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• Pancreatic endocrine neoplasms are often termed "islet cell tumors" because of their origin.
• These tumors typically show monotonous cells with minimal variation and mitotic activity.
• Amyloid deposition is a common characteristic, particularly in insulinomas.
• Clinically, insulinomas lead to episodic hypoglycemia in patients.
• Hypoglycemia can result from various conditions, including abnormal insulin sensitivity, liver disease, glycogen storage diseases, or insulin production by fibromas/fibrosarcomas.
• Self-injection of insulin should also be considered as a potential cause.

Zollinger-Ellison Syndrome (Gastrinoma)

• Results from marked hypersecretion of gastrin, usually from gastrin-producing tumors.
• Gastrinomas can arise in the duodenum, peripancreatic tissues, or the pancreas.
• This condition leads to excessive gastric acid secretion, causing peptic ulceration, often multiple, in the duodenum and stomach.
• Ulcers can be resistant to therapy and occur in unusual locations like the jejunum.
• Zollinger and Ellison identified the link between pancreatic islet cell lesions, gastric acid hypersecretion, and severe peptic ulceration.
• Approximately 50% of gastrin-producing tumors are locally invasive or already metastasized at diagnosis.
• Gastrinomas co-occur with other endocrine tumors in 25% of patients, as part of the MEN-I syndrome.
• MEN-I-associated gastrinomas are often multifocal, while sporadic gastrinomas are usually single.
• Gastrin-producing tumors tend to be histologically bland and rarely show anaplasia.
• Treatment includes controlling gastric acid secretion with H+K+-ATPase inhibitors and excising the neoplasm.
• Complete resection can eliminate the syndrome, but hepatic metastases shorten life expectancy, leading to liver failure within 10 years.
• Glucagonomas are associated with high serum glucagon levels.
• Leads to mild diabetes mellitus, necrolytic migratory erythema (skin rash), and anemia, mainly in postmenopausal women.
• Somatostatinomas are associated with diabetes mellitus, cholelithiasis, steatorrhea, and hypochlorhydria.
• These can be difficult to locate preoperatively, diagnosis requires high plasma somatostatin.

VIPoma

• Induces watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome).
• It's caused by vasoactive intestinal peptide (VIP) release from the tumor.
• Some tumors are locally invasive and metastatic.
• A VIP assay should be done on all patients with severe secretory diarrhea.
• Neural crest tumors like neuroblastomas, ganglioneuroblastomas, and pheochromocytomas can associate with VIPoma.
• Pancreatic carcinoid tumors producing serotonin and an atypical carcinoid syndrome are rare.
• Pancreatic polypeptide-secreting endocrine tumors may not be symptomatic even with high plasma levels. Additional hormones: ACTH, MSH, ADH, serotonin, and norepinephrine.
• These multihormonal tumors are distinguished from MEN syndromes.
• MEN syndromes involve multiple hormones produced by tumors in different glands.

Adrenal Glands

• The adrenal glands are paired endocrine organs.
• They consist of a cortex and a medulla, differing in development, structure, and function.
• The adrenal cortex consists of three zones: glomerulosa, reticularis, and fasciculata.
• Synthesizes glucocorticoids, mineralocorticoids, and sex steroids.
• The adrenal medulla is composed of chromaffin cells.
• Synthesizes and releases catecholamines, mainly epinephrine, allowing rapid environmental adaptations. Adrenal Cortex.
• Diseases are divided into those involving hyperfunction and hypofunction.

Adrenocortical Hyperfunction (Hyperadrenalism)

• Syndromes are caused by overproduction of adrenal cortex hormones. Includes Cushing syndrome (excess cortisol).
• Also includes hyperaldosteronism (excess aldosterone).
• Also includes adrenogenital/virilizing syndromes (excess androgens).

Hypercortisolism (Cushing Syndrome)

• It results from conditions raising glucocorticoid levels.
• Classified into exogenous (iatrogenic) and endogenous causes.
• Most cases are from exogenous glucocorticoid administration.
• ACTH-secreting pituitary adenomas account for 60-70% of endogenous cases (Cushing disease), affecting women more often.
• Usually caused by a pituitary microadenoma.
• Corticotroph cell hyperplasia may be primary, or from hypothalamic CRH-producing tumor.
• Adrenal glands in Cushing disease show nodular cortical hyperplasia, caused by high ACTH levels.
• Cortical hyperplasia causes hypercortisolism.
• Ectopic ACTH secretion by nonpituitary tumors makes up about 5-10% of ACTH-dependent Cushing syndrome cases.
• Often caused by small-cell lung carcinoma, but can also involve other neoplasms.
• Neuroendocrine neoplasms may produce ectopic CRH & cause ACTH secretion and hypercortisolism.
• Adrenal glands experience bilateral cortical hyperplasia, but rapid deterioration limits adrenal enlargement.
• More common in men, usually in their 40s and 50s.
• Primary adrenal neoplasms like adenoma (~10-20%) & carcinoma (~5-7%) are common causes of ACTH-independent Cushing syndrome.
• The biochemical indicator is elevated cortisol with low levels of ACTH.
• Cortical carcinomas tend to produce a greater hypercortisolism than adenomas or hyperplasias.
• Recent gene studies have identified molecular features of adrenocortical carcinomas & mutations in beta-catenin (CTNNB1)& inactivating mutations of TP53, MEN1 & PRKAR1A. Shared Molecular Mechanisms.
• PRKAR1A mutations are in both adenomas and carcinomas, as well as nodular hyperplasia.
• Independent Hyperplasia: Less common than ACTH-dependent, Macronodular type (BMAH), nodules >10mm, Familial forms- mutations ARMC5 Tumour supressor, Spordic-BMAH harbor germline ARMC5mutations.
• Cortisol production is regulated by hormones other than ACTH due to ectopic hormones on the hyperplastic adrenocortical cells. Including gastric inhibitory peptide (GIP), LH & ADH (vasopressin). Subset of BMAH arises seting with McCune Albright syndrome- Ga causes hyperplasia increases intracellular levels.
• Micronodular: small and these arise mainly, primary pignemnt nodular adrenocortical disease/Carney complex- GNAS mutatuions. All mutations increase intracellular cAMP Levles.

