[Column] Rare but deadly parathyroid cancer and atypical parathyroid tumor

Calcium is a mineral that plays an essential role in life support, including heartbeat, muscle contraction, and nerve transmission, and it plays a key role in musculoskeletal health, specifically in the formation and development of bones during growth and the prevention of bone loss in later life. However, having high calcium levels in your blood isn’t necessarily good for your health. On the contrary, if your calcium levels are higher than usual, you should suspect a condition related to calcium metabolism.

The body regulates the concentration of calcium in the blood very precisely. When we consume more calcium, we decrease its absorption and increase its excretion in the urine. Conversely, when we don’t have enough calcium, we dissolve it from our bones to maintain a constant level in the blood. The key hormone that regulates this process is parathyroid hormone (PTH).

The parathyroid glands are endocrine glands about 5 millimeters in size located on the back of the thyroid gland. There are usually four of them. This tiny organ is responsible for sensing blood calcium levels and secreting PTH to keep them steady. This explains why an abnormal calcium level on a blood test is often the first sign of parathyroid dysfunction.

For most people, the parathyroid gland is an unfamiliar organ, but there are cases of cancer. Parathyroid cancer is rare, with a prevalence of only 0.005 percent of all cancers. However, it’s a clinically significant tumor because it’s often diagnosed late, and the complications of hypercalcemia can be severe. If the tumor is completely resected surgically, the five-year survival rate is more than 80 percent. Still, the prognosis is poor if metastases have developed or if there are repeated recurrences after surgery.

Early-stage parathyroid cancer is often asymptomatic. It is often diagnosed by a blood test that accidentally detects hypercalcemia and requires further testing. Primary hyperparathyroidism is suspected if the blood calcium level is high and the parathyroid hormone is not suppressed and is normal or elevated. Imaging studies, such as ultrasound, CT, or Sestamibi scan, are used to locate the lesion, and surgical resection is performed. The final diagnosis of parathyroid cancer is made if the tumor invades the surrounding tissues or blood vessels or if the histopathological examination reveals atypical cell behavior with high cell division. This cancer is characterized by symptoms mainly caused by metabolic abnormalities due to hypercalcemia rather than the tumor itself.

Initially, there are no symptoms, but as the disease progresses, nonspecific symptoms, including nausea, vomiting, constipation, polyuria, dehydration, muscle weakness, and confusion, may occur. These symptoms can be easily mistaken for simple indigestion or fatigue, which often leads to a delay in diagnosis.

The prognosis of parathyroid cancer depends on many factors, including the size of the tumor, whether it has invaded surrounding tissues, and whether it has metastasized. In recent years, researchers have also been focusing on biological factors at the molecular level, such as gene mutations and immune cell responses. For example, there are reports that CDC73 gene mutations are associated with the development and recurrence of parathyroid cancer, and some analyses suggest that the pattern of immune cell infiltration may help predict prognosis.

However, these genetic markers are not yet widely utilized in clinical diagnosis. As for treatment, surgical resection is the only proven radical therapy. Neither chemotherapy nor radiation therapy has a limited effect and does not contribute significantly to improved survival. Therefore, the most important prognostic factor is complete resection of the tumor at the first surgery.

Recently, there has been increasing interest in atypical parathyroid tumors (APT), which are intermediate in nature between parathyroid cancer and benign tumors. These tumors do not have the typical hallmarks of a malignant tumor but are characterized by pathological features intermediate between adenoma and cancer, such as thick fibrotic bands in the tissue and a high cell division index. However, atypical parathyroid tumors still lack clear diagnostic criteria and treatment guidelines, making it difficult to establish treatment and follow-up plans.

The 2022 World Health Organization Classification of Endocrine Tumors recommends that parafibromin immunochemical staining be performed when an atypical parathyroid tumor is identified. CDC73 gene sequencing should be considered in cases with loss of parafibromin staining, as tumor recurrence is more likely in tumors than in adenomas. However, parafibromin staining is limited in its use as a risk assessment indicator in routine practice due to its variable sensitivity and difficult interpretation.

Various staining markers, including PGP9.5 and Ki-67, have been studied as diagnostic aids for parathyroid cancer, but their sensitivity and specificity are unsatisfactory. Therefore, a combination of markers may be more effective than a single staining marker, and the clinical utility of immunochemical staining in atypical parathyroid tumors remains uncertain. New staining markers such as WT1 have been recently explored, and future studies are expected.

Transcriptomic analysis is also being used better to understand the gene expression patterns of parathyroid cancer and to differentiate it from benign adenomas. Using differential gene expression analysis and clustering techniques, these studies have shown distinct expression pattern differences between parathyroid cancer and adenoma at the molecular biology level. Groups of genes that are specifically overexpressed or repressed in parathyroid cancer have been identified, and these genes have been reported to be involved in pathways related to the biology of malignant tumors, including cell proliferation, extracellular matrix reorganization, and immune response.

These transcriptome-based analyses may provide essential clues to differentiate between parathyroid cancer and adenoma, understand the pathogenesis of atypical parathyroid tumors, and segment risk groups in the future. In other words, these analyses may lead to molecular markers that can identify groups at potentially high risk of malignancy at an early stage within atypical parathyroid tumors and serve as a basis for determining the frequency of follow-up and postoperative management strategies.

Parathyroid cancer and atypical parathyroid tumors are sporadic tumors. Still, they are clinically significant in that they are associated with an inferior prognosis if diagnosed late or with poor follow-up. The possibility of a malignant tumor rather than a simple benign adenoma should always be considered, especially in patients with young age, male gender, large tumor size, and uncontrolled hypercalcemia. In the future, a deeper understanding of parathyroid tumors through molecular genetic studies is expected to enable precise diagnosis and personalized treatment, which will improve patients' quality of life and survival.