In sporadic cases, medullary carcinoma manifests most often as a mass in the neck, sometimes associated with compression effects such as dysphagia or hoarseness. In some instances the initial manifestations are caused by the secretion of a peptide hormone (e.g., diarrhea caused by the secretion of vasoactive intestinal peptide). Screening of the patient’s relatives for elevated calcitonin levels or RET mutations permits early detection of tumors in familial cases. As discussed later, all members of MEN-2 kindreds carrying RET mutations are offered prophylactic thyroidectomies to preempt the development of medullary carcinomas; often, the only histologic finding in the resected thyroid of these asymptomatic carriers is the presence of C cell hyperplasia or small (<1 cm) micromedullary carcinomas.
Fig.20.18Medullarycarcinomaofthethyroidgland.Thesetumorstypicallycontainamyloid,visiblehereashomogeneousextracellularmaterial,derivedfromcalcitoninmoleculessecretedbytheneoplasticcells.
Mostthyroidneoplasmsmanifestassolitary thyroid nodules, butonly1%ofallthyroidnodulesareneoplastic.
Follicular adenomas arethemostcommonbenignneoplasms,whilepapillarycarcinomaisthemostcommonmalignancy.
Multiplegeneticpathwaysareinvolvedinthyroid carcinogenesis. SomeofthedrivermutationsthatarefairlyuniquetothyroidcancersincludePAX8/PPARG fusion(infollicularcarcinoma),chromosomalrearrangementsinvolvingtheRET oncogene(inpapillarycancers),andmutationsofRET (inmedullarycarcinomas).
Follicular adenomas and carcinomas botharecomposedofwell-differentiatedfollicularepithelialcells;thelatteraredistinguishedbypresenceofcapsularand/orvascularinvasion.
Papillary carcinomas arerecognizedbynuclearfeatures(groundglassnuclei,pseudoinclusions),evenintheabsenceofpapillae.Theseneoplasmstypicallymetastasizebywayofthelymphatics,buttheprognosisisexcellent.
Anaplastic carcinomas arethoughttoarisebyprogressionofmoredifferentiatedneoplasms.Theyarehighlyaggressive,uniformlylethalcancers.
Medullary cancers arenonepithelialneoplasmsarisingfromtheparafollicularCcellsandcanoccurineithersporadic(70%)orfamilial(30%)settings.MulticentricityandCcellhyperplasiaarefeaturesoffamilialcases.Amyloiddepositsareacharacteristichistologicfinding.
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The parathyroid glands are derived developmentally from pharyngeal pouches that also give rise to the thymus. They are most commonly located in close proximity to the upper and lower poles of each thyroid lobe but may be found anywhere along the pathway of descent of the pharyngeal pouches, including the carotid sheath, the thymus, and elsewhere in the anterior mediastinum. Most of the gland is composed of chief cells which have secretory granules containing parathyroid hormone (PTH). Oxyphil cells are found throughout the normal parathyroid either singly or in small clusters. They are slightly larger than the chief cells, have acidophilic cytoplasm, and are tightly packed with mitochondria.
Parathyroid glands are key regulators of calcium homeostasis. The activity of the parathyroid glands is controlled by the level of free (ionized) calcium in the blood, rather than by trophic hormones secreted by the hypothalamus and pituitary. Normally, decreased levels of free calcium stimulate the synthesis and secretion of PTH, which has the following effects on its target tissues, the kidneys and the bones:
Increased renal tubular reabsorption of calcium