Common ectopic locations for parathyroid glands . (a) Intrathyroidal; (b) Intrathymic
The typical parathyroid gland is a thinly encapsulated ovoid gland measuring roughly 6 mm in greatest dimension, weighing roughly 30 mg and composed of chief cells, oxyphilic cells, transitional oxyphilic cells, clear cells, and stromal fat cells (Fig. 30.2). The chief cells are the primary functional unit of the parathyroid and the cell type from which all other parenchymal cell types are believed to be derived. They are small cells with moderate amounts of slightly eosinophilic to clear cytoplasm containing lipid droplets. They have small hyperchromatic nuclei with neuroendocrine type chromatin. They are typically arranged in nests and cords but may form pseudo-follicular structures which may have an amorphous eosinophilic material. The oxyphilic cells are the true oncocytes of the parathyroid gland and are functionally inactive cells with abundant densely granular eosinophilic cytoplasm filled with mitochondria and small dark nuclei. They are typically absent in children; begin to appear at puberty as single cells and small nests; and increase in number with age. Transitional oxyphilic cells are thought to be cells in transition from chief cell to oxyphilic cells and thus appear in conjunction with oxyphilic cells. Clear cells are a variant of chief cells which derive their appearance from abundant cytoplasmic glycogen. In the setting of normal parathyroids, they are seen primarily in embryos and fetuses and decline dramatically with age. The parenchymal cells of the parathyroid are supported by a rich bed of capillaries supplied by the superior and inferior thyroid arteries [5, 7–9].
Normal parathyroid . (a) Low-power view of a normal parathyroid gland showing a circumscribed but unencapsulated gland composed of nests and cords of parathyroid parenchyma and intervening stromal fat; (b) High-power view of normal parathyroid. Predominantly chief cells but also oxyphilic cells and transitional oxyphilic cells can be seen as well as a rich network of parenchymal capillaries and small vessels
The amount of stromal fat within a normal parathyroid is quite variable and is dependent on many factors. The normal parathyroid is composed almost entirely of chief cells until puberty at which point stromal fat appears and gradually increases to about 40–50 % of the total parathyroid mass. Women in general have more stromal fat and therefore slightly larger parathyroids than men. Percentage total body fat is also correlated with the parathyroid stromal fat content and may account for the gender differences. General health and hereditary factors such as race have also been suggested to affect stromal fat content . Since there is significant variability in the “normal” amount of stromal fat within the parathyroid, “hypercellularity” is somewhat difficult to define. However, in adults, marked hypercellularity (>90 %) or the complete absence of stromal fat within a nodule is a good predictor of parenchymal proliferation.
Non-neoplastic Lesions of Parathyroid
Mild chronic inflammatory infiltrates are not uncommon in the parathyroid and are seen in 10–17 % of patients at autopsy. These infiltrates, tend to be sparse, perivascular, predominantly lymphocytic, and do not appear to be associated with parathyroid dysfunction. Given their association with conditions that affect small vessel integrity such as septicemia, septic shock, and myocardial infarction, these inflammatory infiltrates are speculated to be nonspecific in nature [10, 11].
In contrast, true chronic parathyroiditis is a very rare (<0.1 %) inflammatory process of the parathyroid which presents with diffuse parenchymal involvement, germinal center formation, and evidence of immune-mediated parenchymal reaction, either destructive, in the form of fibrosis and atrophy or alternatively proliferative, in the form of hyperplasia  (Fig. 30.3). This apparently paradoxical reaction to the inflammation may be dependent on the nature of the auto antibodies involved, whether cytotoxic or stimulatory, analogous to the findings in the much more common Hashimoto’s thyroiditis and Grave’s disease of the thyroid [12, 13]. This putative autoimmune etiology is further supported by the identification of autoantibodies to the parathyroid in a subset of patients with this disease and its association with other autoimmune diseases [9, 12]. Treatment is dependent on clinical presentation.
