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T–cell lymphoma
268 Brief communications
Journal of the American Academy of Dermatology February 1999
Nasal and nasal-type natural killer/ T–cell lymphoma Satoshi Hirakawa, MD,a Michiyo Kuyama, MD,a Sachiko Takahashi, MD,a Osamu Yamasaki, MD,a Hiroko Kanzaki, MD,a Takanori Teshima, MD,b Mine Harada, MD,b Yuxiang Ma, MD,c Teruyuki Kawabata, MD,c Tadashi Yoshino, MD,d and Jirô Arata, MDa Okayama, Japan Nasal and nasal-type natural killer (NK)/T-cell lymphomas follow an aggressive course and have a poor prognosis. Recent pathologic studies suggest that the disease is a malignant proliferation of NK cells, which often express CD56. An association with the Epstein-Barr virus has also been reported. Skin involvement occurred in each of the 3 patients studied. Radiation therapy provided some benefit to the patients in the early stages. Conventional chemotherapies were not effective. To overcome this multiple-drug resistance of the tumor cells, cyclosporine and high-dose chemotherapy was combined with peripheral-blood stem-cell transplantation. The average life span from the onset of the disease for our patients was 9.6 months. Further improvement in the management of nasal and nasal-type NK/T-cell lymphomas is necessary. (J Am Acad Dermatol 1999;40: 268-272.)
From the Department of Dermatology,a Internal Medicine II,b Pathology I,c and Pathology II,d Okayama University Medical School. Reprint requests: Satoshi Hirakawa, MD, Department of Dermatology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/54/94732
Nasal and nasal-type natural killer (NK)/T–cell lymphomas, previously referred to as lethal midline granuloma,1 follow an aggressive course and have a poor prognosis. Recent pathologic studies suggest that the disease is a malignant proliferation of NK cells, which often express CD56.2,3
Journal of the American Academy of Dermatology Volume 40, Number 2, Part 1
Brief communications 269
Table I. Clinical characteristics and laboratory findings of the cases Case No. 1
2
M/44 Nasal cavity Reddish nodules with central ulcer IIEB CHOP/PR VACOP-BEP/PR
3
Sex/Age (y) Primary lesion Cutaneous involvement
F/73 Oral cavity Flat mass without ulcer
Stage at diagnosis Treatment/Response
IIEB THP + COP/PR RT/PR MEPP + CsA/PR
Life prognosis (mo) MDR at diagnosis* MDR after chemotherapy* LMP-1 EBER-1 TCR gene rearrangement Immunophenotype Intracytoplasmic CD3† Surface CD3‡ CD4 CD5 CD8 CD16 CD20 CD30 CD45Ro CD56 CD57
7 + Germline configuration
11 + + Germline configuration
F/19 Nasal cavity Reddish nodules with central ulcer IEA CHOP/PR RT/PR EPOCH-B + CsA combined with PBSCT/not carried out completely 11 ND + + Germline configuration
+ Not defined ND ND ND + -
+ + ND + -
+ ND ND ± + -
ND, Not done; PR, partial remission; RT, radiation therapy. *Judgment with MDR in immunohistochemical study was performed as positive if more than 5% of the tumor cells were stained positive. †Rabbit serum (A0452 DAKO A/S, Denmark) was used to stain intracytoplasmic portion of human CD3 ε chain on paraffin section. ‡Monoclonal anti-CD3, Leu-4 (347341 Becton Dickinson) was used to stain ε chain of human CD3 antigen/TCR complex on frozen section.
Genetically, T-cell receptor gene rearrangement, which is a marker of differentiation for T cells, is in a germline configuration in the disease. An association with the Epstein-Barr virus (EBV) has also been reported.4 The terms nasal and nasaltype NK/T-cell lymphomas have been proposed to replace angiocentric lymphoma recognized by the Revised European-American Lymphoma Classification.2 These diseases are more common in Asia than in the United States and Europe. The most common primary lesion is found in the nasal cavity. Skin and subcutaneous tissues may also be involved in primary and metastatic lesions of this disease.1-3,5-9 We report 3 cases of nasal and nasaltype NK/T-cell lymphomas that revealed secondary skin involvement.
