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Natural Killer Cell Lymphoma Report of Two Pediatric Cases, Therapeutic Options, and Review of the Literature
Peter H. Shaw, M.D. Susan L. Cohn, M.D. Elaine R. Morgan, M.D. Paula Kovarik, M.D. Paul R. Haut, M.D. Morris Kletzel, M.D. Sharon B. Murphy, M.D.
BACKGROUND. Natural killer (NK) cell lymphomas are rapidly fatal malignancies
Departments of Pediatrics and Pathology, Northwestern University Medical School and Children’s Memorial Hospital, Chicago, Illinois.
RESULTS. One of the patients in the current study developed two recurrences and
that to the authors’ knowledge are rare in children. In the current study, the authors report the cases of two boys with NK cell lymphomas with refractory disease who both were salvaged with high dose chemotherapy and stem cell transplantation and compare these patients with those in the published experience.
METHODS. A comprehensive literature review was performed to identify other cases of pediatric patients with NK cell lymphomas, their treatment, and outcome. the other patient experienced early disease progression during front-line treatment. Both then were treated with high dose chemotherapy followed by stem cell rescue. At last follow-up, the patients remained free of disease at 15 months and 16 months, respectively, after transplantation (48 months and 22 months, respectively, from the time of diagnosis). In addition to the 2 patients in the current study, the authors found 13 pediatric patients reported in the literature to date. Of the 7 patients with localized (Stage I-II) disease, 5 patients (71%) were reported to be alive 1–107 months after diagnosis. Of the 6 patients with Stage IV disease, only the 2 patients who received high dose chemotherapy and stem cell rescue (33%) were alive at the time of last follow-up (at 30 months and 12 months, respectively). Including the patients reported in the current study, 9 of 15 children with NK cell lymphoma (all stages) (60%) were reported to be alive at the time of last follow-up.
CONCLUSIONS. Although pediatric NK cell lymphomas rapidly can become fatal, it appears that high dose chemotherapy followed by stem cell transplantation is effective therapy, especially in patients with advanced or resistant disease. Further follow-up is needed to determine whether this treatment approach will be curative. Cancer 2001;91:642– 6. © 2001 American Cancer Society.
KEYWORDS: natural killer cell, lymphoma, pediatric, therapy, stem cell transplantation.
The authors acknowledge Dr. Elaine Jaffe of the National Cancer Institute for her review of the tumor tissue, confirming the diagnosis of blastoid natural killer cell lymphoma in Case 1 Address for reprints: Sharon B. Murphy, M.D., Box #30, Division of Hematology/Oncology, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614; Fax: (773) 880-3223; E-mail:
[email protected] Received April 7, 2000; revision received October 5, 2000; accepted November 2, 2000. © 2001 American Cancer Society
I
n adults, natural killer (NK) cell lymphomas are rare and rapidly fatal malignancies.1–5 NK cell lymphomas are a heterogeneous group of tumors, many of which occur in the nasopharyngeal region, are angiocentric in nature, and are associated with the Epstein–Barr virus (EBV). NK cell lymphomas are much more prevalent in China and Japan compared with the rest of the world. NK-lineage lymphomas occur even more rarely in children; to our knowledge, only 13 pediatric patients have been reported in the literature to date.2,3,6 –11 In the current study, we report two additional children with NK cell lymphomas with refractory disease who both were salvaged with high dose chemotherapy and stem cell transplantation.
Pediatric NK Lymphomas/Shaw et al.
