Primary hyperparathyroidism

Abstract

Parathyroid carcinoma is a rare malignancy, and experience with its management is limited. It is generally accepted that surgery is the treatment of choice, and the initial operative intervention might represent the only chance for long-term success. At the time of surgery, a high index of suspicion for carcinoma is vital to performing the appropriate surgical procedures, because frozen section diagnosis of parathyroid carcinoma is notoriously unreliable. In this article, we describe our experience with this rare entity.

Introduction

Malignant transformation within a parathyroid gland is a rare phenomenon; even more so is simultaneous multiple gland involvement by a parathyroid carcinoma. Most cases of parathyroid carcinoma are sporadic. Familial isolated hyperparathyroidism is a rare autosomal-dominant disorder associated with an increased risk of parathyroid carcinoma. Approximately 1 to 2% of cases of hyperparathyroidism are caused by parathyroid carcinoma. The overall incidence of parathyroid carcinoma worldwide ranges from 0.32 to 5.0%, with the higher rate being reported in case studies from the Japanese literature. (1) Because of the small number of cases at any single treatment center, a lack of adequate experience in diagnosis and management is the rule rather than the exception.

Case report

It is generally accepted that surgical management is the treatment of choice for parathyroid carcinomas, and the initial operative intervention might represent the only chance for long-term success. (2-4) At the time of surgery, a high index of suspicion for carcinoma is vital to performing the appropriate surgical procedures, because frozen section diagnosis of parathyroid carcinoma is notoriously unreliable. In one series, 18 of 95 patients (18.9%) who had a confirmed carcinoma initially received a diagnosis of benign disease. (2) In this article, we describe our experience with this rare entity.

A 51-year-old man, an elementary school teacher, was referred to our otolaryngology service with a diagnosis of primary hyperparathyroidism. His chief complaints were anorexia, nausea, vomiting, anxiety, and bone pain. He had received low-dose radiation therapy as a child for adenotonsillar enlargement. At the age of 40 years, he underwent a left thyroid lobectomy at another institution; histopathology identified a benign thyroid goiter. His medical history also included a single episode of hematuria and a 10-year history of anxiety disorder, both of which had been treated successfully prior to his referral to our service. He did not use alcohol or tobacco.

Clinical evaluation revealed a healed scar from his previous thyroid surgery and a soft hemithyroid on palpation. No cervical lymphadenopathy was noted. The rest of the head and neck examination was unremarkable. Laboratory tests measured his serum calcium (14.0 mg/dl), albumin (4.1 mg/dl), phosphorus (2.3 mg/dl), parathyroid hormone (98 pg/ml), and calcitonin (17 pg/ml). Results of his thyroid panel were normal. A kidney, ureter, and bladder examination revealed pelvic calcification, and a technetium 99m (Tc 99m) sestamibi scan showed persistent activity bilaterally in the region of the inferior poles of the thyroid gland (figure 1).

The patient underwent a stepwise bilateral cervical exploration, and only three parathyroid glands could be identified; the left superior gland could not be located and was presumed to have been removed during his first thyroid surgery. The two inferior parathyroid glands were grossly enlarged and exhibited some adherence to the surrounding soft tissues. Analysis of intraoperative frozen-section specimens of the two enlarged inferior glands was inconclusive. A section of the right superior gland exhibited normal histopathologic features.

The decision was made to remove the enlarged inferior glands and leave the remnant of the thyroid gland in situ. This decision was based on the finding of multiple enlarged glands. Malignancy was not suspected nor confirmed at the time of surgery. No lymphadenopathy was noted intraoperatively. On the second postoperative day, the patient experienced a transient bout of hypocalcemia (7.5 mg/dl), which had been detected clinically by a positive Clivostek' s sign and paresthesia in the extremities. It was successfully treated with oral calcium supplementation.

Permanent histopathologic examination at our institution led to a diagnosis of parathyroid carcinoma of both inferior glands; there was also evidence of vascular invasion and involvement of the adjacent thyroid tissue. A consultation with the Armed Forces Institute of Pathology confirmed the diagnosis of bilateral parathyroid carcinoma. Three weeks later, the patient underwent a completion thyroidectomy en bloc with anterior neck dissection, which detected no evidence of residual parathyroid carcinoma.

