Survival time and prognostic factors in dogs clinically diagnosed with haemangiosarcoma in UK first opinion practice

Collette Taylor; Georgina J Barry; Dan G O’Neill; Alexandra Guillén; Phoebe Pickard Price; Julia Labadie; Dave C Brodbelt

doi:10.1371/journal.pone.0316066

. 2025 Jun 6;20(6):e0316066. doi: 10.1371/journal.pone.0316066

Survival time and prognostic factors in dogs clinically diagnosed with haemangiosarcoma in UK first opinion practice

Collette Taylor ^1,^*, Georgina J Barry ¹, Dan G O’Neill ¹, Alexandra Guillén ², Phoebe Pickard Price ¹, Julia Labadie ³, Dave C Brodbelt ¹

Editor: Simon Clegg,⁴

PMCID: PMC12143555 PMID: 40478827

Abstract

Visceral haemangiosarcoma is considered clinically aggressive in dogs, with perceived poor prognosis often leading to euthanasia at presentation. This study aimed to determine survival times and prognostic factors in dogs with haemangiosarcoma under first-opinion care. Dogs clinically diagnosed with haemangiosarcoma in first-opinion practice in 2019 were identified in VetCompass electronic health records and examined to capture variables potentially associated with survival. Median survival time (MST) from diagnosis was calculated for the whole population, those histopathologically confirmed and based on primary tumour location. Binary logistic regression was used to explore differences between dogs that died on the day of diagnosis and those that survived ≥1 day. Cox proportional hazards modelling explored factors associated with time to death in dogs surviving ≥1 day. Across all cases (n = 788), overall MST was 9.0 days (95%CI:5.0–15.0, range: 0–1789) and proportional 1-year survival was 12.0% (95%CI:9.7–15.0%). Dogs with splenic (MST = 4.0 days, 95%CI 0.0–9.0) and cutaneous haemangiosarcoma (MST = 119.0 days,95%CI:85.0–248.0) had MST greater than 0 days. Of dogs with a histopathological diagnosis of haemangiosarcoma, overall MST was longer at 105 days (95% CI 84–133 days) and additionally, location-specific MST were longer. For both clinically diagnosed cases and histopathologically confirmed cases, increasing tumour size was associated with increased hazard of death while cutaneous location and surgery were associated with reduced hazard of death. A very short survival time was identified for haemangiosarcoma under first-opinion care. Although survival time was longest for cutaneous cases, the actualised prognosis was poor overall for haemangiosarcoma. However, a common prevailing view of extremely poor prognosis for haemangiosarcoma could be promoting frequent euthanasia at presentation and therefore leading to a self-fulfilling prophecy and low survival times. Further exploration of the potential effect of perceived prognosis is warranted. This study provides valuable information for contextualised care and dialogues with clients in first-opinion practice.

Introduction

Canine haemangiosarcoma is a malignant neoplasia of vascular endothelial cells or bone marrow-derived-progenitor cells and is most commonly found affecting spleen, heart, liver, cutaneous and subcutaneous tissues [1]. Incidence estimates vary substantially, depending on the population studied, but two UK studies, one of dogs under first-opinion care and one of insured dogs, have estimated 0.007–0.25% of dogs were affected [2,3]. Confirmatory diagnosis of haemangiosarcoma is achieved through histopathological diagnosis on biopsies [1]. As it is a highly aggressive neoplasm, metastases are common at presentation. Staging assesses the number of tumours, lymph node involvement, distant metastases and whether the tumour has ruptured to determine if a haemangiosarcoma is Stage I, II or III [1,4,5].

Treatment options include mainly surgical excision of the mass and/or chemotherapy [1,4]. Use of radiotherapy has also been reported for cardiac and cutaneous haemangiosarcomas [1,5]. Whilst surgical excision can be curative for cutaneous forms, other haemangiosarcomas have a poor prognosis [1,6]. Factors associated with survival outcomes can be broadly split into non-modifiable (such as animal signalment, tumour stage, tumour size and tumour location) and modifiable factors (such as medical or surgical treatments undertaken) (Table 1). The direction and magnitude of these associations can vary by haemangiosarcoma location [7–9].

Table 1. Published factors reported to affect survival post haemangiosarcoma diagnosis ↑ = increased survival time, ↓ = reduced survival time and - = no effect.

Modifiable effect	Effect/s on survival	References	Unmodifiable effect	Effect/s on survival	References
Cutaneous- complete tumour resection	↑	Shiu et al., (2011); De Nardi et al., (2023)	Cutaneous- Tumour size >4 cm	↓	De Nardi et al., (2023)
Cutaneous – incomplete resection + radiotherapy	↑		Cutaneous – tumour in sun exposed location/ solar induced form	↑	Szivek et al., (2012)
Cutaneous- pre-surgical resection chemotherapy (of non-removable mass)	↑	Wiley et al., (2010)	Cutaneous – concomitant neoplasia	↑	Nobrega et al., (2019)
Cardiac – doxorubicin	↑	Mullin et al., (2016)	Cutaneous – breeds predisposed	↑	Nobrega et al., (2019)
Cardiac – surgery	↑	Yamamoto et al., (2013)	Cutaneous – female sex	↓	Nobrega et al., (2019)
Cardiac- surgery and chemotherapy	↑	Yamamoto et al., (2013)	Splenic- thrombocytopaenia at diagnosis	↓	Masyr et al, (2021)
Splenic – chemotherapy after splenectomy	↑ Or −	Wendelburg et al., (2012)	All – disease stage I All – disease stage II or III	↑ ↓	Ward et al., (1994); Wendelburg et al., (2015); Masyr et al., (2021); De Nardi et al., (2023)
Splenic – chemotherapy after splenectomy	↑ Or −	Moore et al., (2017)	All – disease stage I All – disease stage II or III	↑ ↓
Splenic- metronomic chemotherapy post splenectomy	↑ Or −	Batschinkski et al., (2018)	All – presence of metastases at diagnosis	↓	De Nardi et al., (2023)
Splenic- metronomic chemotherapy post splenectomy	↑ Or −	Alexander et al., (2019)
Splenic- polysaccharopeptide	↑	Cimino Brown et al, (2012)
Splenic- polysaccharopeptide	–	Gedney et al., (2022)

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Survival time for these patients vary, according to tumour location and treatment pursued. Cutaneous locations are reported to have the longest survival times (between 172–1189 days) and cardiac haemangiosarcoma the shortest (between 7–189 days) [10]). The reported median survival time for splenic haemangiosarcoma ranges from 23 to 259 days [1,7,11].

Clinical staging is reportedly the most predictive factor associated with survival time in cutaneous and splenic haemangiosarcoma [1,7,12,13].

In visceral forms of haemangiosarcoma, metastases have frequently occurred at point of diagnosis [1]. However, for cutaneous masses, metastases are less common and surgical resection can be curative [1,6,14]. For both visceral and cutaneous forms, dogs with a Stage I haemangiosarcoma have increased survival time when compared to Stage II or III tumours and Stage II tumours have increased survival versus Stage III [1,7,12,13].

For cutaneous masses, smaller tumour size has been associated with increased survival time [1,6], however this association has not been seen for splenic haemangiosarcoma [7,15]. Size does not appear to have been explored as a prognostic factor for cardiac or hepatic haemangiosarcoma locations.

Whilst certain breed types (such as retrievers and shepherds) are at increased risk of diagnosis with haemangiosarcoma [1,16,17], less is known about the effect of breed on survival time. For cutaneous haemangiosarcoma, breeds that are predisposed to developing haemangiosarcoma (such as Whippets, Bull Terriers and Dalmatians) have increased survival time when compared to breeds that are less commonly diagnosed with cutaneous haemangiosarcoma [1,14,18]. The short coat on the predisposed breed types is associated with developing solar induced cutaneous haemangiosarcomas which are associated with increased survival time [1]. For splenic haemangiosarcoma, no survival difference was seen when large and small breed dogs were compared [19] and further breed associations do not appear to have been explored.

For visceral haemangiosarcomas there are no reported associations between sex and neuter status and survival time. One cutaneous haemangiosarcoma study found females to have reduced overall survival time when compared to males [14].

In splenic haemangiosarcoma, chemotherapy and method of chemotherapy administration post-splenectomy had mixed effects on survival time, with some studies reporting an increased survival time associated with chemotherapy [19,20] while others did not [7,8]. For cardiac cases, surgical management and/or chemotherapy are reportedly infrequently pursued due to poor prognosis and the high skill level required for cardiac surgery [9]. However, small studies that pursued surgery and/or chemotherapy did report increased survival time [9,10]. Alternative therapeutics such as Yunnan baiyao and Coriolus versicolor have been explored but evidence for their effect on survival time has not been reported [1,21,22].

Previous studies examining haemangiosarcoma survival time and factors affecting survival time in dogs have largely been limited to smaller numbers of dogs, referral centre populations or submissions to tumour registries [6,10,12,18,23]. Consequently, findings from these studies may generalise poorly to dogs under first opinion care. Therefore, this study aimed to utilise the VetCompass database of first opinion practice attending dogs to explore survival time of haemangiosarcoma (overall and by location) and factors associated with survival time. It was hypothesised that cutaneous haemangiosarcomas have the longest survival time of all locations and that increasing tumour size is associated with reduced survival time. Additionally, it was hypothesised that the subset of dogs that died on day of diagnosis were significantly different from dogs with ≥1 day of survival and therefore there would be factors associated with dying on the day of diagnosis.

Methods

Study population and case identification

The study population included all dogs under first opinion care at participating VetCompass clinics in 2019. Dogs were defined as under veterinary care if they had at least one electronic health record (EHR) —such as a clinical note, treatment, or bodyweight measurement—recorded during 2019 or in both 2018 and 2020. Available data fields include species, breed, date of birth, sex, and neuter status, clinic ID, corporate veterinary group, as well as date-specific information on free-text clinical notes, bodyweight, and billed item treatments.

Potential haemangiosarcoma cases (candidate cases) were identified using the following search terms in the clinical notes: (haemangios*, hemangios*, HSA, angiosa*, haemangiosarcoma~1, hemangiosarcoma~1, hameangios*). A haemangiosarcoma case was defined as a dog with evidence of a final clinical diagnosis (with or without histopathological confirmation) of haemangiosarcoma in the EHRs. As not all cases underwent a definitive histopathological diagnosis, the diagnosis of haemangiosarcoma was considered a clinical diagnosis in some dogs. Only incident cases (those diagnosed between January 1 2019 and December 31 2019) were retained for this study. Ethical approval for the VetCompass programme was granted by the Social Science Research Ethical Review Board at the Royal Veterinary College (SR2018−1652).

Clinical record coding

A total of 4,997 candidate cases were randomly ordered and each EHR was manually reviewed to determine if it matched the haemangiosarcoma case definition. Candidate cases were excluded if haemangiosarcoma was listed only as a differential diagnosis or if there was no final confirmed diagnosis. Haemangiosarcoma cases had additional clinical information extracted and coded. Information from the coded variables was then grouped into further categories for case description, survival time calculations and regression modelling (Table 2). Fixed values of breed, sex, neuter status, date of birth and clinic and corporate group IDs were downloaded automatically from the EHR. The information coded and its groupings are shown in Table 2. Cases were restricted to those first diagnosed at ≥5 years old, as haemangiosarcomas (amongst other cancers) have been shown to be rare in young dogs [3,24].

Table 2. Information extracted from clinical records of haemangiosarcoma cases diagnosed in 2019 in VetCompass EHRs. The ‘Variable’ column shows what information was captured from EHRs and what it was transformed or grouped into for regression analyses (‘Grouped variables’).

