Abstract
Case summary
A 3-year 10-month-old spayed female domestic shorthair cat was presented for subacute progressive hyporexia, vomiting and lethargy. On presentation, the cat was dyspnoeic, and venous blood gas analysis revealed metabolic acidosis, hypercalcaemia (both total and ionised), hyperlactaemia and hyperglycaemia. Physical examination identified a 2 × 3 cm crusted cutaneous lesion on the cranium, reduced mentation, mild tachycardia, harsh bronchovesicular sounds and approximately 5% dehydration. Owing to welfare concerns, the owners elected euthanasia. Post-mortem examination revealed moderate autolytic changes. The organs most affected by vascular lesions included the heart, brain, kidneys, liver and pancreas. Histopathology revealed mild to severe multifocal intraluminal and mural proliferations of atypical endothelial cells, accompanied by multifocal thrombosis and mild perivascular oedema. Immunohistochemistry showed that the proliferating cells were negative for alpha-smooth muscle actin, and quantitative PCR for Bartonella species was also negative. However, 50% of the proliferating cells were positive for factor VIII. These findings supported a diagnosis of feline systemic reactive angioendotheliomatosis.
Relevance and novel information
In the authors’ opinion, this case contributes to the growing body of literature on this rare condition and raises the possibility of an association with hypercalcaemia.
Introduction
Feline systemic reactive angioendotheliomatosis (FSRA) is a rare, idiopathic, multisystemic, proliferative intravascular disorder.1–6 These vascular lesions are characterised by glomeruloid spindle cell proliferations and microthrombi that partially to completely occlude arteriolar lumens.5,7 To the authors’ knowledge, only 15 cases have been reported in the literature since the condition was first described in 1985.2,3,5,7 In the current literature, pathognomonic signs are not apparent, and diagnosis in all cases was made post mortem, based on histopathology and immunohistochemistry. In previous reports, most proliferating cells stained positively for vimentin, and variably for factor VIII and alpha-smooth muscle actin (α-SMA).2–4,7
This report describes the clinical presentation, diagnostic evaluation and post-mortem findings of a cat with histologically confirmed FSRA and concurrent hypercalcaemia.
Case description
A 3-year 10-month-old female spayed domestic shorthair cat was presented for investigation of progressive hyporexia, vomiting, lethargy and a non-healing, non-painful dermal lesion located on the cranium, which had been present for 2 weeks. The patient had received empirical treatment with a 7-day course of amoxicillin–clavulanate (20 mg/kg PO q12h) for the dermal lesion but failed to respond. Haematology and serum biochemistry performed by the referring veterinarian revealed moderate regenerative anaemia, marked thrombocytopenia, mild hyperbilirubinaemia, mildly increased alanine aminotransferase (ALT) activity and mild hypercalcaemia (Table 1).
Haematology and serum biochemistry results performed at the primary veterinary clinic <24 h before admission
Abnormalities are highlighted in bold
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyl transferase; MCHC = mean cell haemoglobin concentration; MCV = mean cell volume; RBC = red blood cell; WBCC = white blood cell count
The patient was referred for further investigation. On physical examination, the cat had a depressed mentation but was arousable. The World Small Animal Veterinary Association body condition score was 3/9 with mild muscle loss. A moderately sized (2 × 3 cm) crusted lesion was noted on the dorsal cranium. Cardiac auscultation revealed a tachycardia of 200 beats/min. Respiratory rate was increased at 48 breaths/min, with markedly increased inspiratory effort and harsh bronchovesicular sounds. The mucous membranes were tacky, with a capillary refill time of less than 2 s. There was no evidence of petechiae or ecchymoses. The patient was estimated to be 5% dehydrated based on a mild loss of skin elasticity. The cat began open mouth breathing and was placed in an oxygen chamber; a single dose of butorphanol was administered (0.02 mg/kg IV). A moderate amount of haematochezia was passed upon arrival at the hospital.
Once the patient was settled, a point-of-care ultrasound was performed, revealing an underfilled left ventricle with possible pseudohypertrophy and mild diffuse B-lines (1–2 per field) bilaterally.
Initial investigations included packed cell volume (PCV), total solids (TS) and venous blood gas analysis. These revealed a PCV of 22% and TS of 68 g/l. Venous blood gas revealed moderate metabolic acidosis with marked hyperlactataemia, hyperglycaemia and mild ionised hypercalcaemia (Table 2). Non-invasive blood pressure via oscillometry was normal at 114/88 (91 mmHg). The patient tested negative for both feline immunodeficiency virus antibody and feline leukaemia virus antigen (SNAP FIV/FELV Combo Test; IDEXX Laboratories).
