Advances in Anatomic Pathology:
Molecular Alterations in Hereditary and Sporadic Thyroid and Parathyroid Diseases
Hunt, Jennifer L. MD
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH
Reprints: Jennifer L. Hunt, MD, Cleveland Clinic, 9500 Euclid Avenue, Department of Anatomic Pathology, Cleveland, OH 44195 (e-mail: email@example.com).
Thyroid and parathyroid diseases are fairly common and can be either hereditary or sporadic in nature. Tumors and tumor-like processes account for the majority of surgical pathology specimens in both of these endocrine organs. Molecular alterations are well known to occur in both the hereditary and the sporadic settings, and include alterations in tumor suppressor genes and oncogenes. The genetic pathways of tumors of parathyroid and thyroid are beginning to be well understood and are proving to be useful diagnostic, prognostic, and potential therapeutic targets. The molecular alterations in parathyroid and thyroid tumors and tumor-like processes are reviewed, with a focus on the potentially clinically useful diagnostic markers.
Thyroid lesions are extremely common in the adult population, with some estimates suggesting that up to 70% of individuals will have thyroid nodules on ultrasound. Most of these thyroid nodules are benign, and in fact, most represent non-neoplastic disease. However, in current practice, the finding of a thyroid nodule necessitates a work-up, which usually includes a thyroid fine needle aspiration (FNA).
Thyroid FNA has revolutionized the care of the patient with thyroid nodules. Before this technique became the standard of care, many more patients were taken to the operating room for diagnostic lobectomies to assess thyroid nodules. Because of the overall excellent sensitivity and specificity of thyroid FNA, patients with benign non-neoplastic disease can now be identified on FNA and managed clinically, not surgically. The diagnostic categories for FNA usually include a benign category that encompasses hyperplastic nodules and nodular goiter, a category that includes follicular lesions and Hürthle cell lesions, a suspicious or atypical category that includes lesions that have atypia, but that lack the diagnostic features of papillary carcinoma, and a malignant category. Malignant tumors that can be diagnosed on FNA include papillary carcinoma and medullary carcinoma, but not follicular-derived carcinomas. Thyroid surgery continues to be the standard therapy for indeterminate or atypical nodules, carcinomas, and for refractory symptomatic goiter or autoimmune disease.
Thyroid nodules are classified on the basis of cell of origin and differentiation. Thyroid follicular-derived processes include benign hyperplastic nodules and follicular adenomas, papillary carcinomas, follicular carcinomas, and poorly differentiated and anaplastic thyroid carcinomas. C-cell derived lesions include c-cell hyperplasia and medullary carcinoma.
Benign Nodules in Goiter and Follicular Adenomas
Benign thyroid follicular derived nodules often present asymptomatically and are either discovered by physical examination or by neck ultrasound. Patients usually have painless nodules, and these can vary in size. Thyroids may demonstrate a background of nodular goiter, or the lesions can be solitary nodules.
Dominant hyperplastic nodule is the terminology used to describe a benign nodule that is nonencapsulated. Thyroids with dominant hyperplastic nodules also often harbor the histologic changes of nodular goiter. Follicular adenomas have well-defined capsules (without invasion) and the growth pattern within the nodule is usually different from the background thyroid parenchyma. Follicular adenomas can be microfollicular, or more rarely, macrofollicular tumors. The cells in both the dominant hyperplastic nodule and the follicular adenoma are bland, small, and round, resembling those seen in normal thyroid follicles. Some lesions will have Hürthle cell (oncocytic) differentiation.
