Granulocytic Sarcoma with Translocation (9;11)(p22;q23): Two Cases

Granulocytic Sarcoma with Translocation (9;11)(p22;q23): Two Cases N. P. Bown, D. Rowe, and M. M. Reid

ABSTRACT: Granulocytic sarcomas are localized deposits of myeloid leukemia cells that may precede or occur concurrently with disseminated disease. In either event, the origins of the cells comprising the malignancy are the same. Published reports of granulocytic sarcomas have described, in the majority of cases, a morphology typical of AML-M2 and the presence of the t(8;21)(q22;q21) typical of that FAB type. In a smaller number of cases, the inv(16)(p13q22) characteristic of AML-M4 has been recorded in cells with a myelomonocytic appearance. We report two patients with granulocytic sarcomas showing monocytic morphology in which the malignant cells showed t(9;11)(p22;q23) typical of AML-M5. This abnormality is seen in up to 7% of childhood AML, but has not previously been reported in granulocytic sarcoma. The detection of this cytogenetic abnormality facilitated the precise characterization of the malignant cells and selection of the most appropriate therapy, emphasizing the value of cytogenetic analysis in cases of granulocytic sarcoma. © Elsevier Science Inc., 1997

INTRODUCTION Granulocytic sarcomas (chloromas) are localized, extramedullary deposits of myeloid leukemia cells. Common sites for these tumors are the cranial and facial bones, lymph nodes, and skin. The tumor may arise concurrently with chronic granulocytic leukemia (CGL), acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS), or may precede the development of a disseminated leukemia by some months; in the latter situation, misdiagnosis as a lymphoma is possible [1]. Cytogenetic studies of granulocytic sarcomas and their associated leukemias have revealed a high frequency of chromosome translocation (8;21)(q22;q21); 37 cases showing this cytogenetic/histopathologic association were reviewed by Tallman et al [2], who concluded that granulocytic sarcomas may occur in up to 18% of t(8;21) AMLs. An AML-associated change not previously described with this clinical manifestation is t(9;11)(p22;q23), which is encountered in approximately 7% of childhood AML and is very strongly associated with the M5 (monocytic) FAB type [3]. We described two pediatric cases presenting with granulocytic sarcomas in which cytogenetic analysis showed t(9;11) in bone marrow and extramedullary tumor cells.

From the Department of Human Genetics, University of Newcastle upon Tyne (N. B., D. R.) and Department of Haematology, Royal Victoria Infirmary (M. R.), Newcastle upon Tyne, United Kingdom. Address reprint requests to: N. Bown, Department of Human Genetics, University of Newcastle upon Tyne, 19-20 Claremont Place, Newcastle upon Tyne, NE2 4AA, United Kingdom. Received May 16, 1996; accepted August 6, 1996. Cancer Genet Cytogenet 96:115–117 (1997)  Elsevier Science Inc., 1997 655 Avenue of the Americas, New York, NY 10010

The morphology and phenotype of the malignant cells corresponded to the monocytic pattern consistent with the translocation. PATIENT 1 A 2-year-old girl presented with left periorbital swelling and proptosis. Computerized tomography (CT) showed a soft tissue mass occupying most of the left infratemporal fossa, extending to envelope the mandible, infiltrating the left maxillary antrum and the ethmoid bone. A provisional diagnosis of rhabdomyosarcoma was made. Peripheral blood count showed Hb 10.9 g/dL, white cells 13.3 3 109/L with a normal differential count, platelets 301 3 109/L, and no primitive cells on the blood film. Biopsy of the primary tumor showed sheets of round primitive cells with prominent nucleoli, moderate amounts of cytoplasm, high mitotic activity, numerous apoptotic figures, and scattered macrophages. Electron microscopy showed some cells with lysosomal membrane bound packages. A staging bone marrow showed 80% replacement with large primitive cells with prominent cytoplasmic projections or handles, staining strongly positive for nonspecific esterase. Cell surface marking was unhelpful, showing a small number of residual normal T and B lymphocytes and myeloid cells, although 55% of cells expressed HLA-DR. There were no abnormal cells in the cerebrospinal fluid (CSF). Serum lysozyme was 60 mg/ml. A diagnosis of malignant tumor of monocytes/histiocytes was made. Following cytogenetic analysis (see below), a final diagnosis of granulocytic (or monoblastic) sarcoma was made. She was treated as though she had acute monoblastic leukemia with the Med-

