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)
Bilateral idiopathic hyperplasia
is marked by diffuse or focal hyperplasia of cells
resembling those of the normal zona glomerulosa.
Clinical feature hyperaldosteronism
The clinical hallmark of hyperaldosteronism is hypertension
cardiovascular
compromise (e.g., left ventricular hypertrophy and reduced diastolic volumes) ,stroke and
myocardial infarction.
Hypokalemia results from renal potassium wasting and, when present, can cause a variety
of neuromuscular manifestations, including weakness, paresthesias, visual disturbances,
and occasionally frank tetany
What regulates adrenal androgen formation?
Adrenal androgen formation is regulated by ACTH.
How do adrenal androgens differ from gonadal androgens?
Unlike gonadal androgens, adrenal androgens require conversion to testosterone in peripheral tissues for their androgenic effects.
What are the two compounds secreted by the adrenal cortex for androgen production?
Dehydroepiandrosterone and androstenedione.
What causes Adrenogenital Syndromes?
Adrenogenital Syndromes are caused by excess production of androgens from the zona reticularis of the adrenal cortex, regulated by ACTH.
What are the possible causes of Adrenogenital Syndromes?
Causes include adrenocortical neoplasms and congenital adrenal hyperplasia (CAH).
What is the most common cause of CAH?
The most common cause of CAH is 21-hydroxylase deficiency due to mutations in the CYP21A2 gene.
How does CAH lead to adrenal hyperplasia?
Decreased cortisol production in CAH leads to compensatory increase in ACTH secretion, resulting in adrenal hyperplasia.
What happens in CAH due to increased adrenal androgen production?
Increased production of cortisol precursor steroids, channeled into synthesis of androgens with virilizing activity.
What is the range of deficiency seen in CAH?
Deficiency may range in degree from total lack to mild loss.
What is the morphology of adrenals in CAH?
Adrenals in CAH are hyperplastic bilaterally, thickened, nodular, and may expand to 10 to 15 times their normal weights.
The widened cortex appears brown due to depletion of lipid.
Proliferating cells are compact, eosinophilic, lipid-depleted cells, intermixed with lipid-laden clear cells
What is adrenomedullary dysplasia in CAH characterized by?
Adrenomedullary dysplasia in CAH is characterized by incomplete migration of chromaffin cells to the center of the gland, with pronounced intermingling of nests of chromaffin and cortical cells in the periphery.
When do clinical symptoms of CAH typically occur?
Clinical symptoms of CAH may occur in the perinatal period, later childhood, or adulthood, depending on the nature and severity of the enzymatic defect.
How do individuals with classic CAH due to 21-hydroxylase deficiency present?
The most severely affected individuals with classic CAH present during the neonatal period and early infancy with adrenal insufficiency and salt wasting, or in the first few years of life with virilization.
What are the clinical features of androgen excess in females with CAH?
Androgen excess in females with CAH can cause acne, hirsutism, virilization, and reproductive dysfunction.
How does androgen excess manifest in males with CAH?
Androgen excess in males with CAH is associated with enlargement of external genitalia and other evidence of precocious puberty in prepubertal patients, and with oligospermia in older patients.
What risk does cortisol deficiency pose for individuals with CAH
Cortisol deficiency in CAH places individuals at risk for acute adrenal insufficiency.
T159 What cells populate the adrenal medulla?
The adrenal medulla is populated by cells derived from the neural crest, known as chromaffin cells, and their supporting (sustentacular) cells.
How do chromaffin cells respond to signals from the sympathetic nervous system?
Chromaffin cells synthesize and secrete catecholamines in response to signals from preganglionic nerve fibers in the sympathetic nervous system.
Where else in the body are similar cells found?
Similar collections of cells are distributed throughout the body in the extra-adrenal paraganglion system.
What is the spectrum of neuroblastic tumors?
The spectrum of neuroblastic tumors includes neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, which arise from primitive sympathetic ganglion cells.
From where do the cells that comprise neuroblastic tumors originate?
The cells that comprise neuroblastic tumors originate from the neural crest during fetal development and are destined for the adrenal medulla and sympathetic nervous system.
What differentiates pheochromocytomas and paragangliomas from neuroblastic tumors?
Pheochromocytomas and paragangliomas arise from chromaffin cells, which migrate from the neural crest to the adrenal medulla and extra-adrenal paraganglion system.
What are pheochromocytomas composed of?
Pheochromocytomas are neoplasms composed of chromaffin cells, which synthesize and release catecholamines, leading to hypertension.
What is the “rule of 10s” associated with pheochromocytomas?
The “rule of 10s” states that 10% of pheochromocytomas are extraadrenal, 10% of adrenal pheochromocytomas are bilateral (rising to 50% in familial syndromes), and 10% of adrenal pheochromocytomas are malignant.
What are the familial syndromes associated with pheochromocytomas and paragangliomas?
Familial cases may be associated with mutations in the RET gene causing type 2 MEN syndromes, the NF1 gene causing type 1 neurofibromatosis, the VHL gene causing von Hippel-Lindau disease, and genes encoding subunits within the succinate dehydrogenase complex involved in mitochondrial oxidative phosphorylation.
