The diagnosis of
parathyroid carcinoma can be challenging, and adjuvant
therapies such as
radiotherapy and
chemotherapy are not particularly beneficial in the management of this disease, creating a challenge when dealing with unresectable recurrent and metastatic
malignancy. We investigated the expression profile of
biomarkers that represent potential markers of
malignancy or targets for novel
therapies in this disease. We constructed a tissue microarray of
parathyroid carcinomas from 10 patients as well as
parathyroid adenomas from 25 patients and stained the slides for 34
proteins involved in angiogenesis (
platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β,
vascular endothelial growth factor receptor-2 (VEGFR-2), and
epidermal growth factor receptor (EGFR)),
inflammation (
cyclooxygenase (COX)-1 and COX-2), cell adhesion (
matrix metalloproteinase (
MMP)-1, CD9, and
keratin 7), cell cycle (Cdc2p34,
cyclin D1,
retinoblastoma (Rb), p27, p21, parafibromin, Bmi-1, 14-3-3σ, and p53), and apoptosis (Bcl-2a, Mcl-1, Bcl-xL, and glutathione-S-transferase-isoenzyme π (Gst-π)) along with some markers of the sonic hedgehog (Smo, SHH, Gli-1, Gli-2, Gli-3, and patched), mTOR (AKT,
mammalian target of rapamycin (mTOR), and Forkhead box O (FoxO)-1), and WNT (Wisp-1, Wisp-2, and β-catenin) signal transduction pathways.
Protein expression was determined using computerized image analysis software (Spectrum Plus©, Aperio). Bcl-2a, parafibromin, Rb, and p27 were significantly decreased to variable degrees in all
parathyroid carcinomas. COX-1/2, CD9, MMP-1, FoxO-1,
VEGFR-2, PDGFR-α/β, Gst-π, Gli-1, Gli-2, Gli-3, and patched were expressed in the majority of benign and malignant
tumor cells. These results indicate that the use of a panel that includes Bcl-2a, parafibromin, Rb, and p27 may be helpful in the assessment of atypical
parathyroid neoplasms. Although the majority of other markers studied are also expressed in both benign and malignant
parathyroid neoplasms, we have identified several potentially important target
proteins related to angiogenesis and cell proliferation along with COX-1/2, Gst-π and members of sonic hedgehog pathway that may be therapeutic targets in
parathyroid carcinoma. While these results are preliminary, a successful outcome of a clinical trial directed against these novel targets would provide much needed systemic adjuvant treatment for patients with metastatic
parathyroid carcinoma.