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Parathyroid hyperplasia is defined as an absolute increase in the mass of the parenchymal cells of the parathyroid gland. The vast majority of cases are secondary to a hyperplasia of the chief cells. Patients present with increased production of parathyroid hormone leading to an increase in serum calcium. The presenting symptoms are similar to patients with parathyroid adenomas. The pathologist is often called upon to render a frozen section diagnosis. The most important bit of information is the status of the other parathyroid glands. If all or most of the glands are enlarged, a diagnosis of hyperplasia is likely. If only one gland is enlarged, a diagnosis of adenoma is favored. This gross clinical impression is then corroborated under the microscope slide.


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SYNONYMS Nodular hyperplasia
Multiple adenomatosis
Chief cell hyperplasia
INCIDENCE Has been found in up to 7% of routinely examined parathyroid glands studied at autopsy


MEN I Parathyroid involved in 90% of cases
MEN II Parathyroid involved in 30-40% of cases

Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene.

Groupe D'etude des Tumeurs a Calcitonine. Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, Chabre O, Boneu A, Caron J, Houdent C, Modigliani E, Rohmer V, Schlumberger M, Eng C, Guillausseau PJ, Lenoir GM.

Laboratoire de Genetique, Hopital Edouard Herriot, Lyon, France.

J Clin Endocrinol Metab 1998 Feb;83(2):487-91 Abstract quote

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial.

To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability.

The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.


In MEN syndromes, the proliferations are actually monoclonal Inherited locus on 11q13 for MEN I
MEN II cases

Locus for INT2 oncogene and MEN I focues closely linked

INT2 encodes a protein of the fibroblast growth factor

Allelic Loss in Parathyroid Neoplasia Can Help Characterize Malignancy.

Hunt JL, Carty SE, Yim JH, Murphy J, Barnes L.

From the Department of *Pathology and daggerSurgery, University of Pittsburgh Medical Center, Pittsburgh, PA.

Am J Surg Pathol. 2005 Aug;29(8):1049-1055. Abstract quote  

Parathyroid carcinoma can be difficult to diagnose, and the final pathologic diagnosis relies on clinicopathologic correlation. Clinical features of malignancy include high preoperative calcium levels and an intraoperative impression that the gland is adherent to local structures.
Histologic features of malignancy include increased mitoses, vascular invasion, and broad bands of fibrosis.

This study used molecular genotyping to assess parathyroid neoplasia for loss of heterozygosity across a panel of known tumor suppressor genes that have been previously identified as being important in the pathogenesis of parathyroid diseases. Parathyroid adenomas, hyperplasia, and carcinomas were included in the study, and a fractional allelic loss was calculated for each lesion. Losses of 1q25, 7q13.3, 10q23, 13q14.3, and 11p15.5 were particularly prevalent. In addition, almost all adenomas and carcinomas had loss of the markers for 1p.

The benign parathyroid diseases (adenomas and hyperplasia) had low mean fractional allelic loss (11% and 15%, respectively). The parathyroid carcinomas, in contrast, showed high mean fractional allelic loss (63%). This difference in the mutational profile suggests that this type of assay may be useful as an adjunctive diagnostic test in cases of parathyroid neoplasia.


Rapid intraoperative parathyroid hormone testing with surgical pathology correlations: the "chemical frozen section".

Guarda LA.

Department of Pathology, Florida Hospital Medical, Center, Orlando.
Am J Clin Pathol. 2004 Nov;122(5):704-12. Abstract quote  

The classic surgical approach to patients undergoing parathyroidectomy for primary or secondary hyperparathyroidism has experienced a dramatic shift owing to preoperative localization of the affected glands and/or the use of rapid intraoperative parathyroid hormone (RI-PTH) assays, allowing for minimally invasive surgical excisions. Institutional experience with 141 patients who underwent parathyroidectomy aided by the use of RI-PTH is reviewed.

