Long-term treatment of Equine Sarcoid in a mare Elsa Kanner, St. George?s University 9 April 2014 Presented Feb 20, 2014 - 19 year old female intact Warmblood 13 years of treatment for severe sarcoids Problem list: sarcoids Importance of equine sarcoid for veterinarians - Most common equine tumor - Accounts for over half of all equine skin tumors - No ?one size fits all? treatment http://balancedecosolutions.com/product/sarcoid-cleansing-salve What are equine sarcoids? -Locally invasive fibroblastic skin tumors -Arise between ages 3-6 -Common locations: head, ventral abdomen, limbs Dr. Hackett ?Cutaneous Neoplasia? lecture Causes of equine sarcoid -Aetiology: Bovine papillomavirus (BPV) types 1 & 2 -Interesting tumor: -Only known cross-species papillomavirus infection -Infection with BPV alone not enough to cause tumor http://calfology.com/library/wiki/wartsand-papillomas bovine papillomavirus in a cow Causes of equine sarcoid cont -3 requirements for sarcoid formation: 1) Exposure to Bovine Papillomavirus 2) Genetic predisposition 3) Skin infection/open wounds bovine papillomavirus in a cow 6 types of equine sarcoid http://www.wetherbyvets.co.uk/info/ Factsheets/Horse/24_269968.shtml 1) occult (flat) 2) verrucous (wart-like) 3) nodular 4) fibroblastic 5) mixed 6) malevolent Differential diagnoses for equine sarcoid http://info.mannapro.com/mannaproanimalcareblog/ equine papillomavirus pythiosis http://veterinarynews.dvm360.com -Infectious: - papilloma (viral) - pythiosis (fungal) - habronemiasis ?summer sores? (parasitic) - staphylococcal folliculitis (bacterial) Differential diagnoses for equine sarcoid http://www.northfloridaequine.com/heel -bulb-laceration/ granulation tissue -Inflammatory: -granulation tissue -granuloma -Neoplastic: -squamous cell carcinoma (SCC) -fibroma/fibrosarcoma -cutaneous lymphoma -mast cell tumor (MCT) -melanoma Diagnosis of equine sarcoid -Presumptive diagnosis: - clinical presentation -Definitive diagnosis: -histopathology -consider exacerbation by biopsy-induced trauma Dr. Hackett ?Cutaneous Neoplasia? lecture H&E stained photomicrograph of an equine sarcoid Back to our case report... - Sarcoids started in 2001, at approx age 3 - Initial lesions were occult (flat) in 2 spots on left flank - Seen by RDVM, no treatment at that time - During 2002 sarcoids became more aggressive and patient was referred to CUHA http://tailsfromprovence.com/2013/05/22/sarcoids-ugh/ Representative occult sarcoid, no pictures of our patient until 2009 History of our patient cont - Referred to CUHA in 2003, treatments managed by RDVM: -2003 - 2007 -Cautery : effective for short periods, sarcoids regrew. -SMZ started to control skin infections. Continued to present. -2007 - 2009 -Equi-salve : to soothe skin -Eq-stim: every 1-2 weeks or EOD for 3 treatments : immunostimulant Common treatments for equine sarcoid -Surgical removal -Laser removal -Cryotherapy -Intratumoral Hyperthermia -Radiotherapy: ionizing radiation to kill neoplastic cells -Chemotherapy: Cisplatin injections/beads -Immunotherapy: -Topical Acyclovir - Topical Immiquimod ?Aldara? -Topical Bloodroot extract ?Xxterra?, ?Sarc-off? -Bacillus Callmette-Guerin (BCG) Injection -Autogenous Vaccines and Sarcoid Implantation -Vaccination w/chimeric virus-like particles Common treatments for equine sarcoid, highlighted those attempted in our patient -Surgical removal -Laser removal -Cryotherapy -Intratumoral Hyperthermia -Radiotherapy: ionizing radiation to kill neoplastic cells -Chemotherapy: Cisplatin injections/beads -Immunotherapy: -Topical Acyclovir - Topical Immiquimod ?Aldara? -Topical Bloodroot extract ?Xxterra?, ?Sarc-off? -Bacillus Callmette-Guerin (BCG) Injection -EquiStim -Autogenous Vaccines and Sarcoid Implantation -Vaccination w/chimeric virus-like particles Common treatments for equine sarcoid, highlighted those attempted in our patient -Surgical removal -Laser removal -Cryotherapy -Intratumoral Hyperthermia -Radiotherapy: ionizing radiation to kill neoplastic cells -Chemotherapy: Cisplatin injections/beads -Immunotherapy: -Topical Acyclovir - Topical Immiquimod ?Aldara? -Topical Bloodroot extract ?Xxterra?, ?Sarc-off? -Bacillus Callmette-Guerin (BCG) Injection -EquiStim -Autogenous Vaccines and Sarcoid Implantation -Vaccination w/chimeric virus-like