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Aleukemic "leukemia cutis" of monocytic lineage
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I
Aleukemic "leukemia cutis" of monocytic lineage M. P. Gil-Mateo, MD, a F. J. Miquel, MD, a M.A. Piris, MD, b M. Sfinchez, MD, c and G. Martin-Aragonts, M D d Valencia and Toledo, Spain We describe aleukemic leukemia cuffs (ALC) in a 50-year-old woman who presented with numerous skin nodular lesions and lack of peripheral blood and bone marrow involvement until late in the evolution of her disease. We emphasize the value of immunohistochemical studies to distinguish ALC from cutaneous large cell lymphoma. (J Am Acad Dermatol 1997;36:837-40.)
The incidence of specific cutaneous leukemic infiltration is higher for the monocytic leukemias (25% to 31%) than for other non-T-cell leukemias. 1 The occun'ence o f specific skin infiltrates preceding systemic leukemia is rare but well documented. Different terms have been given to this condition: aleukemic leukemia cutis (ALC), lymphoma-like presentation o f leukemia, granulocytic sarcoma, and " t r u e " histiocytic l y m p h o m a (THL). W e describe a patient with A L C and also attempt to clarify the varied terminology that has been used for this disorder. CASE REPORT A 50-year-old woman had multiple pmritic skin lesions for I month and intermittent fever for a few days. Examination showed hundreds of erythematous nodules with a brown hue. The lesions were located mainly on the anterior mink. Some were confluent, and others were ulcerated (Fig. 1). On the forehead, there was an edematous erythematous infiltrated plaque. Some nodules were also present on the flexor surface of her extremities. There was no lymph node enlargement, hepatosplenomegaly, or gingival hypertrophy. A biopsy specimen of a nodule showed a dense monomorphous cellular infiltrate (Fig. 2) involving the dermis
ORrl-tO
This article is made possible through an educational grant ~om the Dermatological Division, Ottho Pharmaceutical Corporation.
From the Departments of Dermatology a and Hematology c, Hospital General Universitario, the Department of Pathology, Hospital Virgen de la Salud, Toledo,b mad the Department of Hematology, Hospital Universitari La Fe, Valenciae Reprint requests: M. P. Gil-Mateo, Department of Dermatology, Hospital General Universitario, Av. Tres Cruces, s/n. 46014 Valencia, Spain. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/4/7898g
and subcuffs with perivascular and periadnexal accentuation (Fig. 3). A zone of uninvolved papillary dermis that separated normal epidermis from the underlying dermal infiltrate was observed (Fig. 3). The minor cells were characterized by a large kidney-shaped or oval nucleus with one or more conspicuous nucleoli, and abundant pale, slightly eosinophilic cytoplasm (Fig. 4). Atypical mitotic figures were present. The cells of the infiltrate showed strong reactivity to lysozyme. Other macrophage/monocyte markers such as CD68, CD4, CD45Ra, CD43, and CD15 were also positive. CD20, CD3, CD30, and chloroacetate esterase stains were negative (Table I). These features define the monocytic nature of the neoplastic cells. A complete blood cell count showed the following values: red blood ceils 4.88 x 106/ram 3, hemoglobin 13.6 mg/dl; hematocrit 39.9%; platelets, 294 x 103/mm3; white blood cells, 6.3 x 103/ram 3 with 66% segmented form, 27.5% lymphocytes, 6.5% monocytes, and 0.7% eosinophils. Serum chemistry profile and urinalysis were norreal. Sternal bone marrow aspiration and biopsy failed to demonstrate leukemic changes. A thoracoabdominal computed tomography scan was normal. The patient was initially treated with CHOP (cyclophosphamide, doxombicin, vincristine, and prednisone) with the presumptive diagnosis of lymphoma, because the result of the immunohistochemical study was not yet available and the cutaneous lesions were progressing rapidly. This treatment resulted in partial regression of the skin nodules. Once the monocytic origin of the infiltrates was demonstrated, a second bone marrow aspiration was performed and again showed no abnormalities. At that time, the peripheral blood was free of tumor cells. Five months after the onset of the cutaneous lesions, the patient developed meningeal involvement. Intravenous idarubicine and cytarabine combined with intrathecal methotrexate and cytarabine were administered. Only a partial response of the cutaneous lesions was obtained, and total body electron beam therapy was added. Despite therapy, the patient died 3 months later with disseminated disease. 837
838
Gil-Mateo et al.