METHODS To assess the characteristics of infiltrating cells taken from each patient, the following studies were performed. Immunohistochemical staining was done to identify the immunophenotypes of tumor cells, the EBV-encoded latent membrane protein-1 (LMP-1), and the multidrug resistance-related P-glycoprotein-1 (MDR-1). Expression of the EBV encoding RNA-1 (EBER-1) by tumor cells was determined by in situ hybridization. Southern blot analysis was used to examine the T-cell receptor β-chain gene rearrangement. All results are shown in Table I. CASE REPORTS
Case 1 A 73-year-old woman experienced painful, fetid, gray-to-brown necrotic ulcers on the gingivae. She had
Journal of the American Academy of Dermatology February 1999
270 Brief communications
Fig 1. Case 1. Infiltrating cells throughout dermis are positive for CD56.
Fig 2. Case 2. Firm, red-to-brown nodules with or without central crusted ulcers on the back.
high fever and heavy night sweats. Her nasal cavity was intact on admission. The submandibular lymph nodes were swollen. Biopsy specimens from the lower lip revealed dense small to large atypical lymphoid cells in diffuse necrotic dermis. Infiltration and fibrinoid change of the blood vessel walls were observed. Immunohistochemical analysis did not reveal MDR-1. Laboratory studies disclosed lactate dehydrogenase (708 IU/L) and EBV viral capsid antigen IgG (1:160). The patient was diagnosed with stage IIEB nasal-type NK/T cell lymphoma after general examination. Two courses of THP + COP therapy (pirarubicin hydrochloride, cyclophosphamide, vincristine, and prednisolone) and a total of 42 Gy radiation therapy failed to bring about complete remission. A soybeansized subcutaneous lesion appeared on the right lower limb. This lesion had a dark purple surface without ulcer. Histologic examination revealed CD56 and MDR-1-positive malignant lymphoma (Fig 1). A salvage-modified MEPP therapy with cyclosporine (mitoxantrone hydrochloride, etoposide, carboplatin, prednisolone, and cyclosporine) was instituted, but was not beneficial. The patient died 7 months after the onset of her disease.
adnexal regions in the dermis. The patient was diagnosed with stage IIEB nasal NK/T-cell lymphoma. Three courses of VACOP-BEP therapy (vincristine, doxorubicin hydrochloride, cyclophosphamide, prednisolone, bleomycin, etoposide, and cisplatin) were administered after 1 course of CHOP therapy (cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone), which was not effective. Immunohistochemically, biopsy specimens taken after these therapies revealed the expression of MDR-1 that did not exist before treatment. Although the skin lesions improved slightly after therapy, the patient died 11 months after the first manifestation of the disease because of disseminated intravascular coagulation.
Case 2 A 44-year-old man experienced nasal congestion and, after 6 months, painful ulcers on his palates and gingivae. Seven months later, he began to experience thumb-sized, firm, red nodules with or without central crusted ulcers on his trunk (Fig 2). Superficial lymph nodes were not palpable. After his admission, computed tomography revealed tumors in the maxillary sinus; significant findings with 67Ga-scintigraphy were limited to the nasal area. Histologically, infiltrated large tumor cells with chromatin-rich atypical nuclei were observed in subcutaneous tissue and perivascular or
