- Email: [email protected]
Cutaneous T-cell lymphoma and myelodysplastic syndrome
Journal of theAmerican Academy of Dermatology Volume 31, Number 6
matory effects through binding to nuc1eoproteins and interference with lysosome function.f As shown in our open clinical trial, the use of oral low-dose antimalarials in children with GAD who are unresponsive to topical treatment represents a highly effective therapy. Spontaneous remission can occur in granuloma annulare but is an unlikely explanation for the therapeutic response in all our patients. Close supervision is mandatory, especially with regard to ophthalmologic and hematologic status, liver function, blood urea levels, and creatinine levels of the children treated even with low doses of chloroquine or hydroxychloroquine.
REFERENCES I. Dabski K, Winkelmann RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. 1 AM ACAD DERMATOL 1989;20:39-47. 2. Umbert P, Belcher RW, Winkelmann RK. Lymphokines (MIF)in theserum of patients with sarcoidosis and cutaneous granuloma annulare. BrJ Dermatol 1976;95:481-5. 3. Umbert P, Winkelmann RK. Histologic, ultrastructural,
Brief communications
1065
and histochemical studies of granuloma annulare. Arch DermatoI1977;1l3:1681-6. 4. Buechner SA,Winkelmann RK,Banks PM. Identification of T-cell subpopulations in granuloma annulare. Arch DermatoI1983;119:125-8. 5. Harth W, Richard G. Retinoide in der Therapie des Granuloma anulare disseminatum. Hautarzt 1993;44: 693-8. 6. Ziering CL, Rabinowitz LG,Esterly NB. Antimalarials for children: indications, toxicities, and guidelines. JAM ACAD DERMATOL 1993;28:764-70. 7. Mandel EH.Disseminated granuloma annulare: report of a casetreated with chloroquine phosphate (Aralen). Arch DermatoI1959;79:352-3. 8. Stritzler C. Generalized granuloma annulare (apparently responding well to chloroquine therapy). Arch Dermatol 1961;83:1033-4. 9. Carlin MC, RatzJL.A case ofgeneralized granuloma annulare responding to hydroxychloroquine. Cleve Clin 1 Moo 1987;54:229-32. 10. Frankel DH, Medenica MM, Lorincz AL. A case of generalized granuloma annulare responding to hydroxychloroquine. Cleve Clin 1 Med 1988;55:117. 11. Shaffer B, Cahn MM. Levy El. Sarcoidosis apparently cured by quinacrine (Atabrine) hydrochloride. Arch Dermatol Syph 1953;67:640·1.
Cutaneous T-cell lymphoma and myelodysplastic syndrome Pablo F. Pefias, MD,a Maria Jones-Caballero, MD,a Esteban Dauden, MD,a Javier Fraga, MD,b and Amaro Garcia-Diez, MDa Madrid, Spain An association between cutaneous T-cell lymphoma (CTCL) and monoclonal gammopathies, myeloma, or other B-cell proliferations has been described.l? Coexistence of Hodgkin's disease with mycosis fungoides or Sezary syndrome has also been reported." However, the association of a malignant proliferation involving both myeloid and T-cell lym5 phoid lineages is rare, and the coexistence of CTCL and myelodysplastic syndrome (MDS) appears to be exceptional. CASE REPORT
An 85-year-old man with diabetes had a 3-monthhistory of a red,pruritic, lumbar plaque and the progressive From the Departments of Dermatology' and Pathology.'' Hospital de la Princesa, Universidad Aut6noma. Presented at the Third Congress ofthe European Academy ofDermatology and Venereology, Copenhagen, Denmark, Sept. 28,1993. Reprint requests: Pablo F, Petias, MD, Servicio de Derrnatologia, Hospital de laPrincesa, Diego de Leon 62, 28006 Madrid, Spain. JAM ACAD DERMATOL 1994;31:1065-7.
Copyright ©
1994 by the
American Academy ofDermatology, Inc.
