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Cutaneous extramedullary hemopoiesis in chronic myeloproliferative and myelodysplastic disorders
Cutaneous extramedullary hemopoiesis in chronic myeloproliferative and myelodysplastic disorders Muzlifah A. Haniffa, MRCP,a Bridget S. Wilkins, FRCPath,b Catherine Blasdale, MRCP,a and Nick B. Simpson, FRCPa Newcastle-upon-Tyne, United Kingdom Cutaneous extramedullary hemopoiesis (EMH) is a rare complication of chronic myeloproliferative and myelodysplastic disorders. Chronic idiopathic myelofibrosis (CIMF) is the most common underlying condition. To date, fewer than 30 cases have been reported in the literature and there has been significant confusion with regard to the proposed pathogenesis. In this article, we describe two additional cases of cutaneous EMH associated with chronic myeloid diseases and review the literature with the aim of clarifying the underlying pathogenesis of this unusual clinical condition. The diagnosis of cutaneous EMH in both patients with chronic myeloid diseases was made histopathologically, with immunohistochemistry confirming the presence of differentiating hemopoietic cells associated with dermal components. Cutaneous EMH in chronic myeloid diseases occurs as a result of migration of abnormal neoplastic hemopoietic precursor cells into the skin (in effect, metastasis) and subsequent differentiation along divergent myeloid cell lineages. The diagnosis should be considered in any patient with chronic myeloproliferative or myelodysplastic disease who develops a skin rash. ( J Am Acad Dermatol 2006;55:S28-31.)
C
hronic myeloproliferative and myelodysplastic disorders are terms used to unite a number of hematological diseases which arise because of acquired clonal abnormalities of pluripotential stem cells of the bone marrow. In both myeloproliferative and myelodysplastic disorders, there is overproduction of a neoplastic clone derived from an abnormal hemopoietic stem cell, which leads to excessive (myeloproliferative) or ineffective (myelodysplastic) hemopoiesis. Extramedullary hemopoiesis (EMH) is a well recognized but rare manifestation of chronic myeloproliferative and myelodysplastic disorders, most commonly seen in idiopathic myelofibrosis. It is caused by the metastatic growth of abnormal, clonal hemopoietic stem cells outside of the bone marrow. Foci of EMH are commonly found in the spleen and liver, but may also occur infrequently at other sites. We describe the
Production and distribution supported by an educational grant to the American Academy of Dermatology by Stiefel Laboratories, Inc. From the Departments of Dermatologya and Histopathology,b Royal Victoria Infirmary. Funding sources: None. Conflicts of interest: None identified. Correspondence to: Muzlifah A. Haniffa, MD, Department of Dermatology, Royal Victoria Infirmary, Queen Victoria Road, Newcastleupon-Tyne NE1 4LP, United Kingdom. E-mail: m.a.haniffa@ ncl.ac.uk. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.11.1038
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clinical, histopathologic, and immunohistochemical features of two cases of cutaneous EMH.
CASE REPORTS Patient 1 An 80-year-old male with known chronic idiopathic myelofibrosis (CIMF) presented to the dermatology department with asymptomatic nodules on his abdomen and lower chest that had increased in size and number over the course of the previous two years. On examination, he was found to be cachectic, with hepatosplenomegaly. There were multiple dermal and subcutaneous firm nodules over the abdomen and lower chest (Fig 1). In the past, he had received treatment with a gonadotrophin-releasing hormone (GNRH) analogue for adenocarcinoma of the prostate gland. The diagnosis of CIMF was confirmed by bone marrow aspiration and trephine biopsy. Trephine histology showed fibrotic bone marrow with atypical megakaryocytes but no excess of blast cells. There was also evidence of new bone formation (osteosclerosis). Investigations revealed the following results: hemoglobin, 8.3 g/dL (normal range: 13-18 g/dL); white cell count, 17.7 3 103/L (4-11 3 103/L); neutrophils, 16.51 3 103/L (2-7 3 103/L); metamyelocytes, 7%; myelocytes, 9%; promyelocytes, 1%; blast cells, 1%; nucleated red blood cells, 0.22 3 103/L (0-0); platelets, 110 3 103/L (150-450 3 103/L); alkaline phosphatase, 127 units/L (35-120
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Fig 1. Multiple skin-colored dermal and subcutaneous nodules over the anterior trunk.
