Preface

Agam is a group of budding medicos, who are currently doing their under graduation in
various Medical Colleges across Tamil Nadu and Pondicherry. The group was initiated on 18th
November 2017, in the vision of uniting medicos for various social and professional causes.

We feel delighted to present you Agam Pathology notes prepared by Agam Divide and Rule
2020 Team to guide our fellow medicos to prepare for university examinations.

This is a reference work of 2017 batch medical students from various colleges. The team
took effort to refer many books and make them into simple notes. We are not the authors of the
following work. The images used in the documents are not copyrighted by us and is obtained from
various sources.

Dear readers, we request you to use this material as a reference note, or revision note, or
recall notes. Please do not learn the topics for the 1st time from this material, as this contain just the
required points, for revision.
Acknowledgement

On behalf of the team, Agam would like to thank all the doctors who taught us Pathology.
Agam would like to whole heartedly appreciate and thank everyone who contributed towards the
making of this material. A special thanks to Vignesh M, who took the responsibility of leading the
team. The following are the name list of the team who worked together, to bring out the material in
good form.

• Neelavathi S
• Ishwarya J
• Rajath B
• Santhiya K
• Shalika G
• Shenbhaga Praveen N
• Subhashree B
• Snaha M
• Projatna Chaudhuri
• Sowrathi L K
• Anchita S
• Vignesh. M
 THE ENDOCRINE SYSTEM 1

ESSAY:
1. Diabetes Mellitus

SHORT NOTES:
1. Papillary Carcinoma of thyroid.
2. Medullary Carcinoma of thyroid
3. Multi-nodular goiter.
4. Diabetic nephropathy
5. Hashimoto thyroiditis
6. Grave’s disease
7. Cushing Syndrome
8. Ketone bodies
9. Pheochromocytoma
10.Hyperparathyroidism
11.MEN- I
12.MEN – II
13.Diabetic macrovascular disease
14.Features of Diabetic retinopathy
15.Prolactinoma

SHORT ANSWERS:
1. Features of Addison’s disease
2. Hurtle cell
3. Psammoma bodies
4. Differences between childhood and adult craniopharyngioma
5. Lab Diagnosis of DM
6. Types of thyroiditis
7. Classify thyroid neoplasms
8. Colloid goiter
9. Cretinism

UPDATES

PATHOLOGY AGAM
2ESSAY
1. DIABETES MELLITUS
PATHOGENESIS OF DM TYPE 1& 2:

PATHOGENESIS OF TYPE 1 DM:

1. Genetic susceptibility :
 HLA genes like HLA DR3/4
 Non HLA genes like CTLA4, PTPN22
2. Environmental factors:
 Viral infections – Immune response to virus results in cross reactivity and
destruction of islet tissue – a phenomenon known as molecular mimicry
AGAM PATHOLOGY
MECHANISM OF BETA CELL DESTRUCTION: 3

METABOLIC DEFECTS IN DM TYPE 2

A. INSULIN RESISTANCE

Insulin resistance

Failure of inhibition ↓ Uptake and Failure to inhibit

of gluconeogenesis ↓ glycogenolysis Lipoprotein lipase → ↑ FFA

↑ Fasting glucose levels ↑ Insulin resistance due to ↑ FFA

B. BETA CELL DYSFUNCTION

Beta cell dysfunction

Lipotoxicity Glucotoxicity ↑ Incretin effect → Amyloid depo Genetic

↑ Insulin release -sition in islets causes

PATHOLOGY AGAM
4ACUTE COMPLICATIONS:
 Diabetic ketoacidosis (DKA)
 Hyperglycemic hyperosmolar state (HHS)
 Hypoglycemia

PATHOGENESIS OF ACUTE COMPLICATIONS:

AGAM PATHOLOGY
CHRONIC COMPLICATIONS: 5
 Vascular complications:
 Microvascular :
 Retinopathy
 Nephropathy
 Neuropathy
 Macrovascular:
 Coronary artery disease
 Cerebrovascular disease
 Peripheral arterial disease
 Nonvascular complications:
 Sexual dysfunction
 Skin changes
 Oral complications
 Diabetic retinopathy
 Diabetic nephropathy
 Diabetic neuropathy

PATHOGENESIS OF CHRONIC COMPLICATIONS:

 Formation of Advanced glycation end products :
 Release of cytokines and growth factors including TGF beta causing deposition of
excess basement membrane material,
 VEGF → implicated in diabetic retinopathy
 Generation of ROS in endothelial cells
 Increased pro-coagulant activity on macrophage and endothelial cells.
 Enhanced proliferation of vascular smooth muscle cells and synthesis of ECM
 Activation of protein kinase C
 Oxidative stress and disturbances in polyol pathways
 Hexosamine pathways and generation of fructose 6 phosphate:
 Hyperglycemia → ↑ hexosamine pathway → ↑ fructose 6 phosphate → ↑
Glycosylation of proteins → Generation of excess proteoglycans

PATHOLOGY AGAM
6

AGAM PATHOLOGY
ACTIVATION OF PROTEIN KINASE C: OXIDATIVE STRESS & POLYOL PATHWAY:
7

PANCREAS IN DIABETES MELLITUS:

 Type 1 DM
 Reduction in number and size of islets.
 Leukocytic infiltrates in the islets
especially T-lymphocytes
 Insulitis showing leucocytic infiltrates
 Type 2 DM
 Amyloid deposition within islets
 An increase in number and size of islets – seen
in non-diabetic newborns of diabetic mothers
in response to the maternal hyperglycemia

DIABETIC MACROVASCULAR DISEASE:

 Persistent hyperglycemia and insulin resistance →
endothelial dysfunction → accelerated
atherosclerosis
 Cardiovascular morbidities like MI in coronary
arteries is the most common cause of death in
diabetes.
 Hyaline arteriolosclerosis - vascular lesion
associated with hypertension.

PATHOLOGY AGAM
8DIABETIC MICROANGIOPATHY:
 Diffuse thickening of basement membranes of capillaries of skin, skeletal muscle, retina,
renal glomerulonephritis, renal medulla.
 Diabetic capillaries are more leaky than normal to plasma proteins.
 Hyaline arteriosclerosis with onion skinning appearance

DIABETIC NEPHROPATHY:
 Glomerular lesions-
 capillary basement membrane thickening
 diffuse mesangial sclerosis
 nodular glomerulosclerosis / Kimmelstiel Wilson disease:
 Renal vascular lesions-Renal atherosclerosis and
arteriolosclerosis
 Pyelonephritis – Both Acute (Papillary necrosis) & Chronic pyelonephritis are common.

DIABETIC OCULAR COMPLICATIONS:

 Eye is profoundly affected in DM: Diabetes induced hyperglycemia → acquired
opacification of lens (cataract) → glaucoma → optic nerve damage.
 Non-proliferative diabetic retinopathy- thickening of retinal blood vessel basement
membrane, microaneurysms, macular edema.
 Proliferative diabetic retinopathy:
 neovascularization of the disc,
 posterior vitreous detachment
 traction detachment,
 neovascular glaucoma.