Case One A 9-year-old boy presented to an outside hospital in September 1996 with a painless subcutaneous mass over the left calf and inguinal lymphadenopathy. His complete blood count and serum chemistries were within normal limits. A biopsy of the calf mass demonstrated a circumscribed mass of tumor cells located within the subcutaneous tissue that was comprised of intermediate-sized lymphoid cells. A local lymph node likewise was infiltrated with the lymphomatous cells, but there were no other sites of metastasis. The bone marrow was negative at the time of diagnosis for lymphoma by both microscopic examination and flow cytometry. Both the calf mass and the lymph node were resected completely. Flow cytometric analysis demonstrated intense expression of CD56; intermediate expression of CD38, CD45 and human leukocyte antigen (HLA)-DR; and weak expression of CD2 and CD33. The tumor cells were negative for CD3 and all other cell markers examined. Cytogenetic studies showed a clonal abnormality [t(1,6)], although no Tcell receptor gene rearrangement was detected. The malignant cells did not show staining for EBV latent membrane protein. A diagnosis of NK lymphoma, blastoid subtype, was made based on the presence of a moderate amount of pale cytoplasm (greater than that usually observed in acute lymphoblastic lymphoma) and positive staining with perforin and 12E7 (CD99/MIC-2), which was consistent with an immature NK cell lymphoid malignancy.12 The patient was referred to Children’s Memorial Hospital for further treatment. He was treated with vincristine, doxorubicin, cyclophosphamide, and prednisone as per the Pediatric Oncology Group (POG) Protocol 9219 for localized non-Hodgkin lymphoma. Therapy was discontinued electively after 9 weeks with the patient achieving complete clinical disease remission. Nine months later, the lymphoma recurred in the subcutaneous tissue of the patient’s left posterior thigh. Flow cytometric analysis demonstrated that the cells expressed the same markers as the original tumor. The bone marrow was examined as before (microscopically and by flow cytometry) and was found to be free of disease. The tumor was resected, and the patient was retreated with augmented BFM-type therapy (which is known to be effective for high risk T-cell malignancies) according to the Children’s Cancer Group Protocol 188213 with vincristine, prednisone, dexamethasone, daunorubicin, doxorubicin, cytosine arabinoside, L-asparaginase, 6-mercaptopurine, 6-thioguanine, cyclophosphamide, and methotrexate. Eighteen months after the first recurrence, while the patient still was receiving maintenance chemother-
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apy, he presented with painless enlargement of 1 testicle. Biopsy demonstrated diffuse involvement with lymphoma. Flow cytometry of a bone marrow aspirate taken at that time demonstrated a distinct CD56⫹ population of cells that comprised ⬍ 5% of the total nucleated cells. The patient received two courses of ifosfamide, carboplatin, and etoposide (ICE) while an optimal stem cell source was sought. Autologous stem cell transplantation was not considered because of the bone marrow involvement. The testicular mass decreased in size during this time. A whole body positron emission tomography scan taken at the time was negative. Both testicles received involved field irradiation (1200 centigrays [cGy]) and the patient then was conditioned with total body irradiation (total of 1200 cGy from Day -9 to Day -6), thiotepa (5 mg/kg at Day -5), etoposide (1000mg/m2 at Day -5), and cyclophosphamide (60 mg/kg/day at Day -4 to Day -2) before receiving a 4 of 6 HLA-matched unrelated umbilical cord blood transplantation (matched at the HLA-DR locus). He fully engrafted neutrophils at 21 days and platelets at 66 days after the transplantation. He developed Grade 2 acute skin graft-versus-host disease (GVHD), which resolved. At last follow-up (as of March 2000), the patient had been in disease remission for 15 months posttransplantation with no evidence of chronic GVHD.
