Parathyroid Gland
Last revised 23 January 2008
Last major update March 2003
Copyright (c) 2001-2008, PathologyOutlines.com, Inc.
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Table of contents
Primary references, normal anatomy, parathyroid hormone, parathyroid cysts, ectopic parathyroid tissue, inflammation, other non-neoplastic
Primary hyperparathyroidism, parathyroid gland hyperplasia, primary chief cell hyperplasia, secondary chief cell hyperplasia, secondary due to tuberous sclerosis, water clear cell hyperplasia, neonatal
Secondary hyperparathyroidism, tertiary hyperparathyroidism, calciphylaxis
Hypoparathyroidism, pseudohypoparathyroidism
Neoplasms: adenoma, carcinoma, other, spread from other tumors, other neoplastic, spread from other tumors, frozen section
American Journal of Clinical Pathology (AJCP), Jun 1975 to Feb 2003 [no photos]
American Journal of Surgical Pathology (AJSP), Mar 1977 to Mar 2003
Archives of Pathology and Laboratory Medicine (Archives), Oct 1975 to Jan 2003
Human Pathology (Hum Path), Mar 1970 to Feb 2003
Modern Pathology (Mod Path), Jan 1988 to Feb 2003
Robbins Pathologic Basis of Disease (6th Edition); W. B. Sanders Company, 1999
Rosai, J: Ackerman’s Surgical Pathology (8th Ed); Mosby-Year Book, Inc., 1996
Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999
Please refer to these primary references for more detailed discussions and photographs
4 glands in 2 pairs usually close to upper and lower poles of thyroid lobe
Discovered in 1880 by Ivar Sandstrom, a Swedish medical student, AJSP 1996; 20:1123
May be found anywhere along pathway of descent of branchial pouches
10% have 2-3 glands; 5% have 5 glands, 0.2% have 6 glands
Upper pair arises from fourth branchial cleft and descends with thyroid gland; usually at cricothyroid junction
Lower pair arises from third branchial cleft and descends with thymus; usually near inferior thyroid
Other locations: carotid sheath, anterior mediastinum, intrathyroidal; glands tend to be bilaterally symmetrical
Stromal fat increases to 30% at age 25; percent fat is related to constitutional percent fat, but reduced in dying individuals; mean is 17% with wide variation (Hum Path 1982;13:717)
Gross: yellow-brown, 25-40 mg each gland
Micro: composed primarily of chief cells and fat with thin fibrous capsule dividing gland into lobules; may have a pseudofollicle pattern resembling thyroid follicles (pink material is PAS positive)
Micro image: image1
Chief cells: 6-8 microns, polygonal, central round nuclei, contain granules of parathyroid hormone (PTH)
Basic cell type, other cell types are due to differences in physiologic activity
80% of chief cells have intracellular fat
Chief cell is most sensitive to changes in ionized calcium
Positive stains: PTH, glycogen, keratin, chromogranin A
Oxyphil cells: slightly larger than chief cell (12 microns), acidophilic cytoplasm due to mitochondria; no secretory granules; first appear at puberty as single cells, then pairs, then nodules at age 40
Water clear cell: abundant optically clear cytoplasm and sharply defined cell membranes; chief cells with excessive cytoplasmic glycogen
Release controlled by ionized calcium level with negative feedback system
84 amino acids, derived from cleavage of pre-pro PTH; biologic activity due to 34 amino acids at amino terminus; other portions are inert but may give false positives in detection systems
Binding of PTH to its receptor stimulates cAMP and phosphatidylinositol diphosphate
Five major actions:
1) Activates and increases the number of osteoclasts, which mobilizes calcium from bone
2) Increases renal tubular reabsorption of calcium
3) Increases conversion of Vitamin D to active dihyoxy form in kidneys
4) Increases urinary phosphate excretion, which reduces calcium loss
5) Increases GI calcium absorption
Hypercalcemia of malignancy (breast, lung, kidney, myeloma) due to (a) release of PTH-related protein, usually in advanced disease, or (b) osteolytic metastases with local release of cytokines (IL-1, TNF-alpha)
