Aside from nonhuman primate, the dog is the only nonhuman specie in which spontaneous BPH occurs physiologically. As like in humans, BPH in dogs is an age-related disease which causes a hyperplastic prostate growth (Sun et al. 2017). In a pathological study in 41 intact beagles (1–10 years), DeKlerk et al. (1979) identified two types of spontaneous BPH, glandular hyperplasia and cystic hyperplasia (complex form of hyperplasia). The canine BPH may develop as early as 2–3 years of age as a glandular hyperplasia characterized as an adenomatous disease, which later becomes cystic hyperplasia with hyperplastic epithelium combined with formation of large cysts and increase in the stroma amount (Sun et al. 2017; DeKlerk et al. 1979; Palmieri et al. 2019). Thus, just the cystic or complex form of hyperplasia in dogs shares more similarities to human BPH in pathology and therefore, it would be an ideal canine model in evaluation of PAE technique and associated devices. In addition, in this report was observed that all prostates that weighted more than 18 g had pathological evidence of BPH; whereas all except one that weighted less than 12.8 g were histologically normal. Accordingly, Sun et al. (2017) suggested that the gravimetric criterion of prostate weight larger than 18 g in adult beagles can be used as a standard in screening for spontaneous BPH model in preclinical studies to test new devices in PAE procedures.
Hormone-induced BPH canine models are currently most commonly used in evaluation PAE techniques and interventional devices (Sun et al. 2011; Jeon et al. 2009). According to Sun et al. (2017), hormone-induced BPH is a reliable and reproducible model that can be established in young surgical castrated or intact dogs with common hormonal treatment regimens based on combination of androgens and estrogens for 3 months or longer. One striking feature of this model is its large size of the prostate and large diameter of the prostatic arteries. A report demonstrated that after 3-month hormonal therapy, the prostate volume increased up to 572% (Sun et al. 2011). Another advantage of this model is the use of young beagles (1–2 years), which is of much more commercial availability compared with the older beagles with spontaneous BPH.
However, hormone-induced BPH model in evaluation of PAE techniques has several disadvantages. In pathology, all hormone-induced BPH models represent the glandular hyperplasia rather than the complex form of hyperplasia with mild to moderate increase in the stroma that is observed in old dogs with spontaneous BPH (DeKlerk et al. 1979). The lack of stroma tissue in the hormone-induced model may explain the highly sensitive responses to PAE, such as massive intraprostatic infarction and secondary cavity formation (Sun et al. 2017), in comparison with findings in human patients, where cavity formation rarely occurred after PAE (Frenk et al. 2014). Moreover, hormone-induced BPH models are not suitable for chronic studies with long-term evaluation after PAE because hormonal therapy should last in whole duration of the study; otherwise, the cessation of administration of the hormones may lead to atrophy of the prostate (Jeon et al. 2009). Due to the prostate gland grows rapidly when it is exposed to high serum level of exogenous androgens and estrogen, if the recanalization of the prostatic arteries occurs or the collateral circulation is established after PAE, the residual glandular tissue has a tendency to rapidly regenerate and grow in size (Jeon et al. 2009; Zhang et al. 2020). Obviously, this situation would occur neither in dogs with spontaneous BPH nor in human patients in clinical practice. In addition, hormone-induced BPH cannot be used in evaluation of sexual function following PAE, which can be conducted in spontaneous BPH model.
It is worth noting that canine models of both spontaneous BPH and hormone-induced BPH have their inherent limitations in evaluation of PAE techniques. Unlike in human patients, the canine hyperplastic prostate expands outwardly in all directions, commonly observed clinical signs involve those of rectal obstruction rather than lower urinary tract symptoms (LUTS). Furthermore, prostate specific antigen (PSA), an important biochemical marker in clinical practice in human prostatic disorders, is not detected in canine blood or seminal fluid (Sun et al. 2017). Therefore, evaluation of LUTS, urodynamic study, and test of PSA are not applicable in preclinical studies of PAE techniques in dogs. Alternatively, the only likely parameter to evaluate the therapeutic effects of PAE is the prostate volume change detected by imaging technologies, MRI or ultrasonography.
In the present study, substantial decrease in PV was detected early at 2 weeks, and the prostates further shrank at 1 month after PAE. Compared with the baseline data, the PV reduction was about 34% at 2 weeks and 53% at 1 month, respectively, supporting the therapeutic effects of PAE with polyethylene glycol microspheres. However, no significant change in the PV was noticed at 1 week, which may be explained by the MRI findings detected of intraprostatic infarction and edema of surrounding tissue; with time, as the edema is absorbed and organization or fibrosis occurs in the infarcted tissue, the prostate will shrink (Sun et al. 2016). This mechanism of shrinkage of prostate after PAE was also supported by the pathological findings in our present study. Cavitary necrosis is a common pathological reaction to PAE in dogs, which has also been reported in other studies (Sun et al. 2011; Jeon et al. 2009). This finding is caused by ischemia in glandular prostatic tissue whose area of necrosis gradually sloughts forming an intraprostatic cavity. The present study showed cavitary necrosis in 3 out of 5 dogs; whereas in a previous study on PAE in hormone-induced model, cavitary necrosis was observed in all 7 dogs (Sun et al. 2011). The inconsistent findings may be attributed to the different pathological features between the both BPH models. In PAE procedures of present study, technical success with bilateral embolization was achieved in all cases, highlighting the technical feasibility of the embolic agent as well as reliability of the animal model. In addition, no major complications related to PAE procedures were observed in any animal, indicating the technical safety of PAE by the use of the microspheres.
Interestingly, we observed that the prostatic artery or its main branches reopened in all dogs at 1-month follow-up of angiography. The recanalization varied in morphology, including the wide open lumen as total recanalization and the narrowed lumen or proximal obstruction together with distal fine anastomosis as partial recanalization. It is not surprising that recanalization occurs after arterial embolization with non-absorbable embolic agents. In a report of embolization in porcine renal model, four different embolic agents, spherical and non-spherical particles, were used to embolize the upper pole of the kidney. At 28 days after embolization, the follow-up angiographies showed partial recanalization with non-spherical particles while all but one of the arteries embolized with spherical particles were recanalized (Siskin et al. 2003). Similarly, Bilbao et al. (2008) tested four spherical embolic agents in pig kidney. The follow-up angiographies after 4 weeks postembolization showed variable degree of recanalization with three out of four embolic agents. The underlying recanalization mechanism has been suggested by the inflammatory process related to the injury in the embolized arterial wall that promotes the resorption of thrombus, angiogenesis and capillary regrowth, so as the particles exclusion from the occluded vessel wall (Laurent et al. 2009). Besides, capillary development is induced by releasing of the angiogenic factors under hypoxia conditions associated to embolization (Keussen et al. 2018; Jackson et al. 2018). Recanalization may affect to the long-term effectiveness of embolization and allow the recovery of normal tissue. The findings of the early recanalization of the embolized prostatic artery in the present study suggest it may also happen in human patients. Bilhim et al. (2016) reported that 20%–36% of patients still had moderate to severe LUTS after PAE, among which up to 80% of all were nonresponders who never substantially improved after PAE. However, how many nonresponders might have an early recanalization of the prostatic artery after PAE is unknown. The association of clinical failure with early prostatic recanalization needs to be addressed in clinical practice.
This study has several limitations. The sample size of animal was too small and lacked of comparison with other commonly used embolic agents in control group. The follow-up duration was just for 1 month without long-term observation. The absence of pathological evaluation over the recanalized vessels limited the strength of the study.