Unusual skin lesions in chronic myelomonocytic leukemia. (Case Report).
Chronic myelomonocytic leukemia (CMML) is a protean disease whose features overlap those of the myelodysplastic and myeloproliferative disorders. The first published description of CMML appeared in 1972, and the French-American-British group classified the condition as a subgroup of the myelodysplastic syndromes in 1982. (1,2) The diagnostic criteria for CMML include a peripheral blood monocytosis of 1,000/[mm.sup.3], peripheral blood blasts of <5%, and the absence of Auer rods. In addition, CMML bone marrow samples show dysplasia of the erythrocytic, megakaryocytic, and granulocytic lines; a blast count of less than 5% but occasionally as high as 20%; and an increase in monocytic precursors. (3) This profile is in contrast to that of acute monoblastic leukemia, in which bone marrow aspirate shows a blast count of approximately 30 to 40%. Skin infiltration by leukemic cells, known as leukemia cutis, is a frequent feature of acute monoblastic leukemia but is rare in CMML; only 12 cases of leukemia cutis in CMM L have been reported. (4-9) In the majority of these cases, the skin lesions were a late manifestation in patients with a declining clinical condition. The present case is unusual because of the early presentation and the severity of the patient's dermatologic involvement.
The hematologic presentation of CMML is heterogeneous, ranging from isolated monocytosis without cytopenia, as seen in this patient, to a frank myeloproliferative disorder with leukocytosis and splenomegaly, similar to chronic myeloid leukemia (CML). (10) The median age at diagnosis of this disease is 66 years, and men are more commonly affected than women, at a ratio of 2.4:1. (11) A meta-analysis study of 600 CMML patients reported a median survival of 24 months (range, 8-60 mo). (12) As a subgroup of the myelodysplastic syndromes, CMML shares the characteristics of trilineage dysplasia with refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and refractory anemia with excess blasts in transformation. (2)
The patient's laboratory studies showed trilineage dysplasia. His bone marrow aspirate revealed nuclear-cytoplasmic maturational dyssynchrony in the erythroid series, and his peripheral blood showed signs of dysgranulopoiesis with the appearance of the Pelger-Huet abnormality of polymorphonuclear leukocytes. This abnormality is described as a hyposegmentation of the polymorphonuclear leukocytes with chromatin condensation. (13) Dysmegakaryopoiesis was also evident as small, hypolobate megakaryocytes in bone marrow and abnormally large platelets in peripheral blood.
The notable peripheral blood monocytosis (2,000/ml) and bone marrow blast count of 10% were indicative of CMML, and flow cytometry immunophenotypic analysis and special staining were confirmatory. Although the monocyte-associated antigen CD14 was absent, tests for CD13, CD33, and HLA-DR were positive. CD13 is expressed on approximately 25% of monocytes; CD33 is expressed by myeloblasts, promyelocytes, myelocytes, and mast cells, and throughout monocyte differentiation; and HLA-DR is positive in a myeloblastic population. (14,15) The bone marrow aspirate was positive for Sudan black, confirming the myeloid origin of the blast cells, and was positive for nonspecific esterase, which can identify early monocytic precursors and differentiate them from poorly granulated myelocytes. (13)
Two cytogenetic studies were obtained during the diagnostic process. The first showed a normal male karyotype, whereas the second (performed after the diagnosis of CMML was made) showed a deletion on the long arm of chromosome 13. Clonal cytogenetic aberrations are found in 30 to 50% of cases of myelodysplastic syndromes, but the majority of these abnormalities consist of total or partial chromosome losses. A deletion on chromosome 13 is not one of the major chromosomal abnormalities of CMML but has been noted as a less common aberration of myelodysplastic syndromes in general, specifically, in refractory anemia. (16) Among partial chromosome losses in myelodysplastic syndromes, del 5q predominates, followed by del 20q, del 11q, del 7q, and del 13q. (17) The absence of a Philadelphia chromosome or a bcr-abl fusion gene product is also significant in ruling out CML, because laboratory and clinical features of CMML often closely resemble that of Philadelphia-positive CML. (13)
