Transcript Hashimoto Thyroiditis - Patologos de Puerto Rico

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
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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
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
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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)
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
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Why discuss Hashimoto?
Clinical diagnosis
Clinical presentation
Clinical treatment
But…
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Physical Exam and Clinical
Correlation
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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
Hürthle Cells
Tingible Body
Macrophages
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
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Thyroid Carcinoma
Lymphoma
Graves’ Disease
Riedel’s thyroiditis
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Histologic Variants
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Fibrous variant
Fibrous atrophy variant
Juvenile variant
Cystic variant
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Fibrous Variant
Epidemiology
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10% of cases
Slightly older age group
Marked hypothyroidism
Large, symptomatic goiter
Markedly elevated antithyroglobulin antibody
Elevated TSH
Require surgery due to symptoms
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
Fibrous Atrophy Variant
Epidemiology
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+/- history of Hashimoto
Elderly patients
Elevated antithyroid antibodies
Profound hypothyroidism
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Fibrous Atrophy Variant
Histology
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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 welldifferentiated 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 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
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 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
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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