Chronic parathyroiditis. Chronic parathyroiditis in association with parathyroid hyperplasia
Granulomatous parathyroiditis is a very rare finding usually associated with sarcoidosis and tuberculosis [10, 14]. It typically presents with hyperparathyroidism and in the company of a parathyroid adenoma or hyperplasia but the association is likely coincidental since the vast majority of parathyroidectomies are performed for hyperparathyroidism as a result of parathyroid parenchymal proliferation. The histologic findings are typical of granulomatous inflammation regardless of site and consist of the presence of giant cells and granulomata with or without central necrosis. The presence or absence of necrosis may be helpful in establishing etiology.
Parathyroid cysts are benign cysts of the parathyroid, and are thought to be of developmental or degenerative origin. They may account for up to 5 % of cystic lesions of the neck. They are usually uni-locular with a well-defined capsule and a smooth internal surface. They are variable in size and are usually filled with a clear fluid but may be bloody. Microscopically, they are lined by either chief cells or an attenuated flattened epithelium and may show adjacent normal or hyperplastic parathyroid tissue  (Fig. 30.4). Rarely, they are associated with heterotopic tissues such as salivary gland which supports the argument that they may be developmental in nature . While they may be mistaken for thyroid cysts, the distinction is usually clinical insignificant. Since they can occur anywhere a parathyroid can exist, the differential includes other cysts of the neck and mediastinum, depending on site. If clinically relevant, testing the fluid for parathyroid hormone (PTH) may be helpful . Excision is curative.
Parathyroid cyst. (a) Parathyroid cyst with attenuated lining and adjacent parathyroid tissue; (b) High-power view of a parathyroid cyst whose lining is composed of recognizable chief cells
Parathyroid Parenchymal Proliferations
Parathyroid parenchymal proliferations are classically subdivided into hyperplasias, adenomas, atypical adenomas, and carcinomas. While these categories are conceptually distinct and molecular profiling suggests that they represent discrete entities rather than a spectrum [17–19], there is significant overlap in clinical presentation, gross appearance, histologic features, and immunophenotype. Despite this overlap, there is clinical value to assigning lesions into these discrete categories to stratify risk. We will discuss the classic conceptual categories and their typical histopathologic features and suggest practical considerations for assigning borderline lesions.
Conceptually, parathyroid hyperplasias are expansions of the parenchymal mass of the parathyroid in response to stimuli, either internal (i.e. MEN syndromes) or external (i.e. low serum-free calcium). The expansions may be diffuse or multifocal but they involve all of the parathyroid glands to varying degrees. As such, in parathyroid hyperplasia, there is no “normal” parathyroid. This understanding has been recently complicated by evidence that nodular expansions in hyperplasia are clonal in nature whereas diffuse expansions are polyclonal [20–22]. This finding blurs the distinction between hyperplasias, originally thought to be polyclonal in nature, and adenomas which are by definition monoclonal lesions. However, in any proliferating polyclonal population, individual cells are likely to have different proliferative potentials due to accumulated mutations and over time, nodular monoclonal populations arising from individual hyper-proliferative cells are arguably inevitable, with each nodule in a multi-nodular hyperplasia representing an independent clone.
Parathyroid hyperplasia may be primary, secondary, or tertiary depending on the mechanism of pathogenesis. In primary parathyroid hyperplasia, there is an increase in the functional cell mass of the parathyroid in the absence of a known stimulus (i.e. low serum calcium). While generally sporadic, 20–30 % of primary parathyroid hyperplasias are associated with familial hyperparathyroidism syndromes and multiple endocrine neoplasia (MEN) syndromes. In particular, in MEN 1 and MEN2A, 90 % and 30–40 % of patients exhibit parathyroid hyperplasia respectively [8, 9]. Secondary parathyroid hyperplasia is a physiologic response to chronic hypocalcemia, most commonly as a result of chronic renal failure, vitamin D abnormalities, or pseudohypoparathyroidism (end organ resistance to parathyroid hormone). Tertiary parathyroid hyperplasia is a failure to return to a euparathyroid state after the clinical stimulus for secondary hyperparathyroidism, e.g. chronic renal failure, is removed . The mechanism for tertiary hyperparathyroidism is uncertain but there is evidence for both an elevation of the “set point” (concentration of half maximum PTH secretion) and a failure of the hyperplastic parathyroids to involute after removal of the stimulus for hyperplasia [23–26].