units/L); and prostate-specific antigen 0.25 ng/ml (0-4 ng/ml). Examination of a peripheral blood film showed nucleated red blood cells, immature granulocyte precursors, and teardrop-shaped erythrocytes. Excision biopsy of one cutaneous nodule showed perivascular dermal infiltrates of hemopoietic cells at different stages of maturation (Fig 2). All three main cell lines (erythroid, granulocytic, and megakaryocytic) were represented, with obvious megakaryocyte atypia. The patient was treated with regular red cell and platelet transfusion for the CIMF. The cutaneous lesions were untreated as they were asymptomatic. They remained unchanged at 6-month follow-up. Patient 2 An 87-year-old female presented to the dermatology department with a 2- to 3-month history of tender nodules on her right leg. On examination, erythematous nodules and an ulcerated plaque were found on her right leg (Fig 3, A and B). She was known to have a myelodysplastic syndrome, which had been confirmed by bone marrow aspiration and trephine biopsy. Bone marrow histology showed hypocellular hemopoietic components with increased reticulin and abnormal small megakaryocytes. A hypoplastic variant of primary myelodysplastic syndrome was diagnosed, consistent with classification as refractory cytopenia with multilineage
Fig 2. A, Low-power view of hematoxylin-eosinestained infiltrates. B, High-power view of granulopoietic cells. C, Erythroid precursors with hyperchromatic megakaryocyte precursors. (Original magnifications: A, 3100; B and C, 3400.)
dysplasia. She was also known to have ulcerative colitis, ischemic heart disease, and atrial fibrillation. Investigations showed pancytopenia: hemoglobin, 8.4 g/dL (normal range: 13-18 g/dL); white cell count, 2.0 3 103/L (4-11 3 103/L); neutrophils, 0.89 3 103/L (2-7 3 103/L); lymphocytes, 0.94 3 103/L (1.5-4 3 103/L); and platelets, 58 3 103/L (150-450 3 103/L). Examination of a peripheral blood film revealed teardrop cells and thrombocytopenia without any blast cells. Biopsy of a skin nodule showed perivascular aggregates of myeloid cells within the dermis. These cells represented granulocytes at varying stages of maturation and were mixed with plasma cells and lymphocytes. Patient 2 died from sepsis shortly after her presentation.
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Fig 5. Immunohistochemistry for CD42b showing a cluster of atypical megakaryocytes.
Table I. Immunohistochemistry results Markers
Fig 3. A, Erythematous nodules on the right lower leg. B, Ulcerated plaque on the right shin.
Fig 4. Immunohistochemistry for CD68 showing granulopoiesis (antibody KP1) seen in patient 1.
Immunohistochemistry results from the skin biopsies of both patients confirmed a predominance of promyelocytes and myelocytes within the infiltrates (Fig 4). In patient 1, megakaryocytes were also confirmed (Fig 5). The hemopoietic cells were differentiated sufficiently to have down-regulated markers of primitive cells (CD34 and c-kit). The proliferation marker Ki-67 showed high activity, in keeping with expectations for the predominant haemopoietic cell types seen (Table I).
DISCUSSION Cutaneous EMH is rare. We have found published reports of only 28 cases.1-3 Although the most common underlying condition in EMH (at all sites) is CIMF,4 only one patient with cutaneous EMH was
CD34 CD117 (c-kit) CD68 (myelomonocyte marker) Neutrophil elastase (granulocyte marker) Glycophorin A (erythroid marker) CD42b (megakaryocyte marker) Ki67 (proliferation marker) CD14 (monocyte marker)
Case 1
Case 2
\1% Not done 111
ÿ ÿ 111
111
111
ÿ
ÿ
11 (atypical ÿ megakaryocytes) [50% [50% ÿ Not done
found in three large series of 220 patients with CIMF.5-7 A recent review of 510 patients with EMH revealed 27 patients with non-hepatosplenic EMH, and 18 out of these 27 had underlying CIMF.4 The most common sites of non-hepatosplenic EMH were in or surrounding the vertebral column, lymph nodes, and retroperitoneum.4 Only two patients in this series had cutaneous EMH, both with underlying CIMF.4 The clinical manifestations of cutaneous EMH are protean, ranging from skin-colored to red or purple papules, nodules, plaques, and ulcers. The lesions can be asymptomatic. CIMF is a clonal neoplastic hemopoietic stem cell disease involving myeloid, erythroid, and megakaryocyte progenitors.8 It leads to secondary bone marrow fibrosis as a reactive response to the inappropriate release of platelet-derived growth factor, transforming growth factor-beta, and fibroblast growth factors from abnormal megakaryocytes and monocytes in the marrow.8-10 Neoplastic progenitor cells displaced into the circulation as a result of this marrow fibrosis appear, at least in occasional patients, to be able to survive in certain extramedullary sites, including skin.
