Primary distal femur T-cell lymphoma after allogeneic haematopoietic stem cell transplantation for chronic myeloid leukaemia: A rare case report and literature review

Abstract

Post-transplant lymphoproliferative disorders originating from T lymphocytes are a rare complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) that are not usually associated with Epstein–Barr virus infection. A male patient diagnosed at the age of 15 years with chronic myeloid leukaemia (in the chronic phase) was initially treated with oral hydroxyurea. The disease entered an accelerated phase when the patient was 22 years old. Complete remission was achieved after one course of homoharringtonine and cytarabine. The patient then underwent human leucocyte antigen-matched sibling donor allo-HSCT. Just over 6.5 years after the allo-HSCT, a second primary tumour was located in the distal femur and diagnosed as T-cell non-Hodgkin’s lymphoma (stage IV, group B). This was treated with various chemotherapy and radiotherapy regimens, but the outcomes were poor and the disease progressed. The T-cell lymphoma invaded many sites, including the skeleton, spleen and skin, and the patient died within 8 months of the diagnosis. This current case report highlights the need for the early detection and prevention of subsequent primary malignancies after allo-HSCT.

Introduction

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is used to treat a variety of haematological disorders. ¹ More than 25 000 allo-HSCTs were performed worldwide in 2010, and the number is increasing every year. ² By 2020, there may be up to half a million long-term survivors following allo-HSCT worldwide as a result of their being more options for allo-HSCT use and improvements in survival. ² However, long-term survivors often face considerable morbidity and mortality associated with the late complications of allo-HSCT, including secondary malignancies.^3,4 There are many reports of the occurrence of secondary B-cell lymphoma following allo-HSCT.^5,6 This report presents a very rare case of a second primary distal femur T-cell lymphoma that developed about 6 years after an allogeneic peripheral blood stem cell transplantation using a human leucocyte antigen (HLA)-matched sibling donor was performed for the treatment of chronic myeloid leukaemia (CML).

Case report

A 15-year-old male patient was diagnosed with CML (in the chronic phase) in April 1998 based on morphological, immunophenotypic and cytogenetic examinations in the Department of Haematology, Jingjiang People’s Hospital, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang, Jiangsu Province, China. He was treated with 30 mg/kg hydroxyurea orally, twice weekly for 7 years. The disease entered an accelerated phase in May 2005 when the patient was 22 years old, and complete remission was achieved after one course of 2.5 mg/m² per day homoharringtonine intravenously (i.v.) on days 1–7 and 150 mg/m² per day cytarabine i.v. on days 1–7. In July 2005, allogeneic peripheral blood stem cell transplantation was performed using cells from the patient’s sister who was an identical HLA match. The conditioning regimen included 50 mg/day fludarabine i.v. (on days –7, –6, –5, –4 and –3), 4 mg/kg per day busulfan i.v. (on days –6 and –5), 1.1 g/m² per day cytarabine i.v. (on days –4, –3 and –2) and 25 mg/kg per day cyclophosphamide i.v. (on days –3 and –2). The patient was treated with 2.5 mg/kg per day cyclosporine orally (from day –1) and 1.0 g/day mycophenolate mofetil orally (from day –1) for the prevention of graft-versus-host disease (GVHD). Postoperative haematopoietic reconstitution was satisfactory and only an acute mild skin GVHD reaction occurred 1 month after transplantation that improved after treatment with 80 mg/day methylprednisolone i.v. for 7 days.

The patient’s condition remained stable for 6 years, but in May 2011 the patient felt left knee pain. Routine blood tests, cytogenetics, and reverse transcription–polymerase chain reaction analysis of BCR/ABL fusion gene transcripts and short tandem repeat sequences were performed and revealed normal results. Karyotyping showed 46, XX chromosomes, which was the expected karyotype of the female donor’s peripheral blood stem cells. Nonsteroidal anti-inflammatory drugs were used and the symptoms of pain improved initially.

In February 2012, the patient complained of worsening pain and swelling in his left knee, weight loss of 20 kg, but no fever or night sweats. Oral non-narcotic analgesics did not relieve the pain. An emission computed tomography (CT) scan showed a lesion with abnormally increased uptake of radioactive iodine in the left distal femur. An aspiration biopsy performed in the area of destruction showed small malignant tumour cells. Immunohistochemical analysis showed positive staining for both CD3 (Figure 1) and CD43, weak positive staining for myeloperoxidase and CD15, and strong positive staining for CD99 and LCA. The rate of immunostaining of the proliferation marker antigen KI-67 was 40%; vimentin, smooth muscle actin, CD34, CD20, terminal deoxynucleotidyl transferase, creatine kinase and epithelial membrane antigen were all negative. The patient was considered to have T-cell lymphoma and was admitted to Jingjiang People’s Hospital for further diagnosis and treatment. Physical examination after admission showed no apparent superficial lymph node enlargement, local swelling in the left knee and limited knee mobility. No parts of the liver or the spleen could be palpated below the rib cage. DNA quantification of Epstein–Barr virus (EBV) and cytomegalovirus, and examination of the morphology of the bone marrow cells, showed normal results. The BCR/ABL fusion gene was absent. Karyotyping showed 46 XX chromosomes, and bone marrow was positive for TCRγ gene rearrangement. No abnormal space-occupying lesion was detected on the chest and abdominal CT scans. The patient was diagnosed with T-cell non-Hodgkin’s lymphoma (stage IV, group B). The left knee pain improved significantly after one course of the CHOP anticancer regimen (750 mg/m² cyclophosphamide i.v. on day 1; 50 mg/m² adriamycin i.v. on day 1; 1.4 mg/m² vincristine i.v. on day 1; and 40 mg/m² per day prednisone orally on days 1–5) and was relieved after two courses of the CHOP regimen as consolidation therapy.

