- Email: [email protected]
Orbital extra-medullary granulocytic sarcoma: clinicopathologic correlation with immunohistochemical features
s u r v e y o f o p h t h a l m o l o g y 5 9 ( 2 0 1 4 ) 2 3 2 e2 3 5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/survophthal
Clinical pathologic reviews
Orbital extra-medullary granulocytic sarcoma: clinicopathologic correlation with immunohistochemical features Ekta Aggarwal, MSa,*, Kaustubh Mulay, DNBb, Santosh G. Honavar, MS, FACSc a
Department of Oculoplastics and Ocular Oncology, Vasan Eye Care and L.V. Prasad Eye Institute, Hyderabad, India National Reporting Centre for Ophthalmic Pathology, Centre for Sight, Hyderabad and Department of Ophthalmic Pathology, L.V. Prasad Eye Institute, Hyderabad, India c Department of Oculoplasty and Ocular Oncology, Centre for Sight, Hyderabad, and L.V. Prasad Eye Institute, Hyderabad, India b
article info
abstract
Article history:
Orbital granulocytic sarcoma (chloroma), a rare tumor of immature myeloid cells, has
Received 9 February 2013
nonspecific clinical and radiological features that make it a diagnostic challenge. Light
Received in revised form
microscopy and confirmation by immunostaining aid in the diagnosis. Knowledge of this
18 May 2013
entity is important because early diagnosis and prompt treatment are associated with
Accepted 4 June 2013
better prognosis. We report a series of 31 biopsy-proven orbital granulocytic sarcomas with
Available online 25 October 2013
their immunohistochemical features and review the literature. ª 2014 Elsevier Inc. All rights reserved.
Stefen Seregard and Milton Boniuk, Editors Keywords: granulocytic sarcoma chloroma orbit extramedullary leukemia
Granulocytic sarcoma (GS), an uncommon localized malignant tumor of myeloid precursor cells, was first described by Allen Burns in 1811.21 In 1953, King named these “chloromas” because of their green color (Greek chloros)23 that results from exposure of myeloperoxidase (MPO) enzyme present in tumor cells to ultraviolet light.23 One-third, however, lack this phenomenon.14 Myeloblastoma, myelocytoma, myelosarcoma, myeloid sarcoma, and chloroleukemia are other terms used.4,12 GS may occur with a concomitant hematological malignancy or may progress to acute myeloid leukemia (AML).17 Skin and gums are the most common sites. GS has, however, been described at other locations, such as
lymph nodes, small intestine, mediastinum, uterus, and ovaries.19 Orbital GS is rare.14 Diagnosis may be challenging in cases without any known hematological malignancy. We describe 31 cases of biopsy-proven orbital GS with their clinicopathological and immunohistochemical features and review the literature on GS.
1.
Material and methods
We retrieved 31 cases of biopsy-proven orbital GS from 1995 to January 2013 from our archives. We used hematoxylin
* Corresponding author: Ekta Aggarwal, MS, Vasan Eye Care, 3-6-611, Street No.8, Himayath Nagar, Hyderabad, India. E-mail address: [email protected] (E. Aggarwal). 0039-6257/$ e see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.survophthal.2013.06.004
s u r v e y o f o p h t h a l m o l o g y 5 9 ( 2 0 1 4 ) 2 3 2 e2 3 5
and eosin stained sections to assess morphological details. All 31 cases had immunostaining for MPO, CD34, CD117, CD45, CD43, CD20, CD3, pan-cytokeratin (panCK), CD30, neurone specific enolase (NSE), HMB45, epithelial membrvane antigen (EMA), synaptophysin, and Ki-67 (BioGenex, Freemont, CA).
2.