Case Two A 12-year-old boy presented with a 1-week history of dyspnea. His physical examination was significant for inspiratory stridor and left supraclavicular lymphadenopathy. He was found on chest radiography to have a large mediastinal mass extending into his left neck, compressing and displaced his trachea. A computed tomography (CT) scan of the chest and neck revealed that the tumor mass infiltrated the thyroid gland. The tumor was gallium-avid. The rest of his staging studies, which included an abdominal CT scan and bone scan, were negative for disseminated disease. His serum chemistries and blood counts at the time of diagnosis were within normal limits. A bone marrow aspiration showed normal cellularity and no tumor involvement was detected by flow cytometry or light microscopy. The largest supraclavicular lymph node was biopsied under local anesthesia due to compromise of the patient’s airway, and yielded limited material for diagnosis. The biopsy showed replacement of normal tissue with lymphoblastic cells that were positive by immunocytochemical staining for CD56 and CD45 but were negative for CD2, CD3, CD5, CD7, CD10, and CD19. The stain for EBV latent membrane protein was strongly positive. There was insufficient tissue for cytometry. Based on the biopsy, the patient
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TABLE 1 Case Reports of Pediatric NK Lymphomas Patient
Age
Gender
Primary site
Stage
Treatment
Outcome
Follow-up
Source
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
9 yrs 12 yrs 16 yrs 16 yrs 6 yrs 17 yrs 17 yrs 17 yrs 18 yrs 12 yrs 4 yrs 15 yrs 6 mos 15 yrs 1 mo
Male Male Female Female Male Male Male Female Female Male Male Female Male Female Male
SQ/local LN M/local LN C LN/L/S/M LN/L/K/Lu/M N LN/L/S/BM N N LN/S/BM/L Sk (chin) Sk (face) LN L/S/Meso/BM L/S/BM
II II II IV IV I IV I I IV I I I IV IV
POG #9219, CCG #1882, HDC-SCRa POG #9404, ICE, HDC-SCRb Chemo CHOP, MEPP, HDC-SCRc NHL-BFM 90, HDC-SCRd NA m-BACOD, 2-CDA CHOP CHOP Steroids/splenectomy NA Chemo Chemo CHOP Interferon-␣
CR CR DOD CR CR CR DOD CR CR DOD NA CR DOD DOD DOD
41 mos 15 mos 7 mos 30 mos 12 mos 45 mos 2 mos 27 mos 107 mos 2.5 mos Recent 48 mos 10 mos 18 days 31 days
— — Lei et al.9 Nawa et al.8 Ohnuma et al.6 Emile et al.10 Kwong et al.3 Kwong et al.3 Kwong et al.3 Wong et al.7 Chan et al.2 Chan et al.2 Chan et al.2 Catlin et al.11 Catlin et al.11
NK: natural killer cell; SQ: subcutaneous; LN: lymph node; POG: Pediatric Oncology Group; CCG: Children’s Cancer Group; HDC-SCR: high dose chemotherapy with stem cell rescue; CR: complete response; M: mediastinum; ICE: ifosfamide, carboplatin, and etopside; C: cecum; chemo: chemotherapy, not otherwise specified; DOD: died of disease; L: liver; S: spleen; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisolone; MEPP: mitoxantrone, etoposide, cisplatin, and prednisolone; K: kidney; Lu: lungs; NHL-BFM 90: non-Hodgkin lymphoma–Berlin-Frankfurt-Munich Protocol 90; N: nasal; NA: not available; BM: bone marrow; m-BACOD: bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, and methotrexate; 2-CDA: 2-chloro-deoxyadenosine; Sk: skin; Meso: mesosalpinx; a Received unrelated cord blood. b Received autologous peripheral blood stem cells. c Received syngeneic peripheral blood stem cells. d Received maternal bone marrow.
was diagnosed with lymphoblastic lymphoma of committed NK-precursor type The patient received treatment on the POG T-4 Protocol 9404 with vincristine, methotrexate, doxorubicin, prednisone, 6-mercaptopurine, L-asparaginase, intrathecal cytosine arabinoside, hydrocortisone, and methotrexate, a protocol based on the results reported by investigators at the Dana Farber Cancer Institute.14,15 After an initial partial response, local tumor progression was evident within 6 weeks; therefore the patient was treated with fractionated involved field radiation (3800 cGy total). After radiation therapy, chest radiography revealed a significant decrease in tumor size, and the patient’s respiratory symptoms abated completely. However, the gallium scan demonstrated persistent uptake in his residual mediastinal tumor. The bone marrow was negative for tumor by flow cytometry performed at this time. One month after radiation therapy, the patient received three courses of ICE; peripheral blood stem cells were harvested during times of bone marrow recovery. After the ICE therapy, a repeat gallium scan was negative. The patient received thiotepa (300 mg/m2/day from Day -7 to Day -5) and cyclophosphamide (1500 mg/ m2/day from Day -5 to Day -2) followed by an infusion of autologous peripheral blood stem cells. He fully engrafted neutrophils at 15 days and platelets at 31 days after transplantation. At last follow-up (as of Sep-
tember 2000), the patient had remained disease free 16 months after transplantation.
MATERIALS AND METHODS For our literature review we used MEDLINE to search all journals in all languages from 1966 to the present for related cases. The keywords used were “natural killer cell,” “lymphoma,” “therapy,” and “pediatric.”
