Primary cutaneous T-cell lymphoma occurring after organ transplantation

CLINICAL

REVIEW

Primary cutaneous T-cell lymphoma occurring after organ transplantation Farhana E. Ravat, MRCP,a Margaret F. Spittle, FRCP, FRCR,b and Robin Russell-Jones, FRCP, FRCPathb Cambridge and London, United Kingdom Lymphoma occurring after organ transplantation has been well described. The majority of cases are B-cell lymphomas and are usually associated with Epstein-Barr virus. Only a minority of posttransplant lymphomas are of T-cell origin, and primary cutaneous T-cell lymphoma (CTCL) is extremely rare. In this article, we report a case of cutaneous peripheral T-cell lymphoma, pleomorphic CD301 large-cell type, and review the literature relating to posttransplant primary CTCL. Of the 23 cases of posttransplant primary CTCL, 5 patients had erythrodermic disease, and 8 had primary cutaneous anaplastic large cell lymphoma. In addition, there are two cases of mycosis fungoides, one case of subcutaneous panniculitis-like T-cell lymphoma, one case of CD301 lymphomatoid papulosis, and 6 cases of peripheral T-cell lymphoma, of which 3 were CD301 large cell lymphomas. Seventeen cases had renal transplants and the majority received both cyclosporine and azathioprine. No consistent viral association was noted among these cases. The sex ratio was 18:5 (male/female), and the mean age at diagnosis was 53 years. Mean time from transplantation to diagnosis is 6.4 years and mean survival time from diagnosis is 14.5 months. The prognoses normally associated with particular subsets of CTCL do not apply in the posttransplant setting. ( J Am Acad Dermatol 2006;54:668-75.)

D

iagnosis and classification of posttransplant primary cutaneous T-cell lymphoma can be difficult. Most patients, including the case described below, will develop aggressive disease and are unlikely to survive beyond the first year after diagnosis.

CASE REPORT A 53-year-old white man had received a cadaveric kidney transplant more than 10 years earlier for endstage renal failure secondary to chronic glomerulonephritis. He had subsequently been maintained on immunosuppressive therapy with cyclosporine, 230 mg daily, and prednisolone, 5 mg daily. Two years before referral, a scaly lesion had developed above the right eyebrow. This was initially treated with cryotherapy, but was later curetted and reported as Bowen’s disease. In June 2001, a tumor developed

From the Department of Dermatology, Addenbrooke’s NHS Trust, Cambridge,a and the Skin Tumour Unit, St John’s Institute of Dermatology, St Thomas’ Hospital, London.b Funding sources: None. Conflict of interest: None identified. Reprint requests: Dr Robin Russell-Jones, Director, Skin Tumour Unit, St John’s Institute of Dermatology, St Thomas’ Hospital, Lambeth Palace Road, London, SE1 7EH, UK. E-mail: robin@ russell-jones.demon.co.uk. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.10.015

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Abbreviations used: ALCL: CTCL: EBV: EORTC:

anaplastic large-cell lymphoma cutaneous T-cell lymphoma Epstein-Barr virus European Organization for the Treatment and Research of Cancer HHV: human herpesvirus ISH: in situ hybridization MF: mycosis fungoides NHL: non-Hodgkin’s lymphoma PCALCL: primary cutaneous anaplastic large cell lymphoma PCR/SSCP: polymerase chain reaction/singlestrand conformation polymorphism PTLD: posttransplant lymphoproliferative disorder RR: relative risk WHO: World Health Organization

at the same site as well as lesions involving the scalp, neck (Fig 1), and axilla. In addition, there was bilateral submandibular and axillary lymphadenopathy. The dermal nodules subsequently became more extensive, such that there was confluent involvement of the scalp with hair loss and confluent lesions around the neck with nodules on the trunk and arms. Histology of the cutaneous lesions showed that the entire dermis had been replaced by an infiltrate of large pleomorphic cells containing numerous mitotic figures (Figs 2 and 3). In some areas there was marked epidermotropism with intraepidermal collections of large atypical lymphocytes.

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Fig 1. Multiple extensive tumors on the neck.

Fig 3. High-power view showing large pleomorphic cells containing numerous mitotic figures. (Hematoxylin-eosin stain.)