The right inferior parathyroid measured 1.0 x 1.0 x 0.8 cm, and the left inferior parathyroid measured 1.7 x 0.9 x 1.4 cm. Both glands were nodular, tan-brown, and firm in texture, and both exhibited scant adherent soft tissue and a homogenous cut surface. No hemorrhage or necrosis was noted grossly.

The two parathyroids had identical histologic patterns. The tumor cells had a nodular appearance, and they were separated by sclerotic bands of connective tissue. These bands of acellular hyalinized tissue subdivided the neoplasm into compartments (figure 2). The neoplasm was made up of a uniform proliferation of tumor cells arranged in solid nodules and trabeculae with eosinophilic-to-clear cytoplasm and a moderate variation in nuclear size. The nuclear/cytoplasmic ratio was higher than normal, and pleomorphism and prominent nucleoli were present (figure 3). Small tumor islands were noted within vascular spaces (figure 4).

Since his surgery, the patient has been maintained on calcium supplementation. He has shown no evidence of disease during 27 months of otolaryngologic and endocrinologic follow-up.

Discussion

There are two controversies in the management of parathyroid carcinoma; one is related to the establishment of firm histologic criteria for diagnosis and the other involves its differentiation from benign disease. Clinically, parathyroid carcinoma should be suspected when any of three conditions are observed: severe hypercalcemia (>14 mg/dl), a cervical mass in a hypercalcemic patient, or hypercalcemia associated with unilateral vocal fold paralysis. (5,6) Grayish discoloration caused by adherence to fat and striated muscle has been seen in 50% of cases of parathyroid carcinoma. (5,7) Patterns of fibrosis are common, and they are not considered to be pathognomonic. Some carcinomas have a bland appearance, and they differ from their benign counterparts only by their clinical behavior and aggressiveness. (3) Schantz and Castleman have described the importance of identifying a discrete fibrous capsule with trabeculation, the presence of mitosis, invasion of the capsule and adjacent soft tissue, and angioinvasio n; these are the classic features that point to a firm diagnosis of carcinoma. (7,8)

The histopathologic diagnosis of parathyroid carcinoma is often difficult. (5) Its appearance varies from a resemblance to an adenoma to a resemblance to a frank anaplastic carcinoma. Parathyroid carcinomas are generally larger than adenomas, and they are more likely to adhere to the thyroid and surrounding soft tissues of the neck. Not all of these features are present in any given case, but several are usually present, which can help make the diagnosis of a carcinoma. Fibrous connective-tissue bands are noted in 90% of the cases studied, and they were present in our patient.

Retrogressive changes in an adenoma can result in an appearance that is almost indistinguishable from that of a carcinoma. However, these retrogressive changes are usually associated with chronic inflammation and hemosiderin deposition. Mitosis is present in approximately 80% of cases of parathyroid carcinoma, but it is also seen in approximately 14% of cases of parathyroid hyperplasia and parathyroid adenoma. Vascular invasion is present in 10 to 15% of cases. Although vascular invasion is not a common feature, its presence is virtually diagnostic of malignancy. Invasion of nerve bundles and adherence to the thyroid and soft tissues of the neck are also useful diagnostic features. Those cases that lack unequivocal evidence of malignancy are classified by some authors as atypical adenomas. (9) It is important to note that several authors believe that with adequate follow-up, these tumors will evince their true malignant nature by their recurrence and metastasis. (2,3)

Our patient had unequivocal microscopic evidence of several of the features of parathyroid carcinoma: vascular invasion, thick fibrous bands, nuclear pleomorphism with prominent nucleoli, and invasion of the soft tissues of the neck. These findings were confirmed by the Armed Forces Institute of Pathology.