Regardless of the mechanism of hyperplasia, the gross and histologic features of parathyroid hyperplasia are similar with only minor differences. In general, the parenchymal expansion may be diffuse or nodular (Fig. 30.5) and range from symmetric to markedly asymmetric in both extent and composition across the parathyroid glands (Fig. 30.6). Total parathyroid gland mass can vary widely but is typically between 1 and 3 g . Generally, all four glands are involved to some extent, in contrast to adenomas, which usually involve a single gland. The expansion of the parenchymal mass is usually predominantly composed of chief cells although there may be expansion of other cell types most commonly oxyphils, and pure expansions of other cell types do rarely occur (Fig. 30.7). This expansion of the parenchymal mass, whether nodular, diffuse or mixed, typically involves the entire gland without a discrete rim of residual normal parathyroid; the distinction between normal and hyperplastic tissue may be histologically difficult. The parenchymal cells can be arranged in diverse architectural patterns including solid sheets, cords, acini, and follicles [5, 9] (Fig. 30.8). As with all neuroendocrine lesions, random nuclear atypia may be present and is not a feature of malignancy (Fig. 30.9). However, uniform atypia is not a feature of hyperplasia and should raise the concern for malignancy. Mitotic activity may be present but is generally low (<1 per 10hpf). Atypical mitoses are not seen. Cystic changes, fibrosis, and calcification are uncommon but increase in prevalence with size and duration of the hyperplasia . Hemorrhagic changes may be present, particularly in tertiary hyperplasias, likely due to the extended duration of the hyperplastic process. These changes are most likely degenerative in nature (Figs. 30.10).
Low-power architectural patterns of parathyroid proliferations. (a) Diffuse; (b) Diffuse and nodular; (c) Nodular
Asymetric size and composition of hyperplastic parathyroid glands . (a, b) Right superior parathyroid with marked hypercellularity and oxyphlic cell predominance 2.1 × 2.0 × 1.5 cm; (c, d) Right inferior parathyroid with normal cellularity and water-clear cell predominance 1.1 × 0.7 × 0.3 cm. Both parathyroids are markedly enlarged. The remaining two parathyroids were of grossly normal size and not sampled
Major parenchyma cell types of parathyroid proliferations: chief cell, oxyphilic cell, and water-clear cell
High-power architectural patterns of parathyroid proliferations. (a, b) Solid; (c, d) Cords; (e) Acinar; (f) Follicular
Random nuclear atypia. Note that most of the nuclei are small in regular with only scattered enlarged nuclei
Reactive/degenerative changes in parathyroid proliferations. (a) Myxoid degeneration; (b) Cyst formation; (c) Fibrosis; (d) Hemorrhage
Stromal fat is generally absent within nodular proliferations and decreased in the intervening areas of diffuse proliferation. However, given the inherent variability in the normal stromal fat content and distribution across individuals, hypercellularity is a somewhat tenuous indicator of hyperplasia and is most reliable when marked hypercellularity for age is present. Loss of intracellular fat is common and potentially a more reliable indicator of hyperplasia but some parathyroid hyperplasias can have abundant intracytoplasmic fat and interpretation can occasionally be challenging .
Although typically well circumscribed by the parathyroid capsule, hyperplasias, particularly those associated with genetic syndromes, may exhibit small nests of parathyroid tissue outside the capsule (“parathyromatosis”) [9, 27]. These nests may be primary as in MEN1 or secondary to prior neck surgery. In the latter case, the parathyromatosis is speculated to arise from auto-implantation of cells spilled during the excision of a hyperplastic or neoplastic parathyroid lesion or inadvertent transection of a normal parathyroid [28, 29]. In primary parathyromatosis, these nests can be distinguished from soft tissue invasion by their rounded contours and lack of a desmoplastic reaction. The situation is complicated in secondary parathyromatosis because the reactive fibrosis associated with prior surgery may mimic desmoplasia and produce angulated contours [9, 28]. However, given the relative rarity of parathyroid carcinoma, other criteria should be applied in the face of prior surgery. In either case, care should be taken to exclude lymphovascular invasion which may have a similar morphology.
