—  SHORT COURSE #41  —

Pathology of the Thyroid Gland

Case 1 - Diffuse Toxic Goiter (Autoimmune Hyperthyroidism; Graves' Disease)

Zubair W. Baloch and Virginia A. LiVolsi


Clinical History
A 28 year old woman presented with a goiter and symptoms of thyrotoxicosis. Thyroid function tests supported the clinical findings: elevated T4, markedly suppressed TSH. She refused radioiodine treatment and was allergic to antithyroid drugs. After pretreatment with propanolol and potassium iodide, she underwent subtotal thyroidectomy.

The gross specimen was a diffusely enlarged thryoid weighing 140 grams; no nodules were present.


Case 1 - Figure 1 - Graves Disease
Case 1 - Figure 2 - Graves Disease


Case 1 - Figure 3 - Graves Disease
Case 1 - Figure 4 - Graves Disease

Diagnosis: Diffuse toxic goiter (autoimmune hyperthyroidism; Graves' disease)

Discussion:
This is a case of classical diffuse toxic goiter or the gland of Graves' disease (autoimmune hyperthyroidism). It is characterized by hyperplastic follicular cells with eosinophilic cytoplasm, papillary infoldings and wispy to absent colloid. In the stroma, lymphocyte collections are seen.

Papillary lesions of the thyroid represent either papillary hyperplasia or papillary carcinoma .

Table 1. Papillary Lesions of the Thyroid

1. Papillary hyperplasia, diffuse
2. Papillary hyperplasia, nodular, multifocal
3. Papillary hyperplasia nodule
4. Papillary carcinoma
5. [Papillar variant of medullary carcinoma]

Papillary hyperplasia, characteristic of the histologic pattern seen in the thyroid in autoimmune hyperthyroidism(Graves' disease), can also be found as a focal lesion in nodular goiter(with or without associated clinical toxicity) and in papillary hyperplastic nodule. The very rare condition of dyshormonogenetic goiter can show extensive papillary hyperplasia as well.

The mechanism of papilla formation in Graves' disease (or for that matter dyshormonogenesis) is a stimulation of the thyrotropin (TSH)-receptor complex of the thyroid follicular cell by either immunoglobulin (Graves' disease) or TSH it self (dyshormonogenetic goiter). The follicular cells increase in size and number (hypertrophy and hyperplasia) and no longer "fit" on the "scaffolding" of the follicle - they produce folds or papillae. In autoimmune hyperthyroidism and dyshormonogentic goiter, the process is diffuse (nodules may form in either condition after many years); hence, low power examination under the microscope is important

Whether similar stimuli are operative in the focal lesions in nodular goiter is unknown. In approximately 20% of patients with nodular goiter without toxicity clinically have measurable antithyroid antibodies, suggesting some of these are related to the general group of autoimmune thyroid diseases. In toxic nodular goiter, the percentage of patients with antibodies is much higher (about 50%). The histological counterpart to the autoimmune disorder is the presence of lymphocytes within the stroma of the thyroid gland.

In papillary hyperplasia, the "papillae" are lined by cells which are large, often containing eosinophilic but rarely granular cytoplasm. The nuclei tend to be round, having internal structure and are often polarized. They rarely overlap. In Graves' disease, nuclear enlargement, clearing and grooves can be seen, but nuclei tend to remain round. Prominent vascuoarity is seen in the stroma and may even be identified grossly. Longstanding Graves' disease glands can show the development of nodules, oncocytic metaplasia, and the presence of atypical nuclei (hyperchromatic, enlarged, irregular). The latter tend to be randomly distributed throughout the gland although in glands in which nodules have developed, the greatest concentration of atypical nuclei may be within the nodules. Marked random nuclear atypia is seen frequently in dyshormonogenetic goiters, either within nodules or in the background thyroid. In sporadic nontoxic multinodular goiter, nuclear atypia can be seen in some nodules as well; this may reflect longstanding presence of the goiter or may be related in some patients to response to drug therapy for the thyroid enlargement.

The papillary hyperplastic nodule is a discrete encapsulated (or at least circumscribed) mass, often centrally cystic and composed of a papillary and follicular proliferation. Often prominent edema is found in the cores of the papillae. The nuclei are round, dark and polarized; rarely are they enlarged. These lesions most often occur in teen-age girls; they rarely may be associated with clinical toxicity. (The term"papillary adenoma" is not recommended since it has been applied in the literature to both benign nodules and to encapsulated papillary carcinomas). However, it is likely that the papillary hyperplastic nodule represents an adenoma biologically. The terminology used here is that suggested by Dr. Austin Vickery to avoid the confusion with the "papillary adenoma" designation.

Table 2. Papillary Hyperplastic Nodule

Young (11-18 y.o.)
Females
Encapsulated
2-3 cm
May be toxic
Cystic
Edematous
Nuclei - round, dark, polarized

The differential diagnosis of papillary lesions discussed above is with papillary carcinoma, discussed in other cases in this seminar. Most importantly in distinguishing physiologic or pathophysiological hyperplastic conditions from carcinoma is the recognition of the diffuse nature of the process (even if nodules develop, the majority of cases show multiple nodules) --so low power examination is critical. If diffuse papillary change is present, do not concentrate too much on the nuclear features which can mimic carcinoma nuclei.

In nodules with papillary hyperplasia, the confusion with cancer is greater because there is a discrete lesion; in these cases the high power inspection of the nucler gives the best clue that one is dealing with a benign nodule and not papillary carcinoma.

For completeness, it should be recalled that in diffuse toxic goiters that are treated by surgery, there is usually 2-3 weeks of treatment with potassium iodide. This changes the histology toward a more normal appearance with decrease in the size of follicular cells, decreased vascularity and restoration of colloid storage with decreased scalloping. The lymphocytes remain as do some papillary infoldings. In our patient due to scheduling difficulties, her medications were given for only one week. Hence the histology is close to untreated cases.

Treatment with antithyroid medications does not alter the histology of the untreated gland. radioactive iodine treatment causes fibrosis, follicular atrophy and epithelial and stromal/endothelial cell atypia which can be marked.

Treatment with beta-adrenergic blockers (eg. propanolol) which have their mode of action on the peripheral tissues to block the effects of excess thyroid hormone do not change the histology of the thyroid gland.

References

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