Sarcomas and fibrosarcomas are rare skin diseases of cats.

Sarcomas are neoplasms of mesenchymal (stem cell) origin, and are different to neurofibrosarcoma of nerve tissue origin. Fibrosarcomas are malignant mesenchymal tumours arising from fibroblasts. They can occur at any anatomical location and are common in cats, comprising 24 to 33% of tumours of skin and subcutis. Malignant fibrous histiocytoma is comparatively uncommon in cats^[2][3][4]. Before the 1990s, sarcomas with fusiform cells with cutaneous or subcutaneous locations were known to be rare in cats. They now form part of the most common, if not the most frequent tumors in cats both in France and North America^[5].

Frequency estimations in Northern America have reported 20 cases out of 100,000 cats^[6]. In Europe, a retrospective investigation covering a period of 5 years reported 0.4 pharmacovigilance cases out of 100,000 cats under care. In France, the mean age of cats developing a fibrosarcoma is 9.6 years within a large interval of 3.2-16 years (95% confidence interval), which is little typical of spontaneous tumours. Distribution seems to have evolved from a single peak at 10-12 years towards bimodal distribution with a first peak at 6-7 years and a second at 10-11 years. Moreover, tumours are significantly more often located at classical FeLV-vaccination sites on cats. None have been reported in Australia^[7]. Numerous variants have been diagnosed, including:

• True fibrosarcoma
• Malignant fibrous histiocytoma (MFH)
• Fibromatoses
• Granulomatous panniculitis
• Miscellaneous subcutaneous tumours – osteosarcoma, chondrosarcoma, haemangiosarcoma, rhabdomyosarcoma, haemangiopericytoma and neurofibrosarcoma

Contents 1 Causes 2 Diagnosis 3 Treatment 4 References

Causes

Transition between inflammation or wound healing and tumours has been frequently observed in different animal models of virus- or oncogene-induced tumours, in which inflammatory compounds appear to play a role in carcinogenesis. In cats, early vaccination sites show persistent inflammatory or foreign-body reactions characterized by areas of necrosis, aggregates of lymphocytes and plasma cells, and granulation tissue formation. This reaction is thought to predispose fibroblasts or myofibroblasts to proliferate, leading to neoplastic transformation through different mechanisms including activation of oncogenes and inactivation of tumour suppressor genes. On the other hand, agents that promote inflammation such as acidic fibroblast growth factor (FGF-a) and basic FGF (FGF-b) create a favourable environment for expression of oncogenes and subsequent development of tumors.

The p53 tumour suppressor gene is a transcription factor that regulates the expression of genes involved in cell-cycle control, apoptosis in cells with defective deoxyribonucleic acid (DNA), cellular differentiation, and genetic instability. Mutations in the p53 gene have been associated with human and animal neoplasms. To investigate the role of the p53 gene in oncogenesis in cats, molecular cloning and chromosomal mapping of the feline p53 tumour suppressor gene were carried out. p53 genetic aberrations have been observed in codons 180 and 248 from exons 5–7 in two of 10 feline fibrosarcomas (FS). Of 60 tumours investigated, missense mutations were also detected in two FS, one malignant fibrous histiocytoma (MFH), one undifferentiated carcinoma of the skin, and one mammary carcinoma. The problematic histopathologic overlap between FS and MFH was also identified by Mayr et al (1995) ^[8]. Recently, a single missense mutation in the exons 5 through 8 and intron 5 was found in 5 of the 40 feline vaccine site–associated sarcomas.

The wild-type p53 protein is not detected by immunohistochemistry because of the short half-life of about 15–20 minutes. Missense mutations leading to amino acid substitutions may induce p53 protein stabilization, resulting in accumulations of nuclear p53 proteins that are detectable by immunohistochemistry. p53 protein was detected using immunohistochemistry in various feline cancer types, including carcinomas and sarcomas^[9].

Recently, different authors have confirmed that growth factors (GFs) not only promote proliferation but also induce malignant transformation and regulation of angiogenesis. Overexpression of GFs has been found in different human tumours and is considered to be one of the causes of carcinogenesis^[10].

FGF-b is a prototype member of FGF family that comprises 20 members, with pleiotropic effects in different cells and organ systems. FGF-b is involved in inflammation and wound healing and in promoting nerve survival and regeneration after central nervous system injury^[11]. It is also known that FGF-b can activate DNA synthesis in mesenchymal cells such as fibroblasts and smooth muscles, stimulating growth of tumours derived from these cells. In addition, numerous studies have shown that FGF-b can stimulate division and migration of vascular endothelial cells, essential for sustaining tumour growth and enabling metastasis^[12].

