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Parathyroid gland

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Revised: 19 February 2013
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.

General

Anatomy and Histology


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● 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, (Am J Surg Pathol 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 Pathol 1982;13:717)

Drawings
=========================================================================



Embryological pathway of parathyroid migration, showing possible locations for lower parathyroid glands

Gross description
=========================================================================

● Yellow-brown, 25-40 mg each gland

Micro description
=========================================================================

● 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)

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

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

Micro images
=========================================================================



Normal parathyroid gland


Chief cells


Oxyphilic nodule


Clear cells


Colloid type material, without oxalate crystals

Positive stains
=========================================================================

● Chromogranin A, glycogen, keratin, PTH



General

Parathyroid hormone (PTH)


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● 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
Note: PTH-related protein is rarely produced by benign lesions, (Am J Clin Pathol 1996;105:487)

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)



General

Parathyroid cysts


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Patients usually are normocalcemic and present with an asymptomatic mass
● May be hyperplastic gland (Am J Clin Pathol 1982;77:104), adenoma with cystic degeneration, heterotopic salivary gland like tissue (Am J Surg Pathol 2000;24:837)
● Can diagnose by FNA if PTH in fluid (Am J Clin Pathol 1986;86:776)
● Cystic parathyroid lesions often contain turbid or colored fluid
● Functional parathyroid cysts more common than nonfunctional parathyroid cysts (Arch Surg 2009;144:52)
● During resection, cyst rupture should be avoided, and patients with large cysts should be managed expectantly to forestall the development of symptomatic hypocalcemia

Case reports
=========================================================================

● 50 year old woman with cystic cervical lesion (Med Ultrason 2011;13:157)
● 58 year old woman with rare case of malignant hypercalcemia (Case Report Med 2012;2012:851941)

Treatment
=========================================================================

● Simple aspiration to diagnosis and treat, ethanol ablation for recurrent cases (Eur J Radiol 2013;82:316)

Gross description
=========================================================================

● Usually large, in inferior glands
● Unilocular, thin walled with clear fluid containing PTH

Micro description
=========================================================================

● Lined by flattened parathyroid epithelium without nodules
● May contain granular material resembling colloid

Micro images
=========================================================================



Fibroadipose tissue containing islands of parathyroid tissue

Positive stains
=========================================================================

● Chromogranin A, glycogen, PTH

Negative stains
=========================================================================

● Thyroglobulin



General

Ectopic parathyroid tissue


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Estimated incidence of 35%; due to aberrant migration during early stages of development
● Common etiology of persistent or recurrent hyperparathyroidism when missed at initial diagnosis (Exp Clin Endocrinol Diabetes 2012;120:604)
● Often symptomatic due to hyperplasia associated with secondary hyperparathyroidism
● 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)
● Inability to identify may lead to failure of parathyroid surgery

Sites
=========================================================================

● Axilla (Int Surg 2004;89:6)
● Mediastinum (Ann Thorac Surg 1997;64:238)
● Pyriform sinus (Arch Otolaryngol Head Neck Surg 2002;128:71)
● Thyroid gland (Nihon Rinsho 1995;53:920)
● Vagus nerves of children (Arch Pathol Lab Med 1988;112:304)
● Ectopic inferior parathyroids are most frequently found in anterior mediastinum, in association with thymus or thyroid gland; ectopic superior parathyroids are usually at tracheoesophageal groove or retroesophageal region (Exp Clin Endocrinol Diabetes 2012;120:604)

Case reports
=========================================================================

● 86 year old woman with neck pain and difficulty swallowing (Case of the Week #108)

Micro images
=========================================================================



Case of the week #108


Thymic tissue contains a mass of parathyroid cells

Stain images (parathyroid glands are on upper left):

   
Cytokeratin cocktailChromogranin     SynaptophysinParathyroid hormone



General

Inflammation


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● May have autoimmune etiology

Case reports resembling thyroiditis
=========================================================================

● 57 year old man with renal stones (Am J Clin Pathol 1991;96:348)
● Two cases of chronic parathyroiditis associated with parathyroid hyperplasia and hyperparathyroidism (Am J Surg Pathol 1984;8:211)

Micro images
=========================================================================



CMV parathyroiditis in immunosuppressed child



General

Other non-neoplastic


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● 40 year old man with amyloid goiter with parathyroid involvement (Arch Pathol Lab Med 2000;124:281)

