Feline Gastroenterology

CHAPTER

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Feline gastrointestinal eosinophilic sclerosing fibroplasia Michael Linton, Christine Griebsch

Feline gastrointestinal eosinophilic sclerosing fibroplasia (FGESF) refers to a clinical and pathological entity associated with eosinophilic mass(es) primarily confined to the gastrointestinal (GI) tract.[1,2] However, more recent case reports question the validity of the originally coined title given that lesions have been identified in extra-GI locations and possibly in other species.[3–6] A large distribution of cases have been reported, with case reports/series originating in Oceania (Australia, New Zealand), North America (United States of America), Europe (Slovenia, Czech Republic, Spain, Finland, United Kingdom), and parts of Asia (Japan, South Korea).[1,2,4,6–11] Furthermore, there are unpublished case reports from Austria, Canada, and Sweden.

Based on reports the prognosis is guarded. However, this may be due to mismanagement because of an initial incorrect diagnosis and minimal available information in the literature on how to appropriately treat the condition.

On gross examination and prior to pathologists being made more aware of the entity, lesions were commonly confused as neoplasia or granuloma with misdiagnosis reported.[1,2] In a case series of 25 cats, 24% of cases were euthanised due to the gross appearance of the lesion at laparotomy.[1] In 2009, one study coined the name and hypothesised that some cats have an uncharacterised genetic predisposition to develop eosinophilic inflammation in response to antigens, possibly from bacteria or parasites breaching the intestinal mucosa.[1] In the same year, cases were reported in Australia.[12] Bacteria have been identified in lesions using a range of diagnostic tools in some but not all cats.[1,2] Similar lesions found in the sub-

cutis and abdomen of cats in Japan were proposed to be caused by methicillin-resistant Staphylococcus spp.[9] Other infectious agents have been associated with the condition, including zygomycetes in a domestic cat and nematodes in pumas (Felis concolor).[5,13] Despite a number of interesting case reports and case series appearing in the literature, the aetiology of the disease is still unclear. Additionally, important questions remain unanswered, the most notable of which include: • Is FGESF really a relatively new disease, or has it been around for longer than currently reported due to a history of misdiagnosis?

• If it is a new disease, then what has changed that led to its emergence?

Answers to these questions may provide the key to determining the aetiology of the disease which may aid diagnosis, therapy, and potentially prevention.

EPIDEMIOLOGY AND AETIOLOGY The condition appears to primarily affect the domestic cat, although case reports suggest that it may not be limited to this species alone, with similar cases seen in pumas and a rat.[5,14] However, closer evaluation of histopathology from these species suggests variation and that lesions are not identical to those observed in domestic cats. Specifically, in the puma, the name “sclerosing fibroplasia” was proposed because of the relatively few eosinophils observed infiltrating the lesions, compared to cats. Additionally, all cases reported in pumas have had

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Feline gastrointestinal eosinophilic sclerosing fibroplasia associated nematodes.[5] In the single case report of a rat, there were also relatively few eosinophils infiltrating the lesion and there was no formation of the trabecular sclerosing collagen fibroplasia as seen in cats, therefore the lesion was diagnosed as “fibroplasia”.[14] In a study by one of the authors, most cats were mature adults (median age 7 years), although cats of almost any age were affected (2–11 years).[2] In the literature, the youngest case reported is a 14-week-old neutered male Exotic Shorthair cross Persian that had a primary GI mass involving the duodenum.[1] A number of breeds have been reported, with domestic shorthair cats being the most prevalent. However, in the author’s study, Ragdolls constituted 7/13 cases, and hence were considered predisposed, with males being more commonly reported than females.[2] It has been hypothesised that affected cats suffer from immunological dysregulation triggered by one or more factors.[1,2] The factors which might be involved can only be speculated, but suggestions include dietary causes (food allergy or intolerance), dysbiosis of the gut microbiota, excessive ingestion of foreign material (e.g. hair), or the effect of other endo- or ectoparasites. In one domestic cat, FGESF was associated with fungi, showing numerous pleomorphic, nonparallel-walled, sparsely septate hyphae, characteristic of phycomycetes present within the collagen matrix.[8] In one cat, lymphoma developed at a site of FGESF.[15] It is unknown whether FGESF predisposed to the emergence of alimentary lymphoma in this cat or if they were unrelated.

The search to find a plausible causative microbial pathogen as an underlying cause of FGESF has been the focus of several studies.

Intralesional bacteria have been identified in a relatively high percentage of cases, with two case series reporting an incidence of 56% and 69%, respectively.[1,2] In one study, gram-positive cocci were identified in 23 of 27 cases.[9] It is noteworthy that many cases are not associated with infectious causes. This may reflect diagnostic limitations (not all tests were performed) or that infections are not solely involved in the pathogenesis of this syndrome. The location of most lesions to areas in close proximity to or in actual communication with areas containing normal bacterial flora makes conclusions regarding disease association complicated. Microscopi-

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cally inflammation is focused around bacteria, suggesting that in some patients these bacteria may play a role in initiating or perpetuating the disease process.[1] Alternatively, secondary infection with bacteria, protozoa, fungi, or other infectious agents may be facilitated by a breach in the mucosal integrity of the GI wall due to abnormal architecture from the FGESF lesion. These secondary infections presumably perpetuate the process, causing a vicious cycle of eosinophilic inflammation, fibroplasia, and eventually fibrosis.