Transforming growth factor-α (TGF-α) is a protein of 50 amino acids belonging to the epidermal growth factor (EGF) family that was initially called sarcoma growth factor because of its profound effects on the morphology of rat fibroblasts.7 TGF-α binds the EGF receptor (EGF-R), triggering a cascade of events that leads to regulation of epithelial and mesenchymal cell growth. EGF- or TGF-α–induced mutation in the p53 gene with overexpression of the mutant p53 product causes enhanced signalling in vulvar squamous carcinoma cell line. Expression of TGF-α can be induced by several viral and cellular oncogenes and causes a mitogenic effect in a variety of cells. An increase in TGF-α expression has been detected in several malignant neoplasms in humans, including MFH^[13][14].

Diagnosis

Classically, feline fibrosarcoma develops in the form of firm, nodular or multinodular cutaneous lesions, which are neither painful nor ulcerated. Tumors are preferentially located at the injection site: Interscapular area, dorsal side of the neck: 40-49.5%, Thorax, flanks: 25-29%, Loins and back: 13-14%. Tumors at limb extremities, as they used to be described, have now become rare. FeSV-induced fibrosarcomas, systematically multicentric, are quite rare, too, and mainly affect young kittens. Feline fibrosarcomas are located subcutaneously and therefore rarely ulcerated, except during the terminal stage. They are rarely painful except when they are very large or infiltrated with deep structures.

The speed of evolution of fibrosarcomas is greatly variable. Small-size nodules may persist as such for quite a long time; inversely, other nodules may double in size within a very short period, which would show that tumoral growth accelerates alongside consecutive excisions.

Fibrosarcomas need to be differentiated histologically from rhabdomyoma and rhabdomyosarcoma^[15].

Treatment

Local recurrence rates with surgery are high. Complementary radiotherapy to surgery is particularly suited for tumors with a potentially high risk of local relapses. Sensu stricto fibrosarcomas, malignant fibrohistiocytomas, and all soft tissue sarcomas with a high mitotic index are good indications for adjuvant radiotherapy. On the other hand, radiotherapy is not a good indication for fibromatoses and sarcomas^[16].

Feline fibrosarcoma tumors do not metastize greatly (less than 15%), usually quite late and often when satisfactory local examination has been obtained with adjuvant radiotherapy. Moreover, soft tissue sarcomas are considered chemosensitive in both human and veterinary medicine. The advantage of chemotherapy therefore is disputable for such tumors.

Non-specific immunomodulators, which were widely used twenty years ago, have been abandoned in veterinary medicine due to their low efficiency and little specificity.

The prognosis in most cases is poor.

References

1. ↑ Guaguere, E & Prelaud, P (2000) A practical guide to feline dermatology. Merial, France
2. ↑ Hendrick MJ (1998) Feline vaccine-associated sarcomas: current studies on pathogenesis. J Am Vet Med Assoc 213:1425-1426
3. ↑ Hendrick MJ, Brooks JJ (1994) Postvaccinal sarcomas in the cat: histology and immunohistochemistry. Vet Pathol 31:126-129
4. ↑ Hendrick MJ, Goldschmidt MH (1991) Do injection site reactions induce fibrosarcomas in cats? J Am Vet Med Assoc 199:968
5. ↑ Couto SS, Griffey SM, Duarte PC, Madewell BR: Feline vaccine-associated fibrosarcoma: morphologic distinctions. Vet Pathol 39:33-41, 2002
6. ↑ Esplin DG, Mcgill LD, Meininger AC, Wilson SR: Postvaccination sarcomas in cats. J Am Vet Med Assoc 202:1245-1247, 1993
7. ↑ Burton G, Mason KV (1997) Do postvaccinal sarcomas occur in Australian cats? Aust Vet J 75:102-106
8. ↑ Mayr B, Schaffner R, Kurzbauer M, Schneider A, Reifinger M, Loupal G (1995) Mutations in tumor suppressor gene p53 in two feline fibrosarcomas. Br Vet J 151:707-713
9. ↑ Mayr B, Blauensteiner J, Edlinger A, Reifinger M, Alton K, Schaffner G, Brem G (2000) Presence of p53 mutations in feline neoplasms. Res Vet Sci 68:63-70
10. ↑ Nambiar PR, Haines DM, Ellis JA, Kidney BA, Jackson ML (2000) Mutational analysis of tumor suppressor gene p53 in feline vaccine site-associated sarcomas. Am J Vet Res 61:1277-1281
11. ↑ Madewell BR, Griffey SM, McEntee MC, Leppert VJ, Munn RJ (2001) Feline vaccine-associated fibrosarcoma: an ultrastructural study of 20 tumors (1996–1999). Vet Pathol 38:196-202
12. ↑ Derynck R (1986) Transforming growth factor-alpha: structure and biological activities. J Cell Biochem 32:293-304
13. ↑ Basilico C, Moscatelli D (1992) The FGF family of growth factors and oncogenes. Adv Cancer Res 59:115-165
14. ↑ Bikfalvi A, Klein S, Pintucci G, Rifkin DB (1997) Biological roles of fibroblast growth factor-2. Endocr Rev 18:26-45
15. ↑ Kass PH, Barnes WG, Spangler WL, Chomel BB, Culbertson MR (1993) Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc 203:396-405
16. ↑ VIN.com