It was originally thought that dominant hyperplastic nodules were non-neoplastic and thus nonclonal. However, in several elegant studies which examined the clonality of these lesions using X-inactivation (HUMARA assay) it has been shown that at least some nodules in multinodular goiter are clonal.1–4 Follicular adenomas have always been thought to be clonal proliferations and this has also been shown to be true at the molecular level, through analysis of somatic mutations in oncogenes, loss of heterozygosity analysis of tumor suppressor genes, and through X-inactivation studies.1,5–8
One of the first genes to be described with alterations in thyroid tumors was the RAS gene, which is part of the RAS-RAF-MEK-MAPK pathway.9 Follicular adenomas are known to harbor mutations in all 3 RAS genes, H-RAS, K-RAS, and N-RAS.7,10,11 The RAS mutations are thought to be early mutations in the follicular neoplasia pathway.5
Interesting molecular findings have also been described in toxic nodules, which are also known as “hot” or hyperfunctioning nodules because of their characteristic uptake on radioactive iodine scans. The histologic correlate for these nodules is what has been referred to as a “papillary hyperplastic nodule.” These nodules have been shown to have clonal somatic mutations in the TSH-receptor.12,13
Papillary thyroid carcinoma (PTC) is the most common malignancy in the thyroid gland, representing 80% or more of the carcinomas identified in this organ. Patients with PTC commonly present with a mass lesion, but no other specific symptoms. PTC affects women more commonly than men, and presents in a wide range of age groups. The treatment for clinically relevant PTC is total thyroidectomy, possibly followed by radioactive iodine ablation. The prognosis for PTC is excellent, with most series suggesting a disease-specific survival of over 95%.14
Histologically, PTC is diagnosed based on the cytology of the tumor cells. The classic cytologic features include nuclear clearing, elongation, and enlargement, nuclear overlapping, groove formation, and intranuclear inclusions. The growth pattern and other morphologic features are used to identify variant morphologies of PTC. The variant morphologies include common types, such as follicular variant and tall cell variant, and less common forms, such as diffuse sclerosis variant, columnar cell variant, and cribriform morular variant.
The molecular mutational events in PTC have been well studied and our understanding of their clinical significance is relatively advanced. Mutations occur in both tumor suppressor genes and in oncogenes. The molecular profiles for the less common variants of PTC are not well established.
At the oncogene level, 3 distinctive mutations have been described in PTC: RAS mutations RET/PTC translocations, and BRAF mutations. RAS mutations are found in a minority of PTCs, but this has not become a diagnostic target as RAS mutations are also seen in other benign and malignant tumors of the thyroid gland.
RET/PTC mutations represent a group of translocations between the RET gene, located on chromosome 10q21, and various partner genes, which were originally designated as “PTC” before the genes were characterized (for “papillary thyroid carcinoma”).15,16 The 2 most common partner genes are the H4 gene (PTC1) and the ELE1 gene (PTC3).17 Both H4 and ELE1 are also located on chromosome 10, and therefore the translocation would be better classified as intrachromosomal rearrangements. Overall, it appears that approximately 30% of PTCs harbor a RET/PTC translocation, with RET/PTC1 predominating in sporadic tumors.18 There are more than 10 different partner genes now identified within the RET/PTC category of mutations, and other translocations have also been rarely identified (Table 1).
Both therapeutic radiation, particularly in children, and radiation from nuclear fallouts have been identified as risk factors for the development of PTC.19 Interestingly, radiation-induced PTCs are much more likely to harbor RET/PTC3 rearrangements than sporadic tumors. This has been true in tumors from patients who were exposed to radiation in the Chernobyl disaster, and from patients who received secondary radiation to the thyroid gland as children.20 Radiation-induced tumors also have other unique molecular mutational profiles. For example, radiated thryocytes are genetically unstable and demonstrate multiple chromosomal losses, when examined by comparative genomic hybridization assays.21 Similarly, thyroids and thyroid tumors from patients who were radiated as children have a high rate of loss of heterozygosity at similar genetic locations.22
The other very common somatic mutation in an oncogene that occurs in PTC is the BRAF gene mutation. This is a point mutation in exon 15, at codon 600, nucleotide 1799, where the normal T nucleotide is replaced with an A. This mutation is seen in approximately 50% of PTCs, but has different frequencies in some of the variants of PTC.23–25 For example, follicular variant of PTC has a much lower rate of BRAF gene mutations, whereas tall cell variant has a much higher rate of BRAF mutations.23,26–28 BRAF mutations are uncommon in radiation-induced PTC.29–31
The RET/PTC translocations, RAS mutations, and tumor suppressor gene mutations do not seem to have prognostic significance. But, the BRAF gene mutation is now being shown to have some independent prognostic significance; the mutation is associated with higher clinical risk and more aggressive tumors.32–34 This gene could become an important clinical target, not only for diagnostic and prognostic purposes, but also because there are several drugs that are in clinical trials that target the BRAF gene. These drugs are currently being used in trials treating melanoma, which also frequently harbor BRAF mutations, but there may be extension to treating thyroid-derived malignancies with BRAF mutations as well.33,35
Follicular thyroid carcinomas (FTCs) also present in patients as painless mass lesions. The tumors have a wide range of sizes. Clinically suspicious findings on ultrasound include irregular tumor margins, more solid component, and calcifications, but sensitivity and specificity of these findings remain relatively low.36,37 The treatment for FTC is generally a total thyroidectomy, followed by radioactive iodine ablation.
