1. Hashimoto Thyroiditis: an Update Diagnosis, Pathogenesis, Pitfalls Peter M. Sadow, M.D., Ph.D. ENT, Endocrine, GU Pathology Massachusetts General Hospital Harvard Medical School April 24, 2010 MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

2. Struma Lymphomatosa History Hakaru Hashimoto 1881-1934 Born, Iga-Ueno, Japan Medical School of Kyushu Imperial University 1912 reported 4 cases of goiter All women Chronic thyroid disorder Diffuse lymphocytic infiltration Fibrosis, parenchymal atrophy

3. Hashimoto Thyroiditis History Autoimmune nature of this condition established in 1956, Roitt et al. showed these patients to have antibodies to thyroglobulin 1957, Trotter et al. identified a second antigen, microsomal fractions, later found to be thyroid peroxidase MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

4. Clinical Presentation Epidemiology Disease usually presents in middle-aged women (mean age 59 -- men and women) 5-7 x more common in women than men Present with goiter May present with hypothyroidism Most common cause of sporadic goiter in children (rarely occurs before age 5, but 40% of adolescent goiters)

5. Clinical Presentation Often goiter Compression of trachea or recurrent laryngeal nerve is rare Pain or tenderness not common Feeling of tightness often noted Symmetrically enlarged gland with bosselated surface May be asymmetric and clinically appear to be nodular or have a solitary nodule

6. Clinical Presentation Radiology not particularly helpful as adjunct Uptake (RAI) can be variable and provide misleading results -- normal to elevated Laboratory evaluation demonstrates antithyroglobulin antibodies (60%) and antithyroid peroxidase antibodies (95%)

7. Treatment Thyroid hormone replacement MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

8. Pathology Why discuss Hashimoto? Clinical diagnosis Clinical presentation Clinical treatment But… MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

9. Physical Exam and Clinical Correlation As mentioned, can be asymmetry to gland Possibly palpable, solitary nodule Radiology may show a dominant nodule Symptoms of compression may occur –Trachea –Recurrent laryngeal nerve MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

10. Fine Needle Aspiration Tingible Body Macrophages Hürthle Cells

11. FNA Results Numerous lymphocytes, germinal centers, and tingible body macrophages Numerous Hürthle (oncocytic) cells Occasional cells with irregular nuclei with some changes worrisome for carcinoma MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

12. Post-FNA If germinal centers, Hürthle cells, macrophages, etc, patient diagnosed with Hashimoto thyroiditis (in the appropriate clinical setting) If no symptoms, patient followed and treated clinically MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

13. Surgery? Only Hürthle cells seen on FNA, suspicious for Hürthle cell neoplasm Only lymphocytes seen and no thyroid epithelial cells, at least re-biopsy, rule out lymphoma Rare cells with atypical nuclei, concern about carcinoma would at least warrant re-biopsy Compressive symptoms would necessitate surgery in the absence of response to medical therapy, or at least gland ablation with radioactive iodine (if sufficient uptake and symptoms not emergent)

14. Goiter in Hashimoto Thyroiditis Kumar et al, Robbins Pathology, 7th edition, 2005

15. Histology Hashimoto MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

16. Patterns in Hashimoto MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

17. Differential Diagnosis Thyroid Carcinoma Lymphoma Graves’ Disease Riedel’s thyroiditis MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

18. Histologic Variants Fibrous variant Fibrous atrophy variant Juvenile variant Cystic variant MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

19. Fibrous Variant Epidemiology 10% of cases Slightly older age group Marked hypothyroidism Large, symptomatic goiter Markedly elevated antithyroglobulin antibody Elevated TSH Require surgery due to symptoms

20. Fibrous Variant Histology Larger gland than classic Hashimoto Preserved lobulated pattern of thyroid Atrophic follicular cells with broad bands of fibrosis Hürthle cells, lymphoplasmacytic infiltrate and germinal centers

21. Fibrous Atrophy Variant Epidemiology +/- history of Hashimoto Elderly patients Elevated antithyroid antibodies Profound hypothyroidism MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

