Summary. Case report. DOI /j x

Transcription

1 CASE REPORT DOI /j x Acute myeloid dendritic cell leukaemia with specific cutaneous involvement: a diagnostic challenge M. Ferran, F. Gallardo, A.M. Ferrer,* A. Salar, E. Pérez-Vila,* N. Juanpere,à R. Salgado, B. Espinet, A. Orfao, L. Florensa* and R.M. Pujol Departments of Dermatology, Hematology and Pathology (àlaboratory of Pathology, *Hematologic Cytology and Cytogenetics), Hospital del Mar IMAS, Passeig Marítim 25 29, Barcelona, Spain Department of Cytometry, Hospital Universitario de Salamanca, Salamanca, Spain Summary Correspondence Marta Ferran. mferran@imas.imim.es Accepted for publication 25 October 2007 Key words blastic natural killer-cell lymphoma, CD4+/CD56+ cutaneous neoplasm, dendritic cell leukaemia, haematodermic neoplasm, myeloid dendritic cell Conflicts of interest None declared. Myeloid or type 1 dendritic cell leukaemia is an exceedingly rare haematopoietic neoplasm characterized by a specific immunophenotypic profile close to plasmacytoid dendritic cell and acute myelogenous leukaemia. A 77-year-old man presenting specific cutaneous infiltration by myeloid dendritic cell leukaemia is reported. The clinical features as well as the cutaneous histopathological and immunohistochemical features led to the initial diagnosis of CD4+ CD56+ haematodermic neoplasm. However, extensive immunophenotypic studies performed from peripheral blood blasts disclosed that leukaemic cells expressed myeloid dendritic cell markers, confirming the diagnosis. The diagnostic difficulties of specific cutaneous involvement by myeloid dendritic cell leukaemia on the basis of routine histopathological and immunohistochemical features are highlighted. Mature dendritic cells represent a heterogeneous population of specialized antigen-presenting cells characterized morphologically by an irregular shape with numerous cell membrane processes, including spiny dendrites, bulbous pseudopods and lamellipodiae or veils. Despite some common functions (i.e. antigen processing, T-cell activation), dendritic cells may have distinct origins, stages of differentiation, specific functions and migratory profiles. 1 At least two different human non-langerhans dendritic cell subsets have been identified: myeloid (or dendritic cells type 1) and plasmacytoid (or dendritic cells type 2) dendritic cells. Occasional cases of dendritic cell leukaemia have been described recently, and specific cutaneous involvement has frequently been reported. Most dendritic cell leukaemias comprise plasmacytoid dendritic cells expressing the CD4, CD56 and CD123 antigens with concomitant negativity for other myeloid and lymphoid-associated markers. Myeloid dendritic cell leukaemia is exceptional, and it would differentiate from the former by the expression, as well as of CD4, CD56 and CD123, of some myeloid makers [CD13, CD14, CD15, CD33, myeloperoxidase (MPO), lysozyme] and specific myeloid dendritic cell antigens (BDCA3) instead of plasmacytoid dendritic cell antigens (BDCA2, BDCA4) (Table 1). In the World Health Organization (WHO) European Organisation for Research and Treatment of Cancer (EORTC) classification for cutaneous lymphomas, these cases would be included in the group of CD4+ CD56+ haematodermic neoplasms. 2 Only with additional immunophenotypic features determined either from blood or from cutaneous samples would the final diagnosis of dendritic cell leukaemia be established. Case report A 77-year-old man presented with an asymptomatic, progressively spreading cutaneous eruption, associated with a constitutional syndrome consisting of weight loss and anorexia. His medical history was relevant for a prostate cancer treated 4 years before with radiotherapy, without any complications. Physical examination disclosed multiple red-brown to violaceous papules and nodules, which were indurated on palpation. The eruption had a generalized distribution, with lesions mainly localized on his trunk, head and root of the extremities (Fig. 1). No fever, enlarged lymph nodes or hepatosplenomegaly were noted. Biopsies of several lesions were performed. Histopathological examination disclosed a dense, nonepidermotropic, diffuse infiltrate that created a Grenz zone and infiltrated the whole dermis among collagen bundles, reaching the subcutaneous tissue (Fig. 2). This infiltrate was composed of medium-sized cells, slightly pleomorphic, with moderate cytoplasm and atypical nucleus with prominent nucleoli. No 1129

