Posttransplantation primary cutaneous CD30 (Ki-1)-positive large-cell lymphoma

Posttransplantation primary cutaneous CD30 (Ki-1)-positive large-cell lymphoma

Posttransplantation primary cutaneous CD30 (Ki-1)-positive large-cell lymphoma Deniz Seçkin, MD,a Beyhan Demirhan, MD,b Tülin Og˘uz Güleç, MD,a Ünser ...

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Posttransplantation primary cutaneous CD30 (Ki-1)-positive large-cell lymphoma Deniz Seçkin, MD,a Beyhan Demirhan, MD,b Tülin Og˘uz Güleç, MD,a Ünser Arıkan, MD,b and Mehmet Haberal, MD, FACSc Ankara, Turkey We describe the case of a 51-year-old female renal transplant recipient with primary cutaneous CD30-positive large-cell lymphoma of T-cell origin. Cutaneous T-cell lymphomas are rarely reported in organ transplant recipients, and we believe they should be considered in the differential diagnosis of cutaneous neoplastic and infectious diseases affecting this patient group. (J Am Acad Dermatol 2001;45:S197-9.)

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rgan transplant patients receiving immunosuppressive therapy to prevent allograft rejection are prone to having malignant tumors develop, the majority of which are cutaneous in origin.1 Posttransplantation lymphoproliferative disorders (PTLDs) occur in 1% to 2% of graft recipients and are almost always of B-cell derivation.2 According to the Cincinnati Transplant Tumor Registry (CTTR), 14% of lymphoma cases are of T-cell origin.3 Previously, only rare occurrences of primary cutaneous T-cell lymphoma (CTCL) have been reported.4-7 Here, we describe a primary cutaneous CD30-positive large-cell lymphoma (LCL) of T-cell phenotype in a renal transplant recipient and review the literature.

CASE REPORT In November 1997, a 51-year-old woman was referred to our clinic with a tender, rapidly growing tumor on her left buttock that had been present for 1 month. Her medical history included 2 similar lesions at the same location roughly 3 months earlier, both of which had regressed after oral sulbactam-ampicillin therapy. The patient had been on hemodialysis for end-stage renal disease because of polycystic kidney disease and had undergone cadaveric kidney transplantation in January 1997. She was being immunosuppressed with prednisolone, azathioprine, and cyclosporine. The patient had no history of previous malignancies. On examination, the patient had a well-defined, solitary, redto-violaceous, inflamed, tender tumor of 3-cm diameter on the left buttock. The skin surrounding the lesion was erythematous (Fig 1). Two atrophic macules were also noted lateral to the tumor. We initially diagnosed carbuncle and prescribed oral sulbactam-ampicillin therapy; however, when the lesion did not regress, we performed an incisional biopsy. Histologic examination of the specimen showed a very dense, diffuse, nonepidermotropic, cellular infiltrate throughout the entire reticular dermis and extending into the subcutis. The infiltrate was composed of pleomorphic, large, atypical lymphocytes that exhibited This supplement is made possible through an unrestricted educational grant from Stiefel Laboratories to the American Academy of Dermatology. From the Departments of Dermatology,a Pathology,b and General Surgery,c Baskent University Faculty of Medicine. No reprints available. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/4/102667 doi:10.1076/mjd.2001.102667

Fig 1. Primary cutaneous CD30-positive LCL resembling carbuncle on buttock.

nuclear hyperchromasia and a high mitotic index (Fig 2, A). Vascular proliferation was observed in the stroma. Perivascular atypical lymphocyte infiltration was prominent. Immunohistochemical study revealed that most of the tumor cells were positive for the T-lineage antigens CD45RO (UCHL-1), CD3, and CD30 (Ki-1) (Fig 2, B). None of the atypical cells stained positive for the pan–B-cell antigen CD20 (L26). Staging showed there was no extracutaneous involvement. On the basis of these findings, we diagnosed primary cutaneous CD30-positive LCL. Serologic tests for human immunodeficiency virus type 1 (HIV 1) and HIV 2 were negative. Polymerase chain reaction revealed no sequences of Epstein-Barr virus (EBV) DNA or human herpesvirus-8 (HHV-8) DNA in the lymphoma tissue. Prednisolone and cyclosporine dosages were reduced, azathioprine was discontinued, and localized radiotherapy (24 Gy) was applied to the affected area after tumor resection. Between December 1997 and September 1998, the patient had 4 lymphoma relapses in different regions of the body, but there was no lymphadenopathy or extracutaneous involvement. Each relapse was treated with localized radiotherapy (cumulative dose, 166 Gy). The patient is currently in remission 5 months after the last treatment.

