We describe a rare case of lymphoma as T-cell PTLD after chemotherapy and AHSCT for EBV-positive DLBCL. Our patient was diagnosed with EBV-positive DLBCL of the cervical LN at the age of 53 years, and multiple lung lesions of PTCL-NOS and granulomas, with sustained hypogammaglobulinemia, were observed four years after the achievement of complete remission following chemotherapy and AHSCT for DLBCL.
PTLDs are lymphoid and/or plasmacytic proliferations that develop as a consequence of immunosuppression after solid organ transplant and HSCT. PTLDs are classified into four categories: non-destructive PTLDs (9%), polymorphic PTLDs (6%), monomorphic PTLDs (82%), and classic Hodgkin lymphoma (3%) (1, 30). They are mostly associated with EBV infections but can also present in EBV-negative individuals. PTLDs encompass morphologically heterogeneous entities with variable clinical behavior (1, 30). Majority PTLDs are of B-cell origin, whereas T-cell PTLDs represent 2–15% of all PTLD cases. In T-cell PTLDs, the most common types are PTCL-NOS (19–36%) and hepatosplenic T-cell lymphoma (12–14%) (3, 4).
T-cell PTLDs exhibit a substantially shorter survival than B-cell PTLDs. Montanari et al. demonstrated that the median survival of T-cell PTLDs is 102 days, whereas the median survival of B-cell PTLD is 1.5 years (31). In a study of T-cell PTLDs, Herreman et al. reported that approximately 78% (21 cases of 27) of PTCL-NOS patients died, 90% of which died within one year after diagnosis (3). These reports indicated that beyond the immunological factors that give rise to PTLDs in general, these diseases may share similar biological features to their non-PTLD counterparts (31). Our patient died about eight months after the onset of PTLD with poor response to treatment, including AlloHSCT. Thus, the prognosis of our case is also inferior, which is consistent with the results of previously reported T-cell PTLD cases.
The incidence of PTLDs ranges from 2 to 10% in all transplant recipients, and the incidence of PTLDs after HSCT is less than 1% (2, 3). Fewer reports, mostly case studies, have shown the development of PTLDs following AHSCT in comparison with AlloHSCT (5–25). In addition, the cases of T-cell origin are even fewer. To the best of our knowledge, only six cases out of 25 PTLDs following AHSCT have been reported to be of T-cell origin. Thus, our case is a very rare case of PTLD, which occurred after AHSCT and is of T-cell origin (5–25).
Our patient showed sustained and progressive hypogammaglobulinemia with recurrent respiratory infections after R-CHOP for DLBCL. Because hypogammaglobulinemia has been recognized before AHSCT for DLBCL treatment, this condition could not be related to transplantation. A subset of patients has been reported to develop persistent hypogammaglobulinemia after rituximab treatment (32–39). Thus, hypogammaglobulinemia and respiratory infections, which were the cause and background of our case, led us to consider the possibility of the side effects of rituximab or primary immunodeficiency (PID), such as common variable immunodeficiency (CVID), which is a heterogeneous entity characterized by varying degrees of hypogammaglobulinemia and recurrent bacterial infections (40). In our case, unfortunately, the value of serum immunoglobulin was not measured before R-CHOP treatment against DLBCL. However, the patient's history did not indicate recurrent respiratory infections prior to chemotherapy for DLBCL. Considering the history and age, our case seems unlikely to match typical PID such as CVID.
Most reported cases of PTLDs developing after AHSCT are associated with EBV infections (5–25). Consistent with this phenomenon, in our patient, the EBV DNA level in the blood increased at the onset of T-cell PTLD, and the pathological specimen also showed focal EBER-positive findings. Previous reports of T-cell PTLD suggest that EBV may infect T-cells and cause PTLD or EBV may infect B-cells and indirectly contribute to T-cell PTLD; however, a detailed role for EBV has not been confirmed in T-cell PTLD (17, 41, 42). Because we detected only a small number of EBER-positive lymphocytes in the lung specimen in our case, it is impossible to clearly distinguish whether these positive cells were B-cells or T-cells. However, whether the EBV infected cell type is B-cell or T-cell, EBV infection is thought of as one of the causes of T-cell PTLD.
In a case of DLBCL treated with rituximab, the consecutive development of hypogammaglobulinemia and PTCL-NOS has been reported (36). Hypogammaglobulinemia was accompanied by repeated respiratory infections like CVID (36). We referred to this case because our patient presented persistent hypogammaglobulinemia with gradual aggravation. Thus, PTLD in our case might have been correlated to the advancement of hypogammaglobulinemia in addition to EBV infection.
In our case, the VATS specimen showed notable lymphocyte infiltration and multiple granulomas with fibrotic change. No clinicopathological cause of the granuloma was found such as tuberculosis, fungal infection, sarcoidosis, or granulomatous angiitis. As a differential diagnosis, the granulomatous findings can be cited as being related to Lennert’s lymphoma (LeL), a rare variant of PTCL-NOS characterized by prominent small clusters of epithelioid histiocytes (43, 44). However, LeL was reported to constitute only 0.71% of PTCL and relatively rarely invade the extranodal foci; therefore, this pulmonary lesion is considered to not be a typical LeL-related finding (45, 46). In contrast, considering our case background of hypogammaglobulinemia, this lung granulomatous lesion can also be interpreted as being a lesion associated with the granulomatous lymphocytic interstitial lung disease (GLILD) in addition to a PTCL-NOS lesion. GLILD is defined as distinct interstitial lung disease occurring in patients with persistent hypogammaglobulinemia such as CVID. This is associated with a lymphocytic infiltrate and/or granuloma in the lung that is unexplained by other conditions (47). However, despite the association of this granulomatous lesion to LeL or GLILD-like changes, the occurrence of this lung lesion is very rare and is an interesting finding in addition to the PTCL-NOS lung lesion. The rare pulmonary lesions of T-cell lymphoma with notable granulomatous changes in our case may be relevant to the background PTLD in our case, following treatment including rituximab with the persistent hypogammaglobulinemia.
In conclusion, we report a rare case of T-cell lymphoma mainly affecting the lungs with notable granulomatous findings that developed post-AHSCT against EBV-positive DLBCL. This uncommon presentation of rare lung lesions of granulomatous T-cell lymphoma could be related to the manifestation of a PTLD associated with sustained hypogammaglobulinemia.