particles Treatments and results date treatment type exact treatment 2003-2007 Surgical removal Cautery + SMZ?s to control infection 2007-2009 Immunotherapy EqStim June 2009 Immunotherapy Pythium January 2010 Immunotherapy BCG January - April 2010 Chemotherapy #1 cyclophosphamide and doxorubicin April 2010 Surgical removal #1 surgical debulking Treatments and results cont. date treatment type exact treatment May 2010 Chemotherapy #2 cyclophosphamide and vincristine January 2011 Surgical removal #2 + immunotherapy surgical debulking + Xterra November 2011 Surgical removal #3 surgical debulking September 2012 Surgical removal #4 surgical debulking July 2013 Surgical removal #5 + immunotherapy surgical debulking + autologous implantation February 2014 Surgical removal #6 + chemotherapy surgical debulking + intralesional cisplatin & carboplatin 2007-2009: EqStim -Mechanism of action: Injections with P. Acnes to stimulate immune system -Result: moderate control of tumors during this time period, but became ineffective and was discontinued back June 2009: Pythium immunotherapy -Mechanism of action: Vaccinate with Pythium Insidiosum to stimulate immune system -Result: worked for 3 months (June - September 2009), but became ineffective and was discontinued back lesions in June January 2010: BCG -Mechanism of action of BCG (Bacille de Calmette et Gu?rin) : human TB vaccine used to stimulate immune system - Results: ineffective, stopped after 1 month (February 2010) February January back Jan ? April 2010: First systemic chemotherapy -Mechanism of action of chemotherapy: target tumor cells systemically with cyclophosphamide and doxorubicin - Results: - Slight improvement in tumor surfaces, no reduction in size back http://www.indiamart.com/asterpharma /oncology-anti-cancer.html http://www.indiamart.com/asterpharma /oncology-anti-cancer.html April 2010: first surgical debulking -Mechanism of action: remove necrotic tissue/large tumors for comfort of the patient - Result: temporary reduction in tumor size April before surgery April during surgery April post surgery back May 2010: Systemic chemotherapy #2 - Mechanism of action: target tumor cells systemically with cyclophosphamide and vincristine - Result: tumors growing aggressively, protocol discontinued May June back http://www.indiamart.com www.hospira.com January 2011: Xxterra + surgical debulking # 2 -Mechanism of action of Xxterra: Bloodroot powder + zinc chloride to stimulate the immune system locally at the tumor site - Results of Xxterra: successful on small tumors, but painful, so discontinued January pre surgery January during surgery back September 2012: Surgical debulking # 4 - Result: temporary reduction in tumor size September pre surgery September during surgery back July 2013: Autologous implantation -Mechanism of action: Pieces of sarcoid removed, frozen, and surgically re-implanted to stimulate immune system - Result: temporary reduction in tumor size back http://liquidnitrogentank.com/CT20_Tank.php liquid nitrogen tank to freeze pieces of sarcoid before implantation February 2014: surgical debulking # 6 + first intralesional chemotherapy -Mechanism of action of intralesional chemotherapy: target tumors more locally with Cisplatin and Carboplatin - Result: temporary reduction in tumor size February pre surgery February during surgery next http://www.indiamart.coml Costs, prognosis, questions -Current CUHA bill: > $14,000.00 - Prognosis: - Poor for resolution of lesions -Questions: -Quality of life? Conclusions - Treatments did not work in our patient - Related to her immune system? - More research needed about this disease & treatments http://www.ourdailyjourney.org Lessons learned - No current therapies for sarcoids that are this severe. - Research ongoing - still looking for a breakthrough in this disease. - Extraordinary client & patient Resources 1- Larson, Erica. "Evidence-Based Equine Sarcoid Treatments Reviewed." The Horse 19 Apr. 2012: n. pag. Print. 2- Rohrbach, Barton W., VMD, MPH, DACVPM, et al. Effects of adjunctive treatment with intravenously administered Propionibacterium acnes on reproductive performance in mares with persistent endometritis. Journal of the American Veterinary Medical Association. Volume 231, Number 1, July 1 2007, pp. 107-13. 