Long-term survival in a patient with metastatic parathyroid carcinoma harboring an EGFR sensitizing mutation: a case report

Abstract

Parathyroid carcinoma (PC) is a rare and aggressive endocrine malignancy with limited treatment options. Current treatments such as chemotherapy and radiotherapy have demonstrated limited efficacy. Here, we report the case of a male patient who presented with symptoms including polydipsia, polyuria, and joint pain. Further examination revealed a neck lump, hypercalcemia, and hyperparathyroidism, leading to a diagnosis of PC after en bloc surgery. Seven months later, the patient developed local recurrence and lung metastases, which were resected via left lateral neck dissection and thoracoscopic wedge resection. A 422-gene panel test revealed the presence of epidermal growth factor receptor (EGFR) p.L858R (c. T2573G) mutation, which may sensitize the EGFR-tyrosine kinase inhibitor response, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) p.E545KV (c. G1633A) mutation. After multidisciplinary treatment discussions, the patient was treated with the multi-target tyrosine kinase inhibitor, anlotinib, resulting in survival benefits for 19 months. This case highlights the potential of targeted therapy in terms of long-term survival in patients with distant metastatic PC, as well as the importance of precision therapy guided by genome sequencing to identify potential therapeutic targets.

Introduction

Parathyroid carcinoma (PC) is a rare endocrine malignancy associated with unfavorable outcomes.^1,2 PC accounts for <1% of primary hyperparathyroidism cases in Western countries and approximately 5% in China.^3–5 The functional nature of 90% of PCs mean that most patients present with hypercalcemia as the initial manifestation of the disease.^6,7

The diagnosis and management of PC are complex because of its rarity and the lack of standard clinical management protocols. ⁸ Surgery remains the primary treatment option, with en bloc resection of the tumor and surrounding structures offering the best chance of a cure.^9–12 Chemotherapy is generally ineffective and the role of radiotherapy remains uncertain, although some data suggest a decreased risk of localized disease recurrence with radiation therapy.^13,14

Anlotinib is a multi-target tyrosine kinase inhibitor (TKI) with potent inhibitory activities against vascular endothelial growth factor receptor 2/3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor α/β, c-Kit, and Ret at the nanomolar level. Multiple clinical trials are currently underway to assess its efficacy in various malignancies, including non-small cell lung cancer, soft tissue sarcomas, and medullary thyroid carcinoma.^15–19

Herein, we present the case of a patient with recurrent and metastatic PC with an epidermal growth factor receptor (EGFR) p.L858R (c. T2573G)-sensitizing mutation who responded to anlotinib after failure to respond to gefitinib and everolimus. This report provides new insights into the treatment of metastatic PC in clinical practice.

Case presentation

A male patient in his fifties with a medical history of diabetes mellitus presented to our endocrinology department with polydipsia, polyuria, pain in both knee joints, acupuncture-like pain on the right side of the head, constipation, and severe weight loss that had worsened in recent months. Neck ultrasonography revealed an irregularly shaped hypoechogenic mass measuring 3 × 2.5 cm in the left inferior region of the thyroid gland, containing several strong echo spots (Figure 1(a)). Subsequent 99mTc-MIBI scintigraphy demonstrated focal activity in the lower left thyroid lobe (Figure 1(b)), consistent with the findings of neck computed tomography (CT) imaging (Figure 1(c)). Notably, thoracic CT imaging did not reveal any pulmonary lesions. The patient was initially managed with intravenous hydration, furosemide, and calcitonin, with the addition of zoledronic acid infusion. Based on our empirical evidence and corroborating studies, the diagnostic criteria for PC include: (i) the presence of a palpable neck mass; (ii) a parathyroid gland >3 cm; (iii) marked hypercalcemia, characterized by serum calcium levels >3 mmol/L; and (iv) parathyroid hormone (PTH) levels more than three times the upper limit of normal.^20,21 Considering these criteria, we highly suspected that the observed mass was indicative of PC rather than a functional parathyroid adenoma. In light of this diagnosis, we opted to perform en bloc surgery with ipsilateral central neck dissection after the patient’s serum calcium levels had decreased. Notably, examination of intraoperative frozen section provided uncertain results, ultimately suggesting a parathyroid adenoma as a potential alternative diagnosis. The preoperative serum PTH level was >1400 pg/mL, which decreased immediately following removal of the tumor and had returned to normal levels by the 5th postoperative day (Figure 1(d)). Changes in serum calcium levels occurred more rapidly than the changes in PTH (Figure 1(e)). Gross examination revealed a neoplasm measuring 3 × 3 × 2 cm. Microscopic examination confirmed it to be a PC, with capsular invasion, angioinvasion, and numerous tumor embolisms in the vein (Figure 2(a)).^22,23 Immunohistochemical analysis indicated strong positivity for GATA-binding protein 3, PTH, chromogranin A, and pan-cytokeratin. Expression of the endothelial markers CD31 and CD34 highlighted blood vessels and revealed angioinvasion. In contrast, thyroglobulin and carcinoembryonic antigen staining yielded negative results. The Ki-67 labeling index was approximately 3%. Other staining markers, including Bcl-2, synaptophysin, calcitonin, and thyroid transcription factor 1 were negative, while galectin 3 was diffusely positive (Figure 2(b) and 2(c)).