Fig 2. Low-power view shows widespread tumor infiltration. (Hematoxylin-eosin stain.)

Fig 4. Tumor cells are CD301.

Immunophenotyping showed that the neoplastic cells were CD21, CD31, CD41, and CD301 (Fig 4), CD8ÿ, CD20ÿ, and CD56ÿ, and were negative for cytotoxic granules TIA-1 and granzyme B. Immunostaining for Epstein-Barr virus (EBV) with latent membrane protein-1 and in situ hybridization (ISH) for Epstein-Barr encoded RNA was negative. Anaplastic lymphoma kinase staining for the t(2:5) fusion protein was negative, indicating that this was not a systemic anaplastic large cell lymphoma (ALCL) with secondary cutaneous involvement. Review of the original skin biopsy specimen taken from the right eyebrow showed that at the margin of this lesion, there was an identical infiltrate of large pleomorphic cells. Fine needle aspiration from a submandibular node showed large lymphoid cells with the same cytologic features and immunophenotype as the cutaneous infiltrate. Polymerase chain reaction/singlestrand conformation polymorphism (PCR/SSCP) analysis of the T-cell receptor gene revealed a T-cell clone in the skin and blood using the V gamma 1 consensus primer. The blood film, however, showed no evidence of any atypical cells and the CD4/CD8 ratio was normal. Lactate dehydrogenase was within normal limits and human T-lymphotropic virus serology was negative. Computed tomographic scanning of the neck, chest, abdomen, and pelvis showed extensive subcutaneous thickening of the

skin around the occiput. There was also cervical, supraclavicular, axillary, and inguinal lymphadenopathy. Bone marrow examination was not performed. The classification of this case was problematic. Review of the original histologic material indicated that the initial presentation was cutaneous, as it demonstrated CD301 large cell lymphoma 2 years before nodal involvement. The CD41 phenotype and epidermotropism raised the possibility of mycosis fungoides (MF), but the earliest skin pathology did not show small to medium-sized lymphocytes. According to the European Organization for Research and Treatment of Cancer (EORTC) classification, this case should be classified as a primary cutaneous large cell lymphoma of T-cell origin, and the CD30 positivity would be expected to confer a favorable prognosis.1 However, the World Health Organization (WHO) classification does not recognize CD301 large-cell lymphomas in the skin unless the cytology is anaplastic.2 According to the WHO classification, therefore, our patient has a peripheral T-cell lymphoma with a cutaneous presentation. The new combined WHO-EORTC classification brackets all CD301 large-cell lymphomas with primary cutaneous peripheral T-cell lymphoma (PCALCL); therefore under this joint classification, this case would fit in the spectrum of primary cutaneous CD301 lymphoproliferative disorders.3

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Cyclosporine was reduced and the patient was treated with a two-thirds dose of cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy. There was rapid regression of the cutaneous nodules after the first cycle of chemotherapy, but this was not sustained. After 3 cycles of this therapy, his disease had progressed, and second-line chemotherapy with weekly prednisolone, mitozantrone, cyclophosphamide, etoposide, bleomycin, and vincristine therapy was commenced. Six cycles of this therapy were completed, but his disease continued to progress. Palliative local superficial radiotherapy (800 cGy in 2 fractions at 140 kV) was directed at several cutaneous tumors in the head and neck region. Our patient died 10 months after diagnosis. A postmortem was not performed.

DISCUSSION Swanson and Schwartz4 first suggested that immunosuppressive treatment might be related to an increased risk of malignancy as far back as 1967. Penn et al5 confirmed this hypothesis when they described the increased incidence of lymphomas complicating renal transplants in 1969. There are several possible explanations.6-8 Many studies have implicated the immunosuppressive regimens used, suggesting that the drugs themselves exert direct mutagenic effects. Impaired immune surveillance and increased susceptibility to oncogenic viruses, such as EBV,9 HTLV-1,10 HTLV-2,11 and human herpesvirus (HHV)12 may also be important. These effects are likely to be cumulative. Transplant recipients are more likely to suffer from virally related cancers that are uncommon in the general population, with lymphomas accounting for up to 21% of cancers in a transplant population.6 Posttransplant lymphoproliferative disorders (PTLDs) are usually of the non-Hodgkin’s type— non-Hodgkin’s lymphoma (NHL) accounts for 93% of lymphomas in the transplant population versus 65% in the general population.6 They range from benign polyclonal B-cell hyperplasia (related to EBV infection) to malignant monoclonal B-cell lymphomas. Renal allograft recipients have the lowest frequency (1.4%) and lung recipients have the highest frequency (4.5%) of PTLDs.13 The Cincinnati Transplant Tumor Registry data showed that 86% of lymphomas were of B-cell origin, approximately 14% were of T-cell lineage, and less than 1% were of null origin.6 Posttransplant NHLs are more likely to display extranodal involvement, particularly the central nervous system (28% of extranodal posttransplant lymphomas will affect the central nervous system in comparison to 1% of NHLs in the general population) and the gastrointestinal tract (69% of the transplant

