This report highlights an important differential diagnosis for a predominantly cystic mass within the abdominal cavity of dogs. Differential diagnoses for dogs with intra-abdominal cystic lesions include cystic lymph nodes, congenital duplication cysts, pancreatic pseudocyst, paraprostatic cysts, cystic lesions of the female reproductive tract, parasitic disease, and cystic neoplastic disease. These conditions are generally localized, whereas this case was expansile without clear lesion localisation prior to exploratory celiotomy.
It is speculated that GISTs arise from the interstitial cells of Cajal, which are pivotal to coordination and propagation of intestinal slow waves and allow transduction of neural inputs from the enteric nervous system [6]. These are generally solid neoplasms of spindle cells arising from the gastrointestinal tract of dogs which can be differentiated immunohistochemically from other intestinal mesenchymal neoplasms by positive expression of the type III tyrosine-protein kinase c-Kit (CD117) and discovered-on-GIST-1 (DOG-1) [2, 3, 7].
In humans, it has been speculated that cystic lesions of GISTs may occur due to (a) rapidly expansile growth pattern in which cystic structures occupy the predominant tumor volume, (b) rapid growth or tissue hypoxia with subsequent necrosis (cystic degeneration), (c) cystic metastatic lesions to other organs or omentum, or (d) gross disease treated with appropriate effective therapy in which subsequent cystic lesions develop due to tumor regression [8]. The mechanisms underlying the cystic growth pattern of this neoplasm were not evident on histologic examination. The initial protracted clinical course was suggestive of slow tumor growth; however, cystic degeneration associated with poor vascularization and tissue hypoxia could not be excluded. Interestingly, on computed tomography at time of recheck examination, suspected metastatic lesions also had a cystic structure, implicating a cystic growth pattern in the pathobiology of this mass.
Applying the modified National Institutes of Health (NIH) consensus criteria for defining postsurgical risk of recurrence in humans with GIST, this patient was classified as “high-risk” due to large tumor diameter and mitotic count (> 10/50hpf), and adjuvant tyrosine kinase inhibitor therapy was recommended [9]. Mitotic count has been identified as a prognostic indicator for canine GIST; however, based on the NIH consensus criteria most canine GIST would be classified as “high risk” due to mitotic count alone, and further work to establish risk categories specific for canine patients is recommended [1, 10].
Although imatinib therapy remains the mainstay of treatment of high-risk GISTs in people and has been reported with success in individual dogs, hepatotoxicity is reported in dogs even at low doses which precludes its routine administration [11,12,13]. Sunitinib is another multi-targeted receptor tyrosine kinase inhibitor that has shown benefit in people who progress despite imatinib therapy [14]. Imatinib, sunitinib and toceranib share affinity for the tyrosine-protein kinase (KIT) receptor, which is the pivotal molecular target of therapy in GIST. As such, toceranib is considered a viable alternative in dogs with similar molecular targets to imatinib and has shown promise in the treatment of GIST in dogs [10, 15].
Despite the NIH “high-risk” designation in 85% of human patients with cystic GIST in one report, the 5-year recurrence rate was only 6.6% [5]. In that same study, a control group of patients with solid GISTs showed a 5-year recurrence rate of 33.9%, significantly higher than those with cystic GISTs [5]. The authors concluded that cystic GISTs may display a relatively indolent behavior and have a favorable prognosis in humans [5]. It is unclear if this advantage is also seen in canine patients.
Gain of function mutations in c-kit exon 11 have recently been identified in up to 35% canine GISTs by PCR, and 74% by RT-PCR [16, 17]. The juxtamembrane domain of exon 11 is highly conserved between humans and dogs, being 100% homologous between species [3]. In humans, mutations in c-kit are reported in 80 – 85% of GISTs, though a recent publication of cystic GISTs identified c-kit mutation in only 45% of patients [4, 5]. It is possible that c-kit mutations are less common in human cystic GISTs, though larger studies are required to confirm this finding.
Human patients with mutations of c-kit exon 11 appear to have improved response to imatinib therapy, with poorer responses reported for mutations of c-kit exon 9 or 17 [18]. However, up to 45% of human wild-type GISTs may respond to imatinib therapy, hence even without identified c-kit mutation tyrosine kinase inhibitor therapy may be of benefit [19]. It remains unclear whether genotype analysis and assessment of c-kit mutation holds prognostic significance in canine GIST. This patient did not have genotyping performed, as it would not have changed the treatment recommendation or prognostic information based on current veterinary literature.
In conclusion, GIST should be considered as a differential diagnosis in canine patients identified with predominantly cystic lesions within abdominal cavity. The prognosis for these lesions may be improved in comparison to solid GIST lesions based on human literature, though the significance in canine patients remains unclear.