Histologically, FTC is diagnosed based on invasion at or beyond the level of the tumor capsule. The diagnostic invasion can be in the form of capsular invasion or angio-lymphatic invasion. These tumors are subclassified histologically based on the level of invasiveness, using a 3-tiered system of minimally invasive FTC (with capsular invasion alone), angio-invasive FTC (with vascular invasion) and widely invasive FTC (with widespread intrathyroidal or extrathyroidal invasion). The main reason behind subclassifying FTC into tumors that do and do not have vascular invasion is that tumors with angio-invasion have been found to have a worse prognosis than those with capsular invasion alone.38,39
The molecular profile of FTC again includes both tumor suppressor gene alterations and oncogene mutations.18 At the tumor suppressor gene level, it has been shown that as tumors increase in aggressiveness both clinically and histologically, they acquire more loss of heterozygosity alterations across a broad panel of tumor suppressor genes.6 These alterations also correlate with aggressive behavior, as those patients who die from disease generally have tumors with a much higher mutation rate.40
The most common oncogene mutations in FTC are RAS gene mutations. Again, these do not have significant diagnostic value because they are also found in benign follicular adenomas. However, there is some evidence that RAS oncogene mutations may have prognostic value in FTC.41
Another interesting mutation that was recently discovered in FTC is the PPARγ/PAX8 translocation. This translocation is found in approximately 30% to 50% of FTC.42 It has also been described in rare cases of follicular adenoma, and even in a subset of follicular variant of papillary carcinoma.43–46 This translocation seems to separate 2 different categories of FTC, those with and without the translocation have different expression profiles and different prognosis.47,48 Assays for PPARγ/PAX8 therefore may have diagnostic and prognostic significance, but also may have future therapeutic significance, as drugs that function as PPAR agonist are currently in clinical trials.49
Although Hürthle cell carcinomas are classified according to the same histologic parameters as follicular carcinoma and indeed are considered to be a subset of follicular carcinomas by the latest World Health Organization classification, they seem to have different molecular profiles from follicular carcinomas. For example, Hürthle cell carcinomas have been shown to harbor mitochondrial gene mutations.50,51 In one study, some Hürthle cell lesions were also described as having RET/PTC translocations, brining up the possibility that some of these tumors may be related to papillary carcinoma.52,53
The second major category of thyroid tumors is derived from C cells or parafollicular cells, which secrete calcitonin. Calcitonin is a poorly understood hormone that is involved in calcium homeostasis and bone and cartilage health.54,55 The C cells embryologically originate from the lateral thyroid anlage (from the fourth branchial pouch); this is distinct from the origin of the follicular cells which come from the median anlage.56 The lateral thyroid anlage also gives rise to ultimobranchial body rests (or solid cell rests). C-cell hyperplasia occurs both as a precursor lesion in patients with hereditary conditions that predispose to carcinoma, and can also occur sporadically in patients without carcinoma, through various mechanisms. This benign incidental C-cell hyperplasia (also known as “reactive” or physiologic hyperplasia) is not considered to be a worrisome finding and in fact it has different molecular findings from C-cell hyperplasia in syndromes.57,58