Water-Clear Cell Hyperplasia
Water-clear cell hyperplasia is defined by the proliferation of large cells with abundant clear cytoplasm in multiple parathyroid glands. It is a very rare cause of primary hyperparathyroidism and presents with more severe clinical symptoms although it is unclear if this is inherent to the lesion or a byproduct of it’s generally larger size (47 % of patients have a mean total parathyroid weight >10 g). It is the only type of hyperplasia which frequently shows greater involvement of the upper glands than the lower ones . The etiology of water-clear cell hyperplasia is unknown although it has been speculated that is may represent a variant of longstanding chief cell hyperplasia. Histologically, the parathyroids are replaced by a proliferation of large clear cells with sharp cytoplasmic borders. These cells may be arranged in cords, sheets, or acini with little or no intervening stromal fat. Periodic acid Schiff (PAS) stain with diastase is positive for glycogen and neutral fat stains are negative for intra-cytoplasmic fat [5, 9]. The overall presentation is distinctive and the main histologic differential diagnosis is metastatic renal cell carcinoma, although clear cell lesions of the thyroid including medullary carcinoma are possible considerations.
Conceptually, parathyroid adenomas are benign autonomous monoclonal proliferations of the parathyroid parenchyma. As such they arise in a background of normal parathyroid tissue and are associated with genetic alternations which release them from the normal physiologic control of proliferation. Two genes have been identified which are associated with this uncoupling, the oncogene cyclin D1 (CCND1)/PRAD1 and the tumor suppressor MEN1 . In the case of cyclin D, an inversion has been identified in up to 8 % of parathyroid adenomas which places the cyclin D1 gene adjacent to the 5′ regulatory elements of the parathyroid hormone (PTH) gene resulting in tissue specific upregulation of cyclin D1 expression. Additionally 30–40 % of sporadic parathyroid adenomas overexpress cyclin D1. In the case of MEN1, inactivating mutations have been identified in up to 30 % of sporadic parathyroid adenomas and the gene itself is implicated in the MEN1 syndromes which are strongly associated with parathyroid proliferations [3, 31].
Grossly, parathyroid adenomas tend to be soft, solitary, circumscribed, and tan to red brown in color. They are typically ovoid but may be lobulated and can range greatly in size from as little as 150 mg to greater than 100 g; most fall between 300 mg and 1 g. They may exhibit degenerative changes such as cyst formation, fibrosis, calcification, and hemorrhage. These changes are more common in larger adenomas [5, 8, 9, 32].
Histologically, parathyroid adenomas are markedly hypercellular and composed predominantly of chief cells although oxyphils, transitional oxyphils, and rarely clear cells may be present and occasionally predominate. These parenchymal cells are usually arranged in sheets and cords, although acinar and follicular architectures may be present and are sometimes prominent. These follicles may contain amorphous eosinophilic material reminiscent of colloid. The neoplastic cells are slightly larger than their normal counterpart but this difference is difficult to appreciate without side by side comparison. Stromal fat is typically absent except in the lipoadenoma variant. The lesion is circumscribed and may be thinly encapsulated. A rim of normal or atrophic parathyroid tissue is present in only 60–70 % of cases but when present is a helpful diagnostic discriminator between adenoma and hyperplasia (Fig. 30.11). Random nuclear atypia involving scattered cells and rare giant cells may be present but uniform atypia should not be seen. Mitotic figures are uncommon but when present generally number less than 1/10 hpf although higher mitotic rate are sometimes seen. Atypical mitoses are not seen [5, 8, 9, 32].
