Endocrine + Bone Flashcards
T151 What are the characteristics of the pituitary gland?
Small, bean-shaped structures located at the base of the brain, on the sella turcica.
Connected to the hypothalamus by a stalk composed of axons and a rich venous plexus. Plays a central role in the regulation of other endocrine glands.
Describe the components of the pituitary gland
Composed of two functionally and morphologically distinct components: the anterior pituitary and the neurohypophysis.
What is the anterior pituitary composed of?
Composed of epithelial cells derived embryologically from the developing oral cavity.
In routine histologic sections, it shows an array of cells containing basophilic cytoplasm, eosinophilic cytoplasm, or poorly staining (chromophobic) cytoplasm, related to the presence of various trophic polypeptide hormones within their cytoplasm.
What hormones are secreted by the acidophils and basophils in the anterior pituitary?
Acidophils secrete growth hormone (GH) and prolactin (PRL), while basophils secrete corticotrophin (ACTH), thyroid-stimulating hormone (TSH), and gonadotrophins follicle-stimulating hormone-luteinizing hormone (FSH and LH).
What are the characteristics of the neurohypophysis?
Resembles neural tissue, with glial cells, nerve fibers, nerve endings, and intra-axonal neurosecretory granules. It stores and releases hormones such as vasopressin (ADH) and oxytocin, produced in the hypothalamus.
How can diseases of the pituitary be categorized?
They can be divided into those that primarily affect the anterior lobe and those that primarily affect the posterior lobe.
What is hyperpituitarism, and what causes it?
Hyperpituitarism arises from excessive secretion of trophic hormones.
It most often results from an anterior pituitary adenoma but may also be caused by other pituitary and extrapituitary lesions.
Causes include adenoma arising in the anterior lobe (most common), hyperplasia and carcinoma of the anterior lobe, secretion of hormones by extrapituitary tumors, and hypothalamic disorders.
What are the potential causes of hyperpituitarism?
a. Adenoma arising in the anterior lobe (most common)
b. Hyperplasia and carcinoma of the anterior lobe
c. Secretion of hormones by extrapituitary tumors
d. Hypothalamic disorders
What are pituitary adenomas?
Benign tumors of the anterior lobe found in adults aged 30-50 years old.
Usually composed of a single cell type and produce a single predominant hormone, although some may secrete two hormones.
Plurihormonal adenomas are rare.
How do pituitary adenomas present clinically?
They may be functional (hormone-producing with clinical signs),
nonfunctional (clinically silent), or hormone-negative.
Nonfunctional and hormone-negative adenomas are likely to come to clinical attention at a later stage and may cause hypopituitarism due to compression of normal pituitary tissue.
Functional tumors present with features based on the type of hormone produced.
What are the size classifications of pituitary adenomas?
Most adenomas occur as isolated lesions. Microadenomas are less than 1 cm, while macroadenomas exceed 1 cm in diameter.
What percentage of pituitary adenomas are associated with multiple endocrine neoplasia (MEN)?
Most cases are sporadic, but approximately 3% of adenomas are associated with multiple endocrine neoplasia.
What are the common mutations associated with the pathogenesis of pituitary adenomas?
One of the most common mutations is constitutive activation of a stimulatory G protein, resulting in persistent generation of cAMP and unchecked cellular proliferation.
Pituitary adenomas that arise in the context of familial MEN-1 syndrome harbor mutations from the MEN-1 gene, interfering with checkpoint regulation on p27 and appear at a younger age.
Other abnormalities include P53 mutation, associated with aggressive tumors.
Describe the morphology of pituitary adenomas
Usually well-circumscribed, soft small lesions.
Small tumors are confined by the sella turcica, while larger lesions typically extend into the suprasellar region, compressing the optic chiasm and adjacent structures.
Invasive adenomas, in 30% of cases, are grossly nonencapsulated and infiltrate adjacent bone, dura, and uncommonly, the brain.
Microscopically, they are marked by cellular monomorphism and absence of a reticulin network.
Composed of relatively uniform, polygonal cells arrayed in sheets, cords, or papillae with very little mitotic activity.
Cytoplasm may be acidophilic, basophilic, or chromophobic depending on the type of secretory product. Supportive connective tissue-reticulin is relatively absent, accounting for the soft consistency.
What is a prolactinoma
It is the most common type of pituitary adenoma characterized by hyperprolactinemia due to lactotroph cells secreting prolactin.
Hyperprolactinemia may also be caused by conditions such as pregnancy, high-dose estrogen therapy/dopamine-inhibiting drugs, renal failure, hypothalamic lesions, or the stalk effect.
What are the clinical features of prolactinomas?
- Galactorrhea, amenorrhea, and infertility
- Decreased libido and impotence
- Manifestation of hyperprolactinemia is more obvious in postmenopausal women.
What is a growth hormone-producing adenoma?
It is a type of pituitary adenoma where somatotroph cells produce growth hormone (GH), making it the second most common type of functional pituitary adenoma. Clinical manifestations may be subtle, allowing the adenoma to grow significantly before coming to clinical attention.
Describe the microscopic features of growthhormone-producing adenomas
Densely or sparsely granulated cells containing GH within the cytoplasm.
What laboratory findings are associated with growth hormone-producing adenomas?
Elevated levels of GH and somatomedin C (IGF-1).
What are the clinical manifestations of GH excess in children and adolescents?
Giantism, characterized by tall stature and long extremities, occurring prior to the fusion of growth plates.
What are the clinical manifestations of GH excess in adults?