Note: PTH-related protein is rarely produced by benign lesions, AJCP 1996;105:487
Patients usually are normocalcemic and present with an asymptomatic mass
May be adenomas with cystic degeneration or heterotopic salivary gland like tissue, AJSP 2000;24:837
May represent a hyperplastic gland, AJCP 1982;77:104
Can diagnose by FNA if PTH in fluid, AJCP 1986;86:776
Gross: usually large, in inferior glands; unilocular, thin walled with clear fluid containing PTH
Micro: lined by flattened parathyroid epithelium without nodules; may contain granular material resembling colloid
Positive stains: glycogen, PTH, chromogranin A
Negative stains: thyroglobulin
Estimated incidence of 35%
Often becomes symptomatic due to hyperplasia associated with secondary hyperparathyroidism
Sites: pyriform sinus (Arch Otolaryngol Head Neck Surg 2002;128:71), mediastinum (Ann Thorac Surg 1997;64:238), in or near the thyroid gland or thymus (Nippon Rinsho 1995;53:920), axilla (Int Surg 2004;89:6), vagus nerves of children (Archives 1988;112:304)
Often symmetrical from side to side, even when ectopic, making localization somewhat easier (eMedicine)
Can undergo adenomatous change, and cause primary hyperparathyroidism, hypercalcemia and acute pancreatitis (World J Surg Oncol 2004;2:41).
Case reports: Case of the Week #108
stain images (parathyroid glands are on upper left): cytokeratin cocktail; chromogranin; synaptophysin; parathyroid hormone
Case reports of primary hyperparathyroidism with histology similar to thyroiditis - lymphoid follicles, broad fibrous bands, plasma cells, AJCP 1991;96:348, AJSP 1984;8:211
May have autoimmune etiology
Case report of amyloid goiter with parathyroid involvement, Archives 2000;124:281, image
Primary hyperparathyroidism
Autonomous, spontaneous overproduction of PTH by parathyroid tissue, with no evidence of prior parathyroid stimulation by renal or intestinal disease
Important cause of hypercalcemia (0.3-5.0 cases/1000 adults)
Causes: adenoma (85%), hyperplasia (15%), carcinoma (~1%)
Higher incidence in women; usually age 50+
Associated with irradiation in some; may be associated with sarcoidosis
95% sporadic; also associated with MEN 1 and MEN 2/2A syndromes (usually chief cell hyperplasia)
PRAD1 / cyclin D1 (parathyroid adenoma 1) protein: inversion of gene on #11 puts PRAD1 next to 5’-PTH gene regulatory sequences which are constitutively active; seen in 10% of adenomas
MEN 1: loss of 11q13 tumor suppressor gene usually found; also noted in 20% of sporadic adenomas
MEN 2/2A: may see chief cell hyperplasia and medullary carcinoma at the same time
Clinical course: often asymptomatic (no skeletal or renal lesions); detected via screening studies for serum calcium
To diagnose, PTH level must be elevated inappropriately to level of serum calcium
Associated with low serum phosphorus, high urinary calcium and phosphorus, high serum alkaline phosphatase
Rarely presents with bone disease, AJCP 1993;100:697
Normocalcemic primary hyperparathyroidism also occurs
Symptoms (due to increased PTH and calcium): bones, stones, groans, moans
Bone disease:
Osteoporosis (from osteoclast prominence and remodeling), with later deformities and fractures
Osteitis fibrosa cystica (aka brown tumors, Recklinghausen’s disease [not neurofibromatosis]): thin cortex, marrow with increased fibrous tissue, hemorrhage and cysts; often in jaw
Stones: renal calcium stones in 20%; also nephrocalcinosis (calcification of renal interstitium and tubules); renal stones cause hypertension, are important cause of death; renal abnormalities may progress after treatment
Groans from GI distress: nausea, peptic ulcers (associated with high serum gastrin that decreases after surgical excision), constipation, pancreatitis, gallstones
Moans from CNS disturbance: depression, lethargy, seizures
Also weakness, fatigue, calcifications of aortic and mitral valves; metastatic calcification in stomach, lungs, myocardium, blood vessels
Treatment: surgical excision of enlarged gland plus one additional gland for diagnostic purposes