Micro images
=========================================================================



40 year old man with amyloid goiter



Hyperparathyroidism

Calciphylaxis


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare and life threatening condition of vascular calcification, first described in 1962, that causes ischemic damage to skin (usually lower extremity) and other organs (G Ital Nefrol 2012;29:674, Hum Pathol 1995;26:1055)
● Also known as calcific uremic arteriopathy (CUA), calcifying panniculitis, vascular calcification-cutaneous necrosis syndrome
● Affects 1-4% of dialysis patients; associated with primary, secondary or tertiary hyperparathyroidism
● 60-80% mortality

Diagnosis
=========================================================================

● Bilateral, symmetrical, superficial skin lesions with persistence of dorsal pulses; confirm with biopsy

Case reports
=========================================================================

● 69 year old woman with primary hyperparathyroidism due to parathyroid adenoma (Arch Pathol Lab Med 2001;125:1351)
● 70 year old man with end-stage renal failure secondary to IgA nephropathy (J Med Case Rep 2009;3:9297)

Treatment
=========================================================================

● Parathyroidectomy

Clinical images
=========================================================================



Well-demarcated and gangrenous lesion of right leg

Micro images
=========================================================================



Subcutaneous tissue with calcification


Calcification in medium-sized arteries in subcutaneous fat



Hyperparathyroidism

Primary neonatal hyperparathyroidism


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, < 10 cases reported
● Poor prognosis (Am J Clin Pathol 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

Case reports
=========================================================================

● Infant with severe hypercalcemia (Saudi Med J 2012;33:1340)

Micro description
=========================================================================

● Diffuse hyperplasia of parathyroid glands



Hyperparathyroidism

Parathyroid gland hyperplasia


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● 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
=========================================================================



Three and one-half glands removed

Micro description
=========================================================================

● Usually no rim of compressed normal tissue
● May have mitotic activity

Micro images
=========================================================================



Figures D/E: nodular parathyroid hyperplasia

Molecular / cytogenetics description
=========================================================================

● Sporadic or part of MEN 1 or 2A

Differential diagnosis
=========================================================================

Adenoma: usually encapsulated, affects one gland with compression of adjacent tissue; most important criterion - no recurrence of hypercalcemia after 5 year follow up



Hyperparathyroidism

Primary chief cell hyperplasia


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

Parathyromatosis: microscopic foci of hyperplastic parathyroid tissue in neck associated with chief cell hyperplasia and prior surgery (Hum Pathol 1990;21:234)

Case reports
=========================================================================

● Bilateral primary chief cell hyperplasia associated with loss of APC gene (Am J Surg Pathol 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 description
=========================================================================

● Classically, all glands enlarged (up to 10g) vs. pseudoadenomatous (one gland enlarged) vs. occult (all glands normal size but histologically hyperplastic)

Micro description
=========================================================================

● Sheets of chief cells, minimal fat, rare oxyphils
● Usually no rim of normal tissue

Molecular / cytogenetics description
=========================================================================

● 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)



Hyperparathyroidism

Primary hyperparathyroidism


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Autonomous, spontaneous overproduction of parathyroid hormone / parathormone / 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)
● Higher incidence in women; usually age 50+
● Associated with irradiation in some; may be associated with sarcoidosis
● Rarely presents with bone disease (Am J Clin Pathol 1993;100:697)
● Normocalcemic primary hyperparathyroidism also occurs

Symptoms (due to increased serum PTH and calcium): bones, stones, groans, moans

Bone disease:
● Osteoporosis (from osteoclast prominence and remodeling), with later deformities and fractures
● Osteitis fibrosa cystica (also called 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

Etiology
=========================================================================

● Adenoma (85%), hyperplasia (15%), carcinoma (~1%)

Clinical features
=========================================================================

● 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

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 description
=========================================================================

● Solid and cystic areas, brown due to hemosiderin

Micro description
=========================================================================

● Osteoblastic and osteoclastic activity, cysts, hemosiderin-laden macrophages
● Pale, vacuolated cells arranged in a trabecular pattern are also seen in non PTH-mediated hypercalcemia (Am J Surg Pathol 1985;9:43)

Micro images
=========================================================================



Gland composed mainly of chief cells with a rim of normal parathyroid tissue, no stromal fat


Chief cell hyperplasia and oncocytic cells

Cytology description
=========================================================================