Variable	Grouped variables
Age	Age at first diagnosis (continuous), Age at first diagnosis
Neutering	Neutering status when diagnosed Time between neutering and diagnosis
Breed	- Top 20 most common breed types in VetCompass in 2019 - Breeds with>=5 cases - Breeds with>=10 cases - Ancestral breed grouping [25] - Genotype breed grouping [26]
Clinical signs	Clinical signs (CS): Haematological Cardiac Respiratory Gastrointestinal Urinary Mass specific Other specific Non specific No CS reported Effusion present
Diagnostic tests performed	- Diagnostic test groups: Imaging Laboratory tests Sampling Cardiac diagnostics Abdominal diagnostics No diagnostics done
Surgical management options	- Did they have any surgery performed? - Did they have surgery and medical management performed?
Medical management options	- Did they have any medical management? - Type of medical management: Cardiac Alternative supplementation Transfusion Haemostatic Palliative
Tumour specifics	- Any tumour location: Splenic Hepatic Cardiac Cutaneous - Presence of metastases? - Metastatic tumour location: Abdominal metastases Thoracic metastases Cranial metastases Soft tissue metastases Lymphatic metastases No location specified - Main interest: Cardiac Splenic Hepatic Tumour size Maximum tumour size (quartiles, terciles and continuous)
Referral for advanced clinical management	Did the dog visit a referral centre/specialist?
Death	Survival time (days) Mechanism of death not taken forward into analyses
Indices of Multiple Deprivation (IMD)	IMD quintiles
Urban- rural classification	Urban- rural classification
Clinic ID	Clinic ID

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Due to the aggressive and invasive nature of visceral haemangiosarcoma it was considered unlikely to be able to establish whether a tumour location was primary or metastatic mass based on the EHR information so tumours were additionally grouped more broadly into whether there was any tumour present at the spleen, heart, liver or cutaneous tissues (‘any tumour location’ variables in tumour specifics row in Table 2). A complete list of information coded can be found in S1 Table Supplementary Mateiral.

Survival time

Survival was calculated from date of first diagnosis to death or until the end of the study or the animals last available EHR (if the last EHR was before December 31, 2023). Animals that had not died were censored for survival analysis on December 31, 2023. Median survival time (MST, days) and 1-year survival rates (range, % and 95% confidence intervals, CI) were calculated separately for: all haemangiosarcoma cases and all cases that lived ≥1 day after first diagnosis. These calculations were also performed separately by tumour location for splenic, hepatic, cardiac and cutaneous tumours. Kaplan–Meier survival (i.e., time-to-event) curves were constructed to describe time to death from haemangiosarcoma diagnosis for all cases and then separately for each tumour location group.

Factors associated with dying on day of diagnosis

Binary logistic regression modelling was used to ascertain whether there were distinct associations between a range of factors and an outcome variable of either dying on the day of presentation and or dying ≥1 day after presentation.

Initial univariable binary logistic regression modelling assessed for potentially significantly associated variables. Explanatory variables with liberal associations with survival beyond day of diagnosis (p < 0.2) were carried forward for multivariable binary logistic regression modelling [27]. A correlation matrix was built and Variance Inflation Factor (VIF) was used to assess for collinearity between potentially significant explanatory variables. Substantial collinearity was considered present with correlation ≥0.7, VIF > 5 [27]. For collinear variables, each of the variables were assessed individually in the model and the variable with smallest model AIC value was retained for further modelling. The multivariable model was built using a manual stepwise forwards construction, approach where variables with the smallest p-value from the likelihood ratio test (LRT) and/or smallest Akaike Information Criteria (AIC) value were included first. Variables were retained in the model if the model was deemed improved with variable inclusion through a significant likelihood ratio test (LRT) result. AIC values were used to compare non-nested models that were built with different collinear variables to determine which model balanced goodness of fit and complexity best. Pairwise interactions were assessed for variables in the final model and retained if significant (LRT p < 0.05). Performance of the final model was assessed through Area Under the Curve (AUC) and model fit to data was assessed by a Hosmer-Lemeshow test, where p > 0.05 indicates that the model adequately fits the data [27]. A random effect of clinic ID was added to the model. Intraclass coefficient (ICC) was calculated to compare level of variance within a clinic to level of variance between clinics. Statistical significance was set at the 5% level [27].

Cox regression modelling

Two separate survival analyses were undertaken using Cox proportional hazards regression modelling. In the first model, all dogs with ≥1 day survival after diagnosis (n = 407) were considered to evaluate the hazard of death from both clinically diagnosed and histopathologically diagnosed haemangiosarcoma cases. In order to explore whether factors associated with hazard of death for dogs clinically diagnosed with haemangiosarcoma were consistent in lab confirmed haemangiosarcoma cases, a second model was built using only dogs with a histopathological diagnosis of haemangiosarcoma (n = 272). Explanatory variables with liberal univariable association with hazard of death with haemangiosarcoma (p < 0.2) were carried forward for multivariable Cox proportional hazards regression modelling [27]. A correlation matrix for potentially significant explanatory variables was assessed, as described for the binary logistic regression model approach. Clinical signs were excluded from multivariable Cox regression modelling due to their lack of independence. Both age at diagnosis (years) and maximum tumour size (cm) recorded were both normally distributed and appeared to increase linearly with hazard of death and both variables were explored as a continuous variable and as categorical variables by quartiles. The categorical maximum tumour size variable was taken forward into multivariable Cox regression modelling due to the large number of missing values of tumour size (n = 258) whereas age was retained as a continuous variable as there were no missing records for this.

Multivariable model building used a manual stepwise forwards construction approach. Variables were retained in the model if the model was deemed improved with variable inclusion through a significant likelihood ratio test (LRT) result and the smallest AIC value for separate models built with collinear variables. Pairwise interactions between final model explanatory variables were evaluated and retained if their inclusion significantly improved the model (LRT p value <0.05). The proportional hazards assumption (i.e., the assumption that the hazard ratios (HRs) for category variables remain constant over time) was tested through assessment of Schoenfeld residuals and visualisation of survival curves in Kaplan-Meier plots for each variable [27]. Schoenfeld residuals were assessed for individual variables in the final model and for the global model. If the global model did not violate the proportional hazards assumption (p > 0.05) then this model was used. Model performance and fit to the dataset was assessed through Concordance Index and Xu and O’Quigley R² values [27–29]. Statistical significance was set at the 5% level [27].

All data cleaning and analyses was performed in R Studio (R Core Team, Vienna, Austria) using the following packages: survminer, dynpred, ggsurvfit, ggplot2, finalfit and coxr2.

Results

Study population

From the study population of 2.2 million dogs, there were 4,997 candidate haemangiosarcoma cases. Of these, 788 cases met the case definition for newly diagnosed haemangiosarcoma in 2019. Once age restricted to dogs over five years, the median age at first diagnosis was 10.6 years (interquartile range, IQR, 9.1–12.1 years). Nearly three-quarters of the population were neutered (n = 577,73.4%). Male dogs comprised 53.5% of the cases (n = 422) and females 45.6% (n = 359). The three most common breeds were: Labrador Retriever (n = 96, 12.2%), German Shepherd Dog (n = 84, 10.7%) and Staffordshire Bull Terrier (n = 43, 5.5%). Overall, crossbred dogs were the most common dog type (n = 177, 22.5%).

There were 29 tumour locations recorded with the most common ones being spleen (n = 489, 62.1%) and liver (n = 198, 25.1%) followed by cutaneous haemangiosarcoma (n = 146,18.5%).

Most EHRs reported at least one clinical sign at presentation, with 28 (3.5%) dogs having no clinical signs recorded at presentation. A wide range of clinical signs were recorded, with 64 distinct clinical signs noted. Most commonly, clinical signs were non-specific: lethargy (n = 309, 38.6%), anorexia/hyporexia (n = 287,35.8%) and abdominal distension (n = 197, 25.0%) (Fig 1).

Fig 1 — Bar chart colours indicate the group that an individual variable was grouped into: Clinical signs grouped according to their main body system affected (top bar plot), diagnostic tests performed (middle bar plot) and treatment options undertaken (bottom bar plot).

The most commonly performed diagnostic tests were abdominal ultrasound (n = 547, 68.3%) and blood tests (n = 485, 60.5%). Effusion analysis was performed in 166 patients (20.7%), of these the majority were abdominocentesis (n = 143, 17.8%) and less commonly pericardial effusions (n = 23, 2.9%). In one-third of patients, a confirmatory histopathological diagnosis was performed (n = 277, 34.6%). None of the age-excluded (dogs <5 years old) had histopathology performed.

For staging purposes, 30.2% (n = 238) of patients had their tumour size recorded, only 21.4% (n = 169) of patients had presence of metastases recorded and of these dogs, only 7 (0.9%) recorded metastases to lymph nodes. Therefore, tumour staging was not taken further in the survival analyses. Median tumour size was 6.0 cm (IQR = 3.5–10 cm, range 0.2–23.0 cm).

Surgical excision was the most commonly performed treatment (n = 276/788, 35.0%), with splenectomy being the most common type of surgery (n = 172/276, 62.3%). Palliative care (analgesia or steroid administration) was the next most common treatment (n = 102, 12.9%). Chemotherapy (either high- dose or metronomic) was uncommon (n = 42, 5.3%). Of those, anthracycline-based (doxorubicin or epirubicin) protocols were most commonly used (27 dogs, 64.3% of chemotherapy dogs) followed by metronomic cyclophosphamide (16 dogs, 38.1% of chemotherapy patients).

Whether death was the result of euthanasia or unassisted was recorded in most patients (n = 676, 85.8%), with euthanasia being the mechanism of death in most cases (n = 624, 92.3%).

Survival time

Survival time across all clinically diagnosed haemangiosarcoma cases ranged from 0–1789 days (IQR 0–74 days). The median survival time (MST) of all cases was 9 days from diagnosis (95% CI 5–15 days), with a 1-year survival rate of 12% (9.7–15%) (Table 3). Dogs with cardiac and hepatic haemangiosarcoma had the lowest MST at 0 days (95%CI 0–0) for both (Fig 2). The 1-year survival rate for these locations was 3% (95% CI 0.8–12%) and 3.9% (95% CI 1.8–84%) respectively. The MST for splenic haemangiosarcoma was 4 days (95% CI 0–9 days). Cutaneous haemangiosarcoma had the longest MST at 119 days (95% CI 85–248 days), with a 1-year survival rate of 35% (95% CI 28–44%).

Table 3. Summary table of case numbers, median survival time (MST), interquartile range (IQR) and 1-year survival rate for clinically diagnosed haemangiosarcoma cases diagnosed in first opinion practices in VetCompass in 2019. Cases are grouped by location: any, cardiac, splenic, hepatic and cutaneous. Cases are divided further to separate all cases and cases with ≥1 day of survival time post-diagnosis.

Location	Any location		Cardiac		Splenic		Hepatic		Cutaneous
	All cases	Cases ≥ 1d survival	All cases	Cases ≥ 1d survival	All cases	Cases ≥ 1d survival	All cases	Cases ≥ 1d survival	All cases	Cases ≥ 1d survival
Total case number	788	407	75	17	489	229	198	75	162	139
MST days (95% CI)	9 (5-15)	83 (68-103)	0 (0−0)	26 (16-270)	4 (0-9)	70 (57-83)	0 (0−0)	40 (53-99)	119 (85-248)	171 (114-347)
IQR days,range days)	(0-74.25,0-1789)	(23-194, 4-1789)	(0-0, 0-496)	(4-157, 11-496)	(0-56, 0-1548	(21-136, 4-1548	(0-27.5, 0-1474)	(13-1474, 4-1474)	(17.25-385, 0-1789)	(39-521, 4-1789)
1 year survival rate(95%CI)	12% (9.7-15%)	22% (18-27%)	3.0% (0.8-12%)	12% (3.2-43%)	6.5% (4.4-9.5%)	13% (8.8-19%)	3.9% (1.8-8.4%)	9.6% (4.5-20%)	35% (28-44%)	40% (32-49%)

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Fig 2 — Day 0 designates day of first diagnosis. Shaded areas indicate the 95% CI for each curve and crosses indicate censored cases.