Acromegaly, characterized by a prominent jaw, flat broad forehead,
enlarged hands and feet, and enlargement of internal organs. Additionally, GH excess is associated with other disturbances such as abnormal glucose metabolism and diabetes mellitus, generalized muscle weakness, hypertension, arthritis, osteoporosis, and congestive heart failure.
What are corticotroph cell adenomas?
They are usually small at the time of diagnosis and stain positive with PAS due to the accumulation of glycosylated ACTH proteins.
ACTH is synthesized as part of a larger prohormone that includes melanocyte-stimulating hormone, which may result in hyperpigmentation.
They may be clinically silent or cause hypercortisolism (Cushing syndrome) due to their stimulatory effect on the adrenal cortex.
Cushing disease occurs when hypercortisolism is caused by excessive production by the pituitary gland.
Nelson syndrome may develop after surgical removal of adrenal glands for the treatment of Cushing syndrome, due to the loss of the inhibitory effect of adrenal corticoids on a preexisting corticotroph microadenoma.
What are the characteristics of other anterior pituitary neoplasms?
Gonadotroph (LH and FSH-producing hormones) adenomas are difficult to recognize as they secrete hormones inefficiently and variably, and their secretory products do not cause a recognizable clinical syndrome.
They are most frequent in middle age when the tumor becomes large enough to cause neurological symptoms such as impaired vision, headaches, and diplopia.
FSH is usually the predominant secreted hormone.
Thyrotroph (TSH-producing hormone) adenomas are a rare cause of hyperthyroidism. Pituitary carcinoma is rare and characterized by local extension beyond the sella turcica and always distant metastases.
T152 What is hypopituitarism?
Insufficient production of hormones by the anterior pituitary gland. Symptoms arise when more than 75% of pituitary parenchyma is lost.
What are the causes of hypopituitarism?
Causes may be congenital (very rare) or acquired.
Acquired causes include:
a. Nonfunctioning pituitary adenomas (in adults) or craniopharyngioma (in children) due to mass effect or pituitary apoplexy (bleeding into the adenoma).
b. Destruction of tissue following radiation, surgery, trauma, or elevated intracranial pressure (ICP).
c. Sheehan syndrome, the most common cause of ischemic pituitary necrosis, occurs due to pregnancy-related infarction of the pituitary gland.
It presents as poor lactation, loss of pubic hair, and fatigue.
d. Empty sella syndrome is a congenital defect of the sella, where herniation of the arachnoid and CSF into the sella compresses and destroys the pituitary gland.
Pituitary gland absence is observed on imaging, but it’s congenital and very rare.
e. Disorders that interfere with the delivery of pituitary releasing factors from the hypothalamus, such as hypothalamic tumors.
f. Other less common causes include inflammatory lesions (e.g., sarcoidosis, tuberculosis), metastatic neoplasms, trauma, and congenital abnormalities.
What is Sheehan syndrome?
Sheehan syndrome is the most common cause of ischemic pituitary necrosis, occurring due to pregnancy-related infarction of the pituitary gland.
It presents as poor lactation, loss of pubic hair, and fatigue.
What is empty sella syndrome?
Empty sella syndrome is a congenital defect of the sella, where herniation of the arachnoid and CSF into the sella compresses and destroys the pituitary gland.
Pituitary gland absence is observed on imaging, but it’s congenital and very rare.
What are the less common causes of hypopituitarism?
Other less common causes include inflammatory lesions (e.g., sarcoidosis, tuberculosis), metastatic neoplasms, trauma, and congenital abnormalities.
What are the disorders that interfere with the delivery of pituitary releasing factors from the hypothalamus?
Disorders such as hypothalamic tumors interfere with the delivery of pituitary releasing factors from the hypothalamus.
What are the clinical manifestations of hypopituitarism depending on specific hormones that are lacking?
a. GH deficiency leads to pituitary dwarfism in children.
b. GnRH deficiency results in decreased libido, impotence, loss of pubic hair (for males), and amenorrhea (for females).
c. TSH deficiency leads to hypothyroidism.
d. ACTH deficiency causes hypoadrenalism.
e. Prolactin deficiency results in failure of postpartum lactation.
f. Loss of stimulatory effects of MSH on melanocytes from the anterior lobe can lead to paleness as one manifestation of hypopituitarism.
What are the basic principles of the posterior pituitary gland (neurohypophysis)?
The posterior pituitary is composed of modified glial cells (pituicytes) and axonal processes extending from nerve cell bodies in the hypothalamus.
Antidiuretic hormone (ADH) and oxytocin are made in the hypothalamus and then transported via the axon to the posterior pituitary for release.
What is the role of ADH (antidiuretic hormone)?
ADH acts on the distal tubules and collecting ducts of the kidney to promote free water retention.
It is a nonpeptide hormone.
Released in response to different stimuli, including an increase in plasma oncotic pressure, stress, and increased sympathetic action.
What is the role of oxytocin
Oxytocin mediates uterine contraction during labor and the release of breast milk in lactating mothers.
What is central diabetes insipidus?
It is the inability of water reuptake from urine leading to polyuria.
It can be caused by hypothalamic or posterior pituitary pathology (e.g., tumor, trauma, infection, or inflammation).
Clinical features include polyuria and polydipsia with a risk of life-threatening dehydration (hypernatremia and high serum osmolality).
Low urine osmolality and specific gravity indicate the inability to concentrate urine.
In the water deprivation test, urine osmolality fails to increase.
Treatment involves desmopressin (ADH analogue).
What is nephrogenic diabetes insipidus?
