Endocrine System

ANATOMY/PHYSIOLOGY/EMBRYOLOGY

●● Located in vicinity of thyroid gland or embedded in thyroid gland

●● Two inferior glands arise from third pharyngeal pouch

●● Two superior glands arise from fourth pharyngeal pouch

is 5-10 mg ●● Solid, cellular, mainly chief cells before

puberty ●● After puberty oxyphil cells/adipocytes also

appear

CONGENITAL ANOMALIES

Supernumerary parathyroid glands

thyroidism

Ectopic parathyroid

Agenesis-hypoplasia

●● DiGeorge syndrome (del 22q11.2) = Parathyroid hypoplasia, hypocalcemia, anomalies of aortic arch, hypoplasia of thymus/thyroid, and abnormal facial development

ACQUIRED DISORDERS

Hypercalcemia

●● Increased parathyroid hormone (PTH) secretion by parathyroid adenoma or hyperplasia

ondary to malignancy, vitamin D excess (sarcoidosis, tuberculosis, granulomatous conditions), drugs

Primary hyperparathyroidism

to MEN1, MEN2a, fibro-osseous jaw tumors (mutation of HRPT2 gene)

●● Subperiosteal phalangeal bone resorption genu-valgum, bone cyst formation

mary hyperparathyroidism) from other causes of hypercalcemia)

Secondary hyperparathyroidism

●● Multiglandular hyperplasia secondary to hypocalcemia

●● Hypocalcemia may be due to renal failure, vitamin D deficiency, malabsorption, rickets

Parathyroid adenomas

ished fat, increased mitotic activity, no capsule

●● Compressed out normal glandular tissue seen at periphery of adenoma

●● Intraoperative determination of serum PTH level distinguishes between adenoma (levels come back to normal after removal) and hyperplasia (levels remain raised)

Parathyroid carcinoma

Hypocalcemia

●● Multifactorial causes: Hypoparathyroidism, pseudohypoparathyroidism (resistance to parathyroid hormone = Albright hereditary osteodystrophy), mitochondrial DNA defects, dietary imbalances

Hypoparathyroidism

●● Previous parathyroidectomy, del 22q11.2, autoimmune, infiltrative disorders

●● Parathyroid transplant before thyroidectomy recommended as a preventive measure

ANATOMY/PHYSIOLOGY/EMBRYOLOGY

●● Development starts at third week of gestation

●● Proliferation of endodermal cells on floor of pharynx

●● Bi-lobed gland with isthmus, mid-anterior neck

●● Adult weight (15-20 g) reached by 15 years of age

secretion of TSH by pituitary (regulated by the hypothalamic thyrotropin-releasing hormone by a feedback mechanism)

●● C cells (parafollicular cells) acquired by thyroid when ultimobranchial body incorporated in thyroid gland

carcinoma (MTC) in MEN2a, MEN2b, and familial MTC due to germline mutations in RET gene

CONGENITAL ANOMALIES

Dysmorphism/dysgenesis

●● Inherited defects in enzymes responsible for thyroid hormone synthesis

●● Congenital hypothyroidism: Raised TSH levels, thyroid hyperplasia, and dyshormonogenetic goiter

●● Dysgenesis, hemigenesis, hypoplasia, or ectopic location

●● Mutations in genes responsible for thyroid development

Ectopia

etal muscle fibers of tongue ●● Hypoplastic thyroid

Thyroglossal duct cyst (TDC)

●● Failure of thyroglossal duct to involute during fetal life

●● Located midline anterior neck, overlying hyoid bone

●● Cyst lined by ciliated columnar/coboidal epithelium/squamous metaplasia

●● Surrounded by dense fibrous stroma, lymphoid tissue, and may show thyroid follicles

region, angle of mandible ●● Lined by squamous epithelium/columnar/

respiratory epithelium ●● Fibrotic wall with lymphoid follicles, het-

erotopic cartilage ●● May be infected secondarily

ACQUIRED DISORDERS

●● Goiter: Diffuse/nodular enlargement of thyroid

Chronic lymphocytic thyroiditis

antithyroglobulin antibodies (Hashimoto thyroiditis)

●● Sporadic/associated with HLA types DR3, DR4, and DR5

●● Gland enlarged, nodular, tan-gray, resembles lymph node

●● Lymphoid follicles with germinal centers, scattered infiltrate of plasma cells

●● Diminished/atrophic thyroid follicles, fibrosis

Hyperplasia

Simple non-toxic goiter

licles with colloid in lumen, cystic degeneration, fibrosis, hemorrhage, stromal inflammation

Adenomatous hyperplasia

Multinodular hyperplasia

Diffuse hyperplasia with clinical hyperthyroidism (Graves disease)

●● Autoimmune disorder of thyroid, adolescent girls

●● Hyperthyroidism, ophthalmopathy (exophthalmos), and dermopathy (pretibial myxedema)