Case 3 A 19-year-old girl presented with nasal congestion. After 4 months, she visited our hospital. Laboratory examination revealed no significant changes except EBV viral capsid antigen IgG 1:320. A biopsy was taken from a tumor in the nasal cavity. Histologic study revealed epidermotropism of medium-sized to large atypical lymphoid tumor cells, which had invaded and destroyed dermal and subcutaneous blood vessels. After general examination, this patient was diagnosed with stage IEA nasal NK/T-cell lymphoma. After 1 course of CHOP therapy, MEPP therapy was given (mitoxantrone hydrochloride, etoposide, cisplatin, and prednisolone). A total of 50 Gy radiation therapy administered to the primary lesion resulted in some benefit. After all of these therapies, coin-sized, red, flat-topped nodules with central necrotic ulcers spread on her trunk and four extremities. Biopsy specimens taken from a cutaneous lesion were positive for MDR-1; this was not studied before the first treatment. Peripheral blood stem cell transplantation (PBSCT) combined with EPOCH-B + CsA therapy (etoposide,
Journal of the American Academy of Dermatology Volume 40, Number 2, Part 1
vincristine, doxorubicin hydrochloride, prednisolone, bleomycin, and cyclosporine) was started. Insufficient harvest of the blood stem cells, however, prevented therapy from continuing. Ten months after the onset, a leukemic change was noted. The patient died 11 months after her disease began. DISCUSSION
The cutaneous findings of nasal and nasal-type NK/T-cell lymphomas have been discussed.1-3,5-9 The characteristics of our cases are summarized in Table I. Infiltrating cells of all the patients studied expressed CD56 on the cell surface. It is known that CD56 is expressed on normal dermal microvascular endothelial cells.10 CD56 binds to itself. Therefore, CD56+ tumor cells could invade and destroy dermal vessels. Clinically, necrotic changes of the skin and oral mucosa were present in all 3 patients. Recent studies have suggested a strong association of EBV with nasal and nasal-type NK/T-cell lymphomas.4 The 3 cases in our study were examined to detect EBV-related products in tumor cells; EBER-1 by means of in situ hybridization, and LMP-1 by immunohistochemistry. Although 2 cases (2 and 3) were positive for EBER-1, the other (case 1) was negative. LMP-1 was not detected in any of the 3 patients. Therefore, a strong EBV-association was not clearly indicated from our studies, but general conclusions cannot be drawn from such small numbers. Nasal NK/T-cell lymphoma runs an aggressive course. In the early stage (stage I), however, treatment can result in complete remission, especially after radiation therapy.11,12 All the patients in our study, who each had secondary skin involvement, experienced poor courses. From the recent literature1,3,5-8 and our 3 cases, the mean life survival from the onset of CD56+ lymphomas with secondary cutaneous manifestation is more than 7.7 months (range, 2 to 33 months; δ = 7.17 months; n = 18). Skin-originated nasal-type NK/T-cell lymphoma, however, can have either an aggressive or prolonged course.3,5-9 The mean life survival from the onset of primary cutaneous CD56+ lymphomas is more than 15.5 months (range, 3 to 43 months; δ = 11.8 months; n = 12) among the literature quoted above.3,5-9 Therefore, distinctive variants might be involved in skin-originated nasal-type NK/T-cell lymphoma. In addition, nasal and nasaltype NK/T-cell lymphomas with secondary cuta-
Brief communications 271 neous involvement might be more aggressive than skin-originated nasal-type NK/T-cell lymphomas. The rapid and fatal course of nasal and nasaltype NK/T-cell lymphomas, in spite of repeated chemotherapy, might be attributed to multidrug resistance of tumor cells.13 In both cases 1 and 2, which ran aggressive courses, MDR-1 was not expressed before chemotherapy. In each of these cases, however, MDR-1 was expressed after chemotherapy. Perhaps the expression of MDR-1 contributes to the poor prognosis of the disease. Our trial of PBSCT in combination with sequential high-dose chemotherapy in case 3 did not obtain satisfactory results. The institution of cyclosporine as a resistance-modifying agent in cases 1 and 3 was also without obvious benefit. Considering the very aggressive nature of this lymphoma, however, PBSCT in combination with sequential high-dose chemotherapy and a chemotherapy-supportive method such as cyclosporine should be considered. We thank Mr Akira Matsumoto for his help with the photography. REFERENCES 1. Soler J, Bordes R, Ortuño F, Montagud M, Martorell J, Pons C, et al. Aggressive natural killer cell leukemia/ lymphoma in two patients with lethal midline granuloma. Br J Haematol 1994;86:659-62. 