population vs 24% to 48% of the general population).6 Posttransplant NHLs are also more likely to present at a later stage. Opelz and Henderson14 reported the results of a multicenter collaborative project that quantified the risk of NHL in 45,141 first cadaver-kidney and 7634 first orthoptic heart transplant patients in Europe and North America. They found that the incidence rate of NHL was particularly high in the first posttransplant year for both renal (224/105) and heart (1218/105) transplant recipients when compared with that of the general population and was lower in subsequent years. This is not unexpected, as during the first year, the intensity of immunosuppression is at its greatest and heart transplant recipients receive a particularly intensive regimen. The incidence was higher in North America than in Europe (relative risk [RR] 2.12) and could be related to the fact that doses of immunosuppressants used in North America are higher than those in Europe. There were also significant increases in risk for those who received rejection prophylaxis with either OKT3 (monoclonal anti-T-cell antibody) or antithymocyte/antilymphocyte globulin antibodies (RR 1.8), with some evidence indicating that OKT3 was associated with higher rates of NHL. The estimated relative risk, if both azathioprine and cyclosporine were administered concurrently (irrespective of steroid use), was 1.47. Gaya et al8 showed that in 274 kidney transplant recipients (whose grafts had functioned for at least 3 years), 71 tumors occurred in 54 patients. Skin malignancies were most common (46%), followed by lymphomas (14.1%). They calculated that the actuarial risk of any tumor developing was 33% at 15 years and 50% at 20 years. The overall relative risk of any tumor developing was 6.2 and was higher in men (RR 7.3) compared with women (RR 4.9). The RR of NHL developing was 45, nearly all of which were B-cell lymphomas. The median time to diagnosis of lymphoma was 9 years. Cyclosporine was introduced at their center in 1984. They did not find any evidence to suggest that cyclosporine-treated patients had an increased risk of malignancies. Their data suggested that patients treated with cyclosporine plus low-dose azathioprine (1 mg/kg/d) had a lower incidence of tumors than those treated with higher dose azathioprine (2.5 mg/kg/d) plus prednisolone after more than 5 years. Cyclosporine, a calcineurin inhibitor, is a potent immunosuppressant that reduces the production of several growth factors (especially interleukin 2). Ryffel, Mihatsch, and Fisher15 reviewed the role of cyclosporine as a carcinogenic agent. They concluded that cyclosporine does not have any genotoxic activity or DNA-binding properties. It may