The presentation of CMML as a nonspecific skin nodule is the most unusual aspect of this case. The punch skin biopsy specimen showed neoplastic cells with deep indentations and frequent mitotic figures, indicating a neoplastic process. Several studies were performed to exclude T-cell lymphoma, a common cutaneous neoplasm, because the lesion was myeloperoxidase-negative and CD43-positive, an immunostaining pattern that preferentially, but not exclusively, marks T cells. Tests for CD3, CD4, CD8, and T-cell-receptor gene rearrangement were negative, however. Positive immunostaining for CD45, CD68, [[alpha].sub.1]-antichymotrypsin, and lysozyme strongly supported a leukemia cutis associated with CMML. (18)
Leukemia cutis is not uncommon in blood monocytic dyscrasias, the most characteristic being the plum-colored nodules of acute monoblastic leukemia. However, few cases of cutaneous leukemic CMML have been described. (4-9) These scattered reports describe the lesions dermatologically as an erythematous maculopapular rash, numerous widespread skin nodules <1 mm in diameter, an unusual localized bullous lesion, and a widespread itchy rash. (5-7) Our patient's leukemia cutis was even more unusual in that it began with several small (<2 cm) pigmented nodules and progressed fairly rapidly into the large, contiguous pigmented plaque shown in Figure 2. The majority of reported cases of leukemia cutis coincide with an aggressive clinical shift and blast transformation of CMML, whereas this patient's leukemic skin involvement was the initial presentation.
Myelodysplastic syndromes are often refractory to chemotherapeutic regimens for other hemopathies. This resistance may be related to the origin of myelodysplastic disorders as a neoplastic transformation at a level of differentiation close or identical to the hematopoietic stem cell. (19,20) As a result, myeloid cells, platelets, red cells, and even B and T lymphocytes derive from the same altered clone. This concept of a shared, clonal, multipotent stem cell origin predicts that conventional therapies would be ineffective in eliciting a cure, and only the complete eradication of diseased marrow and replacement with healthy donor marrow would be curative. (21)
Several treatment regimens were instituted in this case, and although the skin lesions regressed for a few weeks, they came back with renewed vigor. If the patient had been younger, he would have been a candidate for allogeneic bone marrow transplantation. In a study of 39 allogeneic bone marrow recipients between the ages of 45 and 68, the incidence of transplant-related complications such as interstitial pneumonia and septicemia was greatly increased, and acute graft-versus-host disease was evident in 79% of individuals between 51 and 62 years old. (20)
CMML is a heterogeneous syndrome categorized by monocytosis and various degrees of dysmyelopoiesis, and its diagnosis is generally straightforward. Because of this unusual presentation, this case should heighten awareness of the inclusion of a leukemic CMML skin infiltrate in the differential diagnosis of a pigmented nodule. The nonspecific appearance of such lesions encourages the use of lesion biopsies, special stains, and immunophenotypic analysis, if indicated, early in the evaluation process.
We thank Elizabeth Caldwell, MD, for assistance in the interpretation of skin biopsy material.
Accepted November 14, 2002.
(1.) Zittoun R, Bernadou A, Bilski-Pasquier G, Bousser J. Subacute myelomonocytic leukemia: Study of 27 cases and review of the literature [in French]. Sem Hop 1972;48:1943-1956.
(2.) Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189-199.
(3.) van der Weide M, Sizoo W, Krefft J, Langenhuijsen MM. Myelodysplastic syndromes: Analysis of morphological features related to the FAB-classification. Eur J Haematol 1988;41:58-61.
(4.) Duguid JKM, Mackie M.J, McVerry BA. Skin infiltration associated with CMML. Br J Haematol 1983;53:257-264.
(5.) Eubanks SW, Patterson JW. Subacute myclomonocytic leukemia: An unusual skin manifestation. J Am Acad Dermatol 1983;9:581-584.
