Parathyroid Involvement by Thyroid Carcinoma: Results from a Single Institution and a Review of the Literature

Malignancy of the PTG, of primary or secondary origin, is extremely rare. Primary parathyroid carcinoma accounts for less than 1% of the cases of primary hyperparathyroidism [8], whereas metastatic involvement of PTG has only been documented in a few reports in the literature [9,10]. However, limited autopsy studies conducted in patients with cancer have reported an incidence of secondary PTG involvement ranging from 0.2% to 11.9% [11]. The most frequently identified primary tumor sites include the breast, bloodstream (leukemia), skin (malignant melanoma), lung, soft tissue, and lymphoid tissue (lymphoma) [11,12]. Consequently, the actual frequency of PTG involvement in metastatic cancers remains unclear. The most frequent findings in the literature were observed in more than 90% of the individual studies. PTG metastasis from TC is thought to occur via two main pathways [2]. The most common pattern of PTG involvement is tumor infiltration through the thyroid capsule, which leads to direct invasion of the adjacent PTG tissue. Although less frequently observed, histological evidence of hematogenous spread with metastatic foci has been reported [4].

The under-recognition of PTG invasion by TC is likely due to both diagnostic challenges and surgical practices that prioritize PTG preservation. [2]. The reported frequency of PTG involvement in thyroid carcinoma does not likely reflect its true incidence. Even in cases of extensive TC, surgeons prioritize PTG preservation to minimize the risk of postoperative hypocalcemia, which may contribute to underreporting of PTG involvement. Consequently, PTG involvement may be overlooked during thyroidectomy, leading to an underestimation of its actual prevalence [2]. Several studies have reported this phenomenon, with a higher prevalence in women. However, it is important to acknowledge that the sample sizes in these studies have been very limited, which may affect the reliability of this observation. Chrisoulidou et al.[2] reported a 0.5% incidence of PTG involvement in patients (10 out of 1,770 cases). However, when analyzing cases in which the PTG was excised, the incidence increased to 3.94% (10 out of 254 cases). Similarly, Al Qahtani et al. [13] reported a 1.94% prevalence of PTG metastasis among all patients, which increased to 8.38% in patients who underwent PTG excision. In addition, Kakudo et al. [7] found an overall prevalence of 3.9%, which increased to 7.9% when only parathyroidectomy samples were analyzed. In the present study, of the 1,032 cases of primary TC, 10 cases of concurrent PTG involvement were detected, accounting for 0.97% of the subjects affected by primary TC. This increased to 3.05% cases where the PTG was excised (10 out of 328 cases). These studies indicate that the prevalence of PTG involvement in TC is likely to be higher than that currently recognized. In many cases, metastatic disease in the PTG may persist in situ due to the routine preservation of PTG during thyroidectomy.

Metastasis of primary thyroid cancer to the PTG remains poorly understood and is likely underdiagnosed, largely because of the standard practice of preserving PTG during thyroidectomy to reduce the risk of post-operative hypocalcemia [2]. The clinical impact of parathyroid metastases remains uncertain, especially when only a single gland is affected. Since serum calcium levels are primarily regulated by the remaining functional parathyroid glands, metastasis to one parathyroid gland is unlikely to cause significant physiological disturbances unless multiple glands are involved [2]. An unresolved question in the current literature is whether parathyroid invasion by TC should be considered a significant risk factor for recurrence and survival or if it is merely an incidental finding with no meaningful clinical or prognostic impact. Several studies have attempted to determine whether the presence of PTG metastases influences the outcomes of TC. Ito et al. [4] suggested that parathyroid gland invasion has minimal clinical significance or prognostic impact and proposed classifying it as T3a disease. However, in the present study, patients with pT4 disease had significantly worse disease-free survival (DFS) rates than those with pT3 disease, regardless of the presence of PTG involvement. Papi et al. [6] found that the most common pattern of spread was direct invasion, observed in six out of 10 cases. This finding is consistent with that of our patient, as evidenced by the pathological specimen. Extension of the primary tumor through an intervening pseudocapsule was also observed but was found to be a less common pattern of spread. One patient with an aggressive tall-cell variant of PTC was included. Additionally, lymph node metastases were identified in three of the 10 patients. Despite these findings, all patients remained disease-free, with undetectable serum thyroglobulin concentrations after a mean follow-up period of 5.6 years, which was an unexpected outcome. All patients were classified into the intermediate-risk category of disease recurrence. However, none of the patients in this study (n = 10) had detectable Tg levels after a mean follow-up period of 5.6 years. Al-Qahtani et al. [13] reported that PTG involvement in patients with differentiated thyroid carcinoma (DTC) is rare and is associated with older age, advanced disease stage, and ETE. The incidence of PTG involvement is high in the presence of ETE. They found DFS rates in patients with PTG metastasis to be similar to those in patients with T4a stage differentiated TC, with a higher risk of recurrence and therefore likely to benefit from post-operative radio-active iodine (RAI). Kakudo et al. [7] also found that PTG involvement was associated with worse DFS rates and was correlated with a more aggressive form of TC. PTG due to PTC was associated with either an advanced disease or a 10-yr DFS rate of 80.8%, mainly in patients older than 55 years. PTG invasion was more commonly observed in older patients and this group had a higher proportion of male patients compared to those without PTG invasion. These patients have a higher incidence of ETE and are more frequently diagnosed at advanced stages of the disease. Lung metastases were observed in two out of the 14 patients, with a significantly higher incidence than that in the control cases. Moreover, male patients with PTG invasion and those older than 55 years had reduced DFS rates compared to patients without PTG invasion. Ito et al. [4] demonstrated that patients with massive ETE had a significantly worse prognosis, regardless of PTG involvement. In fact, TC extension to the PTG itself had no impact on the 10-year DFS rate, which exceeded 95% in cases where only minimal tumor extension was present. In multivariate analysis, additional predictors of poor prognosis, aside from massive ETE, included age more than 55 years, N1b stage disease, and primary tumor size greater than 4 cm. Based on these findings, the authors concluded that "extension to the PTG corresponds to minimal ETE for PTC". The current staging system for DTC does not classify the PTG as a metastatic site [14]. Thus, they validated the appropriateness of pTNM parameters used by the American Joint Committee on Cancer (AJCC/UICC) classification system for thyroid malignancies [5]. Specifically, they supported the classification of tumors as pT3 when they extend beyond the thyroid capsule to invade structures, such as the subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve. Furthermore, in alignment with the current American Thyroid Association (ATA) guidelines [14], patients with TC exhibiting minimal extension to the perithyroid soft tissues and concomitant PTG metastasis should be classified as low-risk. This classification is consistent with the findings in our patient cohort. Further studies are needed to clarify whether PTG involvement warrants the upstaging of TC (e.g. T3a/T4a for direct invasion or M1 for hematogenous spread).

When PTG invasion is confirmed, the surgical approach must be discussed. Preservation of PTG is a crucial strategy for preventing postoperative hypocalcemia. However, when the PTG is invaded by cancerous tissue, it is crucial to determine whether complete resection is necessary. Especially in cases where TC has extensively spread to the adjacent soft tissues and lymph nodes, a more aggressive treatment strategy, including PTG resection, may be necessary. To date, studies have lacked clear criteria for defining the extent of tissue resection, including PTG, during thyroid cancer surgery. Additionally, research on whether PTG invasion impacts the indications for postoperative RAI therapy is limited.