DISCUSSION PTLDs include a clinicopathologically heterogenous group of lymphoid proliferations that range from lymphoid hyperplasias

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B Fig 2. A, Dense, diffuse, nonepidermotropic cellular infiltrate composed of large and atypical lymphocytes throughout reticular dermis. Vascular proliferation is prominent. (Hematoxylin-eosin stain; original magnification, ×115.) B, Most tumor cells are positive for CD30. Membranous and golgi zone staining are observed. (Immunoperoxidase stain; original magnification, ×460.)

to malignant lymphomas. Spontaneous regression may occur after immunosuppressive agents are tapered; however, many cases are rapidly fatal, despite the discontinuation of immunosuppressive drugs and initiation of aggressive therapy.8 In the general population, lymphomas account for 5% of all malignancies; however, excluding nonmelanoma skin cancers and in situ carcinoma of the cervix, they represent 21% of all cancers in transplant recipients.9 The majority of these cases are non-Hodgkin lymphomas (NHLs), most often of B-cell phenotype.3 B-cell PTLDs have a strong association with active EBV infection.8,10 It is postulated that chronic immunosuppression impairs immune surveillance mechanisms, which leads to the reactivation of this latent oncogenic herpesvirus and results in pathologic polyclonal, oligoclonal, or monoclonal lymphoproliferations.10 These clones are susceptible to further genetic alterations of 1 or more oncogene or tumor suppressor genes (eg, Nras gene or p53 gene mutation,8 c-myc gene rearrangement,8 upregulation of bcl-2,11 and EBV-latent membrane protein-1 deletion12), resulting in the emergence of a fully transformed monoclonal B-cell proliferation containing episomal EBV. These genetic alterations are believed to play an important role in the development and progression of the B-cell PTLDs.8 A few T-cell PTLDs have been associated with EBV infection, but this is an uncommon finding.13 Surprisingly, the frequent presence of EBV has been documented in peripheral T-cell NHLs in the nonimmunosuppressed population, whereas most B-cell NHLs were not associated with the virus.14 Similarly, it has been proven that Tcell PTLDs are not related to human T-cell leukemia/lymphoma virus type 1, human T-cell leukemia/lymphoma virus type 2, or HHV-8 infection.15 We also found no evidence that EBV or HHV-8 played any direct role in the pathogenesis of CTCL in our patient. Although 14% of NHL cases in the CTTR are of T-cell origin,3 few articles have been published on posttransplantation T-cell lymphoma. CTCLs in transplant recipients are extremely rare, and we were able to find only 5 cases in the literature (Table I).4-7 Of these patients, 2 had mycosis fungoides (MF), 1 had Sezary

