Metastatic Clear Renal-Cell Carcinoma Mimicking Anaplastic Thyroid Cancer: A Case Report

Abstract

Metastatic renal cell carcinoma to the thyroid is a rare yet aggressive histopathologic diagnosis, which may often be omitted from the initial clinical differential. This is in part due to the long latency period between the initial renal primary and appearance of metastatic disease, coupled with the diagnostic limitations of fine-needle aspiration biopsies. We herein present an interesting case of a metastatic clear-cell renal-cell carcinoma mimicking an aggressive primary thyroid neoplasm, 10 years after a nephrectomy for a renal primary, highlighting key diagnostic and management considerations.

Case Presentation

A 70-year-old Cree woman, known for metabolic syndrome, a multinodular goiter, and left clear-cell renal-cell carcinoma (ccRCC) status post nephrectomy and adrenalectomy in 2011, was first seen in the community hospital for respiratory distress and altered mental status (Glasgow Coma Scale 3). She was intubated in the emergency department, and transferred to our quaternary care center with a working diagnosis of a presumed cardiac event. Urgent cardiac catheterization revealed normal coronaries, hence requiring no intervention. A computed tomography (CT) angiography of the chest demonstrated multifocal patchy areas of consolidation and ground glass opacities consistent with multifocal pneumonia, as well as a large 5.7 × 4.1 cm mass in the right lobe of the thyroid, potentially causing airway compromise at the level of the thoracic inlet. Her primary team began treatment for pneumosepsis and consulted our service for ongoing investigations and management of the thyroid mass.

On examination, the patient had a firm right-sided thyroid mass causing left deviation of the trachea. On ultrasound, it appeared hyperechoic/isoechoic and ill-defined, seemingly merging with the heterogeneous surrounding parenchyma. Our team attempted to attain a tissue diagnosis; however, attempts at ultrasound-guided fine-needle aspirate biopsy (FNAB) yielded Bethesda I (×3) and Bethesda III (×2). While we discussed a core-needle biopsy with our interventional radiologists, they opted to repeat an FNAB as the thyroid appeared significantly vascular.

During interdisciplinary meetings, we decided to perform a wedge biopsy of the thyroid mass for diagnostic purposes, followed by an open tracheotomy due to her significant tracheomalacia and no foreseeable timeline for extubation. A follow-up CT neck and chest were requested prior to surgery, which demonstrated the mass now extending to the posterior surface of the upper trachea, across the midline, and surrounding the trachea by approximately 270° (Figure 1). There was invasion into the tracheal lumen with the mass encircling the endotracheal tube and concern for cartilaginous invasion at the level of the right cricoid cartilage. Additionally, there were multiple bilateral small pulmonary nodules, which were previously obscured by foci of consolidations, and concerning for metastases. A positron emission tomography (PET) scan showed the thyroid mass was significantly hypermetabolic (SUV = 5.1), while the lung nodules had only low-grade non-specific uptake (SUV = 3.8). The main differential diagnosis was anaplastic thyroid cancer (ATC) given the rapid progression, the invasiveness, and aggressive behavior of this mass.

Figure 1.

CT neck in axial orientation demonstrating a thyroid mass extending posterior to the upper trachea, across the midline, and surrounding the trachea by approximately 270° (arrows) with (A) invasion of the tracheal lumen and (B) invasion of the cricoid cartilage.

Intraoperatively, the patient started to bleed excessively from the wedge resection site. Hemostasis was ultimately achieved using a combination of cautery, suture ligation of the severed thyroid edges, and various hemostatic agents including a gelatin and thrombin hemostatic matrix. The total blood loss was of approximately 2 L, necessitating replacement with several blood transfusions. The tracheostomy was deferred, and she was transferred back to the intensive care unit in stable condition. A bedside percutaneous tracheostomy was performed the following week with no complications.

The surgical pathology of the isthmus resection demonstrated a white nodule, and metastatic ccRCC was identified within the thyroid gland and perithyroidal tissues (Figure 2). The largest focus measured 1.6 cm, with angioinvasion. Immunohistochemistry showed positive for RCC, CA-IX and Pax8, focal positivity to EMA, and negative for thyroglobulin, napsin, CK7, and CK20; therefore, the immunohistochemical profile supports the diagnosis of invasive ccRCC rather than a primary thyroidal neoplasia.

