Precursor lymphoblastic lymphoma is an uncommon neoplasm. We report the case of a man who presented with precursor T lymphoblastic lymphoma and ultimately received an allogeneic bone marrow transplant from his human leukocyte antigen–identical sister. Four years later he developed recurrent disease. By means of DNA probing for the amelogenin locus and fluorescence in situ hybridization, the neoplastic cells of the recurrent lesion were found to be of donor origin. We offer the report of a patient with an unusual lymphoblastic lymphoma who, after successful bone marrow transplantation, developed the same disease of donor cell origin; further, we offer a literature review on donor cell lymphoma.
Posttransplant lymphoproliferative disorder (PTLD) encompasses a heterogeneous group of diseases characterized by lymphoid proliferation or lymphoma occurring as a result of immunosuppression in solid organ or bone marrow allograft transplant recipients.1 Lesions arising less than 1 year posttransplantation are predominantly attributable to genomic integration of Epstein-Barr virus (EBV); by contrast, lesions occurring late after transplantation represent a distinct entity that is unassociated with EBV.2,3
Precursor T lymphoblastic lymphoma (T-LBL) comprises the majority of lymphoblastic lymphomas, with most occurring in adolescent males.4 The pathogenesis of these neoplasms remains unknown, and several molecular attributes have been described. Lesions are characterized by T lymphoblasts with medium-sized cells, scant cytoplasm, and variable prominence of nucleoli.4
We report the case of an adult man who presented with T-LBL. He was treated with chemotherapy and autografting and then underwent successful bone marrow transplantation from his human leukocyte antigen–identical sister. Four years later he presented with recurrent T-LBL of donor cell origin. In addition to reporting this case of recurrent T-LBL of donor cell origin, we offer a review of donor-derived lymphoma.
REPORT OF A CASE
In February 1997 a previously healthy 29-year-old man presented with a right testicular mass. Biopsy showed a diffuse infiltrate of the intertubular spaces and tunica albuginea by intermediate-sized lymphoid cells with fine chromatin, high nuclear-cytoplasmic ratio, and prominent small nucleoli. The neoplasm, at an outside facility, was called diffuse large cell non-Hodgkin lymphoma. Staging showed that the disease was limited to the right testis, and he subsequently underwent 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone, followed by local radiation to the scrotum.
The patient remained in remission for just more than a year, when he re-presented with lymphadenopathy of the right groin. Lymph node biopsy confirmed recurrent disease and he received 2 cycles of salvage chemotherapy with dexamethasone, cytarabine, and cisplatin, followed by autologous stem cell transplantation in July 1998. Six months later he developed pancytopenia and bone marrow biopsy showed metastasis to the marrow cavities. After undergoing 3 courses of salvage chemotherapy with carmustine, etoposide, cytarabine, melphalan (mini-BEAM), he received an allogenic bone marrow transplant from his sister, a 6/6 human leukocyte antigen match, in July 1999. Conditioning consisted of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg), and graft-versus-host disease (GVHD) prophylaxis was standard cyclosporine and short-course methotrexate. Despite the prophylaxis, he developed acute GVHD of the gastrointestinal tract and cytomegalovirus viremia that responded to prednisone and ganciclovir, respectively. His course during the next 4 years was complicated by chronic GVHD primarily involving the lungs and recurrent upper respiratory tract infections. He ultimately developed interstitial lung disease.
In September 2003 the patient presented with symptoms of a urinary tract infection. When this did not resolve after an appropriate course of antibiotics, he had a computed axial tomography scan of the abdomen, which showed an ill-defined soft tissue mass within the left renal sinus that extended into Gerota fascia and along the proximal ureter. This was highly suspicious for malignancy and an open biopsy was performed. Histology of the kidney biopsy showed a tumor that markedly effaced the normal renal architecture. The neoplastic cells were composed of intermediate-sized cells with a high nuclear-cytoplasmic ratio, a fine chromatin pattern, and prominent small nucleoli (Figure, A). The immunohistochemical staining pattern was supportive of a T-cell neoplasm (Table; Figure, B and C). Epstein-Barr virus–encoded RNA in situ hybridization testing on the recurrent lymphoma was negative. Molecular gene rearrangement studies for B- and T-cell clonality demonstrated a monoclonal T-cell population with the T-cell receptor γ gene. Results of testing for the breakpoint cluster region/Abelson translocation to rule out Philadelphia chromosome–positive acute lymphoblastic lymphoma were negative.
Peripheral blood revealed only a mild lymphocytosis. Results of a bone marrow biopsy were nonspecific but revealed several nonparatrabecular aggregates of small lymphocytes. A review of the previous pathology confirmed the 2 lesions to be virtually identical morphologically (Table; Figure, A through F). An updated diagnosis of precursor lymphoma/leukemia was rendered for both the initial and recurrent cases, with precursor T-LBL the favored diagnosis. The patient received successful induction therapy with cytarabine and daunorubicin.
Fluorescent in situ hybridization using probes specific for the X and Y chromosomes (Vysis, Inc, Downers Grove, Ill) confirmed the presence of X chromosome–specific signals and the absence of any Y signals within the neoplastic cells in at least 200 nuclei counted (not shown). Cytogenetic sex chromosome differences alone are not reliable as a means of determining the origin of leukemia after bone marrow transplantation5; thus, DNA from the kidney tumor was extracted and amplified using primers specific for 15 short tandem repeat loci and the amelogenin locus (AmpFISTR Identifiler PCR Amplification Kit, Applied Biosystems, Foster City, Calif). Only X chromosomal DNA could be demonstrated using the amelogenin locus (not shown).