3- Mendoza, Alberto L., Robert L. Glass, and Richard D. Hansen. Pythium Immunotherapy. Board of Trustees, Michigan State University, assignee. Patent 12/647,971. 30 June 2011. Print. 4- United States. Centers for Disease Control and Prevention. Division of Tuberculosis Elimination. World Health Organization. Issues Relating to the Use of BCG in Immunization Programmes - A Discussion Document. N.p.: n.p., 1999. Print. 5 - Larson, Ken. "Xxterra." Larson Laboratories. Vetline, Inc., n.d. Web. 5 Apr. 2014. 6 - Espy, Benjamin M.K. "How to Treat Equine Sarcoids by Autologous Implantation." AAEP Proceedings 54 (2008): 68-73. Print. 7 - Taylor, S., and G. Haldorson. ?A Review of Equine Sarcoid.? Equine Veterinary Education 25.4 (2013): 210-16. Print. Acknowledgements Thank you to: Dr. Richard Hackett Dr. Hayley Lang Students & faculty of Cornell University for being so welcoming to St. George?s and Ross students. Questions? picture credit: http://balancedecosolutions.com/product/sarcoid-cleansing-salve/#tab-description Treatment depends on type and presentation, and can be difficult and require research, experimentation and dedication left: dr hackett?s ppt right: http://www.textmed.com/unknown/bovine-papillomavirus.htm#us_heatmap picture credits: http://en.wikipedia.org/wiki/File:Papillomavirus_capsid.png (black and white) http://grigoriefflab.janelia.org/papillomavirus (color picture) http://calfology.com/library/wiki/warts-and-papillomas (cow) 3D Structure of Bovine Papillomavirus (BPV) Capsid. Atomic coordinates taken from PDB id 3IJY convert to a density file using the EMANpackage and imaged using the w:UCSF Chimera molecular viewing program. picture credits left to right: https://www.aqha.com/Museum/Explore/Hall-of-Fame/Horses/Z/Zan-Parr-Bar.aspx http://www.hdpaperwall.com/arabian-horse/ http://en.wikipedia.org/wiki/Appaloosa Sites of skin infection/open wounds increase likelihood of sarcoid formation : possible fly/insect vector related transmission -Incomplete research: appears that the BPV-1 found in equine sarcoid is not the same as is found in bovine papillomatosis. weird. probably flies transmit equine:equine, not bovine: equine. Equine leukocyte antigens source: Immunogenetics. 1986;23(4):221-5. Equine leukocyte antigens: relationships with sarcoid tumors and laminitis in two pure breeds. Meredith D, Elser AH, Wolf B, Soma LR, Donawick WJ, Lazary S. Frequencies of equine leukocyte antigen distribution were determined by complement-mediated cytotoxicity testing among populations of Thoroughbred and Standardbred horses, including animals affected with equine sarcoid and laminitis. A highly significant association is described between the presence or history of sarcoid lesions in Thoroughbreds and the expression of the major histocompatibility complex (MHC)-encoded antigens, W3 and B1. No association was found between antigenic expression frequencies and laminitis in either breed. These findings suggest that a strong relationship exists between the equine MHC and a predisposition to sarcoid. picture credits: Dr. Hackett nodular: http://www.wetherbyvets.co.uk/info/Factsheets/Horse/24_269968.shtml There are 6 distinct types of sarcoid based on gross appearance and behaviour including occult, verrucous, nodular, fibroblastic, mixed and malevolent (Knottenbelt et al. 1995; Pascoe and Knottenbelt 1999). Occult sarcoids are flat and alopecic with mild scaling. Verrucous sarcoids are wart-like and have a raised, scaly, lichenified appearance with epidermal thickening. Nodular sarcoids are firm, well defined, subcutaneous lesions while fibroblastic sarcoids are fleshy and ulcerated with local infiltration. Mixed sarcoids may include any, or all, of the aforementioned types and often become progressively more aggressive as fibroblastic transformation occurs. Finally, malevolent sarcoids are the most infrequent form and are aggressive, invasive tumours that proliferate rapidly and may spread along fascial planes and vessels. picture credits: heel bulb laceration: http://www.northfloridaequine.com/heel-bulb-laceration/ equine papilloma: http://info.mannapro.com/mannaproanimalcareblog/bid/157822/Dealing-With-Seasonal-Horse-Skin-Conditions-Naturally habronemiasis ?summer sores?: http://michaelporterdvm.blogspot.com/2013/06/habronemiasis-summer-sore-in-horse.html