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Infant with Granulocytic Sarcoma of the Ovary: An Unusual Case Presentation of Acute Myelogenous Leukemia (M6)
Case Report Infant with Granulocytic Sarcoma of the Ovary: An Unusual Case Presentation of Acute Myelogenous Leukemia (M6) Mukta Kumar,1 Masayo Watanabe,2 Vivekanand Singh,2 Linda D. Cooley2 Abstract Clinical presentation of acute myelogenous leukemia (AML) in infants as an ovarian tumor is extremely rare, although AML is well reported in older children and adults. Granulocytic sarcoma or chloroma is an extramedullary tumor seen in AML and myeloid and myeloproliferative disorders. We report a case of a 5-month-old female infant who presented with bilateral ovarian masses. Based on a left oophorectomy and bone marrow evaluation, the patient was diagnosed with bilateral ovarian granulocytic sarcoma and erythroleukemia (French-American-British type M6 AML). Our patient has unusual cytogenetics involving rearrangements of chromosomes 1, 11, and 16. The patient has received chemotherapy and is alive at 2 years from the diagnosis. Clinical Leukemia, Vol. 1, No. 4, 247-250, 2007 Key words: Chloroma, Extramedullary leukemia, Mixed-lineage leukemia, Radiation therapy
Introduction Granulocytic sarcoma (GS) or chloroma is an extramedullary myeloid cell tumor composed of immature myeloid cells.1 Granulocytic sarcoma was introduced by Rappaport et al initially to describe only tumorous masses associated with cells of the granulocytic series.2 Despite this intended limited definition, the term “GS” has been expanded in the recent literature to include any tumorous mass related to any form of myeloid leukemia or myelodysplastic syndrome. As a result of this confusing nomenclature, Davey et al proposed the term “extramedullary myeloid leukemia” (EML), which encompassed all forms of extrameningeal, nonmedullary leukemic infiltrates.3 Herein, we report a rare case of bilateral ovarian GS as the presenting manifestation of acute erythroleukemia in an infant with unique cytogenetics involving rearrangements of chromosomes 1, 11, and 16.
Case Report A 5-month-old, white female infant was referred to our institution by her primary care physician for evaluation of vomiting and palpable abdominal mass. Abdominal ultrasonography confirmed lower abdominal and pelvic masses. Physical examination revealed easily palpable masses on both sides of the umbilicus. Initial evaluation showed pancytopenia with white blood cell count 4.2 s 103/μL, hemoglobin 4.7 g/dL, platelet count 59 s 103/μL, and absolute neutrophil count 0.8 s 103/μL. Lactate dehydrogenase was elevated at 5310 U/L. Initial computed tomography scan of abdomen showed 2 large, distinct masses arising from the pelvis with cystic and necrotic components. Chest computed tomography scan revealed a 9-mm, soft-tissue density in the region of the right azygoesophageal recess with the possibility of a lymph node, although intraparenchymal location could not be excluded. The patient was taken to surgery for pelvic mass, which was possibly neuroblastoma or a round blue-cell tumor; there were concerns about metastases to lung and bone marrow (BM). Exploratory laparotomy revealed large bilateral ovarian 1Departments 2Department
of Hematology/Oncology, Children’s Mercy Hospital, Kansas City, MO of Pathology, Phoenix Children’s Hospital, AZ
Submitted: May 2, 2007; Revised: June 25, 2007; Accepted: June 26, 2007 Address for correspondence: Mukta Kumar, MD, MPH, Department of Pediatric Hematology/Oncology, Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, MO 64108 Fax: 913-588-6319; e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Leukemia • June 2007
247
Infant with Ovarian GS: An Unusual Case Report of AML (M6)
Figure 1
Macroscopic Appearance of the Ovarian Mass
A
B
C
(A) Touch imprints of the ovarian mass showing tumor cells with large nucleus and a rim of blue, scanty cytoplasm. (Diff-Quik stain; original magnification ×400). (B) Sheets of tumor cells with increased mitoses and apoptotic cells replacing ovarian architecture (hematoxylin and eosin stain; original magnification ×200). (C) Tumor cells with the cytoplasm showing positive immunostain for hemoglobin (original magnification ×200).