Rim of normal parathyroid tissue associated with parathyroid adenomas
Immunohistochemical studies are not usually necessary for diagnosis but on occasion, the differential includes thyroid neoplasms and clear cell neoplasms from other sites. As with all benign proliferations of the parathyroid, parathyroid adenomas are positive for PTH, parafibromin, chromogranin A, cytokeratin 8/18, Gata-3, Bcl-2, RCC, Pax-8, and mdm2. Pertinent negative stains include TTF-1, thyroglobulin, Pax-2, and CD10. [9, 33–39]. Ki-67 typically shows a proliferative fraction of <5 % [37, 40]. Since a subset of parathyroid adenomas express calcitonin , if medullary carcinoma is in the differential, concomitant staining for TTF-1 is recommended as medullary carcinoma is positive for TTF-1 whereas parathyroid adenomas are not.
Histologic variants of the parathyroid adenoma include oxyphilic adenomas, lipoadenomas, and water-clear cell adenomas.
As implied by the name, oxphilic adenomas are composed predominantly of oxyphilic cells (>90 %). While originally thought to be nonfunctional, the majority are associated with hyperparathyroidism . They tend to be larger and, interestingly, are more easily detected by sestamibi scan than their chief cell counterparts . From a diagnostic standpoint, they are significant for their ability to closely mimic oncocytic thyroid neoplasms (Fig. 30.12), a dilemma which is complicated by their proximity to the thyroid, their rare intrathyroidal location, and occasionally, the presence of follicular architecture. This diagnostic dilemma is readily resolved by immunohistochemical studies due to their differential staining for TTF-1(−), thyroglobulin(−), Gata-3(+), and PTH(+). The key to avoiding this pitfall is to be aware that it exists.
Comparison between oxyphilic variant of parathyroid adenoma and oncocytic thyroid neoplasms. (a) Oxyphilic variant of parathyroid adenoma—note the densely granular eosinophilic cytoplasm and hyperchromatic coarsely granular nuclei; (b) Oncocytic follicular adenoma—note the less granular cytoplasm and lighter nuclei; (c) Hurthle cell adenoma—note the prominent nucleoli, densely granular cytoplasm, sharp cytoplasmic borders
The lipoadenoma is a very rare histologic variant (<50 cases in the literature) showing abundant stromal fat admixed with nests and cords of parathyroid parenchyma (Fig. 30.13). Degenerative myxoid changes and heterologous elements may be present. Whether the lipoadenoma is a true variant of a parathyroid adenoma or a distinct entity is unclear at this time. While most are associated with hyperparathyroidism, the biochemical findings are typically milder than similar size adenomas, likely the result of their relatively lower parathyroid parenchymal mass. They are difficult to localize by sestamibi scan, likely due to their high fat content and may be mistaken for lipoma or normal parathyroid in small biopsies/fine needle aspiration . Histologic diagnosis on excision specimens is usually straightforward due to their size and typical appearance.
Lipoadenoma . (a) Low power showing abundant stromal fat; (b) High power; (c) Adjacent rim of normal tissue. Note the cells of the adenoma are larger than the adjacent normal tissue
The water-clear cell adenomas is an even rarer functional variant of parathyroid adenoma with perhaps a dozen reported cases in the English literature. These adenomas are composed of large clear cells with vacuolated cytoplasm containing abundant glycogen, morphologically identical to those seen in the more common water-clear cell hyperplasias. Unlike water-clear cell hyperplasias , water-clear adenomas usually involve only a single parathyroid gland, although a single case of a water-clear cell double adenoma has been reported . Given their rarity and focality, the main diagnostic consideration is to avoid mistaking these lesions for metastatic clear cell malignancies. This is a significant consideration because water-cell cell adenomas are histologically very similar to metastatic clear cell renal cell carcinomas (Fig. 30.14) which are surprisingly common in and around the thyroid. Many clear cell renal cell carcinomas have low cytologic grade which make them difficult to distinguish from benign clear cell lesions. In addition, water-clear cell adenomas stain for both RCC and Pax8, two markers often used to identify metastatic renal cell carcinomas. Furthermore, renal cell carcinomas can often secrete PTH related peptide (PTHrp) resulting in hypercalcemia and thus have similar clinical presentations, although PTH itself is usually suppressed . Fortunately, as long as the existence of this variant is recognized, an appropriate immunohistochemical panel including CD10, Pax2, TTF-1, Gata-3, and PTH can readily distinguish water-clear cell adenomas from metastatic renal cell carcinoma as well as clear cell lesions of other sites.
