Pathology of the Thyroid Gland
Case 1 -
Diffuse Toxic Goiter (Autoimmune Hyperthyroidism; Graves' Disease)
Zubair W. Baloch and Virginia A. LiVolsi
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.
Diagnosis: Diffuse toxic goiter (autoimmune hyperthyroidism; Graves' disease)
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
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
Table 2. Papillary Hyperplastic Nodule
| Young (11-18 y.o.)|
| 2-3 cm|
| May be toxic|
| 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.
- Wick MR, Sawyer MD. Antigenic alterations in autoimmune thyroid diseases: observations and hypotheses. Arch Pathol Lab Med 1989; 113:77.
- Derwahl M, Huber G, Studer H. Slow growth but intense hypertrophy of thyrocytes in longstanding Graves' goitres. Acta Endocrinol 1989; 121:389.
- Hirota Y, Tamai H, Hayashi Y, et al. Thyroid function and histology in forty-five patients with hyperthyroid Graves' disease in clinical remission more than ten years after thionamide drug treatment. J Clin Endocrinol Metab 1986; 62:165.
- Mizukami Y, Michigishi T, Nonomura A, et al. Autonomously functioning (hot) nodule of the thyroid gland. A clinical and histopathologic study of 17 cases. Am J Clin Pathol 1994; 101:29.
- Moore GH. The thyroid in sporadic goitrous cretinism: a report of three new cases, description of the pathologic anatomy of the thyroid glands and a review of the literature. Arch Pathol 1962; 74:35.
- Ghossein RA, Rosai J, and Hefess C. Dyshormonogenetic goiter: A clinico-pathologic study of 56 cases. Endocrine Pathol 1998; 8: 283.
- Fadda G, Baloch ZW, LiVolsi VA. Dyshormonogenetic goiter. A review of the pathology. Intl J Surg Pathol 1999; 7: 125.
- Vickery, AL. Thyroid papillary carcinoma. Pathological and philosophical controversies. Am J Surg Pathol 1983; 7: 797.
- Carr RF, LiVolsi VA. Morphologic changes in the thyroid after irradiation for Hodgkin's and non-Hodgkin's lymphoma. Cancer 1989; 64:825.