(6.) Pozo-Roman T, Javier Menarquez-Palanca F, Gomez-Pineda A, Gonzalez-Herrada CM, Lazaro-Ochaita P. Specific cutaneous involvement in the course of chronic myelomonocytic leukemia simultaneously with blastic leukemic transformation: Report of a case with histologic and cytochemical study, JAm Acad Dermatol 1985;12:943-948.
(7.) Copplestone JA, Oscier DG, Mufti GJ, Hamblin TJ. Monocytic skin infiltration in chronic myelomonocytic leukaemia. Clin Lab Haematol 1986;8:115-119.
(8.) Braga D, Manganoni AM, Boccaletti V, Pancera C, Marocolo D, Facchetti F, et al. Specific skin infiltration as first sign of chronic myelomonocytic leukemia with an unusual phenotype. J Am Acad Dermatol 1996;35:804-807.
(9.) Avivi I, Rosenbaum H, Levy Y, Rowe J. Myelodysplastic syndrome and associated skin lesions: A review of the literature. Leuk Res 1999;23:323-330.
(10.) Martiat P, Michaux JL, Rodham J. Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): Comparison with Ph+ CML and chronic myelomonocytic leukemia. Blood 1991;78:205-211.
(11.) Tefferi A, Hoagland HG, Therneau TM, Pierre RV. Chronic myclomonocytic leukemia: Natural history and prognostic determinants. Mayo Clin Proc 1989;64: 1246-1254.
(12.) Germing U, Gattermann N, Minning H, Heyll A, Aul C. Problems in the classification of CMML: Dysplastic versus proliferative type. Leuk Res 1998;22:871-878.
(13.) Goasguen JE, Bennett TM. Classification and morphologic features of the myelodysplastic syndromes. Semin Oncol 1992;19:4-13.
(14.) Naeim F. Bone marrow examination: Special procedures, in Pathology of Bone Marrow. Baltimore, Williams & Wilkins, 1998, ed 2, pp 46-60.
(15.) Griffin JD, Linch D, Sabbath K, Larcom P, Schlossman SF, A monoclonal antibody reactive with normal and leukemic human myeloid progenitor cells. Leuk Res 1984;8:521-534.
(16.) Ponzio G, Rege-Cambrin G, Neretto G. Loss of band 13q14 in a myelodysplastic syndrome. Cancer Genet Cytogenet 1987;28:181L182.
(17.) Fenaux P, Morel P, Lai JL. Cytogenetics of myelodysplastic syndromes. Semin Hematol 1996;33:127-138.
(18.) Vidal C, Baer MR, Bloomfield CD. Uncommon patterns of presentation of leukemia. Hematol Oncol 1999;17:ll-29.
(19.) Cambier N, Baruchel A, Schlageter MH, Menot ML, Wattel E, Fenaux P, et al. Chronic muelomonocytic leukemia: From biology to therapy. Hematol Cell Ther 1997;39:41-48.
(20.) Appelbaum FR. Allogeneic bone marrow transplantation for myelodysplastic and myeloproliferative disorders, in Forman SJ, Blume KG, Thomas ED (eds): Bone Marrow Transplantation. Boston, Blackwell Scientific Publications, 1994, pp 629-639.
(21.) Klingemann HG, Storb R, Fefer A, Deeg HJ, Appelbaum FR, Buckner CD, et al. Bone marrow transplantation in patients aged 45 years and older. Blood 1986;67:770-776.
RELATED ARTICLE: Key Points
* The patient had discolored skin lesions that progressed to a severe disease.
* Skin infiltration, known as leukemia cutis, is a frequent feature of acute monoblastic leukemia but is rare in chronic myelomonocytic leukemia.
* The unusual presentation of the case should heighten awareness of the inclusion of a leukemic chronic myelomonocytic leukemia skin infiltrate in the differential diagnosis of a pigmented nodule.