Of those dogs with a confirmed histopathological diagnosis of haemangiosarcoma (n = 272), MST was 105 days (84–133 days), with a 1-year survival rate of of 28% (22–34%). For hepatic, splenic and cutaneous haemangiosarcoma locations, the MST was longer for those with a clinical diagnosis (hepatic MST: 79 days (95% CI 35–112 days), splenic MST: 80 days (95% CI 64–106 days), cutaneous MST: 248 days (95% CI 119–478 days)). The 1-year survival rate for these locations was: 7.2% (95% CI1.9–26.7%), 16% (95%CI 10.1–24.2%) and 43.2% (95% CI 34.8–53.6). The MST and 1-year survival rate for histopathologically confirmed cardiac haemangiosarcoma could not be calculated as there was only one case.

Factors associated with death on day of diagnosis

Due to the high proportion of dogs not surviving for ≥1 day after diagnosis (n = 381/788, 48.3%) identified in survival time calculations it was hypothesised that there were two distinct populations of haemangiosarcoma cases. Therefore, binary logistic regression was performed to ascertain risk factor differences between dogs with <1 day of survival (n = 381) and those with ≥1 day of survival after diagnosis (n = 407). In univariable logistic regression comparing these two groups, 37 variables were found to be potentially significant (LRT p- value <0.2) that were taken forward to multiple logistic regression (S2 Table in Supplementary Material). Of these variables, there were 52 pairs of correlated variables which were assessed in non-nested models to decide on which of the pair to include. The final model comparing differences between the dogs with <1 day survival and ≥1 day survival retained 8 variables: if the patient had surgery or medical treatment, haemangiosarcoma location, whether they visited a referral centre, whether there were mass associated clinical signs present), whether there were haematological abnormality clinical signs present, whether abdominal diagnostic tests were performed and whether there were any clinical signs recorded at presentation. Additionally, corporate group was forced into the model to account for the structure of the data and Clinic ID was retained as a fixed effect (Fig 3). The model showed no evidence of poor fit to the data (Hosmer-Lemeshow p > 0.05) and good discrimination (AUC = 0.93). There was a small amount of clustering at the clinic level (ICC = 0.11).

Fig 3 — Day 0 and Day ≥ 1 columns represent number of animals and percentages for each category in the model. OR indicates the odds ratio for each category and its 95% confidence interval (CI) and p-value.

Dogs that received any surgical or medical management of their haemangiosarcoma were more than 25 times more likely to die on day of diagnosis than those that did not (OR=26.93, 95% CI 17.22–43.41). The presence of haematologically abnormal clinical signs at presentation was associated with double the likelihood of dying on day of diagnosis (OR=2.29, 95% CI 1.43–3.76). Dogs with no clinical signs recorded at presentation were more than ten times less likely to die on day of diagnosis (OR=0.09, 95% CI 0.01–0.44). Dogs with mass associated clinical signs at presentation were half less likely to die on day of diagnosis (OR=0.52, 95% CI 0.31–0.88).

Dogs who visited a referral centre as part of their treatment were 10 times less likely to die on day of diagnosis (OR=0.10, 95% CI 0.04–0.23). A cutaneous location was associated with a seven-fold reduction in odds of dying on day of diagnosis compared to a splenic haemangiosarcoma (OR=0.14, 95%CI 0.03–0.23). Dogs with any abdominal diagnostic tests performed were half as likely to die on day of diagnosis (OR=0.53, 95%CI 0.28–1.00). None of the corporate group variables were significant.

These large variations in odds ratios between dogs that died on day of diagnosis and dogs that survived for ≥1 day indicated that these two dog groups were distinct and not suitable to be combined for survival analyses. In order to evaluate factors associated with survival with haemangiosarcoma diagnosis beyond first day of diagnosis, only dogs with ≥1 day of survival time were taken forwards.

Hazard for death with clinically diagnosed haemangiosarcoma in dogs that survive for ≥1 day after diagnosis

Of the 63 variables examined in univariable analyses, 41 were liberally significant (LRT p-value <0.2). Variables describing clinical signs at presentation were not taken forward due to their lack of independence as factors, leaving 43 factors to be assessed in multivariable modelling (S3 Table in Supplementary material). Of these, 28 variables were potentially correlated which were assessed in non-nested models for inclusion.

In the final Cox proportional hazards regression model, five variables were retained: whether a patient had any form of surgery, location of haemangiosarcoma, sex, maximum tumour size and the corporate group the clinic belonged to. Corporate group was not significant but was forced into the model to better account for the structure of the data. Additionally, a frailty term of clinic ID was incorporated to further account for data structure. The overall model and individual independent variables were assessed for violation of proportional hazards. All individual variables and the overall model satisfied this assumption. The final model performed well, with a pseudo-R² of 0.26 and a Concordance Index of 67.

Hazard of death increased as the maximum tumour size increased, with greatest hazard in dogs with haemangiosarcomas between 8−23 cm when compared to those with 0.2–4.3 cm tumours (HR = 1.94 95% CI 1.19–3.18). Male dogs had an increased hazard of death (HR = 1.32, 95%CI 1.05–1.65) compared to female dogs. Dogs with any surgery performed had a reduction in hazard of death when compared to those that didn’t (HR = 0.48, 95%CI 0.38–0.62). When compared to cardiac haemangiosarcoma cases, dogs with a haemangiosarcoma at other locations had reduced hazard of death with haemangiosarcoma, although this was only significant for cutaneous. Dogs with a cutaneous haemangiosarcoma had a decrease in hazard of death versus dogs with cardiac haemangiosarcoma (HR = 0.53, 95% CI 0.40–0.69) (Fig 4).

Fig 4 — Cases (%) column indicates the number of cases for each category in the model. HR indicates the hazard ratio for each category and its 95% confidence interval (CI) and p-value. The final model included a frailty term of Clinic ID.

Hazard for death with histopathologically confirmed haemangiosarcoma in dogs

Of the 62 variables examined in univariable analyses, 38 were liberally significant (LRT p-value <0.2). Variables describing clinical signs at presentation were not taken forward due to their lack of independence as factors, leaving 29 factors to be assessed in multivariable modelling (S4 Table in Supplementary material). Of these, 15 variables were potentially correlated which were assessed in non-nested models for inclusion.

In the final Cox proportional hazards regression model, seven variables were retained: whether a patient had any form of surgery, location of haemangiosarcoma, maximum tumour size, whether a patient visited a referral centre, whether soft tissue metastases were identified, dog genotype grouping and the corporate group the clinic belonged to (Fig 5). Corporate group was not significant but was forced into the model to better account for the structure of the data. Additionally, a frailty term of clinic ID was incorporated to further account for data structure. The overall model and individual independent variables were assessed for violation of proportional hazards. All individual variables and the overall model satisfied this assumption. The final model performed well, with a pseudo-R² of 0.39 and a Concordance Index of 70.

Fig 5 — Cases (%) column indicates the number of cases for each category in the model. HR indicates the hazard ratio for each category and its 95% confidence interval (CI) and p-value. The final model included a frailty term of Clinic ID.

Surgery, haemangiosarcoma location and size were consistent between this model of histopathologically diagnosed haemangiosarcoma cases and all haemangiosarcoma cases. Dogs that had surgery performed had a reduced hazard of death (HR = 0.39,95%CI 0.25–0.61), when compared to those that did not. Dogs with cutaneous haemangiosarcoma had decreased hazard of death compared to splenic haemangiosarcoma cases (HR = 0.60,95%CI 0.43–0.83). Larger tumour size was associated with an increased hazard of death, this hazard was greatest for tumours between 8−23 cm when compared to 0.2–4.3 cm tumours (HR = 2.59, 95%CI 1.42–4.71). Visiting a referral centre was associated with a two-fold reduction in hazard of death (HR = 0.46, 95% CI 0.31–0.69). Dogs of the genotype group 2 (primarily consisting of spaniel, hound and poodle breeds) had decreased hazard of death (HR = 0.52, 95% CI 0.31–0.89) when compared to crossbred dogs (Fig 5).

Discussion

This is the first study exploring haemangiosarcoma survival time and factors associated with death in a first opinion practice attending in the UK. Existing studies have focussed on referral care populations which exhibit biases [1,6,7,13], as such this work aimed to explore haemangiosarcoma survival from a first opinion perspective, with a first-opinion level of diagnosis. This study identified a short MST overall for haemangiosarcoma (nine days) and for each main tumour location. In hazard regression modelling of dogs with ≥1 day of survival after diagnosis and dogs that had a histopathological diagnosis, dogs with haemangiosarcoma of a cutaneous location and dogs that had any surgical management performed had a reduced hazard of death. Increasing tumour size was associated with increased hazard of death. Males were also found to have increased hazard of death when both clinically diagnosed and laboratory confirmed haemangiosarcoma cases were modelled. Despite not being able to fully disentangle clinical presentation and other influences on haemangiosarcoma, the findings provided here can assist general practitioners to provide location specific and UK first opinion specific survival time estimates.

Survival time after diagnosis with haemangiosarcoma

Visceral haemangiosarcomas are commonly regarded as aggressive neoplasms with a poor prognosis [1,4]. Short median survival times (MST) were consistently seen across all haemangiosarcoma locations in this study. When compared to existing studies, each haemangiosarcoma location had a substantially shorter MST in this study. Whilst dogs with cutaneous haemangiosarcoma had the longest survival time of all locations here (MST = 119 days) it was still shorter than previous studies, which reported MSTs between 172–1189 days [6,13,14,23]. Likewise, in the literature cardiac and splenic cases still have very short MST (7–189 days and 30–259 days, respectively) but these were substantially longer than what was seen here (0 days and 4 days, respectively) [7,9,10,11,30].

In most previous studies exploring haemangiosarcoma survival, studies included small case numbers primarily treated in specialist centres and presence of referral bias is likely [6–9]. This could have affected survival time through the availability of more advanced therapies, owners more motivated to pursue intensive treatment options and less financial concerns if attending a referral centre. Additionally, patients attending a referral centre might have had to present to their primary veterinarian clinically stable enough for referral. Furthermore, some studies excluded patients that did not meet a minimum survival length or did not survive to discharge which would have skewed for a longer MST [7,15]. When MSTs were calculated for cases with ≥1 day of survival after diagnosis or cases with a histologically confirmed diagnosis in this Vet Compass population, MSTs were similar to those reported in previous studies [7,9,10,30,31].

The potential reasons for short survival times are multifactorial. Haemangiosarcomas are reported to be generally aggressive tumours, with high metastatic rates [4]. In the study population here, a low proportion of dogs were receiving chemotherapy and many presented with severe clinical signs leading to potential inferences about low quality of life in haemangiosarcoma patients. However, the common prevailing view of extremely poor prognosis for haemangiosarcoma could be promoting frequent euthanasia at presentation and therefore leading to a self-fulfilling prophecy and low survival times. From reading clinical records it is difficult to be certain on the nuances of why euthanasia has been performed, with factors such as perceived prognosis, financial considerations and emotional distress being more difficult to capture than patient clinical presentation. As a result, it is not clear the proportional contribution of effects from these non-clinical factors on a decision to euthanise are challenging to derive and therefore the impact on survival times reported here.

For cutaneous haemangiosarcoma, the MST reported in the current results was at the lower end of previously reported MSTs in the literature [6,13,14,23,31]. This may have reflected that our categorisation of cutaneous haemangiosarcomas encompassed a wider range of non-visceral, more aggressive forms such as subcutaneous and intramuscular haemangiosarcomas. Additionally, solar radiation induced forms of haemangiosarcoma have been associated with increased survival time than non-solar induced [1,18]. Whilst the solar induced aspect of cutaneous haemangiosarcoma biology was not assessed for in cases here, due to reduced sunlight hours, intensity and UV levels, solar-induced haemangiosarcoma cases may be less frequent in northern Europe, meaning survival time may be reduced in cutaneous haemangiosarcomas in this current UK study [32,33].

