European Society of Toxicologic Pathology (ESTP)
    European Society of Toxicologic Pathology
Guess What! - ESTP Case 9

The case shows H&E stained pictures from the tail of three young male Sprague Dawley rats which have received a single intravenous application and were euthanized after a 2-week post-treatment period. No gross observations were reported.

Click on the images below for a larger view.
Case 9, Fig. 1
Fig. 1: H&E, x10
Case 9, Fig. 2
Fig. 2: H&E, x20
Case 9, Fig. 3
Fig. 3: H&E, x20

Morphologic Description

Case 9 showed three different stages of proliferative changes of veins and arterioles located at the mid-ventral artery in the tail of rats. The lesions were characterized by slight to marked proliferation of the media and intima especially of smaller arterioles and veins up to complete obliteration, and probably to the formation of collateral vessels. An inflammatory response was lacking.

Proposed Diagnosis
Reactive proliferative change of vascular elements around the mid-ventral coccygeal artery due to impairment of venous return after intravenous injection

Differential Diagnoses and Discussion

Sixteen diagnoses were received for this case. Most of the contributors gave a morphological description of the lesions which were frequently found to be difficult to describe. This indeed is true and had motivated the contributor of the case in advance not only to ask for a diagnosis but also for the possible pathogenesis of the lesion.

From the various answers it turned out that it might be useful to refer to the precise anatomical orientation within the rat tail (Figure 4). A helpful publication has been provided by Staszyk et al. in 2003. In general, two lateral veins (LV) and one dorsal vein are accessible for either injection or blood collection. The mid-ventral region has also been proposed for ‘venipuncture’ (Omaye et al., 1987) what however has caused controversy. The mid-ventral artery (VA) is the most prominent vessel and represents a landmark in the tail anatomy since its thickness decreases only slightly from the base to the tip of the tail. Its wall is composed of approximately 6 to 10 layers of smooth muscle cells. Normally, this mid-ventral artery is laterally and dorsally accompanied by smaller veins and arterioles and is enclosed in a groove surrounded by coccygeal tendons and muscles, and covered by a thick fascia. In Guess What Case No. 9, the mid-ventral artery was visible in every illustration and showed no deviation from normal while the accompanying vessels were clearly altered.

Consequently, one respondent suspected an accidental intra-arterial application being the cause for the pronounced lesions. However, such failure most likely would have presumably led to a more severe inflammatory response and to residuals of hemorrhage such as pigment deposition. As perivasculitis was found to be not very pronounced, periveneous administration was excluded also by another contributor. Moreover, accidental fail-application in three animals should not be an acceptable option within a toxicological study.

One contributor suspected a congenital vascular hamartoma. Also this seems unlikely to occur in three animals at a time, but might be possible in litter mates. However, such alteration should be formed by a more regular endothelial lining of the vascular structures. An example of vascular hamartoma has been presented as Guess What Case No. 1.

The treatment of the three animals of Case 9 had been regularly performed via the lateral vein where it had caused local irritation (Figure 5). Three contributors thought that thrombus formation could have led to the formation of collaterals. This can not be excluded, even though organized thrombi were not detected. Several respondents were familiar with the kind of the described lesion and had seen it before in i.v. studies but obviously mostly to a lesser degree. Most contributors suspected impairment of venous return due to vascular compromise of lateral veins. The actual reason for the pronounced proliferation remains open. A compound-related effect (such as growth factor-associated lesions) can be ruled out since the lesions were observed also in vehicle-only treated animals.

The case was chosen to increase the sensibility, to not only observe carefully the application site but also the other functional compartments of the tail after intravenous treatment.

Click on the images below for a larger view.
Case 9, Fig. 4
Fig. 4: H&E, x5
Case 9, Fig. 5
Fig. 5: H&E, x20

References

  • Omaye ST, Skala JH, Gretz MD, Schauss EE, and Wade CE (1987) Simple method for bleeding the unanaesthetized rat by tail venipuncture. Laboratory Animals 21: 261-264
  • Stasczyk C, Bohnet W, Gasse H, and Hackbarth HJ (2003): Blood vessels of the rat tail: a histological re-examination with respect to blood vessel puncture methods. Laboratory Animals 37: 121-125