A 54-year-old male patient with a medical history significant for 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 (US) revealed an irregularly shaped hypoechogenic mass measuring 3×2.5 cm in the left inferior region of the thyroid gland, with several strong echo spots present inside (Fig. 1A). Subsequent scintigraphy using 99mTc-MIBI demonstrated focal activity in the lower left thyroid lobe (Fig. 1B), which was consistent with the findings of neck computed tomography (CT) imaging (Fig. 1C). Notably, thoracic CT imaging did not reveal any pulmonary lesions. To manage the patient's condition, intravenous hydration, furosemide, and calcitonin treatment were initiated, with the addition of zoledronic acid infusion. Based on our empirical evidence and corroborating studies, the diagnostic criteria for parathyroid carcinoma (PC) encompass several key indicators, including (i) the presence of a palpable neck mass; (ii) a parathyroid gland with dimensions exceeding 3 cm; (iii) marked hypercalcemia, characterized by serum calcium levels exceeding 3 mmol/L; and (iv) parathyroid hormone (PTH) levels that exceed three times the upper limit of normal, as evidenced by prior research 19, 20. Given the aforementioned indicators, we highly suspected that the observed mass was indicative of PC as opposed to a functional parathyroid adenoma. In light of this diagnosis, we opted to perform en bloc surgery alongside ipsilateral central neck dissection once serum calcium levels had decreased. Notably, intraoperative frozen section analysis provided uncertain results, ultimately suggesting a parathyroid adenoma as a potential alternative diagnosis. Upon the removal of the tumor, the serum parathyroid hormone (PTH) levels demonstrated an immediate decrease and returned to a normal range by the 5th day postoperatively, as illustrated in Fig. 1D. The changes in the serum calcium levels were observed to occur more rapidly compared to PTH, as depicted in Fig. 1E. Gross examination revealed the neoplasm's size to be 3×3×2 cm. Microscopic examination confirmed it to be PC, with capsular invasion, angioinvasion, and numerous tumor embolisms detected in the vein (Fig. 2A) 21, 22. The immunohistochemical analysis indicated strong positivity for GATA binding protein 3 (GATA3), PTH, chromogranin A (CgA), and pan-cytokeratin (PCK). CD31 and CD34, endothelial markers, highlighted blood vessels, revealing angioinvasion. In contrast, thyroglobulin (TG) and carcinoembryonic antigen (CEA) staining yielded negative results. The Ki-67 labeling index was approximately 3%. Other staining markers, including B-cell CLL/lymphoma 2, synaptophysin, calcitonin, thyroid transcription factor 1, and galectin 3, were negative, while galectin 3 was diffusely positive, as shown in Fig. 2B and 2C.
The patient exhibited an uneventful postoperative course and was discharged on the 7th day following surgery. A 7-month follow-up evaluation indicated the patient to be asymptomatic with serum PTH and calcium levels within the normal range.
In October 2017, the patient was readmitted to the hospital due to hypercalcemia and elevated PTH levels exceeding 5000. Positron emission tomography-computed tomography (PET/CT) revealed focal activity in the left paratracheal space of the neck, while no focal activity was found in the lung (Fig. 3A and 3B). Neck CT also showed cervical masses indicating local recurrence of PC (Fig. 3C). Thoracic CT revealed suspicious nodules that could be cancer metastases (Fig. 3D). 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 (Fig. 3E and 3F). During the surgery, a novel immune colloidal gold technique (ICGT) was utilized to identify suspicious lesions, which were confirmed to be functional PCs (Fig. 3G). The pathology report confirmed metastasis in the lung nodule and 4/8 neck lymph node metastases. Serum PTH levels decreased postoperatively but gradually increased during follow-up (Fig. 4A). When we compared repeated thoracic CT results through the follow-up, the suspicious lesions were found to have gradually grown, and new lesions were observed in the right lower lobe (Supplementary Fig. 1). After multidisciplinary treatment (MDT) discussions, a 422-gene panel test based on next-generation sequencing (NGS) was recommended to identify potential targets for therapy. The major mutations are summarized in Fig. 4B. Among the identified mutations, the EGFR p.L858R (c. T2573G) and PIK3CA p. E545KV (c. G1633A) mutations were targeted using gefitinib and everolimus, respectively. Gefitinib is an inhibitor of EGFR tyrosine kinase that binds to the adenosine triphosphate-binding site of the enzyme. By inhibiting EGFR tyrosine kinase, downstream signaling cascades are also inhibited, resulting in the inhibition of malignant cell proliferation. Gefitinib is used as a first-line therapy to treat NSCLC that meets certain genetic mutation criteria. Wang et al. reported that patients with the L858R mutation exhibit favorable but inconsistent treatment response and survival outcomes to gefitinib 23.The patient was advised to start gefitinib as a first-line therapy on April 11, 2018. Unfortunately, after 6 weeks, he had progressive disease as PTH levels continued to rise. Hence, he was recommended everolimus as a second line targeting therapy for the PIK3CA mutation. Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway, an important regulator of cell signaling with known roles in physiological processes (including cell growth, survival, and autophagy) and cancer. As shown in Fig. 4D, when everolimus inhibits the activity of mTOR complex 1, it blocks phosphoinositide 3-kinase (PI3K)/AKT/mTOR activation and terminates tumor cell growth and protein synthesis driven by this pathway 24. No response was achieved after 5 weeks, and through MDT discussion, he was recommended a multi-target TKI anlotinib as a trial (12 mg PO qd, on days 1–14 of a 21-day cycle). Fortunately, repeated thoracic CT confirmed partial response (Supplementary Fig. 1), and PTH levels dropped dramatically after anlotinib therapy (Fig. 4A). After 2 months of treatment with anlotinib, comparing the thoracic CT on September 26, 2018, to that obtained last time (July 3, 2018), we found that lesions in the left and right lower lobes showed a necrotic cavity; a new lesion after the second surgery growing rapidly after gefitinib and everolimus treatment showed stability during anlotinib treatment. The patient had a continuous survival benefit for this kind of treatment until March 2020, with toxicity related to treatment being slight and manageable (Fig. 4A shows PTH level during perioperative of the second surgery and the targeting therapy follow-up; 4C shows the patient timeline). On September 25, 2019, the PTH level seemed to start increasing again, while the last CT scan on October 12, 2019, showed no significant changes in metastatic lesions. Based on the sequencing results, we recommended to combine anaplastic lymphoma kinase (ALK) with anlotinib. ALK was first identified in patients with anaplastic large-cell lymphoma and is an oncogenic driver in patients with NSCLC and other cancers. The crizotinib is highly active in ALK+ NSCLC, inducing responses in 60–74% of patients, but the majority of patients show progression in 1 year. Brigatinib (AP26113) was developed as a potent selective inhibitor of ALK, capable of overcoming the mechanisms of resistance associated with crizotinib 25. Unfortunately, in January 2020, during the initial outbreak of COVID-19 in Wuhan City, our hospital was fighting on the front line. We lost contact with the patient for a while, and by the time we finally got in touch, he had died due to COVID-19 in March 2020.