Venous blood gas performed on admission
Abnormalities are highlighted in bold
BE = base excess; Ca++ = ionised calcium; HCO3- = bicarbonate; pCO2 = partial pressure of carbon dioxide
Initial treatment included intravenous fluid therapy (Hartmann’s solution) with an initial bolus (5 ml/kg bolus over 10 mins, followed by a maintenance rate of 4 ml/kg/h). The patient also received maropitant (1 mg/kg IV q24h) and buprenorphine (0.02 mg/kg IV q6h). The following morning, coagulation tests including prothrombin time (PT) and activated partial thromboplastin time (aPTT), as well as repeat haematology and serum biochemistry, were performed. These revealed marked regenerative anaemia and thrombocytopenia (confirmed on blood smear), as well as increased creatine kinase. Mild abnormalities included lymphopenia, eosinopenia, hyperbilirubinaemia, increased ALT and aspartate aminotransferase activities, and total hypercalcaemia (Table 3). Prothrombin time was mildly prolonged at 13 s (reference interval [RI] 7.6–11.6), but aPTT was within normal limits (20 s, RI 12.5–25.0).
Haematology and serum biochemistry results performed 24 h after hospital admission
Abnormalities are highlighted in bold
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyl transferase; MCHC = mean cell haemoglobin concentration; MCV = mean cell volume; RBC = red blood cell; WBCC = white blood cell count
Based on the clinical signs and clinicopathological findings, non-associative immune-mediated anaemia and thrombocytopenia were considered likely. However, a secondary inciting cause, such as an inflammatory, infectious or neoplastic process, could not be ruled out.
Further investigations were offered, including thoracic radiographs, abdominal ultrasound, focal ultrasound of the neck, urinalysis, parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP) levels and bone marrow sampling. However, the owner declined because of financial limitations and ethical concerns. The advantages and disadvantages of a treatment trial with immunosuppressive and antimicrobial medications were discussed. This option was also declined, and after careful deliberation, euthanasia was elected, given the perceived guarded prognosis.
The owner consented to a post-mortem examination. The cadaver was frozen and thawed for a full necropsy (the interval between death and examination was 6 days). Overall, aside from changes related to barbiturate administration or post-mortem alterations, the main gross findings included a 2 × 3 cm area of crusting over a partially healed, circular puncture wound on the dorsal cranium, as well as serosanguinous to blood-tinged effusions measuring 15 ml in the thoracic cavity and 5 ml in the pericardial sac. The liver weight was 67 g (2.06% of body weight), which is mildly to moderately reduced for a cat of this sex, age and species (reference 2.46). 8 The parathyroid glands were macroscopically and histologically unremarkable. Histopathological examination revealed vascular lesions in the majority of examined organs (Table 4).
Distribution pattern and severity of feline systemic reactive angioendotheliomatosis vascular lesions of the patient
– = no changes; +/– = minimal changes; + = mild changes; ++ = moderate changes; +++ = marked changes
The dorsal cranium skin lesion was associated with a subacute, focally extensive, ulcerative and suppurative dermatitis. Microscopic examination revealed that approximately 70% of medium-sized vessels in the myocardium contained variably sized, loosely arranged intraluminal proliferations of bland spindle cells, which partially to completely filled the lumina, occasionally forming a glomeruloid pattern. These spindle cells were characterised by plump, elliptical nuclei with clumped to stippled chromatin and scant eosinophilic cytoplasm (Figures 1–3). The nuclei of the proliferating cells lacked features of atypia, and mitotic figures were extremely rare. The brain was the next most affected organ, with approximately 60% of the arterioles of the leptomeninges and Virchow–Robin spaces showing similar whirling to glomeruloid proliferations of bland spindle cells. The final microscopic diagnoses included lesions in the heart, kidney, brain, liver, pancreas, adrenal glands, mediastinal lymph nodes, stomach, intestine, spleen and bone marrow (Table 4). These were characterised by mild to severe multifocal intraluminal and mural proliferations of atypical endothelial cells accompanied by multifocal thrombosis and mild perivascular oedema (Figures 1 and 3).
Affected myocardial tissue displaying multiple intravascular spindle cells proliferations (haematoxylin and eosin; magnification × 20)
The heart. Approximately 50% of the intravascular proliferating spindle cells show moderate cytoplasmic granular to punctate immunolabelling for factor VIII (3,3-diaminobenzidine [DAB] and haematoxylin; original magnification × 20)
Adrenal cortex with proliferation of multiple intravascular spindle cells (haematoxylin and eosin; magnification × 20)
The following immunohistochemical markers were used: vimentin, which labels mesenchymal cells; factor VIII for endothelial cells; and α-SMA for smooth muscle cells. Immunohistochemical staining was performed on sections from the heart, which revealed that 50% of proliferative vascular structures demonstrated positive labelling for factor VIII, but negative for α-SMA (Figure 2).