Differential diagnoses for equine sarcoid include granulation tissue, granuloma, papilloma, fibroma/fibrosarcoma, cutaneous lymphoma, squamous cell carcinoma (SCC), habronemiasis, mast cell tumour, melanoma and staphylococcal folliculitis (Sullins et al. 1986; Foy et al. 2002). A presumptive diagnosis of equine sarcoid is often based on clinical appearance, and the presence of more than one lesion with characteristics of sarcoid is strongly suggestive. A definitive diagnosis of sarcoid requires histopathology but biopsy-induced trauma or irritation may exacerbate the lesion and induce proliferation (Knottenbelt 2003). Therefore, a biopsy is recommended only if the diagnosis is uncertain due to atypical appearance or anatomical site, and only when owners are aware that subsequent treatment will be warranted if a sarcoid is confirmed. Typical histopathological characteristics of equine sarcoid include epidermal acanthosis, hyperkeratosis and hyperplasia with long rete pegs into the dermal fibroblastic tissue which contains immature fibroblasts with mitotic figures in a whorled fibrocellular mass (Fig 2) (Sullins et al. 1986; Martens et al. 2000; Hewes and Sullins 2009). Histopathologically, equine sarcoid may be confused with fibroma or fibrosarcoma; therefore, an experienced pathologist is often required for an accurate diagnosis. picture credits: heel bulb laceration: http://www.northfloridaequine.com/heel-bulb-laceration/ equine papilloma: http://info.mannapro.com/mannaproanimalcareblog/bid/157822/Dealing-With-Seasonal-Horse-Skin-Conditions-Naturally habronemiasis ?summer sores?: http://michaelporterdvm.blogspot.com/2013/06/habronemiasis-summer-sore-in-horse.html Differential diagnoses for equine sarcoid include granulation tissue, granuloma, papilloma, fibroma/fibrosarcoma, cutaneous lymphoma, squamous cell carcinoma (SCC), habronemiasis, mast cell tumour, melanoma and staphylococcal folliculitis (Sullins et al. 1986; Foy et al. 2002). A presumptive diagnosis of equine sarcoid is often based on clinical appearance, and the presence of more than one lesion with characteristics of sarcoid is strongly suggestive. A definitive diagnosis of sarcoid requires histopathology but biopsy-induced trauma or irritation may exacerbate the lesion and induce proliferation (Knottenbelt 2003). Therefore, a biopsy is recommended only if the diagnosis is uncertain due to atypical appearance or anatomical site, and only when owners are aware that subsequent treatment will be warranted if a sarcoid is confirmed. Typical histopathological characteristics of equine sarcoid include epidermal acanthosis, hyperkeratosis and hyperplasia with long rete pegs into the dermal fibroblastic tissue which contains immature fibroblasts with mitotic figures in a whorled fibrocellular mass (Fig 2) (Sullins et al. 1986; Martens et al. 2000; Hewes and Sullins 2009). Histopathologically, equine sarcoid may be confused with fibroma or fibrosarcoma; therefore, an experienced pathologist is often required for an accurate diagnosis. Fig 2: Haematoxylin & eosin stained photomicrograph of equine sarcoid characterised by disorganised neoplastic fibroblasts in the dermis with epidermal proliferation including long rete pegs (200? magnification). Differential diagnoses for equine sarcoid include granulation tissue, granuloma, papilloma, fibroma/fibrosarcoma, cutaneous lymphoma, squamous cell carcinoma (SCC), habronemiasis, mast cell tumour, melanoma and staphylococcal folliculitis (Sullins et al. 1986; Foy et al. 2002). A presumptive diagnosis of equine sarcoid is often based on clinical appearance, and the presence of more than one lesion with characteristics of sarcoid is strongly suggestive. A definitive diagnosis of sarcoid requires histopathology but biopsy-induced trauma or irritation may exacerbate the lesion and induce proliferation (Knottenbelt 2003). Therefore, a biopsy is recommended only if the diagnosis is uncertain due to atypical appearance or anatomical site, and only when owners are aware that subsequent treatment will be warranted if a sarcoid is confirmed. Typical histopathological characteristics of equine sarcoid include epidermal acanthosis, hyperkeratosis and hyperplasia with long rete pegs into the dermal fibroblastic tissue