Revista Societatii de Medicina Interna
Articolul face parte din revista :
Nr.3 din luna 2012
Autor Mădălina Begu, Ana-Maria Vlădăreanu, Mihaela Gaman, Cristina Ciufu, Ana-Maria Neagu, Horia Bumbea, M
Titlu articolCD117 –POOR OR GOOD PROGNOSTIC FACTOR IN MULTIPLE MYELOMA
Cuvinte cheiecelule plasmatice, citometrie de flux, mielofibroză, prognostic.
Articol
Mădălina Begu, Ana-Maria Vlădăreanu, Mihaela Gaman, Cristina Ciufu, Ana-Maria Neagu, Horia Bumbea, Minodora Onisai, Andreea Alexe, Cristina Enache, Anamaria Iova, Oana Cazaceanu
Hematology Department Emergency University Hospital
Address for corespondence:
Mădălina Begu, clinical laboratory MD, Hematology Department, Emergency University Hospital, 169 Splaiul Independenței, zip code 050098, Bucharest, Romania.
E-mail: madalinabegu@yahoo.com
Introduction
Multiple myeloma represents aprox 1% of malignant tumours and 10-15% of haematopoietic neoplasms. It is more common for men than women and the average age at diagnosis is 71 years. Multiple myeloma is a neoplastic plasma cell dyscrasia characterized by: a monoclonal protein in the serum or urine or both, anemia, abnormal bone radiographs and bone pain, hypercalcemia, renal insufficiency and more than 10%myeloma cells in bone marrow. The immunophenotype of myeloma cells is complex. Usually, myeloma cells are CD45 negative, CD38 positive, CD138 positive, CD56 is strongly positive in about 55-78% of cases, but CD56 can be negative in more aggressive disease. Other surface antigens such as CD10, CD28, CD117, CD13, CD33, CD 20 might be found(1, 2).
Case report
The patient is a 58 years old male with progressive fatigue from two month ago.
On physical examination, the patient had no fever, pallor skin, small laterocervical and axillary lymph nodes. Heart and lung were normal. No hepatosplenomegaly. Normal neurological exam.
Hematologic exam showed: hemoglobin 8,2g/dl, reticulocytes 4,8%, leukocytes 12.900/mmc with a left shift differential, and platelets 60.000/mmc.
Peripheral blood smear revealed: a left shift differential (Bl5%, Mi2%, Mt1%, N3%, S44%, E1%, B1%, L33%, M10%, Erbl 32/100cells, plasma cell 1/100 cell)(Figure 1). Morphology examination: hipogranular granulocytes, some of them with Pelger-Huet abnormality, binucleated erythroblasts with Cabot rings, few with blooming nucleus. Plasma cell is a medium – large size cell with round nucleus, eccentrically placed or sometimes with two nucleoli, with condensate chromatin and abundant basophilic cytoplasm (Figure 2). Different types of cytoplasmatic inclusions were noted (Russel bodies, eosinophilic granules, Mott cells).
Bone marrow aspiration was inconclusive and bone biopsy was recommended (Figure 3, Figure 4).
Figure 1. The peripheral blood smear. May Grunwald Giemsa stain, objective X 100. Mieloblast in leukoeritroblastic feature and rouleau formation
Figure 2. The peripheral blood smear. May Grunwald Giemsa stain, objective X 100. Myeloma cell and rouleau formation
Figure 3. Bone marrow. May Grundwal Giemsa stain, objective X 100. Hypocelular bone marrow with rouleau formation
Figure 4. Bone marrow. May Grundwal Giemsa stain, objective X 100. Hypocelular bone marrow with myeloma cells
Biochemical tests. Total protein 10,4 g/dL. The serum ALT, LDH, BUN and uric acid were minimally increased over upper limit.
