Cauda equina syndrome in a 65-year-old man, status post-bone marrow transplant for chronic myeloid leukemia. (Pathologic Quiz Case).

A 65-year-old man with a history of chronic myeloid leukemia (CML) presented with fatigue, a 9-kg weight loss, and increasing low back and buttock pain. He had received an allogeneic stem cell transplant 11 months previously. His medications on admission included cyclosporine and prednisone.

On arrival, he noted difficulty initiating urination and complained of the inability to completely void. Presenting vital signs were normal except for temperature up to 39.4 [degrees] C. Back and extremity examination revealed exquisite tenderness over the lumbosacral spine and associated leg pain with straight leg testing. Motor examination revealed 4/5 normal strength of the hip flexors. Sensation to light touch and vibration was absent below the ankles bilaterally, and reflexes were diminished or absent at the knees and ankles. Laboratory data revealed a white blood cell count of 9700/[micro]L, hematocrit of 0.29, and platelet count of 126 000/[micro]L. The patient's lactate dehydrogenase level was elevated at 966 U/L. The peripheral blood was unremarkable except for the presence of rare metamyelocytes. Chimerism studies performed on the peripheral blood showed 100% donor cells. Magnetic resonance imaging of the spine revealed patchy diffuse replacement of vertebral bodies throughout the cervical, thoracic, and lumbar spine. Multiple epidural masses were noted in the lumbar spine, most prominent at L4-S1, with severe spinal canal stenosis at all levels (Figure 1).

[FIGURE 1 OMITTED]

A bone marrow biopsy and aspirate were performed. The aspirate showed malignant cells characterized by moderate to abundant basophilic vacuolated cytoplasm, round to irregular nuclei, dispersed chromatin, and prominent macronucleoli. Many of the malignant cells had 2 or more nuclei (Figure 2). The biopsy showed single and large aggregates of malignant cells (Figure 3). The cells were immunoreactive for CD34 (Figure 4) and CD43 (Leu-22), but were negative for CD20 (L26), the latent membrane protein (LMP-1) of Epstein-Barr virus, CD45RB (leukocyte common antigen), CD45RO (UCHL-1), CD3, pan-cytokeratin, CD30 (Ber-H2), factor VIII, CD68 (KP-1), and hemoglobin peroxidase. Rare malignant cells were immunoreactive for myeloperoxidase and lysozyme.

[FIGURES 2-4 OMITTED]

What is your diagnosis?

Extramedullary myeloid tumor is conventionally considered to represent the first manifestation of systemic relapse after bone marrow transplant (BMT) in patients with CML in clinical remission. (1) Extramedullary myeloid tumor has a broad spectrum of clinical characteristics at presentation, reflecting involvement of the various organs. This malignancy commonly presents in the skin and is also described in the thoracic cavity, stomach, bladder, orbit, base of the skull, limbs, and spinal canal. (1) Isolated extramedullary relapse after BMT for CML is rare and occurs in only 0.21% of BMT recipients. (2,3) The majority of patients who relapse following BMT for chronic-phase CML show the features of chronic phase at presentation (3,4); however, rare post-BMT patients relapse in blast crisis. (3,4) This case represents an example of simultaneous extramedullary and intramedullary CML blast crisis following transplant.

The unusual presentation of this case also raised the possibility of posttransplantation lymphoproliferative disorder (PTLD). Posttransplantation lymphoproliferative disorder affects approximately 0.6% of patients who undergo BMT and presents at a variable intervals following transplantation. (5) Most cases of PTLD are B-cell malignancies, although T-cell malignancies are also described. (6) Patients on regimens utilizing cyclosporine (as in this case) may present with PTLD within 1 month after BMT, but PTLD tends to occur later in older BMT patients (mean age 48 years). (5) Central nervous system disease is not usually found in patients on protocols using cyclosporine. Inclusion of this drug in the treatment regimen usually restricts involvement of the central nervous system to patients with advanced stage disease. (5) Posttransplantation lymphoproliferative disorder was excluded in this case using immunohistochemical studies. The malignant cells were negative for markers of B-cell differentiation (CD20 and CD79a) and T-cell differentiation (CD3 and CD45RO), and expressed markers associated with immature myeloid cells (CD34, CD43, myeloperoxidase, and lysozyme). The cells also failed to demonstrate immunoreactivity for LMP-1 of Epstein-Barr virus. It is important to note that immunoreactivity for Epstein-Barr virus is helpful in establishing a diagnosis of PTLD, but a negative study does not exclude the presence of PTLD. (5) Flow cytometry in this case was nondiagnostic and demonstrated only reactive T cells. Possible explanations for these findings include malignant cells falling outside the gates normally utilized for flow cytometry analysis and/or loss of malignant cells during processing.

Other malignancies considered in the differential diagnosis included anaplastic large cell lymphoma and poorly differentiated carcinoma. These malignancies were excluded by lack of immunoreactivity for CD3 and CD30, and pan-cytokeratin, respectively.

The immature appearance of the malignant cells in concert with the finding of strong immunoreactivity for CD34 and CD43 supported the diagnosis of CML in myeloid blast crisis that had not peripheralized. The cellular morphology suggested possible erythroid differentiation, however a hemoglobin peroxidase study was negative. The diagnosis was later corroborated by chromosomal analysis, which demonstrated the BCR-ABL protein, associated with the Philadelphia chromosome. Chimeric studies on the patient's bone marrow showed 45% donor and 55% recipient bone marrow cells, in contrast to a study a few months earlier that demonstrated 100% donor cells.

We thank Joe Brady from Medical Photography and David R. DeLone, MD, from the Department of Neuroradiology, Wilford Hall Medical Center, Lackland AFB, Tex, for their expert assistance.

References

(1.) Bekassy AN, Hermans J, Gorin NC, Gratwohl A, for the Acute and Chronic Leukemia Working Parties of the European Group for Blood and Marrow Transplantation. Granulocytic sarcoma after bone marrow transplantation: a retrospective European multicenter survey. Bone Marrow Transplant. 1996;17:801-808.

(2.) Au WY, Chan AL, Lie AW, So JC, Liang R, Kwong KL. Isolated extramedullary relapse after allogeneic bone marrow transplantation for chronic myeloid leukemia. Bone Marrow Transplant. 1998;22:99-102.

(3.) Thomas ED, Clift RA, Fefer A, et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med. 1986;104:155-163.

(4.) Cullis DI, Marks AP, Schwarer AJ, et al. Relapse into blast crisis following bone marrow transplantation for chronic myeloid leukaemia: a report of five cases. Br J Haematol. 1992;81:378-382.

(5.) Craig FE, Gulley ML, Banks PM. Posttransplant lymphoproliferative disorders. Am J Clin Pathol. 1993;3:265-276.

(6.) Hanson MN, Morrison VA, Peterson BA, et al. Posttransplant T-cell lympho-proliferative disorders: an aggressive, late complication of solid-organ transplantation. Blood. 1996;9:3626-3633.

Accepted for publication January 26, 2001.

From the Departments of Pathology (Drs Dalton and Neuhauser) and Hematology/Oncology (Dr Ririe), Wilford Hall Medical Center, Lackland AFB, Tex; and the Department of Pathology, Brooke Army Medical Center, Ft Sam Houston, Tex (Dr Dalton).

Reprints not available from the authors.