DIABETIC NEUROPATHY:
 Most common feature is distal symmetric sensorimotor neuropathy
 Pathologic findings are :
 axonal damage,
 degeneration of myelin sheaths
 Regenerating axonal clusters may be present.
 Endoneurial arterioles show
 thickening,
 hyalinization,
 intense Periodic Acid Schiff positivity of their walls
 Extensive reduplication of basement membranes.
AGAM PATHOLOGY
SHORT NOTES: 9
1. PAPILLARY CARCINOMA OF THYROID:
 Most common type of thyroid carcinoma (75-85% of cases).
 More common in females and often between the age of 25 and 50.
 Most common papillary carcinomas have Gain of function mutation involving the genes
encoding the RET/NTRK1 receptor Thyrosine Kinases or Serine/Threonine Kinase BRAF
First manifestation may be a mass in cervical lymph node ( due to metastasis and it is
called as lateral abberant thyroid)
 Most carcinomas are single nodules that move freely with thyroid gland during
swallowing.
 C/F: Hoarseness, Dysphagia, cough or Dyspnea suggests advanced disease.
 Prognosis: Good
MORPHOLOGY:
 Gross-
 Microscopic foci to nodules (upto10 cm in diameter)
 Some tumors are well circumscribed and even capsulated; while some may infiltrate
adjacent parenchyma and may be ill defined.
 Cut surface-grayish-white, hard and scar-like.
 The cut surface sometimes reveals papillary foci that points to diagnosis.
 Papillary cystadenocarcinoma- tumor transforms into cyst with papillae projecting.
 Microscopy
 Papillary pattern: Papillae composed of fibrovascular stalk, covered by a single layer to
multiple layers of cuboidal epithelial cells (Branching Pattern)
 Tumor cells: The nuclei of the papillary carcinoma cells has finely dispersed chromatin
which imparts an optically clear or empty appearance (ground glass or orphan annie
eye nuclei).
 Invasion: The tumour cells invade the capsule and intrathyroid lymphatic but invasion
of blood vessels is rare.
 Calcified circular structures called Psammoma bodies are often present within the
cores of papillae.
 There are many Histological variants of papillary carcinoma such as
 follicular variant (Lindsay Tumour)
 tall cell variant
 Diffuse sclerosing variant.

PATHOLOGY AGAM
102. MEDULLARY CARCNOMA OF THYROID:
 Less frequent (5%)
 Medullary carcinoma are neuroendocrine neoplasm derived from Para follicular cells or C
cells. Similar to C cells they secrete Calcitonin.
 In some instance it may also secrete ACTH, serotonin and vasoactive intestinal peptide
(VIP).
 They are associated with activating point mutations in RET proto onco gene.
 70% cases are sporadic.
 Remaining occurs in the setting of MEN syndrome 2A or 2B or familial tumors without
association with MEN (Familial Medullary Thyroid Carcinoma).
 Sporadic and familial cases peaks at 40s and 50s.
 Those associated with MEN syndrome occurs in younger patients.
MORPHOLOGY:
 Gross
 Unilateral solitary nodule (sporadic form) (or) bilateral and multicentric (familial form).
 Cut surface: Well-defined tumor areas ,firm to hard, gray to tan with areas of
hemorrhages and necrosis
 Microscopy
 Medullary carcinomas composed of polygonal to Spindle shaped cells, which may form
nests, trabeculae or even follicles.
 Acellular amyloid deposits derived from calcitonin polypeptides are present in stroma
in many cases.
 Multicentric C-cell hyperplasia (feature of familial medullary carcinoma) in surrounding
thyroid parenchyma is believed to be a precursor lesion in familial cases.
 Immunohistochemistry: Chromogranin + , Synaptophysin +

AGAM PATHOLOGY
3. MULTI-NODULAR GOITRE: 11
 Recurrent episodes of hyperplasia and involution combine to produce more irregular
enlargement of the thyroid, termed multi nodular goiter.
 Tumour-like enlargement of the thyroid gland and characteristic nodularity.
 Functionally, Euthyroid or may have subclinilical hyperthyroidism.

CLINICAL FEATURES:
 Mostly due to mass effects. In addition to cosmetic effects it may obstruct the airway
(Stridor), dysphagia and compression of large vessels in neck and upper thorax (superior
vena cava syndrome).
 On long term it may be develop into Toxic Multinodular Goiter, a condition called
plummer’s disease.

PATHOGENESIS:
 It is believed that multinodular goiter arises due to the variation among follicular cells in
their response to external stimuli such as trophic hormones.
 Both polyclonal and monoclonal nodules are found to co-exist in multi nodular goiter.
 Repeated cycles of hyperplasia with growth and involution with fibrosis

MORPHOLOGY:
 Gross
 Asymmetric, multiloulated and extreme enlargement (>2000 gms)
 Cardinal macroscopic features:
 Irregular nodule containing brown gelatinous colloid.
 Older lesions have areas of Hemorrhage, fibrosis, calcification and cystic change.
 Microscopy
 Colloid rich follicles lined by flattened, inactive epithelium and areas of follicular
hyperplasia.
 Incomplete encapsulation, nodularity, variable-sized follicles.
 Fibrous scarring, hemorrhages, calcification.
 Cyst formation.

PATHOLOGY AGAM
124. DIABETIC NEPHROPATHY:
 Kidneys are the prime targets of diabetes mellitus, renal failure is major cause of death in
DM patients secondary to the cardiac macrovascular causes.
 The lesions include :
 glomerular lesions
 renal vascular lesions
 pyelonephritis

GLOMERULAR LESIONS:
 Capillary basement membrane thickening- widespread thickening of the glomerular
capillary basement membrane occurs and it’s a part and parcel of diabetic
microangiopathy.
 Diffuse mesangial sclerosis- mesangial cell proliferation + basement membrane thickening
 Nodular glomerulosclerosis (kimmelstiel Wilson lesion)-the nodules are PAS positive
 Nodular lesions are frequently accompanied by prominent accumulation of hyaline
material in capillary loops (fibrin caps) or adherent to bowman capsules (capsular drops).
 both afferent and efferent hilar arterioles show hyalinosis as a consequence kidney
suffers from ischemia, develops tubular atrophy and interstitial fibrosis
 overall contraction in kidney size occurs and another lesion called Armani ebstein lesion is
also seen but not a pathognomic lesion of diabetic nephropathy

RENAL VASCULAR LESION:

 Atherosclerosis and arteriosclerosis
 The changes in arteries and arterioles of kidney are similar to that of other parts f the
body
 Hyaline arteriosclerosis affects both afferent and efferent arterioles

PYELONEPHRITIS:
 Is an acute or chronic inflammation of kidney initially involving intersititial tissue and later
tubules
 Both acute and chronic forms are common in diabetic and non-diabetic patients, but one
special pattern of pyelonephritis papillary necrosis is commonly seen among diabetics.