Results
The clinicopathological and immunohistochemical features of our patients with orbital GS are shown in Table 1. None of these had been previously diagnosed with a hematological malignancy. Bone marrow and peripheral blood examination done immediately upon diagnosis of orbital GS showed a concomitant hematological malignancy in 13 (41.9%) patients. Of the remaining 18 (59.1%) cases of isolated orbital GS, 13 (72.2%) patients developed AML within 3 to 21 months (median, 11.3 months). All presented with proptosisdbilateral in three patients. Other presenting findings were visual disturbances, ptosis, diplopia, and lid edema. An orbital mass was palpable in 22 (70.7%) (Fig. 1A and 1B). Motility was restricted to varying degrees in 16 (51.6%). Fundus examination showed disk edema in seven (22.5%), retinal hemorrhages in six (19.3%), and dilated vessels in two (6.4%). Computed
Table 1 e Clinicopathological and immunohistochemical features of orbital granulocytic sarcoma Total cases Sex distribution Males Females Age distribution Range (years) Children (<18 years) Adults (18 years) Laterality Right Left Presenting symptoms Proptosis Lid edema Diminution of vision Ptosis Diplopia Association with hematological malignancy Concomitant Diagnosed during follow-up Isolated granulocytic sarcoma Type of associated hematological malignancy AML with maturation (FAB, AML-M2) Acute myelomonocytic leukemia (FAB, AML-M4) Chronic myeloid leukemia (CML) Myelodysplastic syndrome Immunohistochemical features Myeloperoxidase (MPO) CD34 CD117 CD 45 CD 43
31 11 (35.5%) 20 (64.5%) 3e59 (median, 12) 23 (74.2%) 8 (25.8%) 13 (41.9%) 18 (58.1%) 31 4 3 2 1
(100%) (12.9%) (9.7%) (6.5%) (3.3%)
13 (41.9%) 13 (41.9%) 5 (16.2%) 17 (65.4%) 6 (23%) 2 (7.7%) 1 (3.8%) 31 31 31 22 31
(100%) (100%) (100%) (70.9%) (100%)
233
tomography revealed a diffuse orbital mass, mostly in the superomedial region, with globe indentation in eight (25.8%) (Fig. 1C). Gross examination of the biopsy showed a fleshy, solid cut surface. Microscopic examination in all cases revealed diffusely infiltrating, discohesive, round cells in sheets and trabeculae. These cells had scant to moderate cytoplasm and a large, vesicular nucleus with prominent nucleoli and minimal indentation of nuclear membrane in some (Fig. 1E). Immunostaining showed reactivity to MPO (Fig. 1F), CD34, CD43, and CD117 in all cases. CD45 (leucocyte common antigen) was positive in 22 (70.9%) patients. In all cases tumor cells were negative for CD20, CD3, EMA, panCK, NSE, CD30, synaptophysin, and HMB45. All were periodic acid Schiff negative. Ki-67 activity ranged from 56% to 89%. AML with maturation (WHO, AML-not otherwise specified) (FAB classification, AML-M2) was the most common associated hematological malignancy (17/26 patients, 65.4%) (Fig. 1D). This was followed by acute myelomonocytic leukemia (WHO, AML-not otherwise specified) (FAB classification, AML-M4) in six (23%) and chronic myeloid in two (7.7%). Five patients have not yet developed any hematological malignancy (mean follow-up, 18.6 months).
3.
