—  SPECIALTY CONFERENCE  —

Cytopathology

Case 7 - Extramedullary Blast Phase in Chronic Myelogenous Leukemia.

Dr. Ann T. Moriarty
Ameripath Indiana
Indianapolis, Indiana


Click on each slide thumbnail image for an enlarged view
Clinical History:
The patient is a 42 year old male who presented with a painful right mandible and submandibular area. He had a firm, fixed, "woody" infiltration of the skin and soft tissue overlying the entire right mandible. A CT scan of the mandible demonstrated a 4.4 x 1.8 cm mass extending along the lingual aspect of the anterior right hemi-mandible, without direct osseous extension. There was enlargement of the right mental foramen and inferior alveolar nerve.(Image 7A) There were also two enlarged lymph nodes, one in the submental triangle and one high in the superior cervical chain. The patient denied fevers, weight loss, night sweats or other adenopathy. A fine needle biopsy was performed. (Images 7A-7D)

Cytologic Findings:
The smears were cellular and are composed of single cells. There are small lymphocytes in the background and a second population of intermediate sized cells. (Image 7B). The intermediate sized lymphocytes have delicate chromatin and inconspicuous nucleoli. Lymphoglandular bodies are evident in the background. (Image 7C, 7D)


Figure 7B - The smears are cellular and are composed of single cells. There is a background of small lymphocytes and a second population of cells that are "intermediate" in size and have nuclei approximately the same size as histiocyte nuclei. They have scant cytoplasm. (Romanowsky stain, high power)
Figure 7C - In a thinner portion of the smear, background lymphoglandular bodies are seen. The delicate blast like chromatin pattern is noted in the intermediate sized cells. Nucleoli are inconspicuous. (Romanowsky stain, high power)
Figure 7D - The Papanicolaou stained smears demonstrate delicate chromatin pattern. Nucleoli are inconspicuous, and there is little cytoplasm. (Papanicolaou stain, high power)

Discussion: Extramedullary blast phase in chronic myelogenous leukemia.
The cytologic findings lead to the differential diagnosis of abnormalities of "intermediate size" lymphocytes. This includes: precursor T cell lymphoma, precursor B cell lymphoma, Burkitt lymphoma and myeloid sarcoma (extramedullary acute myelogenous leukemia.) Other entities to consider would be peripheral B or T cell lymphoma composed of large cells. Small round blue cell tumors such as rhabdomyosarcoma or Ewing's/PNET could also be considered in this case because of the dispersed single cells and the age of the patient and the site of presentation.

Flow cytometric analysis was performed on the needle rinses. Using forward versus side scatter and CD45 versus side scatter, a population of cells was identified that dimly expressed CD45, in a "blast" distribution. The cells fall into an intermediate cell size on the forward versus side scatter, corresponding to the morphologic appearance. The cells expressed dim CD45, CD34, CD19, CD10, and TdT. Conspicuously absent are CD20 and light chain expression.

Flow Cytometry Analysis of Case 7:


Differential Diagnosis:
The morphologic differential diagnosis includes Burkitt lymphoma, which is characterized by intermediate sized cells. The cells usually have abundant deep blue cytoplasm with vacuoles, best seen on Romanowsky stained preparation. They have coarse chromatin and multiple small nucleoli or chromocenters. Burkitt lymphoma usually demonstrates bright CD45 intensity, bright light chain intensity, CD19, CD20, CD22 and dim CD10 expression. Their immunophenotype is of peripheral B cell type. All cases have MYC translocation, either t(8;14), t(8;11)or t(8;22). Although the endemic form of African Burkitt lymphoma is associated with jaw and face involvement in 50% of cases, the sporadic cases seen in the United States are associated with the gastrointestinal tract and abdomen. Jaw presentation on the sporadic US form of Burkitt lymphoma is rare. Burkitt lymphoma is highly aggressive, but may be curable. Immediate aggressive chemotherapy is desirable. Relapses usually occur within the first year of diagnosis. After two years of remission, Burkitt lymphoma is considered "cured."1

Precursor T cell lymphoblastic lymphoma is more common than its precursor B cell counterpart. Morphologically the two are indistinguishable. Both are a malignant lymphoma that is identical in cell type to acute lymphoblastic leukemia. Precursor T cell lymphoblastic lymphoma is a disease of adolescent males. The immunophenotype of precursor T cell lymphoblastic lymphoma recapitulates thymocyte differentiation. CD2, CD5, CD7, CD1a, co-expression of CD4 and CD8, and TdT expression are often seen in T cell lymphoblastic lymphoma.2 The immunophenotyping studies in this case do not indicate a T cell process.

Myeloid sarcoma (extramedullary acute myeloid leukemia) is a tumor of myeloblasts or immature myeloid cells occurring outside of the marrow either concurrently or preceding acute myeloid leukemia. Myeloid sarcoma may be the initial site of acute leukemia relapse. Myeloid sarcomas occur in subperiosteal locations in the skull, paranasal sinuses, sternum, ribs and vertebrae. Lymph node and skin are also sites of involvement by myeloid sarcoma. Flow cytometry studies demonstrate myeloid differentiation (CD33, CD13, cytoplasmic myeloperoxidase) or monocytic differentiation (CD14, CD11c, CD61). Immunocytochemical stains for myeloperoxidase, CD68, and lysozyme may be helpful in identifying myeloid sarcoma.3

Large cell lymphoma is a morphologic descriptor, not a diagnostic entity. As cytologists, we are usually able to identify that the cells are abnormal, and larger than small lymphocytes.4 Further classification usually requires ancillary immunological and (sometimes) chromosomal studies.