A 59-year-old white man presented to his local physician with a 3-month history of a discolored nodule on his back. The patient had no constitutional complaints, and he specifically denied any weight loss, fever, chills, or loss of appetite. He reported sinus congestion as his only problem. When the skin lesion did not respond to antibiotic therapy, a biopsy was performed. Although the biopsy report at that time was not available, the lesion was reported to be suggestive of lymphoma, and the patient was referred to the university's hematology department. Chest radiography and computed tomography performed before referral showed no enlarged lymph nodes or other abnormalities.
At presentation to the hematology clinic, the patient had three painless purplish black nodules on his back and one adjacent to his right nipple, each measuring 1.0 to 1.5 cm in diameter. Physical examination revealed a well-nourished, well-developed man in no acute distress who was afebrile and showed no signs of lymphadenopathy or hepatosplenomegaly.
A complete blood cell count revealed a hemoglobin of 12.6 mg/dl, a platelet count of 125,000/[mm.sup.3], and a white blood cell count of 7,400/[mm.sup.3], with a differential of 18% segmented forms, 5% band cells, 45% lymphocytes, 27% monocytes, 2% metamyelocytes, and 3% myelocytes. In addition to the notable monocytosis (2,000/[micro]l), a peripheral smear showed an occasional atypical lymphocyte and several unusual giant platelets and a rare Pelger-Huet cell. Cytogenetic studies revealed a normal male karyotype.
Bone marrow aspirate showed slight nuclear-cytoplasmic maturational dyssynchrony in the erythroid series, small hypolobate megakaryocytes, an orderly myeloid maturation, and rare bizarre mitotic figures. Hematoxylin and eosin and periodic acid-Schiff stains showed hypercellularity (80-90%), with an increased blast population of 10%. These immature blasts appeared to be of myeloid origin and stained positively with both Sudan and nonspecific esterase. Immunophenotypic studies of the bone marrow were positive for CD13, CD33, and human leukocyte antigen (HLA)-DR and were negative for CD14. The most significant diagnostic findings were bone marrow trilineage dysplasia and a 10% blast count with positive identification of myeloid origin. Collectively, these findings indicated CMML.
The punch skin biopsy obtained at initial evaluation showed neoplastic cells with deep indentations, nuclear irregularities, and pleomorphism (Fig. 1). Immunophenotypic studies were positive for CD43, CD45RO, CD68, [[alpha].sub.1]-antichymotrypsin, and lysozyme, and were negative for CD3, CD4, CD8, T-cell-receptor gene rearrangement, and myeloperoxidase.
At the time of initiation of treatment, the number of nodules had increased and new nodules had appeared on the patient's face. The nodules ranged from 1 to 3 cm in diameter and were pruritic but nontender. The peripheral monocytosis had also increased from 27% to 31%. Treatment was started with hydroxyurea (1,000 mg/d), but the lesions continued to enlarge, covering the back, chest, face, and scalp. After 2 weeks, medication was changed to a low dose of cytarabine (10 g every 12 h). Because of the increased severity of the leukemia cutis, the patient was admitted a week later for systemic chemotherapy induction, with a course of cytarabine (100 mg/[m.sup.2] for 7 d), etoposide (100 mg/[m.sup.2] for 5 d), vincristine (0.4 mg/[m.sup.2] for 4 d), and daunorubicin (20 mg/[m.sup.2] for 3 d), given as a continuous infusion.
Although the patient complained of significant lethargy and weakness during systemic chemotherapy, the lesions regressed. Treatment was then changed to maintenance therapy with oncovorin (2 mg administered intravenously for 5 d), cytarabine (25 mg/d for 5 d), and prednisone (100 mg/d for 5 d). Three weeks later, the lesions on the scalp and face began to enlarge and became more pigmented (Fig. 2). Electron beam therapy to the facial lesions was then begun. His face has shown limited signs of improvement, but the peripheral blood monocytosis has thus far been refractory to chemotherapy.
From the Division of Hematology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS.
Supported by funds from the Department of Medicine, University of Mississippi Medical Center.
Reprint requests to Joe C. Files, MD, Division of Hematology, Department of Medicine, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216. Email: email@example.com
Copyright [C] 2003 by The Southern Medical Association