What are the components of von Hippel-Lindau disease (VHL) associated with pheochromocytoma?
VHL disease is associated with pheochromocytoma, cerebellar hemangioblastoma, renal cell carcinoma, and renal and pancreatic cysts.
What role does the VHL gene play in VHL disease?
Mutations in the VHL gene cause VHL disease, encoding a protein involved in cilia formation, regulation of cellular senescence, and the oxygen-sensing pathway.
Describe the morphology of pheochromocytomas.
Pheochromocytomas range in size from small, circumscribed lesions to large, hemorrhagic masses.
Smaller tumors are yellow-tan, well-defined lesions that compress the adjacent adrenal gland.
Incubation with potassium dichromate solutions turns the tumor dark brown.
Histologically, chief cells are polygonal with coarsely granular chromatin, arranged in “Zellballen” nests, surrounded by sustentacular cells.
The surrounding adrenal cortex is typically compressed.
What is the definitive diagnosis of malignancy in pheochromocytomas based on?
The definitive diagnosis of malignancy in pheochromocytomas is based exclusively on the presence of metastases, involving regional lymph nodes as well as more distant sites such as the liver, lung, and bone.
What are the clinical features of pheochromocytoma?
Clinical features include hypertension associated with tachycardia, palpitations, headache, sweating, and tremor.
Sudden cardiac death may occur, likely due to catecholamine-induced ventricular arrhythmias.
How is pheochromocytoma diagnosed in the laboratory?
The laboratory diagnosis of pheochromocytoma is based on demonstrating increased urinary excretion of free catecholamines and their metabolites.
How are isolated benign pheochromocytomas treated?
Isolated benign pheochromocytomas are treated with surgical excision.
What is included in the term “neuroblastic”?
“Neuroblastic” includes tumors of the sympathetic ganglia and adrenal medulla derived from primordial neural crest cells, with neuroblastoma being the most prominent member.
What is the incidence and peak age of neuroblastoma?
Neuroblastoma is the second most common solid malignancy of childhood after brain tumors, with a peak incidence between 0 and 4 years of age.
What unique features are seen in the natural history of neuroblastomas?
Neuroblastomas demonstrate spontaneous regression and spontaneous or therapy-induced maturation.
What percentage of neuroblastomas are familial, and what is the mode of transmission?
Most neuroblastomas occur sporadically, but 1% to 2% are familial with autosomal dominant transmission. In familial cases, neoplasms may involve both adrenal glands or multiple primary autonomic sites.
What gene mutation is associated with familial predisposition to neuroblastoma?
Germ line gain-of-function mutations in the anaplastic lymphoma kinase gene (ALK) are a major cause of familial predisposition to neuroblastoma. Somatic gain-of-function ALK mutations are also seen.
Where do most neuroblastomas arise in childhood?
About 40% of neuroblastomas arise in the adrenal medulla, while the remainder can occur anywhere along the sympathetic chain, with common locations being the paravertebral region of the abdomen (25%) and posterior mediastinum (15%).
Describe the macroscopic morphology of neuroblastomas
Neuroblastomas range in size from small nodules to large masses.
On cut surface, they are composed of soft, gray-tan tissue.
Larger tumors may have areas of necrosis, cystic softening, and hemorrhage. Some have a fibrous pseudocapsule, while others are more infiltrative.
What are the microscopic features of classic neuroblastomas?
Classic neuroblastomas are composed of small, primitive-appearing cells with dark nuclei and poorly defined cell borders growing in sheets.
The background often contains faintly eosinophilic fibrillary material (neuropil) corresponding to neuritic processes of the primitive neuroblasts.
Homer-Wright pseudo-rosettes may be present.
How can neuroblastomas be detected immunohistochemically?
Neuroblastomas can be detected immunohistochemically by the presence of neuron-specific enolase and demonstration of catecholamine-containing secretory granules.
What are the histologic features of ganglioneuroblastomas?
Ganglioneuroblastomas show signs of maturation, with larger cells resembling ganglion cells in various stages of maturation admixed with primitive neuroblasts.
What histologic prerequisite is required for the designation of ganglioneuroblastoma and ganglioneuroma?
Maturation of neuroblasts into ganglion cells, accompanied by the appearance of Schwann cells and fibroblasts, is a histologic prerequisite. The presence of only ganglion cells is not sufficient.
What are the most important factors influencing the prognosis of neuroblastomas?
The most important factors are the stage of the tumor and the age of the patient.
What is stage 4S neuroblastoma, and what is the prognosis for these patients?
Stage 4S neuroblastoma refers to tumors with limited metastases to liver, skin, and bone marrow, without bone involvement. Patients with stage 4S tumors have an excellent prognosis, often undergoing spontaneous regression with minimal therapy.
How does age influence the prognosis of neuroblastomas?
Children younger than 18 months have a much more favorable prognosis compared to older children at a comparable stage of disease.
What morphological features are indicative of a favorable prognosis in neuroblastomas?
Evidence of schwannian stroma and gangliocytic differentiation is indicative of a favorable histologic pattern.
What genetic factor is associated with a worse prognosis in neuroblastomas?
Amplification of the NMYC oncogene in neuroblastomas is present in advanced-stage disease, and the greater the number of copies, the worse the prognosis.
