Australian Society of Cytology

Case of the Month

December 2004 - Answer and Discussion

Papillary thyroid carcinoma arising in Hashimoto's thyroiditis

Answer

Cytological assessment of the sample revealed a Hashimoto's thyroiditis with an associated papillary carcinoma confirmed on subsequent histology one month after the FNB. Hashimoto's thyroiditis was confirmed with a raised thyroid antibody titre of 1600.

Cytological Description:

Polymorphous population of lymphocytes
Occasional plasma cells and tingible-body macrophages
Lymphoid tangles
Reactive follicle cells some with oncocytic metaplasia
Intimate association of lymphocytes with follicle cells
1 slide showed numerous crowded sheets, fragments and microfollicles. Some strips of columnar cells.
Nuclear chromatin in these groups -finely granular & dust-like
Intranuclear vacuoles & longitudinal grooves seen within some pale nuclei

Histology:

The total thyroidectomy revealed a 9mm focus of papillary carcinoma in association with chronic lymphocytic thyroiditis / Hashimoto's thyroiditis


Figure 7	Figure 8	Figure 9	Figure 10

Discussion

Clinical characteristics of Hashimoto's thyroiditis

Painless bilateral, symmetrical, firm or rubbery lobular diffuse enlargement of the thyroid.
Disease of women F/M 10:1.
>Caucasian women 30-50 years of age.
70 -80% of patients show signs of hypothyroidism.
Defined by the presence of antithyroid antibodies, > antimicrosomal antibodies and the presence of a lymphocytic infiltrate.
90% of patients will be positive for antithyroglobulin or antimicrosomal (antiperoxidase) antibodies.

Clinical characteristics of papillary thyroid carcinoma

Most common thyroid carcinoma
Any age, mean = 40, > females
Associated in patients with hx of radiation exposure.
Common presentation - solitary "cold" nodule.
May have a adjacent palpable cervical lymph node.
Multicentricity (bilateralism) in 20% due to intrathyroid metastases.

Pitfalls in clinical presentation

Hashimoto's thyroiditis may present as a single nodule
Co-existence of neoplasms namely non Hodgkin's lymphoma of B-cell type and papillary thyroid carcinoma (PTC)
PTC not always solitary nodule

Cytological findings in Hashimoto's thyroiditis

Polymorphous population of lymphocytes, occasional plasma cells and tingible-body macrophages.
Lymphoid tangles.
Scant to absent colloid.

Oncocytes and reactive follicle cells
Punctate nuclear chromatin

Intimate association of follicle cells with lymphocytes

Cytological findings of papillary carcinoma

Cellular smears unless cystic (common)
Papillary tissue fragments +/- fibrovascular core
Syncytial cell aggregates, sheets of epithelial cells with a distinct anatomical border (well defined edge), strips or single columnar cells, polygonal cells
Nuclear crowding and overlapping
Enlarged oval nuclei, with fine dust-like chromatin
Intranuclear vacuoles and grooves
Dense cytoplasm, with distinct cell borders
Viscous ropey colloid ('chewing gum')
Psammoma bodies (25%), multinculeated giant cells
>Lymphoid infiltrate

Diagnostic features in PTC

Papillae and psammoma bodies diagnostic of PTC, not always seen.
Nuclear features are critical - "Orphan Annie" or optically clear nucleus
Nuclear grooves occasionally seen in non-papillary neoplasms and non-neoplastic thyroid lesions. Not often associated with other thyroid cancers.
When seen in abundance (>=20%) can be considered a reliable criterion for the diagnosis of PTC

Incidence of Hashimoto's thyroiditis with PTC

Thyroid stimulating hormone (TSH) implicated in the formation of PTC, with raised levels often demonstrated in Hashimoto's thyroiditis (HT).
Incidence of PTC with associated Hashimoto's thyroiditis 0.5% to 32% - solitary 'cold' nodule.
Prognosis in patients with PTC + HT is better than PTC alone

Diagnosis of PTC by other ancillary techniques

Immunohistochemical stains :
Expression of CK 19, HBME-1, Galectin3 & p63
Molecular profile studies:
RET/PTC1 & 3 gene re-arrangements.

Nuclear PTC-like changes in altered thyroid follicle cells in HT

Nuclear enlargement, overlapping, cleared chromatin, membrane changes, grooves and inclusions seen in 1/3 of HT cases

Similarities in papillary thyroid cancer and Hashimoto's thyroiditis on a molecular level

Focal expression of proteins associated with PTC ie CK19, HMBE-1, GAL3 & CITED1 in the altered follicle cells of HT, not in the oncocytes
Shows a link between molecular, genetic and morphological features between these altered follicle cells and PTC
? PTC associated genes are activated in HT

p63 expression in papillary carcinoma & Hashimoto's thyroiditis

P63 expression negative in normal thyroid tissue, nodular goitres & oncocytic follicular adenomas.
P63 +ve foci commonly expressed in Hashimoto's thyroiditis (78.8% of cases) and PTC (81.8%)
Weak or no expression in follicular & medullary carcinomas.
Could p63 expression therefore be a pathobiologic link between PTC & Hashimoto's thyroiditis?

Expression of the RET/PTC Fusion Genes as a Marker For PTC & Hashimoto's thyroiditis

RET/PTC gene rearragements are highly specific markers of early stages of papillary carcinoma, in particular oncogenes RET/PTC1 & RET/PTC3.
RET/PTC1 - classical, diffuse PTC
RET/PTC3 - follicular/solid variant, short latent period, aggressive course eg Chernobyl
RET/PTC1 & RET/PTC3 oncogene rearrangement reported in Hashimoto's thyroiditis patients. (95%, 58%)

Does Hashimoto's thyroiditis share features with early papillary carcinoma?

Patients with Hashimoto's thyroiditis are at increased risk of PTC
Overlap in immunohistochemical staining patterns
Similarities in molecular expression between Hashimoto's thyroiditis & PTC. HT has been found to harbour a genetic re-arrangement strongly associated with PTC

CONCLUSION

The link between Hashimoto's thyroiditis & papillary carcinoma is likely but not conclusive.
Be aware of the co-existence of the two conditions
Long term follow-up of patients with HT to enable early diagnosis of thyroid cancer

References:

Diagnostic Cytopathology. Edited by Winifred Gray. Churchill Livingstone. Pp520-535
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