Unusual skin lesions in chronic myelomonocytic leukemia. (Case Report).
Abstract: Chronic myelomonocytic leukemia (CMML) is a relatively rare, heterogeneous syndrome classified as a myelodysplastic syndrome according to the French-American-British classification system. The patient's presenting symptom was a pigmented skin nodule nodule: see concretion.
In geology, a rounded mineral concretion that is distinct from, and may be separated from, the formation in which it occurs. that, although common for cases of acute monoblastic leukemia, is peculiar for CMML. This case should increase awareness of the inclusion of CMML in the differential diagnosis of a discolored nodule and highlight the clinicopathologic considerations and therapeutic challenges consistent with the diagnosis of CMML.
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 mon·o·cy·to·sis
An abnormal increase in the number of monocytes in the blood, occurring in infectious mononucleosis and certain bacterial infections such as tuberculosis. Also called monocytic leukocytosis. 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 granulocytic
pertaining to granulocytes.
see myelocytic leukemia.
extramedullary growth of multiple, focal granulocytic neoplasm. They may be neutrophilic or eosinophilic. 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 as·pi·rate
To take in or remove by aspiration.
A substance removed by aspiration.
The removal by suction of a fluid from a body cavity using a needle. 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 (Capability Maturity Model) A process developed by SEI in 1986 to help improve, over time, the application of an organization's supporting software technologies. 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 hematological, hematologic
pertaining to or emanating from blood cells.
total and differential white cell counts, hematocrit estimation, erythrocyte count. presentation of CMML is heterogeneous, ranging from isolated monocytosis without cytopenia, as seen in this patient, to a frank myeloproliferative disorder with leukocytosis Leukocytosis Definition
Leukocytosis is a condition characterized by an elevated number of white cells in the blood.
Leukocytosis is a condition that affects all types of white blood cells. and splenomegaly splenomegaly /sple·no·meg·a·ly/ (-meg´ah-le) enlargement of the spleen.
congestive splenomegaly Banti's disease; splenomegaly secondary to portal hypertension. , similar to chronic myeloid leukemia (CML 1. CML - A query language.
["Towards a Knowledge Description Language", A. Borgida et al, in On Knowledge Base Management Systems, J. Mylopoulos et al eds, Springer 1986].
2. CML - Concurrent ML. ). (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 refractory anemia with excess blasts Hematology A myelodysplastic syndrome of older persons characterized by anemia or pancytopenia and BM hypercellularity Clinical Nonspecific–anemia of gradual onset, fatigue, weakness, exacerbation of underlying heart , 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 erythroid /er·y·throid/ (er´i-throid)
1. of a red color; reddish.
2. pertaining to the cells of the erythrocytic series.
1. 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 monocytes,
n.pl the largest of the white blood cells. They have one nucleus and a large amount of grayish-blue cytoplasm. Develop into macrophages and both consume foreign material and alert T cells to its presence. ; CD33 is expressed by myeloblasts, promyelocytes, myelocytes, and mast cells, and throughout monocyte monocyte /mono·cyte/ (mon´o-sit) a mononuclear, phagocytic leukocyte, 13µ to 25µ in diameter, with an ovoid or kidney-shaped nucleus, and azurophilic cytoplasmic granules. 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 esterase /es·ter·ase/ (es´ter-as) any enzyme which catalyzes the hydrolysis of an ester into its alcohol and acid.
Any of various enzymes that catalyze the hydrolysis of an ester. , which can identify early monocytic precursors and differentiate them from poorly granulated myelocytes. (13)
Two cytogenetic cytogenetic /cy·to·ge·net·ic/ (-je-net´ik)
1. pertaining to chromosomes.
2. pertaining to cytogenetics.
pertaining to or originating from the origin and development of the cell. 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 neoplastic /neo·plas·tic/ (ne?o-plas´tik)
1. pertaining to a neoplasm.