Serum protein electrophoresis: albumin 40,9% (low), alpha 1 globulin 1,8% (normal), alpha 2 globulin 5,5% (low), beta globulin 50,4% (high), gamma globulin 2% (low); biclonal profile in the beta area of biclonal mobility; peak beta 1 - 45,4% and beta 2 - 4%. Serum IgG 3,15g/l (low), IgA 54,4g/l (high), and IgM 0,178g/l (low).
Serum imunofixation determined lambda light chains. The urine was positive for Bence Jone lambda protein;
Urinary protein: undetectable;
Urinary immunofixation:absence of light chains.
Flow cytometry: The bone marrow aspiration was poor, but FC revealed: 10% plasma cells with intense positive CD38, intense positive CD138 (Figure 5), CD56 positive (Figure 7), CD19 negative, CD14 negative, CD20 negative, a typical flowcytometry pattern of myeloma cells - CD117 positive (prognostic factor)(Figure 6) expressed by 10% of myeloma cells highlighted on inconclusive bone marrow.
Figure 5. Flow cytometry. Myeloma cells with CD 138 and CD38 intense positive
Figure 6. Flow cytometry. Myeloma cells with CD 117 positive and CD38 intense positive
Figure 7. Flow cytometry. myeloma cells with CD 56 positive and CD38 intense positive
Others exam. Skeletal survey: normal aspect of skull, rib bones with punched-out lesions and osteolysis lesions (5-15mm) of thoracic and lumbar vertebras (T11-L5); The patient was also screened for other neoplasms.Tumoral markers were negative (PSA, CEA, AFP, CA 19-9).
Bone marrow biopsy revealed hypercelular bone marrow with diffuse infiltration of myeloma cells, (over 90%), plasmocytic type, with hematopoiesis dislocation (2,8); Special stains with Gomory argentic impregnation: diffuse reticulin fibrosis and collagen fibers; on Giemsa stain isolated erythroblasts were noted. Immunohistochemistry was positive for CD38 in tumor, and L26/CD20 in rare small reactive lymphocytes. The diagnosis established by bone marrow biopsy was: multiple myeloma plasmocytic type 3rd grade marrow infiltration and secondary myelofibrosis.
Positive and differential diagnosis
Positive diagnosis is multiple myeloma: the diagnosis of multiple myeloma was based on these biological data: high total protein, high erythrocyte sedimentation rate, high immunoglobulin, lambda light chains in serum, abnormal serum protein electrophoresis, myeloma cells infiltration, imunophenotype markers and radiological changes, but the only element that does not support this diagnosis is bone marrow myelofibrosis.
Analyzing gathered information the following diagnosis was established: stage IIIA multiple myeloma IgA(lambda) (9) with secondary myelofibrosis
Possible differential diagnosis could include :
1) Myelodysplastic/myeloproliferative syndrome and chronic idiopatic myelofibrosis. Leukocytosis with left shift, disgranulopoiesis signs, inconclusive bone marrow aspiration, secondary myelofibrosis and hepatosplenomegaly could suggest this diagnosis.
2)Bone marrow metastases. Because osteolytic lessions were revealed on skeletal survey, bone marrow metastases should be excluded. All these diagnosis were excluded by performing bone marrow biopsy, which established the multiple myeloma diagnosis.
Therapy
After the diagnosis, treatment options have been discussed. The decision was for VAD chemotherapy (Vincristine 0,4mg/m2, Adriamicine 9mg/m2, Dexamethasone 40mg/ m2). After 5 chemotherapy cycles clinical and biological data have not improved. Of these we mention: Hb =8,8g/dl, PLT =135.000/mmc, Pro 1%, Mi 5%, Mt 2%, N 2%, S 52%, E 1%, B 1%, Ly 33%, Erbl 5/100 elements. High erythrocyte sedimentation rate 90mm/h, totale protein 9g/dl, with beta 1 monoclonal peak of 37,4% and beta 2 of 4%. Bone marrow biopsy revealed diffuse infiltration of myeloma cells (above 90%) with myelofibrosis.
