Bone-Invasive Oral Squamous Cell Carcinoma in Cats

Abstract

Feline oral squamous cell carcinoma (OSCC) is the most common oral tumor in cats. There is no effective treatment, and the average duration of survival after diagnosis is only 2 months. Feline OSCC is frequently associated with osteolysis; however, the mechanisms responsible are unknown. The objective of this study was to characterize the epidemiology and pathology of bone-invasive OSCC in cats and to determine the expression of select bone resorption agonists. In sum, 451 cases of feline OSCC were evaluated. There was no sex or breed predisposition, although there were more intact cats in the OSCC group compared to the control group. Gingiva was the most common site, followed by the sublingual region and tongue. Cats with lingual OSCC were younger (mean, 11.9 years) compared to cats with gingival OSCC (mean, 13.6 years). In addition to osteolysis, there was periosteal new bone formation, osseous metaplasia of tumor stroma, and direct apposition of OSCC to fragments of bone, suggestive of bone-binding behavior. Eighty-two cases were selected for immunohistochemical detection of parathyroid hormone-related protein (PTHrP). Specimens with osteolysis had increased PTHrP expression and nuclear localization, compared to OSCC without osteolysis. Thirty-eight biopsies of OSCC with osteolysis were evaluated for tumor necrosis factor α expression, and only 4 biopsies had such expression in a small proportion of tumor cells. Increased tumor expression of PTHrP and increased localization of PTHrP to the nucleus were associated with osteolysis and may play an important role in bone resorption and tumor invasion in cats with OSCC.

Animal Models of Bone Metastasis

“…52 The majority of bone-invasive HNSCCs are suspected to be mediated by PTHrP and RANKL, similar to cancers that metastasize to bone. 52,76,133 PTHrP contributes to bone lysis by inducing RANKL expression in osteoblasts, resulting in binding of RANKL to its receptor, RANK, on osteoclasts and stimulating osteoclastogenesis. 133 Osteoprotegerin (OPG), the soluble decoy receptor of RANKL, is regulated by the Wnt/β-catenin signaling pathway and counterbalances the actions of RANKL.…”

“…Ten percent of all tumors diagnosed in cats are oral tumors, and 75% of feline oral cancers are SCC. 76,127,136 The tongue, especially the ventral tongue, and gingiva were reported as the most commonly affected sites for feline HNSCC. 76 Remarkably, cats and humans are the only 2 species that commonly develop spontaneous lingual SCC.…”

“…76,127,136 The tongue, especially the ventral tongue, and gingiva were reported as the most commonly affected sites for feline HNSCC. 76 Remarkably, cats and humans are the only 2 species that commonly develop spontaneous lingual SCC. 33,52,168 Similar to humans, HNSCC frequently occurs in aged cats with no apparent breed or sex predisposition.…”

“…75,76 Orthotopic xenograft models using feline-derived OSCC cell lines (SCCF1, F2, and F3) demonstrated that bone-invasive feline OSCC (SCCF2) had greater PTHrP messenger RNA (mRNA) expression compared with non-bone-invasive cell lines (SCCF1 and SCCF3). 75 The feline HNSCC cell line, SCCF2, closely mimicked bone-invasive SCC when tumor cells were injected into the submucosa of the maxilla (Figs.…”

Combined zoledronic acid and meloxicam reduced bone loss and tumour growth in an orthotopic mouse model of bone‐invasive oral squamous cell carcinoma

“…2 In most cases of gingival OSCC there is invasion and lysis of adjacent bone which is characterized by osteoclastic bone resorption. 3 Since most cats present with deep invasion of bone, treatment options are limited because feline OSCC is resistant to both chemotherapy and radiation. 2 …”