Introduction

Transplantation made significant progress in the last century, from an experimental technique to an established therapy for end-stage organ dysfunction. However, it is not without complications. One of the most serious of these is post-transplant lymphoproliferative disease (PTLD), which may present early or late, be nodal or extranodal, be polymorphic or monomorphic and run an indolent or aggressive clinical course [1]. Extranodal disease has been reported in allografted organs, the gastrointestinal tract and peritoneum, the central nervous system, bone marrow and skin. However, presentation of PTLD in bone is uncommon in solid organ transplant recipients.

Case

A 44-year-old male with adult polycystic kidney disease and a subsequent transplant presented with a 3 month history of pain around his left knee. He had returned to haemodialysis for 3 months following the failure of his renal transplant from chronic rejection. The transplant had been performed 8 years previously. He had received triple immunosuppression with cyclosporin, azathioprine and prednisolone initially, but at his presentation with knee pain he was on a reducing dose of immunosuppressive therapy.

An X-ray examination (Figure 1A) showed lytic and sclerotic changes in the proximal tibia. A subsequent magnetic resonance imaging scan (Figure 1B) confirmed extensive medullary infiltration and early soft tissue extension. A 99 mTc isotope bone scan did not reveal any other lesions, indicating that the tibial lesion was solitary.

Fig. 1.

A lateral radiograph of the left knee (A) demonstrates mixed lytic and sclerotic changes in the proximal tibia. The lateral tibial cortex is less distinct and there is early periosteal shadowing, indicating early extension beyond the bone into the soft tissue. In coronal T1 weighted images (B), marrow signal from the proximal tibia is diffusely abnormal with replacement of the marrow fat signal by a heterogeneous one. There is joint effusion and soft tissue oedema surrounds the bone. Compare this with the normal signal from bone marrow in the distal femur.

Fig. 1.

A lateral radiograph of the left knee (A) demonstrates mixed lytic and sclerotic changes in the proximal tibia. The lateral tibial cortex is less distinct and there is early periosteal shadowing, indicating early extension beyond the bone into the soft tissue. In coronal T1 weighted images (B), marrow signal from the proximal tibia is diffusely abnormal with replacement of the marrow fat signal by a heterogeneous one. There is joint effusion and soft tissue oedema surrounds the bone. Compare this with the normal signal from bone marrow in the distal femur.

An incisional biopsy of the lesion showed grey-white, partly necrotic bony tissue with areas of viable tumour composed of sheets of plasmablasts (Figure 2). Immunohistochemistry showed that the tumour cells expressed CD45 heterogeneously (some weakly and some negative; Figure 3A) while lacking expression of CD79a, CD20 and CD3. They were strongly positive for p63 (antibody V538c), which is a rough endoplasmic reticulum-associated protein expressed by plasma cells. Although not uniquely specific to this lineage, p63 is a more reliable marker of plasma cell differentiation in lymphoproliferative diseases than antigens such as CD138, which may be expressed in other lymphoma types. Ki67 immunostaining showed a high proliferation fraction of ∼50%. The cells showed cytoplasmic expression of lambda light chains and gamma heavy chains, but no expression of kappa, alpha or mu (Figures 3C and 3D) immunoglobulin proteins. In situ hybridization for Epstein–Barr virus (EBV)-EBER was strongly positive (Figure 4). Iliac crest bone marrow biopsy was negative. A diagnosis was made of monomorphic PTLD, morphologically consistent with a plasmablastic variant of myeloma or plasmacytoma [2].

Fig. 2.

Tumour infiltrate showing plasmablastic features. Haemotoxylin and eosin stain. Original magnification: ×1000.

Fig. 2.

Tumour infiltrate showing plasmablastic features. Haemotoxylin and eosin stain. Original magnification: ×1000.

Fig. 3.

Immunohistochemistry using a streptavidin–biotin immunoperoxidase technique (original magnification: ×400) for p63 (A), immunoglobulin gamma heavy chain (B), lambda light chain (C) and CD45 (D) shows the tumour to consist of plasma cells with immunoglobulin G and lambda light chain restriction.

Fig. 3.

Immunohistochemistry using a streptavidin–biotin immunoperoxidase technique (original magnification: ×400) for p63 (A), immunoglobulin gamma heavy chain (B), lambda light chain (C) and CD45 (D) shows the tumour to consist of plasma cells with immunoglobulin G and lambda light chain restriction.

Fig. 4.

Tumour cells stained to demonstrate EBV expression by EBV-EBER in situ hybridization. Original magnification: ×400.

Fig. 4.

Tumour cells stained to demonstrate EBV expression by EBV-EBER in situ hybridization. Original magnification: ×400.

Reduction in immunosuppression proved unsuccessful in producing regression of the lesion and the patient underwent radiotherapy (40 Gray over 4 weeks) followed by chemotherapy (five courses of 15 mg/month melphalan monotherapy). Currently, the patient remains tumour-free after 3 years and is awaiting retransplantation for graft failure following chronic rejection.