In cats, eosinophilic inflammation is a defining feature of the condition. Eosinophils produce numerous mediators that can lead to tissue destruction (e.g. major basic protein [MBP], transforming growth factor beta [TGF-β], and interleukin [IL]-1β), while elaboration of IL-6 and MBP can result in fibroplasia and fibrosis. This leads to a self-perpetuating process presumably giving rise to various abdominal masses. These masses then cause structural alteration to the stomach, intestines, mesenteric lymph nodes, enteric nervous system, and lymphatic drainage, leading to vomiting, diarrhoea, and a poor appetite.[16] As mentioned, a notable difference between the intestinal nodules of the puma and domestic cat were the number of eosinophils within the lesions, suggesting that large numbers of eosinophils are not required for the development of this unique sclerotic response or that the current number of eosinophils is not representative of more acutely inflamed lesions.[5] Interestingly, feline herpesvirus 1 is linked with an eosinophilic response in cats, especially eosinophilic dermatitis, conjunctivitis, and keratosis.[17,18] However, in one study, immunohistochemistry for feline herpesvirus 1 of FGESF lesions was negative in all cats tested (n = 12).[2] Hyperglobulinaemia and a low albumin:globulin ratio are a common finding in cats with FGESF. A major differential diagnosis is feline infectious peritonitis (FIP).

Additionally, pyogranulomatous lesions and mesenteric lymphadenomegaly are seen in both conditions. Immunohistochemistry is needed to differentiate between the two and was negative for coronavirus in all cats tested (n = 12) excluding FIP.[2] As noted, Ragdolls seem to be overrepresented worldwide, with Ragdoll cases reported in the United States of America, the United Kingdom, Sweden, Japan, and Australia (published and unpublished).[2,12] This may be 255

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due to genetic predisposition to mount an unregulated immune response or may be due to their own unique behaviours (e.g. overgrooming predisposing to trichobezoar and GI trauma).

Subsequently, multifactorial events might play a role in the pathogenesis of FGESF. This might include genetic predisposition (e.g. immune dysregulation), ingestion of foreign material (e.g. plant matter, hair), penetration of foreign material into the GI mucosa especially at sites of increased peristaltic pressure such as the pylorus and ileocaecocolic junction, and subsequent secondary pathogen invasion perpetuating the process. Indeed, the pylorus and ileocaecocolic junction are the most common locations for FGESF.

HISTORY AND PHYSICAL EXAMINATION Given that the majority of reported lesions are localised to the GI tract, it seems logical that the most common clinical signs reported are consistent with disease of these organs. However, because of occasional involvement in other organs or body cavities, the main presenting complaint can appear more obscure or misleading.

Lastly, some cases reported have no prior clinical signs, and lesions were identified incidentally during physical examination being performed for another reason (e.g. vaccination).[2] The most consistent historical features include chronic vomiting and/or diarrhoea. In one study, vomiting was the most common presenting sign (21/25, 84%).[1] There was wide variation in duration of signs, from days to years.

Weight loss was the second most common presenting sign (15/22, 68%).[1] When chronic, these signs were typically ascribed to dietary hypersensitivity, food intolerance, or inflammatory bowel disease (IBD).[2] However, when histopathology was evaluated in the normal GI tract adjacent to a lesion, there was no evidence of eosinophilic enteritis or IBD.[2] In these cases, it would be informative to examine other portions of the GI tract to confirm or refute the presence of more widespread alimentary disease. Vomiting can occur relatively acutely (perhaps owing to complete or partial obstruction from the lesion).

Less common historical information includes excessive grooming (5/10, 50% in one study), anorexia (6/13,

46% in one study), coughing due to pleural effusion (seen in one case), and constipation due to mechanical obstruction of the colon by extra-GI lesions (seen in one case).[2,15,19] One cat had an unusual presentation with incontinence, pollakiuria, vomiting, and weight loss. In this case, an abdominal mass was identified and localised to the jejunum. Fine needle aspiration of the bladder wall identified numerous eosinophils on cytology.[6] In addition, mycoplasma was cultured from the urine. The authors of that study speculated that the mycoplasma may be the cause of the cat’s cystitis given that clinical signs of cystitis improved using fluroquinolones. The relationship between FGESF and mycoplasma cystitis in this case is uncertain because the mycoplasma was not identified at the intestinal sites.

If there is suspicion of FGESF (often after additional tests), then specific questions should be asked (if not already done). These include: • GI anthelmintic history • dietary history (e.g. access to bones) that may indicate if there has been a risk of intestinal trauma • history of overgrooming or foreign body ingestion • history of vomiting, diarrhoea, or comorbidities • travel history (i.e. assess exposure to parasites) • history of foreign body obstruction.