It is caused by impaired renal response to ADH due to inherited mutation or drugs.
Clinical features are similar to central diabetes insipidus, but there is no response to desmopressin.
What is the syndrome of inappropriate ADH (SIADH) secretion?
Excess ADH secretion leads to an excessive amount of free water, resulting in hyponatremia.
What are the common causes of SIADH?
a. SIADH is most often due to ectopic production (e.g., small cell carcinoma of the lung).
Other causes include CNS trauma (injury to the hypothalamus or neurohypophysis), pulmonary infection, and drugs (e.g., cyclophosphamide).
What are the clinical features of SIADH?
a. Hyponatremia and low serum osmolality.
b. Mental status changes and seizures due to hyponatremia leading to neuronal swelling and cerebral edema.
c. Water retention without edema.
What is the treatment for SIADH?
Treatment involves free water restriction.
T153 What is Graves’ disease?
Graves’ disease is an autoimmune disease characterized by producing IgG autoantibodies to the TSH receptor, leading to endogenous hyperthyroidism.
It is more common in females than males, typically occurring between the ages of 20 and 40.
What are the manifestations of Graves’ disease?
a. Hyperthyroidism (Thyrotoxicosis) and goiter.
b. Ophthalmopathy: Exophthalmos (40% of patients) or proptosis, which may affect only one eye, seen only in Graves’ disease.
c. Localized infiltrative dermopathy: Peritibial myxedema, characterized by thickening of the dermis due to deposition of glycosaminoglycans and lymphocyte infiltration, occurs in a minority of cases.
What is the pathogenesis of Graves’ disease?
a. Graves’ disease is characterized by a breakdown in self-tolerance to thyroid autoantigens, particularly the TSH receptor, leading to the production of multiple autoantibodies.
b. These include thyroid-stimulating immunoglobulin (stimulates adenylate cyclase), thyroid growth-stimulating immunoglobulins (implicated in the proliferation of thyroid follicular epithelium), and TSH-binding inhibitor immunoglobulins (prevent TSH from binding to its receptor).
c. T cell-mediated autoimmune phenomenon is involved in the development of infiltrative ophthalmopathy, leading to forward displacement of the eyeball.
d. Genetic susceptibility is associated with certain human leukocyte antigen (HLA) haplotypes, especially HLA-DR3, as well as polymorphisms in genes coding for the inhibitory T cell receptor CTLA-4 and tyrosine phosphatase PTPN22.
What is the morphology of Graves’ disease?
a. Gross:
i. The thyroid gland is enlarged, usually symmetrically, due to diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells.
ii. It appears smooth, soft, and the capsule is intact.
b. Micro:
i. Follicular epithelial cell proliferation results in the formation of small papillae, lacking a fibrovascular core, which project into the follicular lumen.
ii. The colloid appears pale, reflecting reduced matter due to hyperactivity of the epithelium. iii. There is a presence of lymphoid chronic inflammatory infiltrate, predominantly T cells, throughout the interstitium.
What are the laboratory findings in Graves’ disease?
a. Elevated serum free T3 and T4 levels. b. Depressed TSH serum level.
c. Radioiodine scans show diffuse uptake of iodine due to ongoing stimulation of thyroid follicles by thyroid-stimulating immunoglobulins (TSIs), resulting in increased radioactive iodine uptake.
What is a thyroid storm?
A thyroid storm is an acute event of severe hyperthyroidism that may lead to life-threatening arrhythmias.
It is most commonly seen in patients with underlying Graves’ disease.
What is a goiter?
A goiter is an enlargement of the thyroid gland, the most common manifestation of thyroid disease.
What are diffuse and multinodular goiter, and what causes them?
Diffuse and multinodular goiter reflect impaired synthesis of thyroid hormone, most often caused by dietary iodine deficiency.
This leads to compensatory rise in TSH, hypertrophy, and hyperplasia of follicular cells, resulting in enlargement of the gland and a euthyroid metabolic state.
If the underlying disorder is severe, such as a congenital biosynthetic defect, the compensatory response may be inadequate, resulting in goiter hypothyroidism.
Describe the morphology of diffuse goiter
Diffuse goiter:
Macroscopically, there is symmetric overall gland enlargement.
Microscopically, there is hypertrophy and hyperplasia of the follicular epithelial cells, which may lead to papillaztion (pseudopapillae protruding into the colloid lumen).
Colloid in the follicles may decrease, leading to colloid goiter if dietary iodine deficiency continues.
Describe the morphology of multinodular goiter
Multinodular goiter:
Over time, recurrent episodes of hyperplasia and involution result in irregular enlargement of the gland.
Grossly, it appears as a multilobulated, asymmetrically enlarged gland with irregular nodules containing variable amounts of brown, gelatinous colloid.
Microscopically, there are colloid-rich follicles lined by flattened, inactivated epithelium and areas of follicular epithelial hypertrophy and hyperplasia.
What are the clinical features of goiter?
Caused by the mass effect of the enlarged thyroid gland, leading to a cosmetic problem on the neck and a risk for airway obstruction/dyspnea, and compression of large vessels in the neck (superior vena cava syndrome).
Clinical manifestations may include hyperthyroidism signs/symptoms or hypothyroidism, depending on the patient.
The incidence of malignancy in long-standing multinodular goiter is low.
T154 What is Chronic Lymphocytic (Hashimoto) thyroiditis?
a. Hashimoto’s thyroiditis, also known as chronic autoimmune thyroiditis, is the most common cause of hypothyroidism in iodine-sufficient areas of the world.