Parathyroid carcinoma has a subtle appearance and requires a high index of suspicion to ensure an accurate diagnosis. The importance of an early diagnosis cannot be overemphasized because the duration of undetected malignancy has a direct impact on the extent of surgical intervention, and it has been clearly shown that the extent of surgery affects recurrence and long-term survival. (1-3) Patients who have undergone simple parathyroidectomy without en bloc resection of surrounding structures (e.g., the adjacent thyroid gland and the paratracheal and paraesophageal lymph nodes) experience a higher recurrence rate. (1-3,5,7,8,10)

Because parathyroid carcinoma is so rare, our experience in managing it is limited. Some authorities believe that the management of this disease is better left in the hands of specialists at major tertiary-care centers, which have wider experience and which have reported larger series. (2,3) In our case, our inexperience with this disease precluded an initial intraoperative diagnosis and an initialen bloc resection. The gland's firmness and adherence to surrounding soft tissues, although subtle, should have raised a red flag, which would have ensured that the appropriate surgical approach would have been taken at the outset.

Making a histopathologic diagnosis, especially an intraoperative frozen-section diagnosis, can be a significant challenge. Diagnoses often remain inconclusive even on permanent sections. Parathyroid carcinomas are indolent in their behavior, and the diagnosis is often not confirmed until the inevitable recurrence or metastasis occurs. (1,4) Therefore, the operating surgeon must rely on the accumulated experience of others to guide the course of surgery because the initial operation appears to offer the best chance for cure.

Any evidence of firmness or tissue adherence in a parathyroid gland that appears grayish mandates an en bloc resection and at minimum a paraesophageal node dissection. (1-3,7,8) A more extensive dissection would be guided by the extent of the disease (i.e., cervical or mediastinal node involvement). A local recurrence or single focal metastasis should not be a deterrent to reoperation. The results of surgery and efforts to control the severe adverse metabolic states associated with high serum calcium levels in these patients have been encouraging. (1,4,6,10,11)

References

(1.) Fujimoto Y, Obara T, Ito Y, et al. Localization and surgical resection of metastatic parathyroid carcinoma. World J Surg 1986;10:539-47.

(2.) Sandelin K, Auer G, Bondeson L, et al. Prognostic factors in parathyroid cancer: A review of 95 cases. World J Surg 1992;16:724-31.

(3.) Bondeson L, Sandelin K, Grimelius L. Histopathological variables and DNA cytometry in parathyroid carcinoma. Am J Surg Pathol 1993;17:820-9.

(4.) Fujimoto Y, Obara T, Ito Y, et al. Surgical treatment often cases of parathyroid carcinoma: Importance of an initial en bloc tumor resection. World J Surg 1984;8:392-400.

(5.) Holmes EC, Morton DL, Ketcham AS. Parathyroid carcinoma: A collective review. Ann Surg 1969;169:631-40.

(6.) Levin KE, Galante M, Clark OH. Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia. Surgery 1987;101:649-60.

(7.) Schantz A, Castleman B. Parathyroid carcinoma. A study of 70 cases. Cancer 1973;31:600-5.

(8.) Castleman B. Tumors of the parathyroid glands. In: Atlas of Tumor Pathology. Washington, D.C.: Armed Forces Institute of Pathology, 1952:50-4.

(9.) DeLellis R. Tumors of the parathyroid glands. In: Atlas of Tumor Pathology. 3rd series, fascicle 6. Washington, D.C.: Armed Forces Institute of Pathology, 1993:53-63.

(10.) Wang CA, Gaz RD. Natural history of parathyroid carcinoma. Diagnosis, treatment, and results. Am J Surg 1985;149:522-7.

(11.) Flye MW, Brennan MF. Surgical resection of metastatic parathyroid carcinoma. Ann Surg 1981;193:425-35.

From the Department of Otolaryngology-Head and Neck Surgery (Dr. Brown, Dr. Williams-Smith, Dr. Osborne, and Dr. Coker) and the Department of Pathology (Dr. Mohamed and Dr. Yee), Charles R. Drew University School of Medicine and Science, Martin Luther King Jr. Drew Medical Center, Los Angeles.

Reprint requests: Jimmy J. Brown, DDS, MD, Charles R. Drew University, 1731 E. 120th St., Los Angeles, CA 90059. Phone: (310) 668-4836; fax: (310) 668-4554; e-mail: jimbrown@cdrewu.edu

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