Hashimoto Thyroiditis: an UpdateDiagnosis, Pathogenesis, Pitfalls

Peter M. Sadow, M.D., Ph.D.ENT, Endocrine, GU PathologyMassachusetts General Hospital

Harvard Medical SchoolApril 24, 2010

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Struma LymphomatosaHistory

Hakaru Hashimoto1881-1934

Born, Iga-Ueno, JapanMedical School of Kyushu Imperial University

•1912 reported 4 cases of goiter•All women•Chronic thyroid disorder•Diffuse lymphocytic infiltration•Fibrosis, parenchymal atrophy

Hashimoto ThyroiditisHistory

• 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

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Clinical PresentationEpidemiology

• 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)

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

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%)

Treatment

• Thyroid hormone replacement

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Pathology

• Why discuss Hashimoto?

• Clinical diagnosis

• Clinical presentation

• Clinical treatment

• But…

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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

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Fine Needle Aspiration

Tingible BodyMacrophages

Hürthle Cells

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

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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

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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)

Goiter in Hashimoto Thyroiditis

Kumar et al, Robbins Pathology, 7th edition, 2005

Histology Hashimoto

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Patterns in Hashimoto

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Differential Diagnosis

• Thyroid Carcinoma• Lymphoma• Graves’ Disease• Riedel’s thyroiditis

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Histologic Variants

• Fibrous variant

• Fibrous atrophy variant

• Juvenile variant

• Cystic variant

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Fibrous VariantEpidemiology

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

Fibrous VariantHistology

• 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

Fibrous Atrophy VariantEpidemiology

• +/- history of Hashimoto

• Elderly patients

• Elevated antithyroid antibodies

• Profound hypothyroidism

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Fibrous Atrophy VariantHistology

• 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

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

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

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

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

Dominant Nodule UpdateSummary

• 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

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

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

Understanding PathogenesisPrevailing 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

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

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

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

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

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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

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