The WHO classification separates lymphocytic disorders into two large subgroups, 1) B cell neoplasms and 2) T cell/Natural Killer (NK) cell neoplasms.5 The flow cytometric findings in this case demonstrate a B cell neoplasm. Unlike large B cell lymphomas, the scatter characteristics of case 7 are those of smaller cells, and CD45 intensity is lower than large cell lymphoma. Although large B cell lymphoma may not express light chains, they tend to express CD20.

Small round blue cell tumors, such as rhabdomyosarcoma may mimic lymphoma, because of smears with dispersed single cells. However, these neoplasms do not react with B cell antibodies on flow cytometric analysis. Ancillary immunocytochemical tests and cytogenetic studies are essential for the diagnosis.6 (See table below.)

Small Round Blue Cell Tumors:
Tumor Age (mean) Chromosome Desmin MSA CD99 MyoD/ Myogenin Epithelial
Alveolar Rhabdomyosarcoma 9 2 and 13 PAX3(FKHR) PAX7(FKHR) + + rare (weak) + -*
Embryonal Rhabdomyosarcoma 7 Loss of 11, changes in 8,20,2 + + - + -*
Ewings/PNET 20 q12 chrom 22 (EWS) rare - + - scattered
Desmoplastic Small Round Cell Tumor (DSRCT) 22 t(11;22) (p13;q12) + - - - +
Neuroblastoma** 2 No consistent change _   - - -

* Epithelial markers are positive in less than 10% of cases
**Neuroblastoma associated with NSE positivity and serologic increase in catecholamines

Additional information:
The patient was referred to a hematologist/oncologist. Prior to his initial visit to the hematologist, a complete blood cell count was obtained. At that time, the white cell count was 83,100/uL, hemoglobin was 13 g/dL, and platelets were 329,000/ul. The differential was 22% segmented neutrophils, 42% bands, 8% lymphocytes, 1% monocytes, 2% eosinophils, 4% basophils, 4% metamyelocytes, 17% myelocytes and 1% promyelocytes. A bone marrow aspirate and core biopsy demonstrated 100% cellularity with panmyelosis and 40% blasts. The blasts demonstrated the same immunophenotype as those seen in the jaw aspirate. Cytogenetic studies were obtained and demonstrated the Philadelphia chromosome (t(9;22)(q34;q11).

This is a case of extramedullary blast phase in chronic myelogenous leukemia (CML-BP) of lymphoblastic type. Lymphoblastic blast crisis of CML occurs in approximately 20-30% of all CML-BP. It usually demonstrates the immunophenotype of precursor B cell lymphoblastic lymphoma or leukemia (CD19+/CD34+/ CD10+/TdT+). Patients with lymphoid blast crises usually have abrupt onset of their blast crisis, with "limited" organ involvement, mild blood basophilia, and usually respond better to chemotherapy.7 This patient responded rapidly to an acute lymphoblastic regimen, and is currently awaiting bone marrow transplantation.

References

  1. Diebold J, Jaffe ES, Raphael M, Warneke RA. " Burkitt Lymphoma." In Jaffe ES, Harris NL, Stein H, Vardiman JW (eds.) Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer (IARC) Press
  2. Lyon, 2001
  3. Leith CP, CareyJ. "Flow Cytometric Analysis of Acute Leukemias." In Keren DF, McCoy JP, Carey JL(eds). Flow Cytometry in Clinical Diagnosis (3rd ed).ASCP Press: Chicago 2001
  4. Brunning RD, Matutes E, Flandrin G, Vardiman J,Bennett J, Head D, Harris NL." Acute myeloid Leukemia , not otherwise categorized." In Jaffe ES, Harris NL, Stein H, Vardiman JW (eds.). Pathology and Genetics of Tumours of Haematopoietic andLymphoid Tissues. International Agency for Research on Cancer (IARC) Press
  5. Lyon, 2001
  6. Young NA, Al-Saleem T. Diagnosis of lymphoma by fine-needle aspiration cytology using the Revised European-American classification of lymphoid neoplasms. Cancer(Cytopathol) 1999;87:325-45.
  7. Isaacson PG. The current status of lymphoma classification. Br J Haematol 2000;109:258-266
  8. Kempson Rl, Fletcher CD, Evans HL, Hendrickson MR, Sibley RK. Tumors of the Soft Tissues. Atlas of Tumor Pathology Series, no 30, third series. AFIP: Washington DC, 2001.
  9. Cervantes F, Villamor N, Montoto, S, Rives S, Rozman C, Montserrat E. "Lymphoid " blast crisis of chronic myeloid leukemia with distinct clinicohaematological features. Br J Haematol 1998
  10. 100:123-128.