Submitting Author: Manny, Julia S., MD
Institution: Wake Forest University School of Medicine, Winston-Salem, NC
Additional authors:Changlee S. Pang, M.D.
Session: Therapy-related myeloid neoplasms

A 68-year-old man with a history chronic lymphocytic leukemia (treated with fludarabine, rituximab, and then bendamustine) with presented to his oncologist for a suspected abscess on his left buttock. The patient had recently noted fatigue and easy bruising. He had also required 2 platelet transfusions in the past week due to thrombocytopenia. Physical examination revealed a large erythemic mass in the left buttock. Multiple, nontender subcutaneous nodules were present on the trunk and extremities. CT imaging noted mesenteric adenopathy and hepatosplenomegaly, in addition to the left buttock subcutaneous lesion. Biopsy of the buttock lesion at an outside institution revealed myeloid sarcoma with monocytic differentiation. He was admitted for induction chemotherapy with cytarabine and daunorubicin (7+3). Bone marrow biopsy at admission revealed involvement by acute myeloid leukemia with monocytic differentiation and focal involvement by chronic lymphocytic leukemia. Repeat skin and bone marrow biopsies revealed persistent disease which was treated by re-induction with mitoxantrone, etoposide and Ara-C (MEC). Complete remission was eventually achieved following a 2nd shorter course of MEC. Three weeks later his bone marrow biopsy revealed early relapse of his acute myeloid leukemia. Due to repeated gastrointestinal bleeding the patient was determined not to be a candidate for further treatment. He died 4 months after the initial diagnosis.

Case number on left buttock lesion is S11-9621.

Case number on bone marrow specimen is B11-586.

Tissue from the left buttock lesion was formalin fixed, paraffin embedded, and stained with hematoxylin-eosin. Tissue from the bone marrow core biopsy was B+ fixed, paraffin embedded, and stained with hematoxylin-eosin. Bone marrow aspirate smears and peripheral blood smears were stained with Wright-Giemsa.

Sections of the left buttock lesion reveal infiltration of the subcutaneous adipose and collagen by sheets of large monomorphic cells. At high power the cells demonstrate moderate amounts of cytoplasm, irregular or indented nuclear contours, and prominent nucleoli. Frequent mitotic figures and apoptotic cells are seen.

The bone marrow aspirate demonstrates numerous (59% of nucleated cells) large blasts/blast equivalents. Small mature appearing lymphocytes with clumped chromatin are seen in the background. At higher power there the blasts have delicate chromatin and prominent nucleoli. Many of the blasts/blast equivalents exhibited large folded or bizarre nuclei. There is abundant basophilic cytoplasm with cytoplasmic blebbing and extensive vacuolization. Prominent eosinophilic peri-nuclear hofs are present, which range in appearance from collections of eosinophilic granules to collections of small vacuoles. Hemophagocytosis is also seen.

Examination of the bone marrow core biopsy reveals a variably hypercellular marrow for age (60%) with effacement of the marrow spaces by sheets of large mononuclear cells. At higher power these cells exhibited a similar morphologic appearance to that of the cells in the left buttock lesion biopsy with abundant eosinophilic cytoplasm and large irregular nuclei. Many of the nuclei were cleaved or indented and appeared to be pushed to the periphery by brightly eosinophilic cytoplasm. Also seen in the core biopsy are ill-defined interstitial lymphoid aggregates composed of small mature appearing lymphocytes are noted in addition to the blasts.

In the peripheral blood numerous mature appearing lymphocytes with coarsely clumped chromatin and smudge cells are present. Occasional atypical immature mononuclear cells with similar morphologic features to those in the bone marrow are also identified.

Immunohistochemistry for the left buttock lesion revealed diffusely and strongly positive CD45, CD33, lysozyme, and CD68. CD34, CD117, and myeloperoxidase were not expressed. Additionally, CD56, cytokeratin AE1/AE3, cytokeratin 17, cytokeratin 20, Melan-A, PSA, S-100, CD1a, CD3, CD20, CD21, CD35, CD56, CD123, CD138, CD163, and PAX-5 were negative.

By immunohistochemistry the atypical cells in the bone marrow core biopsy expressed CD45, CD33, muramidase, CD99, and focal weak CD68. CD34, CD117 and myeloperoxidase were negative. Additionally the lymphoid aggregates are positive coexpressed CD20 and CD5 by immunohistochemistry. CD3 highlights scattered T-cells.

Flow cytometry of the left buttock lesion was not performed.

Although hemodilute, flow cytometric analysis of the bone marrow revealed a population of blasts (1% of cells) that expressed CD64, CD14, CD36, CD33 (75%), and CD38 with dim expression of CD4 and CD11b. The blasts were negative for CD34 and CD117. Analysis of lymphocytes revealed an atypical B-cell population (93% of cells) which expressed CD19, CD20 (dim), CD23, and CD5. Kappa and lambda light chain expression, as well as, CD10 and FMC7 were negative.

Cytogenetic analysis of the bone marrow specimen revealed the presence of two cell lines with the karyotype 92<4n>,XY,+X,+Y,+Y,-7,+8,+8,-9,-10,-11,-12,-15,+19,+20[cp14]/46,XY[5].

None.

Our case of therapy-related myeloid sarcoma/AML with monocytic differentiation and tetraploidy illustrates many interesting morphological points. Like the majority of myeloid sarcoma associated cases, our case demonstrated monocytic differentiation. In our case the monocytic features of the blasts/blast equivalents were quite visually striking, including indented or folded nuclei, cytoplasmic blebbing and vacuolization, and hemophagocytosis. In addition, the majority of cells demonstrated atypical large peri-nuclear vacuoles and clear zones, suggestive of abnormally prominent golgi zones and granule production.

However, unlike many cases of myeloid sarcoma/AML which are associated with t(8;21) or inv(16), our case was associated with tetraploidy. Near-tetraploid/tetraploid AMLs, not just those associated with myeloid sarcoma, tend to display similar morphologic features (cytoplasmic blebs, vacuoles, irregular nuclear contours), even when not classified as monocytic in lineage. However, one of the most conspicuous features of these cases is the tendency to have large blast size, such that some studies have indicated a direct relationship between ploidy status/DNA content and blast size. In our case the blast/blast equivalents were extremely large, more so than expected due to its monocytic nature alone, which is in keeping with the cytogenetic finding of tetraploidy.

Also of note is the presence of chronic lymphocytic leukemia in this case. While the involvement of the bone marrow is not unexpected given his history, it is important to note that the patient’s prior treatment for CLL predisposed him to an increased risk of developing AML, hence the diagnosis of therapy-related AML.

Left Buttock Lesion: Myeloid sarcoma with monocytic differentiation.

Bone Marrow: Acute myeloid leukemia with monocytic differentiation, therapy-related. Focal involvement by chronic lymphocytic leukemia/small lymphocytic lymphoma.

Left buttock lesion: Therapy-related myeloid neoplasm, myeloid sarcoma (monocytic)

Bone marrow: Therapy-related myeloid neoplasm, acute myeloid leukemia (monocytic), and focal involvement by chronic lymphocytic leukemia/small lymphocytic lymphoma.

Case 85