0190-9622/94 $3.00 + 0 16/54/57256
appearanceofsimilarconfluent plaqueson the rest of the body. Two weeks before admission developed fever, asthenia, and anorexia. Examination revealed generalized erythroderma with redness, scaling, and infiltration of the skin, including the palms and soles.The most representative lesions were on the abdomen, lumbar region, and arms (Fig. I). Generalized, firm, nontender lymphli was t ender, fi rm and adenopathy was present. Thelver enlarged by 4 em, There was no splenomegaly. Hematologic investigation showed an erythrocyte countof2.84 x 106/ mm3 with hemoglobin of 8.8gm/dl; a platelet count of 227,000 and leukocytosis of 38,700/ mrrr' with 44% polymorphonuclear cells, 8% lymphocytes, 20%monocytes, 6%eosinophils, 10%basophils, 6% myelocytes, and 6% metamyelocytes. The peripheral blood smear also revealed hypogranular neutrophils, occasional blasts, and erythrocyteswith morphologic alterations. No Sezary cells were found. Immunologicstudies showed normal lymphoid markers on peripheral blood cells. Bonemarrow examination disclosed hypercellularity with increased number of small, hypolobulated megakaryocytes, dysplastic, hypogranular granulocytes, and several Pelger-Huet cells. Also present were 6% myeloblasts,and a marked increasein eosinophils and basophils was noted. The bone marrow karyotype was normal. A
1066
Brief communications
Journal of the American Academy of Dermatology December 1994
Fig. 2. Bandlike dense infiltrate composed of atypical lymphocytes with conspicuous epidermotropism. (Hematoxylin-eosin stain; X 100).
Fig. 1. Erythematous, scaling, well-defined plaques on back of the left arm.
refractory anemia with an excess of blasts was diagnosed according to French-American-British criteria." Values of the serum chemistry (including renal and liver function tests, electrolytes, calcium, and phosphorus), prothrombin time, partial thromboplastin time, and urinalysis were normal, except for that of lactate dehydrogenase (482 lUlL). Serum proteins were 5.3 grri/dl with albumin 3 gm/dl. The other globulin levels except IgE (885 kU IL) were normal. Serum iron was 44/-,g/dl, saturation 39%, and serum transferrin 89 mg/dl, No serologicevidenceofinfection by Epstein-Barr virus, herpes varicella-zoster, cytomegalovirus, hepatitis B, hepatitis C, human T-celllymphotrophic virus type I or HIV was found. A 1:512 titer of anti-herpes simplex antibody was detected. Mantoux test was negative. A chest radiograph and thoracic and abdominal computed tomographic scans disclosed only degenerative changes. Several skin biopsy specimens showed an upper dermal lymphomatoid infiltrate characterized by a preponderance of atypical cells with a convoluted hyperchromatic nucleus. The epidermis showed parakeratosis and was infiltrated by atypical lymphoid cells with a convoluted nucleus, both singly and in clusters (Fig. 2). The architecture of a lymph node biopsy specimen was partially
obliterated. The paracortical area was hypertrophic, infiltrated by numerous cerebriform, atypical lymphocytes, with increased interdigitating cells, Immunohistochemical studies showed that these atypical cells were T cells (CD2,+ CD3,+ CD6,+ and CD7+) of the helper type (CD4+) with T-cell receptor ali. Expression of Ki-67 antigen was limited to 10% of the cells. The patient stage was T4NJMo according to the classification of the CTCL cooperative group." Two weeks after admission, the patient died of pneumonia and septic shock. No autopsy was allowed. DISCUSSION The coexistence of lymphoid and myeloid malignancies in the same patient is known. 5,8-10 Oneofthe most common associations is between multiple myeloma and acute myeloid leukemia. Although attributed to the leukemogenic effect of the chemotherapy used to treat the myeloma, some cases occur without the intervention of cbemotherapy.' In addition, one third of the blast crisis of chronic myeloid leukemia is of lymphoid type, almost always of the 8-cell type. Tscell lineage involvement is rare." The association ofCTCL and MDS appears to be exceptional. It has been reported in two patients with Sezary syndrome 1I, 12 and in two patients with CTCL without epiderruotropism.f t3 Three of these patients- 12, 13 and our patient initially had refractory anemia with an excess of blasts. Several mechanisms may explain this association. First, a mutation in a common progenitor cell ofboth myeloid and lymphoid lineages produces stem cells characterized by a lack of stability with the risk of additional mu tations and development of neoplastic
Journal of the American Academy of Dermatology Volume 31, Number 6