Water-clear cell parathyroid proliferations versus metastatic renal cell carcinoma. (a) Water-clear cell adenoma; (b) Metastatic renal cell carcinoma. The two lesions are virtually indistinguishable on histology
The concept of double and even triple adenomas is controversial . Much of the debate centers not so much on the existence of these lesions but rather, their prevalence. While there is no logical reason to believe that multiple parathyroid adenomas cannot arise independently, given the rarity of parathyroid adenomas in the general population (<1 %) , if they are independent events, the incidence of double adenomas should be quite low, and triple adenomas should be reportable. Despite this, the incidence of double adenomas has been reported to be as high as 15 % . Supporters of the higher rate of multiple adenomas typically point to biochemical cure as proof [48, 49]. However, since parathyroid surgeries remove the significant bulk of the parenchymal mass and hyperplasias are typically slow growing lesions, the remaining tissue may simply be insufficient to produce a biochemical abnormality for some time. Certainly, the well documented, if uncommon, recurrence of hyperparathyroidism after parathyroidectomy for an “adenoma” suggests some asymmetric nodular hyperplasias are mistaken for adenomas . This reality is highlighted by the fact that the incidence of “double adenomas” appears to be dependent on the surgical approach (unilateral versus bilateral) [51, 118], yet biochemical cure rates do not appear to be significantly impacted by approach, at least in the short term .
It is unclear how much parathyroid tissue is minimally required for a euparathyroid state or how much is needed to produce clinical hyperparathyroidism. The presence of parathyroid incidentalomas in normocalcemic patients , and the transient effect of the inadvertent partial parathyroidectomies which occur during thyroid surgery [54–57] suggest that there is a relatively broad range of parathyroid parenchymal mass which will produce a euparathyroid state. Molecular studies suggest that “double adenomas” may arise in the background of hyperplasia , which leads to the question of what distinguishes an adenoma from a nodular hyperplasia? While these debates are important, from a practical standpoint, they may be academic. With the advent of intraoperative monitoring of PTH and goal of surgery to bring intraoperative PTH levels to normal range, sufficient tissue may be removed to make it a moot point whether the remaining tissue is normal or hyperplastic . The major consideration of this debate is arguably long-term follow-up. Given the results of molecular studies which suggest that double adenomas may arise in hyperplasias  and long-term follow-up studies that show that both hyperplasia and double adenomas show higher recurrence rates of hyperparathyroidism than single adenomas [50, 52], it may be prudent to follow all patients with double adenomas for an extended period.
Adenoma vs. Hyperplasia: The Example of Lithium Induced Hyperparathyroidism
A prime example of the difficulties in reliably distinguishing between adenoma and hyperplasia is lithium induced hyperparathyroidism. Lithium induced hyperparathyroidism occurs in approximately 10 % of patients taking lithium. The mechanism of lithium induced hyperparathyroidism is unknown but it has been speculated lithium competitively binds to CaSRs, effectively increasing the free calcium set-point as well as increasing renal tubule reabsorption of calcium . Since lithium exposure is systemic and withdrawal of lithium is often curative , lithium induced hyperparathyroidism should logically be due to hyperplasia [62, 63] analogous to the case of chronic renal failure. However, when surgeries are performed to treat lithium induced hyperparathyroidism, the bulk of the lesions are called adenomas [62, 64, 65]. While it has been speculated that lithium therapy may unmask subclinical primary hyperparathyroidism, this does not explain the observation that cessation of lithium therapy is often curative. It is much more likely that asymmetric parathyroid hyperplasias are being diagnosed as adenomas. This is supported by the high recurrence rate of lithium induced hyperplasias . Given that nodular proliferations in secondary hyperplasias are clonal, it is not surprising that they would be individually indistinguishable from adenomas. The fact that there is low inter-observer concordance between parathyroid adenoma and hyperplasia does not help the situation .