which contains immature fibroblasts with mitotic figures in a whorled fibrocellular mass (Fig 2) (Sullins et al. 1986; Martens et al. 2000; Hewes and Sullins 2009). Histopathologically, equine sarcoid may be confused with fibroma or fibrosarcoma; therefore, an experienced pathologist is often required for an accurate diagnosis. Picture credit: http://tailsfromprovence.com/2013/05/22/sarcoids-ugh/ Sarcoids approx 2009 picture credits (L) https://www.horseloverz.com/product/other/690766-silver-lining-equi-salve.html (R) http://www.neogen.com/AnimalSafety/pdf/Catalogs/EqstimBrochure_0708.pdf source: http://en.wikipedia.org/wiki/BCG_vaccine BCG is a human vaccine against tuberculosis that is prepared from a strain of the attenuated (weakened) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its virulence in humans by being specially subcultured in a culture medium, usually Middlebrook 7H9. Cancer immunotherapy/cancer vaccine: A number of cancer vaccines use BCG as an adjuvant to provide an initial stimulation of the patients' immune systems. BCG is used in the treatment of superficial forms of bladder cancer. Since the late 1980s, evidence has become available that instillation of BCG into the bladder is an effective form of immunotherapy in this disease.[30] While the mechanism is unclear, it appears a local immune reaction is mounted against the tumor. Immunotherapy with BCG prevents recurrence in up to 67% of cases of superficial bladder cancer. Colorectal cancer[31] Lung cancer Melanoma MPNST Equine sarcoid (in horses) picture credits: http://www.indiamart.com/asterpharma/oncology-anti-cancer.html Dr. Ken Larson developed Xxterra at the Colorado State University?s College of Veterinary Medicine in 1970. Xxterra was first used on a resident horse at the Colorado State University Teaching Hospital. A large sarcoid on the front leg, below the carpus has been surgically removed several times, but returned after each removal, and had now been present for months. XXTERRA is an herbal formulation of bloodroot powder and zinc chloride solution, combined and stirred into a smooth brown paste. Bloodroot contains sanguinarine (the primary component), chelarathrine and protopine, all of which are alkaloids. Zinc chloride promotes inflammation of the sarcoids surface and with the alkaloids, alters the sarcoid cells so they become antigenic to the host. Accordingly, XXTERRA? alters the antigenicity of a sarcoid to stimulate the host's immune system and result in an immune rejection reaction of the sarcoid. picture credit: http://www.ourdailyjourney.org/2011/01/20/the-easy-button/ - What defines success in this case? picture credit: http://ohhivetschool.blogspot.com/2010/07/origins-of-veterinary-medicine.html - why was this mare unresponsive to all attempts at treatment? - immune problem, not treatment problem - breed/genetic predisposition - how ethical is continued palliation of such a severe condition? - daily quality of life - how painful are equine sarcoids? - pain/suffering caused by repeated anesthesia/surgery/chemo - stress of repeated hospitalizations - what is our role as veterinarians in guiding clients who wish to pursue extreme efforts in prolonging life? - We do not have current therapies that are effective for equine sarcoids that are this severe. However, research in the field is ongoing, as there are many aspects of this disease and its treatment we do not yet understand. - Clients may be willing to try experimental treatments - time to do some research!! Maybe you will be the next person to make a breakthrough in this disease. - Sometimes the whole story can change your mind - do not make assumptions/judgements before you have all the information and have seen the patient and talked to the owner about his/her motivations face to face. You may be surprised -- I was. picture credits: https://www.google.com/search?q=fail&rlz=1C5CHFA_enUS519US526&espv=210&es_sm=91&source=lnms&tbm=isch&sa=X&ei=EFQ8U43fL8insQTFhYDACQ&ved=0CAgQ_AUoAQ&biw=1264&bih=636#q=cornell%20university%20veterinary%20school&tbm=isch&facrc=_&imgdii=_&imgrc=0hoENECvatL9UM%253A%3BfGfpTJIFar1skM%3Bhttp%253A%252F%252Fwww.sgu.edu%252Fimages%252Fcornellvet.jpg%3Bhttp%253A%252F%252Fwww.sgu.edu%252Fnews-events%252Fnews-archives08-SGUSVM-Cornell.html%3B435%3B95