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Treatment of cutaneous EMH in CIMF is recommended for symptomatic lesions. Low-dose radiation, electron beam therapy, and treatment of the underlying CIMF have all been helpful.4,11 Topical corticosteroids have been used on deposits of cutaneous EMH without effect.4 The prognosis of patients with CIMF and nonhepatosplenic EMH is poor. The median survival of the 18 patients with non-hepatosplenic EMH in CIMF was 13 months,4 in contrast to overall median survival of 5 years in patients with CIMF but without non-hepatosplenic EMH.8 It is not known currently whether these data also apply to patients with cutaneous EMH. In summary, we have presented two patients with cutaneous EMH arising in association with CIMF and a myelodysplastic syndrome, respectively. The diagnosis of cutaneous EMH should always be considered in any patient with a chronic myeloid disorder presenting with a skin rash. REFERENCES 1. Patel BM, Su WP, Perniciaro C, Gertz MA. Cutaneous extramedullary hematopoiesis. J Am Acad Dermatol 1995;32:805-7.
2. Revenga F, Horndler C, Aguilar C, Paricio J. Cutaneous extramedullary hematopoiesis. Int J Dermatol 2000;39:957-8. 3. Fernandez Acenero MJ, Borbujo J, Villanueva C, Penalver J. Extramedullary hematopoiesis in an adult. J Am Acad Dermatol 2003;48:S62-3. 4. Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 2003;78: 1223-33. 5. Ward HP, Block MH. The natural history of agnogenic myeloid metaplasia and a critical evaluation of its relationship with the myeloproliferative syndrome. Medicine 1971;50:357-420. 6. Bourancie BA, Doan CA. Myelofibrosis. Clinical, hematologic, and pathologic study of 110 patients. Am J Med Sci 1962; 243:697-715. 7. Pitcock JA, Reinhard EH, Justus BW, Mendelsohn RS. A clinical and pathological study of seventy cases of myelofibrosis. Ann Intern Med 1962;57:73-84. 8. Tefferi A. The forgotten myeloproliferative disorder: myeloid metaplasia. Oncologist 2003;8:225-31. 9. Groopman JE. The pathogenesis of myelofibrosis in myeloproliferative disorders. Ann Intern Med 1980;92:857-8. 10. Castro-Malaspina H, Gay RE, Jhanwar SC, Hamilton JA, Chiarieri DR, Meyers PA, et al. Characteristics of bone marrow fibroblast colony-forming cells (CFU-F) and their progeny in patients with myeloproliferative disorders. Blood 1982;59:1046-54. 11. Hocking WG, Lazar GS, Lipsett JA, Busuttil RW. Cutaneous extramedullary hematopoiesis following splenectomy for idiopathic myelofibrosis. Am J Med 1984;76:956-8.
C
hronic myeloproliferative and myelodysplastic disorders are terms used to unite a number of hematological diseases which arise because of acquired clonal abnormalities of pluripotential stem cells of the bone marrow. In both myeloproliferative and myelodysplastic disorders, there is overproduction of a neoplastic clone derived from an abnormal hemopoietic stem cell, which leads to excessive (myeloproliferative) or ineffective (myelodysplastic) hemopoiesis. Extramedullary hemopoiesis (EMH) is a well recognized but rare manifestation of chronic myeloproliferative and myelodysplastic disorders, most commonly seen in idiopathic myelofibrosis. It is caused by the metastatic growth of abnormal, clonal hemopoietic stem cells outside of the bone marrow. Foci of EMH are commonly found in the spleen and liver, but may also occur infrequently at other sites. We describe the
Production and distribution supported by an educational grant to the American Academy of Dermatology by Stiefel Laboratories, Inc. From the Departments of Dermatologya and Histopathology,b Royal Victoria Infirmary. Funding sources: None. Conflicts of interest: None identified. Correspondence to: Muzlifah A. Haniffa, MD, Department of Dermatology, Royal Victoria Infirmary, Queen Victoria Road, Newcastleupon-Tyne NE1 4LP, United Kingdom. E-mail: m.a.haniffa@ ncl.ac.uk. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.11.1038
S28
clinical, histopathologic, and immunohistochemical features of two cases of cutaneous EMH.
