Thyroid & parathyroid
Parathyroid nonmalignant
Parathyroid gland hyperplasia
Authors: Rita Hayes, M.D., Sylvia L. Asa, M.D., Ph.D.
Editorial Board Member: Marc Pusztaszeri, M.D.
Deputy Editor-in-Chief: Kelly Magliocca, D.D.S., M.P.H.
Last author update: 19 June 2025
Last staff update: 19 June 2025
Copyright: 2003-2025, PathologyOutlines.com, Inc.
PubMed Search: Parathyroid gland hyperplasia
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Additional references | Practice question #1 | Practice answer #1 | Practice question #2 | Practice answer #2Cite this page: Hayes R, Asa SL. Parathyroid gland hyperplasia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/parathyroidpthhyper.html. Accessed August 31st, 2025.
Definition / general
- Absolute increase in nonneoplastic parathyroid parenchymal cells in multiple parathyroid glands
- Secondary hyperparathyroidism: compensatory proliferation of parathyroid parenchyma
Essential features
- Primary hyperparathyroidism, required to be in the absence of a physiological stimulus, is very rarely if ever associated with an increase in nonneoplastic parathyroid cells; it has now been classified as neoplastic and the previous use of hyperplasia in patients with germline predisposition (e.g., multiple endocrine neoplasia [MEN] syndromes) is now recognized as multiglandular adenomas
- Secondary hyperparathyroidism is a compensatory diffuse hyperplastic response to persistent low calcium levels, high serum phosphate or vitamin D deficiency
- Tertiary hyperparathyroidism is neoplastic proliferation arising in hyperplasia and giving rise to autonomous secretion of parathyroid hormone (PTH) in the setting of prolonged secondary hyperparathyroidism; necrosis, fibrosis or hemorrhage in a dominant nodule should prompt evaluation for malignancy
ICD coding
Epidemiology
- Primary hyperparathyroidism: see multiglandular adenomas
- Water clear cell hyperplasia: no known cause or specific genetic predisposition
- Secondary hyperparathyroidism: chronic kidney disease, vitamin D deficiency
- ~50% of the world population has vitamin D deficiency (Front Nutr 2023;10:1070808)
- Chronic kidney disease affects ~15% of the U.S. population (Kidney Int Suppl (2011) 2022;12:7)
- Tertiary hyperparathyroidism: neoplasm arising in a background of secondary hyperplasia
Sites
- Parathyroid glands, usually perithyroidal but also in the mediastinum
Pathophysiology
- Secondary: renal insufficiency leading to hypocalcemia, hyperphosphatemia and low 1,25 dihydroxyvitamin D3 with compensatory increase in parathyroid hormone and chief cell proliferation
- Tertiary: loss of parathyroid hormone receptors and mutation accumulation in parathyroids with secondary hyperplasia
Etiology
- Secondary: renal failure, hypocalcemia, low 1,25 dihydroxyvitamin D3 (Clin J Am Soc Nephrol 2011;6:913)
- Tertiary: prolonged untreated secondary hyperparathyroidism (Clin Ter 2021;172:241)
Clinical features
- Bone remodeling, deformities, fractures (J Am Soc Nephrol 2004;15:2208)
- Extraosseous calcification, kidney stones (Urol Clin North Am 2000;27:275)
- Psychologic and neurologic manifestations (Front Surg 2022;9:885188)
Diagnosis
- PTH, calcium, phosphorus, vitamin D levels, renal function (Clin J Am Soc Nephrol 2011;6:913)
Laboratory
- Increased PTH (Clin J Am Soc Nephrol 2011;6:913)
- Decreased vitamin D
- Decreased calcium
- Biochemical features of renal failure
Radiology description
- Parathyroid enlargement (not usually visible on imaging)
- Sestamibi scan unusually nonlocalizing (Sci Rep 2019;9:14634)
- Brown tumors of bone (rare) (Am J Otolaryngol 1996;17:407)
Prognostic factors
- Increased chance of recurrence if multiple foci are present, increased mitotic index, nodularity or persistent renal disease (Cancer 2007;110:255)
Case reports
- 49 year old man with surgically managed secondary parathyroid hyperplasia (Medicine (Baltimore) 2022;101:e31362)
- 50 year old woman with chronic malabsorption, renal disease and tertiary hyperparathyroidism (Cureus 2024;16:e70179)
- 58 year old woman with tertiary hyperparathyroidism after longstanding end stage renal disease with renal transplantation (CEN Case Rep 2021;10:208)
- 61 year old man with secondary hyperparathyroidism due to stage 4 chronic kidney disease in a background of autosomal dominant polycystic kidney disease and hypertension (Clin J Am Soc Nephrol 2020;15:1041)
Treatment
- Surgical excision
- Renal transplant (secondary hyperparathyroidism due to chronic kidney disease) (Ann Surg 2008;248:18)
- Recurrence - parathyromatosis; can make treatment more difficult, especially with the following features (Cancer 2007;110:255)
- Markedly nodular
- Highly proliferative
- Persistence of chronic renal failure
Gross description
- Secondary: diffuse enlargement > 1.2 g (Mod Pathol 2011;24:S78)
- Tertiary: dominant nodule present in an enlarged parathyroid
- Primary water clear cell hyperplasia > 1 g
- Upper glands heavier than lower glands
Gross images
AFIP images
Secondary
hyperparathyroidism,
diffuse parathyroid
hyperplasia
Secondary
hyperparathyroidism,
diffuse and nodular
parathyroid hyperplasia
Images hosted on other servers:
3.5 glands removed
Frozen section description
- Frozen section is not usually performed on the enlarged hyperplastic parathyroids
- If used, it is typically performed on a biopsy that is used only to confirm that the tissue is parathyroid, rather than lymph node or other mimics
Frozen section images
Contributed by Sylvia L. Asa, M.D., Ph.D.