2 1130 Acute myeloid dendritic cell leukaemia with cutaneous involvement, M. Ferran et al. Table 1 Immunophenotypic differences among normal myeloid and plasmacytoid dendritic cells, and blast cells in our case Myeloid dendritic cells Plasmacytoid dendritic cells Our case T lymphoid CD2 a + + ) CD3 a,b ) ) ) CD4 a,b CD8 a,b ) ) ) CD7 a,b ) ) ) TdT a,b ) ) ) TCRab d ) ) ) TCRcd d ) ) ) B lymphocyte CD10 a,b ) ) ) CD19 a ) ) ) CD20 a,b ) ) ) CD43 a,b ) ) + cl a ) ) ) CD79a a,b ) ) ) NK CD16 a ) ) ) CD56 a,b ) + ) + + CD57 a,b ) ) ) Myelomonocytic CD13 a,b + ) + CD33 a + ) + CD14 a ) ) ) CD36 a CD64 a ) ) + CD117 a,b ) ) ) CD11b a ) ) + Myeloperoxidase b,c ) ) ) Butyrate esterase c ) ) + clysozyme a ) ) + Dendritic IREM-2 a + ) + BDCA2 a ) + ND BDCA3 a + ) + BDCA4 CD304 a ) + ND CD85j a Others CD123 a,b HLA-DR a,b a ) ) + Fig 1. Multiple red to violaceous, indurated papules and nodules distributed on the trunk. Markers studied by a flow cytometry, b immunohistochemistry (paraffin), c cytochemistry and d polymerase chain reaction. ND, not done. evidence of angiocentric or angiodestructive growth pattern was detected. Immunohistochemical studies on formalin-fixed, paraffinembedded specimens showed that neoplastic cells expressed the CD4, CD56, CD68, CD43 and CD123 antigens, with a percentage Ki67 expression of 90%. CD79a, CD20, CD3, CD8 and MPO were not expressed (Fig. 3) (Table 1). In situ hybridization study for Epstein Barr virus genome yielded negative results. No clonal T-cell receptor rearrangement was detected. Fig 2. Histological examination disclosed a dense infiltrate involving the whole dermis (haematoxylin and eosin; original magnification 4). Inset: the infiltrate was composed of medium-sized and slightly pleomorphic cells with moderate cytoplasm and atypical nucleus (haematoxylin and eosin; original magnification 60).

3 Acute myeloid dendritic cell leukaemia with cutaneous involvement, M. Ferran et al (a) Fig 4. Blood smear disclosed the presence of large monocytoid blasts with a vacuolated cytoplasm and pseudopodia-like expansions. (b) Fig 3. Infiltrating cells expressed CD4 (a) and CD56 (b) antigens. Laboratory investigations showed normocytic normochromic anaemia (haemoglobin 9Æ9 g dl )1 ) with neutropenia (0Æ L )1 ) and thrombocytopenia ( L )1 ). Elevated serum lactate dehydrogenase (684 IU L )1 ) and b 2 -microglobulin levels (2Æ94 mg L )1 ) were detected. Blood smear disclosed the presence of 5% large blasts with reticulated chromatin and evident nucleoli, as well as a vacuolated cytoplasm with pseudopodia-like expansions (Fig. 4). The blasts did not express MPO but intensively stained for butyrate esterase. A bone marrow aspirate revealed infiltration by 21% of blasts. Bone marrow biopsy showed an almost complete substitution of adipocytes by foci of infiltrating immature cells with the same immunohistochemical features as in skin biopsy. In addition, an erythrocytic hyperplasia and some areas with haemorrhage were found. Analysis of the blast cells by flow cytometry revealed negative staining for CD34, CD117, TdT, CD79, CD3 and CD2, and positive staining for HLA-DR, CD13, CD33, CD15, CD123, CD56 and CD4 (Table 1). At this point, blast cells had myeloid immunohistochemical and cytochemical markers, as well as monocytoid morphological features. However, they were strongly positive for CD123, a dendritic cell-associated marker. In order to distinguish between a monoblastic acute leukaemia (FAB M5c) and a myeloid dendritic cell leukaemia, further cytometric analyses were performed. The extension of immunophenotypic studies showed that leukaemic cells were positive for the CD36, CD64, lysozyme, IREM-2, BDCA3 and CD85j antigens but negative for CD14. Additionally, there was bright expression of the 7.1 monoclonal antibody. These results suggested a myeloid dendritic cell leukaemia. Cytogenetic analysis was performed, showing tetrasomy 8 (48, XY, +8, +8 [18] 46, XY [2]) (Fig. 5). Chest X-ray, abdominal ultrasonography and whole body bone scan disclosed no abnormalities. The patient received systemic polychemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, liposomal adriamycin and methylprednisolone, and achieved partial remission. However, a clinical and cytogenetic relapse was noted the next month and despite administering new cycles of polychemotherapy, the patient died 4 months after the first consultation.