In previous referral centre studies tumour staging has been shown to be a key prognostic factor [1]. However, tumour staging in accordance with adapted WHO guidance (tumour size, evidence of regional and distant metastases) was rarely recorded in clinical records in this study. Therefore, it was not possible to explore how the MSTs reported here relate to cancer stage.

Factors associated with dying on day of diagnosis

The binary logistic regression model aimed to explore clinico-pathologic and treatment factors associated with dogs that died on day of diagnosis versus dogs that survived for at least one day. Two factors were associated with dying on day of diagnosis: having surgical or medical management of their haemangiosarcoma and the presence of haematologically abnormal clinical signs. The management of haemangiosarcoma being associated with increased odds of death on day of diagnosis seems counter-intuitive initially, however this most likely reflects unstable patients requiring urgent surgery (for example, an actively bleeding splenic mass requiring emergency surgery) being associated with poorer outcomes. Likewise, the reduced likelihood of visiting a specialist centre in dogs that die on day of diagnosis also supports this, as dogs may need to be clinically stable before travelling for specialist care. As anticipated, based on survival times in existing literature [1,6,14], presence of a cutaneous haemangiosarcoma was associated with reduced odds of dying on day of diagnosis. Perhaps expectedly, an absence of clinical signs at diagnosis was associated with increased odds of surviving longer than one day. It seemed plausible that these would be more likely to be cutaneous lesions as these would be less likely to have clinical manifestations, however most of these cases were actually splenic (n = 22/28). Although the case numbers for this variable are small, this might be of clinical relevance to practitioners finding an incidental splenic mass on a work-up.

This model indicated that dogs dying on day of diagnosis had different associations with both modifiable and unmodifiable haemangiosarcoma factors than those that survived longer.

Factors associated with time to death with haemangiosarcoma

Previous survival analyses on haemangiosarcoma tended to focus on single locations for haemangiosarcoma. However, factors identified in this current study represent associations across all types of haemangiosarcoma. Cutaneous haemangiosarcomas were at significantly reduced hazard of death when compared to splenic haemangiosarcoma cases. The association of cutaneous haemangiosarcoma location with lowest hazard of death was consistent with median survival times reported in the literature across haemangiosarcoma locations [1,6–8,15], but this has not been explored through multi-location haemangiosarcoma survival analyses with a single study before.

In the current study, increasing tumour size was associated with increased hazard of death. Whilst larger masses (>6 cm) have been shown to be associated with a reduced survival time in cutaneous haemangiosarcoma [6], in several previous splenic haemangiosarcoma studies size has not been associated with prognosis [7,15]. Reasons for this lack of association in previous studies was survival to discharge post-splenectomy as an inclusion criterion might select for smaller masses as these might make better surgical candidates. Tumour size has not consistently been found to be a predictor of splenic malignancy as there is overlap between benign (specially hematomas) and malignant lesions, as well as between malignant lesions [26]. Tumour size may only be associated with prognosis for certain haemangiosarcoma locations. Since other studies exploring tumour size have focused on a single haemangiosarcoma location, our model which includes all locations makes interpreting this size association more complicated. For example, cardiac haemangiosarcomas have a very short survival time but are limited by cardiac anatomy to the extent they can grow to [9]. Both location and tumour size associations were consistent for both the model built with all clinically diagnosed cases and the model of only histologically diagnosed cases.

Male dogs had an increased hazard of death with haemangiosarcoma in the clinically diagnosed cases model. An association between sex and haemangiosarcoma survival time or diagnosis does not appear to be frequently identified in haemangiosarcoma studies [9,16,34]. Besides cancers of reproductive organs with their obvious sex associations there does not appear to be strong evidence for sex being associated with canine cancer survival time. This contrasts with humans, where men are often reported at increased risk of diagnosis and also poorer survival times across several cancers [35–37]. In human oncology, the exact mechanism of sex on both diagnosis and survival is not well understood [38]. There are sex hormone associations but also lifestyle and environmental differences between human sexes which contribute to this variation [35–37]. Sex hormones are involved in the regulation of physiological process such as stem cell renewal and the immune response and androgen receptor expression has been identified in angiosarcomas (a human neoplasm similar to haemangiosarcoma in dogs), indicating a potential sex hormone association for this cancer [38]. However, the extent to which the sex difference is translatable to veterinary is unclear given how commonplace neutering is, which minimises the potential role of sex hormones [39]. Neuter status was not retained in the final hazards model, further indicating that there are other factors beyond sex hormones contributing to this finding.

No significant effect on survival time was seen in the current study when medical treatments such as chemotherapy or alternative medicines (such as Yunnan baiyao or Coriolus versicolor) were utilised. The use of these therapeutics was uncommon (40 dogs for chemotherapy, 9 for alternative medicine), likely leading to a lack of power to detect an effect. However, as there is currently minimal evidence to suggest alternative medicines improve survival time it is also probable this association would not exist in the data here [22,34].

Previous studies reported some breed associations with haemangiosarcoma diagnosis but there is limited work evaluating the breed associations on survival after diagnosis [17,40]. Only cutaneous haemangiosarcomas has been previously reported to have some breed associations with survival time [14]. When histologically confirmed cases were examined, rather than variation in hazard for single dog breeds, dogs of the genotype group that consisted of spaniel, poodle, dachshund and beagle breeds were found to have a reduced hazard of death [26]. These were not the same breeds identified to have increased survival by Nóbrega and colleagues (2019) [14]. No breed associations were identified in the model of all haemangiosarcoma cases, nor with the survival time overall, in agreement with other existing literature [6,19].

Due to the very short survival times and high uptake of euthanasia in this study, it must be considered that these factors are not the primary drivers of survival time.

Limitations

Whilst working with large volumes of clinical records in VetCompass has the advantage of providing high number of cases there are some limitations to working with anonymised, retrospective records. For example, full laboratory records such as histopathology on masses or blood tests are often not available in the EPRs. In addition, the current first opinion study included many patients that did not have a definitive diagnosis pursued (only one-third had histopathology performed) or blood samples taken (only 60% of cases). This meant that the study was unable to assess the effect of variables associated with prognosis identified in other studies such as the mitotic count of a mass, Ki67 expression or thrombocytopaenia [8,12].

Relying on clinical diagnoses rather than exclusively histopathological diagnosis could have led to inclusion of misdiagnosed patients, as not all bleeding spleens are malignant masses and not all malignancies are haemangiosarcoma. Application of the ‘double two-thirds’ rule (where two-thirds of splenic masses are malignant and of these a further two-thirds are haemangiosarcoma) here indicates that the potential for misdiagnosis due to a lack of definitive diagnosis could have had an impact on survival time and factors associated with it identified here [11]. Meta-analyses by Schick and Grimes (2022) indicated that both splenic malignancies and haemangiosarcoma might be more common than the rule suggests [41] (Schick &Grimes, 2022). Achieving a definitive diagnosis can prognosticate better for owners and avoid a potentially unwarranted euthanasia (if benign). However, as this is often not feasible in acute, critical clinical presentation scenarios and in first opinion practice, presumptive diagnoses were included in the current analyses. Given the variation in proportions of biopsies between haemangiosarcoma locations in this study, three-quarters of cutaneous haemangiosarcoma cases were biopsied here versus just 2% and 28% of cardiac and splenic cases, it seems plausible that the severity of clinical presentation and the ability of first-opinion vets to perform haemangiosarcoma surgeries would have affected the uptake of biopsies. [1] Additionally, cytological diagnosis has limitations (such as blood contamination of samples) and an invasive biopsy may not be considered justifiable in patients with advanced disease [1]. Furthermore, histopathology alone can be insufficient to differentiate splenic haemangiosarcoma from other sarcomas, requiring immunohistochemistry confirmation which has additional time and cost implications [1]. Thus, if the study only included histologically diagnosed dogs, a large proportion of dogs would be excluded and survival would be biased to dogs with early stage haemangiosarcoma and longer survival times.

Euthanasia will undoubtedly have impacted survival risk factors. However, this study was interested in reporting the survival pattern overall and therefore both dogs euthanised due to the disease and dogs that died from the disease need to be included.

The reported effect of surgical removal on haemangiosarcomas on patient survival time varies widely. Whilst surgical removal has been shown to be potentially curative for cutaneous masses [6], it has been shown to lead to increased survival time in other locations with varying magnitude [1,7,9,19]. Therefore, the effect of surgery on survival time was a variable of interest for the current study. Unfortunately, due to the first opinion nature of these clinics and the fact that many haemangiosarcoma surgeries are highly complex and potentially require specialist surgeons (e.g., liver lobectomy) the effect of specific surgical procedures on survival time could not be assessed. As surgical procedures other than splenectomy were performed infrequently in the current caseload, all surgeries were all grouped into a binary variable which led to a loss of resolution between individual surgical types. Insurance status likely has an effect on both diagnosis and survival time. Unfortunately, these data are often not up-to-date in EHRs. Due to this, the relationship between insurance status and haemangiosarcoma cases was not explored.

Whilst these findings are likely applicable across wider UK first-opinion veterinary practices, it is unclear how applicable these findings are to other countries in the world. Factors such as breed genetic differences in other countries, access to diagnostics, standards of care and owner attitudes to euthanasia and treatment might vary between countries and lead to different associations than those seen here.

Although the mechanism of death was recorded in most EHRs in this study, it was still not possible to disentangle the multiple potential reasons for euthanasia such as perceptions around poor prognosis, financial considerations or whether the perceived acute quality of life deterioration prompted euthanasia. From the clinical notes in this study, it was not possible to determine whether dogs that died on the day of presentation and had surgery (n = 29) were euthanised intra-operatively or after exploratory surgery, only that the majority were recorded to have ‘inoperable tumour/s’ (n = 26) and the majority of these were euthanised (n = 27) rather than died (n = 2). Clinical notes pertaining to euthanasia consults are often brief and not able to capture non-clinical aspects. Therefore, qualitative research might be useful to explore haemangiosarcoma euthanasia considerations. Additionally, a small prospective study by Stewart and colleagues (2020) found that dogs presenting with splenic mass rupture (both benign and malignant) had more favourable outcomes than existing literature informing views on prognosis would suggest [42]. This highlights the potential role of prospective studies in exploring outcomes and euthanasia rates and reasons in haemangiosarcoma cases. Whilst it was not within the scope of this project to explore factors motivating owners to pursue euthanasia, it is likely that it was not only related to the tumour aggressive behaviour, but also other factors such as the severity of the clinical signs and perceived acute deterioration in quality of life, together with the age at presentation (adult to elderly for large breeds), probable presence of age-related comorbidities and treatment costs.

Future work could also attempt to identify a control population of other splenic tumours to evaluate whether the presumed haemangiosarcoma group truly has distinct survival and could improve the external validity of the study. However doing this has some challenges that would need to be taken into consideration: other neoplasms within the spleen are rare (only account for 25% of malignant splenic tumours) and include (aside from lymphoma) mainly other sarcomas (histiocytic sarcoma, leiomyosarcoma, fibrosarcoma, undifferentiated sarcomas and liposarcoma) for which survival data in the literature is scarce [4]. Additionally, histologically these sarcomas can often be challenging to distinguish from haemangiosarcoma and immunohistochemistry may be needed to achieve a definitive diagnosis, which may not be commonly pursued in the general practice setting.