Medullary thyroid carcinoma (MTC) occur in both the sporadic setting, about 75% of the tumors, and in some specific hereditary diseases, representing the other 25% of cases59; the molecular genetics of each will be discussed separately. Histologically, MTCs are similar, whether they are sporadic or hereditary. MTC can have a wide range of morphologic appearances, with cell types ranging from epithelioid, to spindled, to plasmacytoid, and others. In fact, it has been noted that MTC can mimic almost any other tumor in the thyroid gland and this diagnosis should be always be considered when faced with a tumor with an unusual morphology. Approximately 95% of MTCs will express calcitonin and nearly 100% will express carcinoembryonic antigen.60 Immunohistochemical stains for calcitonin and carcinoembryonic antigen are used diagnostically to confirm a diagnosis of MTC. In hereditary cases, it is common to find C-cell hyperplasia in the background thyroid gland.57
The treatment for MTC has always relied upon primary surgery, in both hereditary and sporadic cases. In hereditary disease, early surgery is recommended, as even young children are likely to develop MTC.61,62 Additional therapy for recurrent disease has been tried, including radiation and chemotherapy, but with little benefit.63–66 There is great hope that some molecular targeted therapies will be able to be used as second line agents to treat patients with recurrent or refractory disease.64,65,67
Sporadic Medullary Carcinoma
Clinically, patients with sporadic MTC present at an average age of almost 50 years, often with an asymptomatic thyroid mass.68 If serum calcitonin levels are obtained, it will usually be high in these patients.69 FNA may be able to identify the unique cells of MTC, but also may yield a diagnosis of “atypical.”70,71 On resection specimens, sporadic MTCs tend to be unilateral, and C-cell hyperplasia is usually not seen in the background thyroid.68
The molecular genetics of sporadic MTC has been extensively studied, though the mutational pathways are not entirely well understood. There is substantial evidence that RET oncogene mutations are found as somatic mutations in up to half of sporadic tumors, though the distribution may be somewhat different from the RET mutations in hereditary disease.72,73 It is argued, though, whether RET mutations are causative in sporadic MTC or are later mutations, as this is likely to be a tumor with complex gene interactions and tumor suppressor gene involvement as well.74,75 Interestingly, there is some evidence that patients with medullary carcinomas with RET mutations have a worse prognosis, with higher rates of nodal and distant metastases, and higher relapse rates.72,73
One very interesting finding that has arisen from the molecular studies of apparently sporadic MTC is that a subset of patients with no clinical suspicion of genetic disease, do in fact have a germline mutation. In fact, several studies have suggested that between 4% and 8% or apparently sporadic MTC patients will have one of these unsuspected germline mutations.61,72,76 Because of this high rate of unsuspected genetic disease, some clinicians are now testing all patients with MTC for germline RET mutations.
MEN2A and MEN2B
Kindreds with multiple endocrine neoplasia syndromes 2A (MEN2A, also known as Sipple syndrome) and 2B (MEN2B) have MTC as a characteristic tumor finding (Table 2). Patients with syndromic MTC in the MEN syndromes present at an earlier age than sporadic MTC patients, with an average age of onset of MTC in MEN2A being 20 years and in MEN2B being 15 years. Many patients who are known carriers of a germline RET mutation will now undergo a prophylactic thyroidectomy very early in life, before there is evidence of thyroid disease.77–80 Even in very young infants who undergo thyroidectomy, there may be evidence of early MTC and C-cell hyperplasia, which justifies this early intervention.81–83
The molecular mutations in MEN2A and MEN2B involve the RET oncogene, which is located on chromosome 10q21. The distribution of genetic mutations is different for the 2 syndromes, with MEN2A being more likely to involve codons 609, 611, 618, 620, 634, and MEN2B usually involving codon 918 (Fig. 1). But, all mutations constitutively activate the RET gene which encodes for a receptor tyrosine kinase.
