Clear cell renal cell carcinoma is the most common type of renal cell carcinoma, occurring in 80-85% of patients with renal tumors worldwide¹ and comprising 90% of renal malignancies worldwide.² Approximately 30% of renal cell carcinomas metastasize to distant sites,³ most commonly to the lung (71%), followed by lymph nodes (49%), bones (36%), liver (21%), adrenal (9%), brain (9%), pancreas (5%), pleura (4%), and thyroid (0.6%).⁴

On surgical pathology, clear cell renal cell carcinoma generally appears as a solid, highly vascular mass containing sheets of cells with distinct borders. The cytoplasm is abundantly vacuolated and contains glycogen and lipid. In low grade clear cell carcinomas, the nuclei are small and the atypia is only minimal, bearing almost no distinction from the nuclei of normal renal tubular cells. In high grade clear cell carcinomas, the cytoplasm can become granular, and the nuclei are larger, hyperchromatic, and have irregular borders. Nucleolar prominence increases with increasing tumor grade. In fine needle aspiration cytology samples, the tumor shows loosely cohesive groups of cells with abundant foamy cytoplasm with borders that can be indistinct. The appearance on cytology is similar to what is demonstrated on surgical pathology, and the nuclear features become more irregular and hyperchromatic as the nuclear grade increases. The cytoplasmic vacuolization (clear cell appearance) that characterizes clear cell renal cell carcinoma is represented better on Diff-Quik than on Papanicolaou stain because the alcohol fixation can dissolve the cytoplasmic lipid, resulting in stripped nuclei.⁵ In some cases of metastatic clear cell renal cell carcinoma, the cytomorphology of the metastases can be different from the primary tumor due to dedifferentiation that occurs as the disease progresses. Some metastatic lesions can contain a nonclear cell component, which can show eosinophilic cytoplasm and rhabdoid or sarcomatoid features.⁶

With an incidence of 2%,⁷ metastasis to the thyroid gland is rare, but when it does occur, it can be via direct extension or via hematogenous/lymphatic spread from distant sites. By direct extension, head and neck cancers such as esophageal, laryngeal, or pharyngeal squamous cell carcinomas are common culprits. In cases of distant metastasis to the thyroid, kidney is the most common primary site, making up 34% of cases. This is followed by lung, then GI tract, and breast cancers at 15%, 14%, and 14%, respectively.⁸ Because renal cell carcinoma can take many years to metastasize (sometimes more than 20 years), in patients with a history of renal cell carcinoma who later present with thyroid nodules, renal cell carcinoma metastasis should always be considered in the differential diagnosis.

Typically, metastatic disease is suspected in cases with multiple nodules versus a solitary nodule appearing in a particular organ; however, thyroid can be tricky, as numerous patients with benign thyroid nodules present with multiple rather than solitary nodules! Therefore, a definitive diagnosis cannot be made on imaging alone. Immunohistochemistry can be performed to rule out other foamy type cells (i.e. CD163 for macrophages) or thyroid origin cells (i.e. TTF-1, PAX-8, thyroglobulin, calcitonin). However, it is important to keep in mind that kidney tumors are also PAX-8 positive, presenting a potential pitfall. Clear cell renal cell carcinomas, however, would be negative for additional thyroid markers (TTF-1, thyroglobulin, calcitonin) and would express markers such as vimentin, carbonic anhydrase IX (CAIX), and CD10. Clear cell renal cell renal cell carcinomas are often negative for CK7, which are positive in thyroid tumor cells.