Physical examination findings will vary with lesion location. However, in two larger series, a palpable abdominal mass was identified in 100% and 85% of cats included in the study, respectively.[1,2] The mass has been further described as a firm, irregular, fixed abdominal mass, in some cases initially being mistaken for impacted faeces. Critically, when the mass lesions are subjected to palpation, aspiration, biopsy, or excision, they have a gritty hard feel likely due to abundant trabecula of mature organised collagen. Although not pathognomonic, this is a useful point of differentiation from other common intra-abdominal masses such as large-cell lymphoma, mast cell tumour (MCT) and nonscirrhous adenocarcinoma.

Abdominal discomfort may be appreciated. Ascites was seen in one case, and dyspnoea secondary to a pleural effusion was seen in another.[2,4]

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Feline gastrointestinal eosinophilic sclerosing fibroplasia Lesions are located at a number of sites both in the GI tract and at extra-GI tract locations (Table 19.1).

Table 19.1. Lesions in the gastrointestinal tract and at extragastrointestinal tract locations.

Lesion location

Number of cases

Studies

Ileocaecocolic and colic region

10/25 8/13

Craig et al.[1] Linton et al.[2]

Pylorus

12/25

Craig et al.[1]

Subcutaneous tissue or lymph nodes

9/27

Ozaki et al.[9]

Stomach (greater curvature)

1/13

Linton et al.[2]

Jejunum

3

Craig et al.[1] Brloznik et al.[6] Weissman et al.[15]

Mesentery

1

Kambe et al.[4]

Retroperitoneal space

1

Thieme et al.[19]

Pancreas

1

Craig et al.[1]

Liver

2

Weissman et al.[15]

Common bile duct with local spread to the proximal duodenum

2

Craig et al.[1] Weissman et al.[15]

DIAGNOSTIC INVESTIGATION As noted before, history and physical examination findings may be relatively nonspecific. Therefore, diagnostic investigation for the “unwell cat”, “vomiting cat”, or “cat with a palpable abdominal mass” is often initially undertaken. Differential diagnoses for these signs are discussed in Chapters 1 and 2, and diagnostic workup can include a variety of laboratory tests (see Chapter 3) and diagnostic imaging procedures (see Chapter 5).

When there is a suspicion of FGESF, evaluation should involve the following: • specific historical questions should be asked/physical examination (see above) • serum haematology and biochemistry • diagnostic imaging followed by cytology • histopathology with special stains or immunohistochemistry as necessary • microbial testing including special stains or fluorescence in situ hybridisation (FISH) as necessary and available.

Figure 19.5 provides a diagnostic algorithym for FGESF.

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Haematology

On haematology, the most pertinent finding is an absolute eosinophilia seen in approximately 50% of cases. Differential diagnoses for eosinophilia include hypersensitivity reactions, infectious disease (most commonly parasitic, less commonly fungal, viral, bacterial, algal), neoplasia (i.e. MCT, lymphoma), and hypereosinophilic syndrome.

In any cat with eosinophilia and an abdominal mass, FGESF should be considered.[20] A nonspecific mild non- or preregenerative anaemia has been identified in some cases.[2]

Serum biochemistry

Hyperglobulinaemia is identified in approximately 50% of cases and is thought to be due to an inflammatory response. Serum protein electrophoresis (reported in two cases) revealed polyclonal gammopathy in both.[2,19] Two cases had reported biliary obstruction due to infiltration from FGESF lesions of the common bile ducts, with hyperbilirubinaemia and elevated serum liver enzyme activities suggestive of hepatocellular damage in one case.[1,15] In cats that were successfully treated, both eosinophilia and hyperglobulinaemia resolved.[2]

Diagnostic imaging

Diagnostic imaging is useful to determine the location of the lesion, which has implications for management and the exclusion of other intra-abdominal pathologies.

A number of imaging modalities is suitable, such as abdominal ultrasound, radiography, or a computed tomography (CT) scan. However, weighing up the benefit of cost, practicality, and availability, abdominal ultrasound would seem to be an appropriate first choice.

Ultrasonographic changes are nonspecific. Findings usually include a solitary mass with occasional (albeit rarer) involvement of other organs. For example, one case had a jejunal mass with hepatomegaly and liver nodules eventually characterised as FGESF lesions through histopathology.[15] Ultrasound can show mural thickening and loss of layering in the stomach, duodenum, jejunum, or colon (Fig. 19.1). In one case report, lesions were confined to the mesentery.[4] Regional lymph node enlargement is a common finding (7/25) (Fig. 19.2).[1] Histopathology from lymph nodes either suggests reactive changes or changes specific to FGESF. 257

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Figure 19.1. Ultrasound image from the pyloric lesion (between callipers). Note the loss of layering with the mixture of hypoechoic and hyperechoic regions within the tissue. It is thought that the hyperechoic regions correspond with the fibrotic zones described histologically.

Figure 19.2. Note the marked enlargement of the lymph nodes (arrow) at the root of the mesentery. This is a common feature of feline gastrointestinal eosinophilic sclerosing fibroplasia and other disease entities such as lymphoblastic B-cell lymphoma. Image courtesy of Agnieszka Zoltowska, School of Veterinary Medicine and Science, University of Nottingham, UK (photograph taken whilst working at Your Vets, Coventry, UK).