Figure 1.

Histological and immunohistochemical examinations of an aspiration biopsy sample of primary T-cell lymphoma localized to the distal femur from a male patient who was originally diagnosed with chronic myeloid leukaemia at the age of 15 years and who was subsequently given an allogeneic peripheral blood stem cell transplant at the age of 22 years. (A) Haematoxylin and eosin staining showing tumour cells distributed diffusely with irregular nuclei and sparse cytoplasm. (B) Immunohistochemical staining showing cluster of differentiation 3-positive tumour cells. The colour version of this figure is available at: http://imr.sagepub.com.

The patient had fever and felt pain in the left knee again on 2 June 2012. A magnetic resonance imaging (MRI) scan of the left knee showed abnormal signals in the medial and lateral condyles of the left femur and the tibial plateau, together with a local soft tissue mass in the lateral condyle of the femur. The lesion invaded the anterior cruciate ligament and the lateral collateral ligament. The patient was considered to have lymphoma based on his medical history. Whole body diffusion weighted imaging showed scattered high signals in the spleen and no abnormal signals in other organs. The diagnosis was considered to be non-Hodgkin’s lymphoma with spleen invasion. The patient underwent 60 Gy of local radiotherapy of the left lower extremity, which reduced the pain in the left knee.

On 25 June 2012, local pain, tenderness, local skin redness without increased skin temperature, and a peanut-size mass appeared in the right upper limb. Antibiotic therapy was ineffective and the mass was removed by surgery. The postoperative pathological examination suggested peripheral T-cell lymphoma (PTCL). Immunohistochemical analysis showed positive staining for CD3 (Figure 2), CD43, CD99 and LCA, and the rate of KI-67 immunostaining was 60%; staining for CD20, CD79α, Bcl-2 and PAX-5 were all negative. The left knee pain was relieved by one course of the DHAP anticancer regimen (100 mg/m² cisplatin i.v. on day 1; 4 [2 g/12 h] g/m² cytarabine i.v. on day 2; and 40 mg/day dexamethasone i.v. on days 1–4).

Figure 2.

Histological and immunohistochemical examinations of an infiltration of the skin by T-cell lymphoma in the form of a peanut-sized mass in the upper right limb of a male patient who was originally diagnosed with chronic myeloid leukaemia at the age of 15 years and who was subsequently given an allogeneic peripheral blood stem cell transplant at the age of 22 years. The peanut-sized mass developed 7 years after the allogeneic peripheral blood stem cell transplant. (A) Haematoxylin and eosin staining showing tumour cells invading the tissue around the sweat gland (arrow). (B) Immunohistochemical staining showing cluster of differentiation 3-positive tumour cells. The colour version of this figure is available at: http://imr.sagepub.com.

On 9 August 2012, the patient felt left ankle pain. X-ray examination showed changes in the left tibia and left foot, which were considered to be caused by lymphoma invasion. Several days later, the patient had a high fever with bone pain throughout the body. A chest CT scan showed flat soft tissue nodules in the upper thoracic (T) vertebrae (Figure 3A). Whole spine MRI showed flat signals in the T2 and T3 vertebrae, which were considered to be lymphomas. The MINE anticancer regimen (1.3 g/m² ifosfamide i.v., 1.3 g/m² mesna i.v., and 65 mg/m² etoposide i.v. on days 1–3; and 12 mg/m² mitoxantrone i.v. on day 1) was implemented, which normalized body temperature and reduced bone pain.

Figure 3.

Computed tomography image of the chest of the male patient showing that the T-cell lymphoma had invaded the soft tissue left of the thoracic vertebrae (arrow identifies tumour nodules) (A) and of the abdomen showing splenomegaly (B).

On 5 October 2012, lower back pain occurred and gradually worsened. There was significant tenderness. An abdominal CT showed splenomegaly and further enlargement of the spleen compared with the previous examination (Figure 3B). The patient received symptomatic treatment and died a few days later.

Written consent was obtained from the Ethics Committee of Jingjiang People’s Hospital and the Institutional Review Board of Jingjiang People’s Hospital (reference no. 1204228) to undertake the allo-HSCT in this current case. Written informed consent was obtained from the patient’s parent for publication of this case report.