CASE REPORTS Patient 1 An 80-year-old male with known chronic idiopathic myelofibrosis (CIMF) presented to the dermatology department with asymptomatic nodules on his abdomen and lower chest that had increased in size and number over the course of the previous two years. On examination, he was found to be cachectic, with hepatosplenomegaly. There were multiple dermal and subcutaneous firm nodules over the abdomen and lower chest (Fig 1). In the past, he had received treatment with a gonadotrophin-releasing hormone (GNRH) analogue for adenocarcinoma of the prostate gland. The diagnosis of CIMF was confirmed by bone marrow aspiration and trephine biopsy. Trephine histology showed fibrotic bone marrow with atypical megakaryocytes but no excess of blast cells. There was also evidence of new bone formation (osteosclerosis). Investigations revealed the following results: hemoglobin, 8.3 g/dL (normal range: 13-18 g/dL); white cell count, 17.7 3 103/L (4-11 3 103/L); neutrophils, 16.51 3 103/L (2-7 3 103/L); metamyelocytes, 7%; myelocytes, 9%; promyelocytes, 1%; blast cells, 1%; nucleated red blood cells, 0.22 3 103/L (0-0); platelets, 110 3 103/L (150-450 3 103/L); alkaline phosphatase, 127 units/L (35-120
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Fig 1. Multiple skin-colored dermal and subcutaneous nodules over the anterior trunk.
units/L); and prostate-specific antigen 0.25 ng/ml (0-4 ng/ml). Examination of a peripheral blood film showed nucleated red blood cells, immature granulocyte precursors, and teardrop-shaped erythrocytes. Excision biopsy of one cutaneous nodule showed perivascular dermal infiltrates of hemopoietic cells at different stages of maturation (Fig 2). All three main cell lines (erythroid, granulocytic, and megakaryocytic) were represented, with obvious megakaryocyte atypia. The patient was treated with regular red cell and platelet transfusion for the CIMF. The cutaneous lesions were untreated as they were asymptomatic. They remained unchanged at 6-month follow-up. Patient 2 An 87-year-old female presented to the dermatology department with a 2- to 3-month history of tender nodules on her right leg. On examination, erythematous nodules and an ulcerated plaque were found on her right leg (Fig 3, A and B). She was known to have a myelodysplastic syndrome, which had been confirmed by bone marrow aspiration and trephine biopsy. Bone marrow histology showed hypocellular hemopoietic components with increased reticulin and abnormal small megakaryocytes. A hypoplastic variant of primary myelodysplastic syndrome was diagnosed, consistent with classification as refractory cytopenia with multilineage
Fig 2. A, Low-power view of hematoxylin-eosinestained infiltrates. B, High-power view of granulopoietic cells. C, Erythroid precursors with hyperchromatic megakaryocyte precursors. (Original magnifications: A, 3100; B and C, 3400.)
dysplasia. She was also known to have ulcerative colitis, ischemic heart disease, and atrial fibrillation. Investigations showed pancytopenia: hemoglobin, 8.4 g/dL (normal range: 13-18 g/dL); white cell count, 2.0 3 103/L (4-11 3 103/L); neutrophils, 0.89 3 103/L (2-7 3 103/L); lymphocytes, 0.94 3 103/L (1.5-4 3 103/L); and platelets, 58 3 103/L (150-450 3 103/L). Examination of a peripheral blood film revealed teardrop cells and thrombocytopenia without any blast cells. Biopsy of a skin nodule showed perivascular aggregates of myeloid cells within the dermis. These cells represented granulocytes at varying stages of maturation and were mixed with plasma cells and lymphocytes. Patient 2 died from sepsis shortly after her presentation.
S30 Haniffa et al
J AM ACAD DERMATOL AUGUST 2006
Fig 5. Immunohistochemistry for CD42b showing a cluster of atypical megakaryocytes.
Table I. Immunohistochemistry results Markers
Fig 3. A, Erythematous nodules on the right lower leg. B, Ulcerated plaque on the right shin.
Fig 4. Immunohistochemistry for CD68 showing granulopoiesis (antibody KP1) seen in patient 1.
Immunohistochemistry results from the skin biopsies of both patients confirmed a predominance of promyelocytes and myelocytes within the infiltrates (Fig 4). In patient 1, megakaryocytes were also confirmed (Fig 5). The hemopoietic cells were differentiated sufficiently to have down-regulated markers of primitive cells (CD34 and c-kit). The proliferation marker Ki-67 showed high activity, in keeping with expectations for the predominant haemopoietic cell types seen (Table I).