The presence of the two prognostic factors (CD117, Lactate dehydrogenase) indicate a lack of response to treatment of the patient (VAD protocol). CD 117 is still highly positive on myeloma cells. In this situation, another chemotherapy protocol was started (Thalidomide and Dexametasone). After completing the last treatment, clinical and biological status did not improve Hb 8,3g/dl, Plt 120.000/mmc, left shift deviation (Pro 2%, Mi4%, Mt2%, S40%, E3%, B3%, L38%, M8%, Erbl 5/100 elem), highly erythrocyte sedimentation rate (over 140mm/1h), highly immunoglobulinA (41,5g/l); highly total protein 9,5g/dl; highly lactate dehydrogenase (280U/l); low albumin (42,3%) and peak beta1 -29,6% and beta2 -4%; CD 117 highly positive on all myeloma cells.
MRI revealed the presence of a 92mm diameter plasmacytom on the proximal 1/3 of left femoral bone and few other osteolitic lessions on the left femoral neck, bilateral pertrohanterian region, right sacral wing and right femoral shaft. After completing two treatment option (5 X VAD, 5 X Thalidomide/Dexametazon), no improvement was noted, therefore Velcade/Dexametazon/Caelix protocol was the next choice of treatment.
After completing 8 X Velcade /Dex /Caelix the lab tests revealed minimal changes: Hb =9,7 g/dl, Plt= 100 000/mmc , erythrocyte sedimentation rate 76 mm/1 , lactate dehydrogenase 280 U/l, peak beta 1- 24,6%, beta 2 – 5.9%, CD117 positive on myeloma plasma cells.
Finally, after multiple treatment regimens (5 X VAD, 5 X Thali/Dex and 8 Velcade /Dex/Caelix), the patient had significant improvement in terms of hematological and biological problems, most likely because of femoral plasmacytoma evolution.
According to literature data CD 117 is a good prognostic factor in multiple myeloma evolution. A working group led by Jesús F. San Miguel, Servicio de Hematología, Hospital Universitario de Salamanca, Spain analyzed the prognostic impact of immunophenotyping in patients with multiple myeloma. Simultaneous assessment of CD28 and CD117 antigens allowed risk stratification of these patients diagnosed with multiple myeloma into three main categories: poor risk (CD28 positive CD117 negative), intermediate (either both markers negative or both positive), and good risk (CD28 negative CD117 positive)(13). Considering the lack of response to treatment from this case, CD 117 does not represent a good prognostic factor in the evolution of multiple myeloma patients.
During prolonged treatment, the constant presence of a poor prognosis factor was found CD 117 - tyrosine transmembrane III receptor on myeloma cell surface. Our observation that the presence of CD 117 is a factor of poor prognosis in myeloma and explains the lack of response to treatment(12).
Conclusions
This clinical case was chosen because of the diagnostic difficulties, particular fenotype of myeloma cells and the presence of prognostic factor (CD117), that plays the negative role of CD117 in multiple myeloma evolution. Due to unsuccessful treatment with Velcade, transplantation remains the only curative therapeutic approach in multiple myeloma. However, it is associated with a high mortality and morbidity.
References
1.Wintrobes Clinical Hematology 12 th 2009.
2.Who Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 th Edition 2008.
3. Kyle RA, Rajkumar SV. Plasma cell disorders. In: Goldman L, Ausiello DA, eds. Cecil textbook of medicine. 22nd ed. Philadelphia: W.B. Saunders, 2004:1184-9.
4. Graham RC Jr, Bernier GM. The bone marrow in multiple myeloma: correlation of plasma cell ultrastructure and clinical state. Medicine (Baltimore) 1975;54:225-243.[
5.Pavlovsky S, Saslavsky J, Tezanos Pinto M, et al. A randomized trial of melphalan and prednisone versus melphalan, prednisone, cyclophosphamide, MeCCNU, and vincristine in untreated multiple myeloma. J Clin Oncol 1984;2:836-840.