RESULTS AND DISCUSSION In the current study we describe the clinical course of two pediatric cases of NK lymphoma. Our literature review documented only 13 children with NK cell lymphoma (Table 1): 10 from Asia, 1 from Europe, and 2 from the U.S. (1 of whom acquired the disease transplacentally). Of the 13 patients described, 6 had disseminated disease at the time of presentation (Stage IV) and 7 had local disease (Stages I or II). Both patients described in the current study had localized disease (Stage II) at the time of diagnosis, but one boy developed two recurrences after surgery and chemotherapy whereas the other child developed progressive disease early during therapy. Clinically, NK cell lymphoma occurs almost exclusively in Asian adults, and in the majority of cases originates in the nasopharynx.1,2,15,16 These tumors are angiocentric and are associated strongly with EBV. In 1997, Chan et al. published what to our knowledge
Pediatric NK Lymphomas/Shaw et al.
is the largest series to date of NK neoplasms (49 cases in Hong Kong), in which they reported 3 distinct types and 1 heterogeneous group.2 Patients with the first type, nasal T-cell/NK lymphoma, presented with extranodal disease in multiple sites (mainly the upper respiratory tract) and 94% harbored EBV. The tumors were locally destructive, angioinvasive, and rapidly fatal. Patients with the second type, aggressive NK cell leukemia/lymphoma, presented with hepatosplenomegaly, lymphadenopathy, and bone marrow involvement. Similar to the nasal NK lymphomas, these tumors also were EBV positive. All patients died within 6 weeks of diagnosis. Blastoid NK cell lymphoma was the third type mentioned by Chan et al.2 This type was noted in only two patients, both of whom were alive at the time of last follow-up, but the follow-up period was short. A fourth, more amorphous group of malignancies also was described. These patients had variable sites of presentation, with the spleen, bone marrow, and lymph nodes being the most commonly involved. All these tumors were EBV negative, and all 6 patients died at a median of 25 weeks.2 The majority of patients in the series by Chan et al. received chemotherapy and surgery with little success.2 The first patient reported in the current study falls into the blastoid NK cell lymphoma group whereas the second patient presented herein appears to be in the less well defined fourth group because although the tumor was found to stain positively for EBV latent membrane protein, the patient presented with a mediastinal mass. Smaller series and published case reports further demonstrate the heterogeneous presentations of these neoplasms, and the rarity of a nonnasal primary site.17 Kwong et al. reported 24 cases of NK lymphoma, and 19 of these patients had disease localized to the nasopharynx. Primary disease presentations in the calf (Case 1 in the current study) and mediastinum (Case 2 in the current study) appear to be unique in the literature. However, to our knowledge, testicular involvement, as noted at the time of recurrence in the first patient reported in the current study, previously has been reported in four patients.18,19 Within the classification of non-B lineage lymphoblastic lymphomas, 70% of tumors express TCR gene rearrangements and 30% are divided into T-cell/NK bipotential progenitors, early stage T-cell precursors without TCR rearrangements, and NK precursors.20 Therefore, it would appear that the clone in NK lymphomas develops from a transformed T-cell/NK bipotential progenitor cell after irreversible commitment to the NK cell line. There are abundant in vitro data that support this theory.21,22 Rodewald et al. identified a fetal mouse thymocyte population that had the ca-
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pacity to differentiate into both T cells and NK cells. When the cells were maintained in a thymic microenvironment, they developed into mature T cells. However, when the cells were removed from this environment, they became functional NK cells.23 NK precursors also have been found in most fetal hematopoietic organs, indicating that NK differentiation is not restricted to one type of tissue.24 The diffuse widespread distribution of the NK cells would explain its clinical variability when a malignant clonal population develops. The long-term disease free survival for adult patients with nasal-type NK lymphomas is reported to be ⬍ 15%.1,2,10 Adults with nonnasal NK lymphomas have an equally poor prognosis. Only 19 of 95 patients (20%) were reported to be alive at last follow-up despite treatment including surgery, chemotherapy, and radiation therapy.1–5,10,16,17,19,25–27 It is interesting to note that the outcome for the pediatric patients reported