If we accept that we cannot reliably distinguish between adenomas and asymmetric hyperplasias histologically, where does this leave us? While the current management, i.e. minimally invasive parathyroidectomy, appears to be effective in the short term (5 years or less), the higher recurrence rates seen in cases of “double adenoma” and lithium induce hyperparathyroidism suggest that we should treat them as hyperplasias with bilateral exploration and possibly subtotal parathyroidectomy.
Conceptually, an atypical parathyroid adenoma is a neoplasm which shows some histologic features worrisome for malignancy (Figs. 30.15 and 30.16) but does not have diagnostic malignant features such as infiltrative growth (capsular or soft tissue invasion), lymphovascular invasion, perineural invasion, or metastasis. These worrisome features include a thickened capsule, irregular capsular contours, entrapped intracapsular nests, trabecular growth pattern (Fig. 30.17), internal fibrosis, increased mitotic activity (>1 per HPF but <5 per HPF), atypical mitoses, coagulative necrosis, uniform atypia, and prominent nucleoli [5, 7–9]. Immunohistochemical studies also show a profile which is intermediate between adenoma and carcinoma [35, 37, 38, 67, 68]. Since molecular profiling studies do not support a progression from adenoma to carcinoma [17–19], this category most likely represents a heterogenous mix of adenomas and low-risk carcinomas which have overlapping histologic features rather than a true intermediate entity. Long-term follow-up in patients with atypical adenomas is quite scant but what little data there is suggests that these lesions are indolent with only rare cases of subsequent identification of overt malignancy [68–70]. As such, while patients require more aggressive follow-up for recurrence and surveillance for metastasis, the clinical course will most likely be benign.
Worrisome low-power features of parathyroid proliferations. (a) Thick capsule; (b) Internal fibrosis; (c) Lobulated architecture; (d) Intracapsular nests; (e) Capsular irregularities
Worrisome high-power features of parathyroid proliferations. (a) Trabecular growth pattern; (b) Increased mitotic activity; (c) Uniform nuclear atypia; (d) Prominent nucleoli (also uniform atypia)
Cords versus trabeculae. (a, b) Cords; (c, d) Trabeculae. While both cords and trabeculae form both linear and branching patterns, cords are thinner (1–2 cells thick) while trabeculae are thicker (3+ cells in thickness)
Conceptually, parathyroid carcinoma is a malignant neoplasm arising from the parenchymal cells of the parathyroid which has both locally invasive and metastatic potential. Parathyroid carcinoma arises de novo rather than as a malignant transformation of existing adenomas [17–19]. It is a very rare malignancy and usually presents with marked hypercalcemia but may be nonfunctional . Aberrant expression of various oncogenes and tumor suppressor genes have been identified in parathyroid carcinoma  but the HRPT2 gene is thought to play the primary role in carcinogenesis [35, 38, 73–78].
Grossly, parathyroid carcinomas tend to be somewhat larger than their benign counterparts but there is significant overlap. They typically presents as solitary white, firm, irregular, adherent masses, often described as difficult to dissect from surrounding tissues [5, 8, 9, 79]. This is in contrast to hyperplasias and adenomas which are tan to red brown, soft, well circumscribed, and easily excised.
The histologic diagnosis of parathyroid carcinoma is challenging. Histologic evaluation does not correlate well with clinical behavior [80, 81]. Likely factors producing this inconsistency include the inexperience on the part of the pathologist and surgeon due to the rarity of this disease; it is generally low-grade cytology; the locally aggressive nature of parathyromatosis, whether benign or malignant in nature; diagnostic dilemmas associated with prior fine needle biopsy or previous neck surgery; and the evolution of diagnostic criteria for malignancy .