6.Monconduit M, Menard JF, Michaux JL, et al. VAD or VMBCP in severe multiple myeloma: the Groupe d'Etudes et de Recherche sur le Myelome (GERM). Br J Haematol 1992;80:199-204.
7.Gahrton G, Tura S, Ljungman P, et al. Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 1991;325:1267-1273.
8. Rajkumar SV, Gertz MA, Kyle RA, Greipp PR. Current therapy for multiple myeloma. Mayo Clin Proc 2002;77:813-22.
9. Greipp PR, San Miguel JF, Durie BG, et al. A new international staging system (ISS) for multiple myeloma (MM) from the International Myeloma Working Group. Blood 2003;102:190a-190a. abstract.
10. Barlogie B, Alexanian R, Pershouse M, Smallwood L, Smith L. Cytoplasmic immunoglobulin content in multiple myeloma. J Clin Invest 1985;76:765-769.
11. Miettinem , Merkku MD , Lasota , Jerzy MD.Kit (CD117):A review on expression in normal and neoplastic tissues , and mutations and their clinic-pathologic correlation .Lippincott Williams and Wilkins Inc 2005 .
12.Kraj M, Poglod R, Kopec- Szlezak J, Sokolowska U, Wozniak J,Kruk B.C-kit receptor (CD117) expression on plasma cells in monoclonal gammopathies.Department of Hematology , Institute of Hematology and Blood Transfusion Warsaw , Poland , 2004.
13. Prognostic Value of Immunophenotyping in Multiple Myeloma: A Study by the PETHEMA/GEM Cooperative Study Groups on Patients Uniformly Treated With High-Dose Therapy
Gema Mateo, M. Angeles Montalbán, Maria-Belén Vidriales, Juan J. Lahuerta, Maria V. Mateos, Norma Gutiérrez, Laura Rosiñol, Laura Montejano, Joan Bladé, Rafael Martínez, Javier de la Rubia, Joaquín Diaz-Mediavilla, Anna Sureda, José M. Ribera, José M. Ojanguren, Felipe de Arriba, Luis Palomera, Maria J. Terol, Alberto Orfao, Jesús F. San Migue
Journal of Clinical Oncology, Vol 26, No 16 (June 1), 2008: pp. 2737-2744
© 2008
Nr.3 din luna 2012
Mădălina Begu, Ana-Maria Vlădăreanu, Mihaela Gaman, Cristina Ciufu, Ana-Maria Neagu, Horia Bumbea, Minodora Onisai, Andreea Alexe, Cristina Enache, Anamaria Iova, Oana Cazaceanu
Hematology Department Emergency University Hospital
Address for corespondence:
Mădălina Begu, clinical laboratory MD, Hematology Department, Emergency University Hospital, 169 Splaiul Independenței, zip code 050098, Bucharest, Romania.
E-mail: madalinabegu@yahoo.com
Introduction
Multiple myeloma represents aprox 1% of malignant tumours and 10-15% of haematopoietic neoplasms. It is more common for men than women and the average age at diagnosis is 71 years. Multiple myeloma is a neoplastic plasma cell dyscrasia characterized by: a monoclonal protein in the serum or urine or both, anemia, abnormal bone radiographs and bone pain, hypercalcemia, renal insufficiency and more than 10%myeloma cells in bone marrow. The immunophenotype of myeloma cells is complex. Usually, myeloma cells are CD45 negative, CD38 positive, CD138 positive, CD56 is strongly positive in about 55-78% of cases, but CD56 can be negative in more aggressive disease. Other surface antigens such as CD10, CD28, CD117, CD13, CD33, CD 20 might be found(1, 2).
Case report
The patient is a 58 years old male with progressive fatigue from two month ago.
On physical examination, the patient had no fever, pallor skin, small laterocervical and axillary lymph nodes. Heart and lung were normal. No hepatosplenomegaly. Normal neurological exam.
Hematologic exam showed: hemoglobin 8,2g/dl, reticulocytes 4,8%, leukocytes 12.900/mmc with a left shift differential, and platelets 60.000/mmc.