AGAM PATHOLOGY
5. HASHIMOTO THYROIDITIS 13
 An auto-immune disease that results in destruction of thyroid gland, gradual and
progressive thyroid failure, mostly seen in an iodine sufficient area.
 Increased risk of developing thyroid B cell lymphoma and follicular carcinoma of thyroid
(on long standing goitre)

PATHOGENESIS:
 It is an auto immune disease characterised by the presence of autoantibodies against
Thyroglobulin and Thyroid peroxidise.
 This occurs mainly due to breakdown of self-tolerance to thyroid auto antigens, resulting
in production of auto antibodies.
 Polymorphism in genes Cytotoxic T Lymphocyte Associated Antigen 4 (CTLA4) and protein
tyrosine phosphatise 22 (PTPN22) leads to Hashimoto thyroiditis

Breakdown of self-tolerance

T cell mediated cyto Thyrocyte injury Antibody dependent cell

-toxicity by CD8+ cells by ↑ TH1 cells mediated cytotoxicity (ADCC)

MORPHOLOGY:
 Gross:
 Diffuse and symmetric enlargement of thyroid gland.
 Thyroid gland is pale, yellow-tan, and firm on cross section.
 Capsule is intact.
 Microscopy:
 Destruction of thyroid parenchyma
 Hurthle cell metaplasia (eosinophilic ,granular cytoplasm )
 Mononuclear inflammatory infiltrate,small lymphocytes and plasma cells with well-
developed germinal centres are seen

CLINICAL MANIFESTATION:
 Painless enlargement of thyroid gland.
 Initially hyperthyroidism may occur followed by Gradual hypothyroidism.

PATHOLOGY AGAM
146. GRAVES DISEASE
The most common endogenous hyperthyroidism which is characterized by the triad of
 Hyperthyroidism
 Exophthalmos (due to infilrative ophthalmopathy)
 Infiltrative dermopathy
PATHOGENESIS
It is an auto immune disorder which is characterized by production of auto antibodies
against thyroid proteins (especially against TSH receptor)
 Thyroid stimulating immunoglobulin – Binds to TSH receptor and mimics its action and
therefore increased thyroid secretion.
 Thyroid growth stimulating growth immunoglobulin – Binds to TSH receptor and the
produced auto antibodies induce thyroid follicular proliferation.
 TSH binding inhibitor immunoglobulin – Binds to TSH receptor and inhibits the thyroid
function.
INFILTRATIVE OPHTHALMOPATHY:
 The orbital preadipocyte fibroblast express TSH receptor and initiate autoimmune action.
 Increased infiltration of mononuclear cells( mostly T-cell)
 Inflammatory edema, swelling of extraocular muscles
 Accumulation of extracellular matrix components
 Increased fatty deposition leads to protrusion of eyeball.(exophthalmos)
MORPHOLOGY:
 Gross:
 Symmetrically enlarged
 Intact capsule
 Soft and meat like appearance on cross section.
 Microscopy :
 Hypertrophy and hyperplasia of follicles.
 Irregular papillary folds are formed
 Colloid within follicular lumen is pale with scalloped margin.
 Lymphocytic infiltration is seen
CLINICAL MANIFESTATION
 Increased free T3 and T4 levels
 Decreased serum TSH levels.
 Dermopathy and ophthalmopathy
 Symphathetic overactivity resulting in diarrhoea, sweating, palpitations
AGAM PATHOLOGY
7. CUSHING SYNDROME 15
 Syndrome of adrenal hyperfunction; hypercortisolism.
 Pathogenesis: Caused by conditions that produce elevated glucocorticoid levels.
CAUSES OF CUSHING SYNDROME
Exogenous Endogenous

 Administration of ACTH-Dependent ACTH-Independent

exogenous
 Cushing disease due to  Adrenal adenoma
glucocorticoids
pituitary ACTH adenoma  Adrenal carcinoma
(iatrogenic).
 Ectopic ACTH due to  Macronodular hyperplasia
 Most Common
para-neoplastic  1o pigmented nodular adrenal disease
Cause
syndromes.  McCune-Albright syndrome

CUSHING DISEASE
 70% cases of endogenous hypercortisolism.
 ACTH-secreting pituitary adenoma.
 Mostly ACTH-secreting microadenoma.
 Rarely Corticotroph Cell Hyperplasia (primary or secondary to CRH-producing tumour).
 Characterized by variable degrees of nodular cortical hyperplasia in adrenal gland. Hence,
hypercortisolism.

SECRETION OF ECTOPIC ACTH

 10% of ACTH-dependent Cushing syndrome.
 More common in men in 40s and 50s.
 Mostly due to small-cell carcinoma of lung; can be caused by other ACTH-secreting
tumours also.
 Bilateral adrenal cortical hyperplasia is seen.
 Downhill course of cancers limits adrenal enlargement.

PRIMARY ADRENAL NEOPLASMS

 Pituitary adenoma (10%) and Pituitary carcinoma (5%).
 Elevated serum cortisol with low levels of ACTH.
 In case of unliteral neoplasms, uninvolved adrenal cortex undergoes atrophy due to
suppression of secretion of ACTH.

PATHOLOGY AGAM
16MACRONODULAR HYPERPLASIA
 Sporadic; Observed in adults.
 Nodules > 3mm
 Cortisol production is regulated by non-ACTH circulating hormones (Gastric Inhibitory
Peptide, LH, ADH) due to ectopic overexpression of their receptors in adrenocortical cells.
MCCUNE-ALBRIGHT SYNDROME
 Somatic mutations → Activate GNAS → Stimulatory Gsα encoded → ↑ intracellular cAMP
→ Hyperplasia
 Characterized by café-au-lait spots, polyostotic fibrous dysplasia, precocious puberty,
pituitary adenoma

MORPHOLOGY
 In pituitary: Crooke hyaline change (Ant. Pituitary ACTH-producing cells – homogenous,
pale cytoplasm due to accumulation of intermediate keratin filaments).
 In adrenal glands
1. Cortical atrophy (Exogenous glucocorticoids)
2. Diffuse hyperplasia (ACTH-dependent Cushing syndrome)
3. Macronodular or micronodular hyperplasia
4. Adenoma or carcinoma

CLINICAL COURSE
 Develops slowly.
 Early stages: Hypertension and weight gain.
 With time, truncal obesity, moon facies and accumulation of fat in the posterior neck
and back (buffalo hump) is seen.
 Hypercortisolism Selective atrophy of fast twitch muscles → ↓Muscle mass and
proximal limb weakness.
 Secondary diabetes (Hyperglycemia, glucosuria, polydipsia).
 Catabolic effects: Thin, fragile, easily bruising skin; poor wound healing; cutaneous striae
on abdomen; osteoporosis backache, increased susceptibility to fractures.
 Increased risk of infections.
 Mood swings, depression and frank psychosis.
 Hirsutism; Menstrual abnormalities.

AGAM PATHOLOGY
LAB DIAGNOSIS 17
 Based on:
 24-hour urine free cortisol concentration (increased).
 Loss of normal diurnal pattern of cortisol secretion.
 Serum ACTH and dexamethasone suppression test to determine cause.
 Pituitary Cushing Syndrome: Elevated ACTH levels; Reduced ACTH secretion on
administration of high doses of dexamethasone.
 Ectopic ACTH: Elevated ACTH; Insensitive to dexamethasone.
 Adrenal tumour: Low ACTH levels; Insensitive to dexamethasone.

8. KETONE BODIES
The insulin deficiency stimulates the lipoprotein lipase which results in the breakdown of
fatty acids. These fatty acids gets esterified to produce fatty acyl CoA which on oxidation
produce ketone bodies.
 Acetoacetic acid and ẞ-hydro butyric acid are the major ketone bodies.
 The ketone bodies contribute to ketonemia and ketonuria which leads to metabolic
ketoacidosis.