Fig. 1. Numerous nodules on trunk.
Jotlinal of the AmericanAcademyof Dermatology May 1997
Fig. 3. Dense infiltrate of dermis and subcutis with perivascular and periadnexal accentuation. (Hematoxylin-eosin stain; original magnification x20.)
Fig. 2. Diffuse dense monomorphous infiltrate of leukemic cells. Note high mitotic rate. (Hematoxylin-eosin stain; original magnification x200.)
Bone marrow and peripheral blood showed leukemic blast cells premortem.
Fig. 4. Cytologic features of neoplastic cells. Kidneyshaped nuclei, prominent nucleoli, large granular cytoplasms evident. (Hematoxylin-eosin stain; original magnification xl000.)
DISCUSSION Specific cutaneous lesions in leukemia, i.e., leukemia cutis, are characterized by skin infiltration by malignant hematopoietic cells and usually occur in the setting of marrow, peripheral blood, and internal organ involvement. Infiltration of the skin and subcutaneous tissue is especially common in acute monocytic leukemia. 1 Some reports describe the appearance of cutaneous involvement in the absence of other signs of leukemia. These cases have been designated ALC. 2, 3 In all reported instances, overt
leukemia with bone marrow infiltration evolved within a few months after the diagnosis of ALC, and was usually associated with internal organ or peripheral blood involvement as well. Much confusion exists in the literature about the term ALC. Some authors define this as the invasion of the skin by leukemic cells in the absence of peripheral blood or bone marrow involvement.2 Several cases have been described as ALC although marrow aspirate was initially positive or not per-
Journal of the American Academy of Dermatology Volume 36, Number 5, Part 2
Gil-Mateo et al.
839
Table I. Immunophenotyping of leukemic cells in skin biopsy specimen Specificity
Marker
CD20 CD3 CD4 CD45Ra Lysozyme CD68 CD43 CD15 CD30 Chloroacetate esterase
Re~lt
B lymphocytes
T lymphocytes T helper/inducer cells, macrophages Lymphocytes, granulocytes, monocytes Granulocytes, monocytes Monocytes T lymphocytes, granulocytes, monocytes Activated T cells, neutrophil, monocytes Activated T cells Well-differentiated granulocytes
formed.4, 5 Other terms have also been used to describe identical cases: lymphoma-tike presentation of leukemia 6' 7 and isolated leukemia cutis, s Granulocytic sarcoma 9 and THL 1° are other proposed terms. THL is considered a neoplasm with tumor cells that show the histologic and immunophenotypJc properties of cells of the monocyte/macrophage system. It is thought to be extremely rare and doubts have arisen about its existence. THL and monocytic leukemia may be part of a spectrum of related diseases 7, 10 in which proliferation of a malignant clone of monocytic lineage is the cardinal feature. At one end of the spectrum, rare cases presenting as localized rumors of skin, bone or lymph nodes could be designated as THL and the cutaneous form would be synonymous with monocytic ALC. At the opposite end, full-blown acute monocytic leukemia would be the usual presentation. Transition from the localized type to the disseminated one is the role and takes place in a few months in most patients. The diagnosis of ALC can be difficult. Clinically, the skin manifestations of ALC resemble a cutaneous lymphoma, and range from a solitary nodule 6 to erythroderma. 3 Most patients have multiple papulonodules with rapid growth and widespread distribution.2, 8 HistopathologicaJly, malignant cells are similar to those of cutaneous large cell lymphoma. Therefore, it is not surprising that most rumors are originally diagnosed as lymphomas. 1~ Immunohistochemical study is necessary to characterize immunophenotype of rumor cells. 12"14 Negativity of the usual pan-T and pan-B markers (CD3 and CD20), and positivity of monocyte-macrophage or granulocyte markers are key diagnostic featmes. Leukemia cutis is considered as a grave prognostic sign in a patient with aggressive systemic leuke-