Familial Medullary Carcinoma Syndrome
Equation (Uncited)Image Tools
Familial medullary thyroid carcinoma kindreds have medullary carcinomas without the other clinical findings of the MEN syndromes. They have been shown to have mutations in the same cysteine encoding codons as MEN2A patients (609, 611, 618, 620, or 634), and rarely codons 768 or 804. However, the distribution of mutations is different, with 618 and 620 being the most common. Mutations in codons 618 and 620 seem to activate RET to a lesser extent than the 634 mutation.84
Poorly Differentiated Carcinoma and Anaplastic Carcinoma
Many poorly differentiated thyroid carcinomas (PDTCA) and anaplastic thyroid carcinomas (ATCs) derive from well-differentiated lesions of the thyroid, and thus present in patients with preexisting thyroid disease. This can include a history of nodular goiter or of a well-differentiated thyroid carcinoma (papillary or follicular carcinomas). Patients with PDTCA present with symptomatic mass lesions, at a somewhat more advanced age than those with well-differentiated carcinoma, ATCs tend to present in the elderly. These patients will also present with symptomatic thyroid disease. In the extreme situation of ATC, patients can present with severe respiratory compromise secondary to invasion and compression of trachea.85 The prognosis for PDTCA is intermediate between FTC and ATC,86 with most series showing around a 50% 5-year survival rate for this tumor. ATC, on the other hand, has a dismal prognosis, with only about a 5% survival rate.87,88
Histologically, PDTCA remains somewhat controversial in terms of the diagnostic criteria.89–92 The most commonly used histologic features are growth pattern, necrosis, vascular invasion, and mitotic activity. The growth patterns that are considered to be within the PDTCA spectrum are solid, trabecular, and insular growth.91,93 However, a growth pattern alone is not enough to classify a tumor as PDTCA.91 The tumors also usually have increased mitotic activity, necrosis, and vascular invasion.89,91,94
ATC has a variety of histologic patterns, but all of the types share marked nuclear atypia as a common feature. The anaplastic or undifferentiated cells vary from spindled, to epithelioid, to giant cells, to rare forms such as rhabdoid type cells. The cell type does not have any prognostic significance. The other common histologic features are necrosis, vascular invasion, and widespread invasion into adjacent local structures.
The molecular mutational events in PDTCA are not well understood and have not been well studied.95 Those in ATC, however, have been fairly well characterized. ATCs harbor widespread DNA mutation damage, both at the tumor suppressor gene level and in terms of somatic oncogene mutations.96,97 Both RAS gene mutations and BRAF gene mutations are also found in ATC, again supporting the notion that many of these tumors arise from preexisting well-differentiated carcinomas.98–103
Parathyroid disease is relatively common in the United States. Hyperparathyroidism is often diagnosed incidentally, with routine blood work that recognizes hypercalcemia. The traditional and standard treatment for hyperparathyroidism is surgical, either with removal of a parathyroid adenoma or a subtotal parathyroidectomy in parathyroid hyperplasia. In recent years, a medication called cinacalcet, which is a calcimimetic agent has become available.104,105 This drug causes an increase in the parathyroid gland's sensitivity to calcium levels, which will decrease parathyroid hormone production.106 Although the front-line therapy for hyperparathyroidism remains surgical treatment, cinacalcet is being reported to be successful for treating recurrent or refractory cases of hyperparathyroidism, patients who are not surgical candidates, and even as a primary therapy.107
Hypoparathyroidism is extremely rare, and is most often found in the postsurgical patient, either with intentional parathyroid surgery, or unintentional parathyroidectomy during another surgical procedure, such as a thyroidectomy.108,109 Hypoparathyroidism is difficult to treat, as these patients require massive doses of calcium. In parathyroidectomy patients, there is the possibility of cryopreserving some of the native parathyroid tissue to be reimplanted if the patient is found to be hypoparathyroid after surgery. The fragments of parathyroid tissue are reimplanted in the forearm musculature, where they can function and produce parathyroid hormone with excellent clinical results.110
Clinically, the most significant patient population at risk for parathyroid hyperplasia (secondary type) are those with chronic kidney disease.111 Even after successful renal transplantation, some patients are at risk for persistent hyperparathyroidism.112 Most of these patients are currently treated with surgery, though the use of the cinacalcet is also gaining momentum as a first-line therapy.111
The pathologic features in parathyroid hyperplasia are relatively nonspecific, and essentially demonstrate enlargement and hypercellularity of all 4 parathyroid glands.113,114 The size of these glands varies widely, ranging from within the normal range (<50 mg) to very large glands over 10 g in weight. These parathyroid glands can be somewhat misleading at the histologic level, because they can also have substantial reactive findings, particularly in the patients who have secondary hyperparathyroidism. The reactive features include extensive fibrosis, hemosiderin deposition, and possibly focal cystic or degenerative changes within particularly large glands. Rare cases of parathyroid carcinoma have been reported to arise in a background of parathyroid hyperplasia.115
At the molecular level, the genetic alterations in nonsyndromic or secondary parathyroid hyperplasia are poorly understood. Molecular alterations of the parathyroid hormone gene are not thought to be involved in activation in parathyroid hyperplasia.116 Specific molecular contributions are unlikely to be very important in most of the cases of parathyroid hyperplasia, as this condition is well known to be primarily a function of calcium imbalance secondary to the kidney dysfunction.
