Biomarkers of Parathyroid Carcinoma

Abstract

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.

The Regulatory Roles of MicroRNA-146b-5p and Its Target Platelet-derived Growth Factor Receptor α (PDGFRA) in Erythropoiesis and Megakaryocytopoiesis

“…After ligand binding, the fully activated phosphorylated kinase domains from PDGFRA then phosphorylate multiple tyrosine residues of the receptor cytoplasmic part, which act as docking sites for Src homology 2 domains of various signal transduction proteins, including signal transducers and activators of transcription (STATs), phospholipase C␥, phosphatidylinositol 3-kinase, SRC family kinases, and SHP2 phosphatase (39 -42). These pathways lead to the regulation of numerous transcription factors that regulate cell growth and survival, such as c-MYC, AP1, FOXO, or SREBP (43)(44)(45)(46). The PDGFR-mediated pathways are crucial for embryonic development, cell proliferation, cell migration, and angiogenesis (44).…”

Clinicopathological correlates of hyperparathyroidism

“…Occasionally, the use of immunohistochemistry (positivity for PTH, GATA3 or GCM-2) is helpful to confirm the primary parathyroid origin of an unusual neoplasm (figure 6). 94 Although scattered mitotic figures can be present, the proliferative index of most adenomas, as assessed by Ki-67 (MIB-1), is generally <5% 38–40 42 44–46 98 99 133 135…”

“…Their cytological composition is similar to parathyroid adenomas, with varying proportions of chief cells, oncocytes, transitional oncocytes and scattered water-clear cells 42–44 46 123. Most parathyroid carcinomas show mild-to-moderate nuclear atypia, which is indistinguishable from adenomas 39 40 42–44 46 51 97 98 123. Overall, the distinction between parathyroid carcinomas and adenomas is extremely difficult on cytology, with the exception of a subset of carcinomas that exhibit significant nuclear pleomorphism with macronucleoli 39 40 42–44 46 51 97 98 123.…”

“…Most parathyroid carcinomas show mild-to-moderate nuclear atypia, which is indistinguishable from adenomas 39 40 42–44 46 51 97 98 123. Overall, the distinction between parathyroid carcinomas and adenomas is extremely difficult on cytology, with the exception of a subset of carcinomas that exhibit significant nuclear pleomorphism with macronucleoli 39 40 42–44 46 51 97 98 123. A triad of high-risk histopathological features (necrosis, macronucleoli, >5 mitoses per 50 high-power fields) has been reported to predict malignant behaviour in some parathyroid tumours 42 120 154…”

“…In the parathyroid glands, these represent borderline neoplasms showing some histopathological findings of parathyroid carcinomas (band forming fibrosis, increased mitotic activity, presence of tumour cell within a thickened capsule) but lacking the definite diagnostic features of malignancy (invasion into adjacent tissues, vascular invasion and/or metastases) 38 40 42–44 46 98 123 153–156. The practising pathologist should be aware of the fact that fibrosis can occur in many situations including previous manipulations (post-FNA biopsy for PTH measurements or cytological examination, or ethanol injection), MEN1/MEN4 syndrome, lithium intake or long-standing chronic renal failure related-parathyroid hyperplasia, in the setting of parathyroiditis or in large degenerated adenomas 153.…”