How do neuroblastomas typically present in children younger than 2 years?
Children younger than 2 years with neuroblastomas typically present with a protuberant abdomen resulting from an abdominal mass, fever, and weight loss.
What is a characteristic manifestation of disseminated neuroblastomas in neonates?
Disseminated neuroblastomas in neonates may manifest with multiple cutaneous metastases associated with deep blue discoloration of the skin, often referred to as “blueberry muffin baby.”
What diagnostic feature is common in neuroblastomas, and how does it differ from pheochromocytomas?
About 90% of neuroblastomas produce catecholamines, constituting an important diagnostic feature. However, hypertension is much less frequent with neuroblastomas compared to pheochromocytomas.
T160 What are MEN syndromes?
MEN syndromes are a group of inherited diseases resulting in proliferative lesions (hyperplasias, adenomas, and carcinomas) of multiple endocrine organs.
What distinctive features do endocrine tumors in MEN syndromes have compared to sporadic counterparts?
Tumors occur at a younger age than typical for sporadic cancers.
They arise in multiple endocrine organs, either synchronously or metachronously.
Tumors are often multifocal within one organ.
Tumors are usually preceded by an asymptomatic stage of endocrine hyperplasia involving the cell of origin.
They are usually more aggressive and recur in a higher proportion of cases than similar endocrine tumors that occur sporadically.
How is Multiple Endocrine Neoplasia Type 1 (MEN-1) inherited?
MEN-1 is inherited in an autosomal dominant pattern.
Where is the MEN1 gene located, and what is its function?
The MEN1 gene is located at 11q13 and is a tumor suppressor gene.
It encodes the protein menin, which regulates transcription and genome stability. Menin appears to be located in the nucleus where it interacts with histone modifiers and the transforming growth factor-beta signaling pathway.
What are the organs most commonly involved in MEN-1
Parathyroid: Primary hyperparathyroidism is the most common manifestation of MEN-1, occurring in 80% to 95% of patients around the age of 40-50.
Parathyroid abnormalities include both hyperplasia and adenomas.
Pancreas: Endocrine tumors of the pancreas, often aggressive and metastatic, are the leading cause of death in MEN-1.
These tumors are usually functional, with common manifestations including Zollinger-Ellison syndrome (gastrinomas) and hypoglycemia (insulinomas).
Pituitary: The most frequent pituitary tumor in MEN-1 patients is a prolactin-secreting macroadenoma. Acromegaly may also develop due to somatotropin-secreting tumors.
What is the basis for tumorigenesis in MEN-1?
Inactivation of both alleles of the MEN1 tumor suppressor gene at 11q13 is believed to be the basis for tumorigenesis in MEN-1.
What are the unifying characteristics of Multiple Endocrine Neoplasia Type 2 (MEN-2)?
MEN-2 is characterized by the occurrence of activating gain-of-function mutations of the RET proto-oncogene at chromosomal locus 10q11.2.
How is MEN-2 inherited?
MEN-2 is inherited in an autosomal dominant pattern.
What is the function of the RET proto-oncogene?
The RET proto-oncogene encodes a putative tyrosine kinase receptor, playing a critical role in pathways involved in enteric nervous system neurogenesis and renal organogenesis.
What genotype-phenotype correlation has been recognized for MEN-2 syndromes?
There is a strong genotype-phenotype correlation for MEN-2 syndromes, with differences in mutation patterns accounting for variable features in the two subtypes
What organs are commonly involved in MEN type 2A?
Organs commonly involved in MEN type 2A include:
Thyroid: Virtually all untreated cases develop medullary carcinoma of the thyroid, often multifocal with adjacent C cell hyperplasia.
Familial medullary thyroid cancer, a variant of MEN-2A, typically occurs at an older age and follows a more indolent course.
Adrenal medulla: About 50% of patients develop adrenal pheochromocytomas, most of which are non-malignant.
Parathyroid: Approximately 10% to 20% of patients develop parathyroid gland hyperplasia with manifestations of primary hyperparathyroidism.
What distinguishes MEN-2B from MEN-2A in terms of genetic mutation?
Patients with MEN-2B harbor a distinct germline RET mutation involving a single amino acid change.
What organs are commonly involved in MEN-2B?
Organs commonly involved in MEN-2B include the thyroid and the adrenal medulla.
What are the extraendocrine manifestations characteristic of MEN-2B?
Extraendocrine manifestations in MEN-2B include ganglioneuromas of mucosal sites (gastrointestinal tract, lips, tongue) and a marfanoid habitus,
characterized by overly long bones of the axial skeleton resembling Marfan syndrome.
What is the recommendation for individuals carrying germline RET mutations?
Individuals carrying germline RET mutations are advised to undergo prophylactic thyroidectomy to prevent the inevitable development of medullary carcinomas.
What are the phenotype differences between MEN 2A and MEN 2B?
MEN 2A patients do not have the phenotypic abnormalities of mucosal neuromas and marfanoid habitus found in MEN 2B patients.
How does the virulence of medullary thyroid carcinoma differ between MEN 2A and MEN 2B?
MEN 2A patients generally have a less virulent form of medullary thyroid carcinoma compared to MEN 2B patients.