Figure 1.

Imaging and serology findings prior to the first surgery. (a) Ultrasound of the neck showing the mass (arrow). (b) 99mTc-MIBI scintigraphy scan demonstrating parathyroid adenoma. (c) Neck computed tomography scan. (d) Perioperative serum parathyroid hormone (PTH) levels and (e) perioperative serum calcium levels.

Figure 2.

Histological and representative immunohistochemistry features of the parathyroid tumor. (a) Hematoxylin and eosin staining of angioinvasion and embolus (arrow) in the vein. (b, c) Strong positive staining for GATA-binding protein 3 (GATA3), parathyroid hormone (PTH), chromogranin A (CgA), pan-cytokeratin (PCK), CD31, and CD34 (endothelial markers) highlighted the blood vessels showing angioinvasion. Thyroglobulin (TG) and carcinoembryonic antigen (CEA) were negative and the Ki-67 labeling index was approximately 3%.

The patient exhibited an uneventful postoperative course and was discharged on the 7th day following surgery. At a 7-month follow-up evaluation, the patient was asymptomatic with serum PTH and calcium levels within the normal ranges.

The patient was subsequently readmitted to the hospital 10 months later with hypercalcemia and elevated PTH levels >5000 pg/mL. Positron emission tomography-CT revealed focal activity in the left paratracheal space of the neck, but no focal activity in the lung (Figure 3(a) and 3(b)). Neck CT also showed cervical masses indicating local recurrence of PC (Figure 3(c)), while thoracic CT revealed nodules suspicious for cancer metastases (Figure 3(d)). The metastatic tumors were resected by left lateral neck dissection, thoracoscopic wedge resection of multiple nodules in the right lower lobe, and wedge resection of the left upper lobe segmentectomy (Figure 3(e) and 3(f)). A novel immune colloidal gold technique (ICGT) was used during surgery to identify suspicious lesions, which were confirmed to be functional PCs (Figure 3(g)). The pathology report confirmed metastasis in the lung nodule and 4/8 neck lymph node metastases. The patient’s serum PTH levels decreased postoperatively but then increased gradually during follow-up. Repeated thoracic CT results during follow-up showed that the suspicious lesions had gradually grown, and new lesions were observed in the right lower lobe (Supplementary Figure 1). After multidisciplinary treatment discussions, a 422-gene panel test based on next-generation sequencing (NGS) was recommended to identify potential therapeutic targets. Among the identified mutations, EGFR p.L858R (c. T2573G) and PIK3CA p.E545KV (c. G1633A) mutations were targeted using gefitinib and everolimus, respectively. Gefitinib is an EGFR TKI that binds to the ATP-binding site of the enzyme. Unfortunately, the patient showed progressive disease after 6 weeks and his PTH levels continued to rise. He was therefore recommended everolimus as a second-line therapy targeting the PIK3CA mutation. No response was achieved after 5 weeks, and following further multidisciplinary discussions, the patient was recommended the multi-targeting TKI anlotinib (orally 12 mg/day, on days 1–14 of a 21-day cycle), after which repeated thoracic CT confirmed a partial response (Supplementary Figure 1), and the patient’s PTH levels dropped dramatically. Thoracic CT after 2 months of treatment with anlotinib showed necrotic cavities in the lesions in the left and right lower lobes, while a new lesion that developed after the second surgery and grew rapidly after gefitinib and everolimus treatment became stable during anlotinib treatment. The patient showed continued survival benefit with this treatment until March 2020, with only slight and manageable treatment-related toxicity. Unfortunately, we lost contact with the patient in January 2020, during the initial outbreak of COVID-19 in Wuhan City, and by the time we finally got back in touch, the patient had died in March 2020 due to COVID-19.

Figure 3.

Screening and surgery for lung metastases of parathyroid carcinoma. (a, b) Single-photon emission computed tomography-computed tomography (CT) with 99mTc-MIBI showed no signs in the lung but localized high uptake in left cervical lesions. (c) Neck and (d) thoracic CT scans. (e, f) Intraoperative image during tumor removal in the neck and lung, respectively and (g) rapid intraoperative parathyroid hormone assay identified both the neck lymph nodes and lung lesions as metastatic parathyroid carcinoma.

