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A 38-Year History of Natural-Killer-Cell Lymphoma
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     To the Editor: In February 1965, a 19-year-old man presented with an extranodal natural-killer-cell–T-cell lymphoma, nasal type, affecting the nasal cavity. One of us made the diagnosis of "granuloma gangraenescens," which was considered to be an unclassifiable sarcoma of the reticulohistiocytic system.1 The biopsy specimens (Figure 1) were also reviewed in 1965 by Friedrich Wegener, who confirmed the diagnosis and ruled out Wegener's granulomatosis. Surgical resection and radiotherapy induced a complete remission, which lasted for 33 years.

    Figure 1. Nasal-Biopsy Specimens Obtained in 1965.

    In Panel A, a vessel infiltrated by a typical angiocentric natural-killer-cell–T-cell lymphoma is evident (hematoxylin and eosin, x400); Panel B shows tumor cells stained for CD2 (x1000); and Panel C shows staining for intracellular T-cell antigen for identification of cytotoxic granules in the tumor cells (x1000).

    In 1998, the now 52-year-old patient had a relapse with skin lesions, which responded to radiochemotherapy. In 2002, the disease progressed, with nasal involvement at the same location as in 1965 (Figure 2). After remission was induced by chemotherapy (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]),2 the patient underwent autologous hematopoietic stem-cell transplantation, in January 2003. In April 2003, the patient had a second relapse, with fatal leukemic disease.

    Figure 2. Cranial Magnetic Resonance Image Obtained in 2002.

    The relapse occurred in the right fossa pterygopalatina and measured 5.7x3.1 cm (arrows). X indicates the area of the resection in 1965.

    Reanalysis of stored slides stained with Giemsa and hematoxylin–eosin from 1965 showed an immunophenotype typical of natural-killer-cell lymphoma with expression of CD2, CD45, CD56, and cytotoxic granular intracellular T-cell antigen. Review of the samples of the primary tumor (from 1965), skin (1998), nasal tissue (2002), and blood (2003) revealed similar histologic findings and an identical natural-killer-cell immunophenotype. The tumor-biopsy specimens collected in 1998 and 2002 contained Epstein–Barr virus (EBV)–encoded RNA transcripts indicative of latent EBV infection, which is a typical finding in natural-killer-cell lymphoma, nasal type.3 In line with the diagnosis, T-cell–receptor rearrangements in the skin-biopsy and nasal-biopsy specimens and the leukemic cells showed a polyclonal pattern.

    The leukemic cells had a complex karyotype with loss of the Y chromosome and gains of chromosomes X and 1, as well as deletions in 6q, 11q, and 13q, which are known to be frequent in natural-killer-cell–T-cell lymphomas. Interphase cytogenetic studies showed that the gain of one X chromosome and the loss of the Y chromosome were evident in the nasal-biopsy specimen from 2002 and in the skin-biopsy specimen from 1998, suggesting that all lesions were derived from the same malignant clone. A derivative chromosome 9 with loss of 9p21 was present in leukemic cells, suggesting inactivation of the tumor-suppressor gene p16 during disease progression, as has been shown for other T-cell lymphomas.4 Our findings suggest that some tumor cells must have survived radiotherapy of the nasal cavity and must have remained in a dormant state, spreading to the skin 33 years later.

    Carsten Schrader, M.D.

    Dirk Janssen, M.D.

    Michael Kneba, M.D.

    Karl Lennert, M.D.

    University Hospital Schlewig-Holstein

    24116 Kiel, Germany

    c.schrader@med2.uni-kiel.de

    References

    Lennert K, Mohri N, Stein H, Kaiserling E. The histopathology of malignant lymphomata. Br J Haematol 1975;31:Suppl:193-203.

    Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 2003;348:2386-2395.

    Jaffe ES, Chan JK, Su IJ, et al. Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas: definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 1996;20:103-111.

    Navas IC, Algara P, Mateo M, et al. p16(INK4a) is selectively silenced in the tumoral progression of mycosis fungoides. Lab Invest 2002;82:123-132.