masses with no visible normal ovarian tissue and no evidence of torsion. The left ovarian capsule was ruptured, and there was intraperitoneal blood present. A unilateral, left oophorectomy was performed. The left ovarian tumor was an ellipsoidal mass that measured 6 cm s 5 cm s 3 cm with irregular outer surface. Its cut surface presented a solid, red-brown, beefy appearance with a rare focus of hemorrhage and a solitary cystic area. A frozen section of the ovarian mass appeared to be a malignant neoplasm, although a definitive diagnosis was rendered only on the permanent sections. Bilateral BM aspirates and biopsies were done simultaneously with the oophorectomy for purposes of solid tumor staging. Microscopically, the mass showed effacement of ovarian architecture by sheets of round blue cells (Figure 1A) with areas of alveolar and trabecular pattern. The tumor cells had a
Figure 2
Karyogram of Tumor Cells
1
6
2
7
3
8
13
14
19
20
4
9
15
21
5
10
16
22
11
12
17
18
X
Y
Karyotype written in long-form International System for Human Cytogenetic Nomenclature 1995 nomenclature: 46,XX,der(1)t(1;11)(1qter->1p32::11q23->11q13:),der(11)t(1;11)(1pter->1p35::11p15>11q12::11q23->11qter),der(16)t(1;16)(16pter->16q24::1?q32->1?q43)[19] The arrows point to derivative chromosomes.
248
minimal amount of cytoplasm and large nuclei with variably sized nucleoli (Figure 1B). There were scattered foci of necrosis as well as numerous mitotic figures and apoptotic bodies. Immunohistochemical stains demonstrated the tumor cells to be positive for hemoglobin (Figure 1C) and epithelial membrane antigen. Markers (cytokeratins [wide spectrum and AE1/AE3], vimentin, desmin, myogenin, MYOD1, CD45, CD30, CD68, Alk-1, NSE, NB84, WT-1, A-fetoprotein, and TdT to work up round blue-cell tumors) were negative. An enzyme histochemical stain for myeloperoxidase was negative. Periodic acid-Schiff staining showed strong positivity that was abolished by diastase treatment. Flow cytometry showed expression of CD71 and glycophorin A with negative lymphoid, monocytic, and megakaryocytic markers (CD13, CD33, CD34, CD45, CD61, and myeloperoxidase). Electron microscopic study revealed hematopoietic blast cell morphology. These results indicated the diagnosis of leukemic infiltration (GS) of the ovary by acute erythroid leukemia. Bone marrow examination showed high cellularity with 42% blasts. Few maturing erythroid precursors were identified. Flow cytometric analysis of the BM aspirate showed similar immunophenotypic expression as ovarian tumor cells consistent with the diagnosis of acute myelogenous leukemia (AML)–M6. Cytogenetic analysis demonstrated a complex rearrangement of chromosomes 1, 11, and 16 (Figure 2). Fluorescent in situ hybridization analysis of metaphase cells and interphase nuclei using the Vysis DNA probe for the mixed-lineage leukemia (11q23) gene showed the mixed-lineage leukemia gene moved from chromosome 11 to the short arm of chromosome 1 (Figure 3A). The mixedlineage leukemia gene signal localizes next to the chromosome 1 breakpoint, indicating the translocated segment of chromosome 11 that is inverted. The mixed-lineage leukemia gene was not rearranged by this move and only relocated along with other chromosome 11q material: fluorescent in situ hybridization analysis using the Cytocell OctoChrome whole chromosome paint probes confirmed movement of 11q to 1p, 1p to 11p, and an unidentified piece of chromosome 1 material to 16q (Figures 3B-3D).
