Pathology of Endocrine Glands - III Adrenals Jaroslava Dušková Inst. Pathol. 1st Med. Fac. Charles Univ. Prague Endocrine Pancreas

Adrenals u cortex –definitive –fetal (90% regression by 6 months of age) u neonate 8g (3,5kg) 0,002 u healthy adult 9g (70kg) 0,0001 – zones G,F,R 20x u medulla

normhypoplasia congenitalis

Adrenals - syndromes u hypofunction - panhypocorticalism – acute – chronic – Adison – peripheral – central u hyperfunction – AGS – Cushing – hyperaldosteronism Conn, Bartter

m Adison: peripheral central

Adrenals - syndromes u hypofunction - panhypocorticalismus – acute – chronic – Adison – periferic – central u hyperfunction – Cushing – hyperaldosteronism Conn, Bartter – AGS

WHO Clasification of Tumours of the Adrenal Gland (WHO 2004) v Adrenal cortical tumours v Adrenal cortical carcinoma v Adrenal cortical adenoma v Adrenal medullary tumours v malignant phaeochromocytoma v benign phaeochromocytoma v composite phaeochromocytoma/paraganglioma v Extra-adrenal paraganglioma v carotid body v jugulotympanic v vagal v laryngeal v aorticopulmonary v cauda equina…..

Adrenal Cortical Carcinoma M8370/3 u two peaks of incidence – middle to old age & preschool children u mostly hormonally active – androgens only –androgens + glucocorticoids –androgens + glucocorticoids+mineralocorticoids –estrogens (exceptional)

Adrenal Cortical Carcinoma M8370/3 Malignancy criteria u high nuclear grade (Fuhrman) u mitoses incl. atypical u diffuse architecture u necrosis u invasion into veins, capsule

m. Cushing periph.hypothalamic

m. Cushing paraneopl.15% pituitary C.>50%

Androgen overproductionAGS

WHO Clasification of Tumours of the Adrenal Gland (WHO 2004) v Adrenal cortical tumours v Adrenal cortical carcinoma v Adrenal cortical adenoma v Adrenal medullary tumours v malignant phaeochromocytoma v benign phaeochromocytoma v composite phaeochromocytoma/paraganglioma v Extra-adrenal paraganglioma v carotid body v jugulotympanic v vagal v laryngeal v aorticopulmonary v cauda equina…..

Pheochromocytoma Def.: benign tumour deriving from chromaffin cells (intraadrenal paraganglioma) Clin.: resistence, hypertension Macro: whittish, solid, regressive changes Micro: solid alveolar (Zellballen) Behaviour: benign (15% bilateral, 10% children,10% malignant) part of MEN II and von Hippel-Lindau disease

Biology Behaviour of Pheochromocytoma u Diffuse growth u Central necroses u High cellularity u Monotonous u Fusocellular u Mitoses >3/10 HPF u Atypical mitoses u Invasion into fatty tissue u Invasion to vessels u Transcapsular invasion u Pleomorphic cells u Nuclear hyperchromasia Thompson L.D.R.: Phaeochromocy toma of the Adrenal Gland Scoring Scale (PASS) to separate benign from malignant neoplasms. A clinicopathologic and immunophenotypic study of 100 cases. Am. J. Surg. Pathol. 26(5), 2002, PASS score PASS score <4/20 benign

Neuroblastoma (WHO: Neuroblastic tumours of adrenal gland and sympathetic nervous system) Def.: childhood embryonal tumours of migrating neuroectodermal cells derived from the neural crest and destined for the adrenal medulla and sympathetic nervous system Age /sex – 96% in the 1 st decade, no sex predilection Incidence: most common solid extracranial malignant tumours during the first two years of life Histogenesis: see definition Clinic: palpable mass (retroperit, abd., cervical), X-ray - thoracic Macro: soft gray-tan mass, regressive changes Micro: undiff. + differentiating neuroblasts Variants: neuroblastoma (undiff.), ganglioneuroblastoma intermixed, ganglioneuroblastoma nodular, ganglioneuroma Behaviour: malignant, dependent on age and histology variant

Islets of Langerhans (1869) u adults u cell types: B - insulin A - glucagon D – somatostatin PP – pancreatic polypeptide D – vasoactive intestinal polypeptide

Islets of Langerhans - regressive changes u fibrosis (postinflamm.) - DM I u mucoviscidosis DM frequency 10x u hyalinosis, amyloidosis

Islets of Langerhans - progressive changes u hyperplasia – diabetic embryopathy u nesidioblastosis

Islets of Langerhans - tumours u nesidioma ( event. in MEN I) insulinoma, glucagonoma, somatostatinoma,VIPoma, PP-oma, G cells - gastrinoma, EC – serotonin - carcinoid u neuroendocrine carcinoma

