Key Points

Introduction

Parathyroid carcinoma is a rare endocrine neoplasm. Its incidence ranges from 0.5% to 5.0% of the cases with primary hyperparathyroidism. Parathyroid carcinoma commonly has an indolent growth with a tendency for local invasion, and it occurs with equal frequency in men and women. The age at presentation for parathyroid carcinoma compared with adenoma is reported to be a decade earlier. It was first described by the Swiss surgeon Fritz De Quervain. In 1904, he described a case of nonfunctioning metastatic parathyroid carcinoma, and 26 years later, Sainton and Millot described the first case of functioning metastatic parathyroid carcinoma. Armstrong in 1938 described another patient with metastatic parathyroid carcinoma and hypercalcemia, and in 1968, Holmes and colleagues reviewed 50 cases of parathyroid carcinoma reported in the literature. Of those, 46 tumors were functioning with a mean serum calcium level of 15.9 mg/dL. Fewer than 10% of parathyroid carcinoma cases present as nonfunctional tumors. Although most patients with parathyroid carcinoma present with hyperparathyroidism, a diagnosis of hyperparathyroidism attributable to carcinoma may be difficult to arrive at preoperatively or even intraoperatively. In many cases, because of the rarity of the disease and clinical features mimicking benign parathyroid pathology, preoperative diagnosis of parathyroid carcinoma is difficult. In addition, the pathologic diagnosis of malignancy is challenging; however, severe hypercalcemia combined with high parathyroid hormone levels and gross operative findings should arouse suspicion of parathyroid carcinoma. This article reviews the relevant literature on parathyroid carcinoma in an attempt to provide diagnostic and therapeutic strategies.

Introduction

Parathyroid carcinoma is a rare endocrine neoplasm. Its incidence ranges from 0.5% to 5.0% of the cases with primary hyperparathyroidism. Parathyroid carcinoma commonly has an indolent growth with a tendency for local invasion, and it occurs with equal frequency in men and women. The age at presentation for parathyroid carcinoma compared with adenoma is reported to be a decade earlier. It was first described by the Swiss surgeon Fritz De Quervain. In 1904, he described a case of nonfunctioning metastatic parathyroid carcinoma, and 26 years later, Sainton and Millot described the first case of functioning metastatic parathyroid carcinoma. Armstrong in 1938 described another patient with metastatic parathyroid carcinoma and hypercalcemia, and in 1968, Holmes and colleagues reviewed 50 cases of parathyroid carcinoma reported in the literature. Of those, 46 tumors were functioning with a mean serum calcium level of 15.9 mg/dL. Fewer than 10% of parathyroid carcinoma cases present as nonfunctional tumors. Although most patients with parathyroid carcinoma present with hyperparathyroidism, a diagnosis of hyperparathyroidism attributable to carcinoma may be difficult to arrive at preoperatively or even intraoperatively. In many cases, because of the rarity of the disease and clinical features mimicking benign parathyroid pathology, preoperative diagnosis of parathyroid carcinoma is difficult. In addition, the pathologic diagnosis of malignancy is challenging; however, severe hypercalcemia combined with high parathyroid hormone levels and gross operative findings should arouse suspicion of parathyroid carcinoma. This article reviews the relevant literature on parathyroid carcinoma in an attempt to provide diagnostic and therapeutic strategies.

Anatomy, etiology, and epidemiology

The parathyroid glands are endodermal in origin and develop from the dorsal wing of the third and fourth pharyngeal pouches. They produce parathyroid hormone (PTH), which regulates the circulating level of calcium through intestinal and renal absorption and bone remodeling. There are typically 4 parathyroid glands; however, supernumerary glands and fewer than 4 glands have been reported. The superior parathyroid glands originate from the fourth pharyngeal pouch, and they attach to the posterior surface of the inferiorly migrating thyroid. They have a much shorter migration distance compared with the inferior parathyroid glands, accounting for their more predictable location. The dorsal wing of the third pharyngeal pouch gives rise to the inferior parathyroid glands, whereas the ventral wing gives rise to the thymus during the fifth week of gestation. Both primitive glands join the thymus as it travels caudally and medially to its final position in the mediastinum. This migration of the inferior parathyroid glands with the thymus results in the inferior parathyroid gland to be in a plane that is usually ventral to that of the superior parathyroid glands. For this reason, ectopic inferior parathyroid glands can be found anywhere along this large area of descent up to the superior border of the pericardium.