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allow dose-dependent growth of initiated tumor cells in vivo and, at high concentration, EBV-infected B lymphocytes might escape the control of specific cytotoxic T lymphocytes. Cyclosporine use is associated with an increased incidence of lymphoproliferative disorders compared with the general population. These lesions regress after dose reduction or cessation of treatment. Nalesnik et al16 found that there was no difference in the incidence of PTLDs in transplant recipients whose immunosuppressive regimen included cyclosporine when compared with those who did not receive cyclosporine. This suggests that it is the duration and degree of immunosuppression rather than a specific drug or drug combination that is relevant in the development of PTLDs.17,18 Costes-Martineau et al19 noted that 77 cases of T-cell PTLDs have been reported. More than 80% of these cases were EBV negative. HTLV-1 (with the exception of Japanese kidney transplant patients), HTLV-2, and HHV-8 are also usually negative. Primary T-cell lymphoma as a subset of PTLDs seems to be extremely rare.2,13,20,21 In 1986, Bencini et al22 described, in their series of 67 kidney transplant recipients, a patient in whom multiple ulcerated plum-colored nodules developed. Their patient died suddenly before a skin biopsy could be performed, and no postmortem was performed. Their case could possibly have been a primary CTCL. Rafftery et al23 described two cases that seemed to be primary cutaneous T-cell lymphoma in 1988. These cases were subsequently reclassified as B-cell lymphomas following further immunohistochemical studies. In 1991, Tomson et al25 reported a case of ‘‘Se´zary cell lymphoma’’ occurring 20 months after kidney transplantation. However, their patient did not have erythroderma or lymphadenopathy, so the diagnosis of Se´zary syndrome could not be sustained. Schuneman, Winfield, and Ahmed26 have also reported a case of primary CTCL arising in a 48-yearold male patient 5 years after a kidney/pancreatic transplantation who survived for 2 weeks after diagnosis. A T-cell clone was present in the skin and EBV PCR was negative. Unfortunately, the abstract does not contain any details of the immunophenotype or further subclassification of the lymphoma. Apart from our case, there are only 22 other documented cases of posttransplant primary CTCL.24,27-44 One of us (R. R-J.) also has personal experience of cases 12 and 13, which have been written up separately.36,37 Tables I and II summarize the details of all 23 cases. Five cases (1, 2, 3, 8, and 10) had erythrodermic CTCL, of which two cases (3 and 10) had Se´zary syndrome; 8 cases (12, 14-18, 21, and 22) had PCALCL; two cases had nonerythrodermic MF

(11 and 13), one of which had the syringotropic variant; and 5 cases (5, 6, 7, 9, and 23) had peripheral T-cell lymphoma under the WHO classification. Of these 5 cases, 4 were pleomorphic and one immunoblastic (case 7). Three were CD30ÿand two were CD301 (9 and 23). Classification of case 4 is problematic as the infiltrate was predominantly subcutaneous, but the immunophenotype was CD31, CD41, and CD301, which is not typical of subcutaneous panniculitis-like T-cell lymphoma. On balance, this should perhaps be classified as another case of peripheral T-cell lymphoma. Case 20 was a subcutaneous panniculitis-like T-cell lymphoma of ab derivation with a CD561 phenotype. This is unusual as subcutaneous panniculitis-like T-cell lymphomas of ab derivation are normally CD81 and CD56ÿ. Finally, case 19 had lymphomatoid papulosis with a CD301 phenotype. All of the patients had received a kidney transplant with the exception of cases 10, 18, 19, 20, and 21 who had received a heart transplant and case 13 who had received a heart/lung transplant respectively. Nineteen of 23 cases had received cyclosporine, 21 of 23 had received prednisolone, 17 of 23 cases had received azathioprine, 3 of 3 cases had received tacrolimus, and 3 of 3 cases had received mycophenolate mofetil. Antithymocyte globulin and OKT3 were administered in cases 18 and 22, respectively. The sex ratio from these cases is 18:5 (male/female) and the mean age at diagnosis of primary CTCL was 53 years (range, 15-72 years). The mean time between transplantation and diagnosis of cutaneous lymphoma is 6.4 years (range, 10 months-16 years). The mean duration of survival from lymphoma diagnosis is 14.5 months (range, 11 days-49 months) or 7.6 years (range, 2-16.5 years) from transplantation, for the entire group. Ten of 10 cases were negative for HTLV-1 (case 6 had positive serology 10 years after transplantation, but was negative before transplantation), 6 of 6 were negative for HIV-1/2, and 2 of 2 were negative for HHV-8. EBV was not detected in the skin by either PCR or ISH in 14 of 18 cases, although case 3 (Se´zary syndrome followed by a nodal immunoblastic T- and B-cell lymphoma) was positive in the lymph node but not in the skin by ISH and had positive serology. EBV serology was positive in the 5 cases in which it was performed; cases 8 and 22 had positive serology, but were negative using PCR in the skin and negative in blood by ISH. Cases 7, 15, 17, and 18 showed EBV positivity in the skin by ISH (including one Japanese patient). From Table I it can be seen that there are two groups of patients: those who have disease that follows an aggressive course (14 patients who died

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Table I. Reported cases of cutaneous T-cell lymphoma following solid organ transplantation

