European Society of Toxicologic Pathology (ESTP)
    European Society of Toxicologic Pathology
Guess What! - ESTP Case 24
Morphologic Description

Figures 2 and 4 show the thymus of a rat, Crl: WI (Han) treated with a low molecular weight compound for 14 days (once daily, oral by gavage). Figures 1 and 3 are from a corresponding control animal of the same study. The main findings are thinning of the cortex and enlargement of the medulla. There are increased numbers of darker stained lymphocytes in the medulla leading to blurring of the normally distinct border between cortex and medulla.

Click on the images below for a larger view.
Case 20, Fig. 1
Fig. 1: Thymus, control rat, 5x
Case 20, Fig. 1
Fig. 2: Thymus, high-dose rat, 5x
Case 20, Fig. 1
Fig. 3: Thymus, control rat, 20x
Case 20, Fig. 1
Fig. 4: Thymus, high-dose rat, 20x

Proposed Diagnosis
Conventional histopathology:
Atrophy, cortex; Hyperplasia, lymphoid, medulla; Loss of corticomedullary distinction
Enhanced histopathology:
Lymphocytes decreased, cortex; lymphocytes increased, T-lymphocytes, medulla; Loss of corticomedullary distinction

For this case, the conventional diagnosis of lymphoid hyperplasia, medulla is not optimal, since it should be clearly distinguished from a pre-neoplastic process. Therefore the enhanced diagnoses are preferred.


Ten contributions were received for this case.

Increased size, cellularity or hyperplasia of the medulla and/or altered cortico-medullary ratio were suggested by eight of the contributors. One contributor mentioned the changed tinctorial aspect (more basophilic thymocytes in the medulla) and another mentioned prominent epithelium-free areas. Two contributors suggested alteration in lymphocyte trafficking as the mechanism for the morphological alterations (inhibition of egression, e.g. caused by Sphingosis-1-phospate analogues).

T-lymphocytes originate from a common lymphoid progenitor cell in the bone marrow and they migrate to the thymus for further development. The thymic cortex contains immature lymphocytes, whereas mature lymphocytes are found in the medulla. Afterwards, some of the mature lymphocytes leave the thymus. A critical factor for the egress of lymphocytes from the thymus as well as secondary lymphoid organs is sphingoside-1-phosphate receptor 1 (S1PR1) expression on lymphocytes. The egress requires a gradient on S1P concentrations at the site of transmigration (under normal conditions, S1P concentrations are higher in blood and lymph compared to the interstitial fluid of lymphoid organs).

S1P receptors are involved in the regulation of fundamental processes, including cell proliferation, angiogenesis, migration, cytoskeleton organization, endothelial cell chemotaxis, immune cell trafficking, mitogenesis. They are divided into 5 subtypes S1P1-5, expressed in a variety of tissues with each subtype showing differences in cell specificity; highest density generally on leucocytes. S1P1, 2 and 3 are ubiquitously expressed; S1P4 in lymphoid/hematopoietic tissues, S1P5 in the CNS.

The rat was treated for 14 days with fingolimod. Fingolimod binds to S1P receptors 1, 3 and 4 on lymphocytes and 1, 3 and 5 on neural cells in the CNS. It acts as functional antagonist of S1P receptors on lymphocytes. As a consequence after treatment with fingolimod, the S1P gradient is lost in lymphoid organs, including thymus. The mature lymphocytes can no longer egress from the medulla and stay there. The size of the medulla increases and the usually clear histological distinction between cortex and medulla is blurred due to the large number of mature lymphocytes in the medulla.

Two contributors also noted an increase in epitheloid cells or macrophage activation. This was not a constant feature of the thymic alterations and may have been more prominent in the selected image for this case.

Two contributors suggested thymoma as the diagnosis. Although the normal architecture of the thymus is changed, the regular distinction between cortex and medullar is still present and the increased cellularity in the medulla is due to an inhibition of the egression of the lymphocytes and not cause by proliferation. It is therefore not a neoplastic process.