CT scan may be useful for surgical planning and determining the origin of a lesion. One case report described CT scan findings for lesions localised in the mesentery.[4] Specifically, the FGESF was identified as a multilobulated, heterogeneous soft tissue mass. Multiple lobules of the mass were peripherally contrast enhancing with nonenhancing areas centrally. A few small mineralattenuating foci were present within the centre of the mass. There was lymphadenomegaly with no contrast enhancement.

Histopathology (including special stains/immunohistochemistry as detailed below) sections should be examined closely to exclude poorly differentiated cell neoplasia and atypical lymphoma and to search for foreign material (to exclude trichobezoars).

Histopathology has been well described.[1] In domestic cats, lesions were characterised by eosinophilic inflammation, large reactive fibroblasts, and trabeculae of dense collagen. Specifically, all lesions consisted of branching and anastomosing trabeculae of dense collagen separated by a densely cellular population of

Cytology and histopathology

Cytology alone is generally nonspecific and cannot be used to a make a definitive diagnosis of FGESF. In some cases, it can be helpful to exclude differential diagnoses such as MCT and lymphoma.[10] Histopathology is needed to confirm a diagnosis of FGESF. Given the extent of the disease process and heterogeneous nature of the condition, definitive staging and therapy require laparotomy with resection or biopsy of masses in most cases (Fig. 19.3). Other options include Tru-Cut biopsy or laparoscopy but carry their own inherent risks of complications.

When submitting a sample for histopathology it is critical to provide the pathologist with a succinct history, clinicopathologic findings, and the differential diagnoses considered to allow for adequate and thorough investigation.

Figure 19.3. Image of a resected lymph node next to the splenic hilus. Histopathology was consistent with feline gastrointestinal eosinophilic sclerosing fibroplasia of the lymph node. Image courtesy of Ivo Stehlík, Pet Care Clinic, Prague, Czech Republic.

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Feline gastrointestinal eosinophilic sclerosing fibroplasia large spindle-shaped cells (Fig. 19.4). The trabecular collagen merged gradually into more typical granulation tissue at the periphery of the lesions. All lesions contained variably dense infiltrates of eosinophils, mast cells, and fewer neutrophils, lymphocytes, and plasma cells within the fibroplasia as well as within the surrounding tissues.

Lesions were either transmural or affected the inner layers of the GI wall. Inflammation in the GI tissue is mixed but is predominantly eosinophilic. The presence of other inflammatory cells may be affected by other factors such as the presence or absence of bacteria. As noted, in more than 50% of cases bacterial colonies were present within microabscesses and necrotic foci within the lesion.

In one study the bacteria included gram-negative rods, gram-positive rods, and gram-positive cocci.[1] In cats with intralesional bacteria, the dense collagen trabeculae formed irregular radiating and concentric bands around central microabscesses containing the bacteria.[1] The authors suggest that, at a minimum, biopsies are collected from the GI tract (both at the site of a lesion and away from the lesion, even if the GI tract looks morphologically normal), any enlarged lymph nodes, liver, and from any other organ or area with gross evidence of disease.

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Special histology stains and immunohistochemistry to differentiate from neoplasia

Based on histopathology, FGESF has been misdiagnosed as MCT, osteosarcoma, fibrosarcoma, and haematopoietic neoplasia.[1,2] This is not surprising given the similarity between some of these conditions.

Intestinal mast cell disease commonly involves the small intestines and is grossly characterised by marked transmural expansion by a firm, homogeneous tan mass with mucosal ulceration.[21] Like FGESF, mast cell disease has occasionally been associated with peripheral eosinophilia.[22] Histopathology of FGESF cases will often identify mast cells. Histopathology of MCTs can be relatively straightforward. However, in some cases, mast cells may be sparse with variable granule uptake, and differentiation between inflammation and neoplasia might be challenging.[21] In one case series, the diagnosis of FGESF or sclerosing MCTs was vigorously debated.[21,23–24] Clues may lie in the lesion location (the majority of FGESF are seen in the pylorus and ileocaecocolic junction), the presence of intralesional bacterial organisms, and lastly the response to therapy.[1,2,23–24]

50 µm Figure 19.4. Histological image from a lymph node. The characteristic network of coarse collagen trabeculae (stained pink) throughout the lesion is an important distinguishing feature of feline gastrointestinal eosinophilic sclerosing fibroplasia. This abundance of collagen causes the hard, gritty texture of these lesions, which is most obvious during biopsy procedures (or during dissection at necropsy).

Haematoxylin–eosin, ×40. Image courtesy of Dr Ladislav Novotný, Finn Pathologists, Harleston, UK. 259

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Similar to mast cell neoplasia, lymphoma may also present as either nodular or diffuse disease, with transmural thickening associated with altered to absent GI wall layering. The most common solitary site is the ileocaecocolic junction. Special stains (CD3, CD79) can be utilised to determine the cell of origin and may help distinguish between FGESF and lymphoma if there is doubt based on histopathology.

