Oligometastatic Parathyroid Carcinoma Presenting as Neck Pain: A Case Report

Abstract

Background:

Parathyroid carcinoma (PC) is an exceedingly rare, slow-growing but progressive endocrine malignancy that represents a diagnostic and therapeutic challenge. Vertebral metastasis of PC is remarkable, with only 3 prior cases of spinal metastasis reported in the literature.

Case Description:

A 62-year-old woman presented with 1 week of neck pain radiating down her right arm. Cervical x-ray revealed a lytic lesion of the C4 vertebral body. Lab work revealed hypercalcemia with an elevated parathyroid hormone level. Computed tomography and magnetic resonance imaging revealed frank destruction of the C4 vertebral body and pedicles by PC. She was treated with corpectomy, mass excision, anterior cervical discectomy and fusion, postoperative radiotherapy, and nonspecific inhibitors of active tumor pathways. Her symptoms resolved postoperatively, and she has remained negative for reoccurrence at 15-month follow-up.

Conclusions:

To the authors’ knowledge, we report the first described cervical spine metastasis of PC. Additionally, we review the treatment of this rare neoplasm in an extremely rare location in the age of tumor sequencing and morphoproteomic analysis.

Introduction

Parathyroid carcinoma (PC) is a rare, slow-growing but progressive malignancy that can occur sporadically or as part of a genetic syndrome. It accounts for 0.005% of National Cancer Database cases between 1985 and 1995. ¹ Nonfunctional PC was first described by de Quervain in 1904, and neoplasms producing parathyroid hormone (PTH) were described in the 1930s by Sainton and Millot. ^2,3 Most PCs (90%) produce PTH and present with signs and symptoms of hypercalcemia. ⁴ A review of 20,225 cases of primary hyperparathyroidism (PHPT) revealed the prevalence of PC to be 0.74%; most cases of PHPT are due to adenomas (85%) and multiple gland hyperplasia (15%). ⁵ Adenomas and multiple gland hyperplasia occur more often in women aged 50 to 70 with asymptomatic hypercalcemia <14 mg/dL and mildly elevated PTH levels, whereas PC has no gender predilection and usually occurs slightly earlier in life (fourth and fifth decade) with a palpable neck mass, serum calcium >14 mg/dL, markedly elevated PTH levels, and renal and/or skeletal involvement. ^6,7 However, none of these clinical criteria can be used to definitively identify or rule out malignancy.

Histologic differentiation between benign and malignant disease can also be problematic. The original histologic criteria of PC were published in 1973, but subsequent series have differed in which criteria are most associated with malignancy. ^6,8,9 To further complicate matters, rare cases of PC have a bland cytological appearance and are only identified by invasiveness; additionally, other tumors do not meet criteria for benign disease or carcinoma and are classified as atypical parathyroid neoplasms (ANs), which have been described as separate, benign clinical entity. ^9,10 The heterogeneity of PC and the lack of definitive diagnostic criteria can make identification before local invasion or distant metastasis—the definitive diagnostic criteria of any malignancy—difficult.

Only 3 cases of PC with spinal metastasis were found in the literature (2 lumbar, 1 thoracic) using search operators “parathyroid” AND “carcinoma” OR “cancer” AND “spinal” OR “vertebral,” AND “metastasis.” ^{11 -13} We present a case of a metastatic PC to the cervical spine, a previously undocumented finding in the literature.

Case Presentation

History and Physical Examination

A 62-year-old Caucasian woman presented to her primary care doctor complaining of a 1-week history of neck pain that radiated down her right arm when she bore down; she was sent to the emergency department for urgent neurosurgical evaluation after an in office cervical x-ray revealed a lytic lesion of the C4 vertebral body. Physical exam revealed no focal weakness or sensory changes in all 4 extremities. Deep tendon reflexes were normal. Her past medical and surgical history was notable for recurrent nephrolithiasis and removal of an AN 5 years earlier. Follow-up for the latter had been negative for recurrence.

Laboratory and Imaging

Lab work revealed hypercalcemia with an elevated PTH level. Cervical spine computed tomography (CT) revealed frank destruction of the C4 vertebral body and pedicles, the C5 end plate, and the right posterior corner of C3, with protruding soft tissue mass between C3 and C5 causing spinal canal stenosis. Magnetic resonance imaging (MRI) revealed a homogenously enhancing mass lesion completely replacing the C4 vertebral body with involvement of the bilateral pedicles as well as focal involvement of the right side of the inferior end plate of C3 and the right side of the superior end plate of C5 (Figure 1). Anteriorly, the mass extended between the longus coli without definite infiltration. There was no T2 signal cord change. Metastatic workup was negative.

Figure 1.

Magnetic resonance imaging T1 without (A) and with contrast (B), and T2 sagittal (C) and axial (D) at time of presentation.

Operation

The Head and Neck Surgery team performed the approach, parathyroidectomy, parathyroid auto-transplantation, and left thyroid lobectomy. Obvious tumor was visible in front of the spine. The C3-C4 and C5-C6 disc spaces were identified, the inferior end plate of C3 and the superior end plate of C5 were cleared of all soft disc and cartilaginous material, and then all soft tissue and remaining bone between were removed back the posterior longitudinal ligament (PLL). A large tumor-filled cavity beneath the longus coli on the right was identified and evacuated, but the capsule could not be completely resected due to the presence of nerve roots and the vertebral artery. The PLL was removed back to normal dura, and remaining tumor affecting the superior end plate of C3 and inferior end plate of C5 was removed. Intraoperative PTH was <6.3 pg/mL. Polyetheretherketone (PEEK) cage and anterior plate were sized and placed.