+ + +++ + + +
mia.1 This seems also to be the case for ALC, 2 because most patients die within a few months. 2-5, 8 Analysis of previously reported cases 15indicates that systemic chemotherapy adequate to induce and maintain bone man-ow remission fails to control cutaneous leukemic infiltrates. Malignant cells surviving in the skin may then reseed the bone marrow, resulting in relapse. Conversely, electron-beam radiation therapy may eradicate skin disease but has no effect on bone marrow. Therefore, the addition of electron-beam radiation therapy to chemotherapy is advocated.15 These cases of "true" ALC raise questions about the origin of neoplastic clones and their biological behavior. Malignant cells could originate in the bone marrow and subsequently migrate to the skin. These cells have affinity for skin, based on some unknown "homing pattern." Local proliferation of leukemic cells then takes place, giving rise to tumoral cutaneous lesions that are the first clinical manifestation of the disease. In time, the natural history of the disease probably includes some "multistep" process leading to full-blown acute leukemia with mat-row, peripheral blood, and internal organ involvement. REFERENCES 1. Ratnam KV, Khor CJL, Su WPD. Leukemia curls. Dermatol Clin 1994;12:419-31. 2. Ohno S, Yokoo T, Ohta M, et al. Aleukemic leukemia cutis. J Am Acad Dermatol 1990;22:374-7. 3. De Connick A, De Hou MF, Peters O, et al. Aleukemic leukemia curls. An unusual presentation of acute myelomonocytic leukemia. Dermatologica 1986;172:272-5. 4. Hansen RM, Barnett J, Hanson G, et al. Aleukemic leukemia curls. Arch Dermatol 1986;122:812-4. 5. Horlick HP, Silvers DN, Knobler EH, et al. Acute myelomonocyrlc leukemia presenting as a benign-appearing cutaneous eruption. Arch Dermatol 1990;126:653-6. 6. Blaustein JC, Narang S, Palutke M, et al. Extramedullary (skin) presentation of acute monocyfic leukemia resem-
840
7.
8. 9. 10.
11.
Gil-Mateo et al.
bling cutaneous lymphoma: morphological and immunological features. J Cutan Pathol 1987;14:232-7. Bain B, Manoharan A, Lampert I, et al. Lymphoma-like presentation of acute monocytic leukemia. J Clin Pathol 1983;36:559-65. Haubenstock A, Zalusky R, Ghall VS, et al. Isolated leukemia curls - a case report. Am J Hematol 1987;24:437-9. Wiernick PH, Serpick AA. Granulocytic sarcoma (chloroma). Blood 1970;35:361-9. Ralfkiaer E, Delsol G, O'Connor NTJ, et al. Malignant lymphomas of true histiocytic origin. A clinical, histological, immunophenotypic and genotypic study. J Pathol 1990;160:9-17. Long JC, Mihm MC. Mtdtiple granulocyrlc tumors of the skin. Report of six cases of myelogenous leukemia with
Journal of the American Academy of Dermatology May 1997
initial manifestations of the skin. Cancer 1977;39:2004-16. 12. Burg G, Schrnoeckel C, Braun-Falco O, et al. Monocytic leukemia. Clinically appearing as "malignant reticulosis of the skin." Arch Dermatol 1978;114:418-20. 13. Kaiserling E, Horny HP, Geerts ML, et al. Skin involvement in myelogenous leukemia: morphologic and immunophenotypic heterogeneity of skin inftltrates. Mod Pathol 1994;7:771-9. 14. Ratnam KV, Su WPD, Ziesmer SC, et al. Value of immunohistochemistry in the diagnosis of leukemia curls: study of 54 cases using paraffin-secrlon markers. J Cutan Pathol 1992;19:193-200. 15. Baer MR, Barcos M, Farrel H, et al. Acute myelogenous leukemia with leukemia curls. Eighteen cases seen between 1969 and 1986. Cancer 1989;63:2192-200.