The case is presented according to the CARE guidelines. ²⁴ The patient provided signed informed consent for treatment and consented to publication.

Discussion

PC is a rare malignancy with no standard TNM classification. Management of hypercalciuria is the primary focus in most case reports, and effective therapy for recurrence and metastases is lacking. The clinical diagnosis of PC is often challenging, as in the current patient. Despite initial indications of parathyroid adenoma, we chose en bloc surgery, based on our team's experience. The subsequent PC metastases were confirmed by thoracoscopic biopsy, frozen section, and ICGT. ICGT is a novel rapid and inexpensive technique developed by our team to distinguish parathyroid tissue from other structures by reflecting the PTH concentration, ²⁵ with a high diagnostic rate for intraoperative parathyroid identification.

Traditional chemotherapy and radiation therapy generally yield poor results in patients with PC. Notably however, we are currently witnessing rapid advancements in personalized precision medicine. The development of NGS has furthered the discovery of genes, proteins, microRNAs, and other active biological compounds that aid in the diagnosis, prognosis, and therapy of cancers, to improve treatment strategies at localized or metastatic stages. ²⁶ The present patient also benefited from NGS, and fortunately responded to anlotinib after failure to respond to gefitinib and everolimus. Gefitinib is an EGFR TKI that binds to the ATP-binding site of the enzyme. Inhibition of EGFR tyrosine kinase also inhibits downstream signaling cascades, thus inhibiting malignant cell proliferation. We recommend the specific EGFR inhibitor gefitinib as first-line therapy, but intra-patient heterogeneity and multiple resistance mechanisms, including EGFR C797S mutation and alterations in MEK1, KRAS, and PIK3CA, may result in failure to respond.^27–29 Everolimus inhibits the mammalian target of rapamycin (mTOR) pathway, which is an important regulator of cell signaling with roles in physiological processes including cell growth, survival, and autophagy, and in cancer. Everolimus inhibits the activity of mTOR complex 1, blocking phosphoinositide 3-kinase (PI3K)/Akt/mTOR activation and terminating tumor cell growth and protein synthesis driven by this pathway. ³⁰ Combined with other targeted therapies, mesenchymal-epithelial transition inhibitors such as capmatinib may overcome acquired TKI resistance. Zhao et al. used whole-genome sequencing to explore the molecular profiles of sporadic PC and showed that 78.3% of PC tumors had alterations in the pivotal PI3K/Akt/mTOR pathway.^3,4 The current patient also had a PIK3CA mutation, and we therefore recommended targeting mTOR with everolimus as a second attempt. Gefitinib is highly selective for vascular endothelial growth factor receptor and everolimus is a downstream target, allowing bypass signaling to be activated.^31,32 After several multidisciplinary team discussions, we considered that the EGFR mutation in this patient was still worth pursuing and that a multi-targeted TKI may be more effective than a specific inhibitor. We therefore started anlotinib treatment, with a surprising response.

In summary, we present the case of a man in his fifties with EGFR-mutated advanced PC who responded well to anlotinib. This case provides new insights into PC treatments and highlights the importance of personalized precision medicine in treating rare malignancies. Further multicenter studies are needed to standardize the treatment of recurrent or metastatic PC.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241259669 - Supplemental material for Long-term survival in a patient with metastatic parathyroid carcinoma harboring an EGFR sensitizing mutation: a case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605241259669 for Long-term survival in a patient with metastatic parathyroid carcinoma harboring an EGFR sensitizing mutation: a case report by Yushi Ying, Hanning Li, Wenfei Xia, Teng Cheng, Hui Li, Qiang Fu, Tao Ai, Yan Yang, Ni Zhang, Xingrui Li, Qilin Ao, Yaying Du and Zhifang Yang in Journal of International Medical Research

Supplemental Material

sj-pdf-2-imr-10.1177_03000605241259669 - Supplemental material for Long-term survival in a patient with metastatic parathyroid carcinoma harboring an EGFR sensitizing mutation: a case report

Supplemental material, sj-pdf-2-imr-10.1177_03000605241259669 for Long-term survival in a patient with metastatic parathyroid carcinoma harboring an EGFR sensitizing mutation: a case report by Yushi Ying, Hanning Li, Wenfei Xia, Teng Cheng, Hui Li, Qiang Fu, Tao Ai, Yan Yang, Ni Zhang, Xingrui Li, Qilin Ao, Yaying Du and Zhifang Yang in Journal of International Medical Research