●● Anti-TSH receptor antibodies, elevated serum T3 and T4, decreased serum TSH

●● Symmetrical diffuse enlargement of thyroid gland, red-brown (increased vascularity)

●● Follicular cells are tall columnar, cell crowding, intrafollicular papillary infoldings

●● Pale watery colloid, scalloping, lymphoid infiltrate in stroma

Papillary thyroid carcinoma (PTC)

●● Most common thyroid carcinoma in children

ular variant of papillary carcinoma ●● Most cases are sporadic ●● Familial cases in MEN1 ●● Classic papillary pattern/follicular variant/

sclerosing variant ●● Nuclear features diagnostic in all types:

Crowded, overlapping nuclei, nuclear grooves, optically clear, nuclear pseudo inclusions

●● Psammoma bodies, squamous metaplasia, desmoplastic stroma, lymphocytic infiltrate

●● Stain positively for cytokeratins, thyroglobulin, TTF1

●● Regional lymph nodes commonly involved by metastases

Follicular neoplasms of thyroid

Follicular adenoma

Follicular carcinoma

●● Thick fibrous capsule, transcapsular invasion

●● Capsular microvascular invasion (adherence of tumor cells to vascular endothelium)

●● Extensive capsular sampling/endothelial markers help in diagnosis

lar adenoma, and dominant adenomatous nodule) on frozen section

Medullary thyroid carcinoma (MTC)

●● Familial; RET mutations, MEN2a, and MEN2b

●● Tumor is small, microscopic, multifocal, always associated with diffuse C-cell hyperplasia

●● Neoplastic cells rounded/spindled, fine chromatin, conspicuous nucleoli

ing growth in colloid of follicles ●● However, MTC shows interstitial infiltra-

tion and aggregates of neoplastic cells ●● C cells/MTC stain positive for calcitonin,

chromogranin, synaptophysin, and CEA ●● Negative for TTF-1 and thyroglobulin

Cervical thyroidal teratoma

cal treatment necessary ●● Mature and immature (neuroepithelium)

components ●● Nodal gliomatosis common

ANATOMY/PHYSIOLOGY/EMBRYOLOGY

medulla (contains chromaffin cells, secretes catecholamines)

●● Cortex subdivisions: Zona glomerulosa (secretes mineralocorticoids), zona fasciculata (secretes glucocorticoids), and zona reticularis (secretes androgens)

●● During fetal life, subcapsular provisional fetal cortex (bright yellow cortical rim), involutes after birth

●● Zona fasciculata: Major part of cortex, large lipid-laden cells, cortisol provides negative

feedback on pituitary to stop further ACTH secretion

CONGENITAL ANOMALIES

●● Unilateral adrenal agenesis (mostly with ipsilateral renal agenesis)

Wolman disease

lipid-laden foamy macrophages, accumulate cholesterol, triglyceride

Adrenoleukodystrophy (ALD)

long-chain fatty acids ●● Inflammatory demyelination of axons, loss

of oligodendrocytes, atrophy of adrenals

Adrenal cytomegaly

●● Enlarged cytomegalic cells in adrenal fetal cortex

larger, hyperchromatic pleomorphic nuclei, nuclear pseudo inclusions, vacuolated cytoplasm

Congenital adrenal hypoplasia

Cytomegalic (most common), anencephalic, and miniature

Congenital adrenal hyperplasia

genitalia

tive feedback → persistent ACTH secretion → synthesis of cortisol precursors

●● Diagnosed prenatally, by maternal chorionic villus sampling in first trimester

●● Neonatal screening by 17-hydroxyprogesterone to detect 21-hydroxylase deficiency

●● Classic salt-wasting form: Hyponatremia, hyperkalemia, acidosis, shock, and death

●● Increased androgen production, female pseudohermaphroditism, virilization of male and female infants

●● Bilateral hyperplasia of adrenals, increased weight, cerebriform appearance, compact eosinophilic cells in zona fasciculata

●● TART (bilateral testicular adrenal rest tumor) with male infertility associated

Primary pigmented (micronodular) adrenocortical disease

●● Associated with Carney complex (PRKAR1A) and Cushing syndrome

●● Multiple small pigmented nodules in adrenal cortex

Adrenocortical hyperplasia

●● Beckwith-Wiedemann syndrome (BWS), multiple autoimmune syndrome (MAS), MEN1

Adrenocortical insufficiency

●● Congenital (ALD, congenital adrenal hypoplasia, congenital adrenal hyperplasia)

●● Acquired (infections, drugs, autoimmune disorders, adrenal hemorrhage)

ACQUIRED DISORDERS

Adrenal cysts

Bacterial fungal parasitic and viral infections

●● Congenital intrauterine infections (HSV, CMV, varicella-zoster virus, histoplasmosis, tuberculosis)

Adrenal hemorrhage

●● Intrauterine asphyxia, birth trauma, underlying coagulopathy, extracorporeal membrane oxygenation (ECMO), umbilical artery catheterization

