Thyroid Gland – Applied Pathology

Dr Sunila BHMS,MD(Hom)
The thyroid gland in an adult weighs 15-40 gm and is composed of 2 lateral lobes connected in the midline by a broad isthmus. Thyroid gland is composed of lobules of colloid- filled spherical follicles or acini. The follicles are the main functional units of the thyroid gland.

The major function of thyroid gland is to maintain a high rate of metabolism which is done by means of iodine containing thyroid hormones, thyroxine (T4) and Triiodothyronine (T3). T3 and T4 are formed by sequential reactions occurring in the thyroglobulin molecule under the control of TSH. Total plasma level of T4 is 4-8µ g/ dl. And T3 is 150-250 n g/ dl. Normal range of TSH is up to 5 µ units per ml.

Diffuse enlargement of the thyroid gland is described as goiter (goiter or bronchocele). It is derived from the Latin word, Gutter– the throat. Goitre is merely a symptom of a more serious thyroid condition, such as:

• Hyperthyroidism
• Hypothyroidism etc

Classification of Goitre

1. Simple goiter

• a.  Physiological goiter
• b.  Parenchymatous goitre
• c.  Colloid goiter
• d.  Multinodular goiter

2. Toxic goiter

• a. Grave’s disease
• b. Secondary thryotoxicosis in M N G
• c. Solitary nodule

3. Neoplastic goiter

• a. Benign adenoma (follicular adenoma)
• b. Malignant tumours
•             i. Primary
•            ii. Metastatic (Secondary)

4. Thyroiditis

•  i.    Autoimmune thyroiditis
• ii.    Infectious thyroiditis
• iii.   Granulomatous thyroiditis
• iv.   Riedel’s thyroiditis

SIMPLE GOITRE
This may be endemic or sporadic. Puberty goiter, colloid goiter, and parenchymatous goiter are included in this group. The thyroid gland is diffusely enlarged, painless and non-tender. It may be soft or firm in consistency.

Etiology : Simple goiter is the result of iodine deficiency.

• Endemic goiter:

Prevalence of goiter in a geographic area in more than 10% of the population is termed endemic goiter. Such endemic areas are high mountainous regions far from the sea where iodine content of drinking water and food is low. Some cases occur due to goitrogens and genetic factors. Goitrogens are substances which interfere with the synthesis of thyroid hormones. These substances are drugs used in the treatment of hyperthyroidism and certain items of food such as cabbage, cauliflower, turnips and cassava (tapioca) roots. Cabbage contains thiocyanates which inhibit iodine uptake. Cassava contains cyanogenic glycosides which are converted to thiocyanate.

• Sporadic goiter:

Sporadic goiter is less common than the endemic variety. In most cases the etiology of sporadic goitre is unknown. A number of causal influences have been attributed. These include:

• Suboptimal iodine intake in conditions of increased demand as in puberty and pregnancy.

• Genetic factors.

• Dietary goitrogens.

• Hereditary defect in thyroid hormone synthesis and transport (dyshormonogenesis).

• Inborn errors of iodine metabolism 

Pathologic Changes :Grossly, the enlargement of in simple goiter is moderate (weighing up to 100-150 gm), symmetric and diffuse. Cut surface is gelatinous and translucent brown.

Histologically two stages are distinguished:

Ø  Hyper plastic stage: It is the early stage and characterized by tall columnar epithelium showing papillary infoldings and formation of small new follicles.

Ø  Involution stage: This stage generally follows hyper plastic stage. This stage is characterized by large follicles distended by colloid and lined by flattened follicular epithelium.

The cells may undergo hyper involution. In this case the acini become filled with colloid and diffuse colloid goiter may develop. With repeated episodes of iodine depletion and repletion, multi nodular goiter may develop.

Preventive measures : Fortification of common salt with iodide (1 part to 100000 parts) and distribution in endemic areas has been partially successful in many regions.

Treatment : Administration of thyroxine up to .3mg/ day brings about a favorable response in 60% of subjects. The gland shrinks within 3 months of starting treatment. 