Discussion
Rappaport introduced “granulocytic sarcoma” to describe tumors only of granulocytic origin.17 The term is now often applied to any tumor related to acute leukemia or myelodysplastic syndrome (MDS).1 GS has been reported in 2.5e9.1% of patients with AML, occurring concomitantly or prior to the onset of bone marrow leukemia.11,15,24 Only a few reports describe GS in the absence of leukemia, MDS, and a positive bone marrow biopsy.5 Though it may occur at any age, GS usually affects children and young adults. Our median age of patients at presentation was 12 years (range, 3e59 years). Previous studies by Zimmerman et al26 and Stockl et al21 found a median age of 7 years and 8.8 years at presentation, respectively. Reports on sex predilection have been variable. A male preponderance has been reported by Davis et al4 and Zimmerman et al,26 whereas a slight female predilection was seen in Murthy et al.14 We had a female preponderance (M:F, 1:1.8) in our series. Although skin, gums, and lymph nodes are common sites of involvement, GS is described at multiple sites.2 Various studies report orbital GS in 9.3e36% of children with AML.3,20 In Zimmerman et al’s series, 88% of orbital GS developed before the systemic leukemia.26 In isolated cases of orbital GS, systemic disease usually develop within a year.14 Zimmerman et al reported leukemia within 2 months in 12 of 29 patients.26 In our study, 13 patients (41.9%) had a concomitant hematological malignancy at presentation. Of the remaining 18, 13 (72.2%) developed AML within 3e21 months (median, 11.3 months) of diagnosis. Clinical and radiological features do not aid in diagnosis as these features are not specific for GS. Like Zimmerman et al, we found lymphoma to be the most common misdiagnosis in both adults and children.26 Immunohistochemistry is the mainstay of diagnosis. GS is immunoreactive for MPO, CD117,
234
s u r v e y o f o p h t h a l m o l o g y 5 9 ( 2 0 1 4 ) 2 3 2 e2 3 5
Fig. 1 e Granulocytic sarcoma presenting with abaxial proptosis due to a superolateral mass (A) and a diffuse superior orbital mass (B). Diffuse supero-orbital swelling in a 4-year-old child. Computed tomography (coronal section) showing a diffuse, nearly homogenous orbital mass with globe indentation (C ). Myeloid blasts with Auer rods seen in bone marrow aspirate (D, Giemsa 31,000). Round cells of granulocytic sarcoma with scant cytoplasm, vesicular nuclei and slightly indented nuclear membranes (E, hematoxylin and eosin 3400). Tumor cells exhibiting immunoreactivity for MPO (F, MPO 3400).
and CD68; CD43 is positive in most cases, and 75% are reactive for CD45.22 A variety of chromosomal abnormalities have been reported in patients with AML with extra-medullary involvement. t (8; 21) has been associated with orbital GS in children.18 Nucleophosmin (NPM) 1 mutations with consequent aberrant cytoplasmic expression of NPM represent the most common genetic abnormality in AML. NPM1 mutations in the absence of FLT3-ITD identify a subgroup of patients with favorable prognoses.7 Falini et al have suggested the addition of anti-NPM antibodies to the panel in immunohistochemical staining of granulocytic sarcomas as they predict NPM1 mutations and might help in prognostication of these tumors.6 We did not perform immunostaining with anti-NPM antibodies. A recent study describes a 12p-deletion in a FAB M1 orbital myeloid sarcoma.16 Data on prognostic significance of GS are limited. The Children’s Oncology Group concluded that patients with myeloid sarcoma (MS) involving orbital and central nervous system (CNS) sites had a significantly better survival than patients with non-CNS MS, with CNS leukemia, or without extra medullary leukemia.10 There are no consensus guidelines on how to treat GS. Delayed or inadequately treated isolated GS almost always progresses to AML.13 Therapy involving daunorubicin- and cytarabine-based chemotherapy for AML should be instituted promptly, including a two-partinduction phase to achieve complete remission and a consolidation phase to maintain this.1,9 Low-dose radiation therapy is an option in cases that require debulking or where chemotherapy has failed. In the present study, patients with GS and a concomitant hematological malignancy were treated with chemotherapy involving an induction phase, followed by a consolidation phase. The induction phase regimen comprised cytarabine and daunorubicin with cytarabine given
as a continuous intravenous (IV) infusion on 7 consecutive days and daunorubicin given as IV-push on 3 consecutive days. The consolidation phase comprised five cycles of cytarabine. Six patients with isolated orbital GS received highdose methyl prednisolone treatment (3 days 30 mg/kg/day and 4 days 20 mg/kg/day) administered initially, followed by the Acute Myeloid Leukaemia-Berlin Frankfurt Mu¨nster 2004 treatment protocol. Two (33.3%) of these patients later developed AML. Twelve patients with isolated GS received only external beam radiotherapy. Eleven of these (91.7%) developed AML during the follow-up period. Median survival of patients with GS without AML is about 36 months, and those progressing to AML have a poor prognosis, with median survival between 6 and 14 months.25 Our patients with isolated orbital GS and those who progressed to AML survived an average of 43 months and 9.2 months, respectively. Targeted therapies use tyrosine-kinase inhibitors such as imantib, C-kit inhibitors, and monoclonal antibodies. Studies suggest a combination of new drugs and conventional chemotherapy to be more effective.8
4.