Histopathology

Pathology was consistent with a neuroendocrine neoplasm of parathyroid origin given the morphology and clinical history (Figure 2).

Figure 2.

A composite photomicrograph of histologic and immunostains of parathyroid carcinoma involving C4 vertebrae. (A) Hematoxylin and eosin (H&E) stain ×40, showing an infiltrating neuroendocrine neoplasm with fibrotic bands in a diffuse and nested pattern. Focal vertebral fibro-osseous tissue present in the upper left corner of the panel. No necrosis is identified. (B) H&E stain ×100, neoplastic cells are monotonous with round nuclei and indistinct nucleoli and rare mitosis (1/50 high-power field). Magnification at ×100 shows the tumor cells are positive for pancytokeratin AE1/AE3 (diffuse) (C), chromogranin A (diffuse) (D), and parathyroid hormone (PTH) (patchy) (F). Inset show high-power photomicrograph ×400 with PTH stain. (E) Ki67 labeling index is 5% to 10% in tumor cells. The tumor cells are negative for synaptophysin, calcitonin, TTF-1, CDX-2, and S100 immunostains (not shown).

Postoperative Course

Postoperatively, her serum calcium dropped from 11.5 to 8.7 mg/dL, and intact PTH dropped from 138.5 to <6.3 pg/mL. Postoperative imaging demonstrated spinal canal decompression and satisfactory alignment of cervical instrumentation. At 2-month follow-up, her neck and radicular pain had resolved and she had no new neurologic complaints. Restaging with positron emission tomography (PET) CT revealed no evidence of other metastasis and no fluorodeoxyglucose (FDG) uptake in the spine; however, cervical MRI showed an abnormal, enhancing soft tissue mass 1.6 cm × 1.2 cm axially, expanding the residual right transverse process of the right pedicle of C4, surrounding the transverse foramen, and suspicious for residual tumor. She received adjuvant radiotherapy, 30 Gy over 10 sessions, which was well tolerated. Three- and 12-month postoperative cervical spine CTs demonstrated proper hardware positioning, good spinal alignment, and evidence of bony fusion. Repeat cervical MRI at 6- and 9-month follow-up revealed no change in the mass. Positron emission tomography CT at 15-month follow-up showed no FDG uptake in the neck. She remains pain free. Third party molecular profiling of the tumor was ordered to identify active tumor pathways that could be targeted. The patient was already taking nonspecific inhibitors of active tumor pathways, which have been continued. Additional targeted therapy has not yet been pursued as she remains negative for reoccurrence.

Discussion

Parathyroid carcinoma mortality is related to hypercalcemia, not tumor burden. A report of 733 patients from 1985 to 2006 revealed 5- and 10-year survival rates of 82.3% and 66%, respectively. ¹⁴ The most effective treatment of PC remains en bloc surgical resection, but recurrence or persistent disease has been seen to occur from 40% to 85% of patients. ^10,15 Metastasis locations are usually the lung, cervical lymph nodes, and the liver, but recurrence is typically local. ^4,6,8 Resection of local recurrence or distant metastases provides significant palliation of hypercalcemia. ⁶ We present, to our knowledge, the first reported case of PC affecting the cervical spine. The other reported cases of metastatic PC to the spine (2 lumbar, 1 thoracic) were treated with laminectomy, laser ablation, and surgical excision. ^{11 -13} These tumors were not as extensive or destructive as our patient’s lesion and were excised completely. For unrespectable disease, hypercalcemia is usually controlled with bisphosphonates, octreotide, calcimimetics, or denosumab.

The role of postoperative radiotherapy for PC remains controversial, as most studies show no benefit and the only published reports that could suggest benefit are small retrospective series. ^{6,7,16 -19} However, after extensive multidisciplinary discussion with our patient regarding the existence of known residual tumor, the natural history of the disease, the published possibility of postoperative radiotherapy (PORT) benefit to residual tumor, and the lack of other well-studied therapeutic options, the patient opted to receive radiotherapy. Her residual tumor was unchanged in size and inactive on PET CT 1 year after radiotherapy.

Advances in tumor molecular profiling and morphoproteomics may offer a better prognosis for patients with spinal metastasis that are not amenable to gross-total resection, especially in cases of rare neoplasms without an established optimal treatment paradigm. This tumor had rare and weak PD-L1 expression and a lack of TILs, suggesting limited value in PD-L1 inhibitors. Inactivating mutations of the tumor suppressor genes NF1 and MEN1 and strong expression of the downstream pathways Ras/MEK/ERK and mTOR were found, which have rarely been reported in PC. ^20,21 The patient was already taking some of the recommended nonspecific inhibitors of these pathways, including metformin, atorvastatin, and aspirin. The benefit of targeted inhibition of the Ras/MEK/ERK pathway has been reported in PC, and insurance approval is being pursued for our patient should the need for these arise in the future. ²²

Conclusion

Differentiation of PC from benign causes of PHPT at first operation remains challenging. Close follow-up is essential even if the more benign diagnosis is made. The role of PORT and targeted therapies based on genomic and morphoproteomic analysis for unresectable disease remains undefined. We report on the first described cervical metastasis of PC; the patient was treated with C4 corpectomy and mess resection, C3-C5 anterior cervical discectomy and fusion, PORT, and nonspecific inhibitors of tumor pathways. Her symptoms resolved postoperatively, and she has remained negative for reoccurrence at 15-month follow-up.