syndrome (SS), 1 had subcutaneous T-cell lymphoma, and 1 had pleomorphic-type CTCL. In 1 of the patients with MF,4 lymph node and liver specimens were infiltrated by the cutaneous lymphoma. This individual was treated with topical steroids for 2 weeks, and chemotherapy was started when fever, pulmonary infiltration, and hepatic insufficiency were observed. The patient died of cardiorespiratory insufficiency because of pulmonary involvement. Topical mechlorethamine hydrochloride improved erythroderma in the other patient with MF.4 When the disease became disseminated, the patient was started on oral prednisone and chlorambucil, and remained asymptomatic. In the SS case reported by Euvrard et al,5 no systemic involvement was noted initially. Azathioprine was discontinued, but the disease progressed to the tumor stage. Despite treatment with chlorambucil and etretinate, the number of skin tumors increased, and nodal B-cell lymphoma was also diagnosed. The patient did not respond to chemotherapy, including cyclophosphamide, doxorubicin, vindesine, and bleomycin, and died. Primary subcutaneous T-cell lymphoma of the vulva6 was associated with hemophagocytosis in lymph nodes and bone marrow. This patient died shortly after admission because of multiorgan failure. Finally, the patient with CTCL reported by McGregor et al7 was treated with radiotherapy. The clinical course was also aggressive, and the patient died 9 months after the diagnosis of cerebral lymphoma. The details surrounding the primary CTCL in our immunosuppressed patient made clinical diagnosis problematic. At admission, the patient had an indurated, tender lesion showing fluctuation, and a history of similar lesions that had resolved either spontaneously or because of concomitant antibiotic therapy. This picture clinically resembled a bacterial infection, which affects allograft recipients with significant frequency.16 Although the regression of 2 previous similar lesions, either spontaneously or after antibiotic treatment, was a convincing factor about the diagnosis of a bacterial infection, studies have shown that the skin of patients with CTCL is heavily colonized, and that many immunologically active bacterial proteins (or “superantigens”)

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Table I. Review of the literature: Posttransplantation cutaneous lymphomas of T-cell origin Posttransplantation time

Age (y)

Sex

Classification

52 53 57 55 NR 51

M M M F M F

MF 4y MF 1.5 y SS 11 y Subcutaneous 5y Pleomorphic NR Pleomorphic LCL 10 mon

Clinical outcome

Deceased Remission Deceased Deceased Deceased Remission

CD30 expression

HTLV-I (skin)

NR NR NR NR NR Negative Positive Negative Negative NR Positive Not performed

EBV (skin)

NR NR Negative Negative Negative Negative

Gene rearrangement

Reference

NR 4 NR 4 Clonal 5 Clonal 6 Clonal 7 Not performed Present case

HTLV-I, human T-cell lymphotropic virus type I; EBV, Epstein-Barr virus; MF, mycosis fungoides; SS, Sezary syndrome; M, male; F, female; LCL, large cell lymphoma; NR, not reported.

can stimulate and activate the clonally expanded T cells of CTCL.17 The inflammation associated with CTCL is a result of the proinflammatory nature of the malignant cells and the antitumor response itself. In some patients, the latter can even destroy the tumor cells, leading to spontaneous remission of the CTCL lesion, but when the immune response is weak, the disease progresses unchecked.18 Although we did not examine the earlier lesions, we speculate that they might also have been CTCL lesions, which regressed spontaneously. Some skin cancers seen in organ transplant recipients, such as squamous cell carcinoma, can present with atypical features that make it easy to confuse them with benign diseases.19 Because of our patient’s unusual clinical presentation, resembling an infectious process, we initially missed the correct diagnosis of cutaneous lymphoma. Histopathologically, lymphomatoid papulosis (LYP) should be included in the differential diagnosis of CD30-positive LCL. Although distinguishing CD30-positive LCL from LYP is challenging, a recent article by Demierre et al20 highlights the useful histologic criteria for differentiating these 2 diseases. A wedgeshaped infiltrate is typically observed in LYP. Both CD30-positive LCL and LYP have CD30 expression of anaplastic cells. Usually, CD30-positive LCL has a predominance (75%) of CD30-positive cells with moderate or fewer inflammatory cells, whereas LYP demonstrates CD30-positive cells scattered among abundant inflammatory cells. Another feature of lymphoma is infiltration of atypical cells into the subcutis, which is not observed in LYP. Given the histopathologic features, we diagnosed CD30-positive LCL in our case. In light of the limited number of reported cases to date, it should be noted that T-cell PTLDs might arise by coincidence rather than as a consequence of immunosuppression. In summary, primary cutaneous CD30-positive LCLs of T-cell origin are uncommonly observed posttransplantation. Even though these tumors are rarely seen, they should be considered in the differential diagnosis of cutaneous neoplastic and infectious conditions that arise in immunosuppressed patients. REFERENCES 1. Gupta AK, Cardella CJ, Haberman HF. Cutaneous malignant neoplasms in patients with renal transplants. Arch Dermatol 1986;122:1288-93. 2. Penn I. Cancer is a complication of severe immunosuppression. Surg Gynecol Obstet 1986;162:603-10. 3. Penn I. Cancers complicating organ transplantation. N Engl J Med 1990; 323:1767-9. 4. Pascual J, Torrelo A, Teruel JL, Bellas C, Marcen R, Ortuno J. Cutaneous T cell lymphomas after renal transplantation. Transplantation 1992;53: 1143-5.