Enlarged and hypercellular gland
Microscopic (histologic) description
- Secondary: increased parenchymal cells with decreased stroma (Chirurgia (Bucur) 2019;114:594)
- Increased fibrosis and nodularity with later development
- May have mitotic figures, necrosis and hemorrhage with later development
- May indicate carcinoma if nodular
- Water clear cell hyperplasia: clear cytoplasm, distinct cell borders, diffuse (Pathology 2021;53:852)
Microscopic (histologic) images
Contributed by Sylvia L. Asa, M.D., Ph.D.
Hyperplasia in vitamin D deficiency
Early secondary parathyroid hyperplasia
Diffuse parathyroid hyperplasia
Diffuse and nodular hyperplasia
Diffuse and nodular hyperplasia
Dominant adenoma arising in diffuse hyperplasia
Dominant adenoma arising in diffuse and nodular hyperplasia
Atypical parathyroid neoplasm
Diffuse and nodular hyperplasia
Water clear cell hyperplasia
Positive stains
- Parathyroid hormone, synaptophysin, chromogranin A, GATA3, CAM 5.2, CK7, CK8, CK18 and CK19 (Endocr Pathol 2018;29:113)
- GATA3 (Diagn Cytopathol 2021;49:70)
- Polyclonal PAX8 is nonspecific because monoclonal PAX8 is negative in parathyroid (Endocr Pathol 2018;29:91)
- CDC73 (parafibromin)
Negative stains
Sample pathology report
- Parathyroid, left superior, parathyroidectomy:
- Diffuse and nodular hyperplasia
Differential diagnosis
- Parathyroid adenoma:
- Nodules with surrounding unremarkable parathyroid tissue
- Individual glands involved
- PTH and calcium both elevated
- Parathyroid lipoadenoma:
- Enlarged parathyroid, > 1 g
- Grossly, yellow surface
- > 50% adipose component of the nodule
- Parathyroid carcinoma:
- Significantly elevated PTH and calcium
- Poorly circumscribed or invasive nodule
- Vascular or perineural invasion
- Metastasis
- Follicular thyroid adenoma:
- Well encapsulated nodule
- Abundant to scant colloid present
- Micro or macrofollicular architecture
- Cuboidal to columnar epithelium
- Clear to eosinophilic cytoplasm
- Uniform round nuclei with coarse chromatin
- No capsular or vascular invasion
- Often solitary but may arise in the setting of follicular nodular disease
- Atypical parathyroid tumor:
- Cytological atypia, calcifications, fibrosis or increased mitotic rate
- Negative for full thickness capsular invasion, angioinvasion or perineural invasion
- Positive for PTH, GATA3 and chromogranin A
- Elevated PTH and calcium levels between those of a parathyroid adenoma and carcinoma
- Often associated with prior neck manipulation
Additional references
Practice question #1
A 70 year old man with end stage renal disease undergoes surgical resection of an enlarged parathyroid gland. On examination, which of the following features is most concerning?
- Fibrosis within multiple small nodules
- Hemorrhage within a dominant nodule
- Markedly decreased stroma
- Weight over 1.2 g
Practice answer #1
B. Hemorrhage within a dominant nodule. The presence of hemorrhage within a dominant nodule warrants further evaluation for possible neoplastic changes. Answer D is incorrect because 1.2 g is the lower limit of weight for secondary parathyroid hyperplasia. Answer A is incorrect because fibrosis and multinodular development are routine findings in longstanding secondary parathyroid hyperplasia. Answer C is incorrect because decreased stroma is a feature of secondary parathyroid hyperplasia.
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Practice question #2
A 63 year old woman has surgical resection of an enlarged parathyroid gland. The specimen has the above histology. What lab values would be expected in this patient prior to excision?
- Decreased Ca2+, decreased PTH, decreased vitamin D
- Decreased Ca2+, increased PTH, decreased vitamin D
- Decreased Ca2+, increased PTH, increased vitamin D
- Increased Ca2+, decreased PTH, decreased vitamin D
- Increased Ca2+, increased PTH, increased vitamin D
Practice answer #2
B. Decreased Ca2+, increased PTH, decreased vitamin D. The finding of secondary parathyroid hyperplasia is a physiologic response to chronically decreased calcium levels, most often due to inadequate vitamin D production causing increased PTH levels. Answers D and E are incorrect because decreased calcium levels are a primary driver of increased PTH production. Answer A is incorrect because PTH levels should be elevated in the setting of parathyroid hyperplasia. Answer C is incorrect because increased vitamin D is a suppressor of parathyroid hyperplasia.
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