Morphology of Cushing Syndrome

• Main lesions are in the pituitary and adrenal glands.
• High glucocorticoids, which, result in "Crooke hyaline change" (basophilic cytoplasm of ACTH-producing cells, and becomes pale.
• This is intermediate kertatin filaments & seen in cell Corticotroph Adenoma.
• Cortical atophy
• Diffuse hyperplasia
• Macronodular/micronodular hyperplasia Most Common- Nodular Hyperplasis. Exogenous Glucocorticoids- ACTH suppression results in bi-lateral atrophy, Zonae fasciculta/reticularis. In contrast endogenous glucocorticoids results in hyperplasis and neoplasms.

Diffuse Hyperplasia

• Found in the Individuals with ACTH dependent cushing syndrome Enlargement of both glands. Thickness varries, and Nodular- Less prononuced than independent nodular hyperplasia. The microscope shows expanded lipid- poor cells of Zona Reticularis (compact, eosinophilic surrounding vacuolated lipid outer cells.
• nodules composed of lipid rich cells in Zona Fasciculata.

MacroNodular Hyperplasia

• Entire Adrenals replaced by prominent nodules- lipid poor and cells.

MicroNodular Hyperplasia

• Composed 1-3mm, darkly pigmented/ black/brown micronodules- intervening area. pigment= lipofuscin.

Neoplasms

• Benign or malignant
• functional Adenomas
• Morphogrically Not Distnct.

Functioning Adenomas

• In women 30s - 50s- cortex/ contralateral adrenal cortex is atrophic as there is no longer ACTH due to cortisol

Clinical Features

• Early- hypertension/ weight gain.
• Trunk obesity/ moon faces- buffalo hump.
• decrease muscle mass/proximal limbs due to type 2 atrophy myofibers.

Glucongenesis and Inhibition

• glucose uptake by cells causes hyperglycaemia, glucosurmia.

• Catabolic leads Collagens loss, wounds are Poor, bone loss leads to - osteoporosis/ infection

• Diagnosis, based on :

  • 24-h urine free-cortisol- more
  • no Dirunal concentration (normal normal hormone)

Classification of Cushing Syndrome

• dependant
• independant

primary hyperaldosteronism

• elevated from gland= hypertension supressed rening- Decreases system plasma
• Adenoma (most)- high K
• Glucocorticoid suppress
• secondary low
• Renal artery low perfusion volume. Morphology Almost alone, <2cm more oftern on Right. and buried= cant identify

Hyperplasia

• wedge shaped centre- centre adenomas must be carefully excluded casues from hyperaldosteronism.
• high prevelance- >10 non selective
• low - hypertension- increase vasopresssion
• hyperlasia/ low cortisol from kidneys.

Syndormes of Adrenal Excess = Adrenal Excess. Virilation/females caused by gonatal issues from several adrenal disorders = the androgren formaiton regulaltred / excess syndrome.

• Excess of androgen
• corticolneapslasm Congenital Adrenal Hyperplasia caused by enz deficiencies

Morphology

• Adrenals are hyperplastic increased atch cortex with

21-hydroxylase deficiency 21-

Salt wasting

• not convert progsterone to deoxycoster

2 types

• Simple virtilizling genital ambig
• Nonclassic

In All: the adrenals (Bilateral = Thick medulla - increased. This the cortical is thickend. prolified are lip depleted

Adrenogenital Sytndromes (Arenal excess/ corticial

• Decrease cortisol compensatory
• High acth- adrogenizing leads in
• females genital in - oligo
• Males- large gentitils (precocious) - oligo
• CAH be suspicous- with genetials

Medulla - high gluco - required- Catechalomine - synthesis (epinephrine and Norepiphrine

Hypofunction- Adrenocortical

• Primamry- destruction/ disease

• Secondary- decreased stimulates - ACTH Three

• Crisis- stress needs steoid out puts can not function -Addison (insufficient )

• Secondary

Causes

• Adrenal insuff
• Autoimmune: AIRE1

TB AIIDS - Kopsosi Meta -lung and breast Genetic adreno leukemia by Adreno + mutation ABCD)

Loss cortex is common is AI

TB Gland= irregulary.

Hypodermia. GIST - distressance/ vomits/diarhea loss. High Acth Secondary- low acth= similar .

Pheocrhromacytomas

• Tumors - chromatin- Catecholmines , 10% rules
• Metastis

MEn Sybdptmes Multiple Endocrine Sybdpmes

Men is a group. multpme.

Hereditary and Cancer genetics

• 20 and tumors. MUltpoe and
• 2 men = high aggression

2a- sipple

• Pheno - Med thryroid - and parathyroidism mutple caliciolin.40- 50
• 2- b= clinical over - lap throid / no hormo= germinal

MEN"1 - - kmin - supressor not in the cell . and is now on gen. The Dominant.

Melantonin Gland

• Pineal 3

The NEapsoms. The Pineoblamos:

• differenitation= The Men Sybdmros:
• are group or inheritad diesases.
• reasultung Proflerastive.Lesions of Mutple Endocrine Organs: in the same ways Multpe Endocrine Neaplasima types the Men group mutplea enocrin = and types mutple organ