It is characterized by immune destruction of the thyroid gland and hypothyroidism.
b. It is more common in females than males, typically occurring between the ages of 45 and 65, during middle age.
Describe the pathogenesis of Hashimoto’s thyroiditis.
a. It is caused by the breakdown of self-tolerance to thyroid autoantigens, leading to diffuse lymphocytic infiltration of the thyroid gland, predominantly by thyroid-specific B and T cells, resulting in tissue destruction.
b. Mechanisms include CD8+ cytotoxic T cell-mediated cell death, cytokine-mediated cell death, and binding of antithyroid antibodies followed by antibody-dependent cell-mediated cytotoxicity.
c. Increased susceptibility is associated with polymorphisms in multiple immune regulation-associated genes, including cytotoxic T lymphocyte-associated antigen-4 gene (CTLA-4) and HLA-DR5.
Describe the morphology of Hashimoto’s thyroiditis.
a. Grossly, the thyroid gland is firm, pale, diffusely, and symmetrically enlarged.
b. Microscopically:
- There is a mononuclear inflammatory infiltrate (small lymphocytes and plasma cells) with germinal centers.
- Thyroid follicles show atrophy and are lined in many areas by epithelial cells with abundant eosinophilic granular cytoplasm (Hurthle cells), characterized by numerous prominent mitochondria, representing a metaplastic response of the low cuboidal epithelium to injury.
- There is an increase in connective tissue and fibrosis, with a fibrosing variant showing atrophic small thyroid instead of goiter.
What are the clinical presentations of Hashimoto’s thyroiditis?
a. Painless enlargement of the thyroid gland (goiter).
b. Hypothyroidism, with T3 and T4 levels falling accompanied by a compensatory increase in TSH.
Initial inflammation may cause transient hyperthyroidism due to disruption of thyroid follicles (hashitoxicosis).
c. Anti-thyroglobulin and anti-thyroid peroxidase antibodies are seen in the patient’s blood.
d. Increased risk for the development of B-cell non-Hodgkin lymphoma from lymph follicles within the thyroid later in the course of the disease.
e. It may be associated with other autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren syndrome.
What are the clinical features of Subacute Granulomatous Thyroiditis?
It is the second most common form of thyroiditis, much less common than Hashimoto’s.
It is classically seen in younger female adults, typically around the age of 30.
It presents as a tender, firm, enlarged thyroid gland, usually preceded by a viral illness, often an upper respiratory infection.
It is not an autoimmune attack.
The condition is self-limiting and typically resolves within 6-8 weeks, with no progression to hypothyroidism.
Describe the morphology of Subacute Granulomatous Thyroiditis.
Grossly, the thyroid gland appears firm, with an intact capsule, and may be unilaterally or bilaterally enlarged.
Histologically:
There is disruption of thyroid follicles, with extravasation of colloid leading to a polymorphonuclear infiltrate, which is replaced over time by lymphocytes, plasma cells, and macrophages.
Granulomatous inflammation occurs in the thyroid, provoked by extravasated colloid, leading to an exuberant granulomatous reaction with giant cells.
Healing occurs by resolution of inflammation and fibrosis
What is Subacute Lymphocytic Thyroiditis?
a. It is a self-limiting disease often occurring following pregnancy, known as postpartum thyroiditis.
b. It is typically painless with mild symmetric enlargement characterized by lymphocyte infiltration into the thyroid gland, including germinal centers.
c. The etiology is autoimmune. d. Clinical features include a painless neck mass or features of thyroid hormone excess, followed by a return to a euthyroid state within a few months.
In a minority of patients, the condition may progress to hypothyroidism.
What is Riedel Thyroiditis
a. Riedel Thyroiditis is a rare disease of unknown etiology characterized by dense fibrosis of the thyroid and surrounding structures, such as the trachea and esophagus.
b. Circulating antibodies in most patients suggest an autoimmune etiology.
c. Clinical features include a female predominance, with irregular, hard, fixed thyroid masses.
It may mimic carcinoma, but patients are typically younger (in their 40s), and malignant cells are absent.
d. Microscopically, there is dense fibrous replacement of the thyroid gland and chronic inflammation.
T155 What are Thyroid Adenomas?
Thyroid adenomas are benign neoplasms derived from follicular epithelium, typically appearing as solitary nodules.
(Note: A multinodular pattern is characteristic of multinodular goiter, not adenomas.)
Describe the pathogenesis of Thyroid Adenomas.
In toxic adenomas, which produce thyroid hormone, mutations are observed in components of the TSH receptor signaling pathway, leading to gain of thyroid autonomy (i.e., independent of TSH stimulation).
Mutations may occur in the gene encoding the TSH receptor or, less commonly, in the alpha subunit of the G protein involved in the TSH receptor signaling pathway.
Some non-functional follicular adenomas exhibit mutations in genes such as RAS or PIK3CA, which are shared with subsets of follicular carcinomas, suggesting a potential pathway for adenoma progression to carcinoma.
What is the morphology of Thyroid Adenomas?
Thyroid adenomas typically present as solitary nodules that compress the non-neoplastic thyroid tissue.
They have a well-defined capsule. (Contrast this with multinodular goiter, which lacks a capsule and presents with multiple nodules without compression of the parenchyma.)
Microscopically, the neoplastic cells are arranged in uniform follicles containing colloid.
Neoplastic cells may exhibit bright eosinophilic granular cytoplasm and small nuclei, characteristic of oxyphil or Hurthle cells.