Clinical Leukemia • June 2007
Mukta Kumar et al
Figure 3 A
Fluorescence in Situ Hybridization of Tumor Cells B
C
D
Images by fluorescence in situ hybridization. (A) The MLL probe is not rearranged and is located on the normal chromosome 11 and on chromosome 1 (arrow). The location of the MLL probe signal on chromosome 1 indicates that the distal 11q23 region is more proximal in the derivative chromosome 1 than is expected for a direct translocation; this indicates the segment of chromosome 11q that is inverted. (B) and (C) show chromosome 1 material as red, chromosome 16 as aqua, and chromosome 19 as green. Chromosome 1 material appears on the normal chromosome 1, the abnormal chromosome 1 (long arrow), which is not completely painted, chromosome 16 (aqua plus red chromosome), and chromosome 11 (short arrow). (D) Chromosome 9 is red, chromosome 11 is aqua, and chromosome 22 is green. Chromosome 11 material appears on the normal chromosome 11, the abnormal chromosome 11 (short arrow), and chromosome 1 (long arrow).
Bone scan and spinal fluid examination were normal. The patient recovered uneventfully from surgery and tolerated well 5 cycles of chemotherapy (weight-based because of her age) per Children’s Oncology Group protocol AAML03P1, a pilot study designed for treatment of newly diagnosed childhood AML using intensive Medical Research Council (in the United Kingdom)–based therapy and gemtuzumab ozogamicin (GMTZ). All children with previously untreated primary AML or isolated GS were eligible for this study. For induction I, patients receive high-dose cytarabine intravenously (I.V.) on days 1-10; daunorubicin I.V. on days 1, 3, and 5; etoposide I.V. days 1-5; and GMTZ on day 6. Patients with central nervous system (CNS)–negative disease receive cytarabine intrathecally on day 1. Induction II involves cytarabine I.V. on days 1-8, cytarabine intrathecally on day 1, and daunorubicin and etoposide. In intensification course I, patients receive cytarabine I.V. on days 1-5; cytarabine intrathecally; and etoposide. Patients with a 5/6 or 6/6 matched family donor proceed to allogeneic BM transplantation. All other patients in complete remission proceed to intensification course II, which entails cytarabine I.V. on days 1-4; cytarabine intrathecally; mitoxantrone I.V. on days 3-6; and GMTZ I.V. on day 7. For the last course, intensification course III, patients receive cytarabine I.V. on days 1, 2, 8, and 9 and asparaginase intramuscularly on days 2 and 9. The patient was in remission on day 28 after her first round of chemotherapy and is alive with no evidence of disease > 2 years from diagnosis. She did not receive radiation therapy (RT) or a transplant. The patient only had an episode of infectious complication of Staphylococcal cellulitis followed by Clostridium difficile infection, which were adequately treated by antibiotics.
Discussion Granulocytic sarcoma or EML is a rare extramedullary tumor composed of myeloid progenitor cells. These occur most often in bone such as the skull, sternum, and ribs, and in soft tissues around the dura, nasal sinuses, and orbit. Lymph nodes and skin are additional common sites.4 Our patient was unusual in presentation because she is an infant with AML presenting with bilateral ovarian GSs with French-
American-British M6 morphology and interesting cytogenetic findings. Extramedullary myeloid leukemia is well described in infants, and ovarian EML is well described in older children and adults; however, no case has been previously reported of an infant with erytholeukemia and ovarian GS as an EML site. There is only 1 case report of AML presenting as ovarian GS in an infant in literature, which was myelomonocytic in origin and the most common type of infant AML (M4 and M5 subtype).5 The cytogenetic findings in this case are unique. The genes involved by the rearrangements of chromosomes 1, 11, and 16 in this case are unknown. Review of reports of GS and EML indicates