CLINICAL MANIFESTATION:
 Fruity odour and deep, Laboured breathing (Kussmaul breathing).
 Depression of Cerebral consciousness  Nausea
 Abdominal pain  Fatigue
 Coma  Vomiting

PATHOGENESIS insufficiencyNo insulin + glucagon over excess due to

hypoglycaemia
↑ Lipolysis → ↑ FFA

FFA enters mitochondria

↑ Expression of Carnitine (due to ↑ glucagon)

↑ Acetyl Co-A

Ketogenesis
PATHOLOGY AGAM
189. PHEOCHROMOCYTOMA
 Neoplasms composed of chromaffin cells, which synthesize and release catecholamines
and in some instances, peptide hormones.
 Rare cause of surgically correctable hypertension.

PATHOGENESIS
 The features of pheochromocytomas have been summarized by the “rule of 10s”.
 10% of pheochromocytomas are extra-adrenal. If they develop in extra-adrenal
paraganglia, they are called paragangliomas.
 10% of sporadic adrenal pheochromocytomas are bilateral.
 10% of adrenal pheochromocytomas are biologically malignant. Malignancy is more
common in extra-adrenal paragangliomas.
 10% of adrenal pheochromocytomas are not associated with hypertension.
 25% of individuals with pheochromocytomas and paragangliomas harbour a germline
mutation in one of at least 6 known genes. These individuals are typically younger and
more often harbour bilateral disease.
 The affected genes fall into 2 broad classes:
 Genes that enhance growth factor receptor pathway signalling (RET,
NF1{neurofibromatosis -1 associated })
 Genes that increase the activity of the transcription factor HIF-1α
 MEN 2a and MEN 2b syndromes
 Von hippel lindau syndrome.
 Other familial cases of pheochromocytoma are associated with germline mutations in
genes encoding components of the succinate dehydrogenase complex (SDHB, SDHC,
and SDHD). These mutations also lead to upregulation of HIF-1α.

MORPHOLOGY
 Range from small, circumscribed lesions confined to the adrenal to large haemorrhagic
masses.
 Larger tumours are well-demarcated by connective tissue or compressed cortical or
medullary tissue.
 Richly vascularized fibrous trabeculae within the tumour produces a lobular pattern.
 On section, cut surface of smaller pheochromocytomas are yellow while the larger ones
are haemorrhagic, necrotic and cystic.

AGAM PATHOLOGY
HISTOLOGY 19
 Tumours are composed of clusters of polygonal to spindle-shaped chromaffin cells or
chief cells that are surrounded by supporting sustentacular cells, creating small nests or
alveoli (zellballen).
 Cytoplasm has granules containing catecholamines.
 Nuclei are usually round to ovoid, with a stippled “salt and paper” chromatin.
 Immunopositivity for chromogranin and synaptophysin is seen in the chief cells.
 Peripheral sustentacular cells stain with antibodies against S-100 (a calcium binding
protein).
 There is no histologic feature that reliably predicts clinical behaviour.
 Therefore, the definitive diagnosis of malignancy in pheochromocytomas is based
exclusively on the presence of metastases. (These may involve regional lymph nodes,
liver, lung and bone).

CLINICAL COURSE
 Hypertension is observed in 90% of patients.
 2/3rds of patients with hypertension demonstrate paroxysmal episodes (abrupt,
precipitous elevation in BP, associated with tachycardia, palpitations, headache, sweating,
tremor and a sense of apprehension).
 Paroxysms may be precipitated by emotional stress, changes in posture, exercise and
palpation in the region of tumour; patients with bladder paragangliomas occasionally
precipitate a paroxysm during micturition.
 Catecholamine cardiomyopathy: Catecholamine-induced myocardial instability and
ventricular arrhythmias and is the Most common cause of death in pheochromocytoma
 In some cases, pheochromocytomas secrete other hormones such as ACTH and
somatostatin and are therefore associated with clinical features related to the secretion
of these hormones.

LAB DIAGNOSIS: Based on urinary excretion of free catecholamines and their metabolites
(VMA and metanephrines).

TREATMENT
 Isolated benign tumours are treated with surgical excision after preoperative and
intraoperative medication with adrenergic-blocking agents to prevent hypertensive crisis.
 Multifocal lesions require long term medical treatment for hypertension.

PATHOLOGY AGAM
2010. HYPERPARATHYROIDISM
 Caused by elevated parathyroid hormone (PTH) or parathyroid hormone related
peptide(PTH-RP)
 Classified into:
 Primary hyperparathyroidism: autonomous overproduction of PTH, usually due to an
adenoma or hyperplasia of parathyroid tissue.
 Secondary hyperparathyroidism: compensatory hypersecretion of PTH in response to
prolonged hypocalcemia, mostly due to chronic renal failure.
 Tertiary hyperparathyroidism: persistent hypersecretion of PTH even after the cause
of prolonged hypocalcemia is corrected (after renal transplant).

PRIMARY HYPERPARATHYROIDISM
 One of the most common endocrine disorders; important cause of hypercalcemia.
 More common in women; occurs in the 50s or later in life.

PATHOGENESIS
 Most common cause: Solitary parathyroid adenoma arising sporadically.
 Most sporadic parathyroid adenomas are monoclonal.
 There are 2 molecular defects that have an established role in the development of
sporadic adenomas:
 Cyclin D1 gene inversions leading to overexpression of cyclin D1.
 (Present in 10-20% of adenomas)

Pericentromeric Relocation of the cyclin D1 Overexpression of

inversion on gene to the 5'-flanking cyclin D1 protein
chromosome 11 region of the PTH gene

Adenoma Proliferation of cells

 MEN1 Mutations
 20-30% of sporadic parathyroid tumours have mutations in both copies of MEN1.
 Germline mutations of MEN1 are also found in patients with familial parathyroid
adenomas.

AGAM PATHOLOGY
 Familial syndromes are also a cause of primary hyperparathyroidism. 21
 Genetic syndromes associated with familial parathyroid adenomas:
 Multiple Endocrine Neoplasia (Types 1 and 2)
 Familial hypocalciuric hypercalcemia (caused by loss-of-function mutations in
parathyroid CA-SR gene, resulting in decreased sensitivity to extracellular calcium).

MORPHOLOGY
Parathyroid adenomas
 Parathyroid adenomas are almost always solitary; may lie near thyroid gland or in an
ectopic site.
 Typical parathyroid adenoma: 0.5 to 5 gm; well-circumscribed, soft, tan to reddish-brown
nodule invested by a delicate capsule; glands outside the adenoma are normal in size or
slightly shrunken due to feedback inhibition.
 Histology
 Mostly composed of uniform, polygonal chief cells with small, centrally placed nuclei.
 Few nests of larger oxyphil cells are also present.
 Bizarre and pleomorphic nuclei seen within adenoma at times (endocrine atypia).

Primary hyperplasia
 Occurs sporadically or as a component of MEN syndrome.
 Frequently asymmetric with sparing of one or two glands.
 Histology
 Chief cell hyperplasia, which may involve the glands in diffuse or multinodular
pattern.
 Sometimes, abundant water-clear cells are seen.
 Islands of oxyphils and poorly developed, delicate fibrous strands may envelope the
nodules.

Parathyroid carcinomas
 Circumscribed lesions or clearly invasive neoplasms.
 One parathyroid gland enlarged; grey-white, irregular masses.
 Histology
 Uniform; resemble normal parathyroid cells.
 Arrayed in nodular or trabecular patterns.
 Invasion of surrounding tissues and metastasis are the only reliable criteria for diagnosis.