4 1132 Acute myeloid dendritic cell leukaemia with cutaneous involvement, M. Ferran et al. Fig 5. Cytogenetic analysis showing the tetrasomy 8. Discussion Malignancies showing a CD4+ CD56+ phenotypic profile have been variably classified. They have been named histiocytic lymphomas or histiocytic-associated haematological malignancies, CD4+ CD56+ lineage-negative malignancies, CD56+ blastic tumours, and agranular CD4+ CD56+ cutaneous neoplasms, according to their morphological and immunophenotypic features. Based on CD56 expression, they were initially considered to develop from transformed natural killer (NK) progenitors and, therefore, were classified as blastic or blastoid NK-cell leukaemia lymphoma. 1 However, CD56 is not lineage specific and no other markers specific for NK cells are typically found in these cells. 2 In the last WHO EORTC classification for cutaneous lymphomas, the name of CD4+ CD56+ haematodermic neoplasm was adopted for this group of malignancies. 3 Recent studies demonstrated that most CD4+ CD56+ haematodermic neoplasms arise from malignant plasmacytoid dendritic cells. 4 Dendritic cell malignancies seem to be exceedingly rare and most of them appear to correspond to the malignant counterpart of plasmacytoid dendritic cells. 2 They frequently present as cutaneous lesions with concomitant or rapidly appearing extranodal skin involvement. 5,6 Skin lesions are usually infiltrating purple papules and nodules, which rapidly become widespread. The disease is characterized by a rapid aggressive malignant clinical course and evolution towards leukaemia. Prognosis is very poor, independent of the treatment administered, which usually leads to an initial response followed by a quick relapse. Histological examination of skin lesions in dendritic cell leukaemia usually shows a dense dermal infiltration by medium to large pleomorphic cells, with dispersed chromatin and inconspicuous nucleoli, sparing the epidermis and creating a Grenz zone. 5,6 The diagnosis of dendritic cell malignancies is based on specific immunophenotypic features. The conjunction of positivity for CD123, CD4 and CD56 along with the absence of myelomonocytic lineage markers (e.g. CD13, CD14, CD15, CD33, MPO) would help in distinguishing plamacytoid dendritic cell malignancies from myelomonocytic leukaemia. 7 The case reported here, however, does not fulfil either of these two phenotypes but shares immunophenotypic features of both neoplastic myeloid dendritic cells expressing antigens typical of dendritic cell leukaemia (CD123, CD4 and CD56) as well as some myeloid-associated antigens (CD64, CD13, CD33) including 7.1, which has been reported as positive in most dendritic cell leukaemias, and IREM-2, a protein that shows a pattern of expression in normal haematopoietic cells restricted to the monocytic and myeloid dendritic cell lineages. 8 This profile is consistent with a myeloid dendritic cell leukaemia. To the best of our knowledge, no other cases of myeloid dendritic cell leukaemia with cutaneous involvement have been reported so far. However, some cases diagnosed as myeloid NK-cell acute leukaemia or myeloid NK-cell precursor acute leukaemia showing a mixed myeloid NK-cell immunophenotype with similar clinical and morphological features have previously been described Myeloid NK-cell acute leukaemia shows a mature myeloid morphology and immunophenotype, whereas myeloid NK-cell precursor acute leukaemia is characterized by immature blastoid morphology and immunophenotype (with absence of MPO) but expressing myelomonocytic antigens. 9,11 Extramedullary involvement, including skin infiltration, has been more often described at initial presentation in myeloid NK-cell precursor acute leukaemia. Therefore, most of the cases diagnosed as myeloid NK-cell precursor acute leukaemia present with an identical clinical picture and similar histopathological and immunophenotypic features to the present case. As data on expression of important markers distinguishing this entity from myeloid and dendritic cell leukaemia are lacking, we cannot confirm the possibility that these cases might represent myeloid dendritic cell haematological neoplasms. The main differential diagnosis of acute myeloid dendritic cell leukaemia is acute myeloid leukaemia (AML). In fact, some authors consider myeloid dendritic cell leukaemia as a morphological variant of AML. 14 AML blast cells frequently express the dendritic cell-associated marker CD86, especially among acute monocytic leukaemia cells. Dendritic cell features can be found in AML cells after chemotherapy. In addition, using cytokines and CD40 ligands, a dendritic cell phenotype strikingly similar to the blast cells of myeloid dendritic cell leukaemia can be induced from AML blast cells. 14 As specific immunophenotypic studies are needed to diagnose a dendritic cell malignancy, dendritic cell leukaemias are difficult to identify in routine immunophenotypic studies and may be easily misdiagnosed. Evaluation of specific cutaneous involvement (paraffin-embedded skin biopsies) can lead to the generic diagnosis of haematodermic neoplasm CD4+ CD56+, if no additional data (peripheral blood, additional immunophenotypic studies) are available. Bueno et al. showed that 0Æ76% of malignancies initially diagnosed by basic immunophenotypic studies as acute myeloid leukaemia, and 0Æ27% of