In one case, macroscopic findings and ultrasound had characteristics of FGESF, lymphoma, and MCTs.[25] Immunohistochemistry was required to distinguish between these conditions. Antibodies used were CD3, CD79a, and CD117. These stains allowed a final diagnosis of T-cell lymphoma with reactive fibroplasia, effectively excluding FGESF. In this case, Giemsa staining and CD117 were negative and needed to exclude an interstitial MCT. The intense labelling with CD3 (associated with T-cell receptor) and the absence of positivity for CD79 (associated with B-cell antigen receptor) subsequently allowed the pathologist to make a diagnosis of T-cell lymphoma with extensive reactive fibroplasia.[25] In FGESF lesions, it would be expected that Giemsa and CD117 would be negative (excluding MCTs), as would strong staining with CD3 and CD79a (excluding lymphoma). Trichrome staining could be used and would be expected to stain positive, highlighting collagen in tissue sections.

Microbial testing including stains for pathogens

Multiple studies have identified bacteria in GI FGESF lesions. In one study, bacteria, including gram-negative rods, gram-positive cocci, and gram-positive rods, were found in the majority of cases.[1] In another study, similar eosinophilic sclerosing lesions were described in the subcutis and abdomen, with gram-positive cocci accompanying most lesions.[9] Additionally, bacteria were identified in a retroperitoneal FGESF mass in one case.[19] Given the relatively common presence of pathogens identified intramurally, an investigative approach is recommended both for diagnostic and therapeutic purposes.

Tests include: • special stains for intralesional bacteria or other pathogens • culture and sensitivity of FGESF tissue • FISH. Special stains to consider (but not limited to) include Giemsa (bacteria and protozoa), Gram stain (bacteria), methenamine silver (fungi), period acid–Schiff (fungi), and Ziehl–Neelsen stain (mycobacteria and nocardia).

On their own, each modality has limitations in detecting potential pathogens. For example, in one study, two cases negative for bacteria using FISH could be identified using histology and special stains.[2] This observation is supported by a human review where eubacterial FISH only identified 56% of bacteria on average (range 1%–100%).[26] Subsequently, a eubacterial probe is recommended initially to determine if bacteria are present within the walls of the biopsy specimen.[2] If there is fluorescence of bacteria, new slides can be prepared with specific probes to classify the species of bacteria, such as those specific for Clostridium, Staphylococcus, Actinomyces, Escherichia coli, and Enterococcus.[2] Despite a number of different bacteria have been cultured/identified and the current limited availability of specific probes, it may not always be possible to speciate the bacteria in every case with the current resources available.

Overall, to maximise diagnostic sensitivity, a combination of histopathology, special stains, immunohistochemistry, culture and sensitivity, and FISH is recommended.

However, it is noteworthy that up to 44% of cases are not associated with infection.[2] This might reflect diagnostic limitations (not all tests were performed) or that infections are not solely involved in the multifactorial pathogenesis of this syndrome.

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Feline gastrointestinal eosinophilic sclerosing fibroplasia

History • Vomiting (≈84% of cases) • Weight loss (≈68% of cases)

Physical examination • Palpable abdominal mass (>85% of cases) • Mass often has a gritty feel

Serum biochemistry/ haematology • Hypereosinophilia (≈50% of cases) • Hyperglobulinaemia (≈50% of cases) • Comorbidities

Cytology Exclude lymphoma/MCT

Other

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Other diagnosis See appropriate chapter

Suspicion of FGESF Imaging Abdominal ultrasound + thoracic radiography • Single or multiple masses. GI tract: mural thickening and loss of layering in the stomach, duodenum, jejunum, or colon • Location: typically seen in the pylorus or ileocaecocolic junction

FGESF

Infectious causes • C&S • Special stains • Gram stain • Giemsa (bacteria, protozoa) • Methenamine silver (fungi) • Period acid–Schiff (fungi) • Ziehl–Neelsen (mycobacteria, nocardia) • Fluorescence in situ hybridisation

FGESF

Biopsy collection • Generally through exploratory laparotomy • Complete resection if possible (see Fig. 19.6) • Biopsy: abnormal lesions • Lymph nodes, liver, and morphologically normal regions of GI tract

Histopathology • Lesions characterised by eosinophilic inflammation, large reactive fibroblasts, trabeculae of dense collagen • Discussion with pathologist if questionable diagnosis Diagnostic query— consult pathologist Special stains • CD3, CD79a: consider lymphoma • CD117/Giemsa staining: MCT • Trichrome staining: FGESF (if other differentials not excluded e.g. extraskeletal osteosarcoma)

Other

Other diagnosis See appropriate chapter

Figure 19.5. Diagnostic algorithm for feline gastrointestinal eosinophilic sclerosing fibroplasia (FGESF) cases. C&S, culture and sensitivity; GI, gastrointestinal. MCT, mast cell tumour.

TREATMENT A number of therapeutic regimens have been trialled including surgery, various combinations of antimicrobial agents, corticosteroids, alkylating agents, GI tract protectants, analgesia, and dietary management. Notably, cases have responded very differently to both the same and different therapeutic regimens, although some trends are beginning to be appreciated.