● 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, paravacuolar granules (Hum Pathol 1995;26:338)

Positive stains
=========================================================================

● Cyclin D1 (61%, Mod Pathol 1999;12:412)

Electron microscopy description
=========================================================================

● 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 Pathol 1986;17:1036)

Molecular / cytogenetics description
=========================================================================

● ~ 40% monoclonal
● 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

Differential diagnosis
=========================================================================

● Familial hypocalciuric hypercalcemia: young patients with family history, autosomal dominant, usually mild parathyroid hyperplasia (Hum Pathol 1981;12:229)
Giant cell reparative granuloma: similar histology and both in jaw, so 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 (Am J Surg Pathol 1983;7:535)
● Also hyperthyroidism, myeloma, sarcoidosis, vitamin A or vitamin D intoxication
● Tumor related hypercalcemia: has PTH-related protein, more common in squamous cell carcinomas, renal cell carcinoma, ovarian clear cell carcinoma, rarely leukemia (Am J Clin Pathol 1981;75:149), Kaposi’s sarcoma (Am J Clin Pathol 1976;66:998)



Hyperparathyroidism

Secondary chief cell hyperplasia


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● 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
=========================================================================



Enlarged glands due to chronic renal failure with impaired phosphate excretion

Differential diagnosis
=========================================================================

Adenoma: rim of normal, non-hyperplastic tissue around the mass and at least one normal parathyroid gland



Hyperparathyroidism

Secondary hyperparathyroidism


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Hyperparathyroidism due primarily to non-PTH disease
● Bone changes usually less severe than primary hyperparathyroidism
● Dialysis patients may have discrete, punched-out bone lesions with minimal resorption or osteoblast activity (Am J Surg Pathol 1987;11:205)

Etiology
=========================================================================

● 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

Gross description
=========================================================================

● Hyperplastic glands, may not be symmetrical

Micro description
=========================================================================

● Similar to primary hyperparathyroidism

Molecular description
=========================================================================

● ~ 60% monoclonal



Hyperparathyroidism

Secondary parathyroid hyperplasia due to tuberous sclerosis


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● 49 year old man with two parathyroid glands with collections of large, eosinophilic ganglion-like endocrine cells (Am J Surg Pathol 2002;26:260)

Micro description
=========================================================================

● Large, eosinophilic ganglion-like endocrine cells, similar to subependymal giant cell astrocytoma, tubers and atypical angiomyolipoma



Hyperparathyroidism

Tertiary hyperparathyroidism


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Autonomous parathyroid hyperplasia/adenoma arising from secondary hyperparathyroidism
● Often detected after hemodialysis or transplantation corrects the renal disease

Treatment
=========================================================================

● Surgical excision

Gross description
=========================================================================

● 10-40x increase in parathyroid mass

Micro description
=========================================================================

● Marked hyperplasia, with predominance of chief cells and abundance of oxyphil cells (Hum Pathol 1985;16:772)



Hyperparathyroidism

Water clear cell hyperplasia


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Extreme enlargement of all parathyroid tissue with weights up to 100g; causes primary hyperparathyroidism
● Incidence has decreased over past 20 years, now very rare
● No familial incidence, not associated with MEN (unlike chief cell hyperplasia)
● Associated with blood group O (Hum Genet 1994;94:195)

Gross description
=========================================================================

● Superior glands larger than inferior glands
● 2 giant glands may appear as one
● Soft, chocolate-brown, with cysts and hemorrhages
● Pseudopods also common

Micro description
=========================================================================

● 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

Micro images
=========================================================================



Water clear cell hyperplasia



Hypoparathyroidism


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Causes
=========================================================================

● Condition of parathyroid hormone (PTH) deficiency.(eMedicine-hypoparathyroidism)
● 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
● Familial: syndrome of chronic mucocutaneous candidiasis, then hypoparathyroidism, then primary adrenal insufficiency
● Idiopathic atrophy: antibodies directed against calcium-sensing receptor in parathyroid gland
● Radiation
● Surgery (including thyroidectomy)

Symptoms
=========================================================================

● Cataracts
● Circumoral numbness or paresthesias of distal extremities
● Dental abnormalities during early development: dental hypoplasia, failure of eruption, defective enamel and root formation, abraded carious teeth
● Laryngospasm
● Prolonged QT interval
● Seizures
● Tetany / neuromuscular irritability