5. Euvrard S, Noble CP, Kanitakis J, Ffrench M, Berger F, Delecluse HJ, et al. Brief report: successive occurrence of T-cell and B-cell lymphomas after renal transplantation in a patient with multiple cutaneous squamous cell carcinomas. N Engl J Med 1992;327:1924-6. 6. Kaplan MA, Jacobson JO, Ferry JA, Harris NL. T-cell lymphoma of the vulva in a renal allograft recipient with associated hemophagocytosis. Am J Surg Pathol 1993;17:842-9. 7. McGregor JM, Yu CCW, Lu QL, Cotter FE, Levison DA, MacDonald DM. Posttransplant cutaneous lymphoma. J Am Acad Dermatol 1993;29: 549-54. 8. Knowles DM, Cesarman E, Chadburn A, Frizzera G, Chen J, Rose EA, et al. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 1995;85:552-65. 9. Penn I. Lymphomas complicating organ transplantation. Transplant Proc 1983;15:2790. 10. Hanto DW, Sakamoto K, Purtilo DT, Simmons RL, Najarian JS. The Epstein-Barr virus in the pathogenesis of posttransplant lymphoproliferative disorders. Surgery 1981;90:204-13. 11. Chetty R, Biddolph S, Kaklamanis L, Cary N, Stewart S, Giatromanolaki A, et al. bcl-2 protein is strongly expressed in post-transplant lymphoproliferative disorders. J Pathol 1996;180:254-8. 12. Scheinfeld AG, Nador RG, Cesarman E, Chadburn A, Knowles DM. Epstein-Barr virus latent membrane protein-1 oncogene deletion in post-transplantation lymphoproliferative disorders. Am J Pathol 1997; 151:805-12. 13. Dockrell DH, Strickler JG, Paya CV. Epstein-Barr virus-induced T cell lymphoma in solid organ transplant recipients. Clin Infect Dis 1998;26:1802. 14. Hamilton-Dutoit SJ, Pallesen G. A survey of Epstein-Barr virus gene expression in sporadic non-Hodgkin’s lymphomas. Detection of Epstein-Barr virus in a subset of peripheral T-cell lymphomas. Am J Pathol 1992;140:1315-25. 15. Hanson MN, Morrison VA, Peterson BA, Stieglbauer KT, Kubic VL, McCormick SR, et al. Posttransplant T-cell lymphoproliferative disorders-an aggressive, late complication of solid-organ transplantation. Blood 1996;88:3626-33. 16. Seçkin D, Oguz Güleç T, Demirag A, Bilgin N. Renal transplantation and skin diseases. Transplant Proc 1998;30:802-4. 17. Tokura Y, Heald P, Yan SL. Stimulation of cutaneous T-cell lymphoma cells with superantigenic staphylococcal toxins. J Invest Dermatol 1992;98:33-37. 18. Heald PW, Shapiro PE, Madison JF, LeBoit PE, Edelson RL. Cutaneous Tcell lymphoma. In: Arndt KA, LeBoit PE, Robinson JK, Wintroub BU, editors. Cutaneous medicine and surgery. Philadelphia: WB Saunders; 1996. p. 1639-59. 19. Penn I. Immunosuppression and skin cancer. Clin Plast Surg 1980;7: 361-8. 20. Demierre MF, Goldberg LJ, Kadin ME, Koh HK. Is it lymphoma or lymphomatoid papulosis? J Am Acad Dermatol 1997;36:765-72.