Conclusion

This study identified a short survival time for haemangiosarcoma presenting to first opinion practices in the UK. Survival times were shortest for cardiac and hepatic haemangiosarcoma. Tumour location, size, sex and surgical management factors were associated with death with haemangiosarcoma. The wide-ranging survival times seen in haemangiosarcoma cases here (visceral forms ranged from 0–1548 days of survival) indicate that further exploration of tumour biology and potential biomarkers is important, to potentially understand some of the variation between locations and individual dogs. The potential effect of perceived prognosis on patient euthanasia should be assessed further as prevailing views of an extremely poor prognosis may result in more frequent euthanasia at presentation and create a self-fulfilling prophecy and short survival times.

Supporting information

S1 Table. Complete list of information coded on clinical signs, diagnostic tests, surgical and medical management options and tumour size and location from clinical records of haemangiosarcoma cases diagnosed in 2019 in VetCompass EPRs.

‘Variable’ and ‘information from EPRs’ columns show what information was captured from EPRs and what it was transformed or grouped into for regression analyses (‘Grouped variables’).

(DOCX)

pone.0316066.s001.docx^{(24.7KB, docx)}

S2 Table. Descriptive statistics and univariable logistic regression results of haemangiosarcoma cases diagnosed in first-opinion practices in VetCompass in 2019 with <1 day survival (‘Day 0’, n = 381) and ≥1 day of survival post presentation (‘Day 1’, n = 407).

Percentages shown are column percentages.

(DOCX)

pone.0316066.s002.docx^{(46.8KB, docx)}

S3 Table. Descriptive statistics and univariable Cox proportional hazards regression results of risk factors evaluated for hazard of time to death in haemangiosarcoma cases diagnosed in first-opinion practices in VetCompass in 2019 with ≥1 day of survival post presentation (n = 407).

Percentages shown are column percentages.

(DOCX)

pone.0316066.s003.docx^{(42.5KB, docx)}

S4 Table. Descriptive statistics and univariable Cox proportional hazards regression results of risk factors evaluated for hazard of time to death in haemangiosarcoma cases diagnosed with histopathology in first-opinion practices in VetCompass in 2019 (n = 272).

Percentages shown are column percentages.

(DOCX)

pone.0316066.s004.docx^{(43.5KB, docx)}

Acknowledgments

The authors are grateful to Morris Animal Foundation for their funding of this research. Thanks to Noel Kennedy (RVC) for VetCompass software and programming development. We acknowledge the Medivet Veterinary Partnership, Vets4Pets/Companion Care, Goddard Veterinary Group, CVS Group, IVC Evidensia, Linnaeus Group, Beaumont Sainsbury Animal Hospital, PDSA, Blue Cross, Dogs Trust, Vets Now and the other UK practices who collaborate in VetCompass. We are grateful to The Kennel Club Charitable Trust, Agria Pet Insurance and The Kennel Club for supporting VetCompass.

Data Availability

The dataset supporting the conclusions of this article is publicly available from Figshare at: https://doi.org/10.6084/m9.figshare.28907357.

Funding Statement

This work was supported by the Morris Animal Foundation (Grant No. D23CLP-550), which funded the postdoctoral researcher position of CT and the Master’s by Research degree of GB. JL is a permanent employee of the Morris Animal Foundation. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JL, as an employee of the funder, was involved in study design, analysis, and manuscript preparation.

References

1.De Nardi AB, de Oliveira Massoco Salles Gomes C, Fonseca-Alves CE, de Paiva FN, Linhares LCM, Carra GJU, et al. Diagnosis, prognosis, and treatment of canine hemangiosarcoma: A review based on a consensus organized by the Brazilian Association of Veterinary Oncology, ABROVET. Cancers. 2023;15. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Dobson JM, Samuel S, Milstein H, Rogers K, Wood JLN. Canine neoplasia in the UK: estimates of incidence rates from a population of insured dogs. J Small Anim Pract. 2002;43(6):240–6. doi: 10.1111/j.1748-5827.2002.tb00066.x [DOI] [PubMed] [Google Scholar]
3.Barry G. The epidemiology of canine haemangiosarcoma. 2024.
4.Withrow SJ, Vail DM, Page RL. Withrow & MacEwen’s small animal clinical oncology. 5th ed. Missouri: Elsevier Saunders; 2013. [Google Scholar]
5.Hillers KR, Lana SE, Larue SM. Effects of palliative radiation therapy on nonsplenic hemangiosarcoma in dogs [Internet]. J Am Anim Hosp Assoc. 2007;43(4). Available from: http://meridian.allenpress.com/jaaha/article-pdf/43/4/187/1333045/0430187.pdf?casa_token=r-p2ShSSR2sAAAAA:rCqLI7JTdLZyb7VVOSi9pK1RD8TpdmMWDzz8052L4fuJu4GR-Lak7CRthZ-yD9hHd6Giu1PMr3dz [DOI] [PubMed] [Google Scholar]
6.Shiu KB, Flory AB, Anderson CL, Wypij J, Saba C, Wilson H. Predictors of outcome in dogs with subcutaneous or intramuscular hemangiosarcoma. J Am Vet Med Assoc. 2011;238(4):472–9. [DOI] [PubMed] [Google Scholar]
7.Wendelburg KM, Price LL, Burgess KE, Lyons JA, Lew FH, Berg J. Survival time of dogs with splenic hemangiosarcoma treated by splenectomy with or without adjuvant chemotherapy: 208 cases (2001-2012). J Am Vet Med Assoc. 2015;247(4):393–403. doi: 10.2460/javma.247.4.393 [DOI] [PubMed] [Google Scholar]
8.Moore AS, Rassnick KM, Frimberger AE. Evaluation of clinical and histologic factors associated with survival time in dogs with stage II splenic hemangiosarcoma treated by splenectomy and adjuvant chemotherapy: 30 cases (2011-2014). J Am Vet Med Assoc. 2017;251(5):559–65. doi: 10.2460/javma.251.5.559 [DOI] [PubMed] [Google Scholar]
9.Yamamoto S, Hoshi K, Hirakawa A, Chimura S, Kobayashi M, Machida N. Epidemiological, clinical and pathological features of primary cardiac hemangiosarcoma in dogs: a review of 51 cases. J Vet Med Sci. 2013;75(11):1433–41. doi: 10.1292/jvms.13-0064 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Mullin CM, Arkans MA, Sammarco CD, Vail DM, Britton BM, Vickery KR, et al. Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs†. Vet Comp Oncol. 2016;14(4):e171–83. doi: 10.1111/vco.12131 [DOI] [PubMed] [Google Scholar]
11.Johnson KA, Powers BE, Withrow SJ, Sheetz MJ, Curtis CR, Wrigley RH. Splenomegaly in dogs. Predictors of neoplasia and survival after splenectomy. J Vet Intern Med. 1989;3(3):160–6. doi: 10.1111/j.1939-1676.1989.tb03092.x [DOI] [PubMed] [Google Scholar]
12.Masyr AR, Rendahl AK, Winter AL, Borgatti A, Modiano JF. Retrospective evaluation of thrombocytopenia and tumor stage as prognostic indicators in dogs with splenic hemangiosarcoma. J Am Vet Med Assoc. 2021;258(6):630–7. doi: 10.2460/javma.258.6.630 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Ward H, Fox LE, Calderwood‐Mays MB, Hammer AS, Couto CG. Cutaneous hemangiosarcoma in 25 dogs: a retrospective study. J Vet Intern Med. 1994;8(5):345–8. [DOI] [PubMed] [Google Scholar]
14.Nóbrega DF, Sehaber VF, Madureira R, Bracarense APFRL. Canine cutaneous haemangiosarcoma: biomarkers and survival. J Comp Pathol. 2019;166:87–96. [DOI] [PubMed] [Google Scholar]
15.Bray JP, Orbell G, Cave N, Munday JS. Does thalidomide prolong survival in dogs with splenic haemangiosarcoma? J Small Anim Pract. 2018;59(2):85–91. doi: 10.1111/jsap.12796 [DOI] [PubMed] [Google Scholar]
16.Robinson KL, Bryan ME, Atkinson ES, Keeler MR, Hahn AW, Bryan JN. Neutering is associated with developing hemangiosarcoma in dogs in the Veterinary Medical Database: an age and time-period matched case-control study (1964-2003). Can Vet J. 2020;61. [PMC free article] [PubMed] [Google Scholar]
17.Carnio A, Eleni C, Cocumelli C, Bartolomé Del Pino LE, Simeoni S, Spallucci V. Evaluation of intrinsic and extrinsic risk factors for dog visceral hemangiosarcoma: a retrospective case-control study register-based in Lazio region, Italy. Prev Vet Med. 2020;181. [DOI] [PubMed] [Google Scholar]
18.Szivek A, Burns RE, Gericota B, Affolter VK, Kent MS, Rodriguez CO. Clinical outcome in 94 cases of dermal haemangiosarcoma in dogs treated with surgical excision: 1993-2007. Vet Comp Oncol. 2012;10(1):65–73. [DOI] [PubMed] [Google Scholar]
19.Story AL, Wavreille V, Abrams B, Egan A, Cray M, Selmic LE. Outcomes of 43 small breed dogs treated for splenic hemangiosarcoma. Vet Surg. 2020;49(6):1154–63. [DOI] [PubMed] [Google Scholar]
20.Batschinski K, Nobre A, Vargas-Mendez E, Tedardi MV, Cirillo J, Cestari G. Canine visceral hemangiosarcoma treated with surgery alone or surgery and doxorubicin: 37 cases (2005-2014). Can Vet J. 2018;59. [PMC free article] [PubMed] [Google Scholar]
21.Wirth KA, Kow K, Salute ME, Bacon NJ, Milner RJ. In vitro effects of Yunnan Baiyao on canine hemangiosarcoma cell lines. Vet Comp Oncol. 2016;14(3):281–94. doi: 10.1111/vco.12100 [DOI] [PubMed] [Google Scholar]
22.Brown DC, Reetz J. Single agent polysaccharopeptide delays metastases and improves survival in naturally occurring hemangiosarcoma. Evid Based Complement Alternat Med. 2012;2012:384301. doi: 10.1155/2012/384301 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Hargis AM, Ihrke PJ, Spangler WL, Stannard AA. A retrospective clinicopathologic study of 212 dogs with cutaneous hemangiomas and hemangiosarcomas. Vet Pathol. 1992;29(4):316–28. doi: 10.1177/030098589202900406 [DOI] [PubMed] [Google Scholar]
24.Fonti N, Parisi F, Lachi A, Dhein ES, Guscetti F, Poli A, et al. Age at tumor diagnosis in 14,636 canine cases from the pathology-based UNIPI Animal Cancer Registry, Italy: one size doesn’t fit all. Vet Sci. 2024;11(10). [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Parker HG. Genomic analyses of modern dog breeds. Mamm Genome. 2012;23(1–2):19–27. doi: 10.1007/s00335-011-9387-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Davies O, Taylor AJ. Refining the “double two-thirds” rule: Genotype-based breed grouping and clinical presentation help predict the diagnosis of canine splenic mass lesions in 288 dogs. Vet Comp Oncol. 2020;18(4):548–58. doi: 10.1111/vco.12574 [DOI] [PubMed] [Google Scholar]
27.Dohoo I, Martin W, Stryhn H. Veterinary epidemiological research. VER Inc; 2009. 865 p. [Google Scholar]
28.Therneau TM, Grambsche PM. Modeling survival data: extending the cox model. New York: Springer; 2000. [Google Scholar]
29.O’Quigley J, Xu R, Stare J. Explained randomness in proportional hazards models. Stat Med. 2005;24(3):479–89. [DOI] [PubMed] [Google Scholar]
30.Schultheiss PC. A retrospective study of visceral and nonvisceral hemangiosarcoma and hemangiomas in domestic animals. J Vet Diagn Invest. 2004;16(6):522–6. doi: 10.1177/104063870401600606 [DOI] [PubMed] [Google Scholar]
31.Bulakowski EJ, Philibert JC, Siegel S, Clifford CA, Risbon R, Zivin K, et al. Evaluation of outcome associated with subcutaneous and intramuscular hemangiosarcoma treated with adjuvant doxorubicin in dogs: 21 cases (2001-2006). J Am Vet Med Assoc. 2008;233(1):122–8. doi: 10.2460/javma.233.1.122 [DOI] [PubMed] [Google Scholar]
32.Rehfuess E. Global solar UV index: a practical guide. A joint recommendation of the World Health Organization,World Meteorological Organization, United Nations Environment Programme, and the International Commission on Non-Ionizing Radiation Protection. World Health Organization; 2002. [Google Scholar]
33.Royal Netherlands Meteorological Institute (KNMI). Clear-sky UV index forecast and archives [Internet]. [cited 2024 Oct 28]. Available from: https://www.temis.nl/uvradiation/UVindex.php [Google Scholar]
34.Gedney A, Salah P, Mahoney JA, Krick E, Martins R, Scavello H. Evaluation of the anti-tumour activity of Coriolus versicolor polysaccharopeptide (I’m-Yunity) alone or in combination with doxorubicin for canine splenic hemangiosarcoma. Vet Comp Oncol. 2022;20(3):688–96. [DOI] [PubMed] [Google Scholar]
35.Radkiewicz C, Johansson ALV, Dickman PW, Lambe M, Edgren G. Sex differences in cancer risk and survival: a Swedish cohort study. Eur J Cancer. 2017;84:130–40. [DOI] [PubMed] [Google Scholar]
36.Jung KW, Park S, Shin A, Oh CM, Kong HJ, Jun JK, et al. Do female cancer patients display better survival rates compared with males? Analysis of the Korean national registry data, 2005-2009. PLoS One. 2012;7(12). [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Cook MB, McGlynn KA, Devesa SS, Freedman ND, Anderson WF. Sex disparities in cancer mortality and survival. Cancer Epidemiol Biomarkers Prev. 2011;20(8):1629–37. doi: 10.1158/1055-9965.EPI-11-0246 [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Jain R, Bitterman P, Lamzabi I, Reddy VB, Gattuso P. Androgen receptor expression in vascular neoplasms of the breast [Internet]; 2013. Available from: www.appliedimmunohist.com [DOI] [PubMed] [Google Scholar]
39.Trevejo R, Yang M, Lund EM. Epidemiology of surgical castration of dogs and cats in the United States. J Am Vet Med Assoc. 2011;238(7):898–904. doi: 10.2460/javma.238.7.898 [DOI] [PubMed] [Google Scholar]
40.Dobson JM. Breed-predispositions to cancer in pedigree dogs. ISRN Vet Sci. 2013;2013:941275. doi: 10.1155/2013/941275 [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Schick AR, Grimes JA. Evaluation of the validity of the double two-thirds rule for diagnosing hemangiosarcoma in dogs with nontraumatic hemoperitoneum due to a ruptured splenic mass: a systematic review. J Am Vet Med Assoc. 2022;261(1):69–73. [DOI] [PubMed] [Google Scholar]
42.Stewart SD, Ehrhart EJ, Davies R, Khanna C. Prospective observational study of dogs with splenic mass rupture suggests potentially lower risk of malignancy and more favourable perioperative outcomes. Vet Comp Oncol. 2020;18(4):811–7. doi: 10.1111/vco.12621 [DOI] [PubMed] [Google Scholar]