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 change:
● Anxiety, depression, confusion, psychosis
● Movement disorders, papilledema



Pseudohypoparathyroidism


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Resistance of organs to PTH (Wikipedia-pseudohypoparathyroidism)

Type 1:
● Deficiency of Gs alpha protein or abnormalities in the level of the hormone receptor complex
● Associated with decreased cAMP response
● Also called Albright hereditary osteodystrophy (round facies, short stature, short metacarpal and metatarsal bones)

Type 2:
● Blunted response to second messenger



Neoplasms

Parathyroid adenoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually monoclonal, but hyperplastic glands may also be monoclonal
● Difficult to diagnose - best criterion is lack of hypercalcemia for 5 years after excision
● 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

Epidemiology
=========================================================================

● Demographics: 75% women, usually in 30’s, solitary lesions, functionally active, clonal

Clinical features
=========================================================================

● May deform esophagus or trachea
● 10% in mediastinum, behind thyroid gland, within thyroid gland (Mod Pathol 1989;2:652), or other abnormal sites
● Double adenomas very rare (< 1%, Arch Pathol Lab Med 2001;125:178)
● Mitotic activity does not predict behavior (Am J Clin Pathol 1981;75:345)

Case reports
=========================================================================

● 42 year old man with back pain (Arch Pathol Lab Med 2002;126:1541)
● 48 year old man with 11 year history of chronic renal insufficiency (Ann Thorac Cardiovasc Surg. 2012 Nov 30. [Epub ahead of print])
● 67 year old woman with primary hyperparathyroidism (Arch Pathol Lab Med 1996;120:883)
● 67 year old woman with papillary adenoma (Arch Pathol Lab Med 1996;120:883)
● 68 year old woman with primary hyperparathyroidism (Int J Surg Case Rep 2013;4:105)
● Rare ectopic parathyroid adenomas near/in esophagus (Arch Pathol Lab Med 1978;102:242)
● Case with papillae formation (Arch Pathol Lab Med 1988;112:99)

Clinical images
=========================================================================



Various images of parathyroid gland and adenoma

Gross description
=========================================================================

● Solitary, 0.5 to 5.0 g, well circumscribed tan nodule with delicate capsule
● May undergo cystic change or hemorrhage
● May have rim of normal tissue

Gross images
=========================================================================



Various images


Figure C: red-brown mass within the cystic lesion


Various images contributed by Dr. Mona Kandil, Menoufiya University, Egypt


Right: parathyroid adenoma; left: thymoma

Micro description
=========================================================================

● Encapsulated, cellular, homogenous lesions, rarely papillary, composed of chief cells with some oxyphil cells in 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 (Am J Surg Pathol 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
=========================================================================



Figure B: FNA shows elongated nuclei and nuclear groove; D: histologic section


Adenoma with rim of normal parathyroid tissue and small benign parathyroid cyst


Rim of normal parathyroid tissue admixed with adipose tissue cells compressed to lower edge of adenoma


Various images contributed by Dr. Mona Kandil, Menoufiya University, Egypt

Positive stains
=========================================================================

● Parathyroid hormone, glycogen, keratin, cyclin D1 (40%, Mod Pathol 1999;12:412), neurofilament, renal cell carcinoma marker (Am J Surg Pathol 2001;25:1485)

Negative stains
=========================================================================

● TTF-1 (Am J Surg Pathol 2001;25:815)

Electron microscopy description
=========================================================================

● 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, associated 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 Pathol 1985;16:511)

Molecular description
=========================================================================

● Loss of heterozygosity in 1p (Mod Pathol 2001;14:273)

Differential diagnosis
=========================================================================

● Papillary adenomas resemble papillary carcinoma of thyroid (Arch Pathol Lab Med 1996;120:883)



Neoplasms

Atypical adenoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Clinical features
=========================================================================

● Has some features of malignancy (broad fibrous bands crossing the tumor, trabecular growth, pseudocapsular invasion [clusters of parathyroid cells trapped within the capsule in 50%]), but no vascular invasion, no metastases, rarely increased mitotic activity (Hum Pathol 2003;34:54)
● Unpredictable clinical behavior

Case reports
=========================================================================

● 63 year old woman with ectopic atypical parathyroid lipoadenoma (J Bone Miner Metab 2012 Dec 22 [Epub ahead of print])

Micro images
=========================================================================