PATHOLOGY AGAM
22Skeletal system
 Symptomatic, untreated primary hyperparathyroidism manifests with 3 interrelated
skeletal abnormalities:
 Osteoporosis
 Brown tumours
 Generalized osteitis fibrosa cystica (hallmark of severe hyperparathyroidism; also
called von Recklinghausen disease of bone; rarely encountered nowadays due to
early diagnosis and treatment).

Urinary tract
 PTH induced hypercalcemia favours nephrolithiasis and nephrocalcinosis.

CLINICAL COURSE
 Maybe asymptomatic or associated with classic clinical manifestations.

Asymptomatic Hyperparathyroidism
 Incidental diagnosis on the basis of clinically silent hypercalcemia.
 Primary hyperparathyroidism is the most common cause of asymptomatic hypercalcemia.
 Serum PTH levels are inappropriately elevated for the level of serum calcium.

Symptomatic Hyperparathyroidism
 Due to combined effects of increased PTH secretion and hypercalcemia.
 “Painful bones, renal stones, abdominal groans and psychic moans”.
 Bone disease and bone pain secondary to fractures of weakened bones and
pathological fractures are more common.
 Nephrolithiasis in 20% of newly diagnosed patients; Chronic renal insufficiency and
abnormalities in renal function lead to polyuria and polydipsia.
 GI disturbances: nausea, constipation, peptic ulcers, pancreatitis and gallstones.
 CNS alterations: Depression, lethargy, seizures.
 Weakness and fatigue.
 Aortic or mitral valve calcifications (metaststic calcifications).

AGAM PATHOLOGY
SECONDARY HYPERPARATHYROIDISM 23
 Caused by any condition that gives rise to chronic hypocalcemia, which in turn leads to
compensatory overactivity of parathyroid glands.
Pathogenesis
 Most common cause: Renal failure
 Other causes: Inadequate dietary intake of calcium, steatorrhea, Vitamin D deficiency.

Vitamin D deficiency resulting in Chronic renal

reduced suppressive effect of
Vit. D on parathyroid gland
Decreased phosphate excretion

Hyperphosphatemia

Elevated serum phosphate levels depress serum calcium levels

Increased parathyroid gland activity

Morphology
 Parathyroid glands are hyperplastic.
 Degree of glandular enlargement is not necessarily symmetric.
 Histology
 Increased number of chief cells or water-clear cells in a diffuse or multinodular
distribution.
 Fat cells are decreased in number.
 Metastatic calcification may be seen in many tissues.

Clinical Course
 Clinical features are usually dominated by the inciting chronic renal failure.
 Milder skeletal abnormalities. Control of hyperparathyroidism allows bony changes to
regress or disappear.
 Vascular calcification results in ischemic damage to skin and other organs (calciphylaxis).
 Patients respond to dietary Vit D supplements and phosphate binders.
 In a minority of patients, parathyroid activity may become autonomous and excessive
(tertiary hyperparathyroidism). Parathyroidectomy may be necessary in such patients.

PATHOLOGY AGAM
2411. MEN TYPE -1 - Also called Wermer syndrome.
 Caused by germline mutations in the MEN-1 tumour suppressor gene, which encodes a
protein called menin - a component of several different transcription factor complexes;
promotes or inhibits tumorigenesis.
Menin

Association with Mixed Lineage Partners with JunD

Leukemia (MLL) protein.
Blocks transcriptional activation by JunD
Formation of tumour promoting
transcriptional complex
Loss of tumor suppressor
interaction resulting in MEN
Leukemia

Clinical Course 3Ps (Parathyroid, Pancreas, Pituitary)

 Parathyroid:
 Most common manifestation
 Initial manifestation
 Hyperplasia and adenomas.
 Nephrolithiasis by PTH-induced hypercalcemia.
 Pancreas:
 Endocrine tumours of the pancreas – leading cause of morbidity and mortality in
patients with MEN-1.
 Most common tumour is GASTRINOMA >INSULINOMA
 Aggressive and are often metastatic.
 Multiple microadenomas scattered throughout pancreas + 1 or 2 dominant lesions.
 Most tumours fail to produce endocrine hypersecretion.
 Among those that do, Zollinger-Ellison syndrome, hypoglycemia and neurological
manifestations are common.
 Pituitary:
 Most frequent: Prolactinoma
 Sometimes, acromegaly from somatotropin-secreting tumours.
 Malignant behaviour by one or more of these endocrine tumours is the proximate cause
of death.
AGAM PATHOLOGY
 10. MEN TYPE – 2 25
Subclassified into three distinct syndromes.

MEN-2A or Sipple syndrome

 Characterized by pheochromocytoma (50%), medullary carcinoma of the thyroid (100%)
and parathyroid hyperplasia (10-20%).
 Caused by germline gain-of-function mutations in the RET proto-oncogene on
chromosome 10q11.2.
 RET proto-oncogene encoded a receptor tyrosine kinase that binds glial-derived
neurotrophic factor and other ligands in the GDNF family; transmits growth and
differentiation signals.

MEN-2B
 Due to a germline mutation leading to a single amino acid change in RET; Leads to
constitutional activation of RET in the absence of a ligand.
 Significant clinical overlap with MEN-2A.
 Medullary thyroid carcinomas – more aggressive and multifocal.
 Pheochromocytomas are seen.
 Primary hyperparathyroidism is not present.
 Neuromas or ganglioneuromas involving the skin, oral mucosa, eyes, respiratory tract and
GIT.
 Marfanoid habitus, with long axial skeletal features and hyperextensible joints seen.
 Megacolon/hirschprug disease and mucosal neuromas are other features seen in MEN2B
syndrome.

Familial medullary thyroid cancer

 Variant of MEN-2A.
 Develop at an older age; more indolent course.
 Strong predisposition to medullary thyroid cancer, but not other clinical manifestations of
MEN-2A or MEN-2B.
 Diagnosis via screening of at-risk family members in MEN-2A kindred is important; disease
can be prevented by early thyroidectomy.

PATHOLOGY AGAM
2613. DIABETIC MACROVASCULAR DISEASE:
Macrovascular complications such as myocardial infarction, renal vascular insufficiency,
and cerebro vascular accidents are the most common causes of mortality in longstanding
diabetes
 Hyperglycaemia and insulin resistance -atherosclerotic changes.
 Manifestations
 Coronary heart disease (CHD)
 Cerebrovascular disease
 Peripheral artery disease (PAD)
 Mönckeberg arteriosclerosis (medial calcific sclerosis = variant of PAD) – PAD
diagnostic tools unreliable
 Endothelial dysfunction and dyslipidemia (increased LDL and decreased HDL cholesterol)
predisposes to atherosclerosis.
 Hallmark of diabetes macrovascular disease -accelerated atherosclerosis.
 Involves aorta and large and medium sized arteries.
 Myocardial infarction- atherosclerosis in coronary arteries in diabetes.
 Gangrene of lower extremities -peripheral vascular atherosclerosis.
 More common in patients with type 2 diabetes

PATHOGENESIS:
 Releasing of free fatty acids (FFAs) and inflammatory mediators, adipose tissue alters lipid
metabolism.
 FFAs bind to toll-like receptors, PI3-kinase and Akt activity are downregulated.
 Reduced expression ofGLUT-4, decreased response to insulin binding.
 Inactivation of endothelial NO synthase.
 Increased ROS production -endothelial dysfunction and atherosclerotic changes.
 Downregulation of PI3-kinase and Akt activates NF-Kb, triggers transcription of
inflammatory molecules.
 Hyaline arteriosclerosis, vascular lesion in hypertension more severe in diabetes.
 Amorphous, hyaline thickening of wall of arteries, causes narrowing of lumen.
 Thrombosis of atherosclerotic plaque rupture occludes the blood vessels supplying brain,
causes stroke.