Etiology of parathyroid carcinoma is not known. There is an association between multiple endocrine neoplasia type 1, the autosomal dominant form of familial hyperparathyroidism and an increased risk of parathyroid carcinoma. Additionally, there have been reports of carcinoma occurring in an adenoma, hyperplastic gland, or in patients with history of neck irradiation and end-stage renal disease. In the report by Koea and Shaw, 1.4% of the patients with parathyroid carcinoma had prior history of neck irradiation; however, robust causal relationship between parathyroid carcinoma and radiation or lifestyle factors has not been described.

Parathyroid carcinoma by all means is a rare disease with the reported incidence ranging from 0.5% to 5.0%. There may be a geographic variation in the distribution of this disease, with reported incidence of about 1% in Europe and the United States and about 5% in Japan and Italy. Hundahl and colleagues in their review of the National Cancer Data Base (NCDB) between 1985 and 1995 identified 286 cases of parathyroid cancer, accounting for 0.005% of the total NCDB cancer cases. This variation may represent a discrepancy in histopathological and clinical criteria in recognition of malignancy. Parathyroid carcinoma occurs with equal frequency in men and women, whereas a higher female-to-male ratio (3–4:1) has been reported in parathyroid adenoma. On average, it presents a decade earlier than parathyroid adenoma during the fourth and fifth decade of life; however, these demographic data have no value in diagnosing parathyroid carcinoma. In the NCDB study, the investigators were unable to detect any disproportionate clustering by race, income level, or geographic region in their study population. The median age of this cohort at presentation was 55 years with equal gender distribution.

Histopathology

Two cardinal features for the diagnosis of any carcinoma are local invasion and metastasis. Some investigators believe that an unequivocal diagnosis of parathyroid carcinoma should be restricted to those tumors that invade adjacent soft tissues, thyroid gland, blood vessels, or perineural spaces or to those cases with documented metastases ; however, this may underestimate the diagnosis of carcinoma and histologic criteria may be useful in making this challenging diagnosis. Clinical and gross features of the parathyroid tumor at the time of surgical resection can significantly aid in the diagnosis of carcinoma. The size of tumor has been reported to range from 0.75 cm to larger than 6 cm. Parathyroid carcinoma often appears adherent to the surrounding tissue and is poorly circumscribed. Grossly, carcinomas are firm and grayish white compared with adenomas that are usually soft and tan colored. In one series, extent of local invasion was reported with ipsilateral thyroid invasion being the most common in 89% of the cases followed by strap muscles (71%), ipsilateral recurrent laryngeal nerve (26%), esophagus (18%), and trachea (17%).

Histologic features of lesions may be used in diagnosis of carcinoma before infiltration and metastasis has occurred. This approach has presented with difficulty in diagnosis of parathyroid carcinoma with no single feature being pathognomonic of malignancy. In making the diagnosis of carcinoma, some investigators adopt histologic criteria similar to those described by Schantz and Castleman in 1973. In studying 67 cases, they observed certain histologic features that distinguished parathyroid carcinoma from adenoma. These features were fibrous capsule or fibrous trabeculae, or both, a trabecular or rosettelike cellular architecture, the presence of mitotic figures, and capsular or vascular invasion. Similar to other investigators, however, they emphasized the importance of considering the overall picture rather than any single criterion. In one study, presence of vascular or capsular invasion and fibrous trabeculae were the most common indicators of malignancy. Some investigators consider high mitotic rate as an important feature of the diagnosis, whereas other investigators express reservation regarding the significance of vascular and capsular invasion, and feel that mitotic activity alone has limited value in diagnosis of malignancy because high mitotic rate is also observed in benign disease ( Fig. 1 ).

Major capsular and vascular invasion with high mitotic activity confirming diagnosis of parathyroid carcinoma.