What is the difference in parathyroid hyperplasia between MEN 2A and MEN 2B?
Parathyroid hyperplasia may occur in MEN 2A patients but is exceedingly rare in MEN 2B patients.
What is the third subtype of MEN 2?
The third subtype of MEN 2 is familial medullary thyroid carcinoma only (FMTC only).
T161 What are dysostoses?
Dysostoses are abnormalities in a single or group of bones, resulting in the absence of bones, supernumerary bones, or inappropriately fused bones.
Some of these result from mutations in homeobox genes affecting localized migration and condensation of primitive mesenchymal cells.
What are osteodysplasias?
Osteodysplasias are abnormalities in bone genesis or abnormal growth.
These can be caused by mutations affecting signal transduction pathways or components of the extracellular matrix.
What is Achondroplasia and thanatophoric dwarfism caused by?
Achondroplasia and thanatophoric dwarfism occur as a consequence of point mutations in FGFR3, leading to activation.
These mutations inhibit the proliferation and function of growth plate chondrocytes, resulting in severely stunted growth of long bones.
What is Achondroplasia and thanatophoric dwarfism caused by?
Achondroplasia and thanatophoric dwarfism occur as a consequence of point mutations in FGFR3, leading to activation.
These mutations inhibit the proliferation and function of growth plate chondrocytes, resulting in severely stunted growth of long bones.
What is Osteogenesis imperfecta?
Osteogenesis imperfecta, also known as brittle bone disease, is a group of disorders caused by mutations in the genes for type 1 collagen, resulting in bone fragility and susceptibility to fractures.
What is Osteopetrosis caused by?
Osteopetrosis is caused by mutations that interfere with osteoclast function, resulting in dense but architecturally unsound bone due to defective bone resorption.
What is osteoporosis?
Osteoporosis is a disease characterized by decreased bone mass (osteopenia), making patients prone to bone fractures.
What is the epidemiology of osteoporosis?
Osteoporosis is the most common bone disorder in the USA, occurring most commonly in postmenopausal Caucasian women and the elderly.
What is the pathogenesis of osteoporosis?
Osteoporosis occurs when the dynamic balance between bone formation by osteoblasts and bone resorption by osteoclasts tilts in favor of resorption. Primary causes include postmenopausal and senile osteoporosis, while secondary causes include drugs, nutritional deficiencies/malabsorption, and endocrine disorders.
Describe the morphology of osteoporosis.
In osteoporosis, the bone cortex is thinned, and the trabeculae are reduced in thickness and lose their interconnections, often with dilated Haversian canals.
What are the clinical features of osteoporosis?
Clinical presentation includes bone pain and fractures, mainly in weight-bearing bones such as vertebrae, femoral neck, and distal radius. Other features include loss of weight, kyphosis, and pulmonary embolism as a common complication.
How is osteoporosis diagnosed?
Osteoporosis is difficult to diagnose as it is often asymptomatic until fractures occur.
What are the treatment options for osteoporosis?
Treatment options include estrogen replacement therapy (associated with cardiovascular risks), weight-bearing exercise, and calcium and vitamin D supplementation.
What are rickets and osteomalacia?
Rickets is the manifestation of vitamin D deficiency or abnormal metabolism in growing children, while osteomalacia occurs in adults.
What is the fundamental defect in rickets and osteomalacia?
The fundamental defect is an impairment of mineralization, resulting in the accumulation of unmineralized matrix (osteoid).
What are the causes of rickets and osteomalacia?
Causes include a diet deficient in calcium and vitamin D, malabsorption disorders, limited exposure to sunlight, renal disorders causing decreased synthesis of hydroxylase 1,25-(OH)2-D, and phosphate depletion.
Describe the pathogenesis of rickets and osteomalacia.
Deficiency of vitamin D leads to hypocalcemia, stimulating PTH production. PTH activates renal alpha1-hydroxylase, increasing vitamin D and calcium absorption, mobilizing calcium from bone, and decreasing renal calcium excretion, while increasing renal excretion of phosphate. This results in restoration of serum calcium levels but leads to hypophosphatemia, impairing bone mineralization and causing high bone turnover.
What are the microscopic changes seen in rickets?
Overgrowth of epiphyseal cartilage due to inadequate provisional calcification and failure of cartilage cells to mature and disintegrate.
Disruption of the orderly replacement of cartilage by osteoid matrix, leading to enlargement of the osteochondral junction and accumulation of uncalcified osteoid.
Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone due to microfractures and stress on inadequately mineralized bone.
What are the gross skeletal changes observed in rickets?
Deformation of the skeleton due to the loss of structural rigidity, including bowing of the legs, bending of long bones in the upper limbs, and pigeon breast deformity.
Presence of palpable masses known as “rachitic rosary” due to inward bending of the ribs with anterior protrusion of the sternum.
Severity of changes depends on the duration and severity of the problem, as well as stress on the skeleton.
Describe the microscopic features of osteomalacia.
The newly formed osteoid matrix laid down by osteoblasts remains inadequately mineralized.
Unmineralized osteoid appears as a thickened layer of matrix arranged around the more basophilic, normally mineralized trabeculae.