Patient no./ Source

1/Pascual et al27 (1992) 2/Pascual et al27 (1992) 3/Euvrard et al28 (1992) 4/Kaplan et al29 (1993) 5/McGregor et al24 (1993) 6/Ichikawa et al30 (2000) 7/Lye31 (2000) 8/Ward et al32 (2001) 9/Sec¸kin et al33 (2001) 10/McMullen et al34 (2001) 11/DefossezTribout et al35 2003 12/Cooper et al36 (2003) 13/Thein et al37 (2004) 14/Kim et al38 (2004) 15/Coyne et al39 (2004)y 16/Coyne et al39 (2004)y 17/Coyne et al39 (2004)y 18/Lucioni et al40 (2004) 19/Katugampola et al41 (2004) 20/Bregman et al42 (2005) 21/De Nisi et al43 (2005) 22/Salama44 (2005) 23/Current study

Age (y) at Sex diagnosis

Organ transplanted

Time between Immunosuppressive transplant and therapy appearance of lymphoma CsA Aza Other Steroids

Lymphoma subtype

M

52

Kidney

4y

1

1

1

E-CTCL

M

55

Kidney

18 mo

1

1

1

E-CTCL

M

57

Kidney

11 y

NS

1

1

SS

F

55

Kidney

5y

1

1

1

M

NS*

Kidney

NS*

1

1

1

M

43

Kidney

10 y

1

1

1

M

64

Kidney

6y

NS NS

F

64

Kidney

4.5 y

1

F

51

Kidney

10 mo

M

72

Heart

F

52

M

Treatment

Survival after lymphoma diagnosis

Topical steroids then chemo Pred 1mg/kg/d and SAC MAC

Alive at 9 mo 13 mo

Supportive

11 days

RT

9 mo

PTCL

MAC/RT

3 mo

1

PTCL

RI/ EB-RT

1

1

E-CTCL

RI/ECP/TSEB

Alive at 3y 9 mo

1

1

1

7y

1

1

1

Kidney

7y

1

ÿ

Tacro

1

59

Kidney

5.5 y

1

ÿ

MM

1

M

40

5.5 y

1

1

ÿ

M

56

Heart and lung Kidney

16 y

1

1

1

F

33

Kidney

2y

1

1

1

PCALCL

M

56

Kidney

6y

1

1

1

PCALCL

RI/Pred increased/ Acyclovir MAC/RT

M

61

Kidney

9y

1

1

1

PCALCL

RI/MAC

6 mo

M

71

Heart

9.25 y

1

1

ATG

1

PCALCL

Alive at 49 mo

M

15

Heart

6y

1

ÿ

MM

ÿ

LyP

M

50

Heart

3y

ÿ

1

Tacro

1

SPLTCL

RT/RI/MAC/IVIg and IFN-a for EBV Spontaneous regression RI

M

49

Heart

5y

ÿ

ÿ

1

PCALCL

RI/Excision

M

59

Kidney

6y

1

1

MM, Tacro MM, OKT3

1

PCALCL

RI/RT/SAC

Alive at 1y 22 mo

M

53

Kidney

10 y

1

ÿ

RI/MAC/RT

10 mo

NS

NS

1

PTCL (subcutaneous) PTCL

RI/Excision/RT CD301 LCL (pleomorphic) SS RI/ECP/PUVA/SAC/ Antibiotics and topical steroid MF RI/Topical steroids/SAC PCALCL MF (syringotropic) PCALCL

CD301 LCL (pleomorphic)