One interesting debate in the literature centers on the clonality of parathyroids in parathyroid hyperplasia. The long-held belief was that the glands in parathyroid hyperplasia, either primary or secondary types, were truly hyperplastic and not neoplastic; one study of clonality at the molecular level has also supported this theory, showing polyclonality in both adenomas and hyperplasia.117 Several recent studies, however, have shown monoclonality in a significant percentage of parathyroids in both of these clinical conditions.117–122 With this finding, it is now presumed that clonal expansion of specific nodules probably occurs secondarily, after the long-standing polyclonal proliferation of the background parathyroid hyperplasia.
The genetics of hereditary diseases that have parathyroid hyperplasia as a component of the syndrome are fairly well understood and molecular contributions to these processes are clearly important. Syndromic or hereditary diseases are thought to account for approximately 25% of the cases of parathyroid hyperplasia.114 Table 3 lists the syndromes that have hyperparathyroidism, along with the genes responsible and other clinical features seen in the condition.
Patients with parathyroid adenomas also present with hypercalcemia, which again may be discovered incidentally through routine medical examinations. Most of these patients will have a single abnormal gland. Parathyroid adenomas can be located in all the usual locations for parathyroid glands, but can also be located in unusual areas, such as within the cervical thymus, in the thyroid gland, or even within the mediastinum. For that reason, most surgeons prefer an approach that includes preoperative localization of the abnormal gland. The gland can usually be localized preoperatively using a either ultrasound or sestamibi nuclear medicine scans.123
The enlarged glands in parathyroid adenoma in usual locations are often easily recognized intraoperatively. They are usually oval in shape, have a smooth outer surface, and a homogenous tan-red cut surface. The average size of glands in parathyroid adenomas is around 1 g, but the range can be broad. Histologically, the growth pattern and cell types are highly variable, but an almost universal finding is hypercellularity and loss of stromal and intracytoplasmic lipid. There is minimal nuclear pleomorphism and mitotic activity, however, and the neoplastic proliferations are well circumscribed. A rim of normocellular parathyroid tissue can often be appreciated.