The orientation provided by the intraoperative assay is essential in guiding the surgeon in these minimally invasive procedures, it helps reveal the cases of primary hyperparathyroidism with involvement of more than 1 gland, and it replaces the need for performing frozen sections, except for cases of secondary hyperparathyroidism.


Typical All glands are enlarged
Pseudoadenomatous variant Considerable variation in the extent of gland enlargement
Occult All of the glands are minimally enlarged with subtle microscopic evidence of hyperplasia
Secondary hyperparathyroidism

Adaptive increase in parathyroid parenchymal mass secondary to a known stimulus resulting in increased parathyroid hormone secretion

Chronic renal disease
Vitamin D deficiency

Tertiary hyperparathyrodism

Autonomous parathyroid hyperfunction in patients with previously documented secondary hyperparathyroidism

1/3 of kidney transplant patients
Adenomatous or hyperplastic changes



Chief cells arranged in diffuse or nodular pattern

Fat cells usually contain decreased amounts of fat compared to normal or suppressed chief cells

Rarely glands may show prominent deposits of intraparenchymal fat

Parathyromatosis Multiple parathyroid nests in the soft tissues of the neck or mediastinum

Parathyroid hyperplasia in primary hyperparathyroidism: a review of 85 cases.

Castleman B, Schantz A, Roth S.

Cancer 1976 Oct;38(4):1668-75 Abstract quote

Parathyroid hyperplasia of all four glands was found to be the cause of primary hyperparathyroidism in 85 of 557 cases seen at the Massachusetts General Hospital between 1930 and 1973.

There were 66 cases of chief cell hyperplasia and 19 cases of clear cell hyperplasia that were grossly, microscopically, and ultrastructurally distinct. Although the clinical findings overlap, there are several differences in the signs and symptoms between these two forms of hyperplasia. Both types are treated by subtotal removal of all the parathyroid tissue. Removal of insufficient tissue has left residual hyperparathyroidism in 45% of those with chief cell hyperplasia and 11% of those with clear cell hyperplasia after what was thought to be definitive surgery. Postoperative hypoparathyroidism was found in 15% of the patients with chief cell hyperplasia and in none with clear cell hyperplasia.

These findings further suggest that removal of three and one-half glands in the more than 86% of patients with one gland involvement (adenoma or carcinoma) as the cause of primary hyperparathyroidism is unwarranted.

CLEAR CELL HYPERPLASIA Proliferation of water-clear cells in multiple parathyroid glands, usually in diffuse pattern of growth
Secondary Parathyroid Hyperplasia in Tuberous Sclerosis
Report of a Case With Large Eosinophilic Ganglion-Like Cells Similar to Those of Subependymal Giant Cell Astrocytoma, Tubers, and Atypical Angiomyolipoma

Howard L. Martin, M.D ; Edward Lee, M.D. ; Jorge Albores-Saavedra, M.D.

From the Division of Anatomic Pathology, Department of Pathology (H.L.M., J.A.-S.), University of Texas Southwestern Medical Center, Dallas, Texas; and the Department of Pathology (E.L.), Veterans Affairs Medical Center, Dallas, Texas, U.S.A.

Am J Surg Pathol 2002;26:260-265 Abstract quote

We report a case of secondary parathyroid hyperplasia in a 49-year-old man with tuberous sclerosis.

Two parathyroid glands had collections of large, eosinophilic ganglion-like endocrine cells that to our knowledge have not been previously described at this site. These cells are morphologically similar to those of subependymal giant cell astrocytoma, tubers, and atypical angiomyolipoma, all of which may arise in the setting of tuberous sclerosis. These large, eosinophilic ganglion-like cells found in different affected organs appear to be distinctive of tuberous sclerosis.

We suggest these large eosinophilic cells arise from a common stem cell precursor that acquires variable phenotypes according to alterations in the cellular microenvironment.


Parathyroid adenoma

The gross inspection of the other parathyroid glands is most important

In general, for hyperplasia, there should be enlargement of 2 or more glands, adenomas usually involve a single gland

Abundance of intraparenchymal fat in a normal sized gland indicates suppression and would support the diagnosis of adenoma in the enlarged gland

Histologic diagnosis of primary hyperparathyroidism: a concordance analysis between three pathologists.