that the chromosome abnormalities most often associated with these manifestations of leukemia are t(8;21) and inv(16) and rarely rearrangements of 11q23. Our case, which involves rearrangement of the 11q23 region, did not result in rearrangement of the MLL gene as reported in a few cases. Erythroleukemia is often represented by a complex karyotype, but there is no diagnostic chromosome abnormality. Adult erythroleukemia is often found to have abnormalities of chromosomes 5 and 7. Only nonrecurrent chromosome abnormality has been identified in infants and children with erythroleukemia. Extramedullary myeloid leukemia can occur as an isolated lesion in the ovaries without a concomitant leukemia.6-9 In such cases, it presents a diagnostic dilemma for the clinician and the pathologist. However, in our case, the presence of a concomitant leukemic picture was helpful in ascertaining the diagnosis of GS. In pediatric patients, GS can masquerade as a small, round, bluecell neoplasm, frequently leading to misdiagnosis. Differential consists of neuroblastoma, desmoplastic small, round, blue-cell tumor, Wilms’ tumor, primitive neuroectodermal tumor, rhabdomyosarcoma, and lymphoma. Acute myelogenous lymphoma accounts for 6%-14% of all leukemias diagnosed in the first 12 months of life.10,11 An increased maternal consumption of DNA topoisomerase II inhibitor–containing foods have been related to an increased risk of infant AML.12,13 Infant AML is characterized by myelomonoblastic or monoblastic morphology, a high percentage of CNS involvement, and a high leukocyte count. ALL1/MLL/HRX gene arrangements are found in approximately 60% of infant AML cases.11
Clinical Leukemia • June 2007
249
Infant with Ovarian GS: An Unusual Case Report of AML (M6) The high incidence of EML in infants (52%) differs markedly from the much lower incidence of EML or chloromas in older children (2%-13%).14 The most common sites of involvement in children are skin and orbit. Patients with infantile leukemia are predisposed to a higher incidence of isolated CNS/EML relapses compared with older children. Although the overall prognosis for infants is poor, EML does not portend a worse prognosis, with the exception of skin EML.15 Factors that predispose to EML in AML have been proposed to be presence of t(8;21)(q22:q22) and inv(16) chromosomal abnormalities, increased blast differentiation capacity, blast expression of CD56 and T-cell markers, and FrenchAmerican-British M4 and M5.16 The role of RT to EML in patients with AML in preventing extramedullary relapse, seeding from the area of extramedullary disease to marrow (causing marrow relapse), or the optimal dose of radiation is not well defined. Dusenbery et al found no difference in 5-year event-free survival of 42 children with EML who had RT compared with 76 patients who did not (43% vs. 41%, respectively; P = 0.68)15; however, RT alone to treat patients with isolated GS is insufficient. All of these patients eventually develop overt AML. Therefore, standard practice involves combination chemotherapy at a minimum. After successful induction therapy in infants with AML in Medical Research Council trials, relapse was also less common (5-year relapsefree survival, 29% vs. 40% for children aged > 10 years), and there were no differences in deaths in remission, resulting in better diseasefree survival (5-year disease-free survival, 69% vs. 52% for children aged > 10 years) and overall survival (5-year overall survival, 64% vs. 56% for children aged > 10 years).17 Although intensive chemotherapy and/or allogeneic transplantation are improving cure rates of infants with AML, many infants still experience relapse and ultimately die of disease and complications. A need remains for identification of risk factors that can
250
be taken into account to individualize and optimalize treatment options of infant leukemia by further exploring basic biologic mechanisms of leukemic progenitor cells.