PLoS One. 2025 Jun 6;20(6):e0316066. doi: 10.1371/journal.pone.0316066.r001

Author response to Decision Letter 0

4 Dec 2024

PLoS One. doi: 10.1371/journal.pone.0316066.r002

Decision Letter 0

Simon Clegg

11 Mar 2025

PONE-D-24-56041Survival time and prognostic factors in dogs diagnosed with haemangiosarcoma in UK first opinion practicePLOS ONE

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Reviewer #1: This manuscript is an interesting evaluation of a large number of presumptive hemangiosarcoma cases in companion dogs evaluated at primary care veterinary facilities in the United Kingdom. The authors have built a rigorous statistical model to evaluate the variables they have selected to determine contributing factors to survival of dogs with HSA in these primary practices. However, not quite 35% of the cases are confirmed by histopathology and an unknown proportion are confirmed by cytology. Nearly half of the dogs were euthanized at presentation on day 0. The overall median survival time was 9 days and the vast majority of dogs died from euthanasia rather than disease with only a small proportion receiving full care in the form of surgery and chemotherapy. In the end, this manuscript is a description of the euthanasia practices of veterinary general practitioners in the UK with a clear bias against treating hemangiosarcoma aggressively. The applicability in the US or other parts of the world is very unclear.

The manuscript is ponderously long, diluting the message of the manuscript. The greatest flaw of the paper is that the authors have evaluated objective patient factors to determine the contributors to survival from HSA, when the fact that half of the patients were euthanized immediately and half of the rest within nine days makes it unlikely that any of the patient characteristics were the primary driving factor in the euthanasia decision. The fact that histologic confirmation of the disease was not required for the study is a confounding factor, as other diseases that are indistinguishable from HSA using clinical tests could have had better to excellent prognosis and were clearly not considered. For example, how many cases of splenic hematoma were diagnosed in the same year? That would be an interesting evaluation to determine the strength of the bias towards HSA as the diagnosis in hemoabdomen or splenic mass in this group of practitioners. Similarly, adding other splenic tumor diagnoses to the analysis would help evaluate the extent to which the population of veterinarians is simply biased towards HSA as a diagnosis and against its treatment.

Minor comments:

In the dogs eliminated for the 5 year age restriction, did any have a histologic diagnosis of HSA?

The benefit of having "no clinical signs at presentation" is highly questionable, given that this represents only 28 dogs out of the population and the group is not better described to understand the exact presentation. Were these mostly cutaneous HSA dogs?

Hazard of death increased as tumor size increased, yet at least one paper has suggested that larger masses are less likely to be HSA. Given the lack of biopsy confirmation, were other differentials considered and are the veterinarians aware that larger tumors might carry a better prognosis with surgical removal? Again, a control group of dogs with other splenic tumors might identify overall population bias when HSA is the top considered diagnosis.

Harmonizing the language around the hazard ratios would be very helpful. "Increase in hazard" of death is very clear, but "half the reduction in hazard of death" to describe a HR of 0.48 is confusing as it is almost a double negative. Consider "decrease in hazard of death" and list the HR.

The discussion of male sex and hazard of death is perhaps unnecessary as the dogs in question did not die of actual disease complications, but of euthanasia and typically quite early in the course of the treatment. The factors that lead UK veterinarians to not treat HSA effectively is perhaps a better focus of the manuscript.

The likelihood of a "common prevailing view of extremely poor prognosis" is discussed only in the discussion. This is perhaps the headline of the study.

Reviewer #2: The manuscript entitled “Survival time and prognostic factors in dogs diagnosed with haemangiosarcoma in UK first opinion practice” uses a large database of patient records to look at survival and potential prognostic factors.

Overall this is an interesting well described study that adds to the literature. I do have some comments and suggestions.

Title: I feel this title is a bit misleading as these cases do not necessarily have a true diagnosis but are presumed to have this diagnosis in many cases. I recognize that in the discussion this is addressed but I think would be useful to change the title to include presumed hemangiosarcoma or something similar.

Lines 143-145 – I am not sure how this was applied or what is meant. If no histopathology was obtained then these cases have hemangiosarcoma as a differential diagnosis and not actually a diagnosis of hemangiosarcoma.

Line 145 – Again using confirmed here could be misleading if they did not have an actual diagnosis – would suggest changing to suspected or presumed.

Was whether or not someone had insurance looked as a factor? It would be interesting to see if this affected whether a dog survived one day or more – ie was the dog euthanized on the suspected diagnosis if the people did not have insurance for their dog?

Do you know if dogs were euthanized on the table for those dogs not living past the first day – ie the vet opened the dpg and euthanized because it looked bad?

Were cases under 5 removed if they had a histopathological diagnosis – if so how many of these were there?

Minor points:

Line 88 retrievers and shepherds should probably be lower case type.

Line 182 has two periods at the end of the sentence.

Supplemental Table A2 – “Urirary” – typographical error

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Reviewer #2: No

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PLoS One. 2025 Jun 6;20(6):e0316066. doi: 10.1371/journal.pone.0316066.r003

Author response to Decision Letter 0

15 Apr 2025

14th April 2025

RE: Manuscript ID: PONE-D-24-56041

Manuscript title: Survival time and prognostic factors in dogs diagnosed with haemangiosarcoma in UK first opinion practice

Updated manuscript title: Survival time and prognostic factors in dogs clinically diagnosed with haemangiosarcoma in UK first opinion practice

Dear Dr Clegg and reviewers,

Thank you for your advice on how best to revise this manuscript and for the helpful and constructive further feedback from the reviewers. We have addressed all comments from both reviewers, as outlined below, with implementation or justification of all. We are grateful for these suggestions and feel that they have substantially enhanced this paper. We hope that you agree that these changes ensure that the overall paper now meets the standard required for publication in PLOS One.

Reviewer comments appear in normal text followed by any author responses in italics and then the revised manuscript lines and wording in bold. The line numbers quoted refer to the tracked changes version of the re-submission. In the resubmitted manuscript changes are highlighted in yellow.

Once again, thank you to PLOS One and to your reviewers for your excellent advice and support.

Yours sincerely,

Collette Taylor

Thank you to the reviewer for raising these interesting points. Due to the reviewer’s concern about clinically diagnosed versus laboratory-confirmed diagnoses of haemangiosarcoma having very different prognoses we have now examined survival time and created a separated survival model of those cases with a histologically confirmed diagnosis. Many of the findings in this model are similar as to those in the presumptive model (tumour size, surgery, location) and as such we believe the findings from both models together complement each other in this paper to explain haemangiosarcoma (clinically diagnosed and confirmed cases) survival in first opinion practice. This “clinically diagnosed” clarification has been amended throughout the manuscript. Due to the limited sensitivity of cytology in diagnosing sarcomas, particularly haemangiosarcoma, and the reliance on histopathological evaluation of surgically obtained biopsies for a definitive diagnosis, studies that include only histologically confirmed cases are inherently biased toward dogs with localised or loco-regional disease. This is because surgical excision is more likely to be pursued in cases where the tumour is at an early stage and the procedure is clinically justifiable. Consequently, such studies may underrepresent dogs with advanced or metastatic haemangiosarcoma, in whom invasive diagnostic procedures are either contraindicated (due to high risk of bleeding) or provide limited clinical benefit, thereby skewing the population toward earlier disease stages. Also in the oncology referral setting, dogs presenting with widespread metastatic disease will be pressumptively diagnosed and treated for haemangiosarcoma in the absence of histopathology based on signalment, clinical presentation and these biases of cases to only those confirmed would therefore lead to falsely high survival rates and potentially different factors associated with disease than what is truly seen in first opinion practice in the UK.

Whilst the reviewer considers that patient characteristics are not the primary driving factor in the euthanasia decision, we would consider these demographic factors are relevant. For example, owners of older dogs or giant breed dogs could be much more likely to euthanise at presentation due to perceptions of a short life expectancy remaining.

The generalisability (or potential lack of) to other countries in the world has been expanded on in discussion. The following lines have been added or modified as a result of these comments:

Lines 1-3: Survival time and prognostic factors in dogs clinically diagnosed with haemangiosarcoma in UK first opinion practice

Line 32: Dogs clinically diagnosed with haemangiosarcoma in first-opinion practice in 2019 were

Lines 42-46: Of dogs with a histopathological diagnosis of haemangiosarcoma, overall MST was longer at 105 days (95% CI 84-133 days) and additionally, location-specific MST were longer. For both clinically diagnosed cases and histopathologically confirmed cases, increasing tumour size was associated with increased hazard of death while cutaneous location and surgery were associated with reduced hazard of death.