5 Acute myeloid dendritic cell leukaemia with cutaneous involvement, M. Ferran et al non-hodgkin lymphomas, corresponded, in fact, to dendritic cell neoplasms. 2 Tetrasomy 8 is not specific for any dendritic leukaemia. This rare chromosome abnormality has been reported in a few myeloid malignancies, most of which were AML of monocytic lineage, and it is considered as a poor prognostic factor. 15 Sen et al. investigated by fluorescence in situ hybridization directly on skin infiltrates in a series of 11 patients with AML the possible association between chromosome 8 aneuploidy and leukaemia cutis. 16 They found seven of the 11 patients to be aneuploid for chromosome 8 and suggested the importance of trisomy 8 as a factor in predisposition to skin infiltration in AML. In conclusion, acute myeloid dendritic cell leukaemia seems to be a rare malignancy related to both plasmacytoid dendritic cells and AML. Specific cutaneous involvement may be present, and can be the initial manifestation of the disease. The diagnosis of myeloid dendritic cell leukaemia cutis can only be established after performing extensive immunophenotypic studies, and probably, some cases previously diagnosed as blastic or blastoid NK-cell leukaemia lymphoma correspond to examples of this rare disorder. As the diagnosis of acute myeloid dendritic cell leukaemia identifies a specific subset of leukaemias with particular prognostic and evolutionary features, recognition of the clinical, histopathological and immunophenotypic features of specific skin involvement seems important in order to avoid diagnostic delays, especially in cases presenting cutaneous lesions as the initial manifestation of the disease. References 1 Jacob MC, Chaperot L, Mossuz P et al. CD4+ CD56+ lineage negative malignancies: a new entity developed from malignant early plasmacytoid dendritic cells. Haematologica 2003; 88: Bueno C, Almeida J, Lucio P et al. Incidence and characteristics of CD4(+) HLA DRhi dendritic cell malignancies. Haematologica 2004; 89: Willemze R, Jaffe ES, Burg G et al. WHO EORTC classification for cutaneous lymphomas. Blood 2005; 105: Chaperot L, Bendriss N, Manches O et al. Identification of a leukemic counterpart of the plasmacytoid dendritic cells. Blood 2001; 97: Petrella T, Bagot M, Willemze R et al. Blastic NK-cell lymphomas (agranular CD4+ CD56+ hematodermic neoplasms): a review. Am J Clin Pathol 2005; 123: Feuillard J, Jacob MC, Valensi F et al. Clinical and biologic features of CD4(+) CD56(+) malignancies. Blood 2002; 99: Petrella T, Comeau MR, Maynadie M et al. Agranular CD4+ CD56+ hematodermic neoplasm (blastic NK-cell lymphoma) originates from a population of CD56+ precursor cells related to plasmacytoid monocytes. Am J Surg Pathol 2002; 26: Aguilar H, Alvarez-Errico D, Garcia-Montero A et al. Molecular characterization of a novel immune receptor restricted to the monocytic lineage. J Immunol 2004; 173: Suzuki R, Nakamura S. Malignancies of natural killer (NK) cell precursor: myeloid NK cell precursor acute leukaemia and blastic NK cell lymphoma leukaemia. Leuk Res 1999; 23: Inaba T, Shimazaki C, Sumikuma T et al. Clinicopathological features of myeloid natural killer (NK) cell precursor acute leukaemia. Leuk Res 2001; 25: Sun T, Pashaei S, Jaffrey I, Ryder J. A hybrid form of myeloid NKcell acute leukaemia and myeloid NK-cell precursor acute leukaemia. Hum Pathol 2003; 34: Scott AA, Head DR, Kopecky KJ et al. HLA-DR, CD33+, CD56+, CD16) myeloid natural killer cell acute leukaemia: a previously unrecognized form of acute leukaemia potentially misdiagnosed as French American British acute myeloid leukemia M3. Blood 1994; 84: Tanaka M. Aleukaemic leukaemia cutis as an initial manifestation of myeloid NK cell precursor acute leukaemia. J Eur Acad Dermatol Venereol 2006; 20: Lichtman MA, Segel GB. Uncommon phenotypes of acute myelogenous leukaemia: basophilic, mast cell, eosinophilic, and myeloid dendritic cell subtypes: a review. Blood Cells Mol Dis 2005; 35: Beyer V, Muhlematter D, Parlier V et al. Polysomy 8 defines a clinico-cytogenetic entity representing a subset of myeloid hematologic malignancies associated with a poor prognosis: report on a cohort of 12 patients and review of 105 published cases. Cancer Genet Cytogenet 2005; 160: Sen F, Zhang XX, Prieto VG et al. Increased incidence of trisomy 8 in acute myeloid leukaemia with skin infiltration (leukaemia cutis). Diagn Mol Pathol 2000; 9:190 4.