Conclusion
GS in the orbit poses a diagnostic challenge, especially in patients with no prior history of a hematological malignancy. Patients diagnosed with orbital GS should be thoroughly assessed for a concomitant hematological malignancy and should be monitored carefully for progression to leukemia. Early diagnosis and rapid institution of therapy using surgery, chemotherapy, and radiotherapydeither alone or in combinationdconfers a better prognosis as delay often leads to progression to AML.
s u r v e y o f o p h t h a l m o l o g y 5 9 ( 2 0 1 4 ) 2 3 2 e2 3 5
5.
Disclosure
The authors report no conflict of interest in this work.
references
1. Bakst RL, Tallman MS, Douer D, et al. How do I treat extramedullary acute myeloid leukemia. Blood. 2011;118:3785e93 2. Byrd JC, Edenfield WJ, Shields DJ, et al. Extramedullary myeloid cell tumours in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol. 1995;13:1800e16 3. Cavdar AO, Babacan E, Gozdasoglu S, et al. Ocular granulocytic sarcoma (chloroma) with acute myelomonocytic leukemia in Turkish children. Cancer. 1978;41:1606e9 4. Davis JL, Park DW II, Font RL. Granulocytic sarcoma of the orbit. A histopathologic study. Ophthalmol. 1985;92:1758e62 5. Eshghabadi M, Shojania AM, Carr I. Isolated granulocytic sarcoma: report of a case and review of literature. J Clin Oncol. 1986;4:912e7 6. Falini B, Lenze D, Hasserjian R, et al. Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas. Leukemia. 2007;21:1566e70 7. Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMcþ AML): biologic and clinical features. Blood. 2007;109:874e85 8. Ferara F. New agents for acute myeloid leukemia: is it time for targeted therapies? Expert Opin Investig Drugs. 2012;21:179e89 9. Ghafoor T, Zaidi A, Al Nassir J. Granulocytic sarcoma of the small intestine: an unusual presentation of acute myelogenous leukemia. J Pakistan Med Association. 2010;60:133e5 10. Johnston DL, Alonzo TA, Gerbing RB, et al. Superior outcome of pediatric acute myeloid leukemia patients with orbital and CNS myeloid sarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2012;58:519e24 11. Liu PI, Ishimaru T, McGregor DH, et al. Autopsy study of granulocytic sarcoma (chloroma) in patients with myelogenous leukemia, HiroshimaeNagasaki 1949e1969. Cancer. 1973;31:948e55
235
12. Mangla D, Dewan M, Meyer DR. Adult orbital myeloid sarcoma (granulocytic sarcoma): two cases and review of the literature. Orbit. 2012;31:438e40 13. Meis JM, Butler JJ, Osborne BM, et al. Granulocytic sarcoma in nonleukemic patients. Cancer. 1986;58:2697e709 14. Murthy R, Vemuganti GK, Honavar SG, et al. Extramedullary leukemia in children presenting with proptosis. J Hematol Oncol. 2009;2:4 15. Neiman RS, Barcos M, Berard C, et al. Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases. Cancer. 1981;48:1426e37 16. Ple-Plakon PA, Demirci H, Cheng JX, et al. Orbital myeloid sarcoma in an adult with acute myeloid leukemia, FAB M1, and 12p- deletion. Ophthal Plast Reconstr Surg. 2013;29:e73e5 17. Rappaport H. Tumours of the hemopoietic system. in Atlas of Tumour Pathology, Section III, Fascicle 8. Armed Forces Institute of Pathology, Washington, DC, USA;1966, pp 241e3. 18. Schwyzer R, Sherman GG, Cohn RJ, et al. Granulocytic sarcoma in children with acute myeloblastic leukemia and t(8;21). Med Pediatr Oncol. 1998;31:144e9 19. Sen R, Singh S, Qury MS, et al. Chloroma of perianal region masquerading as perianal abscess. Ind J Dermatol. 2013;58:85 20. Sethi A, Ghose S, Gujral S, et al. Childhood proptosis: the invaluable but overlooked peripheral blood smear. Indian J Ophthalmol. 