2. 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/natural killer cell lymphomas: definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 1996;20:103-11. 3. Emile JF, Boulland ML, Haioun C, Kanavaros P, Petrella T, Delfau-Larue M-H, et al. CD5- CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas. Blood 1996;87:1466-73. 4. Chan JKC, Yip TTC, Tsang WYW, Ng CS, Lau WH, Poon YF, et al. Detection of Epstein-Barr viral RNA in malignant lymphomas of the upper aerodigestive tract. Am J Surg Pathol 1994;18:938-46. 5. 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. 6. 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;19:284-96. 7. Savoia P, Fierro MT, Novelli M, Quaglino P, Verrone A, Geuna M, et al. CD56-positive cutaneous lymphoma: a poorly recognized entity in the spectrum of primary cutaneous disease. Br J Dermatol 1997;137:966-71. 8. Ansai S, Maeda K, Yamakawa M, Matsuda M, Saitoh S, Suwa S, et al. CD56-positive (nasal-type T/NK cell)
272 Brief communications lymphoma arising on the skin. J Cutan Pathol 1997;24: 468-76. 9. Dummer R, Potoczna N, Häffner AC, Zimmermann DR, Gilardi S, Burg G. A primary cutaneous non-T, non-B, CD4+, CD56+ lymphoma. Arch Dermatol 1996;132: 550-3. 10. Mizutani H, Roswit W, Hemperly J, Lawley T, Compton C, Swerlick R, et al. Human dermal microvascular endothelial cells express the 140-KD isoform of neural cell adhesion molecule. Biochem Biophys Res Commun 1994;203:686-93. 11. Shikama N, Izuno I, Oguchi M, Gomi K, Sone S, Takei K, et al. Clinical stage IE primary lymphoma of the nasal
Journal of the American Academy of Dermatology February 1999
cavity: radiation therapy and chemotherapy. Radiology 1997;204:467-70. 12. Suzumiya J, Takeshita M, Kimura N, Kikuchi M, Uchida T, Hisano S, et al. Expression of adult and fetal natural killer cell markers in sinonasal lymphomas. Blood 1994; 83:2255-60. 13. Drénou B, Lamy T, Amiot L, Fardel O, CauletMaugendre S, Sasportes M, et al. CD3- CD56+ nonHodgkin’s lymphomas with an aggressive behavior related to multidrug resistance. Blood 1997;89:2966-74.
Journal of the American Academy of Dermatology February 1999
Nasal and nasal-type natural killer/ T–cell lymphoma Satoshi Hirakawa, MD,a Michiyo Kuyama, MD,a Sachiko Takahashi, MD,a Osamu Yamasaki, MD,a Hiroko Kanzaki, MD,a Takanori Teshima, MD,b Mine Harada, MD,b Yuxiang Ma, MD,c Teruyuki Kawabata, MD,c Tadashi Yoshino, MD,d and Jirô Arata, MDa Okayama, Japan Nasal and nasal-type natural killer (NK)/T-cell lymphomas follow an aggressive course and have a poor prognosis. Recent pathologic studies suggest that the disease is a malignant proliferation of NK cells, which often express CD56. An association with the Epstein-Barr virus has also been reported. Skin involvement occurred in each of the 3 patients studied. Radiation therapy provided some benefit to the patients in the early stages. Conventional chemotherapies were not effective. To overcome this multiple-drug resistance of the tumor cells, cyclosporine and high-dose chemotherapy was combined with peripheral-blood stem-cell transplantation. The average life span from the onset of the disease for our patients was 9.6 months. Further improvement in the management of nasal and nasal-type NK/T-cell lymphomas is necessary. (J Am Acad Dermatol 1999;40: 268-272.)