Use selective venous catheterization to localize abnormal gland preoperatively
Also total parathyroidectomy with autotransplantation of parathyroid tissue into forearm muscle, but may get recurrence of hyperparathyroidism, and hyperplastic gland may infiltrate the skeletal muscle and look malignant
Gross: solid and cystic areas, brown due to hemosiderin
Micro: osteoblastic and osteoclastic activity, cysts, hemosiderin-laden macrophages
Pale, vacuolated cells arranged in a trabecular pattern are also seen in non PTH-mediated hypercalcemia, AJSP 1985;9:43
Positive stains: cyclin D1 (61%, Mod Path 1999;12:412)
Cytology: FNA shows organoid or trabecular architecture of cellular tissue fragments with epithelial cells arranged around capillary cores and frequent microacini; cells have round, fairly uniform nuclei 6 to 8 microns; larger oxyphil cells may show considerable anisonucleosis; no features of thyroid tissue such as hemosiderin-laden macrophages, abundant colloid, and paravacuolar granules is significant, Hum Path 1995;26:338
EM: ribosomal-lamellar complexes and groups of centrioles is suggestive of adenoma; examination of normal appearing glands can detect chief cell activity associated with hyperplasia, Hum Path 1986;17:1036
Molecular: ~ 40% monoclonal
DD:
- giant cell reparative granuloma (both in jaw, similar histology, use laboratory findings to differentiate),
- giant cell tumor (evenly spaced giant cells, plump stromal cells, less osteoblastic activity),
- medullary carcinoma of thyroid if intrathyroidal tissue (PTH negative, calcitonin positive, AJSP 1983;7:535)
- tumor related hypercalcemia (should detect PTH-related protein, more common in squamous cell carcinomas, renal cell carcinoma, ovarian clear cell carcinoma, rarely leukemia [AJCP 1981;75:149], Kaposi’s sarcoma [AJCP 1976;66:998]),
- familial hypocalciuric hypercalcemia (young patients with family history, autosomal dominant, usually mild parathyroid hyperplasia, Hum Path 1981;12:229)
- sarcoidosis, hyperthyroidism, multiple myeloma, vitamin A or vitamin D intoxication
Sporadic or part of MEN 1 or 2A
Usually all 4 glands are involved, but may be asymmetrical with lower glands being larger
Weight of all glands usually 1-3 g
Usually chief cell hyperplasia, occasionally water-clear cell hyperplasia; adipose tissue is rare
Some believe adenoma and hyperplasia are different morphologic manifestations of the same process
May show clonality
Gross images: image1
Micro: usually no rim of compressed normal tissue; may have mitotic activity
DD: adenoma (usually encapsulated, affects one gland with compression of adjacent tissue; most important criterion - no recurrence of hypercalcemia after 5 year follow up)
Primary chief cell hyperplasia
Increased production of PTH; associated with MEN 1, 2A/2 in 30% of cases (not MEN 2B/3)
50% have allelic loss on #11 (where MEN 1 gene is located)
Parathyromatosis: microscopic foci of hyperplastic parathyroid tissue in neck associated with chief cell hyperplasia and prior surgery, Hum Path 1990;21:234
Case report: bilateral primary chief cell hyperplasia associated with loss of APC gene, AJSP 2002;26:103
Treatment: excise 3 of 4 glands; some surgeons remove all parathyroid tissue; can use frozen section, touch prep or intraoperative PTH assay to confirm removal
Gross: classically, all glands enlarged (up to 10g) vs. pseudoadenomatous (one gland enlarged) vs. occult (all glands normal size but histologically hyperplastic)
Micro: sheets of chief cells, minimal fat, rare oxyphils; usually no rim of normal tissue
Secondary chief cell hyperplasia
Gland may be normal sized with microscopic hypercellularity or be grossly enlarged
Hyperplasia due to reduced mean serum calcium level
“Secondary” is based on historical, chemical and laboratory findings (not due to primary alteration in PTH)
Micro images: image1
DD: adenoma (rim of normal, non-hyperplastic tissue around the mass and at least one normal parathyroid gland)
Secondary parathyroid hyperplasia due to tuberous sclerosis
Case report in 49 year old man, AJSP 2002;26:260