References
1. Muss HB, Moloney WC. Chloroma and other myeloblastic tumors. Blood 1973; 42:721-728. 2. Rappaport H, Wright DH, Dorfman RF. Suggested criteria for the diagnosis of Burkitt’s tumor. Cancer Res 1967; 27:2632. 3. Davey FR, Olson S, Kurec AS, et al. The immunophenotyping of extramedullary myeloid cell tumors in paraffin-embedded tissue sections. Am J Surg Path 1988; 12:699-707. 4. Neiman RS, Barcos M, Berard C, et al. Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases. Cancer 1981; 48:1426-1437. 5. Morgan ER, Labotka RJ, Gonzalez-Crussi F, et al. Ovarian granulocytic sarcoma as the primary manifestation of acute infantile myelomonocytic leukemia. Cancer 1981; 48:1819-1824. 6. Aguiar RC, Pozzi DH, Chamone DA. Granulocytic sarcoma of the ovary in a nonleukemic patient. Haematologica 1993; 78:53-55. 7. Eshghabadi M, Shojania AM, Carr I. Isolated granulocytic sarcoma: report of a case and review of the literature. J Clin Oncol 1986; 4:912-917. 8. Pressler H, Horny HP, Wolf A, et al. Isolated granulocytic sarcoma of the ovary: histologic, electron microscopic, and immunohistochemical findings. Int J Gynecol Pathol 1992; 11:68-74. 9. Sreejith G, Gangadharan VP, Elizabath KA, et al. Primary granulocytic sarcoma of the ovary. Am J Clin Oncol 2000; 23:239-240. 10. Greaves MF. Infant leukaemia biology, aetiology and treatment. Leukemia 1996; 10:372-377. 11. Pui CH, Kane JR, Crist WM. Biology and treatment of infant leukemias. Leukemia 1995; 9:762-769. 12. Ross JA, Potter JD, Reaman GH, et al. Maternal exposure to potential inhibitors of DNA topoisomerase II and infant leukemia (United States): a report from the Children’s Cancer Group. Cancer Cause Control 1996; 7:581-590. 13. Spector LG, Ross JA. Infant leukemia: finding the needle in the haystack. Cancer Epidemiol Bio Prev 2006; 15:2331. 14. Pui CH, Kalwinsky DK, Schell MJ, et al. Acute nonlymphoblastic leukemia in infants: clinical presentation and outcome. J Clin Oncol 1988; 6:1008-1013. 15. Dusenbery KE, Howells WB, Arthur DC, et al. Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group. J Ped Hematol Oncol 2003; 25:760-768. 16. Byrd JC, Edenfield WJ, Shields DJ, et al. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol 1995; 13:18001816. 17. Webb DK, Harrison G, Stevens RF, et al. Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia. Blood 2001; 98:1714-1720.
Clinical Leukemia • June 2007
Introduction Granulocytic sarcoma (GS) or chloroma is an extramedullary myeloid cell tumor composed of immature myeloid cells.1 Granulocytic sarcoma was introduced by Rappaport et al initially to describe only tumorous masses associated with cells of the granulocytic series.2 Despite this intended limited definition, the term “GS” has been expanded in the recent literature to include any tumorous mass related to any form of myeloid leukemia or myelodysplastic syndrome. As a result of this confusing nomenclature, Davey et al proposed the term “extramedullary myeloid leukemia” (EML), which encompassed all forms of extrameningeal, nonmedullary leukemic infiltrates.3 Herein, we report a rare case of bilateral ovarian GS as the presenting manifestation of acute erythroleukemia in an infant with unique cytogenetics involving rearrangements of chromosomes 1, 11, and 16.
Case Report A 5-month-old, white female infant was referred to our institution by her primary care physician for evaluation of vomiting and palpable abdominal mass. Abdominal ultrasonography confirmed lower abdominal and pelvic masses. Physical examination revealed easily palpable masses on both sides of the umbilicus. Initial evaluation showed pancytopenia with white blood cell count 4.2 s 103/μL, hemoglobin 4.7 g/dL, platelet count 59 s 103/μL, and absolute neutrophil count 0.8 s 103/μL. Lactate dehydrogenase was elevated at 5310 U/L. Initial computed tomography scan of abdomen showed 2 large, distinct masses arising from the pelvis with cystic and necrotic components. Chest computed tomography scan revealed a 9-mm, soft-tissue density in the region of the right azygoesophageal recess with the possibility of a lymph node, although intraparenchymal location could not be excluded. The patient was taken to surgery for pelvic mass, which was possibly neuroblastoma or a round blue-cell tumor; there were concerns about metastases to lung and bone marrow (BM). Exploratory laparotomy revealed large bilateral ovarian 1Departments 2Department
of Hematology/Oncology, Children’s Mercy Hospital, Kansas City, MO of Pathology, Phoenix Children’s Hospital, AZ
Submitted: May 2, 2007; Revised: June 25, 2007; Accepted: June 26, 2007 Address for correspondence: Mukta Kumar, MD, MPH, Department of Pediatric Hematology/Oncology, Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, MO 64108 Fax: 913-588-6319; e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Leukemia • June 2007
247
Infant with Ovarian GS: An Unusual Case Report of AML (M6)
Figure 1
Macroscopic Appearance of the Ovarian Mass
A
B
C
(A) Touch imprints of the ovarian mass showing tumor cells with large nucleus and a rim of blue, scanty cytoplasm. (Diff-Quik stain; original magnification ×400). (B) Sheets of tumor cells with increased mitoses and apoptotic cells replacing ovarian architecture (hematoxylin and eosin stain; original magnification ×200). (C) Tumor cells with the cytoplasm showing positive immunostain for hemoglobin (original magnification ×200).