Although ultrastructural features of parathyroid carcinoma have been described, in establishing the diagnosis of malignancy, electron microscopic investigation did not add significantly to light microscopy. In almost all cases of carcinoma, the microscopic features were those of the chief cells. Flow-cytometric analysis of parathyroid tumors using fresh material confirms that parathyroid carcinomas are more apt to be aneuploid than are adenomas, and determination of the DNA ploidy pattern is a valuable adjunct to the histologic diagnosis of parathyroid carcinoma. Additionally, special staining, such as Ki-67, may be beneficial in diagnosis of parathyroid carcinoma.

Imaging studies and diagnosis

The same noninvasive imaging studies used for the diagnosis of benign parathyroid disease may be used in aiding the initial diagnosis, and in identifying recurrence and extent of parathyroid carcinoma. Ultrasonography, sestamibi scanning, computed tomography (CT), single-photon emission CT, magnetic resonance imaging (MRI), and positron emission tomography have been used for the initial diagnosis and to detect the recurrence of parathyroid carcinoma ( Figs. 2 and 3 ). Ultrasound is a noninvasive and useful study to localize primary and locally recurrent disease. Typically, parathyroid carcinomas are lobulated, hypoechoic, and relatively large, with ill-defined borders compared with adenomas. In a retrospective study, 69 patients with parathyroid lesions larger than 15 mm were evaluated by ultrasound. A high positive predictive value (PPV) for cancer was identified for infiltration (PPV 100%) and calcification (PPV 100%), and a high negative predictive value (NPV) was found for the absence of suspicious vascularity (NPV 97.6%), a thick capsule (NPV 96.7%), and inhomogeneity (NPV 100%). The investigators concluded that in parathyroid lesions larger than 15 mm, ultrasonography for specific features provides a valuable tool to identify parathyroid cancers before surgery. Other investigators, however, have pointed out that it could be challenging to distinguish a large adenoma from a carcinoma by ultrasound. Additionally, ultrasound may be used to guide fine-needle aspiration (FNA) biopsy when regional nodal metastasis is suspected. Technecium-99 m sestamibi scanning is widely used to localize parathyroid tumors. Sestamibi can also be used to detect primary parathyroid cancer or recurrent disease; however, no specific characteristics exist for distinguishing benign disease from parathyroid carcinoma. Other anatomic studies, such as MRI and CT scan, could be used for localizing recurrence or metastasis, such as in bone and liver. In a retrospective review, the sensitivity of scintigraphy, CT, and ultrasonography in detecting recurrent disease was 86%, 79%, and 100%, respectively. The addition of imaging studies to clinical presentation and the biochemical values as discussed previously may raise the suspicion of parathyroid carcinoma. Once this diagnosis is suspected, FNA biopsy of the primary lesion should be avoided, as it has been associated with tumor seeding of the biopsy tract. Furthermore, FNA cytology will not be able to distinguish benign from malignant parathyroid tumor of the primary lesion. FNA biopsy may be used to help distinguish thyroid from parathyroid tissue or identify metastatic parathyroid carcinoma. Intraoperatively, in the absence of gross local invasion or regional metastasis, the diagnosis of carcinoma can be difficult. Frozen-section analysis is also of little value and unreliable, as the histopathological features of carcinoma may overlap with those of parathyroid adenoma. In the study by Hundahl and colleagues, 86% of patients did not receive the diagnosis of carcinoma intraoperatively, even with experienced parathyroid surgeons.

CT scan showing irregular mass involving the left lower parathyroid, suggestive of parathyroid malignancy.

Sestamibi scan showing intense activity in large left upper parathyroid.

Management

Parathyroid carcinoma is a slow-growing but aggressive malignant tumor and most patients die of the metabolic complications of hypercalcemia. Thus, the goals of treatment of the primary lesion, local recurrence, or metastatic disease should be to eliminate all demonstrable disease when possible and to control the metabolic complications of hyperparathyroidism. Other treatments, however, such as chemotherapy, embolization, and radio frequency ablation, have been attempted.

