ARTICLE
Auteur(s) : Sanae Takahashi1, Daisuke
Watanabe1, Kazuhisa Miura1, Hiroaki
Ozawa2, Yasuhiko Tamada1, Kazuo
Hara2, Yoshinari Matsumoto1
1Department of Dermatology, Aichi Medical University,
Nagakute, Aichi, 480-1195 Japan
2Department of Pathology, Aichi Medical University,
Nagakute, Aichi, Japan
accepté le 31 Janvier 2007
Post-transplant lymphoproliferative disorder (PTLD) is a
well-recognized complication of solid organ transplantation and
hematopoietic stem cell transplantation (HSCT). The overall
incidence of PTLD following HSCT is 1-3% [1]. PTLD may occur after
autologous bone marrow transplant (BMT) or less commonly after
autologous peripheral blood stem cell transplantation (PBSCT). The
majority of PTLD cases are associated with Epstein-Barr virus (EBV)
infection, and appear to represent EBV-induced monoclonal and
polyclonal B-cell or rarely T-cell proliferations. PTLD has been
classified into four categories as (i) early lesions (reactive
plasmacytic hyperplasia and infectious mononucleosis-like PTLD),
(ii) polymorphic PTLD, (iii) monomorphic PTLD and (iv) Hodgkin
lymphoma and Hodgkin lymphoma-like PTLD, by distinctive clinical,
morphologic, and molecular genetic characteristics [2]. Generally,
the prognosis of a monomorphic type of PTLD is worse than the
polymorphic type. PTLD often presents in nodal and extranodal
sites, including lymph nodes, gastrointestinal tract, lungs, liver,
central nervous system, and transplanted organs, but cutaneous
manifestation is rare. The clinical presentation including ulcers,
nodules, or erythematous plaques on face, trunk and extremities has
been observed in cutaneous PTLD [3]. Although the number of cases
reported is small, primary cutaneous PTLD has been characterized by
later onset after transplantation and more favorable responses to
therapy [3]. In this study, we report a patient with primary
cutaneous PTLD associated with hemophagocytic syndrome (HPS) after
autologous peripheral blood stem cell transplantation (PBSCT).
Compared with the data of other patients with previous cutaneous
PTLD, our case was remarkable for its early onset and resistance to
several different treatment regimens against PTLD.
Case report
A 54-year-old woman was diagnosed with a stage IIIA Bence-Jones
gamma-type multiple myeloma and hospitalized in order to receive
high dose therapy with autologous CD34-purified PBSCT. She was
treated with 3 cycles of C-VAD (cyclophosphamide 500
mg/m2 i.v. on days 1 and 8, vincristine 0.5
mg/m2 i.v. on days 1 to 4, adriamycin 10
mg/m2 i.v. on days 1 to 4, and dexamethasone 40 mg/body
i.v. on days 1-4, 9-12), and 1 cycle of HD-CY (high-dose
cyclophosphamide 2g/m2 i.v. for 2days). She was then
treated with L-PAM (melphalan 100 mg/m2 i.v.) on days 2
and 3 before transplantation. Then, autologous PBSCT was performed
with 1.90 cells × 106/kg of CD34 positive cells. She
developed persistent high fever, followed by pancytopenia on day 5.
On day 25, HHV-6 DNA was detected in her serum by PCR. CMV
antigenemia was also observed in 24 of 15000 white blood cells
(WBC) at day 67. After treatment with 5 mg/kg of intravenous
gancyclovir twice daily for 2 weeks, she was recovered from CMV
infection. Her pancytopenia gradually resolved. On day 128 after
PBSCT, the patient noted a 5 mm, nontender, firm nodule with
overlying erythema (2 cm in diameter) on her right breast
(figure 1). A
similar 1 cm nodule was also observed on the right forearm.
Computed tomography of the chest, abdomen, and pelvis was
unremarkable. A biopsy specimen was taken from the breast nodule.
Histologic examination revealed a deep dermal infiltration of
atypical lymphocytes accompanied with prominent necrosis (figures 2A and B).
These atypical lymphocytes had large, monomorphic nuclei with
numerous mitotic figures. Immunohistological analysis showed these
cells to be positive for CD20 and CD79a (figures 3A and B), but
negative for CD3, CD56 and epithelial membrane antigen (EMA) (data
not shown). The infiltrated cells were also positive for EBV latent
membrane protein 1 (LMP1) and EBV nuclear antigen 2 (EBNA2) (figures 3C and D).
