Pathology

Parathyroid glands consist of chief and oxyphil cells, fibrovas-cular stroma, and adipose tissue. Chief cells are identified in children and adults; oxyphil cells are mainly observed in adults. Chief cells constitute almost all the parenchyma and measure 6 to 8 pm in diameter; their cytoplasm contains argyrophilic granules and lipids. Clear cells have an optically clear cytoplasm as a result of glycogen loss during histologic processing. The total number of oxyphil cells grows with increasing age; however, this kind of cell is also identified in pediatric populations. It is associated with secretory functions, contrary to the usual point of view that these are degenerated cells.15

Parenchymal cells are arranged in solid sheets, cords, tubular structures, or, in 2% to 50%, microcystic formations. The admixture of stromal and adipose elements varies with age and function. The parenchyma-to-stroma ratio is used as an indicator of a normocellular or hypercellular gland; the median ratio is 50%, but the adipose tissue content varies from 40% to 70% (Fig. 38-5). Therefore, some authors consider the stromal-parenchymal index inadequate for separating normal from abnormal glands.16'17

Primary hyperparathyroidism can be produced by three different pathologic lesions: adenoma, hyperplasia, and carcinoma. The frequencies of these vary, mainly because of the use of different criteria for their diagnosis in the various series.

Adenoma

An adenoma is a benign neoplasm composed of chief cells, oncocytic cells, transitional oncocytic cells, or a mixture of these cell types. They are responsible for 80% to 90% of hyperparathyroidism cases and usually affect a single gland. Adenomas are more frequent in females than males, at a ratio of 3:1. Macroscopically, the affected gland is enlarged, tan-brown, ovoid, well limited or encapsulated, and occasionally with areas of hemorrhage or cystic spaces (Fig. 38-6). In smaller adenomas, a rim of normal glandular tissue is identified. The remaining glands are normal or atrophic.17

Histologically, adenomas are encapsulated tumors composed of cohesive sheets of cells surrounded by a fine capillary network. Occasionally, insular, tubular, trabecular, or acinar patterns are observed. Stromal fat is scant or absent, and the large, thick-walled veins typical of normal parathyroid glands are lacking. However, these two criteria, classically considered diagnostic of adenoma, have been regarded as less relevant.1718 A rim of normal glandular tissue is always identified in small lesions but is sometimes absent in large adenomas even if serial sections are made. On the other hand, adenomas are occasionally confused with hyperplastic nodules admixed with normal glandular tissue in cases of parathyroid hyperplasia. Because of the poor reproducibility of histologic criteria to differentiate parathyroid adenoma from hyperplasia, close cooperation between the pathologist and surgeon is recommended.19

In conclusion, a remnant of normal tissue is no absolute prerequisite for a diagnosis of adenoma and is identified in only 50% to 60% of proven adenoma cases (Fig. 38-7).

The precise histopathologic definition of parathyroid adenoma has remained elusive. Studies using molecular approaches have established that parathyroid adenomas are clonal proliferations. Some studies demonstrated clonal rearrangements of the parathyroid hormone gene and further evidence for clonality through the analysis of the hypoxan-thine phosphoribosyltransferase gene.20 Thus, the mono-clonality of adenoma cells is usually reflected by their monomorphic appearance, although cases with a mixed r.

FIGURE 38-5. A close 1:1 relation of epithelial and stromal cells is observed in normal glands from adults.

FIGURE 38-6. Macroscopic aspect of a parathyroid adenoma showing a nodular configuration with cystic degeneration in a brown gland.

FIGURE 38-7. Parathyroid adenoma. A rim of normocellular parathyroid tissue with adipose cells surrounds a proliferation of chief and oncocytic cells.

cellular population exist. The cells are larger than normal, and the nuclei show hyperchromasia, atypia, and an increased DNA content.21 Focally, there is syncytia formation, with variable numbers of nuclei surrounded by basophilic cytoplasm, probably as a result of cell degeneration.

Adenoma Variants

Oncocytic adenomas are rare neoplasms composed of oncocytic cells. Ultrastructural studies have revealed the presence of abundant mitochondria in the cytoplasm of oncocytic cells. The major criteria for the diagnosis of oncocytic adenomas, according to Wolpert and coworkers,22 are as follows:

(1) more than 90% of cells showing oncocytic features,

(2) histologically normal parathyroid tissue in a biopsy of another gland, and (3) postoperative normocalcemia.