What are the macroscopic characteristics of bones affected by osteomalacia
The contours of the bone are not affected, but the bone becomes weak and vulnerable to gross fractures and microfractures, predominantly affecting vertebral bodies and the femoral neck.
T162 What are the effects of parathyroid hormone (PTH) on serum calcium levels?
Activation of osteoclasts, leading to increased bone resorption and calcium mobilization.
PTH indirectly increases osteoclast activity by upregulating RANKL expression on osteoblasts.
Increased resorption of calcium by renal tubules, accompanied by increased urinary excretion of phosphate.
Stimulation of active vitamin D synthesis by the kidneys, enhancing calcium absorption from the gut.
What are the two forms of hyperparathyroidism?
Primary hyperparathyroidism:
Characterized by autonomous parathyroid secretion.
Secondary hyperparathyroidism:
Associated with renal disease, resulting from inadequate synthesis of 1,25(OH)2D by the kidneys or hyperphosphatemia in renal failure.
What skeletal changes are associated with hyperparathyroidism?
Significant skeletal changes due to unabated osteoclast activity affect the entire skeleton.
Decreased bone mass increases susceptibility to fractures, bone deformation, and joint problems.
Reversal of bone changes is possible by reducing PTH levels to normal.
Describe the morphological features of primary hyperparathyroidism.
Increased osteoclastic activity leads to bone resorption, with cortical and trabecular bone being replaced by loose connective tissue.
Microscopic features include increased osteoclasts in bone trabeculae, expansive haversian canals, loose fibrovascular tissue in the marrow space, and hemosiderin deposits.
Brown tumor of hyperparathyroidism may be present, consisting of osteoclasts, reactive giant cells, and hemorrhagic debris.
What are the symptoms associated with primary hyperparathyroidism?
Symptoms are related to abnormalities in calcium homeostasis, summarized as “stones, bones, moans, and groans”:
“Stones” refer to kidney stones.
“Bones” denote skeletal changes.
“Moans” describe psychiatric depression and other abnormalities associated with hypercalcemia.
“Groans” characterize gastrointestinal irregularities associated with high serum calcium levels.
What are the characteristic stages of Paget disease?
Osteolytic stage: Regional osteoclastic activity and bone resorption.
Mixed osteoclastic-osteoblastic stage: Exuberant bone formation.
Osteosclerotic stage: Apparent exhaustion of cellular activity, resulting in increased bone mass but with disordered and weak bone.
What is the pathogenesis of Paget disease?
Assigned to an inflammatory process called osteitis deformans.
Linked to paramyxovirus infection inducing secretion of IL-1, IL-6, and M-CSF from infected cells, activating osteoclasts.
Mutations in the SQSTM1 gene observed in 10% of affected patients, increasing osteoclastogenesis.
Describe the morphology of Paget disease
May manifest as solitary (monostotic) or multiple (polyostotic) lesions.Initial lytic phase:
Numerous, large, multinucleated osteoclasts with Howship lacunae.
Mixed phase: Osteoblasts line bone surfaces, marrow replaced by loose connective tissue and blood vessels.
Remodeled bone: Abnormal lamellar bone with a mosaic pattern.
Softened cortex prone to deformation and fracture.
What are the clinical features of Paget disease?
Most cases clinically mild.
Elevated serum alkaline phosphatase and increased urinary hydroxyproline.
Hypervascular lesions may cause warmth of overlying skin.
Skull involvement can lead to headache and sensory disturbances.
Vertebral lesions cause back pain and nerve compression.
Deformed long bones in legs, brittle and prone to fractures.
Sarcomas may develop in 1% of cases.
T163 What is osteomyelitis?
Inflammation of the bone and marrow, which can occur as a primary isolated focus or secondary to systemic infection.
What are the routes of infection for pyogenic osteomyelitis?
Hematogenous spread: Most common, seeding of bone after bacteremia, commonly affects the metaphysis.
Spread from adjacent site of infection.
Traumatic implantation after compound fractures or orthopedic procedures.
What are the common microbiological causes of pyogenic osteomyelitis?
Staphylococcus aureus (most common).
E. coli and Group B streptococci in neonates.
Salmonella in sickle cell disease.
Mixed bacterial infections in trauma-related osteomyelitis.
What are the clinical features of pyogenic osteomyelitis?
Acute systemic illness with fever and leukocytosis.
Localized pain, erythema, and swelling.
Describe the morphology of pyogenic osteomyelitis.
Depends on chronicity and location, may involve sequestrum (necrotic bone), subperiosteal abscess, and involucrum (new bone formation around sequestrum).
Diagnosis: X-ray shows lytic focus with surrounding edema and sclerotic rim.
How is pyogenic osteomyelitis diagnosed and treated?
Diagnosis: Blood culture, bone biopsy, and culture.
Treatment: Antibiotics and/or surgical drainage.
What are the complications of pyogenic osteomyelitis?
Fracture, endocarditis, secondary amyloidosis, sinus tract formation, squamous cell carcinoma at the site of a persistent draining sinus tract, and rarely, osteogenic sarcoma.
Describe tuberculous osteomyelitis.
Occurs in 1-3% of cases of pulmonary TB.