TOXIC GOITRE- THYROTOXICOSIS
It is a complex of disorder which occurs due to increased levels of thyroid hormones (Hyperthyroidism) and manifests clinically with various signs and symptoms. The causes of thyrotoxicosis are:

1. Primary thyrotoxicosis (Grave’s disease, exophthalmic goiter) 

2. Secondary thyrotoxicosis secondary to multi nodular goiter (Plummer’s disease). 

3. Solitary toxic nodule: Autonomous nodule which is not under the influence of TSH, but occurs due to hypertrophy and hyperplasia of gland (tertiary thyrotoxicosis).There is an increase in T3 and T4 level. Iodine 131 scan can demonstrate a hot nodule. Histological diagnosis can be made by FNAC. 

4. Other causes of thyrotoxicosis 

      I. Thyrotoxicosis facticia: False thyrotoxicosis occurs due to over dosage of thyroxine, given for puberty goiter.

 II.Jod Basedow’s thyrotoxicosis: Jod means iodine in German language, Basedow means toxic goiter.Iodine induced thyrotoxicosis (iodine given for hyperplastic endemic goiters).

                         III.            Initial stage of thyroiditis.

                         IV.            Very rarely, malignant goiters can be toxic.

                            V.            Neonatal thyrotoxicosis occurs in babies born to thyrotoxic mothers.

GRAVE’S DISEASE (Diffuse toxic goiter, Parry’s disease, Base Dow’s disease).

Etiology : Exact etiology is unknown. Possible etiological factors are:

1. Autoimmune disorder is the first possible cause due to the demonstration of auto antibodies in the circulation.

2. Familial: The disease can run in families.

3. Thyroid Stimulating Immunoglobulins (TSI) and long acting thyroid stimulator (LATS) are responsible for pathological changes in the thyroid gland in Grave’s disease.

4. Exophthalmos producing substance (EPS) is responsible for ophthalmopathy which is seen in Grave’s disease.
5.  Female sex, emotions, stress, young age also have been considered as the other factors responsible for the disease.

Pathology
Thyroid is diffusely enlarged due to hyperplasia of acinar cells and increased vascularity. Histologically the acinar cells are hyper plastic, with absorption of colloid. Varying degrees of lymphocytic infiltration is also seen.

Thyroid associated eye disease is a frequent manifestation of thyroid disorders, particularly hyper thyroidism. Extra ocular muscles are the target of auto immune response. The interstitium shows diffused mono nuclear infiltration, primarily by activated T-cells with some B-cells and occasional macrophages. The retro bulbar fibroblasts and skin fibroblasts are affected by the auto immune process. Grave’s ophthalmopathy and dermopathy are strongly associated.

Clinical features : Grave’s disease is more frequent in young women. The general symptoms attributable to hyper metabolic state includes:-

• Anxiety
• Irritability
• Fatigue
• Weight loss
• Good appetite
• Palpitations
• Heat intolerance
• Tremor
• Sweating
• Diarrhoea
• +/- Eye signs
• Tachycardia

Rarely mental changes like sever agitations and frank psychosis may be the presenting features.

Examination of the neck shows the thyroid to be diffusely enlarged, but some times it may be asymmetrical. It is soft, warm, pulsatile and tender. Arterial thrills and bruit may be detectable. These phenomena indicate increased vascularity.

Thyroid associated eye disease may present in several ways, 90% have overt hyperthyroidism. 10% have no obvious thyroid dysfunction. Those with no signs of thyrotoxicosis are known as ophthalmic Grave’s disease. Main clinical features include diplopia with vertical separation of visual images, asymmetry of palpebral fissures, movement disorders of eye balls and lids and compression of the optic nerve. Sympathetic over activity leads to lid lag, stare, increased watering and infrequent blinking. These subside with correction of thyroid function. There is abnormal protrusion of eye ball (exophthalmos) and partial or complete ophthalmoplegia. In severe cases there is chemosis of the conjunctiva, prolapse of the eye ball, failure of closure of the eye lids, corneal ulsarations and blindness can occur. These constitute malignant exophthalmos.