Discussion

With the increase in the number of haematopoietic stem cell transplantations, more attention is being paid to the occurrence of post-transplantation tumour development.^7–9 A report published in 1999 that analysed data from more than 1000 patients who had undergone bone marrow transplantation showed that the incidence of secondary malignancies was about 3.5% at 10 years and 12.8% at 15 years, which was 3.8-fold higher than that of an age-matched control population. ¹⁰ A more recent update of this research published in 2008 indicated that compared with the age-matched control population, the incidence of secondary malignancies was increasing, with a longer follow-up time. ¹¹ There is evidence that the incidence of secondary solid tumours following allo-HSCT in Japan is comparable with that reported in Western countries. ¹²

Secondary tumours following haematopoietic stem cell transplantation are chronologically divided into post-transplant lymphoproliferative disease (PTLD), myelodysplastic syndrome/leukaemia and solid tumours. PTLD usually occurs 1 year after transplantation, but can occur as early as 1 week or as late as 9 years post-transplantation. ¹³ According to the 2008 World Health Organization classification, ¹⁴ PTLD is classified as follows: (i) early lesions, infectious mononucleosis-like reactive plasma cell hyperplasia; (ii) polymorphic PTLD; (iii) monomorphic PTLD, including B-cell lymphoma and T-cell lymphoma; and (iv) classical Hodgkin’s lymphoma-type PTLD. B-cell PTLD associated with EBV infection is the most common of these. ¹⁵ The clinicopathological spectrum and EBV status of PTLD after allo-HSCT has been reported. ¹⁵ T-cell PTLD is relatively rare and there are few reports of it. T cell lymphoproliferative disorder following bone marrow transplantation for severe aplastic anemia was reported in 2000, and primary cutaneous T-cell lymphoproliferative disorder of donor origin after allo-HSCT for mantle-cell lymphoma was reported in 2009.^16,17 Compared with B cell PTLD, T cell PTLD tends to occur later. ¹⁸ Furthermore, cutaneous GVHD is composed of polyclonal T lymphocytes. ¹⁹ In the present study, acute cutaneous GVHD occurred after transplantation; T-cell PTLD was diagnosed at just over 6.5 years after the allo-HSCT with the primary site being the distal femur, but it was not associated with EBV infection.

Several risk factors for PTLD after allo-HSCT have been identified, including HLA-mismatched grafts, T-cell depletion of the donor marrow, antithymocyte globulin use, acute and chronic GVHD, and EBV infection. ²⁰ In addition, other risk factors may be involved, such as primary disease, total body radiation and/or chemotherapy in the conditioning regimen, the sex of the donor, and immunodeficiency. ² It was reported that prior to the introduction of the tyrosine kinase inhibitor imatinib, patients with CML had a greater risk of developing secondary malignancies. ²¹ The biological mechanism that links PTLD and CML remains unclear. Transplant patients treated with a busulfan–cyclophosphamide conditioning regimen are at risk of developing secondary solid cancers, and the incidence increases with increasing follow-up time. ²² Moreover, transplant recipients seem to have a higher risk of developing secondary cancers if the stem cells come from a female donor. ²³ The patient described in this present case report was diagnosed with primary CML and never received treatment with imatinib. He received allo-HSCT and a conditioning regimen that contained fludarabine, busulfan, cytarabine and cyclophosphamide, which could have increased his risk for subsequent PTLD. The donor was the patient’s sister who had just given birth to a baby, so the cells transplanted into the recipient might have been abnormal because of her pregnancy. This might have caused chronic inflammation in the recipient and subsequently increased his risk of lymphoma. Recent observations suggest that transfused peripheral blood cells of donor origin might be involved in the development of cancers after allogeneic peripheral blood stem cell transplantation. ²⁴ All of these were potential risk factors for PTLD in this current patient after his allo-HSCT.

When first diagnosed with CML, the patient described in this present case report first received drug therapy, which induced a return to the chronic phase CML from an accelerated phase, before having high-dose conditioning chemotherapy and then allo-HSCT. Six years after transplantation, the patient reported left knee pain, but the bone marrow was still in remission, the BCR/ABL fusion gene was absent, and karyotyping analysis showed 46 XX chromosomes. Although transplantation had been successful, the patient had developed a second primary tumour. Adequate immunophenotyping is required for the diagnosis of T-cell lymphoma. PTCL has variable T-cell associated antigens, and usually lacks B-cell associated antigens. CD3 is a reliable T-cell associated antigen, while CD45RO and CD43 are not specific. Moreover, PTCL is often associated with clonal rearrangements of TCR genes. At just over 6.5 years post-transplantation, the histopathology and immunohistochemistry of an aspiration biopsy of the lesion in his left distal femur showed that it was a T-cell non-Hodgkin’s lymphoma. Subsequent positive bone marrow TCRγ gene rearrangement further confirmed the diagnosis. Several chemotherapy and radiotherapy regimens were utilized, but the treatment outcomes were poor, the disease continued to progress and the patient died within 8 months of the diagnosis. The possible causes of death were as follows: (i) T-cell lymphoma cell invasion of multiple sites, including the skeleton, spleen and skin; (ii) development of a primary or secondary resistance to the anticancer treatment; (iii) development of post-transplant immune dysfunction.

In conclusion, this current case report highlights the need for the early detection and prevention of secondary malignancies after allo-HSCT, so that the long-term goal of maintaining good health and improving the quality of life can be achieved.