in the literature (Table 1) was somewhat better than that of their adult counterparts, with 7 of 13 children surviving at the time of last follow-up (54%). Seven patients had localized disease and five were reported to be alive at the time of last follow-up with follow-up ranging from 1–107 months after chemotherapy and surgery. Of the 6 patients with Stage IV disease, 2 patients were alive at 30 months and 12 months, respectively, of follow-up. Both were treated with high dose chemotherapy and stem cell rescue.6,8 The other 4 patients with Stage IV disease, including Patient 15, an unusual case who acquired his lymphoma transplacentally from Patient 14,11 died at a mean of 6 weeks after diagnosis. High dose chemotherapy and stem cell rescue also were found to be successful in two of three adult nasal NK patients28 and in one patient in the series of adults reported by Nakamura et al.17 Because of the well established poor prognosis in any patient with an advanced NK lymphoma and our patients’ individual poor responses to initial therapy, we treated the current study patients with high dose chemotherapy and stem cell rescue. Both were alive at the time of last follow-up, 48 months and 22 months, respectively, after diagnosis (15 months and 16 months, respectively, after transplantation). Including the patients presented herein, 9 of 15 children with NK cell lymphoma (all stages) (60%) were reported to be alive with varying lengths of follow-up. It is interesting to note that both of the patients presented in the current study were consolidated prior to transplantation with ICE chemotherapy. Both lymphomas responded to this combination of agents, with the first patient’s testicular mass decreasing in size and the second patient’s mediastinal mass be-
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CANCER February 15, 2001 / Volume 91 / Number 4
coming gallium-negative. Even though we described only two cases in the current study, initial treatment with ICE may be considered for pediatric NK lymphoma patients whereas high dose chemotherapy and stem cell rescue could be reserved for salvage therapy. It is likely that nasal and nonnasal NK lymphomas are in the same family, differing in clinical presentation with some variability in EBV association but sharing CD56 expression, aggressiveness, and overall poor prognosis. In our experience, high dose chemotherapy followed by stem cell rescue appears to be effective salvage treatment for pediatric patients who develop a recurrence of this very rare malignancy. Further follow-up and experience with more uniformly treated cases is needed to define optimal treatment approaches better.
REFERENCES 1.
Cheung MMC, Chan JKC, Lau WH, Foo W, Chan PTM, Ng CS, et al. Primary non-Hodgkin’s lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol 1998; 16(1):79 –7. 2. Chan JKC, Sin VC, Wong KF, Ng CS, Tsang WYW, Chan CH, et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood 1997;89(12):4501–13. 3. Kwong YL, Chan ACL, Liang RHS. Natural killer cell lymphoma/leukemia: pathology and treatment. Hematol Oncol 1997;15:71–9. 4. Liang R, Todd D, Chan TK, Chiu E, Lie A, Kwong YL, et al. Treatment outcome and prognostic factors for primary nasal lymphoma. J Clin Oncol 1995;13(3):666 –70. 5. Tsang WY, Chan JK, Yip TT, Ng CS, Wong KF, Poon YF, et al. In situ localization of Epstein-Barr virus encoded RNA in non-nasal/nasopharyngeal CD56-positive and CD56-negative T-cell lymphomas. Hum Pathol 1994;25(8)758 – 65. 6. Ohnuma K, Toyoda Y, Nishihira H, Iguchi A, Honda K, Nagao T, et al. Aggressive natural killer (NK) cell lymphoma: report of a pediatric case and review of the literature. Leuk Lymphoma 1997;25:387–92. 7. Wong KF, Chan JKC, Ng CS, Lee KC, Tsang WYW, Cheung MMC. CD56 (NKH1)-positive hematolymphoid malignancies: an aggressive neoplasm featuring frequent cutaneous/ mucosal involvement, cytoplasmic azurophilic granules and angiocentricity. Hum Pathol 1992;23:798 – 804. 8. Nawa Y, Takenaka K, Shinagawa K, Deguchi S, Matsumura N, Koyama S, et al. Successful treatment of advanced natural killer cell lymphoma with high-dose chemotherapy and syngeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 1999;23:1321–2. 9. Lei KL, Chow JH, Johnson PJ. Aggressive primary natural killer cell lymphoma of the caecum: a case report and literature review. Clin Oncol (R Coll Radiol) 1997;9(3):191– 4. 10. Emile JF, Boulland ML, Haioun C, Kanavaros P, Petrella T, Delfau-Larue MH, et al. CD5- CD56⫹ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas. Blood 1996;87(4):1466 –73. 11. Catlin EA, Roberts JD Jr., Erana R, Preffer FI, Ferry JA, Kelliher AS, et al. Transplacental transmission of natural-killercell lymphoma. N Engl J Med 1999;341(2):85–91.
