PC is one of the rarest cancers. The 5-year survival rate of PC has been reported to be 78%–85%, and the 10-year survival rate 49%–77%[3-5]. It accounts for about 0.005% of all cancers . The overall annual incidence rate is less than 1 case per million population[7, 8].The Surveillance, Epidemiology, and End Results (SEER) database showed that the incidence rate of parathyroid carcinoma was 3.6/10 million in 2000–2012. The incidence rate of PC in Finland was 7.14/10 million from 2000 to 2013. According to Xing XP, a Chinese scholar, among patients with primary hyperparathyroidism (PHPT) confirmed by surgery and pathology, PC accounted for 3.10%–10.53%, while PC accounted for <1% of all PHPT patients in Europe and the United States, and 5% in Japan[11, 12].
The exact pathogenesis of PC remains unclear. At present, most researchers believe that the occurrence of PC is new rather than transformed from adenoma, which is based on the inference that there are different gene changes between parathyroid adenoma and adenocarcinoma. The major genes reported are cdc73/HRPT2[13-15], gcm2[16, 17]and prune2. The detection rate of cdc73/HRPT2 gene mutation in sporadic PC is 46%–70%[19, 20]. Nonaka et al. considered that gcm2 is the main regulatory gene of parathyroid development, and the marker is only expressed in the parathyroid gland, including normal parathyroid tissue and all forms of benign and malignant parathyroid lesions. Additionally, abnormal expression of noncoding RNA including miRNA and long noncoding (lnc) RNA may also be involved in the development of PC. In the future, lncRNA PVT1, GLIS2-AS1 and anti-Gcm2 antibodies may become markers for the diagnosis of PC.
The diagnosis of PCSD is generally based on the combination of histology, biology and radiology. Multidisciplinary cooperation is the best model. The diagnostic standard is as strict as for thyroid follicular carcinoma. Capsule invasion and/or vascular invasion, perineural space infiltration, tumor perforation into surrounding tissues and/or metastasis should be present. The main criteria for diagnosis are as follows: (1) the cancer cells are arranged in trabecular shape with thick fibrous septum; (2) there is capsule or adjacent structure infiltration; (3) vascular invasion; (4) mitosis; (5) lymph node and/or other organ tissue metastasis; and (6) GATA3, cam5.2, SYN and CGA, which are important regulatory genes in parathyroid development, are positive. The loss of parafibromin and the high expression of PGP 9.5 and galectin-3 are helpful for the diagnosis of PC. At the same time, some tumor suppressor genes such as Rb, APC, p27 and BCL2 are often not expressed or weakly expressed. When Ki-67 index is >5%, physicians should be alert to the possibility of malignant tumor.
Most PC patients have hypercalcemia, and about 3% of them have no clinical symptoms. The results of biochemical tests and the diameter of parathyroid lesions in PHPT patients can predict PC. In PHPT, the best cut-off point for predicting the diameter of parathyroid lesions in PC is 3.0 cm. A retrospective analysis showed that preoperative ultrasound examination of parathyroid lesions >15 mm was valuable in the diagnosis of PC. PCSD is rare and only five cases (including our case) have been reported in the literature (Table 2).
Among these five cases, there were more women than men, and the tumor diameter was >3.5 cm, which was consistent with the report of Bae et al. The optimal cut-off point for predicting the diameter of parathyroid lesions was 3.0 cm. The serum calcium level of most patients with PC was significantly higher than 3.5 mmol/L. Serum PTH levels in patients with PC are usually 3–10 times higher than the upper limit of normal[25, 26]. Elevated serum calcium and PTH are more common in patients with PCSD. Therefore, when the serum calcium level is 3 mmol/L and the parathyroid lesion is >3 cm (i.e., the so-called >3 + >3 rule) or ionic calcium >1.77 mmol/L, physicians should be fully vigilant about the possibility of PC.
Radical resection is the only way to cure PCSD. The first operation is particularly important and should be performed as soon as possible. During the first operation for PC, parathyroid tumor with ipsilateral thyroid en bloc lobectomy including isthmus and ipsilateral central lymph node dissection should be performed[28-30]. If the tumor adheres to peripheral soft tissue, such as banded muscle and esophageal muscular layer, it should be removed as extensively as possible. If the recurrent laryngeal nerve is invaded, it should also be removed. Unfortunately, most of the PCSD have a high degree of malignancy. Most of them had distant metastasis in the early stage after surgery, and most of the patients died within 1 year after surgery.
Prophylactic lateral cervical lymph node dissection is generally not recommended because it does not prolong survival and may increase the incidence of complications. However, if lateral cervical lymph node metastasis is confirmed before surgery, therapeutic dissection is required. The biggest difficulty in the selection of surgical methods is the low accuracy of intraoperative frozen pathological diagnosis of PCSD. Unless there is obvious capsule, vascular invasion or regional lymph node metastasis, there are generally few direct reports of parathyroid cancer. When PCSD is diagnosed by parathyroid pathology after surgery, it is advisable to supplement surgery in time according to parathyroid cancer.
Chemotherapy drugs are generally ineffective against PCSD, and there are only a few successful reports. PCSD is not sensitive to radiotherapy. Although there are reports of adjuvant radiotherapy to reduce local recurrence after the initial operation, due to the small number of cases and short follow-up time, adjuvant radiotherapy may only be used in PCSD patients with high risk of recurrence. For local lesions, such as lung metastasis and vertebral metastasis, there are also individual cases of attempting radiofrequency ablation or absolute alcohol or combined percutaneous vertebroplasty to destroy metastases.
PCSD is a rare type of primary parathyroid tumor with high malignancy and poor prognosis. Definitive diagnosis should be based on histopathological morphology and immunophenotype, and surgical treatment should be performed as soon as possible.