Lipoadenomas (hamartomas) are lesions consisting of proliferation of stromal and parenchymal elements. Grossly encapsulated, lipoadenomas appear soft, yellow-tan, and lobulated. Histologically they are composed mainly of abundant adipose tissue with myxoid changes and fibrosis, admixed with chief and oncocytic cells arranged in thin branching cords.17

Hyperplasia

Primary parathyroid hyperplasia is defined as an absolute increase in chief cells, oncocytic cells, and transitional oncocytic cells mixed with stromal elements in multiple parathyroid glands, in the absence of a known stimulus for parathyroid hormone hypersecretion.17

Clinically, parathyroid hyperplasia does not differ significantly from adenomas. However, parathyroid hyperplasia is associated with the dominantly inherited multiple endocrine neoplasia (MEN) types 1 and 2. In contrast, parathyroid hyperplasia is generally absent in MEN 2B.23 In more than half of the cases, the hyperplastic glands weigh less than 1 g. According to macroscopic and microscopic morphology, three patterns of hyperplasia have been recognized: classic, pseudoadenomatous, and occult.24

FIGURE 38-8. Parathyroid hyperplasia. Nodular proliferation of parenchymal cells admixed with normocellular parathyroid tissue at the periphery of a hyperplastic gland.

In classic chief cell hyperplasia, these cells are mixed with oncocytic and transitional oncocytic cells. Stromal fat cells are decreased, and vascular supply is provided by large, thick-walled vessels. The parenchymal cells frequently show a nodular arrangement, usually at the beginning of the disease. These nodules consist of polygonal cells with abundant cytoplasm and a medium-sized or small, centrally located nucleus. In the internodular tissue, parenchymal cells are mixed with stromal elements (Fig. 38-8). In the occult form of parathyroid hyperplasia, confusion with a parathyroid adenoma or a large normal parathyroid gland can occasionally occur, and its functional significance is uncertain.

To distinguish between parathyroid hyperplasia and parathyroid adenoma, it is important to know the gross appearance of all glands at surgery.17 In primary chief cell hyperplasia, enlargement of more than two parathyroid glands is frequently observed, whereas the great majority of adenomas involve a single gland. Hence, no single morphologic parameter is able to resolve the differential diagnosis (Table 38-1); instead, the distinction between adenoma and hyperplasia is based on the combination of gross features plus histologic parameters. When a normal parathyroid gland is documented histologically, most experts believe that the abnormal gland or glands are adenomas.

TABLE 38-1. Morphologic Differences Between 1

Parathyroid Adenoma and Hyperplasia

f

Variable

Adenoma

Hyperplasia

Thickened capsule

+++

+

Rim of normal tissue

+++

+

Atypia

+++

+

Capillary network

++

+

Adipose tissue

+

+++

Mixed cellularity

+

+++

Lobulations

+

++

Thick-walled vessels

+

++

+ = rare; ++ = less frequent;

+++ = frequent.

FIGURE 38-9. Parathyroid carcinoma. Nodular arrangement of neoplastic parathyroid cells surrounded by fibrous tissue. A, The centers of the nodules show ischemic necrosis and calcification. B, Intrathyroidal metastasis of parathyroid carcinoma: small nests of neoplastic cells mixed with thyroid follicles.

FIGURE 38-9. Parathyroid carcinoma. Nodular arrangement of neoplastic parathyroid cells surrounded by fibrous tissue. A, The centers of the nodules show ischemic necrosis and calcification. B, Intrathyroidal metastasis of parathyroid carcinoma: small nests of neoplastic cells mixed with thyroid follicles.

Carcinoma

Parathyroid carcinoma is responsible for 0.5% to 2% of cases of primary hyperparathyroidism. It is a slow-growing neoplasm of the parenchymal cells.17

On gross examination, parathyroid carcinoma is an ill-defined mass, usually larger than adenomas, with adherence to surrounding tissues. The cut surface is irregularly nodular, gray-tan, and firm. Microscopically, it consists of neoplastic parenchymal cells that show atypia, mitotic figures, capsular and vascular invasion, and, of paramount importance, thick fibrous bands interspersed among the neoplastic cells. Not all of these features can be observed in every case; fibrous bands are present in 90%, mitotic activity in 80%, capsular invasion in 75%, and vascular invasion in 10% of cases in some series.17'25

The tumor cells making up parathyroid carcinoma are arranged in trabecular, sheetlike, or rosette-like patterns. Occasionally, the neoplastic cells form nodular structures with central calcification and necrosis (Fig. 38-9). Nuclear morphology is variable, from minimal atypia to marked pleomorphism with clumped chromatin and enlarged nucleoli.17 Cytoplasm is clear, eosinophilic, and granular, sometimes mimicking the plasmacytoid cytoplasm of the cells of medullary thyroid carcinoma.

Because cytologic features broadly overlap, the distinction between parathyroid carcinoma and parathyroid adenoma is mainly based on the invasive character of the former.'7,25

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