Until more is known, a multimodal approach to therapy of FGESF would seem ideal (Fig. 19.6). That is, when possible, therapy should target the current extent of disease (surgical debulking), underlying cause, and any perpetuating factors (e.g. treating secondary infections, limiting the propensity towards immune dysregulation).

Immediate therapy

In some cases the disease process can be severe, leading to signs of full or partial intestinal obstruction which warrants immediate surgical intervention. The decision to perform surgery is also guided by the location of the lesion and the experience of the surgeon. Specifically, lesion location will influence whether surgical excision or debulking is possible. Masses in the pyloric region might not be amenable to surgical resection due to involvement of surrounding structures. For example, two cats showed apparent expansion of disease from the proximal duodenum to the bile duct.[1,15] Should surgical resection not be possible, treatment trials with antibiotics and immunosuppressive therapy can be considered in an attempt to decrease the size of the mass. Surgery might be considered at a later stage if still warranted.

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Diseases of the gastrointestinal tract Intestinal inflammation

Intestinal obstruction

Yes

No Resectable

Exploratory laparotomy • Mass resection • See “Biopsy collection” in Figure 19.5

Underlying cause resolved (e.g. foreign body) No signs

Monitoring

Ongoing signs, lesion unable to be removed, lesion recurrence Antibiotics • Ideally based on C&S results • Amoxiclav + metronidazole • Marbofloxacin + metronidazole • 4 weeks

Lesion location Pylorus Nonresectable location

Medical management

Underlying disease • Deworming • Diet • Parasitic disease • Hairball control • Foreign body • Fungal disease

Monitoring • Clinical signs • Vomiting • Palpable mass • Weight loss • Other • Biochemistry • Hyperglobulinaemia • Haematology • Hypereosinophilia • Imaging • Recurrence of lesions

Immunomodulatory

Prednisolone contraindicated (e.g. diabetes)

• • •

Chlorambucil Cyclosporin Lomustine

Prednisolone • Starting dose 1–1.5 mg/kg every 12 h • Aim to taper therapy over months

Figure 19.6. Treatment algorithm for feline gastrointestinal eosinophilic sclerosing fibroplasia cases. C&S, culture and sensitivity.

Long-term therapy

Glucocorticoids are currently the mainstay of treatment.

These drugs can interfere with active cytokines, reducing survival times of eosinophils as well as dampening the release of eosinophilic granules. This aims to blunt the hyperactive immune response and therefore can reduce fibrosis. The use of cyclosporin, chlorambucil, hydroxyurea, or lomustine can be considered concurrently or alternatively to target the underlying immune dysregulation and in circumstances where prednisolone use is contraindicated. The duration of such therapy is unknown and appears to vary on a case by case basis; in some cats therapy can be discontinued after months, and others require indefinite therapy.

Parental antibiotics are recommended because of the high percentage of associated infection. One study recommended a combination of amoxicillin–clavulanate plus metronidazole or marbofloxacin plus metronidazole; however, these findings were not based on culture and sensitivity results.[2]

In one study, identified bacteria were gram-positive cocci in 23/27 cases.[9] Gram-positive cocci were identified as Staphylococcus, based on their morphological features and immunoreactivity.[9] In 15/17 lesions, the colonies expressed immunoreactivity to penicillin-binding protein 2, which is a drug-resistance gene product of methicillin-resistant Staphylococcus species, making susceptibility patterns ideal for appropriate antibiotic choice. However, given that in most cases lesions are associated with the GI tract, this may not be possible due to contamination.

Lastly, it would be logical to treat any apparent comorbidity that may be related to the underlying cause (e.g. fungal disease).

In summary, medical management is the mainstay of treatment in most cases, with the occasional exception.

Surgery should be considered for all resectable masses.

Nonresectable lesions may rely on medical treatment alone. Medical management involves a combination of prednisolone (starting dose 1 mg/kg PO every 12 hours)

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Feline gastrointestinal eosinophilic sclerosing fibroplasia and antibiotics (empirical or based on culture and sensitivity results). Prednisolone can be tapered over months depending on response to therapy and monitoring. If prednisolone is contraindicated (e.g. diabetic patient), other agents can be considered possibly allowing for the exclusion of prednisolone in the treatment plan or allowing the dose to be minimised. Antibiotics are administered for at least 4 weeks. Any underlying disease should be treated.

OUTCOME AND PROGNOSIS In a study of 25 cats, survival curves comparing treatment with surgical biopsy and prednisone (with or without antibiotics) (7/25 cats), treatment with surgical biopsy and antibiotics (8/25 cats), and treatment with only surgical biopsy (3/25 cats) were shown.[1] The longest survival times in this study were seen with cases treated with prednisone.[1] In another study, a trend towards improved survival times when prednisolone was included in the treatment regimen and when surgery was not the sole mode of therapy was seen.[2] However, the authors of this study note that this statement may be flawed because not all surgical cases survived sufficiently long enough (perhaps because of poor surgical case selection or surgeon experience) to receive systemic medications, which may have biased the outcomes.[2] One case report described multiple firm masses in the sublumbar retroperitoneal space causing ventral displacement and compression of the descending colon, with extension of the masses into the pelvic canal. In this case, lesions were not amenable to surgery, and the cat was treated with a combination of prednisolone and antibiotics. Repeat evaluation and imaging at day 732 (postoperatively) revealed marked reduction in size of the abdominal mass, resolution of peripheral eosinophilia, and no clinical signs with continued prednisolone therapy (0.5 mg/kg PO every 24 hours).[19] However, inconsistent response to prednisolone is seen.