myeloid, lymphoid, or both clones. MDS is a multistep clonal disease, with the first event located at the level of the pluripotent, hemopoietic stem cell. 14 In patients with MDS, different reports have described common alterations in myeloid and B-lymphoid series 15 or in myeloid and B- and T-lymphoid cells. 16 Furthermore, San-Miguel et al.!" havefound T-cell receptor rearrangements in patients with MDS, with a high frequency of 0 gene, which is the first to be rearranged. Second, perhaps related to the first explanation, the presence of the T-cell neoplasm could predispose the patient to the development of the myeloid neoplasm. T cells are one of the main sources for myeloid growth factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3,17 and the neoplastic T cells of CTCL retain that capacity.'! The neoplastic T-cell clone producing GM-CSF and other lymphokines could induce the proliferation of altered myeloid clones, which is supported by the clinical finding that treatmentofpatients with myelodysplasia with GM-CSF has produced an increase of blast cells and progression to leukemia. 17 Third, it is possible that a common causative agent is present. In animals, viruses are capable of inducing lymphoid and myeloid tumors. 5 REFERENCES I. Kovary PM, Suter L, Macher E, et al. Monoclonal gammopa thies in Sezary syndrome: a report of four new cases and a review of the literature. Cancer 1981;48:788-92. 2. Weiss VC, Barsky GJ, Solomon LM. Cutaneous T lymphocyte lymphoma in association with multiple myeloma. Arch Dermatol 1984;120:499-50 I. 3. Harland CC, WhittakerSH, Ng YL, et al, Coexistentcutaneous T-cell lymphoma and B-cell chronic lymphocytic leukaemia. Br J Dermatol 1992;127:519-23.
Briefcommunications
1067
4. Souquet PJ, Mauduit G, Coiffier F, et al. Association mycosis fongoYde et maladie de Hodgkin. Ann Dermatol Venereol 1984;I II :98 1-90. 5. Copplestone JA, Mufti GJ, Hamblin TJ, et al. Immunological abnormalities in myelodysplastic syndromes: IL Coexistent lymphoid or plasma cell neoplasm. Br J Haematol 1986;63:149-59. 6. Bennet J, Catowsky D, Daniel M, et al. Proposals for the classification of the myelodysplastic syndromes. Br J HaematoI1982;51:189-99. 7. Bunn PA, Lamberg SI. Report of the Committee on Staging and Classification of Cutaneous T-cell Lymphomas. Cancer Treat Rep 1979;63:725-8. 8. Sigal-Nahum M, Rostoker G, Gaulier A, et al. Association mycosis fongoYde et leucemie myeloide chronique. Ann Dermatol VenereoI1988;115:159-66. 9. Advani SH, Malhotra H, Kadam PR, et al. T-Iymphoid blast crisis in chronic myeloid leukemia. Am J Hernatol 1991;36:86-92. 10. San-Miguel JF, Hernandez JM, Gonzalez-Sarmiento R, et al. Acute leukemia after a primary myelodysplastic syndrome: irnmunophenotypic, genotypic and clinical characteristics. Blood 1991;78:768-74. 11. Shirley JA, Sparrow GP. Sezary syndrome associated with sideroblastic anemia. Scand J Haematol 1979;23:373-7. 12. Rostoker G, Raphael M, Boisnick S, et al. Coexistence of Sezary syndrome and dysmyelopoiesis with an excess of myeloblasts [Letter]. J AM ACAD DERMATOL 1986;15: 1296-8. 13. Sainty D, Horschowski N, Fossat C, et at. Dysmyelopoiese et lymphome T. Ann Med Intern 1987; 138:101-4. 14. Beris P. Primary clonal myelodysplastic syndromes. Semin Hernatol 1989;26:216-33. 15. Lawrence HJ, Broudy VC, Magenis RE, et al. Cytogenetic evidence for involvement of B lymphocytes in acquired idiopathic sideroblastic anemias. Blood 1987;70: 1003-5. 16. Tsukamoto N, Morita K, Maehara T, et al. Clonality in myelodysplastic syndromes: demonstration of pluripotent stem cell origin using X-linked restriction fragment length polymorph isms. Br J Haematol 1993;83:589-94. 17. Groopman JE, Molina JM, Scadden DT. Hematopoietic growth factors: biology and clinical applications. N Engl J Med 1989;321:1449-59. 18. Rook AH, Vowels BR, Jaworsky C, et al. The immunopathogenesis of cutaneous T-cell lymphoma. Arch Dermatol 1993;129:486-9.
matory effects through binding to nuc1eoproteins and interference with lysosome function.f As shown in our open clinical trial, the use of oral low-dose antimalarials in children with GAD who are unresponsive to topical treatment represents a highly effective therapy. Spontaneous remission can occur in granuloma annulare but is an unlikely explanation for the therapeutic response in all our patients. Close supervision is mandatory, especially with regard to ophthalmologic and hematologic status, liver function, blood urea levels, and creatinine levels of the children treated even with low doses of chloroquine or hydroxychloroquine.
REFERENCES I. Dabski K, Winkelmann RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. 1 AM ACAD DERMATOL 1989;20:39-47. 2. Umbert P, Belcher RW, Winkelmann RK. Lymphokines (MIF)in theserum of patients with sarcoidosis and cutaneous granuloma annulare. BrJ Dermatol 1976;95:481-5. 3. Umbert P, Winkelmann RK. Histologic, ultrastructural,
Brief communications
1065
and histochemical studies of granuloma annulare. Arch DermatoI1977;1l3:1681-6. 4. Buechner SA,Winkelmann RK,Banks PM. Identification of T-cell subpopulations in granuloma annulare. Arch DermatoI1983;119:125-8. 5. Harth W, Richard G. Retinoide in der Therapie des Granuloma anulare disseminatum. Hautarzt 1993;44: 693-8. 6. Ziering CL, Rabinowitz LG,Esterly NB. Antimalarials for children: indications, toxicities, and guidelines. JAM ACAD DERMATOL 1993;28:764-70. 7. Mandel EH.Disseminated granuloma annulare: report of a casetreated with chloroquine phosphate (Aralen). Arch DermatoI1959;79:352-3. 8. Stritzler C. Generalized granuloma annulare (apparently responding well to chloroquine therapy). Arch Dermatol 1961;83:1033-4. 9. Carlin MC, RatzJL.A case ofgeneralized granuloma annulare responding to hydroxychloroquine. Cleve Clin 1 Moo 1987;54:229-32. 10. Frankel DH, Medenica MM, Lorincz AL. A case of generalized granuloma annulare responding to hydroxychloroquine. Cleve Clin 1 Med 1988;55:117. 11. Shaffer B, Cahn MM. Levy El. Sarcoidosis apparently cured by quinacrine (Atabrine) hydrochloride. Arch Dermatol Syph 1953;67:640·1.
Cutaneous T-cell lymphoma and myelodysplastic syndrome Pablo F. Pefias, MD,a Maria Jones-Caballero, MD,a Esteban Dauden, MD,a Javier Fraga, MD,b and Amaro Garcia-Diez, MDa Madrid, Spain An association between cutaneous T-cell lymphoma (CTCL) and monoclonal gammopathies, myeloma, or other B-cell proliferations has been described.l? Coexistence of Hodgkin's disease with mycosis fungoides or Sezary syndrome has also been reported." However, the association of a malignant proliferation involving both myeloid and T-cell lym5 phoid lineages is rare, and the coexistence of CTCL and myelodysplastic syndrome (MDS) appears to be exceptional. CASE REPORT
An 85-year-old man with diabetes had a 3-monthhistory of a red,pruritic, lumbar plaque and the progressive From the Departments of Dermatology' and Pathology.'' Hospital de la Princesa, Universidad Aut6noma. Presented at the Third Congress ofthe European Academy ofDermatology and Venereology, Copenhagen, Denmark, Sept. 28,1993. Reprint requests: Pablo F, Petias, MD, Servicio de Derrnatologia, Hospital de laPrincesa, Diego de Leon 62, 28006 Madrid, Spain. JAM ACAD DERMATOL 1994;31:1065-7.
Copyright ©
1994 by the
American Academy ofDermatology, Inc.
0190-9622/94 $3.00 + 0 16/54/57256
appearanceofsimilarconfluent plaqueson the rest of the body. Two weeks before admission developed fever, asthenia, and anorexia. Examination revealed generalized erythroderma with redness, scaling, and infiltration of the skin, including the palms and soles.The most representative lesions were on the abdomen, lumbar region, and arms (Fig. I). Generalized, firm, nontender lymphli was t ender, fi rm and adenopathy was present. Thelver enlarged by 4 em, There was no splenomegaly. Hematologic investigation showed an erythrocyte countof2.84 x 106/ mm3 with hemoglobin of 8.8gm/dl; a platelet count of 227,000 and leukocytosis of 38,700/ mrrr' with 44% polymorphonuclear cells, 8% lymphocytes, 20%monocytes, 6%eosinophils, 10%basophils, 6% myelocytes, and 6% metamyelocytes. The peripheral blood smear also revealed hypogranular neutrophils, occasional blasts, and erythrocyteswith morphologic alterations. No Sezary cells were found. Immunologicstudies showed normal lymphoid markers on peripheral blood cells. Bonemarrow examination disclosed hypercellularity with increased number of small, hypolobulated megakaryocytes, dysplastic, hypogranular granulocytes, and several Pelger-Huet cells. Also present were 6% myeloblasts,and a marked increasein eosinophils and basophils was noted. The bone marrow karyotype was normal. A
1066
Brief communications
Journal of the American Academy of Dermatology December 1994
Fig. 2. Bandlike dense infiltrate composed of atypical lymphocytes with conspicuous epidermotropism. (Hematoxylin-eosin stain; X 100).
Fig. 1. Erythematous, scaling, well-defined plaques on back of the left arm.
refractory anemia with an excess of blasts was diagnosed according to French-American-British criteria." Values of the serum chemistry (including renal and liver function tests, electrolytes, calcium, and phosphorus), prothrombin time, partial thromboplastin time, and urinalysis were normal, except for that of lactate dehydrogenase (482 lUlL). Serum proteins were 5.3 grri/dl with albumin 3 gm/dl. The other globulin levels except IgE (885 kU IL) were normal. Serum iron was 44/-,g/dl, saturation 39%, and serum transferrin 89 mg/dl, No serologicevidenceofinfection by Epstein-Barr virus, herpes varicella-zoster, cytomegalovirus, hepatitis B, hepatitis C, human T-celllymphotrophic virus type I or HIV was found. A 1:512 titer of anti-herpes simplex antibody was detected. Mantoux test was negative. A chest radiograph and thoracic and abdominal computed tomographic scans disclosed only degenerative changes. Several skin biopsy specimens showed an upper dermal lymphomatoid infiltrate characterized by a preponderance of atypical cells with a convoluted hyperchromatic nucleus. The epidermis showed parakeratosis and was infiltrated by atypical lymphoid cells with a convoluted nucleus, both singly and in clusters (Fig. 2). The architecture of a lymph node biopsy specimen was partially
obliterated. The paracortical area was hypertrophic, infiltrated by numerous cerebriform, atypical lymphocytes, with increased interdigitating cells, Immunohistochemical studies showed that these atypical cells were T cells (CD2,+ CD3,+ CD6,+ and CD7+) of the helper type (CD4+) with T-cell receptor ali. Expression of Ki-67 antigen was limited to 10% of the cells. The patient stage was T4NJMo according to the classification of the CTCL cooperative group." Two weeks after admission, the patient died of pneumonia and septic shock. No autopsy was allowed. DISCUSSION The coexistence of lymphoid and myeloid malignancies in the same patient is known. 5,8-10 Oneofthe most common associations is between multiple myeloma and acute myeloid leukemia. Although attributed to the leukemogenic effect of the chemotherapy used to treat the myeloma, some cases occur without the intervention of cbemotherapy.' In addition, one third of the blast crisis of chronic myeloid leukemia is of lymphoid type, almost always of the 8-cell type. Tscell lineage involvement is rare." The association ofCTCL and MDS appears to be exceptional. It has been reported in two patients with Sezary syndrome 1I, 12 and in two patients with CTCL without epiderruotropism.f t3 Three of these patients- 12, 13 and our patient initially had refractory anemia with an excess of blasts. Several mechanisms may explain this association. First, a mutation in a common progenitor cell ofboth myeloid and lymphoid lineages produces stem cells characterized by a lack of stability with the risk of additional mu tations and development of neoplastic
