Unusual presentation and management of parathyroid carcinoma with pulmonary metastasis: a case report

Introduction

Parathyroid carcinoma is an uncommon tumor that arises from any of the four parathyroid glands, constituting 0.005% of all malignancies and 0.5–5.0% of hyperparathyroidism cases (1,2). No gender predilection is noted, and 50 years is the average age most affected (3). The condition usually develops spontaneously. However, it can occur in patients with a family history of parathyroid carcinoma, including hyperparathyroidism-jaw tumor (HPT-JT) syndrome, which is an autosomal dominant disorder characterized by the presence of parathyroid tumors, fibro-osseous jaw tumors, and uterine and renal lesions, all caused by mutations in the CDC73 gene. Parathyroid carcinoma may occur in approximately 20% of cases (4,5). The tumor can be divided into functioning or non-functioning depending on parathyroid hormone (PTH) secretion with around 90% of tumors being functional (6). The signs and symptoms that should increase the suspicion of malignancy include symptoms of refractory hypercalcemia induced by autonomous oversecretion of PTH, leading to symptoms in the musculoskeletal system, gastrointestinal tract, kidneys, and, up to 70% of patients have a palpable neck lump upon physical examination; this is highly unusual in benign adenomas (4). Although radiographic imaging such as ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and ¹⁸F-fluorocholine positron emission tomography/computed tomography (¹⁸F-Choline PET/CT) are sensitive, and specific, for evaluating parathyroid glands, differentiating between adenoma and malignancy remains challenging. Surgical resection followed by a comprehensive histopathological examination of the entire parathyroidectomy specimen is the method of choice for diagnosing parathyroid cancer (7,8). This malignancy has been reported to spread both hematogenously and lymphatically (1,9). Several elements of its etiology, presentation, and treatments remain unknown. Previous case studies described parathyroid cancer with metastasis (10,11). However, we present a case describing an unusual course of parathyroid cancer that developed metastasis, emphasizing the diagnostic and therapeutic challenges. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-94/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

History of illness presentation and physical examination

This case involved a 38-year-old female who was referred to our department from pediatric endocrinology since her newborn was found to have hypoparathyroidism, which consequently led to diagnosing the mother with primary hyperparathyroidism. She complained of fatigue, knee pain, and back pain, which was attributed to the patient’s known anemia. The patient denied compressive symptoms except for occasional dysphagia. No weight loss, loss of appetite, or other constitutional symptoms were found. She also denied any history of fractures or renal stones. The review of systems was unremarkable. Her past medical history was significant for congenital anemia, the type of which was unknown by the patient, and she was followed up in a different hospital with a history of splenectomy at the age of seven. Her family history was significant for her sister who had a parathyroidectomy in her 30s due to hyperparathyroidism. The patient was not a smoker and had never received chemotherapy or radiotherapy. On physical examination, a 2 cm left paramedian neck mass was palpable.

Blood test results

The blood tests showed an elevated level of calcium at the time of diagnosis. The levels of PTH and calcium were monitored and changed significantly by surgical interventions. Table 1 summarizes the results of the adjusted calcium and PTH levels at the time of diagnosis, after the first surgery, and after the second surgery.

Imaging

On neck ultrasound, there was a 2.3 cm hypoechoic nodule on the lower pole of the left thyroid lobe, amenable for fine-needle aspiration (FNA). On the Sestamibi scan, there was an area of focal retention seen within the left lower thyroid lobe. On a low-dose non-enhanced CT scan, there was a 1 cm soft tissue nodule seen below the left thyroid lower pole with trivial activity which could represent a metastatic lymph node or an atypical parathyroid lesion (Figure 1). A bone mineral density scan was performed, which showed low bone mineral density for chronological age. FNA was initially performed based on clinical and imaging findings that suggested a benign parathyroid adenoma. However, we acknowledge that FNA is generally discouraged for parathyroid lesions suspicious of malignancy due to the risk of parathyroid dissemination (parathyromatosis). In retrospect, a more cautious approach would have been warranted given the potential for malignancy.