Some adenomas may exhibit focal nuclear pleomorphism, atypia, and prominent nucleoli, known as endocrine atypia. Importantly, adenomas do not infiltrate the capsule; it remains completely intact, unlike in follicular carcinoma.
What are the clinical features of Thyroid Adenomas?
Thyroid adenomas usually present as painless nodules.
Large masses may produce local symptoms such as difficulty swallowing.
While the vast majority of adenomas are not functional, some may produce thyroid hormone and cause hyperthyroidism, known as toxic adenomas.
After injection of radioactive iodine, most adenomas take up iodine less avidly than normal parenchyma, appearing as cold nodules on radionuclide scanning.
However, toxic adenomas appear as warm nodules on the scan.
What is Papillary Carcinoma?
Papillary carcinoma is the most common form of thyroid cancer, comprising approximately 85% of all cases, although thyroid cancer itself is rare, accounting for only about 1% of cancer cases overall.
It can occur at any age.
Describe the Pathogenesis of Papillary Carcinoma.
Papillary carcinoma can result from environmental factors such as radiation exposure or genetic alterations.
Genetic mechanisms include rearrangements of genes such as RET or NTRK I, which encode tyrosine kinase receptors, leading to fusion genes like RET/PTC that activate the MAP kinase pathway.
Alternatively, point mutations in genes encoding proteins like RAF, an intermediate signaling component in the MAP kinase pathway, can also contribute to tumorigenesis.
What are the Gross and Microscopic Features of Papillary Carcinoma?
Grossly, papillary carcinoma may appear as encapsulated or diffusely invasive nodules, either unifocal or multifocal.
Lesions may contain areas of fibrosis, calcification, and cysts.
Microscopically, a diagnostic feature is the presence of Clear “orphan annie eye” nuclei.
The tumor typically exhibits a papillary pattern with dense fibrovascular cores (true papillae), and neoplastic cells pile up along the rims.
Psammoma bodies, concentrically calcified structures, may also be present.
What are the Clinical Features of Papillary Carcinoma?
Papillary carcinoma may present as non-functional tumors.
It is generally an indolent lesion, with a 10-year survival rate of approximately 95%.
There are over a dozen variants of papillary thyroid carcinoma, with the follicular variant being the most common.
The encapsulated form of papillary carcinoma has a lower incidence of lymph node metastases, primarily to cervical nodes.
Prognosis depends on factors such as age, extrathyroidal extension, and the presence of distant metastases.
What is Follicular Carcinoma?
Follicular carcinoma accounts for approximately 15% of malignant thyroid tumors and is more common in females aged 40-60.
Environmental factors such as ionizing radiation and dietary iodine deficiency, particularly in areas with low iodine intake, may contribute to its pathogenesis.
Describe the Genetic Pathogenesis of Follicular Carcinoma
Genetic alterations in the PI-3K/AKT signaling pathway play a significant role in follicular carcinoma.
These alterations may include gain-of-function point mutations or amplification of PI3K and loss-of-function mutations of PTEN, a tumor suppressor and negative regulator of the pathway.
Fusion genes such as PAX8/PPARG may also impair complete cell differentiation.
PAX8 is a homeobox gene important in thyroid development, while PPARG codes for a nuclear hormone receptor.
What are the Morphological Characteristics of Follicular Carcinoma?
Microscopically, follicular carcinoma exhibits a uniform cell appearance forming small follicles, including colloid.
There may be irregularly shaped areas with back-to-back follicles composed only of tumor cells without surrounding connective tissue or C cells.
It is encapsulated but invades the capsule and may contain Hurthle cells.
Grossly, it may be widely invasive or minimally invasive.
Minimally invasive carcinoma is sharply demarcated and may resemble follicular adenoma on gross examination.
What are the Clinical Features of Follicular Carcinoma?
Follicular carcinoma typically manifests as solitary cold thyroid nodules.
In rare cases, it may be hyperfunctional.Unlike other carcinomas, which usually spread via the lymphatic system, follicular carcinoma tends to disseminate hematogenously to sites such as the lung, bone, and liver.
What is Medullary Carcinoma?
Medullary carcinoma is a neuroendocrine neoplasm that arises from C cells (parafollicular cells) of the thyroid gland and secretes calcitonin.
In some cases, tumor cells may produce other polypeptide hormones such as somatostatin, serotonin, and VIP.
Describe the Epidemiology of Medullary Carcinoma.
The majority of cases are sporadic and occur in adults aged 50-60 years.
A minority are familial and may be associated with multiple endocrine neoplasia (MEN) type 2A or 2B syndromes or not associated with MEN syndrome.
What are the Genetic and Environmental Factors Involved in the Pathogenesis of Medullary Carcinoma?
Familial cases of medullary carcinoma, occurring in multiple endocrine neoplasia type 2 (MEN 2), are associated with germline mutations in the RET proto-oncogene, leading to constitutive activation of the receptor.
RET mutations are also seen in sporadic cases.
Environmental factors such as ionizing radiation may also contribute to its pathogenesis.
Describe the Morphology of Medullary Carcinoma.
Medullary carcinoma may present as a solitary nodule or multiple lesions on both lobes of the thyroid gland.
Microscopically, it is characterized by nests of polygonal neoplastic cells in an amyloid stroma derived from altered calcitonin molecules.
Calcitonin is demonstrated within the cytoplasm of tumor cells and in the stroma.
Electron microscopy reveals a variable number of intracytoplasmic membrane-bound, electron-dense granules.
Familial cases may exhibit multicentricity, with large lesions containing areas of necrosis and hemorrhage that may extend through the capsule of the gland.