Routes of infection: Usually bloodstream, favors long bones and vertebrae, or direct spread from mediastinal lymph nodes.
Morphology: Solitary lesions, granulomatous inflammation, and caseous necrosis.
What is osteomyelitis?
Inflammation of the bone and marrow, which can occur as a primary isolated focus or secondary to systemic infection.
What are the routes of infection for pyogenic osteomyelitis?
Hematogenous spread: Most common, seeding of bone after bacteremia, commonly affects the metaphysis.
Spread from adjacent site of infection.
Traumatic implantation after compound fractures or orthopedic procedures.
What are the common microbiological causes of pyogenic osteomyelitis?
Staphylococcus aureus (most common).
E. coli and Group B streptococci in neonates.Salmonella in sickle cell disease.
Mixed bacterial infections in trauma-related osteomyelitis.
What are the clinical features of pyogenic osteomyelitis?
Acute systemic illness with fever and leukocytosis.
Localized pain, erythema, and swelling.
Describe the morphology of pyogenic osteomyelitis.
Depends on chronicity and location, may involve sequestrum (necrotic bone), subperiosteal abscess, and involucrum (new bone formation around sequestrum).
Diagnosis: X-ray shows lytic focus with surrounding edema and sclerotic rim.
How is pyogenic osteomyelitis diagnosed and treated?
Diagnosis: Blood culture, bone biopsy, and culture.
Treatment: Antibiotics and/or surgical drainage.
What are the complications of pyogenic osteomyelitis?
Fracture, endocarditis, secondary amyloidosis, sinus tract formation, squamous cell carcinoma at the site of a persistent draining sinus tract, and rarely, osteogenic sarcoma.
Describe tuberculous osteomyelitis.
Occurs in 1-3% of cases of pulmonary TB.
Routes of infection: Usually bloodstream, favors long bones and vertebrae, or direct spread from mediastinal lymph nodes.
Morphology: Solitary lesions, granulomatous inflammation, and caseous necrosis.
What are the clinical features of tuberculous osteomyelitis?
Vertebral involvement can lead to deformity, collapse, and posterior displacement (Pott disease) resulting in neurologic deficits, along with psoas muscle abscess formation.
T164 165 What are osteomas?
Osteomas are benign lesions commonly found in the head and neck, including the paranasal sinuses.
How do osteomas typically present?
They typically present in middle age as solitary, slowly growing, hard masses on bone surfaces.
What is a notable association with multiple osteomas?
Multiple lesions are associated with Gardner syndrome.
Describe the microscopical appearance of osteomas.
Microscopically, osteomas consist of a mixture of woven and lamellar bone.
Do osteomas undergo malignant transformation?
No, they do not undergo malignant transformation, although they may cause local mechanical problems and cosmetic deformities.
What are osteoid osteomas and osteoblastomas?
They are benign neoplasms arising from osteoblasts with very similar histologic features.
What is the typical age range for osteoid osteomas and osteoblastomas?
They typically appear during teenage years and 20s, with a male predilection.
How do osteoid osteomas and osteoblastomas differ in size and location?
Osteoid osteomas are usually less than 2 cm in diameter, arise beneath the periosteum or within the cortex of long bones, whereas osteoblastomas are larger and often found in the vertebral column.
What are the clinical manifestations of osteoid osteomas and osteoblastomas?
Osteoid osteomas cause localized pain that is most severe at night and relieved by aspirin, while osteoblastomas cause pain that is more difficult to localize and not responsive to aspirin.
Do osteoid osteomas and osteoblastomas undergo malignant transformation?
Malignant transformation is rare unless the lesion is treated with irradiation.
Describe the macroscopical appearance of osteoid osteomas and osteoblastomas
Macroscopically, both appear as round-to-oval masses of hemorrhagic, gritty tan tissue with a rim of sclerotic bone, more conspicuous in osteoid osteomas.
Describe the microscopical appearance of osteoid osteomas and osteoblastomas
Microscopically, both tumors consist of interlacing trabeculae of woven bone surrounded by osteoblasts in loose, vascular connective tissue containing variable numbers of giant cells.
What is osteosarcoma?
Osteosarcoma is a malignant bone tumor characterized by the proliferation of osteoblasts.
How common is osteosarcoma among primary bone cancers?
It is the third most common primary malignant tumor of bone, after myeloma and lymphoma, accounting for approximately 20% of primary bone cancers.
Where do most osteosarcomas arise?
Most tumors arise in the metaphyseal region of the long bones of the extremities, particularly around the knee.
What are the risk factors associated with osteosarcoma?
Risk factors include Paget disease, familial retinoblastoma, radiation exposure, and spontaneous mutations in the TP53 gene.
Describe the morphology of osteosarcoma.
Macroscopically, osteosarcomas appear as gritty-appearing, gray-white tumors, often with hemorrhage and cystic degeneration.
Microscopically, tumor cells vary in size and shape, with large hyperchromatic nuclei and frequent mitotic figures. The production of mineralized or unmineralized bone (osteoid) by malignant cells is essential for diagnosis.
What are the clinical manifestations of osteosarcoma?
Osteosarcomas typically manifest as painful enlarging masses, often with a pathologic fracture as the first sign.