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ical Research Council (MRC) AML XII regimen, which included intrathecal cytarabine, methotrexate and hydrocortisone. Both the facial mass and the marrow infiltrate resolved completely. She remains in clinical and hematologic remission 18 months after presentation. PATIENT 2 A 4 1/2-year-old boy presented wtih malaise, cough, and shortness of breath. He had bilateral pleural and pericardial effusions, areas of pleural thickening, a mediastinal nodal mass, and an enlarged supraclavicular node. Peripheral blood count showed Hb 13 g/dL, white cells 15 3 109/L with a neutrophil leucocytosis but no primitive cells on the blood film, and platelets 535 3 109/L. Aspirated pleural fluid contained 23 3 109/L of white cells, 90% of which were large primitive monoblastic cells with many cytoplasmic projections, staining strongly for nonspecific esterase. Cell surface marking showed that the primitive cells expressed HLA-DR and CD33 but no other lymphoid or myeloid markers. Serum lysozymes was 100 mg/ml. A staging bone marrow showed normal hemopoiesis with a 10 to 20% infiltrate of primitive cells identical to those in the pleural fluid. Results of the cytogenetic analysis are shown below. A diagnosis was made of granulocytic (or monoblastic) sarcoma with marrow infiltration. He was treated according to the MRC AML XII protocol and at the time of writing, 4 months after diagnosis, there has been complete resolution of the effusions and of the pleural thickening and mediastinal nodal mass. The bone marrow shows chemotherapy-induced hypoplasia but no primitive cells remain. MATERIALS AND METHODS Bone marrows from both cases were cultured for cytogenetics according to standard protocols, and metaphase cells

Figure 1 Representative chromosomes 9 and 11 from both cases, showing translocation (9;11)(p22;q23).

were G-banded by trypsin and Leishmans stain. A biopsy of the tumor from case 1 was disaggregated and then cultured according to the bone marrow protocol, with overnight exposure to 0.01 mg/ml colcemid. A pleural fluid sample from case 2 was cultured overnight in the same way. RESULTS In both cases, bone marrow showed a mixture of karyotypically normal cells, and cells showing a t(9;11)(p22;q23) (Fig. 1). In case 1, nine fully analyzed bone marrow metaphases showed a 46,XX,t(9;11)(p22;q23) karyotype, whereas a single cell showed a normal 46,XX karyotype. Tumor metaphases were of poor quality, but the presence of the translocation

Table 1 Cytogenetic abnormalities other than t(8;21) reported in granulocytic sarcomas (GS) or in associated bone marrows Diagnosis Eosinophilic leukemia and GS Breast GS Two cases of GS with AMMoL GS preceding AMMoL GS GS GS Ovarian GS with AML-M2 Bilateral orbito-ocular GS with AML AML with GSa GS preceding CML GSa GS preceding AML-M2 Two cases of CML in chronic phase with neurological GS GS as extramedullary transformation of CML Two cases of ovarian GS with AMML Eosinophilic BM with concurrent GS a

These two references appear to describe the same case.

Chromosome change

Reference (no.)

del(16q),18,114 in bone marrow cells Trisomy 22 in AML-M2 cells inv (16) (p13q22) inv(16) in AMMoL Ph1 cells in ascites t(1;7)(q11;q11) t(12;13)(p12;q12) in bone marrow Trisomy 22 Hyperdiploidy (60-63) with trisomy 21 and double Ph in bone marrow t(X;1)(q23;q28),inv(3)(p21p27),t(12;22)(p11;q11-12) t(1;12)(p36;p13),t(9;22)(q34;q11),120 inv(3)(p21q27),inv(9)(p13q22),t(12;22)(p11;q11) in bone marrow, t(X;1)(q28;q22) in GS del(9)(q13q22) in bone marrow Ph 1 in bone marrow