New classification of GastroEnteroPancreatic NeuroEndocrine Neoplasms GEP –NEN (2010) 1. NeuroEndocrine Tumour NET 1.NET G1 (carcinoid) - M8240/3 1.if hormonally active – insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma… /Mitoses <2/10HPF, Ki67 <2%/ 2.NET G2 - formerly well diff. neuroendocrine carcinoma - M 8249/3 /Mitoses >2/10HPF, Ki67 >20%/ 2. NeuroEndocrine Carcinoma NEC 1.large cell NEC - M8013/3 2.small cell NEC - M8041/3 3. Mixed AdenoNeuroEndocrine Carcinoma MANEC M8244/3 Exceptions: Tubular appendical carcinoid M8245/1; L-cell NET PP/PYY M8152/1

Islets of Langerhans - syndromes u hyperfunction - insulinoma –hypoglycemia (weekness, sweating, tremor, coma) –Zollinger-Ellison, Werner Morrison, glucagonoma u hypofunction – absolute or relative insulin lack ( DMI/II or glucagonoma) hyperglycemia –acute : polydipsia, ketoacidosis, coma, liver steatosis, brain edema –chronic: diabetes mellitus: microangiopathy, macroangiopathy, neuropathy, retinopathy, embryopathy

Diabetes mellitus Def.: group of disorders with glucose intolerance in common Chronic hyperglycemia and disturbances of carbohydrate, protein, and fat metabolism.

Diabetes mellitus - types u DM I – IDDM – juvenile u DM II – NIDDM -(+MODY) u Other – secondary- pancreatic disease, drugs, chemicals u Gestational - GDM

Diabetes - detailed classification 1. Type I Diabetes 1.beta cell destruction 2. Type II- Diabetes 1. beta +insulin resistence 3. Genetic Defects of Beta Cell Function 1. Maturity Onset Diabetes of the Young (type 1-6 with known mutations) 2.Maternaly inherited diabetes and deafness due to mitochondrial mutations 3.Defects in proinsulin conversion 4.Insulin gene mutation 4. Insulin Receptor Mutations 5. Exocrine Pancreas Diseases 1.Chronic pancreatitis 2.Pancreatectomy 3.Neoplasia 4.Cystic fibrosis 5.Hemochromatosis 6.Fibrocalculous pancreatopathy 6. Endocrinopaties 1.Acromegaly 2.Cushing syndrome 3.Hyperthyroidism 4.Pheochromocytoma 5.Glucagonoma 7. Infections 1.CMV 2.Coxsackie B 3.Congenital rubella 8. Drugs 1.Glucocorticoids 2.Thysroid hormones 3.Beta-adremergic agonists 9. Genetic Syndromes Associates with Diabetes 1.Down syndrome 2.Klinefelter syndrome 3.Turner syndrome 10. Gestational Diabetes

Diabetes mellitus - complications u acute –hypoglycemia (DM I and insulin treatment) –diabetic ketoacidosis : lack of insulin – increased release of fatty acids –increased ketone formation – metabolic acidosis u chronic – AGE – Advanced Glycosylation End-products – diabetic micro- and macroangiopathy –neuropathy –infection

Pešková M., Hvižď R., Dušková, J. Malignant somatostatinoma (brief overview and a case review) Rozhl Chir Dec;86(12): Czech. u Male 73

well differentiated endocrine carcinoma of pancreas head metastasizing into peripancreatic lymph nodes. T 99 M Dg.:

Case Report woman 26 yrs N 571/92

History - 1. u mononucleosis in the childhood u 2 yrs prior to death during her 9th week of pregnancy repetitive amentia statuses, hospitalized in the Psychiatry Clinic u hypoglycemia 1,2mmol/l found u transferred to General Medicine Clinic u two weeks later gravidity interruption

History - 2. u explorative laparotomy - tumour of the pancreas with liver metastases u no tumour in the biopsy sample taken u next two monts – cycles of chemotherapy, the hormonal activity of the neoplasm dissappeared u progression of the neoplasm with the gastric wall infiltration

History - 3. u hormonal activity of the neoplasm reappeared u cytostatics administered into a. hepatica u death two years from the onset of the disease

C- peptide u proteolytic phragment of proinsulin secreted (equimollar quantities) by beta-cells of Langerhans islets

Diagnosis Morbus principalis Carcinoma neuroendocrinum parvocellulare pancreatis ad parietem ventriculi et reproperitoneum progressum Complicationes Metastases carcinomatosae lnn. mesentericorum, hepaticorum, iliacorum. Hyperinsulinismus. Causa mortis Generalisatio carcinomatis

Hyperinsulinism u due to pancreatic tumour – mostly B-cell NESIDIOMA (insulinoma) - BENIGN – rare in pregnancy – malignant B-cell tumour neuroendocrine carcinoma / nesidioblastoma extremely rare u paraneoplastic hypoglycemia – mesenchymal retroperitoneal, adrenocortical, GIT tumours