I
Aleukemic "leukemia cutis" of monocytic lineage M. P. Gil-Mateo, MD, a F. J. Miquel, MD, a M.A. Piris, MD, b M. Sfinchez, MD, c and G. Martin-Aragonts, M D d Valencia and Toledo, Spain We describe aleukemic leukemia cuffs (ALC) in a 50-year-old woman who presented with numerous skin nodular lesions and lack of peripheral blood and bone marrow involvement until late in the evolution of her disease. We emphasize the value of immunohistochemical studies to distinguish ALC from cutaneous large cell lymphoma. (J Am Acad Dermatol 1997;36:837-40.)
The incidence of specific cutaneous leukemic infiltration is higher for the monocytic leukemias (25% to 31%) than for other non-T-cell leukemias. 1 The occun'ence o f specific skin infiltrates preceding systemic leukemia is rare but well documented. Different terms have been given to this condition: aleukemic leukemia cutis (ALC), lymphoma-like presentation o f leukemia, granulocytic sarcoma, and " t r u e " histiocytic l y m p h o m a (THL). W e describe a patient with A L C and also attempt to clarify the varied terminology that has been used for this disorder. CASE REPORT A 50-year-old woman had multiple pmritic skin lesions for I month and intermittent fever for a few days. Examination showed hundreds of erythematous nodules with a brown hue. The lesions were located mainly on the anterior mink. Some were confluent, and others were ulcerated (Fig. 1). On the forehead, there was an edematous erythematous infiltrated plaque. Some nodules were also present on the flexor surface of her extremities. There was no lymph node enlargement, hepatosplenomegaly, or gingival hypertrophy. A biopsy specimen of a nodule showed a dense monomorphous cellular infiltrate (Fig. 2) involving the dermis
ORrl-tO
This article is made possible through an educational grant ~om the Dermatological Division, Ottho Pharmaceutical Corporation.
From the Departments of Dermatology a and Hematology c, Hospital General Universitario, the Department of Pathology, Hospital Virgen de la Salud, Toledo,b mad the Department of Hematology, Hospital Universitari La Fe, Valenciae Reprint requests: M. P. Gil-Mateo, Department of Dermatology, Hospital General Universitario, Av. Tres Cruces, s/n. 46014 Valencia, Spain. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/4/7898g
and subcuffs with perivascular and periadnexal accentuation (Fig. 3). A zone of uninvolved papillary dermis that separated normal epidermis from the underlying dermal infiltrate was observed (Fig. 3). The minor cells were characterized by a large kidney-shaped or oval nucleus with one or more conspicuous nucleoli, and abundant pale, slightly eosinophilic cytoplasm (Fig. 4). Atypical mitotic figures were present. The cells of the infiltrate showed strong reactivity to lysozyme. Other macrophage/monocyte markers such as CD68, CD4, CD45Ra, CD43, and CD15 were also positive. CD20, CD3, CD30, and chloroacetate esterase stains were negative (Table I). These features define the monocytic nature of the neoplastic cells. A complete blood cell count showed the following values: red blood ceils 4.88 x 106/ram 3, hemoglobin 13.6 mg/dl; hematocrit 39.9%; platelets, 294 x 103/mm3; white blood cells, 6.3 x 103/ram 3 with 66% segmented form, 27.5% lymphocytes, 6.5% monocytes, and 0.7% eosinophils. Serum chemistry profile and urinalysis were norreal. Sternal bone marrow aspiration and biopsy failed to demonstrate leukemic changes. A thoracoabdominal computed tomography scan was normal. The patient was initially treated with CHOP (cyclophosphamide, doxombicin, vincristine, and prednisone) with the presumptive diagnosis of lymphoma, because the result of the immunohistochemical study was not yet available and the cutaneous lesions were progressing rapidly. This treatment resulted in partial regression of the skin nodules. Once the monocytic origin of the infiltrates was demonstrated, a second bone marrow aspiration was performed and again showed no abnormalities. At that time, the peripheral blood was free of tumor cells. Five months after the onset of the cutaneous lesions, the patient developed meningeal involvement. Intravenous idarubicine and cytarabine combined with intrathecal methotrexate and cytarabine were administered. Only a partial response of the cutaneous lesions was obtained, and total body electron beam therapy was added. Despite therapy, the patient died 3 months later with disseminated disease. 837
838
Gil-Mateo et al.