Figure 1 Low-dose non-enhanced computed tomography scan: left posterior thyroid gland hypodense lesion measuring 2 cm × 2 cm with enlarged level IV lymph node abutting the esophagus anteriorly. The green line in the coronal view serves as a reference point, showing where the axial view is positioned within the coronal view of the body.

Thyroid FNA

Ultrasound-guided fine needle aspiration of the left thyroid nodule was Bethesda 4, suspicious for follicular neoplasm, Hurthle cell type.

Treatment plan

Based on these findings the patient was scheduled for left hemithyroidectomy with subtotal parathyroidectomy, mainly left inferior parathyroidectomy. Intra-operative findings include an enlarged left inferior parathyroid gland confirmed by a frozen section, likely representing an adenoma. In addition, the patient had a large, hard nodule on the left thyroid lobe abutting the esophagus and left recurrent laryngeal nerve. Both structures were kept intact with a loss of nerve stimulation at the end of the procedure. Pre-laryngeal lymph node dissection was done intra-operatively.

Pathology results

Histopathology results revealed a unifocal parathyroid carcinoma with a maximum dimension size of 2.5 cm. The tumor was sited intra-thyroid within the left thyroid lobe with positive margins of the resected left thyroid lobe. There was extensive vascular and lymphatic invasion, but no perineural invasion. Histologic examination of the permanent sections from the left inferior parathyroid, which was initially sent for frozen section intra-operatively, revealed parathyroid carcinoma almost totally replacing a lymph node with a very small residual lymphoid tissue, which was not seen on the frozen section slides. An extranodal extension is also seen. Therefore, this tissue is considered a lymph node with metastatic parathyroid carcinoma. A review of the dissected lymph nodes revealed positive nodal involvement, the largest measuring 1.5 cm with extranodal extension. In addition, a normal parathyroid tissue gland was seen, most likely representing a normal left superior parathyroid gland. Immunohistochemistry studies were performed, and tumor cells were positive for GATA3, negative for TTF1, and thyroglobulin with a low Ki-67 proliferation index. However, parafibromin immunohistochemistry (IHC) was not performed limiting the immunohistochemistry potential value in such cases. Next-generation sequencing was performed and was positive for CDC73 mutation, MYC rearrangement intron 1, ASXL1. It also showed a tumor mutational burden (TMB) of 11 Muts/Mb with a stable microsatellite status. Therefore, pathological staging would be pT2N1a.

Post-operatively, metastatic work-up was done in an outpatient setting after a review of histopathology revealing a 1 cm pulmonary nodule in the right upper lobe.

¹⁸F-Choline PET/CT imaging was done showing increased uptake in the surgical bed measuring 1 cm ×1.1 cm and mild to moderate choline activity in the right upper pulmonary nodule, which is consistent with pulmonary metastasis. Following tumor board discussion and patient counseling, an extensive surgical approach was undertaken, including completion thyroidectomy, total parathyroidectomy, bilateral lateral and central neck dissection, and right upper lobe video-assisted wedge resection for the pulmonary metastasis. Given these aggressive features, including extensive vascular and lymphatic invasion, positive margins, and the presence of metastasis, this approach was chosen to achieve optimal local control and reduce the risk of recurrence.

Histopathology revealed two unremarkable parathyroid glands and a right thyroid lobe that is negative for malignancy. Two out of 121 lymph nodes were positive for metastatic parathyroid carcinoma in the left side level IV, the largest measuring 1.5 cm without extranodal extension. The complete staging of the patient is advanced stage IV parathyroid cancer, pT2N2M1.

Follow up

The patient was doing well with no renal stones or joint pain. Furthermore, there was no choking or limited neck movement. On examination, the wound had healed well with intact cranial nerves. PTH and calcium levels normalized. No clinical or radiographic evidence of recurrence. Shortly after, the Patient’s PTH started to rise, and chest CT revealed small bilateral lung nodules. After conducting a molecular tumor board, a review of the patient’s next-generation sequencing profile, and counseling of the patient, immunotherapy was initiated with 6 cycles of pembrolizumab.