From the Department of Dermatology,a Internal Medicine II,b Pathology I,c and Pathology II,d Okayama University Medical School. Reprint requests: Satoshi Hirakawa, MD, Department of Dermatology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/54/94732
Nasal and nasal-type natural killer (NK)/T–cell lymphomas, previously referred to as lethal midline granuloma,1 follow an aggressive course and have a poor prognosis. Recent pathologic studies suggest that the disease is a malignant proliferation of NK cells, which often express CD56.2,3
Journal of the American Academy of Dermatology Volume 40, Number 2, Part 1
Brief communications 269
Table I. Clinical characteristics and laboratory findings of the cases Case No. 1
2
M/44 Nasal cavity Reddish nodules with central ulcer IIEB CHOP/PR VACOP-BEP/PR
3
Sex/Age (y) Primary lesion Cutaneous involvement
F/73 Oral cavity Flat mass without ulcer
Stage at diagnosis Treatment/Response
IIEB THP + COP/PR RT/PR MEPP + CsA/PR
Life prognosis (mo) MDR at diagnosis* MDR after chemotherapy* LMP-1 EBER-1 TCR gene rearrangement Immunophenotype Intracytoplasmic CD3† Surface CD3‡ CD4 CD5 CD8 CD16 CD20 CD30 CD45Ro CD56 CD57
7 + Germline configuration
11 + + Germline configuration
F/19 Nasal cavity Reddish nodules with central ulcer IEA CHOP/PR RT/PR EPOCH-B + CsA combined with PBSCT/not carried out completely 11 ND + + Germline configuration
+ Not defined ND ND ND + -
+ + ND + -
+ ND ND ± + -
ND, Not done; PR, partial remission; RT, radiation therapy. *Judgment with MDR in immunohistochemical study was performed as positive if more than 5% of the tumor cells were stained positive. †Rabbit serum (A0452 DAKO A/S, Denmark) was used to stain intracytoplasmic portion of human CD3 ε chain on paraffin section. ‡Monoclonal anti-CD3, Leu-4 (347341 Becton Dickinson) was used to stain ε chain of human CD3 antigen/TCR complex on frozen section.
Genetically, T-cell receptor gene rearrangement, which is a marker of differentiation for T cells, is in a germline configuration in the disease. An association with the Epstein-Barr virus (EBV) has also been reported.4 The terms nasal and nasaltype NK/T-cell lymphomas have been proposed to replace angiocentric lymphoma recognized by the Revised European-American Lymphoma Classification.2 These diseases are more common in Asia than in the United States and Europe. The most common primary lesion is found in the nasal cavity. Skin and subcutaneous tissues may also be involved in primary and metastatic lesions of this disease.1-3,5-9 We report 3 cases of nasal and nasaltype NK/T-cell lymphomas that revealed secondary skin involvement.
METHODS To assess the characteristics of infiltrating cells taken from each patient, the following studies were performed. Immunohistochemical staining was done to identify the immunophenotypes of tumor cells, the EBV-encoded latent membrane protein-1 (LMP-1), and the multidrug resistance-related P-glycoprotein-1 (MDR-1). Expression of the EBV encoding RNA-1 (EBER-1) by tumor cells was determined by in situ hybridization. Southern blot analysis was used to examine the T-cell receptor β-chain gene rearrangement. All results are shown in Table I. CASE REPORTS
Case 1 A 73-year-old woman experienced painful, fetid, gray-to-brown necrotic ulcers on the gingivae. She had
Journal of the American Academy of Dermatology February 1999
270 Brief communications
Fig 1. Case 1. Infiltrating cells throughout dermis are positive for CD56.
Fig 2. Case 2. Firm, red-to-brown nodules with or without central crusted ulcers on the back.
high fever and heavy night sweats. Her nasal cavity was intact on admission. The submandibular lymph nodes were swollen. Biopsy specimens from the lower lip revealed dense small to large atypical lymphoid cells in diffuse necrotic dermis. Infiltration and fibrinoid change of the blood vessel walls were observed. Immunohistochemical analysis did not reveal MDR-1. Laboratory studies disclosed lactate dehydrogenase (708 IU/L) and EBV viral capsid antigen IgG (1:160). The patient was diagnosed with stage IIEB nasal-type NK/T cell lymphoma after general examination. Two courses of THP + COP therapy (pirarubicin hydrochloride, cyclophosphamide, vincristine, and prednisolone) and a total of 42 Gy radiation therapy failed to bring about complete remission. A soybeansized subcutaneous lesion appeared on the right lower limb. This lesion had a dark purple surface without ulcer. Histologic examination revealed CD56 and MDR-1-positive malignant lymphoma (Fig 1). A salvage-modified MEPP therapy with cyclosporine (mitoxantrone hydrochloride, etoposide, carboplatin, prednisolone, and cyclosporine) was instituted, but was not beneficial. The patient died 7 months after the onset of her disease.