At the molecular level, multiple different studies have now shown that parathyroid adenomas are monoclonal.118–122,124 Specific molecular alterations are also seen in parathyroid adenomas. For example, loss of 1p is a very consistent finding in parathyroid adenomas.125,126 The genes that are involved in syndromic cases of hyperparathyroidism have also been implicated in the pathogenesis of both parathyroid adenoma and parathyroid carcinoma. For example, MEN1 gene somatic mutations and loss of heterozygosity of MEN1 have been found in parathyroid adenomas.127–129
An interesting argument has always existed about whether a patient can have 2 adenomas, or if this situation represents asynchronous parathyroid gland hyperplasia. Recent studies have argued that it is possible to have 2 adenomas in up to 15% of patients, though most studies suggest an average incidence of around 7%.130–133 One study examined the genetics of double adenoma, and found that most of the paired abnormal glands had different mutational profiles between the glands, with the exception of the MEN1 gene which showed consistent alterations in several of the cases.127,128
Atypical Parathyroid Adenoma
Atypical parathyroid adenoma is the terminology that is used in situations where the diagnosis of parathyroid carcinoma cannot be reached, but the histologic features are not those of a typical benign parathyroid adenoma. Frequently, these cases exhibit increased fibrosis, either in the form of fibrous bands or a thick fibrous capsule,134 increased mitotic activity, and nuclear pleomorphism, but do not show evidence of invasion either clinically or histologically. The entity is somewhat controversial, because of the nebulous histologic features, the fact that it cannot be distinguished clinically or operatively from either benign or malignant disease, and the fact that the ideal clinical management for these patients is uncertain.135
The molecular genetics of atypical parathyroid adenomas has not been well studied. One report does identify an intermediate immunohistochemical expression profile for atypical adenomas.136
Parathyroid carcinoma is a rare disease and one that tends to be relatively difficult to diagnose. The clinical features of this disease are important to consider, when the diagnosis of parathyroid carcinoma is being entertained. But, unfortunately, none of the clinical or the pathologic features that will be discussed for parathyroid carcinoma are entirely specific or sensitive. Making the diagnosis of parathyroid carcinoma relies on combining the data from both the clinical findings and the pathologic findings.
The literature suggests that patients with parathyroid carcinoma present with a very high serum calcium level.134,137–139 But, recent studies have shown that parathyroid carcinomas can also present in patients with moderately elevated calcium levels as well.134,140 Other clinically worrisome features include a palpable mass lesion, symptomatic hypercalcemia, and hoarseness.134,141
Histologically, the diagnosis of parathyroid carcinoma is also difficult to make. Some of the classically described histologic features of parathyroid carcinoma include broad bands of fibrosis, increased mitotic activity and higher proliferative activity, and nuclear atypia and pleomorphism.139 However, it should be noted that none of these features alone should be used to diagnose parathyroid carcinoma. The most important features of parathyroid carcinoma are invasion into the surrounding tissues, or known metastasis. Invasion can either be detected intraoperatively by the surgeon, who finds the gland to be adherent to local structures, or histologically, where the pathologists finds local stromal invasion at the periphery of the lesion or even more importantly, peritumoral angio-lymphatic or perineural invasion.139,142
Molecular alterations in parathyroid carcinomas have been studied, from the gene expression level to the chromosomal level, to the individual gene level. In fact, most studies do suggest that parathyroid adenoma and parathyroid carcinoma are different at the gene expression and the gene copy number level.125,126,143 However, the techniques of expression microarray, comparative genomic arrays, and assessing panels of tumor suppressor genes may not be practical to use in the diagnostic setting. Therefore, most of the literature has concentrated on the analysis of single genes or the protein products of single genes.
Initial studies of single genes focused primarily on well-understood tumor suppressor genes, such as retinoblastoma (Rb) and MEN1, which have both been shown to harbor alterations in parathyroid carcinoma. Loss of heterozygosity of the Rb gene and loss of protein expression of the Rb protein product are both seen in parathyroid carcinoma.144–149 Similarly, loss of heterozygosity and even somatic point mutations of the MEN1 gene are seen in parathyroid carcinomas, but these can also be found in benign parathyroid adenomas.127–129
The most significant advance in the genetic understanding of parathyroid carcinoma came with the isolation of the genetic mutations in a rare, but illustrative syndrome: hyperparathyroidism jaw tumor syndrome (Table 3). Patients with this syndrome have a combination of tumors that include parathyroid cysts and carcinomas and fibro-osseous lesions of the jaw.150 The genetics of this tumor were resolved when the HRPT2 gene, which encodes for parafibromin, was isolated.151,152 It has now been shown that parathyroid carcinomas both from patient with the syndrome and in the sporadic setting, frequently have loss of heterozygosity of the HRPT2 gene, which causes loss of expression of the parafibromin protein product by immunohistochemistry.153–157 This loss of expression is fairly sensitive and specific, though isolated adenomas may also show inactivation of the gene and loss of expression.158
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