masses with no visible normal ovarian tissue and no evidence of torsion. The left ovarian capsule was ruptured, and there was intraperitoneal blood present. A unilateral, left oophorectomy was performed. The left ovarian tumor was an ellipsoidal mass that measured 6 cm s 5 cm s 3 cm with irregular outer surface. Its cut surface presented a solid, red-brown, beefy appearance with a rare focus of hemorrhage and a solitary cystic area. A frozen section of the ovarian mass appeared to be a malignant neoplasm, although a definitive diagnosis was rendered only on the permanent sections. Bilateral BM aspirates and biopsies were done simultaneously with the oophorectomy for purposes of solid tumor staging. Microscopically, the mass showed effacement of ovarian architecture by sheets of round blue cells (Figure 1A) with areas of alveolar and trabecular pattern. The tumor cells had a
Figure 2
Karyogram of Tumor Cells
1
6
2
7
3
8
13
14
19
20
4
9
15
21
5
10
16
22
11
12
17
18
X
Y
Karyotype written in long-form International System for Human Cytogenetic Nomenclature 1995 nomenclature: 46,XX,der(1)t(1;11)(1qter->1p32::11q23->11q13:),der(11)t(1;11)(1pter->1p35::11p15>11q12::11q23->11qter),der(16)t(1;16)(16pter->16q24::1?q32->1?q43)[19] The arrows point to derivative chromosomes.
248
minimal amount of cytoplasm and large nuclei with variably sized nucleoli (Figure 1B). There were scattered foci of necrosis as well as numerous mitotic figures and apoptotic bodies. Immunohistochemical stains demonstrated the tumor cells to be positive for hemoglobin (Figure 1C) and epithelial membrane antigen. Markers (cytokeratins [wide spectrum and AE1/AE3], vimentin, desmin, myogenin, MYOD1, CD45, CD30, CD68, Alk-1, NSE, NB84, WT-1, A-fetoprotein, and TdT to work up round blue-cell tumors) were negative. An enzyme histochemical stain for myeloperoxidase was negative. Periodic acid-Schiff staining showed strong positivity that was abolished by diastase treatment. Flow cytometry showed expression of CD71 and glycophorin A with negative lymphoid, monocytic, and megakaryocytic markers (CD13, CD33, CD34, CD45, CD61, and myeloperoxidase). Electron microscopic study revealed hematopoietic blast cell morphology. These results indicated the diagnosis of leukemic infiltration (GS) of the ovary by acute erythroid leukemia. Bone marrow examination showed high cellularity with 42% blasts. Few maturing erythroid precursors were identified. Flow cytometric analysis of the BM aspirate showed similar immunophenotypic expression as ovarian tumor cells consistent with the diagnosis of acute myelogenous leukemia (AML)–M6. Cytogenetic analysis demonstrated a complex rearrangement of chromosomes 1, 11, and 16 (Figure 2). Fluorescent in situ hybridization analysis of metaphase cells and interphase nuclei using the Vysis DNA probe for the mixed-lineage leukemia (11q23) gene showed the mixed-lineage leukemia gene moved from chromosome 11 to the short arm of chromosome 1 (Figure 3A). The mixedlineage leukemia gene signal localizes next to the chromosome 1 breakpoint, indicating the translocated segment of chromosome 11 that is inverted. The mixed-lineage leukemia gene was not rearranged by this move and only relocated along with other chromosome 11q material: fluorescent in situ hybridization analysis using the Cytocell OctoChrome whole chromosome paint probes confirmed movement of 11q to 1p, 1p to 11p, and an unidentified piece of chromosome 1 material to 16q (Figures 3B-3D).
