Pathologic Quiz Case: A Young Woman With an Indurated Skin Plaque

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A 31-year-old woman presented to her primary care physician with a 2-month history of a 15 × 8-cm indurated skin plaque with erosion and weeping bullae on the right lower leg. She had a history of insulin-dependent diabetes mellitus. The skin lesion was thought to be related to her diabetes.A skin biopsy was performed when the ulceration remained despite good inpatient glucose control. The skin biopsy revealed a diffuse monotonous infiltrate of medium-sized cells involving dermis (Figure 1). These cells have high nucleus:cytoplasm ratios and fine immature chromatin and resemble blasts (Figure 2). Coagulative necrosis and an angiocentric infiltrate were not present. Immunohistochemical stains revealed that the neoplastic cells expressed CD56 (Figure 3), TDT (Figure 4), TIA-1 (focal), and CD43 and CD68 (weak and focal) but not CD3/CD3ɛ, CD20, CD45RO, CD34, CD79a, CD117, or myeloperoxidase. At the time of the skin biopsy, multiple bilateral breast nodules in both upper outer quadrants were identified. A biopsy of the breast was performed later, and the tissue removed was identical in morphology and phenotype to the skin lesion. The possibility of T-cell receptor gene rearrangement was evaluated with polymerase chain reaction amplification of DNA, but no rearrangements were found. Evaluation of peripheral blood and bone marrow showed no evidence of myeloproliferative disorders, myelodysplasia syndromes, myeloid leukemia, or lymphoma. A computed tomography scan of chest and abdomen showed no evidence of lymphadenopathy.What is your diagnosis?Blastic natural killer (NK) cell lymphoma is a very rare primitive hematopoietic malignancy; to our knowledge, fewer than 60 cases have been reported to date.1–3 According to the recent World Health Organization classification of hematopoietic and lymphoid malignancies, blastic NK cell lymphoma is composed of cells with lymphoblast-like morphology showing evidence of commitment to NK cell lineage differentiation.4 Most patients with blastic NK cell lymphoma are middle-aged or elderly, but no age is exempt. The disease tends to involve multiple sites, with predilection for skin. Lymph node, soft tissue, peripheral blood, and/or bone marrow can be simultaneously involved.56 Very rarely, the nasal cavity is the primary site of involvement.7 Most patients have disseminated disease at presentation.58 The etiology is currently unknown. In contrast to extranodal NK cell/T-cell lymphoma, there is no association with Epstein-Barr virus.Morphologically, blastic NK cell lymphoma is characterized by a diffuse monotonous infiltrate of medium-sized cells with fine chromatin that resemble blasts. In the skin lesions, the tumor cells infiltrate the superficial and deep dermis, with extension to the subcutaneous adipose. Tumor cells are not present in the epidermis. Occasionally, a single-file pattern of infiltration can be identified in some areas. Coagulative necrosis and an angiocentric infiltrate are uncommon. When lymph nodes are involved, tumor cells diffusely expand the paracortical zone or completely efface the node. In Giemsa-stained touch preparations, the tumor cells may or may not contain cytoplasmic azurophilic granules.Immunophenotypically, the neoplastic cells usually demonstrate an immature state of NK cell development. These cells are surface CD3−, CD19/CD20−, and CD56+. CD56, an isoform of the neural cell adhesion molecule, is expressed very early in committed NK cell precursors and in more than 95% of mature NK cells.9 However, other markers of mature NK cells such as cytoplasmic CD3ɛ, CD16, CD57, and cytotoxic granule associate proteins (granzyme B, perforin, and TIA-1) are expressed infrequently. This phenotype indicates an early committed NK cell precursor that has yet to develop a mature cytotoxic phenotype. In some cases, expression of TDT and/or CD34 has been observed, further demonstrating the immature nature of the neoplastic cells. Expression of CD2 and CD7 is variable but usually negative. CD43 and CD4 are usually expressed. CD68 is generally negative or only weakly, focally expressed.2–4On the genetic level, the neoplastic cells show the absence of T-cell receptor rearrangements, suggesting no commitment of T-cell lineage differentiation. All cases studied so far have been negative for Epstein-Barr virus.4 Specific chromosomal aberrations have not been observed.In the current case, the morphologic findings and the immunophenotypic pattern of the neoplastic lymphocytes are consistent with blastic NK cell lymphoma. The major differential diagnosis of this case includes extranodal NK cell lymphoma, nasal type, precursor T- or B-lymphoblastic leukemia involving skin, and granulocytic (myeloid) sarcoma. Tumor cells of extranodal NK cell lymphoma, nasal type, express other NK cell markers such as cytoplasmic CD3ɛ in addition to CD56, which was shown in the present case. Neoplastic cells of extranodal NK cell lymphoma, nasal type, do not have a blastic appearance and do not express TdT. The blastic morphology and the expression of TdT in our case the T-cell receptor gene. The exclusion of granulocytic sarcoma is the most difficult. Neoplastic cells of granulocytic sarcoma frequently express CD56, particularly when the myeloid blasts have monocytic differentiation,10 and may occasionally express TdT. Furthermore, a poorly/minimally differentiated granulocytic sarcoma may lack the expression of myeloperoxidase and express only CD43. However, expression of TIA-1 by myeloid blasts has not been reported to our knowledge. Additionally, in the current case, the evaluation of peripheral blood and bone marrow revealed no evidence of myeloid leukemia, myeloproliferative disorders, or myelodysplastic syndromes. This patient has not developed any significant hematologic abnormalities since the skin biopsy performed 8 months ago. These findings strongly argue against the possibility of granulocytic sarcoma.The clinical course of blastic NK cell lymphoma is aggressive, with a poor response to regimens used for non-Hodgkin lymphomas. In rare cases, partial responses to regimens used for acute leukemia-like disease have been reported. Usually, cases with localized skin lesions have a better prognosis. Our patient underwent 6 chemotherapy cycles of cyclophosphamide-doxorubicin-vincristine-prednisone. The breast nodules decreased significantly in size, and the skin lesion on right lower extremity resolved. She is currently scheduled for an autologous stem cell transplant.