●● Spontaneous resolution with calcifications after birth

Waterhouse-Friderichsen syndrome

●● Bilateral adrenal hemorrhagic necrosis, circulatory collapse, coagulopathy, petechial rash

atrophy with sickle cell anemia

Calcifications

ADRENAL NEOPLASMS

Adrenal cortical neoplasms (ACNs)

●● Adrenocortical adenoma (AA) and adrenocortical carcinoma (ACC)

●● Two peak age distributions = infantile and adolescent

●● Associated with BWS, Li-Fraumeni syndrome, Carney complex

●● Most common clinical manifestation is Cushing syndrome

●● Size/weight of tumor distinguishes between AA and ACC

●● Histological factors not reliable for prognosis

●● Tumor cells positive for vimentin, inhibin, calretinin, Melan-A, synaptophysin, and NSE

adreno-cortical neoplasms (d/d pheochromocytoma and paraganglioma)

Prognostic risk groups for ACNs in children

●● Low risk (adenomas) confined to adrenal gland and weigh <200 g

●● Intermediate risk (atypical adenomas) confined to the adrenal gland and weigh between 200 and 400 g

spleen

Peripheral neuroblastoma (NB)

●● Tumors of neural crest origin: Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma

●● Predominant sites: Adrenal medulla (most common), extra-adrenal retroperitoneum, posterior mediastinum, paravertebral region from neck to pelvis

●● Stage IV NB metastasizes to bone marrow (paratrabecular aggregates of tumor cells) and bone

●● Stage IV metastasizes to skin, liver, and bone marrow

●● Congenital NB may show tumor cells in chorionic villus capillaries of placenta

●● Increased serum/urinary levels of homovanillic acid (HVA) and vanillylmandelic acid (VMA)

●● Positive staining with NSE, NB84, PGP9.5, synaptophysin, chromogranin, CD57, NFP, NCAMS, and tyrosine hydroxylase

●● Undifferentiated neuroblastoma: Positive only for vimentin and PGP9.5

numerous “double minutes” ●● Positive for MYCN on fluorescence in situ

hybridization ●● MYCN amplification and 1p36 deletion;

associated with adverse outcome

Neuroblastoma (Schwannian stroma-poor)

●● Undifferentiated subtype: Resembles small, round, blue cell tumors. No neuropil. Tumor cells have irregular demarcation by fibrovascular septa

●● Poorly differentiated subtype: Most common form of NB. May show neuropil, HomerWright rosettes

●● Differentiating subtype: 5%–49% of cells have an appearance of differentiating neuroblast. Abundant neuropil formation. Tumor cells separated by thin fibrovascular septa. No significant schwannian stroma development

Ganglioneuroblastoma

●● Intermixed (Schwannian stroma rich): Same appearance as schwannoma. Extensive schwannian stromal development (occupying more than 50% of tumor tissue). Pockets of naked neuropil, tumor cells in various stages of neuronal differentiation

●● Nodular (stroma predominant/stroma rich and stroma poor): Grossly/histologically, tumor has appearance of ganglioneuroma with one or more nodules having the appearance of neuroblastoma (friable, hemorrhagic, necrotic cut surface)

Ganglioneuroma (Schwannian stroma predominant)

●● Maturing subtype: Scattered maturing ganglion cells/neuroblasts (≥50%)

●● Mature subtype: Fully mature ganglion cells, surrounded by satellite cells

Prognostic distinction

Based on three morphologic criteria and age:

●● Schwannian stroma development (stroma poor, stroma rich, and stroma predominant)

●● Grade of neuroblastoma differentiation (undifferentiated, poorly differentiated, and differentiating)

●● Mitotic Karyorrhectic Index = on a count of 5000 cells; low (<100 cells), intermediate (100-199 cells), and high (200 cells or more)

Favorable histology

Favorable histology (FH) neuroblastomas fall into an age-appropriate maturational sequence:

●● Neuroblastoma (Schwannian stroma-poor) poorly differentiated subtype. The MKI can be intermediate-up to 1.5 years of age

●● Neuroblastoma (Schwannian stroma-poor) differentiating subtype. The MKI should be low-up to 5 years of age

●● Ganglioneuroblastoma intermixed, and ganglioneuroma → FH (any age group)

Pheochromocytoma

MEN2b)

paraganglia

●● Elevated catecholamines: Hypertension, sweating, palpitations, tachycardia

●● Nesting (zellballen), trabecular, or solid pattern

●● Cytoplasm eosinophilic to basophilic, granular

●● Stain positive for chromogranin, vimentin, synaptophysin

gliomas are malignant

ADH, causes hyponatremic-isovolemic condition

●● Diabetes insipidus: Decreased ADH production (central) or nephrogenic (kidney response is defective)

●● Osmolarity = measure of solute concentration in fixed solvent volume

●● Calculation of predicted serum osmolarity: 2Na + Glucose/18 + BUN/2.8 + other osmolarities

●● Normal range of serum osmolality = 285295 mOsm/kg