Radiographically, they appear as large, destructive, mixed lytic and blastic masses with indistinct infiltrating margins.
A characteristic finding is a triangular shadow (Codman triangle) between the cortex and raised periosteum.
Osteosarcomas typically spread hematogenously, with demonstrable pulmonary metastases being common.
What are the subtypes of osteosarcoma?
Several subtypes are distinguished based on the site of involvement within the bone, degree of differentiation, number of involved sites, presence of underlying disease, and histologic features.
The most common type is primary, solitary, intramedullary, and poorly differentiated, producing a predominantly bony matrix.
Chondroblastic osteosarcoma is characterized by abundant malignant cartilage.
What are osteochondromas?
Osteochondromas are benign tumors of bone characterized by overlying cartilage caps.
When are solitary osteochondromas typically first diagnosed?
Solitary osteochondromas are typically first diagnosed in late adolescence and early adulthood.
How do multiple osteochondromas usually present?
Multiple osteochondromas become apparent during childhood and are associated with multiple hereditary osteochondromas, which is an autosomal dominant disorder.
What genetic mutations are implicated in osteochondromas?
Inactivation of both copies of the EXT1 or EXT2 genes through mutation in chondrocytes is implicated in both sporadic and hereditary osteochondromas.
These genes encode glycosyltransferases essential for polymerization of heparin sulfate, an important component of cartilage.
Where do osteochondromas typically develop in the bone?
Osteochondromas develop only in bones of endochondral origin, arising at the metaphysis near the growth plate of long tubular bones, especially about the knee.
They occasionally develop from bones of the pelvis, scapula, and ribs.
Describe the morphology of osteochondromas.
Osteochondromas range in size from 1-20 cm and have a cartilaginous cap composed of hyaline cartilage.
What are the clinical features of osteochondromas?
Osteochondromas are slow-growing masses that can be painful.
Solitary osteochondromas rarely progress to chondrosarcoma or other sarcomas, but malignant transformation occurs more frequently in those with multiple hereditary osteochondromas.
What are chondromas?
Chondromas are benign neoplasms of hyaline cartilage.
Where do enchondromas typically arise within bones?
Enchondromas typically arise within the medulla of bones and are located in the metaphyseal region of tubular bones, with favored sites being the short tubular bones of the hands and feet.
What are Ollier disease and Maffucci syndrome characterized by?
Ollier disease is characterized by multiple chondromas preferentially involving one side of the body, while Maffucci syndrome is characterized by multiple chondromas associated with soft tissue spindle cell hemangiomas.
What are juxtacortical chondromas?
Juxtacortical chondromas are chondromas located on the bone surface
What genetic mutations are frequently found in enchondromas occurring in Ollier disease and Maffucci syndrome?
Enchondromas occurring in Ollier disease and Maffucci syndrome frequently contain point mutations in either isocitrate dehydrogenase I (IDH1) or IDH2 that create a new enzyme activity. These mutations occur early during embryonic development, representing an example of genetic mosaicism.
Describe the morphology of enchondromas.
Enchondromas are gray-blue, translucent nodules usually smaller than 5 cm in greatest dimension.
Microscopically, they are well circumscribed and composed of hyaline cartilage containing cytologically benign chondrocytes.
At the periphery, there is endochondral ossification, while the center frequently calcifies and dies.
What is the clinical significance of solitary chondromas?
Solitary chondromas rarely undergo malignant transformation, but those associated with enchondromatoses are at increased risk for such change.
Maffucci syndrome is associated with an increased risk for the development of other types of malignancies, including ovarian carcinomas and brain gliomas.
What is chondrosarcoma?
Chondrosarcoma is a malignant connective tissue tumor (sarcoma) characterized by cells that manufacture and secrete neoplastic cartilage matrix.
How is chondrosarcoma subclassified?
Chondrosarcoma is subclassified according to site (e.g., intramedullary versus juxtacortical) and histologic variants.
What is the typical age range of patients with chondrosarcoma?
Most patients with chondrosarcoma are age 40 or older, with men being more affected than women.
Describe the morphology of conventional chondrosarcoma.
Conventional chondrosarcoma, the most common variant, arises within the medullary cavity of the bone to form an expansile glistening mass composed of malignant hyaline and myxoid cartilage.
What are the clinical features of chondrosarcoma?
Chondrosarcomas commonly arise in the pelvis, shoulder, and ribs, and they typically manifest as painful, progressively enlarging masses. Unlike enchondromas, chondrosarcomas rarely involve the distal extremities.
How is tumor grade determined in chondrosarcoma?
Tumor grade in chondrosarcoma is determined by cellularity, degree of cytologic atypia, and mitotic activity. Low-grade tumors may progress to high grade.
What are the metastatic patterns of chondrosarcoma?
Chondrosarcomas metastasize hematogenously to the lung and skeleton.
Adrenal Insufficiency: General Description
Hypofunction of adrenal glands caused by primary adrenal disease or decreased adrenal stimulation by ACTH deficiency.
Acute Adrenal Insufficiency: Definition
Acute onset of decreased production of steroid hormones, specifically cortisol. Can develop from chronic insufficiency during stress or withdrawal of exogenous steroids.