adnexal regions in the dermis. The patient was diagnosed with stage IIEB nasal NK/T-cell lymphoma. Three courses of VACOP-BEP therapy (vincristine, doxorubicin hydrochloride, cyclophosphamide, prednisolone, bleomycin, etoposide, and cisplatin) were administered after 1 course of CHOP therapy (cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone), which was not effective. Immunohistochemically, biopsy specimens taken after these therapies revealed the expression of MDR-1 that did not exist before treatment. Although the skin lesions improved slightly after therapy, the patient died 11 months after the first manifestation of the disease because of disseminated intravascular coagulation.
Case 2 A 44-year-old man experienced nasal congestion and, after 6 months, painful ulcers on his palates and gingivae. Seven months later, he began to experience thumb-sized, firm, red nodules with or without central crusted ulcers on his trunk (Fig 2). Superficial lymph nodes were not palpable. After his admission, computed tomography revealed tumors in the maxillary sinus; significant findings with 67Ga-scintigraphy were limited to the nasal area. Histologically, infiltrated large tumor cells with chromatin-rich atypical nuclei were observed in subcutaneous tissue and perivascular or
Case 3 A 19-year-old girl presented with nasal congestion. After 4 months, she visited our hospital. Laboratory examination revealed no significant changes except EBV viral capsid antigen IgG 1:320. A biopsy was taken from a tumor in the nasal cavity. Histologic study revealed epidermotropism of medium-sized to large atypical lymphoid tumor cells, which had invaded and destroyed dermal and subcutaneous blood vessels. After general examination, this patient was diagnosed with stage IEA nasal NK/T-cell lymphoma. After 1 course of CHOP therapy, MEPP therapy was given (mitoxantrone hydrochloride, etoposide, cisplatin, and prednisolone). A total of 50 Gy radiation therapy administered to the primary lesion resulted in some benefit. After all of these therapies, coin-sized, red, flat-topped nodules with central necrotic ulcers spread on her trunk and four extremities. Biopsy specimens taken from a cutaneous lesion were positive for MDR-1; this was not studied before the first treatment. Peripheral blood stem cell transplantation (PBSCT) combined with EPOCH-B + CsA therapy (etoposide,
Journal of the American Academy of Dermatology Volume 40, Number 2, Part 1
vincristine, doxorubicin hydrochloride, prednisolone, bleomycin, and cyclosporine) was started. Insufficient harvest of the blood stem cells, however, prevented therapy from continuing. Ten months after the onset, a leukemic change was noted. The patient died 11 months after her disease began. DISCUSSION
The cutaneous findings of nasal and nasal-type NK/T-cell lymphomas have been discussed.1-3,5-9 The characteristics of our cases are summarized in Table I. Infiltrating cells of all the patients studied expressed CD56 on the cell surface. It is known that CD56 is expressed on normal dermal microvascular endothelial cells.10 CD56 binds to itself. Therefore, CD56+ tumor cells could invade and destroy dermal vessels. Clinically, necrotic changes of the skin and oral mucosa were present in all 3 patients. Recent studies have suggested a strong association of EBV with nasal and nasal-type NK/T-cell lymphomas.4 The 3 cases in our study were examined to detect EBV-related products in tumor cells; EBER-1 by means of in situ hybridization, and LMP-1 by immunohistochemistry. Although 2 cases (2 and 3) were positive for EBER-1, the other (case 1) was negative. LMP-1 was not detected in any of the 3 patients. Therefore, a strong EBV-association was not clearly indicated from our studies, but general conclusions cannot be drawn from such small numbers. Nasal NK/T-cell lymphoma runs an aggressive course. In the early stage (stage I), however, treatment can result in complete remission, especially after radiation therapy.11,12 All the patients in our study, who each had secondary skin