In one case report of treatment with prednisolone alone for a mass located at the proximal pylorus, the cat had a relatively poor outcome, with death reported at 56 days.[11] Trends with other immunomodulatory drugs cannot be appreciated given the relative sparsity of reported use.

One case report of a lesion confined to the mesentery which was not surgically resectable was treated with a

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short course of prednisolone (22 days), antibiotics, and a prolonged course of cyclosporin (236 days). In this case, this regime resulted in a prolonged remission time.[4] Administration of prednisolone and other immunosuppressive drugs requires monitoring for opportunistic infections. One cat treated with prednisolone and chlorambucil developed systemic toxoplasmosis.[2] In contrast, in some cats immunomodulatory drugs were not used. In one case series, one animal had surgical resection (colonic mass) followed by a single dose of lomustine (due to an initial incorrect diagnosis of a MCT) followed by no further therapy. At the time of publication (43 months), the cat was still alive with no further clinical signs and no evidence of lesion recurrence.[15] In the same case series, another cat was reported alive 24 months after jejunal mass resection.[15] However, surgical therapy alone appeared insufficient in one cat, with a new mass reported 1 year after initial resection.[6] Additionally, another animal was subject to multiple surgeries and antibiotics over a 10-year period and only appeared to be in remission through a combination of immunosupressive medication (prednisolone) and antibiotics (amoxicillin and clavulanic acid).[2] Prognosis is hard to quantify due to marked inconsistencies in outcomes reported. Additionally, data may be severely skewed due to factors unrelated to the pathology itself. For instance, in one study, one case died postoperatively due to an unrelated comorbidity (cardiomyopathy), one case developed postoperative sepsis and was euthanised, one case treated in general practice was found dead 24 hours postoperatively, and one case was euthanised due to an incorrect diagnosis.[2] These are examples of why survival data should be evaluated cautiously.

Reasons for treatment failure may include failure to diagnose and treat an underlying disease, comorbidity or associated infection, inadequate medical management including tapering of immunosuppressive medication too fast, or inappropriate surgical case selection.

According to one study, lesion localisation was not associated with survival, with mean survival times not statistically different when cats with a lesion in the proximal GI tract (pylorus) were compared with those with lesions in the distal/aboral (ileocaecocolic junction or colon) portion.[1] However, the authors of this study comment that lesions in the pylorus tend to have a poorer prognosis.

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II

Diseases of the gastrointestinal tract Intestinal inflammation

This is possibly due to a decreased ability to remove the mass surgically and due to involvement of other local organs (e.g. biliary tract leading to biliary obstruction).

A prolonged survival is appreciated in cats surviving the first months after surgery. For example, survival times reported at the time of writing in one series was

1–10 years providing they survived the perioperative period.[2] Surviving cats have been managed with a number of different therapeutic regimens ranging from prolonged prednisolone use, dietary management only, to discontinuation of all therapy. Therapeutic decisions are based on ongoing monitoring.

Take-home messages •

There are no pathognomonic historical observations, physical examination findings, or routine laboratory results of feline gastrointestinal eosinophilic sclerosing fibroplasia (FGESF). However, a history of vomiting, weight loss, the finding of a firm gritty abdominal mass, and the presence of hypereosinophilia or hyperglobulinaemia are all footprints that may suggest FGESF.

•

Abdominal lesions are usually palpable. Imaging usually localises lesions to the ileocaecocolic junction or stomach, although a number of less frequent locations (gastrointestinal and nongastrointestinal) have been identified.

•

Clinicians should liaise with their pathologist to ensure that special stains are employed if there is any uncertainty with the definitive diagnosis based on histopathology alone.

•

Bacteria have been isolated from lesions in a substantial proportion of cats, but not in all cases of FGESF. Their role in this disease is still uncertain.

•

A multimodal approach to therapy would seem ideal, consisting of prednisolone, additional immunomodulatory agents, and antibiotics following surgical resection if feasible.

REFERENCES [1]

CRAIG LE et al. Feline gastrointestinal eosinophilic sclerosing fibroplasia. Vet Pathol 46:63, 2009.

[2]

LINTON M et al. Feline gastrointestinal eosinophilic sclerosing fibroplasia: 13 cases and review of an emerging clinical entity. J Feline Med Surg 17:392, 2015.

[3]

SUZUKI M, ONCHI M, OZAKI M. A case of feline gastrointestinal eosinophilic sclerosing fibroplasia. J Toxicol Pathol 26:51, 2013.

[8]

GRAU-ROMA L et al. A case of feline gastrointestinal eosinophilic sclerosing fibroplasia associated with phycomycetes. J Comp Pathol 151:318, 2014.