2 wk

Alive at 15 mo 13 mo

Alive at 1y

RI/RT/MAC

18 mo

RT

Alive at 4y Alive at 6 mo 17 mo

RI/RT/MAC

15 mo

Alive at 4 mo 7.5 mo

1, Positive; ÿ, negative; ATG, Anti-thymocyte globulin; Aza, azathioprine; Chemo, chemotherapy; CsA, cyclosporine; CTCL, cutaneous T-cell lymphoma; EB-RT, electron beam radiotherapy; ECP, extracorporeal photophoresis; E-CTCL, erythrodermic CTCL; EBV, Epstein Barr virus; F, female; IFN-a, interferon alfa; IVIg, intravenous immunoglobulin; LCL, large cell lymphoma; LyP, lymphomatoid papulosis; M, male; MAC, multiple-agent chemotherapy; MF, mycosis fungoides; MM, mycophenolate mofetil; NP, not performed; NS, not stated; PCALCL, primary cutaneous anaplastic large cell lymphoma; Pred, prednisolone; PTCL, peripheral T-cell lymphoma; PUVA, psoralen-UVA phototherapy; RI, reduction of immunosuppression; RT, local radiotherapy; SAC, single-agent chemotherapy; SPLTCL, subcutaneous panniculitis-like T-cell lymphoma; SS, Se´zary syndrome; Tacro, tacrolimus; TSEB, total skin electron beam therapy. *Not used for statistical purposes. y Details clarified (written communication F. E. R. with J. D. C., February 2005).

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Table II. Immunophenotype, viral status, and T-cell receptor gene analysis of the reported cases of cutaneous T-cell lymphoma following transplantation Viral association Case no. Diagnosis

EBV CD2 CD3 CD4 CD8

CD30

ISH

NP NP 1 LN/ÿskin ÿ ÿSkin/ cerebral NP

1 2 3 4 5

E-CTCL E-CTCL SS PTCL (sc) PTCL

1 1 NS ÿ NS

NS NS 1 1 1

1 1 1 1 NS

NS NS NS ÿ NS

NS NS 1 1 ÿ

6

PTCL

1

1

1

1

ÿ

7 8

PTCL E-PTCL

1 NS

1 1

NS 1

ÿ NS

9

1

NS

NS

10 11

CD301 LCL NS (pleomorphic) SS 1 MF NS

ÿ 1 Skin 1 ÿ Skin (25%) (PCR)/blood 1 ÿ Skin (PCR)

1 1

NS NS

NS NS

ÿ ÿ

12 13

1 1

ÿ 1

ÿ 1

ÿ ÿ

NS 1 NS NS NS NS 1 NS NS 1

1 ÿ 1 ÿ 1 1 1 1 1 1

1 ÿ ÿ 1 1 1 ÿ ÿ 1 1

NS ÿ ÿ ÿ ÿ NS 1 1 ÿ ÿ

PCALCL MF (syringotropic) 14 PCALCL 15* PCALCL 16* PCALCL 17* PCALCL 18 PCALCL 19 LyP 20 SPLTCL 21 PCALCL 22 PCALCL 23 CD301 LCL (pleomorphic)

TCR gene analysis

LMP-1 Serum

HTLV-1

HIV 1/2

ÿ ÿ ÿ ÿ NP

ÿ ÿ ÿ NP NP

NP NP NP NP NP

NP NP 1 NP NP

NP

NP

1 NP

NP 1

NP

NP

NP

ÿ

NP ?ÿ

1 NP

ÿ ÿ

1 ÿ

NP ÿ Blood (PCR) ÿ ÿ

ÿ ÿ

ÿ ÿ

1 1 1 1 1 1 1 1 1 1

ÿ 1 ÿ 1 1 (40%) ÿ NP ÿ ÿ ÿ

ÿ NP NP NP NP ÿ ÿ NP ÿ ÿ

NP NP NP 1 NP NP NP NP 1 ÿ

ÿPre/ 110 y post NP ÿ

NP

Other

Skin

NP NP CMV1 1 (1 LN) 1 1 (1 cerebral) Hep B/C ÿ 1

Blood

NP NP NP NP NP NP

ÿ 1

NP NP

NP

NP

NP ÿ

1 1

NP 1

ÿ ÿ

NP NP

1 1

1 1

NP NP NP NP NP NP NP NP ÿ ÿ

NP NP NP NP NP NP NP NP ÿ NP

1 1 1 ÿ 1 1 1 1 1 1

NP NP NP NP NP NP NP NP NP 1

NP NP HHV8 ÿ

HHV8 ÿ

CMV1 HTLV-2 ÿ

1, Positive; ÿ, negative; CMV, cytomegalovirus; EBV, Epstein-Barr virus; E-CTCL, erythrodermic CTCL; Hep B/C, hepatitis B/C; HHV8, human herpesvirus-8; HIV 1/2, human immunodeficiency virus /2; HTLV-1/2, human T-lymphotropic virus 1/2; ISH, in-situ hybridization; LCL, large cell lymphoma; LMP-1, latent membrane protein-1; LN, lymph node; LyP, lymphomatoid papulosis; MF, mycosis fungoides; NP, not performed; NS, not stated; PCR, polymerase chain reaction; PCALCL, primary cutaneous anaplastic large cell lymphoma; PTCL, peripheral T-cell lymphoma; pre, pretransplant; post, posttransplant; sc, subcutaneous; SPLTCL, subcutaneous panniculitis-like T-cell lymphoma; SS, Se´zary syndrome; TCR, T-cell receptor. *Details clarified (written communication, F. E. R. with J. D. C., February 2005).