Multicentric C cell hyperplasia may also be present in the surrounding thyroid parenchyma, believed to be precursor lesions for medullary carcinoma.
What are the Clinical Features of Medullary Carcinoma?
Medullary carcinoma typically manifests as a mass in the neck and may be associated with compression effects such as dysphagia and hoarseness.
In some cases, it may manifest as the secretion of peptide hormones, leading to symptoms such as diarrhea caused by VIP.
Early detection of familial cases can be achieved through screening for elevated calcitonin levels and RET mutations in the patient’s relatives.
Describe the Presentation of Anaplastic Carcinoma.
Anaplastic carcinoma of the thyroid gland typically presents with a firm, enlarging, bulky mass in the neck.
It is more common in females and individuals over the age of 60.
There is a tendency for early widespread metastasis and invasion of neighboring structures such as the trachea and esophagus.
A past history of well-differentiated thyroid carcinoma is a risk factor for developing anaplastic carcinoma.
What is the Pathogenesis of Anaplastic Carcinoma?
Anaplastic carcinoma may arise de novo, but more commonly, it develops as a result of dedifferentiation from well-differentiated papillary or follicular carcinoma.
Molecular alterations seen in well-differentiated carcinomas, such as RAS or PIK3CA mutations, may be present.
However, inactivation of TP53 is essentially restricted to anaplastic carcinoma.
Environmental factors such as ionizing radiation may contribute to its development.
Describe the Microscopic Features of Anaplastic Carcinoma.
Anaplastic carcinoma is characterized by undifferentiated, anaplastic cells.
Microscopically, it may consist of large pleomorphic giant cells, spindle cells with sarcomatous appearance, or a mixture of spindle and giant cell lesions.
What is the Prognosis of Anaplastic Carcinoma?
Anaplastic carcinoma of the thyroid gland is very aggressive and rapidly fatal.
It has one of the poorest prognoses among all thyroid malignancies.
T156 What are the origins of the parathyroid glands?
The parathyroid glands are derived from the developing pharyngeal pouches that also give rise to the thymus.
Describe the composition of the parathyroid glands.
Most of the parathyroid gland is composed of chief cells, which contain secretory granules of parathyroid hormone (PTH).
Oxyphil cells, slightly larger than chief cells and packed with mitochondria, are also present in small clusters.
How is the activity of the parathyroid glands controlled?
The activity of the parathyroid glands is primarily regulated by the level of free (ionized) calcium in the bloodstream, rather than by trophic hormones secreted by the hypothalamus and pituitary.
What are the effects of decreased levels of free calcium on PTH secretion?
Decreased levels of free calcium stimulate the synthesis and secretion of PTH, resulting in an increase in renal tubular reabsorption of calcium, an increase in urinary phosphate excretion, enhanced conversion of vitamin D to its active form in the kidneys, and promotion of osteoclastic activity.
How do tumors of the parathyroid glands typically present?
Unlike thyroid tumors, tumors of the parathyroid glands usually come to attention because of excessive secretion of PTH, leading to hyperparathyroidism, rather than mass effects.
HYPERPARATHYROIDISM
Hyperparathyroidism occurs in two major forms, primary and secondary, and, less
commonly, as tertiary hyperparathyroidism.
What are the main causes of primary hyperparathyroidism?
In more than 95% of cases, primary hyperparathyroidism is caused by a sporadic parathyroid adenoma or sporadic hyperplasia. Adenomas account for 85% to 95%, primary hyperplasia (diffuse or nodular) for 5% to 10%, and parathyroid carcinoma for 1%.
What are the genetic defects associated with familial primary hyperparathyroidism?
Familial primary hyperparathyroidism can be associated with multiple endocrine neoplasia syndromes, specifically MEN-1 and MEN-2A.
Additionally, familial hypocalciuric hypercalcemia, a rare condition, is caused by inactivating mutations in the calcium-sensing receptor gene on parathyroid cells, leading to constitutive PTH secretion.
What is the significance of Cyclin D1 gene inversions in primary hyperparathyroidism?
Cyclin D1 gene inversions occur in about 40% of adenomas.
This chromosomal inversion on chromosome 11 results in the relocation of the cyclin D1 gene adjacent to the region of the PTH gene, leading to abnormal expression of cyclin D1 protein and increased proliferation.
How are MEN1 mutations related to primary hyperparathyroidism?
MEN1 mutations are implicated in both sporadic and familial cases of primary hyperparathyroidism. MEN1 is a tumor suppressor gene associated with multiple endocrine neoplasia type 1 syndrome.
Describe the typical morphology of a parathyroid adenoma.
A parathyroid adenoma is usually a well-circumscribed solitary nodule enclosed by a delicate fibrous capsule.
It is almost always confined to a single gland, while the remaining glands may be normal in size or somewhat shrunken due to feedback inhibition by elevated serum calcium levels.
Microscopically, adenomas are composed predominantly of chief cells, with occasional pleomorphic nuclei and rare mitotic figures.
What are the morphological characteristics of parathyroid hyperplasia?
Parathyroid hyperplasia is typically a multiglandular process, although it may sometimes involve only one or two glands, making it challenging to distinguish from adenomas.
Microscopically, chief cell hyperplasia is the most common pattern, which can present in a diffuse or multinodular pattern. “Water-clear cell hyperplasia” may also be observed, characterized by cells containing abundant glycogen in their cytoplasm.
Stromal fat is inconspicuous within foci of hyperplasia.
Describe the morphological features of parathyroid carcinomas.
