Pathology of the parathyroid glands in hyperparathyroidism

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Abstract

This paper reviews the embryology, histology and pathology of the human parathyroid glands. It emphasizes those pathologic lesions which are found in the setting of clinical hyperparathyroidism. Also discussed are certain molecular features of hyperfunctioning parathyroid glands. The difficulties encountered in parathyroid FNA are reviewed and illustrated.

Introduction

Hyperparathyroidism is an ancient disease, examples of which have been found dating back to the Early Neolithic Period, around 7000 years ago. Zink et al.1 performed detailed radiologic and histopathologic examination of a Neolithic skeleton of a 25- to 35-year-old woman and found pathognomonic findings of primary hyperparathyroidism. Similarly, Cook et al.2 using bone histomorphometry reported skeletal manifestations of hyperparathyroidism in a Roman period skeleton from Dakhleh Oasis, Egypt. The link between bone disease and parathyroid gland was first made by Friedrich Schlaugenhaufer in 1915, who observed that most often only one of the four parathyroid glands was enlarged in patients with bone disease and suggested that the parathyroid gland abnormality was the cause and not the consequence of skeletal disease.3., 4., 5.

Most parathyroid specimens seen by the surgical pathologist are obtained from patients with hyperparathyroidism; however, a small number are excised during neck exploration for thyroid or laryngeal disease. A parathyroid gland may be removed purposefully or inadvertently during certain head and neck surgical procedures. In the case of inadvertent removal, the cause may be due to variabilities in the anatomic location of the gland or the misinterpretation of parathyroid tissue as thyroid or lymph node.6., 7., 8.

In this review, we will discuss the embryological development, anatomy, and normal histology and emphasize the pathological conditions associated with hyperparathyroidism.

Parathyroid glands are endodermal in origin and are derived from third and fourth branchial pouches. The superior pair develops from the fourth pouch and is most commonly located near the posterior and middle aspects of the thyroid. The inferior parathyroids originate from the third branchial pouch and are found at the inferior poles of thyroid or in the thyro-thymic ligament. Abnormalities in the descent of the parathyroids from their origin to the final destination can cause the glands to reside anywhere along their embryologic pathway from the upper portions of the neck to the upper thoracic inlet. Some parathyroid glands are located within other organs, such as thymus, thyroid, esophagus, or larynx.9., 10., 11., 12.

A majority of normal individuals (>80%) have four parathyroid glands; however, in some cases, 1–12 glands can be present. Data from autopsy studies indicate that the most common deviations in the number are three glands (approximately 1–7% of cases) and five glands (3–6% of studied individuals).9., 10., 13., 14.

As mentioned above, parathyroid glands can be found in abnormal locations due to variations in their embryologic descent. Variable location is more commonly seen in the inferior glands as compared to superior parathyroids, which are found in their normal position in about 80% of individuals.15., 16., 17. The abnormal locations for inferior parathyroids include posterior to thyroid, para-tracheal area, and close to or within the thymus or thyroid. (Most “intrathyroidal” parathyroid glands are really located within indentations of the thyroid gland appearing surgically to be within the thyroid, but truly still found in the perithyroidal fat.) The deviations in the location of superior parathyroids include posterior neck, retropharyngeal–esophageal space, carotid sheath, and posterior mediastinum.17., 18., 19., 20., 21., 22., 23., 24., 25., 26.

The parathyroid glands are oval to reniform soft and light yellow to brown in color and measure between 2 and 7 mm in length, 2–4 mm in width, and 0.5–2 mm in thickness. The color of parathyroid glands is dependent on fat content, degree of vascular congestion, and number of oxyphil cells. Parathyroid glands can vary in weight from a few milligrams to more than 70 mg (average: around 35–55 mg); the weight is highly dependent on sex, race, and nutritional status of the individual. The average combined weight of the all parathyroids in the normal adult male is approximately 120 mg and in females is 145 mg.13., 27., 28.

A thin fibrous capsule envelops each parathyroid and extends into the parenchyma delineating it into multiple lobules. The parathyroid glands consist of parenchymal cells, fat cells, and fibrovascular stroma (Fig. 1).27., 28. The parenchymal cells are usually arranged in nests and cords, nourished by a rich capillary network. The functional cells of the parathyroid are mainly of chief cell type, although other cell populations (oxyphil cells, clear cells, and transitional oxyphil cells) are also found.27 Most authors believe that these different parenchymal cell types reflect morphologic expression variabilities of chief cells.27., 29., 30., 31. Chief cells are polygonal in shape and contain a slightly eosinophilic cytoplasm and small round nucleus. The oxyphil cells or oncocytes show dense eosinophilic cytoplasm and small nuclei. Clear cells are a form of chief cells with abundant cytoplasmic glycogen; these are usually seen in parathyroids of embryos and fetuses and their number significantly declines with age.31., 32. Cells with cytologic features intermediate between chief cells and oxyphil cells are termed as transitional oxyphil cells. The number of oxyphil and transitional oxyphil cells is small at birth; however, it increases with age (oxyphil cells often arranged in tiny nodules are seen after puberty).33., 34., 35.