Fig. 1. Numerous nodules on trunk.
Jotlinal of the AmericanAcademyof Dermatology May 1997
Fig. 3. Dense infiltrate of dermis and subcutis with perivascular and periadnexal accentuation. (Hematoxylin-eosin stain; original magnification x20.)
Fig. 2. Diffuse dense monomorphous infiltrate of leukemic cells. Note high mitotic rate. (Hematoxylin-eosin stain; original magnification x200.)
Bone marrow and peripheral blood showed leukemic blast cells premortem.
Fig. 4. Cytologic features of neoplastic cells. Kidneyshaped nuclei, prominent nucleoli, large granular cytoplasms evident. (Hematoxylin-eosin stain; original magnification xl000.)
DISCUSSION Specific cutaneous lesions in leukemia, i.e., leukemia cutis, are characterized by skin infiltration by malignant hematopoietic cells and usually occur in the setting of marrow, peripheral blood, and internal organ involvement. Infiltration of the skin and subcutaneous tissue is especially common in acute monocytic leukemia. 1 Some reports describe the appearance of cutaneous involvement in the absence of other signs of leukemia. These cases have been designated ALC. 2, 3 In all reported instances, overt
leukemia with bone marrow infiltration evolved within a few months after the diagnosis of ALC, and was usually associated with internal organ or peripheral blood involvement as well. Much confusion exists in the literature about the term ALC. Some authors define this as the invasion of the skin by leukemic cells in the absence of peripheral blood or bone marrow involvement.2 Several cases have been described as ALC although marrow aspirate was initially positive or not per-
Journal of the American Academy of Dermatology Volume 36, Number 5, Part 2
Gil-Mateo et al.
839
Table I. Immunophenotyping of leukemic cells in skin biopsy specimen Specificity
Marker
CD20 CD3 CD4 CD45Ra Lysozyme CD68 CD43 CD15 CD30 Chloroacetate esterase
Re~lt
B lymphocytes
T lymphocytes T helper/inducer cells, macrophages Lymphocytes, granulocytes, monocytes Granulocytes, monocytes Monocytes T lymphocytes, granulocytes, monocytes Activated T cells, neutrophil, monocytes Activated T cells Well-differentiated granulocytes
formed.4, 5 Other terms have also been used to describe identical cases: lymphoma-tike presentation of leukemia 6' 7 and isolated leukemia cutis, s Granulocytic sarcoma 9 and THL 1° are other proposed terms. THL is considered a neoplasm with tumor cells that show the histologic and immunophenotypJc properties of cells of the monocyte/macrophage system. It is thought to be extremely rare and doubts have arisen about its existence. THL and monocytic leukemia may be part of a spectrum of related diseases 7, 10 in which proliferation of a malignant clone of monocytic lineage is the cardinal feature. At one end of the spectrum, rare cases presenting as localized rumors of skin, bone or lymph nodes could be designated as THL and the cutaneous form would be synonymous with monocytic ALC. At the opposite end, full-blown acute monocytic leukemia would be the usual presentation. Transition from the localized type to the disseminated one is the role and takes place in a few months in most patients. The diagnosis of ALC can be difficult. Clinically, the skin manifestations of ALC resemble a cutaneous lymphoma, and range from a solitary nodule 6 to erythroderma. 3 Most patients have multiple papulonodules with rapid growth and widespread distribution.2, 8 HistopathologicaJly, malignant cells are similar to those of cutaneous large cell lymphoma. Therefore, it is not surprising that most rumors are originally diagnosed as lymphomas. 1~ Immunohistochemical study is necessary to characterize immunophenotype of rumor cells. 12"14 Negativity of the usual pan-T and pan-B markers (CD3 and CD20), and positivity of monocyte-macrophage or granulocyte markers are key diagnostic featmes. Leukemia cutis is considered as a grave prognostic sign in a patient with aggressive systemic leuke-