Papilloedema may develop in advanced cases. Some cases may show optic atrophy.

Skin Changes
The skin is soft and moist. The hair is soft, sweating is excessive and the nails show thinning (Onycholysis). Sometimes localized myxoedematous deposits may occur. The common site is in front of the leg (hence called pretibial myxoedema). Over this site the skin is raised. The lesions may be pruritic. Examination reveals ‘peau de orange’ appearance. Pretibial myxoedema is attributed to local non-responsiveness of tissues to the thyroid hormones. Some cases show clubbing of fingers and toes and hypertrophic oesteoartropathy (thyroid acropachy).

Changes in Skeletal Muscles
There is excessive weakness and fatigue. The proximal muscles of pelvic and pectoral girdles may show myopathy. Myasthenia gravis may coexist with Grave’s disease.

Cardio-Vascular Changes
Cardiac out put increases out of proportion to the rise in basal metabolic rate. Atrial fibrillation occurs in up to 25% of the cases. Other arrythmias such as paroxysmal tachycardia and atrial flutter are also common. Some patients develop effort angina.

Alimentary System : Abdominal cramps, diarrhea and vomiting are common features.

Reproductive System
Menses may be scanty and fertility is reduced. In men libido and potency may be altered variably. Gynecomastia may develop, oligospermia may occur.

Bones : Osteoporosis may develop as a result of increased resorption of bone.

The general clinical picture produced by toxic diffused goiter and toxic nodular goiter is similar in many respects. However eye changes and pretibial myxoedema are more common in toxic diffuse goiter. Grave’s disease is more frequent in younger age group. Toxic adenomas occur usually in later age groups. In them cardiovascular manifestations are more prominent. In toxic adenoma local examination of thyroid may not reveal generalized hypervascularity and bruit, but the condition can be easily diagnosed by palpating nodules.

Diagnosis  : In florid cases clinical diagnosis is easy. In all cases it is advisable to confirm diagnosis and establish its severity by investigations.

Laboratory investigations : I 131 uptakes by the thyroid gland, levels of T4 and T3 are all increased. TSH is low.

NEOPLASTIC GOITRE
Follicular adenoma: is the most common benign thyroid tumor occurring more frequently in adult women. 

Pathologic changes

It is characterized by four features so as to distinguish from a nodule of nodular goiter

• a.   Complete encapsulation
• b.   Solitary Nodule
• c.   Clearly distinctive architecture inside and outside the capsule
• d.   Compression of the thyroid parenchyma outside the capsule

Histologically the tumor cells are benign follicular epithelial cells forming follicles of various sizes or may show trabecular, solid and cord patterns with little follicle formation. Accordingly the following six types of growth patterns are distinguished.

• 1)      Microfollicular (foetal) adenoma.
• 2)      Normofollicular (simple) adenoma
• 3)      Macrofollicular (Collloid) adenoma
• 4)      Trabecular (embryonal) adenoma; resembles embryonic thyroid
• 5)      Hurthle cell (oxyphilic) adenoma: composed of large cells having abundant granular or oxyphilic cytoplasm
• 6)      Atypical adenoma: follicular adenoma which has more pronounced cellular proliferation so that features may be indicative of malignancy.

Papillary carcinoma
It is the most common type of thyroid carcinoma. It is typically a slow growing tumor, most often presenting as an asymptomatic solitary nodule. Involvement of the regional lymph node is common but distant metastases to organs are rare. 

Pathologic changes
Sometimes the tumor is transformed into a cyst, into which numerous papillae project and is termed papillary cystadenocarcinoma. Histologically the following features are present:

• 1)      Papillary pattern
• 2)      Tumor cells have overlapping pale nuclei (ground glass appearance) and clear or oxyphilic cytoplasm.
• 3)      Invasion into the capsule and intrathyroid lymphatics.
• 4)      Half of the papillary carcinomas show typical small, concentric, calcified spherules called psammoma bodies.