Atypical adenoma showing characteristic dense collagenous bands


Atypical adenoma extending close to margins of excision, often due to fibrosis and adherence to adjacent structures



Neoplasms

Chief cell adenoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● 43 year old woman with massive chronic parathyroiditis and hyperparathyroidism (Endocr Pathol 2007;18:42)

Micro images
=========================================================================



Various images



Neoplasms

Oxyphil adenoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Composed of 90% or more oxyphil cells, and another parathyroid gland is normal (rules out hyperplasia)
● Usually non-functioning or normal calcium levels
● Rarely functional (Am J Clin Pathol 1982;78:681, Am J Surg Pathol 1989;13:500, Hum Pathol 1984;15:1121)

Case reports
=========================================================================

● 30 year old man with adenoma producing PTHrP with hypercalcemia and normal PTH (World J Surg Oncol 2008;6:24)
● 82 year old woman with functioning adenoma and ureteral stone (Prog Urol 2009;19:636)
● Causing primary hyperparathyroidism and osteitis fibrosa cystica (Indian J Pathol Microbiol 2006;49:448)

Micro description
=========================================================================

● 90%+ oxyphil cells (abundant granular eosinophilic cytoplasm), no atypia

Micro images
=========================================================================



Oxyphil cells at various magnifications


Strong and diffuse expression of PTHrP in the oxyphil adenoma

Electron microscopy description
=========================================================================

● Packed with mitochondria by EM (Am J Clin Pathol 1983;80:878)



Neoplasms

Water clear cell adenoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare; solitary lesion that compresses normal gland (Arch Pathol Lab Med 1995;119:1072)
● Only a few cases reported (Indian J Pathol Microbiol 2004;47:39)

Case reports
=========================================================================

● 56 year old woman with a 2 cm thyroid nodule and elevated serum calcium (Arch Pathol Lab Med 2001;125:256)
● 64 year old HIV+ patient (Diagn Cytopathol. 2011 Dec 5 [Epub ahead of print])
● Case of intrathyroidal tumor (Hum Pathol 2001;32:889)

Micro description
=========================================================================

● Nests and glands composed of cells with abundant foamy, granular cytoplasm, mild nuclear pleomorphism

Micro images
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Various images

Cytology description
=========================================================================

● Cellular smear with single and loosely clustered tumor cells with finely granular and vacuolated light-purple cytoplasm and central nuclei; occasional microfollicular structures may be present; no colloid seen (Diagn Cytopathol 2011 Dec 5 [Epub ahead of print])

Positive stains
=========================================================================

● PTH

Electron microscopy description
=========================================================================

● Glassy and flocculate material

Differential diagnosis
=========================================================================

Water clear cell hyperplasia of parathyroid gland: diffuse, affects all glands
Parathyroid chief cell adenoma: may have clear cell change, but some normal chief cells present
Clear cell changes in a thyroid tumor: typical thyroid tumor cells present
Metastatic renal cell carcinoma: multiple nodules, optically clear cytoplasm, delicate vasculature, intracytoplasmic glycogen and fat



Neoplasms

Parathyroid carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Somewhat rare - accounts for less than 1% of all cases of primary hyperparathyroidism (J Cancer 2011;2:532)
● Usually detected because of palpable neck mass (75%), excessive PTH secretion, high serum calcium (> 14 mg/dl, may recur after surgery) and clinical effects of hypercalcemia (skeletal disease: 73%, renal disease: 26%), vocal cord paralysis
● Present in 15% with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, a rare autosomal disorder (Semin Oncol 2010;37:580)
● Equal male and female incidence
● Non-functioning tumors are rare (Am J Surg Pathol 1983;7:535)
● Rarely coexists with adenoma and hyperplasia (Arch Pathol Lab Med 1983;107:349)
● 1/3 recur locally; 1/3 have distant metastases
● 79% die of disease after multiple recurrences with repeated resections; 5 year survival 50% (Hum Pathol 2003;34:54)
● Types: chief cell (functional tumors that present with high serum calcium, 50% die of disease), oxyphil (rare, similar characteristics as chief cell carcinomas; higher Ki-67 and lower p27 than oxyphil adenomas, CK14- [usually expressed in oxyphil adenomas, Am J Surg Pathol 2002;26:344], abundant cytoplasmic mitochondria on EM)
● No current staging for parathyroid carcinomas exists

Diagnosis
=========================================================================