Discussion

Parathyroid carcinoma is a rare malignancy with a difficult diagnostic process and specific treatment. The incidence of parathyroid carcinoma has been estimated to be 0.005% of all malignancies and 0.5–5.0% incidence of patients with hyperparathyroidism (1,2). At the time of presentation, 90% of cases had a functioning tumor, which may resemble benign primary hyperparathyroidism, which can result in fatigue, bone disease, nephrolithiasis, and pancreatitis. Up to 90% of patients may experience bone involvement, including osteopenia and osteoporosis. While renal involvement may affect up to 80% of patients (2), evident bone disease and concurrent skeletal and renal involvement are uncommon in benign illness (12).

The case we present is unique in many aspects. The method of diagnosing hyperparathyroidism of this patient carried an unusual event, which was the preceding diagnosis of her newborn with hypoparathyroidism that eventually led to her diagnosis with a rare tumor. Other cases carried different presentations such as patients complaining of bone and joint pain, dyspnea, polyuria, polydipsia, nausea, vomiting, fatigue, and weight loss (10,13,14). The clinical picture of parathyroid carcinoma is primarily impacted by the effects of elevated serum PTH levels in addition to hypercalcemia symptoms (12). This patient also complained of dysphagia which is not part of the classical picture of parathyroid carcinoma. Moreover, a palpable neck mass was found on her physical examination, this finding is present in approximately 30–76% of patients with this tumor (12). This patient was also initially mistakenly diagnosed with vitamin D deficiency and anemia. Some of her symptoms were non-specific; fatigue, knee pain, and back pain; which can be attributed to multiple other illnesses. She is also not a typical age at which parathyroid cancer is most commonly diagnosed as most patients with parathyroid cancer tend to be about 50 years old at diagnosis (12). This patient reported a family history of hyperparathyroidism which was reported to have an association with parathyroid carcinoma (15).

Regarding laboratory and imaging findings, most parathyroid carcinomas are functioning tumors with increased cellular division and a decreased response to humoral feedback. A difference between parathyroid carcinoma and parathyroid adenoma is the endocrine effect detected in laboratory workup. Parathyroid carcinomas showcase a great increase in calcium levels as well as PTH compared to parathyroid adenomas. First, serum calcium levels above >12 or 3–4 mg/dL above the upper limit of the normal range associated with symptoms of hypercalcemia should shift our thinking to parathyroid carcinoma. Moreover, in parathyroid adenoma serum calcium is less increased, mostly up to 1 mg/dL above the upper limit of the normal range. Second, PTH levels in parathyroid carcinoma are often 3–10 times above the normal upper limit, compared to parathyroid adenomas in which the level is not commonly higher than twice the upper normal (16). At the time of diagnosis, this patient had adjusted calcium 3.12 mmol/L, and PTH of 40 pg/mL.

Concerning surgical and postoperative Management, a parathyroid cancer preoperative diagnosis is not possible due to a lack of clinical or bio-humoral evidence. Only with conclusive pathology and immunohistochemistry can an adenoma and carcinoma be distinguished. Patients occasionally present with a palpable neck mass; however, fine needle aspiration biopsies are discouraged since histology cannot differentiate between benign and malignant disease. Additionally, pre-operative biopsy is not recommended as it cannot distinguish parathyroid carcinoma from adenoma and may cause tumor seeding (3). Surgery should be used as a treatment modality since it not only helps in establishing a diagnosis but also local control. Chemotherapy is ineffective in treating parathyroid carcinoma. Furthermore, because parathyroid carcinoma and its metastases are not radiosensitive, total surgical removal of the primary tumor is the mainstay of treatment, which is usually then followed by complete surgical removal of any isolated metastasis (15). This patient was found to have lung metastasis to which lobe wedge resection was done. One case presenting disseminated disease demonstrated that debulking surgery was only useful to control calcium levels, remission could have not been attained, and radiation was ineffective (14).