Micro: large, eosinophilic ganglion-like endocrine cells, similar to subependymal giant cell astrocytoma, tubers and atypical angiomyolipoma
Water clear cell hyperplasia
No familial incidence, not associated with MEN (unlike chief cell hyperplasia)
Incidence has decreased over past 20 years, now very rare
Extreme enlargement of all parathyroid tissue with weights up to 100g
Causes primary hyperparathyroidism
Associated with blood group O in a Swedish study
Gross: superior glands larger than inferior glands; 2 giant glands may appear as one; soft, chocolate-brown, with cysts and hemorrhages; pseudopods also common
Micro: abundant optically clear cells of variable size (hyperplasia and hypertrophy), with spherical clear vacuoles surrounded by thin eosinophilic material; basal nuclei, compact or alveolar patterns
Primary neonatal hyperparathyroidism
Rare, < 10 cases reported
Grave prognosis, AJCP 1975;64:488
Bones show disturbed osteogenesis, resorption, widespread fibrosis of marrow cavities, no cysts; pathologic fractures common
Laboratory: aminoaciduria, anemia, no hypercalciuria, no hyperphosphaturia
Micro: diffuse hyperplasia of parathyroid glands
Hyperparathyroidism due primarily to non-PTH disease
Causes: renal failure (phosphorus retention causes hypocalcemia), inadequate calcium intake, steatorrhea (failure to absorb Vitamin D), vitamin D deficiency or resistance
All cause hypocalcemia, which causes elevated PTH levels
Note: high serum phosphate levels DIRECTLY depress serum calcium levels
Bone changes usually less severe than primary hyperparathyroidism
Dialysis patients may have discrete, punched-out bone lesions with minimal resorption or osteoblast activity, AJSP 1987;11:205
Gross: hyperplastic glands, may not be symmetrical
Micro: similar to primary hyperparathyroidism
Molecular: ~ 60% monoclonal
Autonomous parathyroid hyperplasia/adenoma arising from secondary hyperparathyroidism
Often detected after hemodialysis or transplantation corrects the renal disease
Gross: 10-40x increase in parathyroid mass
Micro: marked hyperplasia, with predominance of chief cells and abundance of oxyphil cells, Hum Path 1985;16:772
Treatment: surgical excision
Aka calcifying panniculitis, vascular calcification-cutaneous necrosis syndrome
First described in 1962
Rare and life threatening condition of vascular calcification that causes ischemic damage to skin (usually lower extremity) and other organs
Associated with end-stage renal disease and dialysis/transplant and primary, secondary or tertiary hyperparathyroidism
Diagnostic clues: bilateral, symmetrical, superficial skin lesions with persistence of dorsal pulses
Treatment: parathyroidectomy
Micro images: image1
References: Archives 2001; 125: 1351, Hum Path 1995;26:1055
Hypoparathyroidism
Causes: surgery (including thyroidectomy), radiation, DiGeorge syndrome, idiopathic atrophy, familial
DiGeorge syndrome: complete or partial absence of third and fourth pharyngeal pouches, causing thymic aplasia and T cell deficiency, conotruncal cardiac defects; -22 by FISH
Idiopathic atrophy: antibodies directed against calcium-sensing receptor in parathyroid gland
Familial: syndrome of chronic mucocutaneous candidiasis, then hypoparathyroidism, then primary adrenal insufficiency
Symptoms (due to hypocalcemia): tetany / neuromuscular irritability; circumoral numbness or paresthesias of distal extremities, laryngospasm, seizures, cataracts, prolonged QT interval, dental abnormalities during early development (dental hypoplasia, failure of eruption, defective enamel and root formation, abraded carious teeth)
Trousseau sign: carpopedal spasm when inflate blood pressure cuff for several minutes
Chvostek sign: tap along course of facial nerve to induce contraction of muscles of eye, mouth, nose
Mental status changes: anxiety, depression, confusion, psychosis; movement disorders, papilledema
Resistance of organs to PTH
Type 1: deficiency of Gs alpha protein or abnormalities in the level of the hormone receptor complex; associated with decreased cAMP response; aka Albright hereditary osteodystrophy (round facies, short stature, short metacarpal and metatarsal bones)