● Based on local invasion and metastases (clinical criteria, NOT microscopic criteria)
● Higher serum PTH and calcium levels than in parathyroid benign disease may be useful in diagnosis; PTH levels higher than 300 pg/ml are indicator of potential malignant disease (J Cancer 2011;2:532)

Prognostic factors
=========================================================================

● Macronucleoli, more than five mitoses per 50 high-power fields, and necrosis were associated with recurrent disease (Am J Surg Pathol 1993;17:820)

Case reports
=========================================================================

● 55 year old woman with pseudofollicular pattern (Mod Pathol 2000;13:210)

Treatment
=========================================================================

● Excise tumor, soft tissue and ipsilateral thyroid lobe
● Can excise isolated metastases
● Post-operative radiation to prevent local recurrence

Gross description
=========================================================================

● May be circumscribed
● Gray-white, firm, irregular, may exceed 10g, may adhere to adjacent structures, rarely within thyroid gland (Mod Pathol 1989;2:652)

Gross images
=========================================================================



Note large size and irregular cut surface


Cystic mass against thyroid lobe

Micro description
=========================================================================

● Uniform cells with minimal atypia in nodular or trabecular patterns with dense fibrous bands
● Tumor cells are spindled, mitotic figures are frequent, atypical mitotic figures relatively specific, capsular invasion present (tongue like protrusion of tumor cells through capsule) but usually NOT diagnostic because it may be due to prior hemorrhage
● Vascular invasion (81% had tumor inside vessel and attached to vessel wall), perineural invasion (19%) and soft tissue invasion usually reliable indicators of malignancy
● May produce amyloid
● Histologically, a definitive diagnosis of malignancy should be restricted to tumors displaying evidence of vascular invasion, capsular invasion with growth into adjacent tissues, or metastases; criteria for vascular and capsular invasion are similar to those used in thyroid pathology: vascular invasion should be observed in the capsule or in the surrounding soft tissues
● As criteria for malignancy are mostly architectural and require adequate sampling, frozen sections are of little value
● Diffuse nuclear enlargement with macronucleoli suggests malignancy (J Cancer 2011;2:532)
● May have pseudofollicular pattern (Mod Pathol 2000;13:210)

Micro images
=========================================================================



Nests of neoplastic cells that are not very pleomorphic


Pseudofollicular pattern resembling thyroid


Invasion of adjacent soft tissue and muscle


Figure 1: infiltrates skeletal muscle
Figure 2: mitotic activity
Figure 3: MIB-1
Figure 4: PTH


Cytology images
=========================================================================



Guided aspirate showing highly cellular smear with stippled nuclear chromatin and moderate pleomorphism

Positive stains
=========================================================================

● Higher Ki-67 (4-6% or more, Mod Pathol 1997;10:12, Hum Pathol 2003;34:54, Hum Pathol 1995;26:135)
● Lower p27kip1 than adenomas/hyperplasia (Am J Surg Pathol 1999;23:288)
● Cyclin D1 (90%, Mod Pathol 1999;12:412)
● PAS (intracellular glycogen)
● PTH

Negative stains
=========================================================================

● TTF

Molecular / cytogenetics description
=========================================================================

● Recently described in multiple endocrine neoplasia type 1 (MEN 1), although not a classic finding (Mayo Clin Proc 2002;77:866, Clin Endocrinol (Oxf) 2007;67:370)
● One case of parathyroid carcinoma has been reported in MEN2A syndrome (Clin Endocrinol (Oxf) 1997;47:747)

Pathogenesis:
● Five genes with a potential role in malignancy have been identified and studied (J Bone Miner Res 2008;23:1869)
  1) p53
  2) Breast carcinoma susceptibility (BRCA2)
  3) Cyclin D1/parathyroid adenomatosis gene 1 (PRAD1)
  4) Retinoblastoma tumor suppressor gene (RB)
  5) Hyperparathyroidism 2 tumor suppressor gene (HRPT2); has provided the best evidence

Differential diagnosis
=========================================================================

Follicular thyroid carcinoma: PTH negative (Am J Surg Pathol 1983;7:535)



Neoplasms

Lipoadenoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare variant of parathyroid adenoma; ~ 35 cases reported
● Glandular elements associated with large areas of mature adipose tissue; usually functional; rarely associated with myxomatous stroma, metaplastic bone (Am J Surg Pathol 1978;2:3, Arch Pathol Lab Med 1977;101:28)
● Formerly called hamartoma (Am J Clin Pathol 1977;67:31)