AGAM PATHOLOGY
14. FEATURES OF DIABETIC RETINOPATHY: 27
 The most common cause of visual impairment and blindness in patients aged 25–74 years
 Retinal vasculopathy of diabetes mellitus
 Symptoms:
 Asymptomatic until very late stages of disease
 Visual impairment
 Progression to blindness

NON-PROLIFERATIVE DIABETIC RETINOPATHY:

 Thickening of basement membrane of retinal blood vessels.
 Number of pericytes decreased.
 Micro aneurysms
 Macular edema, exudates accumulate in outer plexiform layer.
 Intravenous injection of fluorescein used to visualise vascular incompetence and vascular
micro-occlusion.

PROLIFERATIVE DIABETIC RETINOPATHY:

 Neovascularisation of optic disc.
 Newly formed vessels breaches the internal limiting membrane of retina.
 Web of newly formed vessels- neovascular membrane composed of angiogenic vessels
and glial stroma.
 Posterior vitreous detachment.
 Disruption of orientation of retinal photoreceptors and producing visual distortion.
 Traction retinal detachment
 Contraction of iris neovascular membrane- adhesion between iris and trabecular
meshwork.
 Neovascular glaucoma.

PATHOLOGY AGAM
2815. PROLACTINOMA:

 Prolactin secreting lactotroph adenomas are the most frequent type of hyperfunctioning
pituitary adenoma, accounting for about 30% of all clinically recognized cases.
 Small micro adenomas to large, expansile tumors.
 Types:
 Microadenoma (size-less than 1cm)
 Macroadenoma (size-more than 8mm)

MORPHOLOGY:
 Chromophobic cells with juxtanuclear localization of transcription factor PIT-1 - sparsely
granulated lactotroph adenoma.
 Diffuse cytoplasmic PIT-1 expression localization - densely granulated lactotroph
adenoma.
 Dystrophic calcification - pituitary stone.

CLINICAL FEATURES:
 Prolactinemia causes amenorrhea, galactorrhea, loss of libido and infertility.
 Hyperprolactinemia (from causes other than prolactin-secreting pituitary adenomas)
 Prolactinoma
 Pregnancy
 Lactation
 Lactotroph hyperplasia- loss of dopamine mediated inhibition of Prolactin secretion.
 Pituitary adenoma
 Damage of dopaminergic neurons of hypothalamus and damage to pituitary stalk.
 Renal failure and hypothyroidism.

TREATMENT:
 Surgery
 Bromocriptine and Cabergoline -a dopamine receptor agonist

AGAM PATHOLOGY
SHORT ANSWERS: 29
1. FEATURES OF ADDISONS DISEASE:
 Chronic adrenocortical insufficiency due to progressive destruction of adrenal cortex
 progressive weakness and easy fatigability
 GI disturbances - anorexia, nausea, vomiting, weight loss, and diarrhea
 Hyperpigmentation of the skin and mucosa with sparring of tongue, esp. sun- exposed
areas and at pressure points, such as the neck, elbows, knees, and knuckles due to
elevated levels of pro-opiomelanocortin (POMC)
 Potassium retention and sodium loss, with consequent hyperkalemia, hyponatremia,
volume depletion, and hypotension due to decreased mineralocorticoid activity
 Hypoglycemia due to glucocorticoid deficiency
 Infections, trauma, or surgical procedures in such patients can precipitate an acute
adrenal crisis

2. HURTHLE CELLS
 Large, polygonal epithelial cell with eosinophilic granular cytoplasm as a result of
numerous altered mitochondria
 In fine-needle aspiration biopsy samples, the presence of Hürthle cells in
conjunction with a heterogeneous population of lymphocytes is characteristic of
Hashimoto thyroiditis.
 Thyroid follicles are atrophic and are lined in many areas by epithelial cells distinguished
by the presence of abundant eosinophilic, granular cytoplasm, termed Hurthle cells.
 Metaplastic response of the normally low cuboidal follicular epithelium to ongoing injury
 Hurthle cells + heterogeneous population of lymphocytes → Hashimoto thyroiditis

3. PSAMOMMA BODIES:
 They are laminated, concentric spherules with dystrophic calcification.
 Example:
 Papillary carcinoma of thyroid
 Somatostatinoma.
 Meningioma
 Malignant mesothelioma
 Ovarian Serous papillary cystadenocarcinoma
 Prolactinoma

PATHOLOGY AGAM
304. DIFFERENCES BETWEEN ADULT AND CHILDHOOD CRANIPHARYNGIOMA
CRANIOPHARYNGIOMA CHILDHOOD ADULT
Occurrence 90% 10%
Location Suprasellar and sellar Only suprasellar
More common in Males > females Males = females
Histologic variant Adamantinomatous type Papillary type
Consistency Cystic >>> solid Solid
Machinery oil appearance
Wet keratin nodules Present Absent
Calcifications Present Absent

5. LAB DIAGNOSIS OF DM:

 Fasting plasma glucose >126Mg/dl
 Random plasma glucose > 200mg/dl
 2hr plasma glucose >200Mg/dl during OGTT with loading dose of 75gms glucose
 Glycated Hb (hba1c)- 5.7%-6.4%

6. TYPES OF THYROIDITIS
Most common and clinically significant subtypes:
 Hashimoto thyroiditis,
 Granulomatous (de Quervain) thyroiditis
 Subacute lymphocytic thyroiditis.
 Fibrosing thyroiditis (reidel’s thyroididtis)
 Silent / Postpartum thyroiditis
Classification on the basis of duration:
 Acute thyroiditis
 Bacterial -Staphylococcus, Streptococcus
 Fungal -Aspergillus, Histoplasma
 Radiation injury
 Subacute thyroiditis
 Subacute granulomatous - giant cell thyroiditis, viral thyroiditis
 Subacute lymphocytic -postpartum, silent thyroiditis
 Tuberculous thyroiditis
 Chronic thyroiditis
 Autoimmune -Hashimoto’s, chronic lymphocytic thyroiditis
 Riedel’s -invasive fibrous thyroiditis
AGAM PATHOLOGY
7. CLASSIFICATION OF THYROID NEOPLASM: 31
The major subtype of thyroid carcinomas are,
 Papillary carcinoma (>85%)
 Follicular carcinoma (5% to 15%)
 Anaplastic (undifferentiated) carcinoma (<5%)
 Medullary carcinoma (5%)