12. Jaffe ES, Chan JKC, Su IJ, Frizzera G, Mori S, Feller AC, et al. Report of the workshop on nasal and related extranodal angiocentric T/NK lymphomas: definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 1996;20:103–11. 13. Uckun FM, Nachman JB, Sather HN, Sensel MG, Kraft P, Steinherz PG, et al. Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. Blood 1998;91:737– 46. 14. Clavell LA, Gelber RD, Cohen HJ, Hitchcock-Bryan S, Cassady JR, Tarbell NJ, et al. Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 1986;315:657– 63. 15. Schorin MA, Blattner S, Gelber RD, Tarbell NJ, Donnelly M, Dalton V, et al. Treatment of childhood acute lymphoblastic leukemia: results of Dana Farber Cancer Institute/Children’s Hospital Acute Lymphoblastic Leukemia Consortium Protocol 85-01. J Clin Oncol 1994;12:740 –7. 16. Jaffe ES. Classification of natural killer (NK) cell and NK-like T-cell malignancies. Blood 1996;87(4):1207–10. 17. Nakamura S, Suchi T, Koshikawa T, Kitoh K, Koike K, Komatsu H, et al. Clinicopathologic study of CD56 (NCAM)positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract. Am J Surg Pathol 1995;19(3)284 –96. 18. Chan JKC, Tsang WYW, Lau WH, Cheung MMC, Ng WF, Yuen WC, et al. Aggressive T/natural killer cell lymphoma presenting as testicular tumor. Cancer 1996;77(6):1198 –205. 19. Sun T, Brody J, Susin M, Marino J, Teichberg S, Koduru P, et al. Aggressive natural killer cell lymphoma/leukemia: a recently recognised clinicopathologic entity. Am J Surg Pathol 1993;17(12):1289 –99. 20. Ichinohasama R, Endoh K, Ishizawa K, Okuda M, Kameoka J, Meguro K, et al. Thymic lymphoblastic lymphoma of committed natural killer cell precursor origin. Cancer 1996; 77(12):2592– 603. 21. Lanier LL, Spits H, Phillips JH. The developmental relationship between NK cells and T cells. Immunol Today 1992; 13(10):392–5. 22. Sanchez MJ, Muench MO, Roncarolo MG, Lanier LL, Phillips JH. Identification of a common T/natural killer progenitor in human fetal thymus. J Exp Med 1994;180:569 –76. 23. Rodewald HR, Moingeon P, Lucich JL, Dosiou C, Lopez P, Reinherz EL. A population of early fetal thymocytes expressing Fc gamma RII/III contains precursors of T lymphocytes and natural killer cells. Cell 1992;69(1):139 –50. 24. Sanchez MJ, Spits H, Lanier LL, Phillips JH. Human natural killer cell committed thymocytes and their relation to the T cell lineage. J Exp Med 1993;178:1857– 66. 25. Hirakawa Y, Kuyama M, Takahashi S, Yamasaki O, Kanzaki H, Teshima T, et al. Nasal and nasal-type natural killer /T-cell lymphoma. J Am Acad Dermatol 1999;40(2 Pt1):268 – 72. 26. Tamura H, Ogata K, Mori S, An E, Tajika K, Sugisaki Y, et al. Lymphoblastic lymphoma of natural killer cell origin, presenting as pancreatic tumour. Histopathology 1998;32(6): 508 –11. 27. Macon WR, Williams ME, Greer JP, Hammer RD, Glick AD, Collins RD, et al. Natural killer-like T-cell lymphomas: aggressive lymphomas of T-large granular lymphocytes. Blood 1996;87(4):1474 – 83. 28. Liang R, Chen F, Lee CK, Kwong YL, Chim CS, Yau CC, et al. Autologous bone marrow transplantation for primary nasal T/NK cell lymphoma. Bone Marrow Transplant 1997;19(1): 91–3.