The patient's respiratory status continued to decline, likely the result of both chronic GVHD with interstitial fibrosis and recurrent upper respiratory tract infection. He succumbed to progressive respiratory failure, 7½ years after his initial presentation.
The World Health Organization recognizes 4 subcategories of PTLD: early lesions, polymorphic PTLD, monomorphic PTLD, and Hodgkin and Hodgkin lymphoma– like PTLD.1 Monomorphic PTLD is further subclassified on the basis of lymphoma type, namely, B- and T-cell lesions. The former include diffuse large B-cell lymphoma, Burkitt and Burkitt-like lymphomas, plasma cell myeloma, and plasmacytoma-like lesions.1 The 10-year risk of PTLD in bone marrow recipients is 1%; major risk factors include human leukocyte antigen mismatch, T-cell depletion of donor marrow, and the use of GVHD therapies.6 Early PTLD is typically associated with EBV, with integration of viral DNA into the host genome and viral replication associated with ungoverned cell proliferation. In late PTLD—approximately 10% to 20% of cases—the pathogenesis remains poorly understood.7 Posttransplant lymphoproliferative disorder occurring in bone marrow transplant recipients is associated with a poor prognosis,8 which is worse in EBV-negative cases.9
Lymphoma of donor cell origin was initially reported to account for 5% of relapses in bone marrow transplants10; however, the actual incidence is much lower. Including our case, we were able to identify only 36 cases of donor cell–derived leukemia/lymphoma in the English literature. This number may underrepresent the actual number of cases, owing to difficulties in the assessment of chimerism11; conversely, it has been argued that many of these publications predate accurate molecular studies.12 Donor-derived lymphoma may arise through perturbations arising from the donor, recipient, or both. The donor, for example, may harbor malignant cells—or cells with genetic instability13 with the potential for transformation— that, when transferred to the host, progress to lymphoma. Rare reports of this scenario exist14,15 but likely fail to explain the majority of these cases; indeed, in our case, the patient's sister is currently well, with no evidence of lymphoproliferative disease. Alternatively, the host may foster a genetic and/or environmental milieu that predisposes toward transformation (eg, GVHD, side effects of treatment regimen, decreased immune surveillance, viral infection, environmental risk factor[s], inability for normal expansion/development of stem cells, or hereditary cofactors favoring tumorigenesis); conceivably, this may be potentiated when combined with the genetic attributes of a related donor. Interestingly, when the bone marrow donor's sex was known 72.3% of donor-derived lymphomas occurred in sex-mismatched recipients; nevertheless, it is unclear if this represents an actual risk factor or the artifact of a small sample population.
Here the recurrent lymphoma was morphologically and immunophenotypically highly similar to the primary lesion (Table). The immunohistochemical and molecular markers were non–lineage restricted4; therefore, the differential diagnosis includes T-LBL, B-LBL, blast transformation of chronic myelogenous leukemia, and common/ undifferentiated acute leukemia. However, the initial lesion coexpressed CD3, CD5, CD7, and CD43, which suggests a T-cell origin; similarly, the recurrent lesion coexpressed CD5, CD7, and CD43, consistent with a T-cell origin. Although CD10 was observed in both lesions, this can also be seen in T-LBL4; thus, there is no evidence to support a B-cell origin given the lack of CD20, CD79a, and PAX-5 positivity (Table). The most reasonable diagnosis for both lesions is therefore precursor T-LBL.
There is a small body of literature describing reports of donor cell leukemia, with only a single case of PTLD presenting as a donor-derived T-LBL post–stem cell transplantation for T-LBL. In their case, Schmitz et al16 report the diagnosis of T-LBL based on morphology and the cytochemical observation of focal positivity for acid phosphatase. Nowadays such a diagnosis relies heavily on immunohistochemistry; moreover, the use of cytochemistry in such cases is considered of limited value.17 To our knowledge, our case is therefore the only such example in which the diagnosis of T-LBL in the original and recurrent donor-derived lesion was substantiated by immunohistochemical and molecular studies.
Our case would appear to add further support to the inclusion of LBL as a subcategory of monomorphic PTLD. That said, it is unclear if there is sufficient evidence to warrant inclusion of donor cell lymphoma as a distinct category of PTLD. Irrespective of the presenting lymphoma, it is interesting to note that the majority of subsequent donor-derived lymphomas seem to arise from cells that phylogenetically emerge early in immune cell differentiation,12 based on the World Health Organization classification. It is therefore tempting to speculate that perhaps donor cell lymphoma in PTLD may have a tendency to arise at, or near, the level of a lymphoid stem cell.
In summary, we report the case of an adult man who presented with an unusual T-LBL who underwent a bone marrow allograft from his human leukocyte antigen–identical sister. Many years later he presented with de novo T-LBL of donor origin. Possible contributing factors may include GVHD disease with concomitant immunosuppression and immune stimulation arising from antigenic differences, perhaps related to the discordant donor sex. More likely, within the donor and/or recipient there exists a complex array of facilitative genetic and environmental conditions that, combined, predispose to the emergence of this disease. Further research into this uncommon disease and donor cell lymphoma, in the context of PTLD, is necessary.
We are grateful for the technical assistance of Shawn Brennan, BSc, MLT.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Jeffrey H. Lipton, MD, PhD, FRCPC, University Health Network, 610 University Ave, Toronto, Ontario, Canada M5G 2M9 (Jeff.Lipton@uhn.on.ca)