Intrathyroidal parathyroid carcinoma: a case report with clinical and histological findings
© Temmim et al. 2008
Received: 18 August 2008
Accepted: 25 November 2008
Published: 25 November 2008
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© Temmim et al. 2008
Received: 18 August 2008
Accepted: 25 November 2008
Published: 25 November 2008
The chance of an intrathyroidal occurrence of a parathyroid gland is about 1–3%. Among the causes of hyperparathyroidism, parathyroid cases occur in less than 1% of patients. Here we present the case of a 63 year old Saudi female suffering from an intrathryroidal parathyroid carcinoma. The suspicion coming from the clinical investigations that the removed tumor tissue may be a parathyroid carcinoma could be confirmed by histology. Additionally non-radioactive in situ hybridization to localize mRNA transcripts for Cyclin D1 and immunohistochemical localization of Cyclin D1 was performed. Although parathyroid adenoma and carcinoma have disparate natural history, it can be difficult to differentiate between the two entities. Clinical presentation, operative findings may raise suspicion, but may not be conclusive especially if there is no evidence of invasion or metastasis, especially if the gland was intrathyroidal.
Parathyroid adenomas account for 85% of primary hyperparathyroidism . On the other hand, parathyroid carcinoma is a rare disease that accounts only for 1% to 3% of cases of primary hyperparathyroidism [2, 3] and to the best of our knowledge, intrathyroidal parathyroid carcinoma have been reported only three times . The diagnosis and appropriate treatment of intrathyroidal parathyroid carcinoma is difficult and its treatment is more challenging to the surgeons. Adenomas and carcinomas of the parathyroid gland have disparate natural histories, but it can be difficult to differentiate them on the basis of clinical and histological findings alone. Thick fibrous bands, mitotic activity, trabecular growth pattern and capsular, vascular, and adjacent soft tissue invasion have been considered characteristic of parathyroid carcinoma, but some of these morphological features (fibrous bands, mitotic activity, trabecular growth) have been identified in parathyroid adenomas as well . Clarification of the molecular pathogenesis of parathyroid carcinoma can aid in diagnostically difficult cases and may provide important clues for a more effective therapy. Cyclin D1 (CD1) or PRAD1 is a protoncogene located at chromosome band 11q13 and its protein product is a cell cycle regulator . Cyclin D1 gene amplification has been implicated in the pathogenesis of numerous tumors [5–7]. Recently, Hsi et al.  demonstrated the over expression of the cyclin D1 oncogene in 18% of 65 patients with parathyroid tumors. They think that over expressed cyclin D1 plays a role in the pathogenesis of a much larger proportion of parathyroid adenomas than previously assumed. Cyclin D1 overexpression is a feature of typical parathyroid adenomas as had been suggested by early DNA studies . Although His et al studied only three patients with parathyroid carcinoma, two of the patients tumors stained strongly for Cyclin D1, raising the possibility that the frequency of Cyclin D1 overexpression may be greater in carcinoma. Cyclin D1 overexpression appears to highlight a central pathway in parathyroid neoplasia. In our case study, we therefore include the localization of Cyclin D1 at the messenger RNA (in situ hybridization) and protein (immunohistochemistry) level.
The patient was admitted and loaded with intravenous saline followed by Furosemide (10 mg) the day before surgery, which was able to bring the serum calcium to 3.59 on the day of surgery. The patient was taken to the operating room where a video-assisted exploration of the left neck was attempted. The surgeon's plan was to remove the diseased parathyroid gland and to take out the enlarged left hemithyroid, followed by frozen section evaluation. Total thyroidectomy is only performed in our clinic, if frozen sections yield evidence of a differentiated thyroid carcinoma greater than one centimeter in diameter. A normal lower left parathyroid gland was identified in the left thymic horn and preserved. The left thyroid lobe appeared enlarged and showed only one distinct nodule near the upper pole, which was sent for frozen section diagnosis. It turned out to be benign thyroid tissue. The surgeon decided then to remove the left thyroid lobe after full neck exploration including the superior mediastinum that revealed four benign central neck lymph nodes.
Clarification of the molecular pathogenesis of parathyroid carcinoma can aid in diagnostically difficult cases and may provide important clues for a more effective therapy. Therefore, tumor samples (one with a histologically verified parathyroid carcinoma and four additional specimen with histologically diagnosed parathyroid adenoma) were studied using in situ hybridization and immunocytochemistry with monoclonal antibodies. Formalin-fixed (3.7%), paraffin-embedded samples were used to localize mRNA transcripts for Cyclin D1. In situ hybridisation was performed as previously described. The sequences of the oligonucleotides were designed using the program Primer3 http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi. The sequences of the antisense oligonucleotides for Cyclin D1 was as follows: 5'gtt cct cgc aga cct cca gca tcc ag3' Acc.Nr: NM_053056 (NCBI). Immunohistochemical staining was performed with monoclonal anti-Cyclin D1 anti-body (Novocastra/Vector, Burlingame, CA, USA), at dilution of 1:100, using a standard avidin/biotin complex (ABC) method. Breast cancer cases known to express Cyclin D1 served as positive control for Cyclin D1. For negative control, non-immune serum was substituted for primary antibody.