Figure 2.

H&E of thyroid wedge biopsy of isthmus. (A) Metastatic ccRCC in the background of thyroid with follicular hyperplasia. (B) Prominent angioinvasion of ccRCC.

Given the extremely vascular nature of this thyroid tumor and high risk of hemorrhage, it was deemed surgically unresectable. Our medical oncology team started treatment with a tyrosine kinase inhibitor, axitinib, followed by a trial of a highly selective humanized monoclonal IgG4 antibody named pembrolizumab.

Discussion

The thyroid gland is a rare site for metastatic disease to develop. ¹ A study of autopsies on more than one thousand patients who died with all types of disseminated cancers attempting to identify secondary sites of disease isolated metastases to the thyroid in less than 5% of patients. ² In a 10-year review, metastatic solid tumors to the thyroid gland comprised 0.13% of resected thyroid nodules. ³ Breast and lung cancers were historically the most common malignancy metastasizing to the thyroid gland.^4–6 However, in a recent review, ccRCC has outranked the latter, accounting for 48.1% of metastatic disease to the thyroid. ⁵

A challenge in diagnosing metastatic RCC stems from the long latency period following initial diagnosis of the primary malignancy and the appearance of the metastatic disease. Our patient’s thyroid metastases were diagnosed 10 years after her primary renal-cell cancer diagnosis. A recent systematic review similarly showed the time to detection of thyroid metastases of RCC ranges from several weeks to 31 years.^1,7 The delayed presentation and non-specific signs and symptoms thus often lead physicians to first consider primary thyroid disease.

For workup of all thyroid nodules, guidelines suggest FNAB for the first attempt for diagnosis. ⁸ However, FNAB for aggressive thyroid cancers has been challenging and subject to variability in successful diagnosis. ⁹ While FNAB can diagnose undifferentiated thyroid cancer, tumor hemorrhage, necrosis, or excessive fibrosis can cause inadequate sampling.^10,11 In a 2017 study from Korea investigating thyroid FNAB vs core-needle biopsy to diagnose metastatic RCC, FNAB did not have great success. Only one of nine FNABs in 8 nodules (11%) was able to confirm metastatic RCC, whereas all core-needle biopsies confirmed metastatic RCC. ¹² In a systematic review where 65 patients underwent thyroid FNAB, cytology with FNAB was diagnostic in 25 cases but was non-diagnostic or non-confirmatory in 40 cases. ¹

Our initial feared diagnosis was undifferentiated thyroid cancer, or ATC, due to the rapid progression and invasive nature of the mass. Given the clinical picture and radiological concern for tracheal lumen and cartilaginous invasion, we insisted on tissue diagnosis and sought emergency operative time. While she did not have ATC, her prognosis is still guarded. She was risk-stratified as “poor” on the International Metastatic Renal Cell Carcinoma Database Consortium Risk Score, which equates to a median survival of 7.8 months. ¹³

There are different treatments for metastatic ccRCC. Surgery is not curative but can prolong survival in patients with metastatic disease to the thyroid. There is an estimated 5-year survival rate of approximately 50% with surgical excision. ¹⁴ However, given that she had disseminated metastases and a non-resectable disease, the first-line standard of care is treatment with pembrolizumab and axitinib. ¹⁵ Indeed, the recent phase 3 trial, published in the New England Journal of Medicine and the Lancet, demonstrated treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival, progression-free survival, and higher objective response rate than treatment with sunitinib, another receptor tyrosine kinase approved for use for metastatic RCC. With pembrolizumab plus axitinib, the estimated overall survival rate at 24 months can be as much as 74.4% (95% CI: 69.9-78.2)^16,17.

Conclusion

We present the rare case of metastatic ccRCC to the thyroid that clinically mimicked ATC and was treated with a combination of pembrolizumab and axitinib. This unusual case of an aggressive, rapidly progressing thyroid mass diagnosed as an RCC metastasis on final pathology serves as pitfall and a reminder that this entity has been documented to recur even after 31 years of latency and mimic primary thyroid malignancies. ¹ This case additionally highlights the diagnostic limitations of FNAB for metastatic disease to the thyroid, for which tissue biopsy is often required.