AMR Seminar Symposium Split, Croatia Case #65 Vania Nosé, MD, PhD Professor of Pathology Associate Chief and Director, Anatomic and Molecular Pathology

Clinical History 28 y.o. with hypothyroidism in infancy which resolved; again, diagnosed with hypothyroidism in his late teens and started thyroid hormone replacement, but discontinued intermittently for months at a time due to lapses of health insurance

Clinical History He has been fairly disabled from SOB and was admitted and found to have chronic thromboembolic disease He underwent pulmonary thromboendarterectomy It was noted that he had thyroid nodules on a CT scan done during work-up for a PE An U/S done noted bilateral nodules, 2 on the right with microcalcifications, and 2 nodules on the left

Neck Exam and Surgery: ‎‎ Palpable nodules - bilateral multinodular goiter ‎No lymphadenopathy Total Thyroidectomy  

Gross: 97 Grams The specimen has a multinodular mottled tan-pink to gray-yellow cut surface Nodules up to 3.0 cm

Nodules are hypercellular and often have a trabecular pattern Colloid is usually absent Characteristic microcystic pattern in dyshormonogenic goiters with associated thyroglobulin synthetic defect

Colloid is usually absent -When present, colloid frequently has pale, "washed out" appearance Prominent papillary hyperplasia may be present in nodule

THYROGLOBULIN Negative or focally weakly positive

PAX8 Positive

Immunohistochemistry Positive staining for PAX8 and TTF1 Negative staining for thyroglobulin, with only very rare focal and faint staining in one small area of one of the nodules Stains for PTEN are positive (retained; not lost) in multiple distinct thyroid nodules, and membranous staining for B-catenin Ki67 proliferation index in distinct nodules is low (1%) Immunohistochemistry

THYROID, RIGHT LOBECTOMY:   Enlarged right thyroid lobe, 45 gram, multinodular, showing hyperplastic irregular follicles, mostly completely lacking colloid, with numerous hyperplastic and adenomatous nodules (also lacking colloid), with a dominant nodule measuring 1.6 cm, and extensive parenchymal changes most consistent with partially treated dyshormonogenetic goiter THYROID, LEFT LOBECTOMY:   Enlarged right thyroid lobe, 52 gram, multinodular, showing hyperplastic irregular follicles, completely lacking colloid, with numerous hyperplastic and adenomatous nodules (also lacking colloid) measuring up to 3.0 cm and extensive parenchymal changes most consistent with partially treated dyshormonogenetic goiter Diagnosis

Definition Dyshormonogenetic goiters (DHGs) are genetically determined thyroid hyperplasias due to enzyme defects in thyroid-hormone synthesis DHG is one of most common causes of hypothyroidism in children and adolescents in iodine nonendemic areas Familial goiter that develops from defect in metabolism of thyroid hormone secondary to inherited disorder

Multiple inherited biochemical defects lead to decreased thyroid hormone synthesis Resultant alterations in thyroid gland homeostasis, disturbance of feedback system, and chronic TSH stimulation lead to enlarged thyroid glands or goiters Some known gene mutations: DUOX2 TG TPO NIS Pendred Syndrome: autosomal recessive disease classically characterized by DHG; Mutations in SLC26A gene, encoding for pendrin

Thyroglobulin synthesis Deficiencies may be present in multiple steps of thyroid hormone synthesis: Thyroglobulin synthesis Iodine transport (into and out of follicular cell) Iodine oxidation Organification of thyroglobulin Coupling and dehalogenation of iodotyrosine compounds Breakdown of thyroglobulin  

Incidence: 1 in 30,000-50,000 live births in Europe and North America Goiter is usually not present at birth but appears later in life Family history of hypothyroidism or goiter is reported in roughly 20% of patients

The cut surface is firm and tan with nodules of varying size Thyroid Findings Macroscopy: Thyroid gland is enlarged and multinodular, up to 600 grams, with areas of cystic change, fibrosis, old and recent hemorrhage The cut surface is firm and tan with nodules of varying size Microscopy: Markedly cellular nodules exhibiting variety of architectural appearances Nodules often have trabecular pattern with no colloid or rare pale-staining colloid; extensive fibrosis in internodular tissue is present and papillary hyperplasia may be present in nodules By immunohistochemistry, the cells are positive for TTF1 and PAX8, and mostly negative for thyroglobulin Pathology:

Characteristic low-power view of a dyshormonogenetic goiter is shown Characteristic low-power view of a dyshormonogenetic goiter is shown. There is absence of colloid in the lumen of the irregular follicles. There is focal papillae formation and interstitial fibrosis.

Small and larger follicles lack colloid, and only a small of pale pink fluffy material is within the follicles. The density of the follicles and scarcity of colloid may give the false impression of a follicular neoplasm.

There is lacking of thyroglobulin expression in a dyshormonogenetic goiter, but there is preservation of TTF-1 immunoexpression.

High-power photomicrograph shows papillary hyperplasia with projection of the papillae into the follicular lumen. There is a lack of colloid, and the cells show nuclear membrane irregularities, nuclear atypia, and focally striking nuclear clearing (black open arrow).

Banding fibrosis (black open arrow) in the thyroid parenchyma is characteristic of a dyshormonogenetic goiter, usually associated with the highest degree of nuclear atypia. There is a dense eosinophilic colloid-like material and nuclear pleomorphism.

Differential Diagnosis Iatrogenic Goiter: due to intake of antithyroidal drugs; most challenging differential diagnosis Multinodular hyperplasia Adenomatous nodules Radiation thyroiditis Follicular carcinoma Differential Diagnosis

AMR Seminar Symposium Split, Croatia Case #65 Vania Nosé, MD, PhD Professor of Pathology Associate Chief and Director, Anatomic and Molecular Pathology

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