The stromal fat content of a parathyroid gland is on an average 50%. The number varies with nutritional status and weight of the individual.36., 37.

Hypercalcemia in most patients, especially if it is asymptomatic or associated with mild symptoms, is due to pathological lesions of the parathyroids. Up to 90% or more of cases of hypercalcemia are due to primary hyperparathyroidism.38., 39., 40., 41., 42., 43.

Hyperparathyroidism can be divided into primary, secondary, and tertiary types. Primary hyperparathyroidism is characterized by inappropriate secretion of the parathyroid hormone (PTH) from enlarged parathyroid glands in the absence of a known stimulus leading to hypercalcemia.42., 43. Secondary hyperparathyroidism is an increase in parathyroid hormone most commonly in response to hypocalcemia or hyper-phosphatemia associated with renal failure.44., 45. Tertiary hyperparathyroidism refers to autonomous parathyroid hyperfunction in patients with secondary hyperparathyroidism.46

PHP is a common disorder of the parathyroid gland and can occur in all age groups, but peaks in sixth decade, with a female to male ratio between 2 and 3:1; it is rare in children. PHP is defined by an elevation of serum-ionized calcium in the setting of an inappropriate elevation of PTH.15., 42. Serum phosphorus is typically in the lower normal range in PHP due to phosphaturic action of PTH at the proximal renal tubule. There is an elevation of alkaline phosphatase along with other markers of bone formation and resorption; in some cases, elevated serum chloride and bicarbonate are also seen.47., 48. Interestingly, 70–80% of patients affected by PHP are asymptomatic and are diagnosed on routine blood chemistry.49 The clinical presentation of PHP includes hypercalciuria, nephrolithiasis, osteoporosis, and neuromuscular changes (fatigue, weakness, and cognitive changes).49 Advanced disease is characterized by severe skeletal demineralization i.e. osteitis fibrosa cystica.39., 40.

Ultrasonography and 99mTc-sestamibi scintigraphy are commonly utilized imaging modalities in the preoperative localization of the affected parathyroid gland(s). Both modalities share similar sensitivities and specificities in the detection of solitary parathyroid adenoma. Contrast-enhanced CT and MRI are less commonly employed in the preoperative localization of parathyroid adenoma; however, they have been found to be more useful in the event of a failed parathyroidectomy due to ectopic parathyroid glands.14., 50.

The cause of sporadic PHP is unknown. In some patients, head and neck irradiation as low as 0.5 Gy during childhood has been associated with increased incidence of parathyroid adenomas.51., 52., 53., 54., 55.

The cyclin D1 gene (CCND1) or parathyroid adenomatosis 1 (PRAD1) was the first identified oncogene in a study of several large sporadic parathyroid adenomas harboring DNA gene rearrangements that involved the PTH gene locus on chromosome 11. CCND1/PRAD1 is overexpressed in 20–40% of sporadic parathyroid adenomas and even higher in parathyroid carcinomas. Interestingly, no activating missense mutations in cyclin D1 coding region have been found in sporadic parathyroid adenomas. Furthermore, No somatic chromosomal rearrangements involving CCND1/PRAD1 have been found in parathyroid carcinoma or any germline chromosomal translocations or rearrangements involving the same have been seen in familial form of PHP.56., 57., 58., 59. It has been shown that MEN-1 gene could also be involved in the development of sporadic parathyroid tumors. Loss of one MEN-1 allele has been observed in 25–40% of sporadic parathyroid tumors, and an activating mutation of other allele could be demonstrated in 50% of these tumors.60., 61., 62.

The other genes implicated in the development of parathyroid tumors include Menin,63., 64. and germline mutations associated with the hypercalcemia, jaw tumor syndrome.65., 66. Comparative genomic hybridization (CGH) studies have shown recurrent loss of chromosomal DNA at the 1p, 6q, 9p, and 13q loci in both benign and malignant thyroid tumors.67., 68. These results indicate the potential presence of tumor suppressor oncogenes involved in parathyroid neoplasia.