Follicular carcinoma  : It is more common in middle and old age and in females.

Pathologic Changes
It may be either in the form of a solitary adenoma- like circumscribed nodule or as an obvious cancerous irregular thyroid enlargement. Microscopically it is composed of follicles of various sizes and may show trabecular or solid pattern. However, variance like clear cell type and hurthle cell type may occur. Vascular invasion is common but lymphatic invasion is rare.

Medullary Carcinoma
It is a less frequent type derived from parafollicular or C- cells present in the thyroid. It has genetic association with genetic defect in chromosome-10. They secrete calcitonin, the hypocalcaemic hormone. These hormones elaborations are responsible for a number of clinical syndromes such as carcinoid syndrome, Cushing’s syndrome and diarrheoa and they have amyloid deposits in the trauma. The tumour may either appear as a unilateral solitary nodule (sporadic form) or have bilateral and multi centric involvement (familial form).

Anaplastic Carcinoma
Undifferentiated or anaplastic carcinoma comprises less than 5% of all thyroid cancers. The prognosis is poor. The tumour is generally large and irregular. There are three histological variants.

1. Small cell carcinoma
2. Spindle cell Carcinoma
3. Giant cell carcinoma

                                                                                                                                                                                                                                                              THYROIDITIS

Thyroiditis is classified into the following types:

•  i.  Autoimmune thyroiditis
•  ii. Infectious thyroiditis
• iii. Granulomatous thyroiditis
• iv. Riedel’s thyroiditis

I.      Autoimmune (Lymphocytic) Thyroiditis
This is a group of thyroiditis having, in common, infiltration of the thyroid by lymphocytes and plasma cells and occurrence of thyroid specific auto antibodies in the serum. Autoimmune thyroiditis includes:

• a.  Hashimoto’s Thyroiditis
• b.  Atrophic Thyroiditis
• c.  Focal lymphocytic Thyroiditis

a. Hashimoto’s Thyroiditis: Also called diffuse lymphocytic thyroiditis, struma lymphomatosa or Goitrous auto immune thyroiditis.
Etiology

1. HLA association: Hashimoto’s thyroiditis has some association with HLA- DR5.

2. Autoimmune Disease Association: Hashimoto’s disease has been found in association with other auto immune diseases such as Grave’s disease, SLE, Sjogren’s syndrome, rheumatoid arthritis, pernicious anaemia and Type I (juvenile- onset) diabetes.

The following auto antibodies against different thyroid cell antigens are detectable in the sera of most patients with Hashimoto’s thyroiditis:

• Thyroid microsomal auto antibodies (against the microsomes of the follicular cells)
• Thyroglobulin autoantibodies.
• Less frequently TSH receptor autoantibodies
• Less constantly found are thyroid autoantibodies against follicular cell membranes, thyroid hormones themselves and colloid components other than thyroglobulin.

Pathologic changes
Pathologically two varieties of Hashimoto’s thyroiditis are seen: classic form, more common and fibrosing variant found only in 10% cases of Hashimoto’s thyroiditis. Grossly, the classic form is characterized by diffuse, symmetric, firm and rubbery enlargement of the thyroid gland. The fibrosing variant has a firm, enlarged thyroid with compression of the surroundings tissues. Histologically, the classic form shows the following features.

There is extensive infiltration of the gland by lymphocytes, plasma cells, immunoblasts and macrophages, with formation of lymphoid follicles.

There is decreased number of thyroid follicles which are generally atrophic are often devoid of colloid.

The follicular epithelial cells are transformed into their degenerated state termed Hurthle cells (Askanazy cells, or oxyphil cells or onocytes). These cells have abundant oxyphilic or eosinophilic and granular cytoplasm due to large number of mitochondria and contain large bizarre nuclei.

There is a slight fibrous thickening of the septa separating the thyroid lobules.