Clinical Leukemia • June 2007
Mukta Kumar et al
Figure 3 A
Fluorescence in Situ Hybridization of Tumor Cells B
C
D
Images by fluorescence in situ hybridization. (A) The MLL probe is not rearranged and is located on the normal chromosome 11 and on chromosome 1 (arrow). The location of the MLL probe signal on chromosome 1 indicates that the distal 11q23 region is more proximal in the derivative chromosome 1 than is expected for a direct translocation; this indicates the segment of chromosome 11q that is inverted. (B) and (C) show chromosome 1 material as red, chromosome 16 as aqua, and chromosome 19 as green. Chromosome 1 material appears on the normal chromosome 1, the abnormal chromosome 1 (long arrow), which is not completely painted, chromosome 16 (aqua plus red chromosome), and chromosome 11 (short arrow). (D) Chromosome 9 is red, chromosome 11 is aqua, and chromosome 22 is green. Chromosome 11 material appears on the normal chromosome 11, the abnormal chromosome 11 (short arrow), and chromosome 1 (long arrow).
Bone scan and spinal fluid examination were normal. The patient recovered uneventfully from surgery and tolerated well 5 cycles of chemotherapy (weight-based because of her age) per Children’s Oncology Group protocol AAML03P1, a pilot study designed for treatment of newly diagnosed childhood AML using intensive Medical Research Council (in the United Kingdom)–based therapy and gemtuzumab ozogamicin (GMTZ). All children with previously untreated primary AML or isolated GS were eligible for this study. For induction I, patients receive high-dose cytarabine intravenously (I.V.) on days 1-10; daunorubicin I.V. on days 1, 3, and 5; etoposide I.V. days 1-5; and GMTZ on day 6. Patients with central nervous system (CNS)–negative disease receive cytarabine intrathecally on day 1. Induction II involves cytarabine I.V. on days 1-8, cytarabine intrathecally on day 1, and daunorubicin and etoposide. In intensification course I, patients receive cytarabine I.V. on days 1-5; cytarabine intrathecally; and etoposide. Patients with a 5/6 or 6/6 matched family donor proceed to allogeneic BM transplantation. All other patients in complete remission proceed to intensification course II, which entails cytarabine I.V. on days 1-4; cytarabine intrathecally; mitoxantrone I.V. on days 3-6; and GMTZ I.V. on day 7. For the last course, intensification course III, patients receive cytarabine I.V. on days 1, 2, 8, and 9 and asparaginase intramuscularly on days 2 and 9. The patient was in remission on day 28 after her first round of chemotherapy and is alive with no evidence of disease > 2 years from diagnosis. She did not receive radiation therapy (RT) or a transplant. The patient only had an episode of infectious complication of Staphylococcal cellulitis followed by Clostridium difficile infection, which were adequately treated by antibiotics.