The pathologic lesions responsible for primary hyperparathyroidism include adenoma, atypical adenoma, double adenoma, multigland hyperplasia, and rarely, carcinoma.

Parathyroid adenoma is the single most common cause of primary hyperparathyroidism. The incidence of parathyroid adenoma is reported between 30% and 90%; this variation is due to lack of application of standardized diagnostic pathologic criteria. In reality, sporadic hyperparathyroidism is caused by a single adenoma in at least 80% of patients. Adenomas are more common in females than males with a ratio of about 3 to 1.27., 69., 70., 71., 72.

Parathyroid adenoma can originate in any of the four parathyroid glands, but is more common in the lower glands.27., 42. About 10% of the adenomas are found at ectopic sites, including the mediastinum (often within the thymus), thyroid, esophagus, and within the retroesophageal tissue.

Grossly, adenomas are oval or kidney-shaped, red brown in color, and soft in consistency (Fig. 2).15., 17., 42., 72. Larger adenomas (greater than 800 mg) may replace the entire parathyroid gland or a grossly visible yellow-brown rim of residual parathyroid may be identified.73., 74., 75., 76. In some cases the adenoma is multilobated, which may account for its incomplete excision. Some pathologists believe that the remaining normal parathyroid rim is a reliable criterion for the diagnosis of adenoma; however, it is seen in only 50–60% of cases, and its absence does not preclude the diagnosis of adenoma.42., 72., 77. Parathyroid adenomas can markedly vary in size and weight; the size can range from less than 1 to over 3 cm; similarly the weight can range from 150 mg to several grams.43., 72.

By light microscopy, adenomas are usually circumscribed but not encapsulated. The tumor cells are usually arranged in nests and cords surrounded by a rich capillary network. Chief cells are the dominant cell types in the majority of parathyroid adenomas; oxyphil cells and transitional oxyphil cells can also be seen in varying proportions scattered within the collections of chief cells (Fig. 3).43., 78. Some adenomas are comprised exclusively of oxyphil cells, the so-called “oxyphil adenomas” (Fig. 4).79., 80. In our experience, these tumors tend to be larger than the chief cell adenomas and the serum calcium tends to be minimally elevated.81

The chief cells in adenomas can exhibit nuclear pleomorphism, multinucleation, and giant cell formation.42., 43., 78. Some authors have indicated that the presence of random nuclear atypia is reassuring that a parathyroid tumor is benign.82., 83. Mitotic figures are uncommon in adenomas; however, they can be encountered in a few cases.84 It has been suggested that the presence of mitoses in a parathyroid parenchymal cell is indicative of malignancy; however, this observation has been questioned.85., 86. Many authorities believe occasional normal mitotic figures in an otherwise classical adenoma is insufficient evidence of a malignant tumor.77., 84., 87.

Parathyroid adenomas can show cystic degeneration; the fluid within the cyst contains parathyroid hormone.55., 88., 89. Other degenerative changes are more commonly seen in large tumors and include fibrosis, hemorrhage, cholesterol clefts, hemosiderin, and calcification.42., 77. Increasingly, enlarged parathyroids are noted on ultrasound examination of the neck and may be interpreted as thyroid nodules.81., 90. Fine-needle aspiration of these “thyroid” nodules may be performed and posttraumatic changes can occur in the parathyroid tumor (infarction, fibrosis, distortion, cholesterol clefts, hemosiderin, and mitotic figures as part of the healing) (Fig. 5).91

Adenomas are virtually devoid of adipocytes, which are only observed in the normal rim of the compressed parathyroid. Rarely some cases of adenomas can show collections of adipocytes, which can be mistaken for normal parathyroid. Parathyroid adenoma is considered single-gland disease; however, double adenomas have been reported. The proposed criteria for this diagnosis include presence of two enlarged hypercellular glands and the identification of at least one other normal parathyroid. Long-term follow-up after excision of double adenomas must demonstrate lack of recurrence of hypercalcemia to accept this diagnosis; unfortunately, some patients with double adenomas represent metachronous four-gland disease, i.e. hyperplasia and the true nature of the cause of hyperparathyroidism in these cases may become apparent only after prolonged follow-up.92., 93., 94., 95. In a recent study from our institution (unpublished findings), of over 700 consecutive parathyroidectomies performed by one surgeon, the incidence of double adenoma was 3.2%. These operations were performed with intraoperative parathyroid hormone measurements, and the patients were cured (eucalcemic) on follow-up.