Clinical features
The presenting feature of Hashimoto’s thyroiditis is painless, firm and moderate enlargement of the thyroid gland, usually associated with hypothyroidism, in an elderly woman. A few cases however develop hyperthyroidism, termed hashitoxicosis.

b. Atrophic thyroiditis ” In this type the gland is decreased in size and manifests clinically as spontaneous hypothyroidism.

c. Focal lymphocytic thyroiditis: The condition is characterized by focal aggregates of lymphocytes without significant alterations in the epithelium.

II.      Infectious Thyroiditis
Acute thyroiditis by microbial infection with bacteria, viruses and fungi is uncommon and is generally a complication of infection elsewhere in the body.

III. Granulomatous Thyroiditis (De Quervain’s or Subacute or Giant cell Thyroiditis)
It is a distinctive form of self limited inflammation of the thyroid gland. Etiology is unknown; but clinical features of a prodromal phase and preceding respiratory infection suggest a possible viral etiology. The disease is more common in young and middle aged women and may present clinically with painful moderate thyroid enlargement with fever, features of hyperthyroidism in the early phase of the disease and hypothyroidism if the damage to the thyroid gland is extensive.

Pathologic Changes
Grossly there is moderate enlargement of the gland. The cut surface of the involved area is firm and yellowish white. Microscopically the features vary according to the stage of the disease. Initially there is acute inflammatory destruction of the thyroid parenchyma and formation of microabcesses occurs. Later the more characteristic feature of granulomatous appearance is produced. More advanced cases may show fibroblastic proliferation.

Morphologically similar appearance may be produced in cases where vigorous thyroid palpation may initiate mechanical trauma to follicles, so called palpation thyroiditis.

VI. Riedel’s Thyroiditis  (Riedel’s Struma or invasive fibrous thyroiditis)
It is a rare chronic disease characterized by stony hard thyroid that is densely adhered to the adjacent structures in the neck. The condition is clinically significant due to compressive clinical features (e.g.: Dysphagia, dyspnoea). Etiology is unknown but possibly Riedel’s thyroiditis is a part of multifocal idiopathic fibrosclerosis. This group of disorders includes idiopathic retroperitoneal, mediastinal and retro-orbital fibrosis and sclerosing cholangitis, all of which may occur simultaneously with Riedel’s thyroiditis.

Pathologic Changes
Grossly thyroid gland is usually contracted, stony hard asymmetric and firmly adherent to adjacent structures. Microscopically there is extensive fibro-collagenous replacement, marked atrophy of the thyroid parenchyma, focally scattered lymphocytic infiltration and invasion of the adjacent muscle tissue by the process.

Hypothyroidism
It is a hypo metabolic clinical state resulting from inadequate production of thyroid hormones for prolonged periods. The clinical manifestations depend on the age at the onset of disorder and are divided into two forms.

1. Cretenism or congenital hypothyroidism: is the development of severe hypothyroidism during infancy and childhood. There is rise in TSH level and fall in T3 and T4 level. Child is dwarf and mentally retarded.

2. Myxoedema: The adult-onset severe hypothyroidism causes myxoedema. The term denotes non-pitting oedema due to accumulation of hydrophilic mucopolysaccharides in the ground substance of dermis and other tissues. Here also, there is rise in TSH levels and fall in T3 and T4 levels. 

Treatment of goitre
Treatment depends on the cause, the size of the goiter, and whether it is causing symptoms. Goiter caused by iodine deficiency can be helped with the introduction of iodine-rich foods into the diet, such as seafood and iodized salt. Hyperthyroidism is managed with drugs that slow the activity of the thyroid. If these fail to work, part or all of the thyroid gland is surgically removed. Alternatively, some or all of the thyroid’s hormone-producing cells can be destroyed with radioactive iodine treatment. Hypothyroidism is treated by lifelong hormone replacement therapy. Benign thyroid nodules are shrunk with medications, destroyed with radioactive iodine treatment or surgically removed, depending on the type. Cancer of the thyroid is treated by surgical removal of the gland, followed by radioactive iodine treatment.