Goh et al. (4) Turpin et al. (5) Glass et al. (6) Russell et al. (7) Elghetany and Banez (8) Raman et al. (9) Adam et al. (10) Avigdor et al. (11) Cavdar et al. (12)

Ph 1 CML. GS cells: idem,1Y,18,119,121 inv(16)(p13q22) t(3;4)(p13;q12) in bone marrow; idem,18 in GS

Van Dijken et al. (18) Drinkard et al. (19) Myint (20)

Ouchiha et al. (13) Vassollo et al. (14) Heimann et al. (15) Lunde and Allen (16) Mahendra et al. (17)

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was confirmed in ten cells. In case 2, all twenty metaphases from cultures of the pleural fluid showed 46,XX,t(9;11) (p22;q23), whereas the translocation was present in eighteen of thirty cells from concurrent bone marrow cultures; the remaining twelve cells showed a normal 46,XY karyotype.

3. Sandoval C, Head DR, Mirro J, Behm FG, Ayers GD, Raimondi SC (1992): Translocation t(9;11)(p21;q23) in pediatric de novo and secondary acute myeloid leukemia. Leukemia 6:513–519.

DISCUSSION

4. Goh KO, Ho FSC, Tso SC, Ma J (1984): Is hypereosinophilic syndrome a malignant disease? Cancer 55:2395–2399.

In both of these children, but particularly in case 2, the clinical presentation suggested an extramedullary origin of the monoblastic tumors. In other forms of AML and in CGL and MDS, such extramedullary masses are usually, and appropriately, called granulocytic sarcomas. This is, however, a rather inapt term for those tumors with no granulocytic element, as in both of these cases. Where the tumor cells are in effect AML blasts, the diagnosis of granulocytic sarcoma or AML is largely a semantic distinction because many centers will elect to treat such patients as though they had AML. The initial response to such treatment in our cases is encouraging. In both children, cytologic preparations could be obtained that facilitated the emergence of a correct diagnosis. This is not always the case with localized extramedullary tumors. In both cases, however, chromosome analysis provided compelling evidence of the nature of the tumor, indeed, had there not been extensive marrow involvement in case 1, the t(9;11) would have been the most powerful evidence to refute the original clinical diagnosis of rhabdomyosarcoma. In both cases, the karyotype abnormality also excluded a diagnosis of lymphoma. We have reviewed published karyotype findings other than t(8;21) in granulocytic sarcoma (Table 1). This shows that the second most frequent finding is pericentric inversion of chromosome 16, this change is associated predominantly with M4-AML (AMMoL), although it is also occasionally seen in M2; it is not surprising therefore, that the five reported cases of granulocytic sarcoma associated with inv(16) occurred in conjunction with or preceded AMMoL. Other leukemia-associated chromosome changes found in granulocytic sarcoma cases include unbalanced t(1;7), interstitial del(9q), and the Philadelphia translocation, t(9;22). Translocation (9;11)(p22;q23) has not previously been recorded in granulocytic sarcoma. These two cases add to the range of documented karyotype abnormalities associated with granulocytic sarcoma. Cytogenetic analysis is important in cases of localized extramedullary hemopoietic tumors because the finding of a chromosome change associated with AML, CML, or MDS establishes a precise diagnosis of granulocytic sarcoma and allows selection of appropriate therapy. The close correlation between morphologic and karyotypic features, and the encouraging early responses to specific treatment reinforce our view that cytogenetic analysis of extramedullary tumor should be routinely performed when a diagnosis of granulocytic sarcoma is being considered. REFERENCES 1. Neiman RS, Barcos M, Berard C, Bonner H, Mann R, Rydell RE, Bennett JM (1981): Granulocytic sarcoma: A clinicopathologic study of 61 biopsied cases. Cancer 48:1426–1437. 2. Tallman MS, Hakimian D, Shaw JM, Lissner GS, Russell EJ,

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