22. Fibrous Atrophy Variant Histology Small, fibrotic gland (1-6 gm) Present with hypothyroidism Minimal residual thyroid follicles Thyroid parenchyma largely replaced by dense fibrosis and lymphoplasmacytic infiltrate reminiscent of fibrous variant

23. Juvenile Variant Present with hyperthyroidism that progresses to hypothyroidsm with time Lymphoplasmacytic infiltrate with Hürthle cells and squamous cell metaplasia Follicular atrophy and oncocytic metaplasia may be seen Hyperplastic changes may be seen in thyroid follicles

24. Cystic Variant Quite rare Case reports showing branchial cleft-like cysts lined by squamous and columnar epithelium Cysts surrounded by follicular lymphoid tissue and a fibrous capsule Marked atrophy, Hürthle cell change, and lymphoctic infiltrates Minimal fibrosis

25. Dominant Nodules Present in a number of cases of Hashimoto thyroiditis Often detected on clinical or radiologic exam Dominant nodules have worrisome cytologic features and are often a reason for surgical excision of the gland

26. Dominant Nodules Numerous recent and not-so-recent studies have shown a link between Hashimoto thyroiditis and the development of well- differentiated thyroid carcinomas Whether a causal link or an associated finding has not been well-determined Current studies actually have not yet answered this question

27. Dominant Nodule Update Summary Indeed, a strong link between Hashimoto thyroiditis and well-differentiated carcinoma exists Genetic screen by FNA biopsy prior to surgery for BRAF, RET/PTC, or TRK mutations show promise for confirming individuals who do have cancer -- but not ruling out for cancer those with negative analysis Dominant nodules may show increased expression of MAP kinase signaling constituents

30. Mutational Analysis Hashimoto thyroiditis may be associated with papillary carcinoma In order to understand dominant nodules as potential precursor lesions, patients with concomitant dominant nodules and papillary carcinomas were studied No mutations in BRAF or RET/PTC translocations were discovered in dominant nodules, despite their presence in papillary lesions

31. Lymphocytes The main differential diagnosis for a profuse lymphocytic infiltration is lymphoma This possibility is investigated by immunohistochemistry Hashimoto thyroidits shows a mixed B and T cell population of cells, along with admixed histiocytes and plasma cells

32. Understanding Pathogenesis Prevailing Hypotheses Thyroid epithelial cells present antigens associated with certain HLA types Recognized by T cells and facilitate a B cell-mediated immunity Predisposing cause is unclear, whether haptens seen during a bacterial or viral infection, or simply in predisposed individual

33. Susceptibility Genes CTLA-4 (cytotoxic T lymphocyte antigen) –Reduced suppression of T cell activation Protein tyrosine phosphatase-22 –Inactivation of T cell suppression resulting in escape from thymic deletion Thyroglobulin –Alteration in thyroglobulin peptide presentation by HLA-DR to T cells

34. Determining a Mechanism October 2007 issue of Thyroid dedicated to reviewing current knowledge of autoimmune thyroid disease Mouse models of Hashimoto are limited, in that immune infiltration in these animals is limited and resolves No germinal centers form No Hürthle cells develop Relation to human Hashimoto is limited at best Current challenge is to marry knowledge of susceptibility genes with mechanism of action

35. Summary Hashimoto thyroiditis is characterized by lymphoplasmacytic infiltrate, germinal center formation, and Hürthle cell change Diagnosis is possible but limited by FNA May be associated with well differentiated cancers Dominant nodules often prompt surgery Molecular mechanisms of Hashimoto development are still poorly understood

36. Conclusions Molecular studies performed on dominant nodule FNA helpful, if mutation found, for determining cancer Hashimoto thyroiditis may be associated with cancer but nodules appear negative for mutation Immune markers have been identified but mechanism still poorly understood Surgery will still be necessary, and we are still needed MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

37. References RV Lloyd, BR Douglas, Young WF, eds. Atlas of Nontumor Pathology, Endocrine Diseases, AFIP Fascicle, 2002 RV Lloyd, ed. Endocrine Pathology, 2004 Sapio MR et al., Clinical Endocrinology, 66, 2007 Cipolla et al., American Surgeon,71(10), 2005 Kang D-Y et al., Thyroid,17(11), 2007 Sadow et al., Endocr Pathology, 2010 MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL