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Telangiectasia macularis eruptiva perstans and multiple myeloma
Telangiectasia macularis eruptiva perstans and multiple myeloma Claude Bachmeyer, MD,a Jacqueline Guillemette, MD,b Laurent Blum, MD,a Yves Turc, MD,a Robin Dhôte, MD,a Jean-Paul Fermand, MD,c and Selim Aractingi, MDd Creil and Paris, France The association of mast cell diseases and some hematologic malignancies, usually myeloproliferative disorders, myelodysplastic syndromes, and acute leukemia is well recognized. We report the case of a patient with telangiectasia macularis eruptiva perstans, a rare form of cutaneous mastocytosis, and multiple myeloma, an association that has been described only twice in the literature. Parallel improvement of both conditions was observed under chemotherapy regimens for multiple myeloma. Pathogenesis remains unclear, although the abnormalities in the c-kit pathway may play a role in the proliferation of cells from both lineages. (J Am Acad Dermatol 2000;43:972-4.)
M
astocytosis represents a spectrum of disorders characterized by abnormal growth and accumulation of mast cells in various organs of the body.1,2 The most frequent site of involvement is the skin. Cutaneous mastocytosis includes urticaria pigmentosa, mastocytoma, diffuse and erythrodermic cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans (TMEP).1-3 Systemic mastocytosis involves at least 1 extracutaneous organ, such as bone, gut, liver, or lymph nodes, with or without cutaneous lesions. Systemic mastocytosis may be associated with various malignant hematologic disorders such as myeloproliferative disorder, myelodysplastic syndrome, acute leukemia, and non-Hodgkin lymphoma.4-6 We report here a case of TMEP in a patient presenting with multiple myeloma, with parallel improvement of both conditions occurring under chemotherapy regimens for multiple myeloma. Aberrations in the c-kit pathway may explain the abnormal proliferation of both lineages.
This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Département de Médecine Interne, Centre Hospitalier Laënnec, Creila; Laboratoire d’Anatomopathologie, Hôpital Tarnier, Parisb; Service d’Immuno-Hématologie, Hôpital SaintLouis, Parisc; and Unité de Dermatologie, Hôpital Tenon, Paris.d Reprint requests: Claude Bachmeyer, MD, Département de Médecine Interne, Centre Hospitalier Laënnec, Boulevard Laënnec, BP 72, F-60109 Creil Cedex, France. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/4/109254 doi:10.1067/mjd.2000.109254
972
CASE REPORT A 77-year-old man was admitted in June 1997 for management of acute renal failure. Physical examination was unremarkable, except for asymptomatic erythematous telangiectatic macules, 5 to 10 mm in diameter, localized on the trunk. Darier’s sign was absent, and other symptoms of mastocytosis such as flushing, wheezing, diarrhea, or hepatosplenomegaly were not present. Skin biopsy specimen from a macule demonstrated dilated dermal capillaries with increased mast cells scattered around the capillaries and venules of the superficial vascular plexus, and toluidine blue demonstrated metachromasia of mast cells. These features were consistent with a diagnosis of TMEP. Direct immunofluorescence was negative. Blood cell count showed 7.1 × 109/L leukocytes with 60% neutrophils and 30% lymphocytes, hemoglobin 9.0 g/dL, and platelet count 134 × 109/L. The erythrocyte sedimentation rate was 40 mm/h and C reactive protein was within normal limits. Serum creatinine was 545 µmol/L (normal less than 110; creatinine clearance = 10 mL/min). The 24-hour urinary protein was 6 g, consisting mainly of λ light chains. Total serum calcium level was 3.02 mmol/L (normal 2.22.6). Serum protein electrophoresis showed gammaglobulin at 4 g/L (normal 8-12). Serum immunoelectrophoresis disclosed a λ monoclonal component. Bone marrow smear showed the presence of 18% dysplastic plasmocytes and no mastocytes. Skeletal x-ray films revealed multiple lytic lesions of skull and both humeri. The diagnosis of λ light chain multiple myeloma stage IIIB was established. After enacting supportive measures to control serum calcium level, chemotherapy with dexamethasone, vincristine, and adriamycin was started, but
J AM ACAD DERMATOL VOLUME 43, NUMBER 5
quickly withdrawn because of poor tolerance. Between July 1997 and July 1999, the patient first received courses of melphalan, cyclophosphamide, vincristine, prednisolone alternating with adriamycin, vincristine, carmustine, and prednisolone, then courses of melphalan and prednisolone. Progressive improvement of laboratory tests was observed with serum creatinine at 269 µmol/L (creatinine clearance = 40 mL/min), urine protein excretion at 0.24 g per 24 hours, no λ light chain detected in blood and urine, and 1.5% nondysplastic plasmocytes on marrow smear in August 1999. Parallel improvement of the cutaneous lesions was also observed with progressive fading and complete disappearance at this time.
DISCUSSION
This case is peculiar, as TMEP and λ light chain multiple myeloma were diagnosed in the same patient, and their evolution was parallel under chemotherapy regimens for multiple myeloma. The occurrence of various hemopathies in the course of mastocytosis is well known, as up to 40% of adult patients with systemic mastocytosis will present such an association.2,4-6 The reported hematologic diseases consist of myelodysplasia, myeloproliferative disorders such as chronic granulocytic leukemia, polycythemia rubra vera or myelofibrosis, and acute myeloid leukemia. However, lymphoproliferative disorders, particularly malignant lymphoma, have been described in 5% of patients with systemic mastocytosis. In addition, Prokomicer et al7 found a consistent increase in the number of mast cells in bone marrow obtained from patients with lymphoproliferative disorders. Finally, focal collections of lymphocytes adjacent to mast cells have been reported in the spleen and lymph nodes of patients with mastocytosis.8 All these data suggest that mast cell proliferations and lymphoproliferative disorders may result from a common mechanism. The association of mast cell diseases and monoclonal gammopathy with or without multiple myeloma has been rarely described. In a series of patients with systemic mastocytosis, an IgGλ monoclonal gammopathy was found in 1 of 5 cases.9 In another study analyzing 20 patients with mastocytosis, oligoclonal hyperglobulinemia was found in 5 of 5 patients who had malignant mastocytosis and in 10 of 15 patients with benign mastocytosis.10 In addition, coexistence of mast cell disease and multiple myeloma has been described in 2 case reports. In 1996, Ogg et al11 described a patient with urticaria pigmentosa in whom IgG myeloma subsequently developed. In 1998, Hagen et al12 reported a patient with monoclonal IgGλ gammopathy and bone mar-
Bachmeyer et al 973
row mastocytosis, in whom overt multiple myeloma developed 8 years later. In this case, the authors demonstrated that the mast cells and the B cells disclosed different chromosomal abnormalities and therefore did not originate from the same clone. In our patient, features of systemic mastocytosis were not reported; mast cells were not found on marrow smear, although a bone marrow biopsy was not performed. Cutaneous mastocytosis in the form of TMEP was likely and interesting in view of the associated multiple myeloma. The occurrence of both diseases is rare and may be a chance association. A common origin of both cell populations is unlikely because, although mast cells are issued from pluripotent hematopoietic CD34+ progenitor cells, they originate from different cell lineages than B cells.12 However, the fact that cutaneous lesions of TMEP disappeared with the improvement of the Bcell proliferation strongly suggests a link between both diseases. Indeed, a common event could promote both conditions, c-kit being the corner stone. The c-kit proto-oncogene encodes c-kit, a receptor type III tyrosine kinase present on the surface of hematopoietic stem cells and mast cells. With its ligand stem cell factor (SCF), a mast cell growth factor, c-kit is involved in the development and survival of mast cells.13 Deregulation or abnormalities of c-kit or excessive production of its ligand induces mast cell proliferation. Somatic in situ-activating c-kit mutations were demonstrated in patients with urticaria pigmentosa complicated by aggressive systemic mastocytosis.13,14 Recently, such mutations were described in adult patients with sporadic cutaneous mastocytosis, with or without systemic involvement.15 On the other hand, it has been shown that c-kit significantly enhanced the proliferation of myeloma cells responsive to IL-6, the most important cytokine in inducing differentiation and proliferation of myeloma cells, and that c-kit is expressed in about one third of myeloma cells but not on plasma cells from normal bone marrow.16,17 One may therefore hypothesize that abnormalities in the c-kit pathway may induce proliferations of cells from different lineages. Another possibility to explain this association is that mast cells are a source of multiple cytokines such as TNFα, IL-1, IL-3, and IL6.12 In the same way, the plasma cells or other cells in the microenvironment of the marrow may produce chemokines that in a series of unclear events could promote mast cell proliferation. Thus, the 2 conditions may influence each other by secreting growth factors.12 The description of this patient with a parallel evolution of TMEP and multiple myeloma under chemotherapy regimens for multiple myeloma, in
974 Bachmeyer et al
addition to previous reported cases that associate both conditions, suggests a nonrandom association. Future studies are needed to assess the validity of this association. Pending these studies, performing serum protein electrophoresis in addition to initial screening blood tests should be proposed to patients with cutaneous mastocytosis. REFERENCES 1. Soter NA. The skin in mastocytosis. J Invest Dermatol 1991; 96:32S-9S. 2. Golkar L, Bernhard JD. Mastocytosis. Lancet 1997;349:1379-85. 3. Sarkany RPE, Monk BE, Hansfield-Jones SE. Telangiectasia macularis eruptiva perstans: a case report and review of the literature. Clin Exp Dermatol 1998;23:38-9. 4. Hutchinson RM. Mastocytosis and co-existent non-Hogkin’s lymphoma and lymphoproliferative disorders. Leukemia Lymphoma 1992;7:29-36. 5. Travis WD, Li CY, Bergestralh EJ. Solid and haematological malignancies in 60 patients with systemic mast cell disease. Arch Pathol Lab Med 1989;113:365-8. 6. Horny HP, Ruck M, Wehrmann M, Kaiserling E. Blood findings in generalized mastocytosis: evidence of frequent simultaneous occurrence of myeloproliferative disorders. Br J Haematol 1990; 76:186-93. 7. Prokocimer RM, Polliack A. Increased bone marrow mast cells in preleukemic syndromes, acute leukaemia and lymphoproliferative disorders. Am J Clin Pathol 1981;75:34-8. 8. Travis WD, Li CY. Pathology of the lymph node and spleen in systemic mast cell disease. Mod Pathol 1988;1:4-14. 9. Kermarec J, Canioni D, Zafisaona G. An osteomedulary pathology in five cases of systemic mastocytosis. Pseudomyelomatous
J AM ACAD DERMATOL NOVEMBER 2000
10.
11.
12.
13.
14.
15.
16.
17.
forms with dysglobulinemia and benign polyclonal mastocytosis in the bone marrow. Hamazaki-Wesenberg bodies in mastcell granulomas. [in French.] Sem Hop Paris 1983;59:2119-26. Meggs WJ, Frieri M, Costello R, Metcalfe DD, Papadopoulos NM. Oligoclonal immunoglobulins in mastocytosis. Ann Intern Med 1985;103:894-5. Ogg GS, Rosbotham JL, Macdonald DM. Urticaria pigmentosa coexisting with multiple myeloma. Clin Exp Dermatol 1996;21: 365-6. Hagen W, Schwarzmeier J, Walchshofer S, Zojer N, Chott A, Sillaber C, et al. A case of bone marrow mastocytosis associated with multiple myeloma. Ann Hematol 1998;76:167-74. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, et al. Identification of a point mutation in the catalytic domain of the proto-oncogen c-kit in peripheral of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A 1995;92:10560-4. Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in human mast cell neoplasm. Nat Genet 1996;12:312-4. Longley BJ, Matcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, et al. Activiting and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A 1999;96:1609-14. Lemoli RM, Fortuna A, Grande A, Gamberi B, Bonsi L, Fogli M, et al. Expression and functional role of c-kit ligand (SCF) in human multiple myeloma cells. Br J Haematol 1994;88:760-9. Ocqueteau M, Orfao A, Garcia-Sanz R, Almeida J, Gonzalez M, San Miguel JF. Expression of CD117 antigen (c-kit) on normal and myelomatous plasma cells. Br J Haematol 1996;95:489-503.
M
astocytosis represents a spectrum of disorders characterized by abnormal growth and accumulation of mast cells in various organs of the body.1,2 The most frequent site of involvement is the skin. Cutaneous mastocytosis includes urticaria pigmentosa, mastocytoma, diffuse and erythrodermic cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans (TMEP).1-3 Systemic mastocytosis involves at least 1 extracutaneous organ, such as bone, gut, liver, or lymph nodes, with or without cutaneous lesions. Systemic mastocytosis may be associated with various malignant hematologic disorders such as myeloproliferative disorder, myelodysplastic syndrome, acute leukemia, and non-Hodgkin lymphoma.4-6 We report here a case of TMEP in a patient presenting with multiple myeloma, with parallel improvement of both conditions occurring under chemotherapy regimens for multiple myeloma. Aberrations in the c-kit pathway may explain the abnormal proliferation of both lineages.
This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Département de Médecine Interne, Centre Hospitalier Laënnec, Creila; Laboratoire d’Anatomopathologie, Hôpital Tarnier, Parisb; Service d’Immuno-Hématologie, Hôpital SaintLouis, Parisc; and Unité de Dermatologie, Hôpital Tenon, Paris.d Reprint requests: Claude Bachmeyer, MD, Département de Médecine Interne, Centre Hospitalier Laënnec, Boulevard Laënnec, BP 72, F-60109 Creil Cedex, France. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/4/109254 doi:10.1067/mjd.2000.109254
972
CASE REPORT A 77-year-old man was admitted in June 1997 for management of acute renal failure. Physical examination was unremarkable, except for asymptomatic erythematous telangiectatic macules, 5 to 10 mm in diameter, localized on the trunk. Darier’s sign was absent, and other symptoms of mastocytosis such as flushing, wheezing, diarrhea, or hepatosplenomegaly were not present. Skin biopsy specimen from a macule demonstrated dilated dermal capillaries with increased mast cells scattered around the capillaries and venules of the superficial vascular plexus, and toluidine blue demonstrated metachromasia of mast cells. These features were consistent with a diagnosis of TMEP. Direct immunofluorescence was negative. Blood cell count showed 7.1 × 109/L leukocytes with 60% neutrophils and 30% lymphocytes, hemoglobin 9.0 g/dL, and platelet count 134 × 109/L. The erythrocyte sedimentation rate was 40 mm/h and C reactive protein was within normal limits. Serum creatinine was 545 µmol/L (normal less than 110; creatinine clearance = 10 mL/min). The 24-hour urinary protein was 6 g, consisting mainly of λ light chains. Total serum calcium level was 3.02 mmol/L (normal 2.22.6). Serum protein electrophoresis showed gammaglobulin at 4 g/L (normal 8-12). Serum immunoelectrophoresis disclosed a λ monoclonal component. Bone marrow smear showed the presence of 18% dysplastic plasmocytes and no mastocytes. Skeletal x-ray films revealed multiple lytic lesions of skull and both humeri. The diagnosis of λ light chain multiple myeloma stage IIIB was established. After enacting supportive measures to control serum calcium level, chemotherapy with dexamethasone, vincristine, and adriamycin was started, but
J AM ACAD DERMATOL VOLUME 43, NUMBER 5
quickly withdrawn because of poor tolerance. Between July 1997 and July 1999, the patient first received courses of melphalan, cyclophosphamide, vincristine, prednisolone alternating with adriamycin, vincristine, carmustine, and prednisolone, then courses of melphalan and prednisolone. Progressive improvement of laboratory tests was observed with serum creatinine at 269 µmol/L (creatinine clearance = 40 mL/min), urine protein excretion at 0.24 g per 24 hours, no λ light chain detected in blood and urine, and 1.5% nondysplastic plasmocytes on marrow smear in August 1999. Parallel improvement of the cutaneous lesions was also observed with progressive fading and complete disappearance at this time.
DISCUSSION
This case is peculiar, as TMEP and λ light chain multiple myeloma were diagnosed in the same patient, and their evolution was parallel under chemotherapy regimens for multiple myeloma. The occurrence of various hemopathies in the course of mastocytosis is well known, as up to 40% of adult patients with systemic mastocytosis will present such an association.2,4-6 The reported hematologic diseases consist of myelodysplasia, myeloproliferative disorders such as chronic granulocytic leukemia, polycythemia rubra vera or myelofibrosis, and acute myeloid leukemia. However, lymphoproliferative disorders, particularly malignant lymphoma, have been described in 5% of patients with systemic mastocytosis. In addition, Prokomicer et al7 found a consistent increase in the number of mast cells in bone marrow obtained from patients with lymphoproliferative disorders. Finally, focal collections of lymphocytes adjacent to mast cells have been reported in the spleen and lymph nodes of patients with mastocytosis.8 All these data suggest that mast cell proliferations and lymphoproliferative disorders may result from a common mechanism. The association of mast cell diseases and monoclonal gammopathy with or without multiple myeloma has been rarely described. In a series of patients with systemic mastocytosis, an IgGλ monoclonal gammopathy was found in 1 of 5 cases.9 In another study analyzing 20 patients with mastocytosis, oligoclonal hyperglobulinemia was found in 5 of 5 patients who had malignant mastocytosis and in 10 of 15 patients with benign mastocytosis.10 In addition, coexistence of mast cell disease and multiple myeloma has been described in 2 case reports. In 1996, Ogg et al11 described a patient with urticaria pigmentosa in whom IgG myeloma subsequently developed. In 1998, Hagen et al12 reported a patient with monoclonal IgGλ gammopathy and bone mar-
Bachmeyer et al 973
row mastocytosis, in whom overt multiple myeloma developed 8 years later. In this case, the authors demonstrated that the mast cells and the B cells disclosed different chromosomal abnormalities and therefore did not originate from the same clone. In our patient, features of systemic mastocytosis were not reported; mast cells were not found on marrow smear, although a bone marrow biopsy was not performed. Cutaneous mastocytosis in the form of TMEP was likely and interesting in view of the associated multiple myeloma. The occurrence of both diseases is rare and may be a chance association. A common origin of both cell populations is unlikely because, although mast cells are issued from pluripotent hematopoietic CD34+ progenitor cells, they originate from different cell lineages than B cells.12 However, the fact that cutaneous lesions of TMEP disappeared with the improvement of the Bcell proliferation strongly suggests a link between both diseases. Indeed, a common event could promote both conditions, c-kit being the corner stone. The c-kit proto-oncogene encodes c-kit, a receptor type III tyrosine kinase present on the surface of hematopoietic stem cells and mast cells. With its ligand stem cell factor (SCF), a mast cell growth factor, c-kit is involved in the development and survival of mast cells.13 Deregulation or abnormalities of c-kit or excessive production of its ligand induces mast cell proliferation. Somatic in situ-activating c-kit mutations were demonstrated in patients with urticaria pigmentosa complicated by aggressive systemic mastocytosis.13,14 Recently, such mutations were described in adult patients with sporadic cutaneous mastocytosis, with or without systemic involvement.15 On the other hand, it has been shown that c-kit significantly enhanced the proliferation of myeloma cells responsive to IL-6, the most important cytokine in inducing differentiation and proliferation of myeloma cells, and that c-kit is expressed in about one third of myeloma cells but not on plasma cells from normal bone marrow.16,17 One may therefore hypothesize that abnormalities in the c-kit pathway may induce proliferations of cells from different lineages. Another possibility to explain this association is that mast cells are a source of multiple cytokines such as TNFα, IL-1, IL-3, and IL6.12 In the same way, the plasma cells or other cells in the microenvironment of the marrow may produce chemokines that in a series of unclear events could promote mast cell proliferation. Thus, the 2 conditions may influence each other by secreting growth factors.12 The description of this patient with a parallel evolution of TMEP and multiple myeloma under chemotherapy regimens for multiple myeloma, in
974 Bachmeyer et al
addition to previous reported cases that associate both conditions, suggests a nonrandom association. Future studies are needed to assess the validity of this association. Pending these studies, performing serum protein electrophoresis in addition to initial screening blood tests should be proposed to patients with cutaneous mastocytosis. REFERENCES 1. Soter NA. The skin in mastocytosis. J Invest Dermatol 1991; 96:32S-9S. 2. Golkar L, Bernhard JD. Mastocytosis. Lancet 1997;349:1379-85. 3. Sarkany RPE, Monk BE, Hansfield-Jones SE. Telangiectasia macularis eruptiva perstans: a case report and review of the literature. Clin Exp Dermatol 1998;23:38-9. 4. Hutchinson RM. Mastocytosis and co-existent non-Hogkin’s lymphoma and lymphoproliferative disorders. Leukemia Lymphoma 1992;7:29-36. 5. Travis WD, Li CY, Bergestralh EJ. Solid and haematological malignancies in 60 patients with systemic mast cell disease. Arch Pathol Lab Med 1989;113:365-8. 6. Horny HP, Ruck M, Wehrmann M, Kaiserling E. Blood findings in generalized mastocytosis: evidence of frequent simultaneous occurrence of myeloproliferative disorders. Br J Haematol 1990; 76:186-93. 7. Prokocimer RM, Polliack A. Increased bone marrow mast cells in preleukemic syndromes, acute leukaemia and lymphoproliferative disorders. Am J Clin Pathol 1981;75:34-8. 8. Travis WD, Li CY. Pathology of the lymph node and spleen in systemic mast cell disease. Mod Pathol 1988;1:4-14. 9. Kermarec J, Canioni D, Zafisaona G. An osteomedulary pathology in five cases of systemic mastocytosis. Pseudomyelomatous
J AM ACAD DERMATOL NOVEMBER 2000
10.
11.
12.
13.
14.
15.
16.
17.
forms with dysglobulinemia and benign polyclonal mastocytosis in the bone marrow. Hamazaki-Wesenberg bodies in mastcell granulomas. [in French.] Sem Hop Paris 1983;59:2119-26. Meggs WJ, Frieri M, Costello R, Metcalfe DD, Papadopoulos NM. Oligoclonal immunoglobulins in mastocytosis. Ann Intern Med 1985;103:894-5. Ogg GS, Rosbotham JL, Macdonald DM. Urticaria pigmentosa coexisting with multiple myeloma. Clin Exp Dermatol 1996;21: 365-6. Hagen W, Schwarzmeier J, Walchshofer S, Zojer N, Chott A, Sillaber C, et al. A case of bone marrow mastocytosis associated with multiple myeloma. Ann Hematol 1998;76:167-74. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, et al. Identification of a point mutation in the catalytic domain of the proto-oncogen c-kit in peripheral of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A 1995;92:10560-4. Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in human mast cell neoplasm. Nat Genet 1996;12:312-4. Longley BJ, Matcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, et al. Activiting and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A 1999;96:1609-14. Lemoli RM, Fortuna A, Grande A, Gamberi B, Bonsi L, Fogli M, et al. Expression and functional role of c-kit ligand (SCF) in human multiple myeloma cells. Br J Haematol 1994;88:760-9. Ocqueteau M, Orfao A, Garcia-Sanz R, Almeida J, Gonzalez M, San Miguel JF. Expression of CD117 antigen (c-kit) on normal and myelomatous plasma cells. Br J Haematol 1996;95:489-503.