These are rare parathyroid neoplasms, which were initially described as parathyroid “hamartoma.”96 They usually occur in the neck, but cases have been reported in superior and posterior mediastinum. Most of these are functional tumors and are associated with hyperparathyroidism.97., 98., 99. Grossly, lipoadenomas are circumscribed, rarely encapsulated, yellow-tan in color, and show a lobulated cut surface. By light microscopy, these consist of mature adipose tissue or myxoid stroma and nests of parathyroid parenchyma. In some cases, other mesenchymal elements including metaplastic bone can be seen. The parenchymal component of the lipoadenomas includes chief cells and some oncocytic cells. Lipoadenomas are often large and weigh several grams (some have been over 100 g).99., 100. However, the elevation of serum calcium is modest; this probably reflects the amount of parathyroid parenchyma in these tumors, which equals the size and weight of a usual parathyroid adenoma.101

Primary parathyroid hyperplasia is defined as proliferation of the parenchymal cells leading to increase in gland weight in multiple parathyroid glands in the absence of a known stimulus for parathyroid hormone secretion.

Two types of parathyroid hyperplasia are seen, the more common chief cell hyperplasia and the rare water cell or clear cell hyperplasia.80., 82., 83.

It is estimated from the literature that approximately 15% of hyperparathyroidism are caused by parathyroid hyperplasia.80., 82. (Although some reports indicate that about half of all hyperparathyroidism is caused by hyperplasia; this reflects variations in pathologic criteria in evaluating the glands.) Of this group of patients with hyperplasia, about 30% are familial (familial hyperparathyroidism or multiple endocrine neoplasia (MEN) syndrome).102., 103.

It has been shown that hyperplasias and adenomas are monoclonal proliferations.104., 105. Parathyroid hyperplasia associated with MEN I involves allelic deletions on chromosome 11. This suggests that the monoclonal proliferations may develop after a phase of polyclonal hyperplasia.

On gross examination, all four glands are enlarged and the combined weight can range from 150 mg to over 20 g, but usually it is in the range 1–3 g. Chief cells form the dominant cell types; however, one may also observe intermixed oxyphil cells and transitional oxyphil cells. The cells are usually arranged in a solid, trabecular, or nodular pattern (Fig. 6). Nodule formation can also be seen leading to asymmetrical gland enlargement.42., 43., 78.

The cytoplasmic fat in chief cells is either reduced or absent (Fig. 7). The nodular areas are usually devoid of fat, whereas the ones between the nodules may contain fat. Nuclear pleomorphism and mitoses are rarely found in primary hyperplasia.106., 107.

This rare condition is characterized by proliferation of vacuolated water-clear cells in multiple parathyroid glands (Fig. 8). It is more common in females and causes pronounced hypercalcemia and severe clinical disease. This is the only parathyroid disorder in which the superior glands are larger than the lower pair of glands. The affected glands tend to be larger and irregular in shape, and the proliferating cells may infiltrate into the surrounding tissue of the neck.108., 109., 110., 111.

Section snippets

Parathyroid carcinoma

Parathyroid carcinoma is a rare endocrine malignancy112; it is seen in 0.5–2% of cases of primary hyperparathyroidism (PHP). There appears to be an equal sex predilection, whereas adenomas are most commonly seen in females. Patients with parathyroid carcinoma are younger than those with adenoma and usually present with profound hypercalcemia (>14–15 mg/dL), and/or with systemic manifestation related to hypercalcemia, e.g. nephrolithiasis, renal failure, and bone disease.113., 114. Mild

Familial hyperparathyroidism

Primary hyperparathyroidism can present as a manifestation of MEN I and II or as a familial disease without the involvement of other endocrine organs.

Parathyroid cysts

Parathyroid cysts are rare and commonly occur in the neck and usually involve lower parathyroids; however, some have been reported in the mediastinum. Parathyroid cysts are more common in females; these lesions are usually large ranging in size from 1 to 6 cm. Mediastinal parathyroid cysts can be mistaken for superior/anterior mediastinum tumors. These cysts may also contain fragments of thymic tissue and are sometimes referred to as third pharyngeal pouch cysts.78., 89., 150., 151.

Grossly,

Intraoperative assessment of parathyroid—Old and new

The intraoperative assessment of parathyroid gland during parathyroidectomy is usually limited to identification of the tissue. This procedure usually involves, correct labeling, gross examination measurement, and weighing the specimen. The representative sample is frozen and stained with hematoxylin and eosin stains.161., 162., 163. Usually the identification of parathyroid tissue is not difficult (accuracy rates of correct identification of tissue as parathyroid ranges up to 99%)7; however,

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