Peripheral blood smear revealed: a left shift differential (Bl5%, Mi2%, Mt1%, N3%, S44%, E1%, B1%, L33%, M10%, Erbl 32/100cells, plasma cell 1/100 cell)(Figure 1). Morphology examination: hipogranular granulocytes, some of them with Pelger-Huet abnormality, binucleated erythroblasts with Cabot rings, few with blooming nucleus. Plasma cell is a medium – large size cell with round nucleus, eccentrically placed or sometimes with two nucleoli, with condensate chromatin and abundant basophilic cytoplasm (Figure 2). Different types of cytoplasmatic inclusions were noted (Russel bodies, eosinophilic granules, Mott cells).
Bone marrow aspiration was inconclusive and bone biopsy was recommended (Figure 3, Figure 4).
Figure 1. The peripheral blood smear. May Grunwald Giemsa stain, objective X 100. Mieloblast in leukoeritroblastic feature and rouleau formation
Figure 2. The peripheral blood smear. May Grunwald Giemsa stain, objective X 100. Myeloma cell and rouleau formation
Figure 3. Bone marrow. May Grundwal Giemsa stain, objective X 100. Hypocelular bone marrow with rouleau formation
Figure 4. Bone marrow. May Grundwal Giemsa stain, objective X 100. Hypocelular bone marrow with myeloma cells
Biochemical tests. Total protein 10,4 g/dL. The serum ALT, LDH, BUN and uric acid were minimally increased over upper limit.
Serum protein electrophoresis: albumin 40,9% (low), alpha 1 globulin 1,8% (normal), alpha 2 globulin 5,5% (low), beta globulin 50,4% (high), gamma globulin 2% (low); biclonal profile in the beta area of biclonal mobility; peak beta 1 - 45,4% and beta 2 - 4%. Serum IgG 3,15g/l (low), IgA 54,4g/l (high), and IgM 0,178g/l (low).
Serum imunofixation determined lambda light chains. The urine was positive for Bence Jone lambda protein;
Urinary protein: undetectable;
Urinary immunofixation:absence of light chains.
Flow cytometry: The bone marrow aspiration was poor, but FC revealed: 10% plasma cells with intense positive CD38, intense positive CD138 (Figure 5), CD56 positive (Figure 7), CD19 negative, CD14 negative, CD20 negative, a typical flowcytometry pattern of myeloma cells - CD117 positive (prognostic factor)(Figure 6) expressed by 10% of myeloma cells highlighted on inconclusive bone marrow.
Figure 5. Flow cytometry. Myeloma cells with CD 138 and CD38 intense positive
Figure 6. Flow cytometry. Myeloma cells with CD 117 positive and CD38 intense positive
Figure 7. Flow cytometry. myeloma cells with CD 56 positive and CD38 intense positive
Others exam. Skeletal survey: normal aspect of skull, rib bones with punched-out lesions and osteolysis lesions (5-15mm) of thoracic and lumbar vertebras (T11-L5); The patient was also screened for other neoplasms.Tumoral markers were negative (PSA, CEA, AFP, CA 19-9).
Bone marrow biopsy revealed hypercelular bone marrow with diffuse infiltration of myeloma cells, (over 90%), plasmocytic type, with hematopoiesis dislocation (2,8); Special stains with Gomory argentic impregnation: diffuse reticulin fibrosis and collagen fibers; on Giemsa stain isolated erythroblasts were noted. Immunohistochemistry was positive for CD38 in tumor, and L26/CD20 in rare small reactive lymphocytes. The diagnosis established by bone marrow biopsy was: multiple myeloma plasmocytic type 3rd grade marrow infiltration and secondary myelofibrosis.