Histologically, parathyroid carcinomas tend to have low cytologic grade and are composed of the same parenchymal cell types as parathyroid adenomas and hyperplasias. The histologic criteria for parathyroid carcinoma were first proposed by Schantz and Castleman  and included the presence of a thickened fibrous capsule or fibrous intra-lesional trabeculae; trabecular or rosette-like architecture; mitotic activity and capsular or vascular invasion. Later, additional features were noted including lobular architecture, irregular capsular contours, entrapped intracapsular nests, atypical mitoses, coagulative necrosis, uniform atypia, perineural invasion, and prominent nucleoli [5, 8, 9]. However, many of these features have also been identified in atypical adenomas and rarely, typical adenomas. While all of these characteristics are more common in parathyroid carcinomas and should prompt careful evaluation, the diagnosis of parathyroid carcinoma should rest on unequivocal malignant characteristics such as capsular invasion, lymphovascular invasion, perineural invasion, soft tissue invasion, or distant metastasis  (Fig. 30.18).
Diagnostic features of malignancy in parathyroid carcinoma . (a) Capsular invasion; (b) Soft tissue invasion; (c) Lymphovascular invasion; (d) Perineural invasion
Because parathyroid carcinoma has proven to be such a difficult histologic diagnosis, significant research has focused on ancillary studies, in particular, the HRPT2 gene. Molecular studies suggest that up to 77 % of aggressive parathyroid carcinomas have mutations in HRPT2 [74, 75]. Unfortunately, 20 % of mutations lie outside mutational hotspots in exons 1, 2 and 7, and would require total gene sequencing to identify. Furthermore, many mutations are large deletions and some cases of HRPT2 downregulation appear to be epigenetic , neither of which can be identified by sequencing. These factors make the routine HRPT2 sequencing in parathyroid lesions impractical.
This has led to interest in parafibromin , the protein product of HRPT2. Immunohistochemical (IHC) studies of parafibromin in parathyroid carcinoma have been a mixed bag with some authors showing that loss/reduction of parafibromin nuclear staining is highly sensitive and specific for parathyroid carcinoma  while others have had considerably less promising results . These discrepancies can be partially attributed to differences in selection criteria (behavior vs. histology); differences in assay protocols (different primary antibodies and retrieval methods); differences in the criteria for scoring reactivity; and finally, sample size. The results do suggest that loss of parafibromin is a feature of atypical adenomas and carcinomas but not typical adenomas. To improve sensitivity, parafibromin has been incorporated into IHC panels with other proteins associated with parathyroid carcinoma such as APC, Rb, Galectin-3, PGP9.5, and Ki-67, with promising results [40, 67, 85]. Loss of parafibromin also appears to independently predict recurrence/metastasis [68, 86]. Overall, these findings support the use of parafibromin IHC studies in the evaluation of parathyroid carcinomas and atypical adenomas. Given the technically difficult nature of the assay, testing should be done in a lab with significant experience and consistent results.
No standard staging system exists for parathyroid carcinoma. However, a number of histologic features have been identified as negative prognostic indicators including vascular invasion, lymph node metastasis, invasion into surrounding organs, and distant metastasis [87–89]. Based on these indicators Talat and Schulte  have proposed two classification systems, a classic TNM system and a binary high- and low-risk classification system. Both systems appear to be robust on retrospective Kaplan Meyer survival analysis [87, 88]. Immunophenotypic markers have also been correlated with survival/recurrence, including parafibromin, CaSR, and PGP9.5 [68, 86] and may ultimately need to be incorporated into any standard prognostic algorithm.
Other Neoplasms of the Parathyroid
Secondary Malignancies of the Parathyroid
Metastatic disease to the parathyroids is uncommon but has been demonstrated in up to 12 % of patients with widespread metastatic disease at autopsy. This rather high percentage represents an end stage process; metastatic disease to the parathyroid as an initial presenting diagnosis is much rarer (<0.5 % of all parathyroidectomies). The most common primary sites in descending order of prevalence are: breast, melanoma, hematopoietic malignancies, lung, prostate, and kidney . These metastases may present in one or more glands and are not usually associated with hyperparathyroidism. Since most of these metastatic lesions are high grade and present in late stages of the disease, diagnosis of metastatic disease is not usually challenging, although as previously noted, metastatic renal cell carcinoma can be mistaken for water-clear cell adenoma/carcinoma.