Submitting Author: Neppalli, Vishala, MD
Institution: Roswell Park Cancer Institute
Additional authors:George Deeb MD, Eunice S. Wang MD, Sheila N. Jani Sait PhD
Session: Extramedullary manifestations of myeloid neoplasms

The patient is a 50-year-old female who is now status post matched sibling allogeneic peripheral blood stem cell transplantation from her brother for FLT3-ITD positive acute myeloid leukemia. Day zero was on 02/22/2012, with current remission statusstatus, until January of 2013..

At diagnosis (Diagnostic bone marrow date: November 1, 2011), the blast phenotype by flow cytometry studies was reported as positive for CD45, CD117, CD33, CD15 and CD38 and negative for CD34. Cytogenetic studies showed a normal karyotype. Molecular studies were reported as positive for FLT3-ITD and negative for D835 and 836 point mutations. After a period of short remission, sShe experienced first relapse in January 2012. At relapse the marrow was positive for FLT3-ITD, and showed abnormal karyotype with 48,XX,+8,+13[12] and 46,XX,del(7)(q22q34)[7]. She was re-induced with chemotherapy, achieved second remission (remission status was confirmed by a bone marrow biopsy performed pre-transplant, dated February 15th, 2012), and underwent bone marrow transplant (February 22, 2012, only one transplant, allogeneic peripheral blood stem cell transplantation, donor is her brother, hence sex mismatch).

Three bone marrow biopsies were performed for follow up, status post transplant. These biopsies are dated March 23rd, 2013, May 29th, 2012 and September 10th, 2012, and were negative for leukemia. Ancillary studies using molecular and cytogenetic analysis confirmed remission status, and supported the morphologic diagnosis.

She underwent a spinal MRI on 01/17/2013 (about day +330 post-transplant) to evaluate for progressive and persistent low back pain (patient experienced back pain from the end of November of 2012) causing neural deficits. MRI showed a large bilateral soft tissue mass in the lower lumbosacral spinal region. The paraspinous mass infiltrated the spinal column at L4, L5, and S1 and the thecal sac causing cord compression. A needle core biopsy of the mass and a bone marrow biopsy were performed. Peripheral blood indices were obtained, and cytogenetic studies were conducted on peripheral blood to evaluate engraftment status.

H&E stained sections of the needle core biopsy from the paraspinous mass (FFPE tissue) showed an atypical diffuse, medium to large cell, monotonous, discohesive cellular infiltrate.

H&E stained sections from the trephine core biopsy showed a hypercellular marrow with extensive crush artifact and marked reticulin myleofibrosis. Bone marrow aspirate smears stained with wright-giemsa stains showed clusters of large atypical blasts with markedly-irregular multilobated/multi-clefted nuclei. A few blasts with auer rods were also noted.

Peripheral blood smear morphology and differential counts were within normal limits.

Paraspinous mass needle core biopsy:

Immunohistochemistry: Positive: CD45, CD43, Lysozyme, CD15 and BCL2. Ki-67 (60%-80%)

Negative: CD5, CD10, CD20, PAX-5, CD34, CD117, MPO, CD30.

Flow cytometry: Screening panel showed CD45 positive events, negative for CD19, and surface kappa and lambda light chains. Myeloid markers were not performed.

Bone marrow biposy:

Immunohistochemistry: Positive: Lysozyme, CD43.

Negative: CD34, CD117, CD30, factor VIII, CD42b, hemoglobin, CD61, TdT, PAX-5, E-cadherin, CD3 and CD5.

Reticulin stain showed marked fibrosis.

Flow cytometry: Less than 1% CD34 positive blasts. The sample was not representative of bone marrow.

Peripheral blood: 497/500 (99%) cells are of donor origin (FISH with the XY probe)

Bone marrow:

419/500 (84%) cells are of donor origin (FISH with the XY probe).

Complex karyotype in the recipient cells showing: 58~83,XX,+X[3],+1,+1[1],+2[6],+2[1],+3,+3[3],+4[5],+4[1],+4[1]+5[5],+5[2],+6[7],+6[3],+7,+7[1],?add(7q36)[2],+8,+8[3],+9[4],+9[2],+10[7],+10[4],+11[6],+11[3],-11[1],+12[1],+13,+14[6],+14[1],-14[1],+15[4],,+15[1],+16[3],+16[2],-16[1], -17[1],+19[7],+19[3],+20[5],+20[1],+21[5],+21[2],+22[6],+22[2],+2~5mar[cp8]

Paraspinous tissue: FISH studies are pending for chimerism and chromosomal abnormalities.

Positive for FLT-ITD in the needle core biopsy and the bone marrow samples.

1: Status post transplant routine surveillance of peripheral blood indices along with engraftment analysis was not useful in the detection of leukemia relapse or engraftment failure.

2: Oncologist and pathologists should have a heightened suspicion of unusual extramedullary relapse of acute leukemia in post transplant settings.

3: The bone marrow cytogenetics at relapse showed normal functioning (and a dominant component) donor derived hematopoiesis leading to normal peripheral blood counts. The neoplastic cells are recipient derived, and show unconventional blast morphology and complex karyotype evolution.

4: Complete loss of lineage specific antigens can pose diagnostic challenges and pitfalls

5: We hypothesize that the paraspinous mass will show exclusive recipient derived neoplastic cell population (FISH studies are pending at this time, and the results will be presented and compared to the marrow at the meeting).

6: Failure of flow cytometry studies to detect the abnormal blasts in the bone marrow, due to the loss of surface antigens by the blasts. The sample submitted to flow cytometry is blood-diluted and hence may not be representative.

Paraspinal mass: Granulocytic sarcoma.

Bone marrow: Post-transplant relapsed acute myeloid leukemia involving extramedullary site and bone marrow with mixed chimerism and apparently sparing the blood with normal CBC

Acute myeloid leukemia with FLT3 ITD mutation, relapse involving bone marrow and paraspinal mass (myeloid sarcoma) after stem cell transplantations

Case 385