2. pertaining to neoplasia.
pertaining to neoplasia or a neoplasm. process. Several studies were performed to exclude T-cell lymphoma, a common cutaneous neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. , 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 lysozyme: see immunity.
An enyme that was first identified and named by Alexander Fleming, who recognized its bacteriolytic properties. 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 Nodules
A small mass of tissue in the form of a protuberance or a knot that is solid and can be detected by touch.
Mentioned in: Leprosy 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 bullous /bul·lous/ (bul´us) pertaining to or characterized by bullae.
Relating to or characterized by bullae. 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 Hematopoietic stem cell
A cell that can develop into any type of specialized blood cell.
Mentioned in: Umbilical Cord Blood Banking . (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 Bone Marrow Transplantation Definition
The bone marrow—the sponge-like tissue found in the center of certain bones—contains stem cells that are the precursors of white blood cells, red blood cells, and platelets. . 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 septicemia (sĕptĭsē`mēə), invasion of the bloodstream by virulent bacteria that multiply and discharge their toxic products. The disorder, which is serious and sometimes fatal, is commonly known as blood poisoning. 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.
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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 loss of appetite Medtalk Anorexia, see there . He reported sinus congestion The condition of a network when there is not enough bandwidth to support the current traffic load.
congestion - When the offered load of a data communication path exceeds the capacity. 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 enlarged lymph nodes Lymphadenopathy, see there 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 afebrile /afe·brile/ (a-feb´ril) without fever.
afebrile adjective Feverless and showed no signs of lymphadenopathy lymphadenopathy /lym·phad·e·nop·a·thy/ (-op´ah-the) disease of the lymph nodes.
angioimmunoblastic lymphadenopathy , angioimmunoblastic lymphadenopathy with dysproteinemia or hepatosplenomegaly.
A complete blood cell count blood cell count,
n an estimation of the number and types of circulating blood cells (e.g., red blood cells [erythrocytic series], white blood cells, differential). revealed a hemoglobin of 12.6 mg/dl, a platelet count of 125,000/[mm.sup.3], and a white blood cell count white blood cell count,
n a diagnostic clinical laboratory test to determine the number and types of leukocytes present in a measured sample of blood. Overall the normal number of leukocytes ranges from 5000 to 10,000/mm3. 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 hematoxylin /he·ma·tox·y·lin/ (he?mah-tok´si-lin) an acid coloring matter from the heartwood of Haematoxylon campechianum; used as a histologic stain and also as an indicator. 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 human leukocyte antigen
n. Abbr. HLA
A gene product of the major histocompatibility complex; these antigens have been shown to have a strong influence on human allotransplantation, transfusions in refractory patients, and certain disease (HLA HLA human leukocyte antigens.
human leukocyte antigen
HLA (human leuckocyte antigen) )-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 pleomorphism /pleo·mor·phism/ (-mor´fizm) the occurrence of various distinct forms by a single organism or within a species.pleomor´phicpleomor´phous
1. (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 hydroxyurea /hy·droxy·urea/ (-u-re´ah) an antineoplastic that inhibits a step in DNA synthesis, used in treatment of chronic granulocytic leukemia, some carcinomas, malignant melanoma, and polycythemia vera. (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 vincristine /vin·cris·tine/ (vin-kris´ten) an antineoplastic vinca alkaloid; used as the sulfate salt in the treatment of various neoplasms, including Hodgkin's disease, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Kaposi's (0.4 mg/[m.sup.2] for 4 d), and daunorubicin daunorubicin /dau·no·ru·bi·cin/ (daw?no-roo´bi-sin) an anthracycline (q.v.) antibiotic used as an antineoplastic; administered as the hydrochloride salt or as a liposome-encapsulated preparation of the citrate salt. (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 University of Mississippi Medical Center (UMC) is the health sciences campus of the University of Mississippi (Ole Miss). Located in Jackson, Mississippi (USA), it houses the Schools of Medicine, Dentistry, Nursing, Health Related Professions, and Graduate Studies in the Health , 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: firstname.lastname@example.org
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