Positive and differential diagnosis
Positive diagnosis is multiple myeloma: the diagnosis of multiple myeloma was based on these biological data: high total protein, high erythrocyte sedimentation rate, high immunoglobulin, lambda light chains in serum, abnormal serum protein electrophoresis, myeloma cells infiltration, imunophenotype markers and radiological changes, but the only element that does not support this diagnosis is bone marrow myelofibrosis.
Analyzing gathered information the following diagnosis was established: stage IIIA multiple myeloma IgA(lambda) (9) with secondary myelofibrosis
Possible differential diagnosis could include :
1) Myelodysplastic/myeloproliferative syndrome and chronic idiopatic myelofibrosis. Leukocytosis with left shift, disgranulopoiesis signs, inconclusive bone marrow aspiration, secondary myelofibrosis and hepatosplenomegaly could suggest this diagnosis.
2)Bone marrow metastases. Because osteolytic lessions were revealed on skeletal survey, bone marrow metastases should be excluded. All these diagnosis were excluded by performing bone marrow biopsy, which established the multiple myeloma diagnosis.
Therapy
After the diagnosis, treatment options have been discussed. The decision was for VAD chemotherapy (Vincristine 0,4mg/m2, Adriamicine 9mg/m2, Dexamethasone 40mg/ m2). After 5 chemotherapy cycles clinical and biological data have not improved. Of these we mention: Hb =8,8g/dl, PLT =135.000/mmc, Pro 1%, Mi 5%, Mt 2%, N 2%, S 52%, E 1%, B 1%, Ly 33%, Erbl 5/100 elements. High erythrocyte sedimentation rate 90mm/h, totale protein 9g/dl, with beta 1 monoclonal peak of 37,4% and beta 2 of 4%. Bone marrow biopsy revealed diffuse infiltration of myeloma cells (above 90%) with myelofibrosis.
The presence of the two prognostic factors (CD117, Lactate dehydrogenase) indicate a lack of response to treatment of the patient (VAD protocol). CD 117 is still highly positive on myeloma cells. In this situation, another chemotherapy protocol was started (Thalidomide and Dexametasone). After completing the last treatment, clinical and biological status did not improve Hb 8,3g/dl, Plt 120.000/mmc, left shift deviation (Pro 2%, Mi4%, Mt2%, S40%, E3%, B3%, L38%, M8%, Erbl 5/100 elem), highly erythrocyte sedimentation rate (over 140mm/1h), highly immunoglobulinA (41,5g/l); highly total protein 9,5g/dl; highly lactate dehydrogenase (280U/l); low albumin (42,3%) and peak beta1 -29,6% and beta2 -4%; CD 117 highly positive on all myeloma cells.
MRI revealed the presence of a 92mm diameter plasmacytom on the proximal 1/3 of left femoral bone and few other osteolitic lessions on the left femoral neck, bilateral pertrohanterian region, right sacral wing and right femoral shaft. After completing two treatment option (5 X VAD, 5 X Thalidomide/Dexametazon), no improvement was noted, therefore Velcade/Dexametazon/Caelix protocol was the next choice of treatment.
After completing 8 X Velcade /Dex /Caelix the lab tests revealed minimal changes: Hb =9,7 g/dl, Plt= 100 000/mmc , erythrocyte sedimentation rate 76 mm/1 , lactate dehydrogenase 280 U/l, peak beta 1- 24,6%, beta 2 – 5.9%, CD117 positive on myeloma plasma cells.
Finally, after multiple treatment regimens (5 X VAD, 5 X Thali/Dex and 8 Velcade /Dex/Caelix), the patient had significant improvement in terms of hematological and biological problems, most likely because of femoral plasmacytoma evolution.
According to literature data CD 117 is a good prognostic factor in multiple myeloma evolution. A working group led by Jesús F. San Miguel, Servicio de Hematología, Hospital Universitario de Salamanca, Spain analyzed the prognostic impact of immunophenotyping in patients with multiple myeloma. Simultaneous assessment of CD28 and CD117 antigens allowed risk stratification of these patients diagnosed with multiple myeloma into three main categories: poor risk (CD28 positive CD117 negative), intermediate (either both markers negative or both positive), and good risk (CD28 negative CD117 positive)(13). Considering the lack of response to treatment from this case, CD 117 does not represent a good prognostic factor in the evolution of multiple myeloma patients.