8. COLLOID GOITER
 In simple goiter, the entire gland is enlarged and the follicles are filled with colloid. So the
term has been applied to this condition.
 Phases during simple goiter:
 Hyperplastic phase: the thyroid gland is diffusely and symmetrically enlarged. The
follicles are lined by crowded columnar cells.
 Colloid phase: Iodine level increases or the demand for thyroid hormone decreases,
the epithelium involutes to form an enlarged, colloid-rich gland.
 Cut Surface - brown, somewhat glassy, and translucent
 Histologically - epithelium is flattened and cuboidal, colloid is abundant during periods of
involution

9. CRETENISM
 Cretinism refers to hypothyroidism which occurs in infancy or early childhood
 Causes:
 Maternal thyroid deficieny
 Congenital Iodine deficiency – most common cause
 Genetic defects in hormone biosynthesis (rarely).
 Clinical manifestation :
 Impaired development of skeletal system and central nervous system.
 Mental retardation
 DisproportionateShort stature (upper segment not equal to lower segment)
 Coarse facial features (wide eyes, protruding tongue)
 Loss of reproductive functions

PATHOLOGY AGAM
32UPDATES
1. DIFFERENT TRANSCRIPTION FACTORS IN DIFFERENT PITUITARY TUMORS:
 Somatotrophs, mammosomatotrophs, lactotrophs, and thyrotrophs are derived from a
common precursor expressing the transcription factor PIT-1 (lactrotrophs express the
alpha subunit of the estrogen receptor, ERa).
 Corticotrophs are derived from progenitor cells expressing the transcription factor TPIT
(T-box protein 19 or Tbx19),
 Gonadotrophs are derived from precursor cells expressing steroidogenic factor-1 (SF-1)
and GATA-2.
 The expression of these lineage-specific transcription factors is retained in pituitary
adenomas and is used to classify these tumors.

2. ROLE OF USP8:
 Activating mutations of ubiquitin-specific protease 8 (USP8) also occur in 30% to 60% of
corticotroph adenomas.
 The encoded protein is an enzyme that removes ubiquitin residues from proteins like
epidermal growth factor receptor (EGFR), protecting them from proteasome dependent
degradation.
 Aberrant activation of USP8 enhances the activity of EGFR and other pro-growth
signaling pathways in pituitary adenomas.

3. DIFFERENCE BETWEEN MS ADENOMA & LS ADENOMA:

 Bihormonal mammo somatotroph adenomas synthesize GH and prolactin in the same
cell
 Morphologically, most resemble densely granulated somatotroph adenomas, but have
immune histochemical reactivity for prolactin and GH.
 Mixed somatotroph - lactotroph adenomas have GH and prolactin expression in different
cells.

4. CROOKE CELL ADENOMA:

 Nuclear TPIT + in the corticotroph adenoma, consistent with corticotroph lineage.
 A third uncommon variant, called Crooke cell adenoma, is characterized by ring-like
deposition of cytokeratin called Crooke change.
 This variant has an aggressive natural history compared with other subtypes of
corticotroph adenomas.

AGAM PATHOLOGY
5. PATHOLOGY OF PAPILLARY CARCINOMAS 33
 Conventional papillary thyroid carcinomas have
two defining genetic abnormalities:
 translocations that result in gene fusions of
RET or NTRK
 point mutations in BRAF
 Between 50% and 80% of conventional PTCs
harbor gain-of-function mutations in the BRAF
gene, most commonly a valine-to-glutamate
change in codon 600 (BRAFv600E).
 BRAF encodes a serine/threonine kinase that lies
downstream of receptor tyrosine kinases in
growth factor signaling pathways.
 In a subtype of conventional PTCs, known as "tall
cell variant”, BRAF mutations are virtually a
diagnostic sine qua non.
 The presence of BRAF mutations in conventional
PTCs is associated with ↓ expression of thyroid
differentiation markers (such as thyroglobulin and thyroid peroxidase) and may be
associated with higher risk of extra thyroidal extension and recurrence.
 Neoplasms with RAS mutations retain expression of thyroid differentiation factors (eg
thyroglobulin, thyroid peroxidase), which may contribute to their follicular growth
pattern.
 Some noninvasive follicular thyroid neoplasms with papillary- like nuclear features and
invasive encapsulated follicular variant of PTC (up to one-third in some series) also harbor
PAX8-PPARG fusion genes, which are almost never seen in poorly differentiated or
anaplastic carcinomas.

6. PATHOLOGY OF CRANIOPHARYNGIOMA
 Adamantinomatous craniopharyngloma is characterized by recurrent mutations of the
CINNBI (B-catenin) gene, which leads to aberrant activation of the Wnt signaling pathway.
 Papillary craniopharyngiomas is characterizecd by activating mutations of the BRAF
oncogene at codon 600.
 The identification of BRAF V600E mutations has therapeutic implications due to
availability of small-molecule BRAF inhibitor drugs that inhibit the BRAF serine-threonine
kinase.
PATHOLOGY AGAM
347. ROLE OF DICER IN PITUITARY BLASTOMA:
 Pituitary blastoma occurs in children (typically younger than 2 years of age) who carry
germline mutations of DICER1, the gene encoding a micro RNA processing protein.
 Morphologically, these tumors are composed of immature "blastema-like" cells (so-called
"small round blue cells") and rosette-like formations resembling the primitive Rathke
epithelium from which the pituitary develops.
 Pituitary blastoma presents with signs and symptoms of Cushing disease.
 These children also develop primitive "blastema-like" neoplasms in other organs, most
commonly pleuropulmonary blastoma.

8. LIVER STREATOSIS IN DM:

 High circulating levels of FFAs may result in the accumulation of excess fat (steatosis) in
hepatocytes.
 This form of nonalcoholic fatty liver disease (NAFLD) ranges in severity from hepatic
steatosis without evidence of liver injury to nonalcoholic steatohepatitis (NASH) with
evidence of inflammation and hepatocyte injury with or without fibrosis.
 NAFLD is common in those with metabolic syndrome and T2DM, an association that cuts
both ways.
 NAFLD promotes the development of T2D, which in turn increases the risk of developing
the more severe forms of NAFLD.

AGAM PATHOLOGY
9. CORTICAL CARCINOMA PATHOGENESIS 35
 Cortical carcinomas produce more marked hypercortisolism than adenomas/hyperplasias.
 Molecular features of adrenocortical carcinomas include recurrent activating mutations of
beta-catenin (CTNNBT) and inactivating mutations of TP53, MEN1, and PRKAR1A

10. ACTG INDEPENDENT B/L HYPERPLASIA:

 ACTH-independent bilateral hyperplasia can also be micronodular (<10 mm in size), and
these arise mainly in two settings:
 primary pigmented nodular adrenocortical disease (or)
 As part of the so-called Carney complex, a multisystem syndrome resulting in both
endocrine and non-endocrine neoplasms.
 Both are most commonly associated with mutations of the regulatory subunit of cAMP-
dependent protein kinase (encoded by the PRKARIA gene), which, like activating GNAS
mutations, act by increasing intracellular CAMP levels.

PATHOLOGY AGAM
3611. ADRENOCORTICAL NEOPLASM PATHOLOGY
 Up to 50% harbor somatic mutations of KCNJ5, which encodes a potassium ion channel
protein known as GIRKA expressed in zona glomerulosa cells.
 GIRK4 mutations result in loss of selectivity of the channel to potassium ions, leading to
nonspecific influx of sodium, and subsequent calcium-dependent activation of the
aldosterone synthase enzyme.
 These include mutations in CACNATH, which encodes a calcium channel, and ATPIA1,
which encodes a sodium/potassium exchanging ATPase.
 The functional consequence of these mutations is to maintain cells in a chronic state of
depolarization resulting in autonomous aldosterone synthesis.