Bornstein-Quevedo L, Gamboa-Dominguez A, Angeles-Angeles A, Reyes-Gutierrez E, Vargas-Vorackova F, Gamino R, Herrera MF.

Department of Pathology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.

Endocr Pathol 2001 Spring;12(1):49-54 Abstract quote

Primary hyperparathyroidism (HPT) is caused by a parathyroid adenoma, hyperplasia or carcinoma. Difficulties for the histologic diagnosis of abnormal parathyroid tissue are widely recognized.

The aim of the study was to evaluate the reproducibility of the morphologic criteria through a concordance study among three pathologists. Representative slides of 40 patients with biochemically primary HPT stained with hematoxylin and eosin were blindly reviewed by three pathologists. Each pathologist established the diagnosis of adenoma or hyperplasia and assessed the presence of fat cells, a rim of normal tissue, a fibrous capsule, the number of cellular types, the lobular pattern, and the characteristics of the blood vessel's wall. A concordance analysis was then performed. Mean age of the group was 55 +/- 14 yr, 7 were males and 33 females. The concordance analysis among the three pathologists for the differential diagnosis between adenoma and hyperplasia, showed a Kappa index of 0.5. Kappa index for the presence of fat cells was 0.56, for the presence of a rim of normal tissue 0.47, and for the number of cellular types 0.29.

The concordance for the differential diagnosis between parathyroid adenoma and hyperplasia in this study was low.

P53 as a marker of differentiation between hyperplastic and adenomatous parathyroids.

Ricci F, Mingazzini PL, Sebastiani V, D'Erasmo E, Letizia C, De Toma G, Alo PL.

Departments of Experimental Medicine and Pathology, Internal Medicine, and Surgery "Pietro Valdoni," University of Rome La Sapienza, Rome, Italy.

Ann Diagn Pathol 2002 Aug;6(4):229-35 Abstract quote

Primary hyperparathyroidism is the clinical result of parathyroid adenoma or hyperplasia, rarely of carcinoma. Clinical, serologic, and radiologic data are unable to discriminate a single parathyroid adenoma from an enlarged hyperplastic gland. Morphologic features also overlap in adenoma and small hyperplastic gland.

Studying immunohistochemical expression of fatty acid synthase (FAS), p53, Ki67 and bcl-2, we found that among 21 adenomas 19 (90.5%) were positive for FAS, 12 (57.2%) for Ki67, 11 (52.4%) for p53, and 16 (76.2%) for bcl-2; among 12 hyperplasias, 12 (100%) were positive for FAS, 6 (50%) for KI67, 8 (66.7%) for p53, and 8 (66.7%) for bcl-2. Statistical analysis showed that FAS was associated with parathormone (PTH) (P =.001), Ki67 (P =.01), and p53 (P =.01). Moreover, FAS was associated with hyperplastic (P =.0001) and adenomatous glands (P =.0001). Ki67 was associated with both adenomatous (P =.02) and hyperplastic glands (P =.005). P53 protein were associated only with hyperplastic glands (P =.01).

The different occurrence of p53 in parathyroids adenoma and hyperplasia may enable a different management and follow-up of the patients with primary hyperparathyroidism, stratifing them into two groups. The first, with a "false" adenoma having a high risk of relapse, may necessitate exams like serum calcium levels, PTH concentrations, urinary calcium levels for 24 hours, kidney functional tests, and radiology and ultrasound every 3 to 6 months, whereas the second with "true" adenoma, at low risk of relapse, may be checked less frequently with serum calcium levels and PTH concentrations.


Prognostic Factors Following surgery, recurrent hypercalcemia in 16% from 1-16 years following surgery
Treatment Subtotal parathyroidectomy

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
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DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Multiple Endocrine Syndrome (MEN Syndromes)

Parathyroid glands

Parathyroid Adenoma

Parathyroid Carcinoma

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Last Updated August 3, 2005

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