Acute Adrenal Insufficiency: Causes
Chronic insufficiency during stressSteroid withdrawal in patients on exogenous steroidsMassive adrenal hemorrhage (e.g., due to anti-coagulant therapy, DIC)Waterhouse-Friderichsen syndrome (septicemia causing adrenal hemorrhage)
Waterhouse-Friderichsen Syndrome: Description
Septicemia causing adrenal hemorrhage, associated with pathogens like N. meningitidis, Pseudomonas, H. influenzae.
Waterhouse-Friderichsen Syndrome: Description
Septicemia causing adrenal hemorrhage, associated with pathogens like N. meningitidis, Pseudomonas, H. influenzae.
Chronic Adrenal Insufficiency: Definition
Also known as Addison’s disease. Long-term disorder with inadequate production of aldosterone and cortisol, causing progressive destruction of the adrenal cortex.
Chronic Adrenal Insufficiency: Definition
Also known as Addison’s disease. Long-term disorder with inadequate production of aldosterone and cortisol, causing progressive destruction of the adrenal cortex.
Chronic Adrenal Insufficiency: Causes
Autoimmune adrenalitis (60-70% cases)TuberculosisAIDSMetastatic cancer
Chronic Adrenal Insufficiency: Causes
Autoimmune adrenalitis (60-70% cases)TuberculosisAIDSMetastatic cancer
Autoimmune Adrenalitis: Description
Autoimmune destruction of steroid-producing cells, causing primary adrenal insufficiency. Includes APS1 (AIRE mutation) and APS2 (early adulthood onset with thyroiditis and type 1 diabetes).
Autoimmune Adrenalitis: Description
Autoimmune destruction of steroid-producing cells, causing primary adrenal insufficiency. Includes APS1 (AIRE mutation) and APS2 (early adulthood onset with thyroiditis and type 1 diabetes).
APS1 vs. APS2: Differences
APS1: AIRE mutation on chr 21, mucocutaneous candidiasis, skin abnormalities, hypoparathyroidism.APS2: Early adulthood, adrenal insufficiency, autoimmune thyroiditis, type 1 diabetes, no hypoparathyroidism.
APS1 vs. APS2: Differences
APS1: AIRE mutation on chr 21, mucocutaneous candidiasis, skin abnormalities, hypoparathyroidism.APS2: Early adulthood, adrenal insufficiency, autoimmune thyroiditis, type 1 diabetes, no hypoparathyroidism.
Tuberculous Adrenalitis: Context
Previously accounted for 90% of cases. Associated with active infections in other sites such as lungs and genitourinary tract.
Adrenal Insufficiency in AIDS: Details
Patients with AIDS are more susceptible due to infections like cytomegalovirus, Mycobacterium avium-intracellulare, and Kaposi sarcoma.
Metaplastic Neoplasms: Impact
Adrenals are common sites for metastases. Growths may destroy enough cortex to cause insufficiency, especially from lung and breast carcinomas.
Metaplastic Neoplasms: Impact
Adrenals are common sites for metastases. Growths may destroy enough cortex to cause insufficiency, especially from lung and breast carcinomas.
Secondary Adrenal Insufficiency: Definition
Caused by disorders of the hypothalamus or pituitary reducing ACTH secretion. Results in hypoadrenalism similar to Addison’s disease but without hyperpigmentation.
Secondary Adrenal Insufficiency: Definition
Caused by disorders of the hypothalamus or pituitary reducing ACTH secretion. Results in hypoadrenalism similar to Addison’s disease but without hyperpigmentation.
Secondary Adrenal Insufficiency: Clinical Features
No hyperpigmentation due to low melanotropic hormonesLow serum ACTH, quick cortisol response to ACTH administrationSymptoms: weakness, fatigue, anorexia, nausea, vomiting, weight loss, diarrhea
Morphology of Secondary Adrenal Insufficiency
Adrenals small, flat, yellow due to lipids; atrophic cortex surrounds intact medulla; cortical cells atrophy, loss of lipids.
Primary Autoimmune Adrenal Insufficiency: Morphology
Shrunken glands, difficult to identify in adipose, only scattered cortical cells remain, lymphocyte infiltration in cortex and sometimes medulla.
Tuberculosis/Fungal Disease in Adrenals: Morphology
Granulomatous inflammatory reaction similar to other infection sites.
Metastatic Carcinoma in Adrenals: Morphology
Adrenals enlarged, architecture obscured by infiltrating neoplasm.
Clinical Features of Adrenal Insufficiency
Asymptomatic until 90% cortex is compromised; symptoms include weakness, fatigue, anorexia, nausea, vomiting, weight loss, diarrhea.
Primary Adrenal Disease: Hyperpigmentation
Excess ACTH precursor stimulates melanocytes causing hyperpigmentation of face, axilla, nipples, areola, and perineum.
Secondary Adrenal Insufficiency: Hormone Levels
Decreased cortisol, normal aldosterone secretion. Hypoglycemia from glucocorticoid deficiency and impaired gluconeogenesis.
Secondary Adrenal Insufficiency: Hormone Levels
Decreased cortisol, normal aldosterone secretion. Hypoglycemia from glucocorticoid deficiency and impaired gluconeogenesis.