Surgery

The most effective treatment of parathyroid carcinoma remains surgical. Although the diagnosis of carcinoma can be difficult even at the time of initial surgical resection, intraoperatively, parathyroid tumors are usually large and firm, with a whitish capsule and are adherent to adjacent structures. When suspected, en bloc resection of the carcinoma and the adjacent involved structures in the neck, including the ipsilateral thyroid lobe, with gross clear margins and avoidance of tumor spillage, is the gold standard treatment of parathyroid carcinoma. Incomplete tumor extirpation will result in high rates of local recurrence. In such situations, although reoperation can be performed to palliate the symptoms of hypercalcemia, it rarely results in cure of the disease. Patients with parathyroid carcinoma are at high risk of recurrent laryngeal nerve (RLN) invasion during their lifetime and if RLN is grossly involved by tumor, it needs to be sacrificed. When cervical nodes are involved, a therapeutic modified neck dissection is necessary; however, prophylactic neck dissection has not shown to improve survival and is associated with increased morbidity. The extensive surgical resection suggested by Holmes and colleagues that includes removal of the strap muscles, skeletonization of the trachea, and sacrifice of the recurrent laryngeal nerve, in addition to removal of the tumor and ipsilateral thyroid lobe, is not usually undertaken. In the review by Koea and Shaw, en bloc resection of the carcinoma and the adjacent structures in the neck was associated with an 8% local recurrence rate and a long-term overall survival rate of 89% (mean follow-up 69 months). In contrast, simple parathyroidectomy resulted in a 51% local recurrence rate and 53% long-term survival rate (mean follow-up 62 months). In another retrospective review of 13 patients, all of those who underwent local excision of the tumor developed recurrent disease compared with 33% who underwent en bloc resection. Use of rapid PTH assay has been reported to be useful in the management of parathyroid carcinoma. If the diagnosis of carcinoma is suspected before the operation, and the level of PTH falls into the normal range postoperatively, this can provide reassurance that the tumor is likely completely removed. If the PTH levels do not fall into the normal range or the diagnosis of carcinoma is not suspected until the postoperative pathologic evaluation, however, the management becomes controversial. When the tumor has low-grade features and the patient has normal calcium and PTH levels, close and lifelong monitoring and measurement of serum calcium and PTH at 3-month intervals is adequate. However, if aggressive features, such as extensive capsular or vascular invasion, are seen and the patient remains hypercalcemic, additional investigational studies and reoperation may be warranted. During the immediate postoperative period, patients should be closely monitored and treated for symptoms of hypocalcemia owing to hungry bone syndrome. Serum calcium level should be maintained at lower limit of the normal range.

Usually, parathyroid carcinoma recurs 2 to 5 years after initial surgery. It is associated with a local recurrence rate of 33% to 82% within 5 years. The high recurrence rate is likely because of incomplete resection of the tumor or tumor spillage. The rate of nodal metastasis is reported as high as 17% to 32% ; however, this is more commonly in the setting of local recurrence. The incidence of distant metastasis is difficult to determine owing to the rarity of this disease. Metastases occur both via lymphatics and hematogenously, and the most common sites of distant metastases are the lung and liver, with the reported incidence of up to 40% and 10%, respectively. Patients with recurrent disease or distant metastasis have recurrent progressive hypercalcemia along with high PTH level. For this reason, medical management of hypercalcemia and appropriate imaging studies to locate the site of recurrence are essential. Because these tumors are slow growing, repeated resection of local recurrences and/or distant metastases can result in significant palliation. The goal of the operation is to remove all gross disease in the neck, mediastinum, and the distant sites with clear margins. In a retrospective review of 12 reoperations for locoregional control and 2 pulmonary metastatectomies, symptomatic relief in 86% of patients and a transient biochemical remission in 1 patient were achieved. In a series of 6 patients who underwent pulmonary metastatectomies, 50% had biochemical resolution of their hypercalcemia, although some required multiple operations. Patients with recurrent or metastatic parathyroid carcinoma may benefit from an aggressive surgical approach when feasible; however, in most cases, the symptomatic relief and biochemical normalization are temporary.