Line 49-52: However, a common prevailing view of extremely poor prognosis for haemangiosarcoma could be promoting frequent euthanasia at presentation and therefore leading to a self-fulfilling prophecy and low survival times. Further exploration of the potential effect of perceived prognosis is warranted.

Line 133-137: A haemangiosarcoma case was defined as a dog with evidence of a final clinical diagnosis (with or without histopathological confirmation) of haemangiosarcoma in the EHRs. As not all cases underwent a definitive histopathological diagnosis, the diagnosis of haemangiosarcoma was considered a clinical diagnosis in some dogs.

Line 145: confirmed diagnosis. Haemangiosarcoma cases had additional clinical information extracted

Line 197-203: Two separate survival analyses were undertaken using Cox proportional hazards regression modelling. In the first model, all dogs with ≥1 day survival after diagnosis (n=407) were considered to evaluate the hazard of death from both clinically diagnosed and histopathologically diagnosed haemangiosarcoma cases. In order to explore whether factors associated with hazard of death for dogs clinically diagnosed with haemangiosarcoma were consistent in lab confirmed haemangiosarcoma cases, a second model was built using only dogs with a histopathological diagnosis of haemangiosarcoma (n=272).

Line 273: Survival time across all clinically diagnosed haemangiosarcoma cases ranged from 0-1789 days

Line 287: Figure 2 – Kaplan-Meier survival curve estimating the survival time of clinically diagnosed

Line 292-299: Of those dogs with a confirmed histopathological diagnosis of haemangiosarcoma (n=272), MST was 105 days (84-133 days), with a 1-year survival rate of of 28% (22-34%). For hepatic, splenic and cutaneous haemangiosarcoma locations, the MST was longer for those with a clinical diagnosis (hepatic MST: 79 days (95% CI 35-112 days), splenic MST: 80 days (95% CI 64-106 days), cutaneous MST: 248 days (95% CI 119-478 days)). The 1-year survival rate for these locations was: 7.2% (95% CI1.9-26.7%), 16% (95%CI 10.1-24.2%) and 43.2% (95% CI 34.8-53.6). The MST and 1-year survival rate for histopathologically confirmed cardiac haemangiosarcoma could not be calculated as there was only one case.

Line 346: Hazard for death with clinically diagnosed haemangiosarcoma in dogs that survive for ≥1 day after diagnosis

Line 379-412: Hazard for death with histopathologically confirmed haemangiosarcoma in dogs

Of the 62 variables examined in univariable analyses, 38 were liberally significant (LRT p-value <0.2). Variables describing clinical signs at presentation were not taken forward due to their lack of independence as factors, leaving 29 factors to be assessed in multivariable modelling (Table A4 in Supplementary material). Of these, 15 variables were potentially correlated which were assessed in non-nested models for inclusion.

In the final Cox proportional hazards regression model, seven variables were retained: whether a patient had any form of surgery, location of haemangiosarcoma, maximum tumour size, whether a patient visited a referral centre, whether soft tissue metastases were identified, dog genotype grouping and the corporate group the clinic belonged to (Figure 5). Corporate group was not significant but was forced into the model to better account for the structure of the data. Additionally, a frailty term of clinic ID was incorporated to further account for data structure. The overall model and individual independent variables were assessed for violation of proportional hazards. All individual variables and the overall model satisfied this assumption. The final model performed well, with a pseudo-R2 of 0.39 and a Concordance Index of 70.

Surgery, haemangiosarcoma location and size were consistent between this model of histopathologically diagnosed haemangiosarcoma cases and all haemangiosarcoma cases. Dogs that had surgery performed had a reduced hazard of death (HR=0.39,95%CI 0.25-0.61), when compared to those that did not. Dogs with cutaneous haemangiosarcoma had decreased hazard of death compared to splenic haemangiosarcoma cases (HR=0.60,95%CI 0.43-0.83). Larger tumour size was associated with an increased hazard of death, this hazard was greatest for tumours between 8-23cm when compared to 0.2-4.3cm tumours (HR=2.59, 95%CI 1.42-4.71). Visiting a referral centre was associated with a two-fold reduction in hazard of death (HR =0.46, 95% CI 0.31-0.69). Dogs of the genotype group 2 (primarily consisting of spaniel, hound and poodle breeds) had decreased hazard of death (HR=0.52, 95% CI 0.31-0.89) when compared to crossbred dogs (Figure 5).

Figure 5- Forest plot of final mixed effects multivariable Cox proportional hazards regression results for factors associated with time to death with haemangiosarcoma in cases histopathologically diagnosed in first-opinion practices in VetCompass in 2019 with ≥1 day of survival post diagnosis (n=272). Cases (%) column indicates the number of cases for each category in the model. HR indicates the hazard ratio for each category and its 95% confidence interval (CI) and p-value. The final model included a frailty term of Clinic ID.

Line 417-424: with a first-opinion level of diagnosis. This study identified a short MST overall for haemangiosarcoma (nine days) and for each main tumour location. In hazard regression modelling of dogs with ≥1 day of survival after diagnosis and dogs that had a histopathological diagnosis, dogs with haemangiosarcoma of a cutaneous location and dogs that had any surgical management performed had a reduced hazard of death. Increasing tumour size was associated with increased hazard of death. Males were also found to have increased hazard of death when both clinically diagnosed and laboratory confirmed haemangiosarcoma cases were modelled.

Line 445-448: When MSTs were calculated for cases with ≥1 day of survival after diagnosis or cases with a histologically confirmed diagnosis in this Vet Compass population, MSTs were similar to those reported in previous studies (7,10,31–33).

Lines 521-523: Both location and tumour size associations were consistent for both the model built with all clinically diagnosed cases and the model of only histologically diagnosed cases.

Male dogs had an increased hazard of death with haemangiosarcoma in the clinically diagnosed cases model.

Line 547-553: When histologically confirmed cases were examined, rather than variation in hazard for single dog breeds, dogs of the genotype group that consisted of spaniel, poodle, dachshund and beagle breeds were found to have a reduced hazard of death (27). These were not the same breeds identified to have increased survival by Nóbrega and colleagues (2019) (14). No breed associations were identified in the model of all haemangiosarcoma cases, nor with the survival time overall, in agreement with other existing literature (15,20).

Line 576-587: Given the variation in proportions of biopsies between haemangiosarcoma locations in this study, three-quarters of cutaneous haemangiosarcoma cases were biopsied here versus just 2 % and 28% of cardiac and splenic cases, it seems plausible that the severity of clinical presentation and the ability of first-opinion vets to perform haemangiosarcoma surgeries would have affected the uptake of biopsies. (1) Additionally, cytological diagnosis has limitations (such as blood contamination of samples) and an invasive biopsy may not be considered justifiable in patients with advanced disease (1). Furthermore, histopathology alone can be insufficient to differentiate splenic haemangiosarcoma from other sarcomas, requiring immunohistochemistry confirmation which has additional time and cost implications (1) Thus, if the study only included histologically diagnosed dogs, a large proportion of dogs would be excluded and survival would be biased to dogs with early stage haemangiosarcoma and longer survival times.

Lines 588-590: Euthanasia will undoubtedly have impacted survival risk factors. However, this study was interested in reporting the survival pattern overall and therefore both dogs euthanised due to the disease and dogs that died from the disease need to be included.

Line 604-608: Whilst these findings are likely applicable across wider UK first-opinion veterinary practices, it is unclear how applicable these findings are to other countries in the world. Factors such as breed genetic differences in other countries, access to diagnostics, standards of care and owner attitudes to euthanasia and treatment might vary between countries and lead to different associations than those seen here.

Lines 619-638: Additionally, a small prospective study by Stewart and colleagues (2020) found that dogs presenting with splenic mass rupture (both benign and malignant) had more favourable outcomes than existing literature informing views on prognosis would suggest (44). This highlights the potential role of prospective studies in exploring outcomes and euthanasia rates and reasons in haemangiosarcoma cases. Whilst it was not within the scope of this project to explore factors motivating owners to pursue euthanasia, it is likely that it was not only related to the tumour aggressive behaviour, but also other factors such as the severity of the clinical signs and perceived acute deterioration in quality of life, together with the age at presentation (adult to elderly for large breeds), probable presence of age-related comorbidities and treatment costs.

Future work could also attempt to identify a control population of other splenic tumours to evaluate whether the presumed haemangiosarcoma group truly has distinct survival and could impro

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PLoS One. doi: 10.1371/journal.pone.0316066.r004

Decision Letter 1

Simon Clegg

28 Apr 2025

Survival time and prognostic factors in dogs clinically diagnosed with haemangiosarcoma in UK first opinion practice

PONE-D-24-56041R1

Dear Dr. Taylor,

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Additional Editor Comments:

I wish to thank the authors for addressing the reviewer comments.

The manuscript reads well and I am pleased to recommend it for publication

I wish you the very best for your future research

PLoS One. doi: 10.1371/journal.pone.0316066.r005

Acceptance letter

Simon Clegg

PONE-D-24-56041R1

PLOS ONE

Dear Dr. Taylor,

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Supplementary Materials

‘Variable’ and ‘information from EPRs’ columns show what information was captured from EPRs and what it was transformed or grouped into for regression analyses (‘Grouped variables’).

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pone.0316066.s001.docx^{(24.7KB, docx)}

Percentages shown are column percentages.

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pone.0316066.s002.docx^{(46.8KB, docx)}

Percentages shown are column percentages.

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pone.0316066.s003.docx^{(42.5KB, docx)}

Percentages shown are column percentages.

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Data Availability Statement

The dataset supporting the conclusions of this article is publicly available from Figshare at: https://doi.org/10.6084/m9.figshare.28907357.

[pone.0316066.ref001] 1.De Nardi AB, de Oliveira Massoco Salles Gomes C, Fonseca-Alves CE, de Paiva FN, Linhares LCM, Carra GJU, et al. Diagnosis, prognosis, and treatment of canine hemangiosarcoma: A review based on a consensus organized by the Brazilian Association of Veterinary Oncology, ABROVET. Cancers. 2023;15. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref002] 2.Dobson JM, Samuel S, Milstein H, Rogers K, Wood JLN. Canine neoplasia in the UK: estimates of incidence rates from a population of insured dogs. J Small Anim Pract. 2002;43(6):240–6. doi: 10.1111/j.1748-5827.2002.tb00066.x [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref003] 3.Barry G. The epidemiology of canine haemangiosarcoma. 2024.