To complement the post-mortem investigations, molecular testing (quantitative RT-PCR) for Bartonella species was performed on the liver and the results were negative. This Bartonella species assay is validated against Bartonella henselae and Bartonella clarridgeiae. 8
Discussion
To the authors’ knowledge, this is the first reported case of FSRA presenting with concomitant hypercalcaemia, although a causal relationship cannot be established. There is no known human equivalent of FSRA; however, proliferative vascular lesions in immunocompromised human patients have been described in association with Bartonella species, human herpesvirus 8 and other comorbidities.2,9,10 Beerlage et al 11 reported Bartonella vinsonii subspecies berkhoffii genotype III infection in two cats with FSRA, indicating that although this pathogen is associated with a broad range of clinical manifestations in dogs and humans, the development of vasoproliferative lesions in cats is likely multifactorial and not exclusively caused by the infection. In addition, B henselae and Bartonella koehlerae were also identified in FSRA cases. B henselae infection has been associated with host cell production of vascular endothelial growth factor, which is a key event in the angiogenic cascade.10,12 Although Bartonella species quantitative PCR was negative in this case, the assay used had not been validated against B vinsonii subspecies berkhoffii or B koehlerae; therefore, their involvement cannot be ruled out.11,13
The absence of α-SMA staining in this case may be attributed to either low expression, as seen in previous reports (5–50% positivity), or the effects of post-mortem tissue degradation. 2 Positive factor VIII staining supports the endothelial origin of the proliferative cells, consistent with a diagnosis of FSRA.
Typically, young cats are affected with a median age of 4 years, and most reported cases have involved entire or neutered males. 7 Clinical signs reported include lethargy, hyporexia, seizures and respiratory abnormalities, such as dyspnoea. 2 The dermal lesion noted in this patient appeared unrelated to FSRA, given its ulcerative and suppurative nature without histological evidence of vascular proliferation. This differs from previous reports where skin manifestations of FSRA included petechiae and ecchymoses.2,4
Hypercalcaemia has not been previously reported in FSRA. While the cause of hypercalcaemia in this case remains uncertain, differentials include idiopathic hypercalcaemia, chronic kidney disease (CKD) and neoplasia. No biochemical evidence of CKD was found, and there were no gross or histological findings consistent with neoplasia or parathyroid gland abnormalities. Although PTH and PTHrP levels were not evaluated, no parathyroid or kidney pathological changes were present. Had the patient not been euthanased, treatment trials could have helped support or exclude certain conditions. Idiopathic hypercalcaemia remains a common diagnosis in feline patients, and it is possible that the observed hypercalcaemia was incidental. 14
Interestingly, a human case of malignant angioendotheliomatosis (now known as intravascular large B-cell lymphoma) involved concurrent hypercalcaemia with normal PTH levels, which was interpreted as humoral hypercalcaemia of malignancy. 15 Various organs are affected by FSRA, with a proliferative and likely secondary inflammatory state. This is supported by evidence of lymphopenia and eosinopenia, which are often associated with inflammation. Therefore, the release of resorptive factors, such as tumour necrosis factor, prostaglandins, interleukin 1, interleukin 6 or transforming growth factor, could be implicated in the pathogenesis of hypercalcaemia. Many of these factors can be produced by endothelial cells.16,17 If FSRA is causally related to hypercalcaemia, the mechanism remains unknown.
The prognosis for FSRA is poor. Once clinical signs appear, the disease tends to progress rapidly, with spontaneous death reported in over 50% of documented cases.2,7 There is no literature documenting successful treatment of this condition. In all feline cases described in the literature, FSRA was a histopathological diagnosis made post mortem, as the organs typically required for definitive microscopic diagnosis are the heart, brain, liver and kidneys. In humans, reactive angioendotheliomatosis (RAE) is the closest condition to FSRA.2,5 RAE is a self-limiting condition that primarily affects the skin and is commonly associated with various coexisting systemic diseases, such as renal impairment and/or immunosuppression. In humans, it is often managed with topical or systemic steroids. 18
Conclusions
This case report adds to the existing literature on this rare feline condition. To the authors’ knowledge, it is also the first reported case of FSRA presenting with concurrent hypercalcaemia; however, if there is a causal link, its mechanism remains unknown.
Footnotes
Acknowledgements
The authors thank Dave Morris (Langford Vets–University of Bristol) and Georgia Barnard, Pauline Brind and Tizz Couldwell (Veterinary Pathology Service– School of Veterinary Medicine and Science; University of Nottingham).
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
Linnaeus Veterinary Limited supported the costs of the open access publication.
Ethical approval
The work described in this manuscript involved the use of non-experimental (owned or unowned) animals. Established internationally recognised high standards (‘best practice’) of veterinary clinical care for the individual patient were always followed and/or this work involved the use of cadavers. Ethical approval from a committee was therefore not specifically required for publication in JFMS Open Reports. Although not required, where ethical approval was still obtained, it is stated in the manuscript.
Informed consent
Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers, tissues and samples) for all procedure(s) undertaken (prospective or retrospective studies). For any animals or people individually identifiable within this publication, informed consent (verbal or written) for their use in the publication was obtained from the people involved.