involvement, experienced poor courses. From the recent literature1,3,5-8 and our 3 cases, the mean life survival from the onset of CD56+ lymphomas with secondary cutaneous manifestation is more than 7.7 months (range, 2 to 33 months; δ = 7.17 months; n = 18). Skin-originated nasal-type NK/T-cell lymphoma, however, can have either an aggressive or prolonged course.3,5-9 The mean life survival from the onset of primary cutaneous CD56+ lymphomas is more than 15.5 months (range, 3 to 43 months; δ = 11.8 months; n = 12) among the literature quoted above.3,5-9 Therefore, distinctive variants might be involved in skin-originated nasal-type NK/T-cell lymphoma. In addition, nasal and nasaltype NK/T-cell lymphomas with secondary cuta-
Brief communications 271 neous involvement might be more aggressive than skin-originated nasal-type NK/T-cell lymphomas. The rapid and fatal course of nasal and nasaltype NK/T-cell lymphomas, in spite of repeated chemotherapy, might be attributed to multidrug resistance of tumor cells.13 In both cases 1 and 2, which ran aggressive courses, MDR-1 was not expressed before chemotherapy. In each of these cases, however, MDR-1 was expressed after chemotherapy. Perhaps the expression of MDR-1 contributes to the poor prognosis of the disease. Our trial of PBSCT in combination with sequential high-dose chemotherapy in case 3 did not obtain satisfactory results. The institution of cyclosporine as a resistance-modifying agent in cases 1 and 3 was also without obvious benefit. Considering the very aggressive nature of this lymphoma, however, PBSCT in combination with sequential high-dose chemotherapy and a chemotherapy-supportive method such as cyclosporine should be considered. We thank Mr Akira Matsumoto for his help with the photography. REFERENCES 1. Soler J, Bordes R, Ortuño F, Montagud M, Martorell J, Pons C, et al. Aggressive natural killer cell leukemia/ lymphoma in two patients with lethal midline granuloma. Br J Haematol 1994;86:659-62. 2. 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/natural killer cell lymphomas: definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 1996;20:103-11. 3. Emile JF, Boulland ML, Haioun C, Kanavaros P, Petrella T, Delfau-Larue M-H, et al. CD5- CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas. Blood 1996;87:1466-73. 4. Chan JKC, Yip TTC, Tsang WYW, Ng CS, Lau WH, Poon YF, et al. Detection of Epstein-Barr viral RNA in malignant lymphomas of the upper aerodigestive tract. Am J Surg Pathol 1994;18:938-46. 5. 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. 6. 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;19:284-96. 7. Savoia P, Fierro MT, Novelli M, Quaglino P, Verrone A, Geuna M, et al. CD56-positive cutaneous lymphoma: a poorly recognized entity in the spectrum of primary cutaneous disease. Br J Dermatol 1997;137:966-71. 8. Ansai S, Maeda K, Yamakawa M, Matsuda M, Saitoh S, Suwa S, et al. CD56-positive (nasal-type T/NK cell)
272 Brief communications lymphoma arising on the skin. J Cutan Pathol 1997;24: 468-76. 9. Dummer R, Potoczna N, Häffner AC, Zimmermann DR, Gilardi S, Burg G. A primary cutaneous non-T, non-B, CD4+, CD56+ lymphoma. Arch Dermatol 1996;132: 550-3. 10. Mizutani H, Roswit W, Hemperly J, Lawley T, Compton C, Swerlick R, et al. Human dermal microvascular endothelial cells express the 140-KD isoform of neural cell adhesion molecule. Biochem Biophys Res Commun 1994;203:686-93. 11. Shikama N, Izuno I, Oguchi M, Gomi K, Sone S, Takei K, et al. Clinical stage IE primary lymphoma of the nasal
Journal of the American Academy of Dermatology February 1999
cavity: radiation therapy and chemotherapy. Radiology 1997;204:467-70. 12. Suzumiya J, Takeshita M, Kimura N, Kikuchi M, Uchida T, Hisano S, et al. Expression of adult and fetal natural killer cell markers in sinonasal lymphomas. Blood 1994; 83:2255-60. 13. Drénou B, Lamy T, Amiot L, Fardel O, CauletMaugendre S, Sasportes M, et al. CD3- CD56+ nonHodgkin’s lymphomas with an aggressive behavior related to multidrug resistance. Blood 1997;89:2966-74.