EBV gene encoding RNAs were also detected by in situ hybridization
(EBERs-ISH) (figure
3E). Southern blot analysis showed monoclonal proliferation
of EBV-infected lymphocytes (data not shown). By these findings,
the diagnosis of monomorphic PTLD with pathological features of a
large cell-type B-cell lymphoma was made. She again developed
progressive pancytopenia (white blood cell count, 700/μL;
hemoglobin 8.4 g/dL; platelets 45,000/μL) with high fever.
Prothrombin time, international normalized ratio, and activated
partial thromboplastin time was normal. Her lactate dehydrogenase
and ferritin levels were increased to 3270 U/L (normal range,
100-358 U/L) and 24,471.0 ng/mL (normal range, 3.4-89.0 ng/mL),
respectively. On day 143, a bone marrow aspiration demonstrated
involvement of PTLD into the bone marrow, accompanied with
hemophagocytic syndrome (HPS) (figure 3F). Infiltrated
lymphocytes were positive for CD79a by immunohistochemical staining
and EBERs-ISH (data not shown). Real-time PCR revealed
5.4 × 106 copies of EBV-DNA in 1 × 106 of
WBC. The patient was subsequently treated with anti-CD20 monoclonal
antibody (rituximab) and hydroxyurea, but she developed cardiac
failure and lung edema. Approximately 15 subcutaneous nodules
spread to her trunk and extremities. Finally the patient died of
PTLD and its complications on day 155 after transplantation.
Discussion
The case of PTLD we present in this paper is remarkable for several
reasons. First, the primary cutaneous manifestation of PTLD is
quite rare. About 20 cases of PTLD presenting with cutaneous
involvement have been reported in the previous literature including
nodules, and erythematous plaques on face, trunk and extremities
[3]. Consistent with previous reports, the skin lesion of the
present case showed an erythematous nodule on the right anterior
chest. In most cases, PTLD with cutaneous involvement occurs 1-10
years after transplantation, and remission is achieved after
reduction of immunosuppressive therapy with or without other
therapy, and even a case with spontaneous remission has been
reported [4]. In contrast to the typical presentation of cutaneous
PTLD, our case was remarkable for an early onset, a poor response
and generalization under therapy.
Second, cutaneous PTLD after autologous PBSCT with such an early
onset and poor outcome as in the case we present in the current
paper has not been described previously. PTLD has been reported in
a small number of cases after autologous BMT or PBSCT, and it has
been considered that autologous PBSCT is less immunosuppressive
than allogenic transplantation [5]. However, a recent report
revealed that the incidence of EBV-lymphoproliferative disease
(LPD) in pediatric neuroblastoma patients after tandem high-dose
chemotherapy with CD34-selected PBSCT was high. The authors
concluded that increased immunosuppression by high-dose
chemotherapy and T-cell depletion may have elevated the risk of
EBV-LPD [6]. Clinical features of PTLD after autologous HSCT were
summarized by Nash et al. [7]. The data published showed that 16
out of 17 cases of PTLD after autologous HSCT had cutaneous PTLD
with onset by day 100 after transplantation. 10 of these cases were
resistant to treatment.
Treatment for PTLD includes reduction of immunosuppressive
therapy, antiviral agents, immunoglobulin, steroids, chemotherapy,
and interferon [8]. It was recently reported that low-dose oral
hydroxyurea showed effectiveness for the treatment of EBV-LPD [9].
Furthermore, therapies such as monoclonal antibodies and
EBV-specific cytotoxic T-cells have proven to be more effective for
the treatment of PTLD. Rituximab is a highly specific mouse/human
chimeric antibody against CD20+ B-cells. Recently, phase II studies
reported the efficacy and safety of Rituximab in PTLD [10, 11]. In
our case, however, these agents could not suppress the progression
of PTLD.
The association of HPS with PTLD was also interesting. It was
not clear whether that HPS was directly induced by EBV infection or
if PTLD led to secondary hemophagocytosis in our case, because
secondary hemophagocytosis can be caused by various infections,
immunodeficiency status, malignancies, lymphoproliferative, and
autoimmune diseases [12]. To date, two cases of HPS associated with
PTLD have been reported [13, 14], but interestingly, both cases
were EBV-positive T-cell PTLD.
In summary, our case of cutaneous PTLD with unusual clinical
manifestation and fatal outcome indicated the difficulties of
management of individual cases of this disease. The pathogenesis of
PTLD is still unclear and further investigation will be needed to
understand this disease.
Acknowledgements
Funding supports: None. Conflict of Interest: None.
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