At the postoperative patient visit, a week after surgery, the serum calcium has dropped to 2.38 mg/dl (2.10–2.55), the parathormone (PTH) level has returned to normal values, however alkaline phosphatase remained high (628 U/L). CT scan of the brain and lungs revealed no evidence of metastasis. At follow-up three months after surgery, the patient appeared disease free with normal levels of PTH and calcaemia and improvement of the bone disease symptoms. The patient is now, two years from surgery, disease free and her serum calcium and parathormone level remained in the normal range.
Parathyroid carcinoma is a rare malignancy with an incidence of less than 1% in all patients surgically treated for primary hypoparathyroidism [8–12]. A higher rate of about 5% has only reported in few countries, like Japan and Italy . Most reports indicate equal gender distribution and a mean age of 48 years, a decade earlier than adenoma. The clinical manifestations of hyperparathyroidism in parathyroid carcinoma are usually more severe than in patients with parathyroid adenoma with markedly elevated serum calcium levels (and resulting symptoms like muscle weakness, fatigue, depression, nausea, polyuria) and parathormone (PTH) levels [14, 15]. In our case PTH level was more phosphatase was also significantly higher.
The diagnosis of malignancy was made post operatively. The fine needle aspiration performed intra operatively was done to evaluate the left thyroid lobe lesion rather and revealed normal thyroid tissue. None of the preoperative studies raised suspicion of the presence of parathyroid malignancy and the probability to find a parathyroid carcinoma in patients with palpable parathyroid glands, marked elevation of serum calcium and parathormone [14, 15] is less than 5%. Due to the intrathyroidal location [16–18], there was no strong indication of malignancy in this case at the beginning. Severe symptoms of renal disease (impaired renal function, nephrolithiasis, nephrocalcinosis) are also requent in patients with benign parathyroid tumors. Bone pain, "salt and pepper " skull and diffuse osteopenia were the bone symptoms present in our patient. The combination of both renal and bone symptomes at presentation and the presence of a palpable neck mass raised the suspicion of malignancy .
The suspicion that the removed tumor tissue may be a parathyroid carcinoma could be confirmed by histology. In our case, invasion of tumor cells was found in the vessels and neighboring muscle tissue, which has been seen also in other studies [3, 10]. Cellular atypia and variation, also seen in the tumor samples of our case, are not particular useful criteria to diagnose a parathyroid carcinoma, as no specific morphologic criteria exist. In 1993, Bondeson et al.  reported that parathyroid carcinoma may have such bland cytologic appearance that nothing but the invasiveness of the tumor can differentiate them from a benign lesion, although fibrosis, necrosis, nuclear atypia (pleomorphism macronucleoli, large nuclei) and mitotic figures are significantly more frequent in carcinoma. Capsular invasion is present in 60% of the parathyroid carcinomas. They affect the surrounding skeletal muscle, thyroid gland [17, 18] or other tissues. Vascular invasion is characterized by carcinoma cells present within vessels of the fibrous tumor capsule. This is not a very common finding in carcinoma, but was present in our case and can be interpretated as clear sign of malignancy . Solid growth of the parathyroid carcinoma with tumor cells arranged in diffuse masses, small nests or trabeculae are typically found . All these histological features were found in our case. In other cases of parathyroid carcinomas follicular or spindle cell patterns or, rarely, papillary growth has been reported [1, 10].
A change in the expression of CD1 mRNA has been found during the progression from benign to malignant parathyroid tumor cells CD1 oncoprotein is overexpressed frequently in parathyroid carcinoma [5–7]. It was proposed that s could be used as some additional diagnostic criteria . In our case, the only clearly seen difference in the expression of CD1 in benign versus malign parathyroid tissue was the occurrence of strongly CD1 positive giant cells within the carcinoma. Using immunocytochemistry, these cells are easily found and could support the pathohistological diagnosis.
In summary, parathyroid carcinoma is a rare malignancy. Signs and symptoms of hypocalcaemia, hyperparathyroid bone disease and features of renal involvement along with a palpable neck mass are strong predictors of parathyroid malignancy. It is usually difficult to recognize the tumor preoperatively and it is not conclusively identified intraoperatively. Pathologic histology including in situ hybridization and immunohistochemistry of cyclin D1 helps to characterize the lesion and confirms its nature.
The patient has given her consent for the case report to be published.
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