Type 2: blunted response to second messenger
Neoplasms
Demographics: 75% in women, usually in 30’s, solitary lesions, functionally active, clonal
Clinical: May deform esophagus or trachea; 10% in mediastinum, behind thyroid gland, within thyroid gland (Mod Path 1989;2:652), or other abnormal sites
Case reports of rare ectopic parathyroid adenomas near/in esophagus, Archives 2002;126:1541, Archives 1978;102:242
Remaining glands usually normal in size or shrunken due to feedback inhibition from elevated serum calcium (presence of microscopically normal second gland strongly suggests that parathyroid lesion is an adenoma); 10% of patients show minimal hyperplasia in remaining glands
Best criterion for diagnosis of adenoma is lack of hypercalcemia for 5 years after excision
Usually monoclonal, but hyperplastic glands may also be monoclonal
Double adenomas very rare (< 1%), Archives 2001;125:178
Mitotic activity does not predict behavior, AJCP 1981;75:345
Gross: solitary, 0.5 to 5.0 g, well circumscribed tan nodule with delicate capsule; may undergo cystic change or be hemorrhagic; may have rim of normal tissue
Gross images: ectopic adenoma
Micro: encapsulated, cellular, homogenous lesions, rarely papillary, composed of chief cells with some oxyphil cells in a delicate capillary network; microfollicles resembling those in thyroid are common; may see rim of compressed normal tissue if adenoma is very large; adipose tissue is rare (AJSP 1988;12:282); minimal mitotic activity; may see clusters of bizarre nuclei (also seen in other benign endocrine tumors); large tumors often display hemorrhage, cholesterol clefts, fibrosis; usually no capsular invasion, no vascular invasion, no invasion of adjacent tissue
Micro images: image1, image2, ectopic adenoma (figure D)
Positive stains: parathyroid hormone, glycogen, keratin, cyclin D1 (40%, Mod Path 1999;12:412), neurofilament, renal cell carcinoma marker (AJSP 2001;25:1485)
Negative stains: TTF-1 (AJSP 2001;25:815)
Molecular: loss of heterozygosity in 1p (Mod Path 2001;14:273)
EM: long cytoplasmic processes (microvilli) extending into wide intercellular spaces are associated with high serum calcium (17.5 mg/dl) vs. relatively straight plasmalemma with interdigitations and narrow intercellular spaces with moderately elevated calcium (mean 12.4 mg/dl); high serum calcium case also had numerous nuclear pores and annulate lamellae but inconspicuous Golgi apparatus, Hum Path 1985;16:511
DD: papillary adenomas resemble papillary carcinoma of thyroid, Archives 1996;120:883
Atypical adenoma
Exhibit some features of malignancy (broad fibrous bands crossing the tumor, trabecular growth, pseudocapsular invasion [clusters of parathyroid cells trapped within the capsule in 50%]), no vascular invasion, no metastases, rarely increased mitotic activity, Hum Path 2003;34:54
Unpredictable clinical behavior
Chief cell adenoma
Lipoadenoma
Fka hamartomas, AJCP 1977;67:31
Glandular elements associated with large areas of mature adipose tissue; usually functional; rarely associated with myxomatous stroma, metaplastic bone, AJSP 1978;2:3, Archives 1977;101:28
Case report of 190 g tumor presenting as large posterior mediastinal mass, AJCP 1981;76:89
Case report of functioning tumor diagnosed by touch preps at frozen section (difficult to cut fat), Archives 1986;110:645
Lipothymoadenoma
Case report at Archives 1993;117:312
Benign thymic, adipose and parathyroid tissue
Combines features of thymolipoma and lipoadenoma of parathyroid gland
Oxyphil adenoma
Definition: composed of 90% or more oxyphil cells, and another parathyroid gland is normal (rules out hyperplasia)
Usually non-functioning or normal calcium levels
Packed with mitochondria by EM, AJCP 1983;80:878
Rarely functional, AJCP 1982;78:681, AJSP 1989;13:500, Hum Path 1984;15:1121
Papillary adenoma
Case reports of papillary tumor resembling papillary thyroid carcinoma, Archives 1996;120:883, Archives 1988;112:99
Water clear cell adenoma