by endothelial covering or fibrin thrombus .

25. The mere bulging of the neoplastic follicles of the main tumor toward the inner aspect of the capsular vessels does not constitute an adequate criterion for vascular invasion

26. In the thick fibrous capsule, a polypoid tumor plug is present within a blood vessel. It shows attachment to the wall, but this is not an essential criterion for recognition of vascular invasion. The tumor plug lying within the vascular lumen is covered by endothelium which qualifies for vascular invasion.

27. The tumor plug within the vascular space is not covered by endothelium, but this qualifies for vascular invasion because it is associated with thrombus formation

28. Follicular neoplasm. Several tumor fragments are seen within the capsular blood vessel lumen. Since they are irregular shaped, not covered by endothelium, and lack associated thrombus, they do not satisfy the diagnostic criteria of vascular invasion

29. Follicular adenoma, showing fine-needle aspiration–associated capsular rupture , mimicking capsular invasion. (A) A small bud extends into the thick fibrous capsule. (B) Higher magnification shows that this tumor bud is associated with chronic inflammatory cells and hemosiderin deposits.

30. Follicular carcinoma , demonstrating capsular invasion. The tumor bud has actively penetrated through the fibrous capsule, reaching beyond the external contour of the capsule .

31. Capsular invasion in follicular thyroid carcinoma (FTC). This is an example of the so called mushroom configuration of capsular Invasion

32. The criteria for invasion have to be applied strictly to avoid an overdiagnosis of cancer. If the invasion remains doubtful after assessment of multiple deeper levels and multiple sampled blocks, the case is preferably labeled follicular adenoma because the risk of metastasis is close to zero. An alternative suggestion has been made to label such cases follicular tumor of uncertain malignant behavior

33. Sub Classification of Follicular thyroid carcinoma : Minimally invasive Encapsulated angioinvasive Widely invasive

34. Variants of Follicular Neoplasm: Hyalinizing Trabecular adenoma and carcinoma Signet-ring cell variant Mucinous variant Clear cell FN FA with Papillary Hyperplasia Follicular adenoma/carcinoma, oncocytic variant with papillary growth Hyperfunctioning (so-called toxic or hot adenoma) Lipoadenoma (also called adenolipoma ) Infarcted follicular neoplasm following fine needle aspiration Follicular neoplasm with spindle cell metaplasia Atypical adenoma FA with bizarre nuclei Black FA [new entity]

35. Mucinous variant The tumor exhibits multiple cystic spaces filled with mucinous material

36. Follicular adenoma with papillary hyperplasia . (A) The encapsulated tumor comprises complex papillae. (B) The low columnar cells that cover the papillae have regular, basally situated, dark-staining, round nuclei.

37. Thyroid lipoadenoma- Abundant stromal fat cells intermixed with thyroid follicles .

38. Follicular adenoma with bizarre nuclei Scattered cells have huge, highly irregular, hyperchromatic nuclei .

39. Signet ring cell variant with vacuolated cytoplasm and the displacement of nuclei .

40. Clear cell variant . The cytoplasm is not water clear, but it exhibits a fine reticular quality

41. Hyperfunctioning follicular adenoma . Follicles exhibits blunt papillary projections

42. Follicular adenoma with spindle cell metaplasia . There are short fascicles of bland-looking spindle cells, which merge with the neoplastic follicles

43. Hurthle cell adenoma complicated by infarction after fine-needle aspiration. The right field shows the ghost shadows of necrotic cells.

44. Differential diagnosis : Adenomatous (colloid) nodule Hashimoto thyroiditis (vascular invasion absent, different nodules typically show different cytoarchitecture and cellularity) Intrathyroid parathyroid tumor ( hypercalcemia clinically) Medullary carcinoma (presence of fibrovascular septa) Papillary carcinoma

45. Adenomatous nodule Morphologic criteria for the distinction between adenomatoid nodule and follicular adenoma are not well defined. Features favoring diagnosis of follicular adenoma include: (a) solitary rather than multiple nodules (b) presence of a distinct fibrous capsule (c) expansile growth (d) cytoarchitectural features of the follicles differing from those outside the capsule. If morphologic features are indeterminate between an adenoma and adenomatoid nodule, the term benign follicular neoplasm is used

46. Prognosis of FTC ADVERSE FACTORS : Age > 45 yrs Oncocytic variant Extrathyroidal extension Tumour size >4 cm Distant metastases 10 year survival for minimally invasive is 90% and for widely invasive is 50%.

47. Hurthle Cell Adenoma or Carcinoma Hurthle cell neoplasms are follicular neoplasms comprising more than 70% oncocytic cells Older age group (mean 55 years) Female > male A size of 4 cm or larger is strongly correlated with malignancy Old age, male gender, large tumor size (>4 cm), extensive vascular invasion, extensive extrathyroidal extension, and nodal metastasis are correlated with a worse prognosis.