Discussion

PTLDs encompass a heterogeneous spectrum of conditions, ranging from lymphoid hyperplasia and neoplasia. They arise secondary to immunosuppression following transplantation. Most cases are associated with reactivation or new acquisition of EBV infection. Neoplastic forms of EBV-positive PTLD have been defined by the presence of two of the following three characteristics: (i) destruction of tissue architecture; (ii) monoclonality (regardless of morphology); and (iii) evidence of EBV infection in the lesional cells. A working diagnosis is possible in the presence of (i) or (ii) alone in the proper clinical setting. The disease is classified using Knowles–Chadburn classification [3], which has been incorporated into the current WHO classification of haematological neoplasms, and staged using the Cotswold modification of Ann Arbor staging system [4].

EBV is the most common aetiological agent seen in patients with PTLD. Other agents may also play a role in the development of specific subtypes. These include Helicobacter pylori in lymphomas of mucosa-associated lymphoid tissue lymphoma [5] and human herpesvirus-8 in primary effusion lymphoma [6].

Plasmacytomas are rare, terminally differentiated monoclonal plasma cell tumours [7] that were first recognized in transplant recipients in 1969 [8]. Since then, post-transplant plasmacytomas have been described in the allograft, skin, peritoneum, gastrointestinal tract, gingiva and, occasionally, at other sites. One case of plasmacytoma arose in an elbow [9]; the patient subsequently underwent amputation.

The first line of management of post-transplant plasmacytomas is reduction of immunosuppression. This has been reported to be successful on its own [10], but plasmacytomas are generally resistant to such treatment and usually also require chemotherapy, typically anthracycline-based [11].

Our patient had an EBV-positive, late-onset plasma cell neoplasm. Clinically and radiologically this appeared to represent a solitary plasmacytoma, although plasmablastic cytology is unusual in localized plasma cell neoplasms, being more typical of disseminated myeloma. This PTLD presented during immunosuppression withdrawal and responded to combined chemo-radiotherapy.

It is important to note that PTLD can occur even after the allograft has failed and immunosuppression is being curtailed. Despite the rarity of bone involvement, PTLD should be considered in the differential diagnosis of post-transplant patients presenting with bone pain, to avoid undue delay in diagnosis. Awareness will improve the prospects of cure from the disease and survival of the engrafted organ.

Conflict of interest statement. None declared.

References

1
Nalesnik MA, Jaffe R, Starzl TE et al. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A–prednisone immunosuppression.
Am J Pathol
 
1988
;
133
:
173
–192
2
Harris NL et al. Post-transplant lymphoproliferative disorders. In: Jaffe, ES et al., eds.
WHO Classification of Tumours—Pathology and Genetics. Tumours of Haemopoietic and Lymphoid Tissues
 . IARC Press, Lyon:
2001
;
265
–269
3
Knowles DM, Cesarman E, Chadburn A et al. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders.
Blood
 
1995
;
85
:
552
–565
4
Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop.
Semin Diagnostic Pathol
 
1997
;
14
:
8
–14
5
Hsi ED, Singleton TP, Swinnen L, Dunphy CH, Alkan S. Mucosa-associated lymphoid tissue-type lymphomas occurring in post-transplantation patients.
Am J Surg Pathol
 
2000
;
24
:
100
–106
6
Strauchen JA, Hauser AD, Burstein D, Jimenez R, Moore PS, Chang Y. Body cavity-based malignant lymphoma containing Kaposi sarcoma-associated herpesvirus in an HIV-negative man with previous Kaposi sarcoma.
Ann Intern Med
 
1996
;
125
:
822
–825
7
Joseph G, Barker RL, Yuan B, Martin A, Medeiros J, Peiper SC. Posttransplantation plasma cell dyscrasias.
Cancer
 
1994
;
74
:
1959
–1964
8
McKhann CF. Primary malignancy in patients undergoing immunosuppression for renal transplantation.
Transplantation
 
1969
;
8
:
209
–212
9
Po C, Fulton J, Domingo IV Jr, et al. Intramedullary plasmacytoma in an unusual location in a renal transplant patient.
Am J Kidney Dis
 
1996
;
28
:
904
–906
10
Rees L, Thomas A, Amlot PL. Disappearance of an Epstein–Barr virus-positive post-transplant plasmacytoma with reduction of immunosuppression.
Lancet
 
1998
;
352
:
789
11
Green T, Grant J, Pye R, Marcus R et al. Multiple primary cutaneous plasmacytomas.
Arch Dermatol
 
1992
;
128
:
962
–965

Author notes

1Renal/Liver Transplant Unit and 2Department of Radiology, The Freeman Hospital and 3Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK

Comments

0 Comments