Regarding oncological principles and guidelines, there is still no clear consensus in defining total surgical removal of parathyroid cancer. However, surgical management can be divided into intra-operative and post-operative management as the disease is mainly diagnosed post-operatively. Intra-operative management is when findings of parathyroid malignancy are encountered, such as hard enlarged parathyroid with adherence to adjacent structures. It is recommended here to follow oncological principles of tumor resection in case it turns out to be a malignancy which includes en bloc resection of the parathyroid gland with adjacent adherent structures ensuring a gross negative margin which involves excision of the ipsilateral thyroid lobe with avoidance of tumor spillage with excision of suspicious lymph nodes or central neck dissection (2). In the case of post-operative diagnosis of parathyroid cancer, the conundrum lies in whether to take the patient back to the theatre to do proper oncological surgery or to observe the patient for clinical or radiographic manifestations of tumor persistence/recurrence. If malignancy persists or recurs, the tumor is radiologically localized, and the patient should undergo surgery. However, the type of surgery that needs to be done to address the primary site and the neck is still controversial. The goals of surgery include obtaining the needed amount of information to reach pathological staging, clearance of disease, and reduction of hypercalcemia load while maintaining minimum morbidity (12). In our patient, an aggressive surgical approach, including completion thyroidectomy, total parathyroidectomy, and bilateral lymphadenectomy, was chosen due to extensive invasion and metastasis, aiming to ensure local control and reduce recurrence risk.

Common genetic dysregulation helps in confirming the diagnosis of parathyroid malignancy and comprehensive genetic sequencing has identified mutations suitable for molecular therapy. One of the most common genetic mutations identified in parathyroid malignancies is the CDC73 mutation leading to loss of parafibromin expression affecting cell cycle regulation and tumor suppression. CDC73 was also highly associated with sporadic parathyroid cancer (9,17). Cancer genomic studies identified mutations in ASXL1 in a specific subset of cancers including myeloid leukemias, and breast and prostate cancers. No clear studies with strong associations in parathyroid cancers were found (9,18). As parathyroid carcinoma is rare, the use of immunotherapy is even rarer. It has been reported in around 3 cases out of 79 patients with metastatic parathyroid carcinoma in a recent systematic review by Alberti et al. (19). The main immunotherapy used in parathyroid carcinoma is a checkpoint inhibitor that targets programmed-cell death protein-1 (PD-1) (20). Inhibition of PD-1 is believed to suppress the cancer cell properties of evading the immune system, which leads to activation of cytotoxic cells activation and antibodies targeting parathyroid cells leading to inhibition of PTH secretions, and destruction of tumor cells (21). Pembrolizumab was used in our patient, after conducting molecular tumor board and reviewing the patient’s next-generation sequencing profile, for a total of 6 cycles. Taking into account the high TMB, as such patients generally show good responses to therapy (22).

Despite aggressive treatment, the recurrence rate is around 65% (12). As a result, patients should always go through a comprehensive follow-up program that includes PTH and serum calcium evaluations after surgery (10). The main cause of mortality in parathyroid carcinoma is usually the hypercalcemia rather than the tumor load (19). A study of 733 patients from 1985 to 2006 found 5- and 10-year survival rates of 82.3% and 66%, respectively (23). In many cases, serum PTH was found to be an indicator of recurrence and metastasis of parathyroid cancer after the initial surgical management (11,14).

Conclusions

In conclusion, due to the high risk of recurrence and metastasis of parathyroid carcinoma, prolonged surveillance and whole-body imaging are useful. Moreover, due to the nature that the severity and prognosis depend heavily on the hypercalcemia severity, aggressive resection of metastasis and parathyroid carcinoma should be considered. This case is a young lady with intra-thyroidal parathyroid carcinoma who had to undergo total thyroidectomy with total parathyroidectomy with bilateral level II–IV and level VI neck dissection with pulmonary wedge resection. ¹⁸F-Choline PET/CT was suggestive of pulmonary metastasis with the post-operative course of immunotherapy.

Acknowledgments

We extend our gratitude to the patient involved in this study, as well as to the staff members who participated in her care.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-94/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-94/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-94/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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