Discussion Granulocytic sarcoma or EML is a rare extramedullary tumor composed of myeloid progenitor cells. These occur most often in bone such as the skull, sternum, and ribs, and in soft tissues around the dura, nasal sinuses, and orbit. Lymph nodes and skin are additional common sites.4 Our patient was unusual in presentation because she is an infant with AML presenting with bilateral ovarian GSs with French-
American-British M6 morphology and interesting cytogenetic findings. Extramedullary myeloid leukemia is well described in infants, and ovarian EML is well described in older children and adults; however, no case has been previously reported of an infant with erytholeukemia and ovarian GS as an EML site. There is only 1 case report of AML presenting as ovarian GS in an infant in literature, which was myelomonocytic in origin and the most common type of infant AML (M4 and M5 subtype).5 The cytogenetic findings in this case are unique. The genes involved by the rearrangements of chromosomes 1, 11, and 16 in this case are unknown. Review of reports of GS and EML indicates that the chromosome abnormalities most often associated with these manifestations of leukemia are t(8;21) and inv(16) and rarely rearrangements of 11q23. Our case, which involves rearrangement of the 11q23 region, did not result in rearrangement of the MLL gene as reported in a few cases. Erythroleukemia is often represented by a complex karyotype, but there is no diagnostic chromosome abnormality. Adult erythroleukemia is often found to have abnormalities of chromosomes 5 and 7. Only nonrecurrent chromosome abnormality has been identified in infants and children with erythroleukemia. Extramedullary myeloid leukemia can occur as an isolated lesion in the ovaries without a concomitant leukemia.6-9 In such cases, it presents a diagnostic dilemma for the clinician and the pathologist. However, in our case, the presence of a concomitant leukemic picture was helpful in ascertaining the diagnosis of GS. In pediatric patients, GS can masquerade as a small, round, bluecell neoplasm, frequently leading to misdiagnosis. Differential consists of neuroblastoma, desmoplastic small, round, blue-cell tumor, Wilms’ tumor, primitive neuroectodermal tumor, rhabdomyosarcoma, and lymphoma. Acute myelogenous lymphoma accounts for 6%-14% of all leukemias diagnosed in the first 12 months of life.10,11 An increased maternal consumption of DNA topoisomerase II inhibitor–containing foods have been related to an increased risk of infant AML.12,13 Infant AML is characterized by myelomonoblastic or monoblastic morphology, a high percentage of CNS involvement, and a high leukocyte count. ALL1/MLL/HRX gene arrangements are found in approximately 60% of infant AML cases.11
Clinical Leukemia • June 2007
249
Infant with Ovarian GS: An Unusual Case Report of AML (M6) The high incidence of EML in infants (52%) differs markedly from the much lower incidence of EML or chloromas in older children (2%-13%).14 The most common sites of involvement in children are skin and orbit. Patients with infantile leukemia are predisposed to a higher incidence of isolated CNS/EML relapses compared with older children. Although the overall prognosis for infants is poor, EML does not portend a worse prognosis, with the exception of skin EML.15 Factors that predispose to EML in AML have been proposed to be presence of t(8;21)(q22:q22) and inv(16) chromosomal abnormalities, increased blast differentiation capacity, blast expression of CD56 and T-cell markers, and FrenchAmerican-British M4 and M5.16 The role of RT to EML in patients with AML in preventing extramedullary relapse, seeding from the area of extramedullary disease to marrow (causing marrow relapse), or the optimal dose of radiation is not well defined. Dusenbery et al found no difference in 5-year event-free survival of 42 children with EML who had RT compared with 76 patients who did not (43% vs. 41%, respectively; P = 0.68)15; however, RT alone to treat patients with isolated GS is insufficient. All of these patients eventually develop overt AML. Therefore, standard practice involves combination chemotherapy at a minimum. After successful induction therapy in infants with AML in Medical Research Council trials, relapse was also less common (5-year relapsefree survival, 29% vs. 40% for children aged > 10 years), and there were no differences in deaths in remission, resulting in better diseasefree survival (5-year disease-free survival, 69% vs. 52% for children aged > 10 years) and overall survival (5-year overall survival, 64% vs. 56% for children aged > 10 years).17 Although intensive chemotherapy and/or allogeneic transplantation are improving cure rates of infants with AML, many infants still experience relapse and ultimately die of disease and complications. A need remains for identification of risk factors that can
250
be taken into account to individualize and optimalize treatment options of infant leukemia by further exploring basic biologic mechanisms of leukemic progenitor cells.
References
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Clinical Leukemia • June 2007