Journal of the American Academy of Dermatology Volume 31, Number 6
myeloid, lymphoid, or both clones. MDS is a multistep clonal disease, with the first event located at the level of the pluripotent, hemopoietic stem cell. 14 In patients with MDS, different reports have described common alterations in myeloid and B-lymphoid series 15 or in myeloid and B- and T-lymphoid cells. 16 Furthermore, San-Miguel et al.!" havefound T-cell receptor rearrangements in patients with MDS, with a high frequency of 0 gene, which is the first to be rearranged. Second, perhaps related to the first explanation, the presence of the T-cell neoplasm could predispose the patient to the development of the myeloid neoplasm. T cells are one of the main sources for myeloid growth factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3,17 and the neoplastic T cells of CTCL retain that capacity.'! The neoplastic T-cell clone producing GM-CSF and other lymphokines could induce the proliferation of altered myeloid clones, which is supported by the clinical finding that treatmentofpatients with myelodysplasia with GM-CSF has produced an increase of blast cells and progression to leukemia. 17 Third, it is possible that a common causative agent is present. In animals, viruses are capable of inducing lymphoid and myeloid tumors. 5 REFERENCES I. Kovary PM, Suter L, Macher E, et al. Monoclonal gammopa thies in Sezary syndrome: a report of four new cases and a review of the literature. Cancer 1981;48:788-92. 2. Weiss VC, Barsky GJ, Solomon LM. Cutaneous T lymphocyte lymphoma in association with multiple myeloma. Arch Dermatol 1984;120:499-50 I. 3. Harland CC, WhittakerSH, Ng YL, et al, Coexistentcutaneous T-cell lymphoma and B-cell chronic lymphocytic leukaemia. Br J Dermatol 1992;127:519-23.
Briefcommunications
1067
4. Souquet PJ, Mauduit G, Coiffier F, et al. Association mycosis fongoYde et maladie de Hodgkin. Ann Dermatol Venereol 1984;I II :98 1-90. 5. Copplestone JA, Mufti GJ, Hamblin TJ, et al. Immunological abnormalities in myelodysplastic syndromes: IL Coexistent lymphoid or plasma cell neoplasm. Br J Haematol 1986;63:149-59. 6. Bennet J, Catowsky D, Daniel M, et al. Proposals for the classification of the myelodysplastic syndromes. Br J HaematoI1982;51:189-99. 7. Bunn PA, Lamberg SI. Report of the Committee on Staging and Classification of Cutaneous T-cell Lymphomas. Cancer Treat Rep 1979;63:725-8. 8. Sigal-Nahum M, Rostoker G, Gaulier A, et al. Association mycosis fongoYde et leucemie myeloide chronique. Ann Dermatol VenereoI1988;115:159-66. 9. Advani SH, Malhotra H, Kadam PR, et al. T-Iymphoid blast crisis in chronic myeloid leukemia. Am J Hernatol 1991;36:86-92. 10. San-Miguel JF, Hernandez JM, Gonzalez-Sarmiento R, et al. Acute leukemia after a primary myelodysplastic syndrome: irnmunophenotypic, genotypic and clinical characteristics. Blood 1991;78:768-74. 11. Shirley JA, Sparrow GP. Sezary syndrome associated with sideroblastic anemia. Scand J Haematol 1979;23:373-7. 12. Rostoker G, Raphael M, Boisnick S, et al. Coexistence of Sezary syndrome and dysmyelopoiesis with an excess of myeloblasts [Letter]. J AM ACAD DERMATOL 1986;15: 1296-8. 13. Sainty D, Horschowski N, Fossat C, et at. Dysmyelopoiese et lymphome T. Ann Med Intern 1987; 138:101-4. 14. Beris P. Primary clonal myelodysplastic syndromes. Semin Hernatol 1989;26:216-33. 15. Lawrence HJ, Broudy VC, Magenis RE, et al. Cytogenetic evidence for involvement of B lymphocytes in acquired idiopathic sideroblastic anemias. Blood 1987;70: 1003-5. 16. Tsukamoto N, Morita K, Maehara T, et al. Clonality in myelodysplastic syndromes: demonstration of pluripotent stem cell origin using X-linked restriction fragment length polymorph isms. Br J Haematol 1993;83:589-94. 17. Groopman JE, Molina JM, Scadden DT. Hematopoietic growth factors: biology and clinical applications. N Engl J Med 1989;321:1449-59. 18. Rook AH, Vowels BR, Jaworsky C, et al. The immunopathogenesis of cutaneous T-cell lymphoma. Arch Dermatol 1993;129:486-9.