—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 9 - Blastic NK-cell Lymphoma/CD4+/CD56+ Hematodermic Neoplasm

Elaine S. Jaffe
National Cancer Institute
NIH, Bethesda, MD


Click on each slide thumbnail image for an enlarged view
Clinical History
A 7 year old girl presented with an enlarging lesion of the right forehead, over a period of 8 months. A bone marrow biopsy was reported as negative. The skin lesion was biopsied.


Case 9 - Figure 1 - There is a diffuse infiltrate in the dermis, with sparing of the epidermis.
Case 9 - Figure 2 - The cells have an infiltrative growth pattern, and there is a Grenz zone.
Case 9 - Figure 3 - The cells have finely distributed chromatin, and inconspicuous nucleoli.



Case 9 - Figure 4 - The cells are positive for CD4. Staining is weaker than that of normal T-cells, which are focally seen.
Case 9 - Figure 5 - CD56 is strongly positive in neoplastic cells, but negative in normal lymphocytes.
Case 9 - Figure 6 - Neoplastic cells show nuclear staining for terminal deoxynucleotidyl transferase (TdT).

Discussion
A disease once known as Blastic NK-cell lymphoma [1, 2] , is a recently described malignancy now proposed to be derived from a precursor of dendritic cells. An alternative term in the literature is CD4+/CD56+ hematodermic neoplasm, descriptive of the characteristic phenotype of these cells [3] . Recent reports suggest that the cells represent a precursor of a specialized dendritic cell, termed a plasmacytoid dendritic cell (DC2). [4] The cells express the oncogene TCL1 [5, 6] , and are also positive for CD123. Cutaneous involvement is present in approximately 90 % of the cases, [7] but there is a high incidence of lymph node and bone marrow involvement. [3, 8] Most of the patients are middle aged to elderly. However, a recent study identified three cases in children under the age of 10. [8] The clinical course is aggressive with frequent relapse and poor response to regimens used for the treatment of non-Hodgkin's lymphoma. Although the overall prognosis is poor with survival usually less than 3 years, [7] encouraging results have been obtained with anthracycline-containing chemotherapy [9] and stem cell transplantation. [10] In addition, since these tumors lack asparagine synthase expression, [11] asparagine depletion therapy with L-asparaginase has been used successfully in pediatric cases. [12] Favorable prognostic indicators include skin-confined disease and detectable TdT expression. [13]

The tumor is characterized by a monotonous infiltrate of medium-sized cells with fine chromatin, resembling lymphoblasts. Involvement of the overlying epidermis is not observed, and there is a well-preserved Grenz zone. In contrast with other NK-cell neoplasms, cytoplasmic azurophilic granules are usually absent in Giemsa stained preparations, and EBV has been negative in all cases thus far studied. The cells are negative for surface CD3 and positive for CD56. CD4 is also commonly positive. [2, 3, 8] The results of staining for terminal transferase have been inconsistent, with some studies reporting positive reactivity, [8] , and other studies being negative. [3]

The differential diagnosis includes other blastic tumors of hematopoietic lineage, either myeloid or lymphoid. A rare variant of acute myeloid leukemia is positive for CD56 [14, 15] . Therefore, absence of pan-myeloid antigens including CD13 and CD33 is necessary to distinguish the disease from agranular forms of acute myeloid leukemia, not otherwise categorized. Similarly, the absence of a specific T-cell or B-cell immunophenotype helps in the distinction from [16] precursor lymphoblastic leukemia/lymphoma, which in some cases may also show evidence of NK cell differentiation. [17, 18, 19] Precursor B-cell lymphoblastic lymphoma may present with cutaneous involvement, and is common in the pediatric age group [20, 21] . Useful markers for diagnosis include TDT, CD79a, as well as Pax5 expression [22, 23, 24] . Precursor B-cell tumors may be negative for CD20, and sometimes also negative for LCA [25] .

In summary, blastic NK-cell lymphoma is best regarded as a diagnosis of exclusion for clinically suspicious CD56-positive lymphoproliferative disorders with agranular lymphoblastic morphology, lacking immunoreactivity for surface CD3, B-cell antigens (CD19 and CD20), and myeloid markers (myeloperoxidase, CD13 and CD33). Future advances in molecular techniques, including microarrays, may contribute to a more precise diagnosis of this aggressive entity [26] .

References

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  2. DiGiuseppe JA, Louie DC, Williams JE, Miller DT, Griffin CA, Mann RB, et al. Blastic natural killer cell leukemia/lymphoma: a clinicopathologic study. Am J Surg Pathol 1997;21(10):1223-30.

  3. Petrella T, Dalac S, Maynadie M, Mugneret F, Thomine E, Courville P, et al. CD4+ CD56+ cutaneous neoplasms: a distinct hematological entity? Groupe Francais d'Etude des Lymphomes Cutanes (GFELC). Am J Surg Pathol 1999;23(2):137-46.

  4. Chaperot L, Bendriss N, Manches O, Gressin R, Maynadie M, Trimoreau F, et al. Identification of a leukemic counterpart of the plasmacytoid dendritic cells. Blood 2001;97(10):3210-7.

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  8. Cong P, M Raffeld, and ES Jaffe. Blastic NK Cell lymphoma/leukemia: A clinicopathological study of 23 cases. Mod Pathol 2001;14((1)):160A.

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  13. Bekkenk MW, Jansen PM, Meijer CJ, Willemze R. CD56+ hematological neoplasms presenting in the skin: a retrospective analysis of 23 new cases and 130 cases from the literature. Ann Oncol 2004;15(7):1097-108.

  14. Scott AA, Head DR, Kopecky KJ, Appelbaum FR, Theil KS, Grever MR, et al. HLA-DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute leukemia: a previously unrecognized form of acute leukemia potentially misdiagnosed as French-American-British acute myeloid leukemia-M3. Blood 1994;84(1):244-55.

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  17. Koita H, Suzumiya J, Ohshima K, Takeshita M, Kimura N, Kikuchi M, et al. Lymphoblastic lymphoma expressing natural killer cell phenotype with involvement of the mediastinum and nasal cavity. Am J Surg Pathol 1997;21(2):242-8.

  18. Ichinohasama R, Endoh K, Ishizawa K, Okuda M, Kameoka J, Meguro K, et al. Thymic lymphoblastic lymphoma of committed natural killer cell precursor origin: a case report. Cancer 1996;77(12):2592-603.

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  20. Chimenti S, Fink-Puches R, Peris K, Pescarmona E, Putz B, Kerl H, et al. Cutaneous involvement in lymphoblastic lymphoma. J Cutan Pathol 1999;26(8):379-85.

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  23. Mason DY, Cordell JL, Brown MH, Borst J, Jones M, Pulford K, et al. CD79a: a novel marker for B-cell neoplasms in routinely processed tissue samples. Blood 1995;86(4):1453-9.

  24. Krenacs L, Himmelmann AW, Quintanilla-Martinez L, Fest T, Riva A, Wellmann A, et al. Transcription factor B-cell-specific activator protein (BSAP) is differentially expressed in B cells and in subsets of B-cell lymphomas. Blood 1998;92(4):1308-16.

  25. Ozdemirli M, Fanburg-Smith JC, Hartmann DP, Shad AT, Lage JM, Magrath IT, et al. Precursor B-Lymphoblastic lymphoma presenting as a solitary bone tumor and mimicking Ewing's sarcoma: a report of four cases and review of the literature. Am J Surg Pathol 1998;22(7):795-804.

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