[9]

OZAKI K et al. Abscess-forming inflammatory granulation tissue with Gram-positive cocci and prominent eosinophil infiltration in cats: possible infection of methicillin-resistant Staphylococcus. Vet Pathol 40:283, 2003.

[10] SIHVO HK et al. Pathology in practice. Severe chronic multifocal intramural fibrosing and eosinophilic enteritis, with occasional intralesional bacteria, consistent with feline gastrointestinal eosinophilic sclerosing fibroplasia.

(FIESF). J Am Vet Med Assoc 238:585, 2011.

[4]

KAMBE N et al. A case of feline gastrointestinal eosinophilic sclerosing fibroplasia limited to the mesentery. J Small Anim Pract 61:64, 2020.

[5]

ECKSTRAND CD et al. Nematode-associated intramural alimentary nodules in pumas are histologically similar to gastrointestinal eosinophilic sclerosing fibroplasia of domestic cats. J Comp Pathol 148:405, 2013.

[6]

BRLOZNIK M et al. Recurrent feline gastrointestinal eosinophilic sclerosing fibroplasia and presumptive eosinophilic cystitis in a domestic short-haired cat: a case report.

Vet Med (Praha) 62:295, 2017.

[12] NIMMO JS, editor. Three cases of feline gastrointestinal eosinophilic sclerosing fibroplasia (a newly recognised syndrome) in Ragdoll cats. Fremantle, Western Australia, Aust Soc Vet Pathol, 2009.

[7]

MUNDAY JS, MARTINEZ AW, SOO M. A case of feline gastrointestinal eosinophilic sclerosing fibroplasia mimicking metastatic neoplasia. N Z Vet J 62:356, 2014.

[13] CATRO-LOPEZ J, FERNANDEZ M, DE SOUSA AR. A case of feline gastrointestinal eosinophilic sclerosing fibroplasia associated with zygomycetes fungi [abstract, ISFM Feline Congress. Budapest]. J Feline Med Surg 14:650, 2012.

[11] CHO MJ, KIM MC, SEO KW. Feline gastrointestinal eosinophilic sclerosing fibroplasia in a Bengal cat. J Vet Clin 34:481, 2017.

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Feline gastrointestinal eosinophilic sclerosing fibroplasia [14] KAWASAKO K, KANNO T, HAMAMURA M. Jejunal fibroplasia in a rat. J Vet Med Sci 79:830, 2017.

[22] O’KEEFE DA et al. Systemic mastocytosis in 16 dogs. J Vet Intern Med 1:75, 1987.

[15] WEISSMAN A et al. Ultrasonographic and clinicopathological features of feline gastrointestinal eosinophilic sclerosing fibroplasia in four cats. J Feline Med Surg 15:148. 2013.

[23] GAMBLE DA. Letters to the editor and rebuttal regarding the paper recently published in Veterinary and Comparative Oncology, “Feline intestinal sclerosing mast cell tumour: 50 cases (1997–2008) 2010; 8: 72–79” by C. H. C. Halsey, B. E. Powers and D. A. Kamstock. Letter to the editor #2. Vet Comp Oncol 8:235, 2010.

[16] BATCHELOR DJ et al. Mechanisms, causes, investigation and management of vomiting disorders in cats: a literature review. J Feline Med Surg 15:237, 2013.

[17] LEE M, BOSWARD KL, NORRIS JM. Immunohistological evaluation of feline herpesvirus-1 infection in feline eosinophilic dermatoses or stomatitis. J Feline Med Surg 12:72, 2010.

[18] DEAN E, MEUNIER V. Feline eosinophilic keratoconjunctivitis: a retrospective study of 45 cases (56 eyes). J Feline Med Surg 15:661, 2013.

[19] THIEME ME et al. Diagnosis and management of a case of retroperitoneal eosinophilic sclerosing fibroplasia in a cat.

JFMS Open Rep 5:2055116919867178, 2019.

[20] TAKEUCHI Y et al. Intestinal T-cell lymphoma with severe hypereosinophilic syndrome in a cat. J Vet Med Sci 74:1057, 2012.

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[24] SCHULMAN FY, LIPSCOMB TP. Letters to the editor and rebuttal regarding the paper recently published in Veterinary and Comparative Oncology, “Feline intestinal sclerosing mast cell tumour: 50 cases (1997–2008) 2010; 8: 72–79” by C. H. C. Halsey, B. E. Powers and D. A. Kamstock. Letter to the editor #1. Vet Comp Oncol 8:234, 2010.

[25] BROSINSKI K et al. Diagnostic exercise: submucosal gastric masses in a cat. Vet Pathol 50:350, 2013.

[26] BOUVIER T, DEL GIORGIO PA. Factors influencing the detection of bacterial cells using fluorescence in situ hybridization (FISH): a quantitative review of published reports.

FEMS Microbiol Ecol 44:3, 2003.

[21] HALSEY CH, POWERS BE, KAMSTOCK DA. Feline intestinal sclerosing mast cell tumour: 50 cases (1997–2008). Vet Comp Oncol 8:72, 2010.

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