12. FAMILIAL HYPERALDOSTERONISM TYPES:

 Four distinct subtypes (FH-I to FH-IV) have been described, of which FH-I, or
glucocorticoid-remediable aldosteronism, is the most common.
 The remaining three Subtypes of FH are rare, with FH-III being ascribed to germline KCNJ5
mutations and FH-IV to germline CACNA1H mutations, two genes that are also somatically
mutated in subsets of aldosterone-secreting adenomas.

13. PSEUDOHYPOXIA PHENOTYPE:

 Patients with germline mutations are typically tumors younger at presentation than those
with sporadic tumors and more often have bilateral tumors.
 The affected genes tall into two broad classes, those that enhance growth factor receptor
pathway signaling (eg, RET, NF1) and those that increase the activity and stability of two
hypoxia -induced transcription factors, HIF-1αand HIF-2α (thus, creating a so-called
pseudo hypoxia phenotype).
 EPAST encodes HIF-2α, and gain-of-function mutations are found in individuals with the
"polycythemia paraganglioma syndrome" that stabilize HIF-2α by mutating amino acid
residues that are required for its degradation.
 Other familial cases of pheochromocytoma are associated with germline mutations in
genes encoding several components of the succinate dehydrogenase complex (most
commonly, SDHB, SDHC, and SDHD).
 This complex is involved in mitochondrial electron transport and oxygen sensing, and it is
believed that these mutations also lead to up-regulation of HIF protein, recapitulating
pseudohypoxia.

AGAM PATHOLOGY
14. MEN 4: 37
 MEN 4 patients have clinical features that phenocopy MEN-1 patients, but in contrast to
that syndrome, harbor germline CDKNIB mutations, leading to reduced levels of the cell-
cycle checkpoint protein, p27.
 MEN 4 was also called MEN X (#xmen #marvel)

15. PRECURSOR LESIONS:

 Papillary microcarcinoma is a precursor to conventional PTC
 Noninvasive thyroid neoplasma with papillary like nuclear features as a precursor to
invasive encapsulated follicular variant PTC
 Nonfunctioning follicular adenoma is a precursor to follicular carcinoma
 Most poorly differentiated and anaplastic (undifferentiated) carcinomas arise from well-
differentiated PTC or follicular carcinomas, through acquisition of additional mutations

16. PanNET:
 Like other endocrine neoplasms, it is difficult to predict the behavior of a PanNET based
on its light microscopic appearance alone.
 The tumors with a higher proliferation index (measured as 3% or more neoplastic nuclei
expressing Ki-67) can have an aggressive biological potential.
 PanNETs with DAXX or ATRX mutations demonstrate a phenomenon known as
"alternative lengthening of telomeres (ALT), which allows telomeres to be maintained in
neoplastic cells that do not express telomerase.

17. SPARSELY GRANULATED SOMATOTROPH

 Sparsely granulated somatotroph adenomas tend to have a more aggressive course than
densely granulated adenomas.
 Sparsely granulated somatotroph may be less responsive to somatostatin analogues.
 Thus, accurate subtyping of somatotroph adenomas is of prognostic importance.

18. THYROTROPHS
 Thyrotroph (TSH-producing) adenomas are uncommon accounting for approximately 1%
of pituitary adenomas.
 Thyrotrophs are a rare cause of hyperthyroidism.
 Thyrotrophs, due to their shared lineage with lactotroph and somatotroph adenomas,
these tumors also express PIT-1.

PATHOLOGY AGAM
3819. CROOKE HYALINE CHANGE
 The most common alteration, resulting from high levels of endogenous or exogenous
glucocorticoids, is termed Crooke hyaline change.
 In Crooke hyaline change condition, the normal granular, basophilic cytoplasm of the
ACTH-producing cells in the anterior pituitary becomes homogeneous and paler.
 Alteration in Crooke hyaline change is the result of the accumulation of intermediate
keratin filaments in the cytoplasm, a finding that is also seen in "Crooke cell" corticotroph
adenoma.

20. MENIN
 Dichotomy in menin function is best exemplified in the interactions of menin with two
oncogenic transcription factors- Jun D and KMT2A (previously known as MLL), a
chromatin-modifying histone n methyl transferase.
 The association of wild-type menin with KMT2A leads to the formation of a tumor-
promoting transcriptional complex in a subset of acute leukemias through up regulated
expression of HOX genes.

21. FOLLICULAR VARIANTS OF PAPILLARY CARCINOMA THYROID

 Encapsulated follicular variants of papilary thyroid cancer without capsular invasion are
designated noninvasive follicular thyroid carcinoma with papillary-like nuclear features
and have a very low risk of recurrence or metastasis
 Invasive tumors are referred to as invasive encapsulated follcular variant of papillary
thyroid carcinoma.

22. CDC73
 CDC73 encodes a protein known as parafibromin,
 It is mutated in ~70% of sporadic para- thyroid carcinomas, but rarely in adenomas.
 Germline mutations of CDC73 lead to a rare syndrome known as hyperparathyroidism-jaw
tumor syndrome, which includes parathyroid carcinomas and ossifying jaw tumors as part
of the disease spectrum.

AGAM PATHOLOGY
23. ONE LINERS 39
 FH-I stems from a rearrangement in chr. 8 that places CYP1182 (the gene encoding
aldosterone synthase, the enzyme that carries out the last step in aldosterone synthesis).
 APS-4 is a rare condition characterized by adrenalitis plus other autoimmune phenomena
(eg, gastritis , vitiligo , alopecia, pernicious anemia) but neither thyroiditis nor T1D.
 Adrenoleukodystrophy is caused by mutations of the ATP-binding cassette, subfamily D,
potassium retention and sodium loss, with consequent member 1 (ABCD1) gene.
 Congenital adrenal hypoplasia is a rare X-linked disease caused by mutations in the
NROB1 gene encoding DAX1, a transcription factor implicated in adrenal development.
 Mitotic activity is generally inconspicuous, with a Ki-67 labeling index less than 5% (in
contrast to adrenocortical carcinomas).
 Adrenocortical lesions both adenomas and carcinomas express steroidogenic factor-I (SF-
I) and inhibin-alpha.
 Syndrome- Polycythema paraganglioma syndrome,
 Extra renal neuroendocrine tumour
 Gene-EPAS1
 Associated lesion Pheochromocytoma, paraganglioma
 Other features- Polycythemia.
 Rarely, diabetes insipidus has a genetic basis, either because of autosomal dominant
mutations of the arginine vasopressin (AVP) gene, or mutations of arginine vasopressin
receptor type 2 (AVPR2), an X-linked condition that usually presents in young boys.
 Approximately one-third of toxic adenomas harbor activating mutations of enhancer of
zeste, homolog 1 (EZHT), which encodes a histone methyltransferase that functions as an
epigenetic regulator of gene expression.
 Bilateral macronodular adrenal hyperplasia (BMAH), the nodules are usually greater than
10 mm in diameter. Familial forms associated with germline mutations in the armadillo
repeat containing 5 (ARMC5) gene, a putative tumor suppressor gene, have been
reported.

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PATHOLOGY AGAM