[pone.0316066.ref004] 4.Withrow SJ, Vail DM, Page RL. Withrow & MacEwen’s small animal clinical oncology. 5th ed. Missouri: Elsevier Saunders; 2013. [Google Scholar]

[pone.0316066.ref005] 5.Hillers KR, Lana SE, Larue SM. Effects of palliative radiation therapy on nonsplenic hemangiosarcoma in dogs [Internet]. J Am Anim Hosp Assoc. 2007;43(4). Available from: http://meridian.allenpress.com/jaaha/article-pdf/43/4/187/1333045/0430187.pdf?casa_token=r-p2ShSSR2sAAAAA:rCqLI7JTdLZyb7VVOSi9pK1RD8TpdmMWDzz8052L4fuJu4GR-Lak7CRthZ-yD9hHd6Giu1PMr3dz [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref006] 6.Shiu KB, Flory AB, Anderson CL, Wypij J, Saba C, Wilson H. Predictors of outcome in dogs with subcutaneous or intramuscular hemangiosarcoma. J Am Vet Med Assoc. 2011;238(4):472–9. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref007] 7.Wendelburg KM, Price LL, Burgess KE, Lyons JA, Lew FH, Berg J. Survival time of dogs with splenic hemangiosarcoma treated by splenectomy with or without adjuvant chemotherapy: 208 cases (2001-2012). J Am Vet Med Assoc. 2015;247(4):393–403. doi: 10.2460/javma.247.4.393 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref008] 8.Moore AS, Rassnick KM, Frimberger AE. Evaluation of clinical and histologic factors associated with survival time in dogs with stage II splenic hemangiosarcoma treated by splenectomy and adjuvant chemotherapy: 30 cases (2011-2014). J Am Vet Med Assoc. 2017;251(5):559–65. doi: 10.2460/javma.251.5.559 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref009] 9.Yamamoto S, Hoshi K, Hirakawa A, Chimura S, Kobayashi M, Machida N. Epidemiological, clinical and pathological features of primary cardiac hemangiosarcoma in dogs: a review of 51 cases. J Vet Med Sci. 2013;75(11):1433–41. doi: 10.1292/jvms.13-0064 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref010] 10.Mullin CM, Arkans MA, Sammarco CD, Vail DM, Britton BM, Vickery KR, et al. Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs†. Vet Comp Oncol. 2016;14(4):e171–83. doi: 10.1111/vco.12131 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref011] 11.Johnson KA, Powers BE, Withrow SJ, Sheetz MJ, Curtis CR, Wrigley RH. Splenomegaly in dogs. Predictors of neoplasia and survival after splenectomy. J Vet Intern Med. 1989;3(3):160–6. doi: 10.1111/j.1939-1676.1989.tb03092.x [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref012] 12.Masyr AR, Rendahl AK, Winter AL, Borgatti A, Modiano JF. Retrospective evaluation of thrombocytopenia and tumor stage as prognostic indicators in dogs with splenic hemangiosarcoma. J Am Vet Med Assoc. 2021;258(6):630–7. doi: 10.2460/javma.258.6.630 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref013] 13.Ward H, Fox LE, Calderwood‐Mays MB, Hammer AS, Couto CG. Cutaneous hemangiosarcoma in 25 dogs: a retrospective study. J Vet Intern Med. 1994;8(5):345–8. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref014] 14.Nóbrega DF, Sehaber VF, Madureira R, Bracarense APFRL. Canine cutaneous haemangiosarcoma: biomarkers and survival. J Comp Pathol. 2019;166:87–96. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref015] 15.Bray JP, Orbell G, Cave N, Munday JS. Does thalidomide prolong survival in dogs with splenic haemangiosarcoma? J Small Anim Pract. 2018;59(2):85–91. doi: 10.1111/jsap.12796 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref016] 16.Robinson KL, Bryan ME, Atkinson ES, Keeler MR, Hahn AW, Bryan JN. Neutering is associated with developing hemangiosarcoma in dogs in the Veterinary Medical Database: an age and time-period matched case-control study (1964-2003). Can Vet J. 2020;61. [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref017] 17.Carnio A, Eleni C, Cocumelli C, Bartolomé Del Pino LE, Simeoni S, Spallucci V. Evaluation of intrinsic and extrinsic risk factors for dog visceral hemangiosarcoma: a retrospective case-control study register-based in Lazio region, Italy. Prev Vet Med. 2020;181. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref018] 18.Szivek A, Burns RE, Gericota B, Affolter VK, Kent MS, Rodriguez CO. Clinical outcome in 94 cases of dermal haemangiosarcoma in dogs treated with surgical excision: 1993-2007. Vet Comp Oncol. 2012;10(1):65–73. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref019] 19.Story AL, Wavreille V, Abrams B, Egan A, Cray M, Selmic LE. Outcomes of 43 small breed dogs treated for splenic hemangiosarcoma. Vet Surg. 2020;49(6):1154–63. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref020] 20.Batschinski K, Nobre A, Vargas-Mendez E, Tedardi MV, Cirillo J, Cestari G. Canine visceral hemangiosarcoma treated with surgery alone or surgery and doxorubicin: 37 cases (2005-2014). Can Vet J. 2018;59. [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref021] 21.Wirth KA, Kow K, Salute ME, Bacon NJ, Milner RJ. In vitro effects of Yunnan Baiyao on canine hemangiosarcoma cell lines. Vet Comp Oncol. 2016;14(3):281–94. doi: 10.1111/vco.12100 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref022] 22.Brown DC, Reetz J. Single agent polysaccharopeptide delays metastases and improves survival in naturally occurring hemangiosarcoma. Evid Based Complement Alternat Med. 2012;2012:384301. doi: 10.1155/2012/384301 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref023] 23.Hargis AM, Ihrke PJ, Spangler WL, Stannard AA. A retrospective clinicopathologic study of 212 dogs with cutaneous hemangiomas and hemangiosarcomas. Vet Pathol. 1992;29(4):316–28. doi: 10.1177/030098589202900406 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref024] 24.Fonti N, Parisi F, Lachi A, Dhein ES, Guscetti F, Poli A, et al. Age at tumor diagnosis in 14,636 canine cases from the pathology-based UNIPI Animal Cancer Registry, Italy: one size doesn’t fit all. Vet Sci. 2024;11(10). [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref025] 25.Parker HG. Genomic analyses of modern dog breeds. Mamm Genome. 2012;23(1–2):19–27. doi: 10.1007/s00335-011-9387-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref026] 26.Davies O, Taylor AJ. Refining the “double two-thirds” rule: Genotype-based breed grouping and clinical presentation help predict the diagnosis of canine splenic mass lesions in 288 dogs. Vet Comp Oncol. 2020;18(4):548–58. doi: 10.1111/vco.12574 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref027] 27.Dohoo I, Martin W, Stryhn H. Veterinary epidemiological research. VER Inc; 2009. 865 p. [Google Scholar]

[pone.0316066.ref028] 28.Therneau TM, Grambsche PM. Modeling survival data: extending the cox model. New York: Springer; 2000. [Google Scholar]

[pone.0316066.ref029] 29.O’Quigley J, Xu R, Stare J. Explained randomness in proportional hazards models. Stat Med. 2005;24(3):479–89. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref030] 30.Schultheiss PC. A retrospective study of visceral and nonvisceral hemangiosarcoma and hemangiomas in domestic animals. J Vet Diagn Invest. 2004;16(6):522–6. doi: 10.1177/104063870401600606 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref031] 31.Bulakowski EJ, Philibert JC, Siegel S, Clifford CA, Risbon R, Zivin K, et al. Evaluation of outcome associated with subcutaneous and intramuscular hemangiosarcoma treated with adjuvant doxorubicin in dogs: 21 cases (2001-2006). J Am Vet Med Assoc. 2008;233(1):122–8. doi: 10.2460/javma.233.1.122 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref032] 32.Rehfuess E. Global solar UV index: a practical guide. A joint recommendation of the World Health Organization,World Meteorological Organization, United Nations Environment Programme, and the International Commission on Non-Ionizing Radiation Protection. World Health Organization; 2002. [Google Scholar]

[pone.0316066.ref033] 33.Royal Netherlands Meteorological Institute (KNMI). Clear-sky UV index forecast and archives [Internet]. [cited 2024 Oct 28]. Available from: https://www.temis.nl/uvradiation/UVindex.php [Google Scholar]

[pone.0316066.ref034] 34.Gedney A, Salah P, Mahoney JA, Krick E, Martins R, Scavello H. Evaluation of the anti-tumour activity of Coriolus versicolor polysaccharopeptide (I’m-Yunity) alone or in combination with doxorubicin for canine splenic hemangiosarcoma. Vet Comp Oncol. 2022;20(3):688–96. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref035] 35.Radkiewicz C, Johansson ALV, Dickman PW, Lambe M, Edgren G. Sex differences in cancer risk and survival: a Swedish cohort study. Eur J Cancer. 2017;84:130–40. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref036] 36.Jung KW, Park S, Shin A, Oh CM, Kong HJ, Jun JK, et al. Do female cancer patients display better survival rates compared with males? Analysis of the Korean national registry data, 2005-2009. PLoS One. 2012;7(12). [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref037] 37.Cook MB, McGlynn KA, Devesa SS, Freedman ND, Anderson WF. Sex disparities in cancer mortality and survival. Cancer Epidemiol Biomarkers Prev. 2011;20(8):1629–37. doi: 10.1158/1055-9965.EPI-11-0246 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref038] 38.Jain R, Bitterman P, Lamzabi I, Reddy VB, Gattuso P. Androgen receptor expression in vascular neoplasms of the breast [Internet]; 2013. Available from: www.appliedimmunohist.com [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref039] 39.Trevejo R, Yang M, Lund EM. Epidemiology of surgical castration of dogs and cats in the United States. J Am Vet Med Assoc. 2011;238(7):898–904. doi: 10.2460/javma.238.7.898 [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref040] 40.Dobson JM. Breed-predispositions to cancer in pedigree dogs. ISRN Vet Sci. 2013;2013:941275. doi: 10.1155/2013/941275 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0316066.ref041] 41.Schick AR, Grimes JA. Evaluation of the validity of the double two-thirds rule for diagnosing hemangiosarcoma in dogs with nontraumatic hemoperitoneum due to a ruptured splenic mass: a systematic review. J Am Vet Med Assoc. 2022;261(1):69–73. [DOI] [PubMed] [Google Scholar]

[pone.0316066.ref042] 42.Stewart SD, Ehrhart EJ, Davies R, Khanna C. Prospective observational study of dogs with splenic mass rupture suggests potentially lower risk of malignancy and more favourable perioperative outcomes. Vet Comp Oncol. 2020;18(4):811–7. doi: 10.1111/vco.12621 [DOI] [PubMed] [Google Scholar]

PERMALINK

Survival time and prognostic factors in dogs clinically diagnosed with haemangiosarcoma in UK first opinion practice

Collette Taylor

Georgina J Barry

Dan G O’Neill

Alexandra Guillén

Phoebe Pickard Price

Julia Labadie

Dave C Brodbelt

Roles

Abstract

Introduction

Table 1. Published factors reported to affect survival post haemangiosarcoma diagnosis ↑ = increased survival time, ↓ = reduced survival time and - = no effect.

Methods

Study population and case identification

Clinical record coding

Table 2. Information extracted from clinical records of haemangiosarcoma cases diagnosed in 2019 in VetCompass EHRs. The ‘Variable’ column shows what information was captured from EHRs and what it was transformed or grouped into for regression analyses (‘Grouped variables’).

Survival time

Factors associated with dying on day of diagnosis

Cox regression modelling

Results

Study population

Fig 1. Grouping of clinical variables coded from electronic health records of dogs presenting with haemangiosarcoma to VetCompass clinics in 2019 (n = 788).

Survival time

Fig 2. Kaplan-Meier survival curve estimating the survival time of clinically diagnosed haemangiosarcoma cases diagnosed in first-opinion practices in VetCompass in 2019 separated by location affected: cardiac, cutaneous, hepatic, splenic.

Factors associated with death on day of diagnosis

Fig 3. Forest plot of final multivariable logistic regression model of haemangiosarcoma cases diagnosed in first-opinion practices in VetCompass in 2019 who died on day of diagnosis (‘Day 0’, n = 381) and those who died ≥1 day of survival post diagnosis (‘Day ≥1’, n = 407).

Hazard for death with clinically diagnosed haemangiosarcoma in dogs that survive for ≥1 day after diagnosis

Fig 4. Forest plot of final mixed effects multivariable Cox proportional hazards regression results for factors associated with time to death with haemangiosarcoma in cases diagnosed in first-opinion practices in VetCompass in 2019 with ≥1 day of survival post diagnosis (n = 407).

Hazard for death with histopathologically confirmed haemangiosarcoma in dogs

Discussion

Survival time after diagnosis with haemangiosarcoma

Factors associated with dying on day of diagnosis

Factors associated with time to death with haemangiosarcoma

Limitations

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Author response to Decision Letter 0

Decision Letter 0

Simon Clegg

Roles

Author response to Decision Letter 0

Decision Letter 1

Simon Clegg

Roles

Acceptance letter

Simon Clegg

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

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