48. Hurthle Cell Adenoma The follicles are lined by cells with abundant eosinophilic granular cytoplasm

49. Hurthle Cell Adenoma The commonly found calcified colloid may be mistaken for psammoma bodies.

50. Hurthle cell carcinoma with vascular Invasion. Neoplastic cell embolus (E) in a blood vessel of the tumour capsule.

51. Some encapsulated follicular-patterned neoplasms of the thyroid pose diagnostic difficulties due to uncertainty as to whether the nuclear changes are sufficient to justify a diagnosis of papillary thyroid carcinoma (PTC), or due to uncertainty about the presence of capsular or vascular invasion Other encapsulated follicular-patterned thyroid tumours

52. 2014 Armed Forces Institute of Pathology (AFIP) : recommended nomenclature for encapsulated well-differentiated follicular-patterned tumors on the basis of the presence or absence of nuclear features of papillary thyroid carcinoma (PTC) and capsular invasion.

53. 2017 WHO classification: recommended nomenclature for encapsulated follicular-patterned tumours on the basis of the presence or absence of nuclear features of papillary thyroid carcinoma (PTC) and capsular or vascular invasion

54. Questionable capsular invasion in well differentiated tumour of uncertain malignant potential . A) Hook-like protrusion of tumour cells deeply into but not completely through the capsule. B) Broad-based bulge of tumour cells into the capsule that does not extend beyond its outer contour.

55. Questionable Vascular invasion in well-differentiated tumour of Uncertain Malignant potential A) Irregular outgrowth of neoplastic cells within vascular spaces of the tumour capsule B) Tumour cells closely intermixed with vascular spaces of the tumour capsule

56. Non-invasive neoplasm of thyroid follicular cells with a follicular growth pattern and nuclear features of papillary thyroid carcinoma (PTC) Has an extremely low malignant potential The patients usually present with solitary thyroid nodule, but the tumors can be bilateral or multifocal. Female-to-male ratio is 3-4:1 with a wide patient age range, but mostly present during fourth to sixth decade of life. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

57. Grossly:- Tumour has smooth contour, a thin capsule, and a homogeneous tan-yellow cut surface with focal haemorrhage

58. Nuclear score 1: The cells of this lesion have enlarged nuclei as compared with the adjacent normal thyroid parenchyma (inset), but show no substantial irregularity of the nuclear membrane and no chromatin clearing. These features are insufficient for a diagnosis of NIFTP. Score 2: These cells have enlarged nuclei as compared with the adjacent normal thyroid parenchyma (inset) and show substantial irregularity of the nuclear contours, but no chromatin clearing. This meets the criteria for NIFTP. Score 3: These cells show enlarged nuclei as compared with the adjacent normal thyroid parenchyma (Inset), pronounced irregularity of the nuclear contours, and chromatin clearing . This meets the criteria for NIFTP.

59. The tumour can have a thick capsule Thin capsule No capsule but be sharply demarcated from the adjacent normal thyroid parenchyma

60. NIFTP (A) The follicular-patterned tumor is surrounded by a fibrous capsule. A nuclear score of 3 with nuclear enlargement, marked nuclear irregularity, and ground-glass nuclear matrix was compatible with a diagnosis of NIFTP after confirming the noninvasive nature

61. Invasive Carcinoma UMP Papillary carcinoma nuclear features? Adenoma NIFTP Use nuclear assessment guide Questionable YES NO NO YES Score 0-1 Score 2-3 Algorithm for the evaluation of encapsulated follicular lesions, including invasion and nuclear features

62. D/D of NIFTP- Follicular adenoma and hyperplastic nodules - absence of nuclear features of papillary carcinoma. Conventional PTC - presence of papillae Invasive encapsulated FVPTC - presence of capsular or vascular invasion

63. This variant is completely or almost completely composed of small- to medium-sized follicles lined by cells with variable nuclear features of PTC. The follicles vary in size and shape but are often elongated or irregular shaped, with abortive papillary formation. The colloid is usually deep staining and scalloped. FVPTC is now the most common variant of PTC and represents nearly 30% of PTCs in some series. There are two main subtypes: -Infiltrative -Encapsulated Follicular variant of PTC (FVPTC)

64. Infiltrative growth pattern Shows obvious infiltration of the thyroid parenchyma, often accompanied by sclerosis, similar to conventional papillary carcinoma, except that papillae are absent. Associated with frequent lymph node metastases, a risk of recurrence BRAF mutations Encapsulated pattern Characterized by a follicular growth pattern and total tumor encapsulation Similar to follicular carcinoma, with distant lung and bone metastases and infrequent lymph node metastases. In the absence of capsular or vascular invasion, encapsulated FVPTCs have a very low risk of recurrence or extrathyroidal spread Frequently harbor RAS mutations

65. Infiltrative type : (A) Tumor islands infiltrate a sclerotic stroma. (B) The follicles are elongated, and the colloid is typically dark staining and scalloped

66. Encapsulated type: (C) The tumor is completely surrounded by a fibrous capsule (D) The follicles are lined by cells with pale-staining oval nuclei that lack polarity. Some nuclei are crescent shaped

67. Nuclear features of invasive encapsulated follicular variant papillary thyroid carcinoma . Nuclear enlargement, nuclear membrane irregularity, and chromatin clearing are observed. Note the nuclear irregularity and groove (yellow arrow) and pseudo-inclusion (blue arrow)