within 2 years of diagnosis) and 9 ‘‘long survivors’’ whose disease follows a relatively indolent course. Cases 2, 7, 9, 11, 13, 14, 18, 19, and 21 belong to this latter group. Among the 14 patients whose disease follows an aggressive course, the mean duration of survival from diagnosis was 10.2 months (range, 11 days-22 months) and from transplantation was 7.2 years (range, 3-12 years). Several patients in this category had lymph node infiltration. Of the 6 peripheral T-cell lymphomas, 4 pursued an aggressive course (cases 4, 5, 6, and 23) and two of these were CD301 (4 and 23). Even if one accepts the EORTC view that all cutaneous CD301 large-cell lymphomas have a favorable prognosis, it is clear that this does not hold true for posttransplant T-cell

lymphomas. In addition, 5 of 6 cases of PCALCL (cases 12, 15-17 and 22) fared badly, whereas normally this tumor has a 5-year survival rate of 95%.45 Four of the 5 cases of erythrodermic CTCL pursued an aggressive course, but only 2 had circulating Se´zary cells (cases 3 and 10). The presence of a T-cell clone in tumor tissue is a useful diagnostic test in patients with CTCL. With the exception of case 7, all patients who were tested exhibited a T-cell clone in lesional skin biopsies (Table II). The presence of a peripheral blood T-cell clone is recognized as a poor prognostic indicator in patients with MF46 and a high tumor burden in the peripheral blood is associated with a worse prognosis in erythrodermic CTCL.47 Our patient exhibited an identical clone in both skin and blood using

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PCR/SSCP analysis, but most reports of posttransplant CTCL have not looked for a peripheral blood T-cell clone. Cases 3 and 5 reported a T-cell clone in lymph node and cerebral tissue, respectively. Only cases 3, 10, and 11 had circulating Se´zary cells and they were present at 8% in case 11. Cases 2, 6, 12, 13, and 23 did not have circulating atypical cells and details are not given in an additional 15 cases. The 9 cases with relatively indolent disease had a male/female ratio of 7:2 and a mean age of 50 years (range, 15-71 years). The long survivors include two cases of MF, one case of CD301 lymphomatoid papulosis, one case of erythrodermic CTCL without circulating Se´zary cells (ie, erythrodermic MF), 2 cases of CD301 ALCL, one case of PCALCL (CD301), and two peripheral T-cell lymphomas, of which one was CD301 and one CD30ÿ. There was no difference in the mean interval between transplantation and diagnosis in the group with a poor prognosis and the long-term survivors. In conclusion, CTCL develops approximately 6 years after transplantation. The majority of patients will develop aggressive disease, resulting in death in less than a year. A minority of patients will pursue a more indolent course, and in this situation, withdrawal of immunosuppressive therapy may lead to partial regression of CTCL. However, this needs to be balanced against the likelihood of graft rejection or worsening of the original disease. Whereas PTLDs of B-cell origin are commonly associated with EBV infection, no equivalent agent has been identified for cases of posttransplant CTCL. The favorable prognosis associated with specific subtypes of CTCL, such as PCALCL, does not apply in the posttransplant setting. We thank the late Professor J. Crocker from the Department of Cellular Pathology, Birmingham Heartlands Hospital, UK for carrying out the EBV in situ hybridization. REFERENCES 1. Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S, et al. EORTC classification of primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organisation for Research and Treatment of Cancer. Blood 1997;90:354-71. 2. Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organisation classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol 3. Lyon: IARC Press; 2001. 3. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Steven H, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85. 4. Swanson MA, Schwartz RS. Immunosuppressive therapy: the relation between clinical response and immunologic competence. N Engl J Med 1967;227:163. 5. Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc 1969; 1:106-12.

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