CD4+’CD56+ hematodermic neoplasm is the current term for “blastic natural killer cell lymphoma.” Other terms which have been used for this entity include NK-cell lymphoblastic lymphoma’leukemia, blastoid NK-cell lymphoma, blastic NK-cell lymphoma’leukemia, and monomorphic agranular NK-cell lymphoma’leukemia (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22).

The cell of origin for this tumor has been reconsidered. Once believed to be the immature NK cell, it is now attributed to the immature plasmacytoid dendritic cell, a CD34+ hematopoietic precursor cell capable of differentiating into antigen-presenting dendritic cells.

CD4+’CD56+ hematodermic neoplasm occurs de novo. Patients may present in childhood or adulthood with systemic symptoms, skin lesions, and cytopenias. Characteristically present in the skin, it also occurs in lymph nodes, mediastinum, bone marrow, and other sites. The clinical course is typically rapid, with development of disseminated disease, leukemia, and death.

The peripheral blood may show leukoerythroblastosis. The leukemic phase may be present initially or develop during the course of the disease. When present, the cells resemble blasts.

Bone marrow aspirate smears and sections show diffuse infiltration in approximately 50% of cases. The malignant blastoid cells are variably sized with oval to irregular nuclei, dispersed chromatin, nucleoli, and variable amounts of agranular cytoplasm. Granules are not visible with light microscopy, but minute granules may be identified by electron microscopy. Cohesive cell aggregates and pseudorosettes have been described.

Immunophenotyping typically shows expression of CD4, CD43, CD45, CD56, and HLA-DR. Cytoplasmic CD3ε, CD7, CD34, CD99, and terminal deoxynucleotidyl transferase may also be expressed. Tumor cells also express CD123 (IL-3 receptor alpha), CLA, and TCL1, all considered to be dendritic cell antigens. CD2, surface CD3, CD5, CD8, CD16, CD20, CD57, TIA-1, and myeloperoxidase are not typically expressed. Exceptional cases show expression of CD2, cytoplasmic CD3, CD5, CD13, CD16, or CD34, or lack expression of CD3ε, CD4, or CD56. Cases that have relapsed after therapy may show a change to a myelomonocytic phenotype.

Genetic studies show no recurrent karyotypic anomalies. Clonal immunoglobulin and T-cell receptor gene rearrangements are typically absent. Rare cases have shown T-cell receptor gene rearrangement. Evidence of Epstein-Barr virus is not found in tumor cells.

The differential diagnosis includes other neoplasms, chronic myeloid leukemia with NK-cell blast crisis, and nonhematopoietic small round cell tumors.

Langerhans cell histiocytosis (LCH) is a clonal disease of epithelial dendritic cells (Figs. 22.1 and 22.2) (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58). LCH may present at any age but is usually seen in the first two decades of life.

LCH may be localized or generalized at the time of diagnosis; some cases proceed from a localized form to disseminated disease. The latter is characterized by involvement of bone marrow, bone, liver, spleen, lymph nodes, and visceral organs. Acute, disseminated disease is usually seen in children under 3 years of age, and chronic unifocal or multifocal disease in older children and adults.

The course of the disease is often indolent, even spontaneously regressing, but may occasionally show aggressive or even malignant clinicopathologic features.

The peripheral blood may show eosinophilia, monocytosis, and’or thrombocytopenia. Circulating Langerhans cells have been reported.

Bone marrow aspirate smears show ovoid to elongated histiocytes containing a bland, eccentric nucleus and moderately abundant, pale-staining cytoplasm. The nucleus shows a central linear groove, indentation, or twist; a small distinct nucleolus; and finely granular chromatin. Electron microscopy shows Birbeck granules.

Histologic sections of the bone marrow show interstitial clusters or sheets of histiocytes, admixed with variable numbers of eosinophils and lymphocytes. Other findings may include fibrosis and dysplastic hematopoiesis. Hemophagocytosis is often prominent, and hemophagocytic syndrome may be the presenting disorder in LCH.

Electron microscopy shows Birbeck granules in the cytoplasm of Langerhans cells. These granules are considered specific for Langerhans cells. They have also been described in cells of an atypical bone marrow infiltrate, eventually replaced by acute monoblastic leukemia (37).