Parathyroid carcinomas may appear as circumscribed lesions that are difficult to distinguish from adenomas or clearly invasive neoplasms.
These tumors enlarge one parathyroid gland and consist of gray-white, irregular masses.
The cells usually resemble normal parathyroid cells, and cytologic details are unreliable for diagnosis.
Invasion of surrounding tissues and metastasis are the definitive criteria for diagnosis.
What are the morphological changes in other organs associated with primary hyperparathyroidism?
Skeletal changes include increased osteoclastic activity, leading to erosion of bone matrix, particularly in the metaphyses of long tubular bones.
Bone resorption is accompanied by increased osteoblastic activity and the formation of new bone trabeculae.
Severe cases may exhibit thinned cortex and increased fibrous tissue in the marrow, along with hemorrhage and cysts (osteitis fibrosa cystica).
Additionally, nephrolithiasis, renal interstitial and tubular calcification (nephrocalcinosis), and metastatic calcification in various organs, such as the stomach, lungs, myocardium, and blood vessels, may occur.
What is the most common manifestation of primary hyperparathyroidism in terms of laboratory findings?
The most common manifestation is an increase in serum ionized calcium levels.
Serum parathyroid hormone (PTH) is elevated in primary hyperparathyroidism, whereas it is low in hypercalcemia caused by nonparathyroid diseases or malignancy.
Other laboratory alterations associated with PTH excess include hypophosphatemia and increased urinary excretion of both calcium and phosphate.
What are some symptoms commonly observed in primary hyperparathyroidism?
Symptoms may include “painful bones” due to fractures resulting from bone weakening caused by osteoporosis, renal stones, gastrointestinal disturbances, and central nervous system alterations such as depression, lethargy, and seizures.
Neuromuscular abnormalities like weakness and hypotonia may also be present.
What are the main causes of secondary hyperparathyroidism?
Secondary hyperparathyroidism is caused by any condition associated with chronic low serum calcium levels, leading to compensatory overactivity (hyperplasia) of the parathyroid glands.
The most common cause is renal failure, which is associated with decreased phosphate excretion.
Elevated serum phosphate levels directly depress serum calcium levels, stimulating parathyroid gland activity.
Additionally, loss of renal substances reduces the availability of the α1-hydroxylase enzyme necessary for the synthesis of the active form of vitamin D, further reducing intestinal absorption of calcium. Vitamin D deficiency is another cause.
What are the histological features of the parathyroid glands in secondary hyperparathyroidism?
In secondary hyperparathyroidism, the hyperplastic glands contain an increased number of chief cells or cells with more abundant, clear cytoplasm (water-clear cells), typically in a diffuse or multinodular distribution.
Fat cells are decreased in number.
What are the typical clinical findings in secondary hyperparathyroidism?
Patients with secondary hyperparathyroidism usually have a low-normal calcium level and elevated parathyroid hormone.
Symptoms may relate to renal failure, such as renal osteodystrophy, and other symptoms seen in primary hyperparathyroidism, although to a lesser extent due to the normal calcium levels.
What is tertiary hyperparathyroidism?
Tertiary hyperparathyroidism is a state of excessive secretion of parathyroid hormone (PTH) that occurs after longstanding secondary hyperparathyroidism, leading to hypercalcemia.
What is the pathophysiology of tertiary hyperparathyroidism?
Tertiary hyperparathyroidism commonly occurs in patients with chronic secondary hyperparathyroidism, often following renal transplantation.
The hypertrophied parathyroid glands fail to return to normal and continue to oversecrete PTH, despite serum calcium levels within the reference range or even elevated.
The etiology is not fully understood, but it may involve changes in the calcium-sensing mechanism or monoclonal expansion of parathyroid cells, leading to nodule formation within hyperplastic glands.
Most patients with tertiary hyperparathyroidism have involvement of all four parathyroid glands.
What are the major causes of hypoparathyroidism?
Surgical removal of the parathyroid gland.
Congenital absence, often associated with thymic aplasia (Di George syndrome) and cardiac defects, secondary to deletions on chromosome 22q11.2.
Autoimmune hypoparathyroidism, a hereditary polyglandular deficiency syndrome caused by mutations in the autoimmune regulator gene (AIRE).
What are the major clinical manifestations of hypoparathyroidism?
The major clinical manifestations of hypoparathyroidism are secondary to hypocalcemia and include:
Increased neuromuscular irritability, such as tingling, muscle spasms, or tetany.
Cardiac arrhythmias.
Increased intracranial pressures and seizures.
What are some morphologic changes associated with hypoparathyroidism?
Morphologic changes generally include cataracts, calcification of the cerebral basal ganglia, and dental abnormalities.
T157 Adrenal Cortex structure
Composed of three layers: zona glomerulosa, zona fasciculata, and zona reticularis.
Zona glomerulosa: Produces mineralocorticoids, primarily aldosterone.
Zona fasciculata: Produces glucocorticoids, mainly cortisol.
Zona reticularis: Produces sex steroids, such as estrogens and androgens.
Adrenal Medulla structure
Composed of chromaffin cells.
Synthesizes and secretes catecholamines, predominantly epinephrine (adrenaline).
Adrenocortical hyperfunctiin (hyper adrenalism)
(1) Cushing syndrome, characterized by an excess of cortisol;
(2) hyperaldosteronism;
(3) adrenogenital or virilizing syndromes, caused by an excess of androgens.
Hypercortisolism and Cushing Syndrome
Cushing syndrome, clinical manifestation of condition that produces an elevation in glucocorticoid levels.
