Renal cell carcinoma comprises approximately 3% of all adult malignancies13
and is increasingly diagnosed as an incidental finding during routine radiologic imaging.6,16
However, ccRCC may present with metastatic lesions in patients with concurrent clinically undiagnosed primary or a remote history of renal cancer; approximately one third of patients are diagnosed with metastatic disease at the time of presentation.16
Metastatic ccRCC most frequently involves the lung, bone, liver, and brain, but ccRCC also characteristically involves “unusual” sites of metastasis and can involve nearly any organ in the body such as the thyroid and pancreas.16
Metastatic ccRCC is the most common metastasis to involve the thyroid gland, accounting for approximately 33% of all metastases in the thyroid in clinical material.17
In the thyroid, metastatic ccRCC could be misinterpreted as a clear-cell change in adenomatoid nodules, follicular adenomas, or parathyroid gland adenomas. In one series of metastatic ccRCC in the thyroid gland, 36% of metastases were the initial manifestation of renal cell carcinoma in these patients.10
PAX8 is a transcription factor expressed by both thyroid and renal-lineage cells.7,8,12,14,20
In the thyroid, its role has long been established as a transcriptional regulator by binding to the thyroperoxidase promoter.7,14
Translocations involving chromosomes 2 and 3 create a fusion product of PAX8 and peroxisome proliferator-activated receptor-γ, which can be seen in follicular adenomas and carcinomas.8
Immunolabeling for PAX8 is not routinely used in metastatic thyroid lesions, whereas immunolabeling for the transcription factor TTF1 is more commonly used.8
The detection of PAX8 by IHC has been variable in thyroid neoplasms.18,19
In contrast, PAX8 IHC labeling is frequently used to support the diagnosis of metastatic renal neoplasms.2
CAIX is a downstream effector of the von Hippel-Lindau hypoxia inducible pathway, which plays a major role in the pathogenesis of ccRCC, and CAIX can be detected by IHC in ccRCC and other renal neoplasms.1,3,4,9
Its expression has been extensively and controversially investigated as an independent predictor of survival in ccRCC.5,15
CAIX expression has been studied in a wide range of normal and neoplastic human tissues,11
but its expression in thyroid has not been studied.
Although the diagnosis of metastatic ccRCC may be strongly suspected on the basis of histomorphology, IHC studies are often necessary to confirm the diagnosis, especially in patients with no known history of primary ccRCC. No previous study has evaluated the diagnostic use of PAX8 and CAIX in the setting of metastatic ccRCC in the thyroid. Here, we investigated the expression of PAX8, CAIX, TTF, and TGB in 12 cases of metastatic ccRCC in the thyroid and in parathyroid glands and adenomas with clear-cell change, papillary thyroid carcinomas, thyroid follicular adenomas, and adenomatoid nodules.
As expected, PAX8 is not a useful immunomarker in distinguishing metastatic ccRCC from primary thyroid lesions. Although PAX8 will be negative in parathyroid lesions, the marker still has limited use because positive staining does not further distinguish between thyroid and renal lesions. Additional markers that are specific for parathyroid, such as parathyroid hormone and chromogranin, can also be used in this setting. Histologic clues that support the diagnosis of parathyroid tissue include the presence of acidophilic oxyphil cells and admixed fibroadipose tissue ().
An immunoprofile of “TTF1(−)/TGB(−)/CAIX(+)” was 100% sensitive and specific for metastatic ccRCC in the thyroid. The reverse profile “TTF1(+)/TGB(+)/CAIX(−)” supported a primary thyroid lesion. However, this study is limited to 12 cases, and these findings should be validated in a larger series.
Thyroid nodules are routinely sampled by FNA for diagnostic evaluation.21
One of the cases of metastatic ccRCC included in this series was initially diagnosed as an adenomatoid nodule on preoperative FNA. A high index of suspicion must be maintained for metastatic ccRCC in the thyroid in an FNA containing cells with a prominent clear cytoplasm and fine vasculature, as ccRCC may present as an isolated metastasis with an occult or remote primary.16
The potential use of the immunopanel of TTF, TGB, and CAIX in thyroid FNAs will be explored in a separate study.