During prolonged treatment, the constant presence of a poor prognosis factor was found CD 117 - tyrosine transmembrane III receptor on myeloma cell surface. Our observation that the presence of CD 117 is a factor of poor prognosis in myeloma and explains the lack of response to treatment(12).
Conclusions
This clinical case was chosen because of the diagnostic difficulties, particular fenotype of myeloma cells and the presence of prognostic factor (CD117), that plays the negative role of CD117 in multiple myeloma evolution. Due to unsuccessful treatment with Velcade, transplantation remains the only curative therapeutic approach in multiple myeloma. However, it is associated with a high mortality and morbidity.
References
1.Wintrobes Clinical Hematology 12 th 2009.
2.Who Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 th Edition 2008.
3. Kyle RA, Rajkumar SV. Plasma cell disorders. In: Goldman L, Ausiello DA, eds. Cecil textbook of medicine. 22nd ed. Philadelphia: W.B. Saunders, 2004:1184-9.
4. Graham RC Jr, Bernier GM. The bone marrow in multiple myeloma: correlation of plasma cell ultrastructure and clinical state. Medicine (Baltimore) 1975;54:225-243.[
5.Pavlovsky S, Saslavsky J, Tezanos Pinto M, et al. A randomized trial of melphalan and prednisone versus melphalan, prednisone, cyclophosphamide, MeCCNU, and vincristine in untreated multiple myeloma. J Clin Oncol 1984;2:836-840.
6.Monconduit M, Menard JF, Michaux JL, et al. VAD or VMBCP in severe multiple myeloma: the Groupe d'Etudes et de Recherche sur le Myelome (GERM). Br J Haematol 1992;80:199-204.
7.Gahrton G, Tura S, Ljungman P, et al. Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 1991;325:1267-1273.
8. Rajkumar SV, Gertz MA, Kyle RA, Greipp PR. Current therapy for multiple myeloma. Mayo Clin Proc 2002;77:813-22.
9. Greipp PR, San Miguel JF, Durie BG, et al. A new international staging system (ISS) for multiple myeloma (MM) from the International Myeloma Working Group. Blood 2003;102:190a-190a. abstract.
10. Barlogie B, Alexanian R, Pershouse M, Smallwood L, Smith L. Cytoplasmic immunoglobulin content in multiple myeloma. J Clin Invest 1985;76:765-769.
11. Miettinem , Merkku MD , Lasota , Jerzy MD.Kit (CD117):A review on expression in normal and neoplastic tissues , and mutations and their clinic-pathologic correlation .Lippincott Williams and Wilkins Inc 2005 .
12.Kraj M, Poglod R, Kopec- Szlezak J, Sokolowska U, Wozniak J,Kruk B.C-kit receptor (CD117) expression on plasma cells in monoclonal gammopathies.Department of Hematology , Institute of Hematology and Blood Transfusion Warsaw , Poland , 2004.
13. Prognostic Value of Immunophenotyping in Multiple Myeloma: A Study by the PETHEMA/GEM Cooperative Study Groups on Patients Uniformly Treated With High-Dose Therapy
Gema Mateo, M. Angeles Montalbán, Maria-Belén Vidriales, Juan J. Lahuerta, Maria V. Mateos, Norma Gutiérrez, Laura Rosiñol, Laura Montejano, Joan Bladé, Rafael Martínez, Javier de la Rubia, Joaquín Diaz-Mediavilla, Anna Sureda, José M. Ribera, José M. Ojanguren, Felipe de Arriba, Luis Palomera, Maria J. Terol, Alberto Orfao, Jesús F. San Migue
Journal of Clinical Oncology, Vol 26, No 16 (June 1), 2008: pp. 2737-2744
© 2008
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