+ + +++ + + +
mia.1 This seems also to be the case for ALC, 2 because most patients die within a few months. 2-5, 8 Analysis of previously reported cases 15indicates that systemic chemotherapy adequate to induce and maintain bone man-ow remission fails to control cutaneous leukemic infiltrates. Malignant cells surviving in the skin may then reseed the bone marrow, resulting in relapse. Conversely, electron-beam radiation therapy may eradicate skin disease but has no effect on bone marrow. Therefore, the addition of electron-beam radiation therapy to chemotherapy is advocated.15 These cases of "true" ALC raise questions about the origin of neoplastic clones and their biological behavior. Malignant cells could originate in the bone marrow and subsequently migrate to the skin. These cells have affinity for skin, based on some unknown "homing pattern." Local proliferation of leukemic cells then takes place, giving rise to tumoral cutaneous lesions that are the first clinical manifestation of the disease. In time, the natural history of the disease probably includes some "multistep" process leading to full-blown acute leukemia with mat-row, peripheral blood, and internal organ involvement. REFERENCES 1. Ratnam KV, Khor CJL, Su WPD. Leukemia curls. Dermatol Clin 1994;12:419-31. 2. Ohno S, Yokoo T, Ohta M, et al. Aleukemic leukemia cutis. J Am Acad Dermatol 1990;22:374-7. 3. De Connick A, De Hou MF, Peters O, et al. Aleukemic leukemia curls. An unusual presentation of acute myelomonocytic leukemia. Dermatologica 1986;172:272-5. 4. Hansen RM, Barnett J, Hanson G, et al. Aleukemic leukemia curls. Arch Dermatol 1986;122:812-4. 5. Horlick HP, Silvers DN, Knobler EH, et al. Acute myelomonocyrlc leukemia presenting as a benign-appearing cutaneous eruption. Arch Dermatol 1990;126:653-6. 6. Blaustein JC, Narang S, Palutke M, et al. Extramedullary (skin) presentation of acute monocyfic leukemia resem-
840
7.
8. 9. 10.
11.
Gil-Mateo et al.
bling cutaneous lymphoma: morphological and immunological features. J Cutan Pathol 1987;14:232-7. Bain B, Manoharan A, Lampert I, et al. Lymphoma-like presentation of acute monocytic leukemia. J Clin Pathol 1983;36:559-65. Haubenstock A, Zalusky R, Ghall VS, et al. Isolated leukemia curls - a case report. Am J Hematol 1987;24:437-9. Wiernick PH, Serpick AA. Granulocytic sarcoma (chloroma). Blood 1970;35:361-9. Ralfkiaer E, Delsol G, O'Connor NTJ, et al. Malignant lymphomas of true histiocytic origin. A clinical, histological, immunophenotypic and genotypic study. J Pathol 1990;160:9-17. Long JC, Mihm MC. Mtdtiple granulocyrlc tumors of the skin. Report of six cases of myelogenous leukemia with
Journal of the American Academy of Dermatology May 1997
initial manifestations of the skin. Cancer 1977;39:2004-16. 12. Burg G, Schrnoeckel C, Braun-Falco O, et al. Monocytic leukemia. Clinically appearing as "malignant reticulosis of the skin." Arch Dermatol 1978;114:418-20. 13. Kaiserling E, Horny HP, Geerts ML, et al. Skin involvement in myelogenous leukemia: morphologic and immunophenotypic heterogeneity of skin inftltrates. Mod Pathol 1994;7:771-9. 14. Ratnam KV, Su WPD, Ziesmer SC, et al. Value of immunohistochemistry in the diagnosis of leukemia curls: study of 54 cases using paraffin-secrlon markers. J Cutan Pathol 1992;19:193-200. 15. Baer MR, Barcos M, Farrel H, et al. Acute myelogenous leukemia with leukemia curls. Eighteen cases seen between 1969 and 1986. Cancer 1989;63:2192-200.