68. (A) The tumor is composed mostly of large follicles distended with colloid, mimicking colloid nodule. (B) The characteristic nuclear features may not be evident in the large follicles but are better seen in the small follicles (left upper field)

69. Rare aggressive form of papillary carcinoma occurring in young patients (mean age 21.3 years). Characterized by diffuse involvement of the entire thyroid without formation of discernible nodules. Exclusive or predominant follicular pattern, and absence of fibrosis. Shows a high frequency of lymph node (87.5%), pulmonary (75%), and bone (25%) metastasis. However, the outcome is still favorable because of the excellent response to radioactive iodine therapy and the favorable impact of young age. Diffuse follicular variant

70. Diffuse follicular growth pattern and minimal sclerosis

71. IHC Papillary carcinoma typically stains for pancytokeratin , thyroglobulin, TTF1, and PAX8, but not neuroendocrine CD56 has emerged as a helpful marker in diagnosis—its expression is lost in most cases of papillary carcinoma, but rarely in normal thyroid, benign thyroid lesions, and other thyroid carcinomas.

72. Medullary carcinoma can form follicles containing eosinophilic secretion or empty glands . The luminal side is often more deeply eosinophilic granular because of neurosecretory granules. This variant can be distinguished from a follicular neoplasm by the stippled chromatin, finely granular cytoplasm, delicate fibrovascular septa , and calcitonin immunoreactivity Medullary thyroid carcinoma {follicular variant}

73.  Medullary carcinoma.  A, The tumour packets are interspersed with follicle-like spaces.  B, Tumour with follicle-like spaces containing secretion, mimicking follicular neoplasm.  

74. POORLY DIFFERENTIATED CARCINOMA Follicular cell neoplasms that show limited evidence of structural follicular cell differentiation and occupy both morphologically and behaviourally an intermediate position between differentiated (follicular and papillary CA)and undifferentiated carcinoma. Mostly arise de novo, some tumors appear to arise from pre-existing papillary and follicular thyroid carcinoma.

75. Middle/old age (mean age 60 yrs ) F:M - 1.6-1.2:1 C/F- mostly appear as solitary large thyroid masses Frequently history of recent growth in a long-standing uninodular or multinodular thyroid. L.N, lung , bone metastases are frequent at time of diagnosis

76. Microscopy Three different histologic patterns are recognized : Insular, trabecular and solid . Small abortive follicles are interspersed. Infiltrative pattern of growth, necrosis and obvious vascular invasion. Cells are small and uniform and contain round hyperchromatic or vesicular nuclei with indistinct nucleoli. Mitotic figures common.

77. Tumor form insular pattern separated by sclerotic septa Tumor shows trabecular growth pattern

78. Sheets and large islands of tumor with foci of coagulative necrosis Tumor cells show uniform nuclei and relatively high nucleus cytoplasm ratio, mitotic figures are seen

79. IHC - Thyroglobulin(confined to abortive follicles) and TTF-1 + ve . PAX-8+ve. Ki-67 index increased. POOR PROGNOSIS- Age >45yr, Tumor size >4cm, Extra thyroid extension, Presence of metastasis, undifferentiated carcinoma component. IHC expression of insulin-like growth factor –II messenger RNA binding protein-3 .

80. D/D MEDULLARY CARCINOMA ( more prominent vasculature, granular cytoplasm, and finely stippled chromatin also by IHC) SOLID VARIANT OF PAPILLARY CARCINOMA (extensive presence of the typical nuclear features) UNDIFFERENTIATED (ANAPLASTIC) THYROID CARCINOMA (completely lacks evidence of follicular cell differentiation and generally shows prominent nuclear pleomorphism and frequent mitoses; immunostaining for thyroglobulin and TTF1 is negative)

81. COLLISION TUMOR Collision tumors comprise two recognizable types of thyroid carcinoma: 1. Follicular carcinoma + medullary carcinoma 2. Papillary carcinoma + medullary carcinoma The two components occur synchronously and grow in proximity, but they are not intermingled. The behavior of these tumors is little known but probably is determined by the more aggressive component

82. Mixed medullary and follicular cell carcinoma Also known as follicular- parafollicular carcinoma or differentiated carcinoma of intermediate type The tumors are usually non-encapsulated. They show features of medullary carcinoma with admixed follicular structures. Ultrastructural studies demonstrate cells with neurosecretory granules, follicular cells, cells with intermediate features All cases are immunoreactive for thyroglobulin (most conspicuous in follicular and cribriform areas and sometimes solid component) and calcitonin (most conspicuous in solid areas). To be considered part of the neoplasm, the follicles should be located deep within the tumor and are lined by cells with enlarged hyperchromatic nuclei.

83. SUMMARY Most common malignancy of endocrine system F>M PTC>FTC >MTC>UTC Mostly present with thyroid nodule or symptoms due to compression of surrounding structures Follicular tumors couldn't be diagnose by cytology ALONE ,so excision & histopathological examination is recommended Benign tumours are treated by complete excision