Case reports
=========================================================================

● 40 year old man with myxoid lipoadenoma (Ann Diagn Pathol 2006;10:294)
● 41 year old woman with elevated serum calcium and parathyroid hormone levels (Indian J Pathol Microbiol 2006;49:404)
● 63 year old woman with ectopic atypical parathyroid lipoadenoma (J Bone Miner Metab 2012 Dec 22 [Epub ahead of print])
● Patient with large functioning parathyroid lipoadenoma in posterior mediastinum (Am J Clin Pathol 1981;76:89)
● Functioning tumor diagnosed by touch prep at frozen section (Arch Pathol Lab Med 1986;110:645)
● Two cases of functioning parathyroid hamartomas, one accompanied by proliferating fat and the other by a myxomatous, fibrillar stroma (Am J Clin Pathol 1977;67:31)

Micro images
=========================================================================



Islands of chief cells in abundant fat



Neoplasms

Lipothymoadenoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Benign thymic, adipose and parathyroid tissue
● Combines features of thymolipoma and lipoadenoma of parathyroid gland

Case reports
=========================================================================

● 54 year old woman with 10 year history of hyperparathyroidism (Arch Pathol Lab Med 1993;117:312)



Neoplasms

Other neoplasms


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Langerhans cell histiocytosis (Mod Pathol 2001;14:111)

Micro images
=========================================================================



Langerhans cell histiocytosis cells spilling into the adjacent parathyroid gland, composed of clear cells



Neoplasms

Spread from other tumors


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

Papillary thyroid carcinoma: parathyroid gland involvement found in 2%; either
(a) direct invasion with infiltrative pattern
(b) direct invasion with expansile growth pattern and formation of pseudocapsule
(c) metastases (Arch Pathol Lab Med 2002;126:1511)

Gross description
=========================================================================

● Usually >1 cm; 30% are 1 cm or less

Micro images
=========================================================================



Various images of papillary carcinoma invading parathyroid gland



Neoplasms

Frozen section


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update January 2013
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Communication with surgeon important
● Weigh, measure and freeze largest gland
● Algorithm: presumed adenoma if rim of normal tissue, diffuse chief cell growth, no fat, bizarre nuclei; if these criteria not met, examine at least one more gland
● Oil Red O fat stain may be helpful if little fat in suspect gland and abundant fat in normal appearing gland (Am J Surg Pathol 1981;5:381, Hum Pathol 1985;16:1255)
● Density gradient measurements: denser tissue sinks in 25% mannitol solution, implies more parenchymal cells / abnormal glands
● Parathyroid tissue usually lacks birefringent calcium oxalate crystals detectable by polarized light microscopy that are present in thyroid tissue (Am J Surg Pathol 2002;26:813)
● Fewer thyroid frozen sections are now performed (Virchows Arch 2008;453:433)

Micro images
=========================================================================



Various images


Thyroid with a pattern resembling parathyroid neoplasm (DD)

Cytology description
=========================================================================

● In touch preparations, parathyroid tissue appears as clusters of cells vs. discohesive lymphocytes and histiocytes in lymph nodes mistaken as parathyroid gland (Am J Surg Pathol 2000;24:158)
● Parathyroid: moderately cellular, small uniform cells in isolation/small groups with round/oval nuclei, salt and pepper chromatin, occasional naked nuclei, delicate vacuoles in cytoplasm and in background (Arch Pathol Lab Med 2003;127:64)
● Cytology plus frozen section is more accurate than either alone (Am J Clin Pathol 2002;118:895)
● Rapid intraoperative parathyroid hormone assay of needle aspirates is an accurate method of distinguishing parathyroid from nonparathyroid tissues during FNA as well as parathyroidectomy (Am J Otolaryngol 2011;32:574, World J Surg 2010;34:538)

Differential diagnosis
=========================================================================

● Coexisting parathyroid and nodular thyroid disease
● Intrathyroidal parathyroid glands with conspicuous follicle formations or abundant oncocytic cells mimics thyroid tissue
Solitary thyroid nodules with fatty stroma: see Am J Surg Pathol 1998;22:538
● Thyroid tissue with parathyroid pattern: see Mod Pathol 2000;13:210

End of Parathyroid gland > Superpage


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