DISCUSSION Cutaneous EMH is rare. We have found published reports of only 28 cases.1-3 Although the most common underlying condition in EMH (at all sites) is CIMF,4 only one patient with cutaneous EMH was
CD34 CD117 (c-kit) CD68 (myelomonocyte marker) Neutrophil elastase (granulocyte marker) Glycophorin A (erythroid marker) CD42b (megakaryocyte marker) Ki67 (proliferation marker) CD14 (monocyte marker)
Case 1
Case 2
\1% Not done 111
ÿ ÿ 111
111
111
ÿ
ÿ
11 (atypical ÿ megakaryocytes) [50% [50% ÿ Not done
found in three large series of 220 patients with CIMF.5-7 A recent review of 510 patients with EMH revealed 27 patients with non-hepatosplenic EMH, and 18 out of these 27 had underlying CIMF.4 The most common sites of non-hepatosplenic EMH were in or surrounding the vertebral column, lymph nodes, and retroperitoneum.4 Only two patients in this series had cutaneous EMH, both with underlying CIMF.4 The clinical manifestations of cutaneous EMH are protean, ranging from skin-colored to red or purple papules, nodules, plaques, and ulcers. The lesions can be asymptomatic. CIMF is a clonal neoplastic hemopoietic stem cell disease involving myeloid, erythroid, and megakaryocyte progenitors.8 It leads to secondary bone marrow fibrosis as a reactive response to the inappropriate release of platelet-derived growth factor, transforming growth factor-beta, and fibroblast growth factors from abnormal megakaryocytes and monocytes in the marrow.8-10 Neoplastic progenitor cells displaced into the circulation as a result of this marrow fibrosis appear, at least in occasional patients, to be able to survive in certain extramedullary sites, including skin.
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Treatment of cutaneous EMH in CIMF is recommended for symptomatic lesions. Low-dose radiation, electron beam therapy, and treatment of the underlying CIMF have all been helpful.4,11 Topical corticosteroids have been used on deposits of cutaneous EMH without effect.4 The prognosis of patients with CIMF and nonhepatosplenic EMH is poor. The median survival of the 18 patients with non-hepatosplenic EMH in CIMF was 13 months,4 in contrast to overall median survival of 5 years in patients with CIMF but without non-hepatosplenic EMH.8 It is not known currently whether these data also apply to patients with cutaneous EMH. In summary, we have presented two patients with cutaneous EMH arising in association with CIMF and a myelodysplastic syndrome, respectively. The diagnosis of cutaneous EMH should always be considered in any patient with a chronic myeloid disorder presenting with a skin rash. REFERENCES 1. Patel BM, Su WP, Perniciaro C, Gertz MA. Cutaneous extramedullary hematopoiesis. J Am Acad Dermatol 1995;32:805-7.
2. Revenga F, Horndler C, Aguilar C, Paricio J. Cutaneous extramedullary hematopoiesis. Int J Dermatol 2000;39:957-8. 3. Fernandez Acenero MJ, Borbujo J, Villanueva C, Penalver J. Extramedullary hematopoiesis in an adult. J Am Acad Dermatol 2003;48:S62-3. 4. Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 2003;78: 1223-33. 5. Ward HP, Block MH. The natural history of agnogenic myeloid metaplasia and a critical evaluation of its relationship with the myeloproliferative syndrome. Medicine 1971;50:357-420. 6. Bourancie BA, Doan CA. Myelofibrosis. Clinical, hematologic, and pathologic study of 110 patients. Am J Med Sci 1962; 243:697-715. 7. Pitcock JA, Reinhard EH, Justus BW, Mendelsohn RS. A clinical and pathological study of seventy cases of myelofibrosis. Ann Intern Med 1962;57:73-84. 8. Tefferi A. The forgotten myeloproliferative disorder: myeloid metaplasia. Oncologist 2003;8:225-31. 9. Groopman JE. The pathogenesis of myelofibrosis in myeloproliferative disorders. Ann Intern Med 1980;92:857-8. 10. Castro-Malaspina H, Gay RE, Jhanwar SC, Hamilton JA, Chiarieri DR, Meyers PA, et al. Characteristics of bone marrow fibroblast colony-forming cells (CFU-F) and their progeny in patients with myeloproliferative disorders. Blood 1982;59:1046-54. 11. Hocking WG, Lazar GS, Lipsett JA, Busuttil RW. Cutaneous extramedullary hematopoiesis following splenectomy for idiopathic myelofibrosis. Am J Med 1984;76:956-8.