Hypercortisolism and Cushing Syndrome definition and causes
Cushing syndrome is the clinical manifestation of a condition that produces an elevation in glucocorticoid levels.
Causes include:
Administration of exogenous glucocorticoids (iatrogenic).
Endogenous causes
Cushing’s Disease
Manifests as primary hypothalamic-pituitary disease characterized by increased ACTH release, more common in women during early adulthood. Accounts for 70% of endogenous Cushing syndrome cases.
Pituitary Gland Abnormalities
The pituitary gland contains an ACTH-producing microadenoma that does not produce mass effects in the brain. In some cases, corticotroph cell hyperplasia may be present, either primary or secondary to excessive ACTH release by a hypothalamic corticotropin-releasing hormone (CRH)–producing tumor.
Adrenal Gland Manifestation
Increased ACTH leads to adrenal gland manifestation, resulting in nodular cortical hyperplasia, which is responsible for hypercortisolism.
Ectopic ACTH Secretion
Characterized by the secretion of ACTH by non-pituitary neoplasms.
Common Tumor Associations
The most common tumor associated with ectopic ACTH secretion is Small cell carcinoma of the lung. Other neoplasms include carcinoids and medullary carcinomas of the thyroid.
Adrenal Gland Changes
Elevated ACTH levels lead to bilateral cortical hyperplasia in the adrenal glands. However, in patients with rapidly progressing cancers, adrenal enlargement may be short-lived.
Primary adrenocortical neoplasms (adenoma or carcinoma) and rarely, primary cortical hyperplasia
This form of Cushing syndrome is also designated ACTH-independent Cushing syndrome, or adrenal Cushing syndrome, because the adrenals function autonomously. The biochemical hallmark of adrenal Cushing syndrome is elevated levels of cortisol with low serum levels of ACTH.
Morphology of Cushing syndrome, with pituitary gland
The most common alteration, Crooke hyaline change, occurs where the normal granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary is replaced by homogeneous, lightly basophilic material.
This alteration results from the accumulation of intermediate keratin filaments in the cytoplasm.
Morphology of Cushing syndrome adrenal gland
- Cortical bilateral atrophy
- Diffuse hyperplasia
- Macronodular or micronodular hyperplasia
- Adenoma or carcinoma
Cushing syndrome Cortical bilateral atrophy
Seen in iatrogenic glucocorticoid administration.
Diffuse hyperplasia cushing syndrome
Found in ACTH-dependent Cushing syndrome, characterized by enlarged glands with variable nodularity and yellow color from lipid-rich cells.
Macronodular or micronodular hyperplasia cushing syndrome
Present in primary cortical hyperplasia, where the cortex is replaced by macro/micro nodules (1-3 mm).
Dark pigment indicates lipofuscin.
Adenoma or carcinoma cushing syndrome
Adrenocortical adenomas: Yellow tumors surrounded by thin or well-developed capsules, usually weighing less than 30 g.
Histochemically, they resemble cells of the normal zona fasciculata.
Carcinomas: Larger than adenomas, nonencapsulated masses often exceeding 200 to 300 g, exhibiting anaplastic characteristics of cancer.
Adjacent/contralateral atrophy may be observed due to ACTH suppression.
Clinical Features of Cushing syndrome
Hypertension and weight gain
Characteristic centripetal distribution of adipose tissue resulting in truncal obesity and “moon facies”Selective atrophy of fast-twitch (type II) myofibers, leading to decreased muscle mass and proximal limb weakness
Glucocorticoid-induced gluconeogenesis causing hyperglycemia, glucosuria, and polydipsia, mimicking diabetes mellitus
Catabolic effects on proteins resulting in loss of collagen, skin thinning, fragility, easy bruising, and cutaneous striae, especially in the abdominal area
Bone resorption leading to osteoporosis and fractures
Suppression of the immune response causing mental disturbances
Extra-adrenal Cushing syndrome, caused by pituitary or ectopic ACTH secretion, often associated with increased skin pigmentation.
Hyperaldosteronism
a group of closely related conditions characterized by chronic excess aldosterone
secretion.
Hyperaldosteronism may be primary, or it may be secondary to an extra adrenal cause
aldosterone release occurs in response to activation of the renin-angiotensin system
characterized by increased levels of plasma renin and is encountered in association with
o Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)
Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic
syndrome)
o pregnancy (caused by estrogen-induced increases in plasma renin substrate)
Primary hyperaldosteronism
- a primary, autonomous overproduction of aldosterone, with
resultant suppression of the renin-angiotensin system and decreased plasma renin
activity. causes of primary hyperaldosteronism:
o Bilateral idiopathic hyperaldosteronism, characterized by bilateral nodular
hyperplasia of the adrenal glands.
o Adrenocortical neoplasm, either an aldosterone-producing adenoma
conn
syndrome (the most common cause) or, rarely, an adrenocortical carcinoma. In
approximately 35% of cases
o Rarely, fami
lial hyperaldosteronism may result from a genetic defect that leads to
overactivity of the aldosterone synthase gene, CYP11B2.
Aldosterone-producing adenomas morphology
are almost always solitary, small well-circumscribed
lesions.
They are bright yellow on cut section and composed of lipid-laden cortical cells
more closely resembling fasciculata cells than glomerulosa cells the cells tend to be
uniform in appearance
A characteristic feature of is the presence of eosinophilic,
laminated cytoplasmic inclusions, known as spironolactone bodies
these typically are
found after treatment with the antihypertensive agent spironolactone(antagonist)