2001;49:121e3 21. Stockl FA, Dolmetsch AM, Saornil MA, et al. Orbital granulocytic sarcoma. Br J Ophthalmol. 1997;81:1084e8 22. Traweek ST, Arber DA, Rappaport H, et al. Extramedullary myeloid cell tumours. An immunohistochemical and morphological study of 28 cases. Am J Surg Pathol. 1993;17:101e19 23. Uyesugi WY, Watabe J, Peterman G. Orbital and facial granulocytic sarcoma (chloroma): a case report. Pediatr Radiol. 2000;30:276e8 24. Wiernik PH, Serpick AA. Granulocytic sarcoma (chloroma). Blood. 1970;35:361e9 25. Yamauchi K, Yasuda M. Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and review of 72 cases in the literature. Cancer. 2002;94:1739e46 26. Zimmerman LE, Font RL. Ophthalmic manifestations of granulocytic sarcoma (myeloid sarcoma or chloroma). The Third Pan American Association of Ophthalmology and Journal of Ophthalmology Lecture. Am J Ophthalmol. 1975;80:975e90
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/survophthal
Clinical pathologic reviews
Orbital extra-medullary granulocytic sarcoma: clinicopathologic correlation with immunohistochemical features Ekta Aggarwal, MSa,*, Kaustubh Mulay, DNBb, Santosh G. Honavar, MS, FACSc a
Department of Oculoplastics and Ocular Oncology, Vasan Eye Care and L.V. Prasad Eye Institute, Hyderabad, India National Reporting Centre for Ophthalmic Pathology, Centre for Sight, Hyderabad and Department of Ophthalmic Pathology, L.V. Prasad Eye Institute, Hyderabad, India c Department of Oculoplasty and Ocular Oncology, Centre for Sight, Hyderabad, and L.V. Prasad Eye Institute, Hyderabad, India b
article info
abstract
Article history:
Orbital granulocytic sarcoma (chloroma), a rare tumor of immature myeloid cells, has
Received 9 February 2013
nonspecific clinical and radiological features that make it a diagnostic challenge. Light
Received in revised form
microscopy and confirmation by immunostaining aid in the diagnosis. Knowledge of this
18 May 2013
entity is important because early diagnosis and prompt treatment are associated with
Accepted 4 June 2013
better prognosis. We report a series of 31 biopsy-proven orbital granulocytic sarcomas with
Available online 25 October 2013
their immunohistochemical features and review the literature. ª 2014 Elsevier Inc. All rights reserved.
Stefen Seregard and Milton Boniuk, Editors Keywords: granulocytic sarcoma chloroma orbit extramedullary leukemia
Granulocytic sarcoma (GS), an uncommon localized malignant tumor of myeloid precursor cells, was first described by Allen Burns in 1811.21 In 1953, King named these “chloromas” because of their green color (Greek chloros)23 that results from exposure of myeloperoxidase (MPO) enzyme present in tumor cells to ultraviolet light.23 One-third, however, lack this phenomenon.14 Myeloblastoma, myelocytoma, myelosarcoma, myeloid sarcoma, and chloroleukemia are other terms used.4,12 GS may occur with a concomitant hematological malignancy or may progress to acute myeloid leukemia (AML).17 Skin and gums are the most common sites. GS has, however, been described at other locations, such as
lymph nodes, small intestine, mediastinum, uterus, and ovaries.19 Orbital GS is rare.14 Diagnosis may be challenging in cases without any known hematological malignancy. We describe 31 cases of biopsy-proven orbital GS with their clinicopathological and immunohistochemical features and review the literature on GS.
1.
Material and methods
We retrieved 31 cases of biopsy-proven orbital GS from 1995 to January 2013 from our archives. We used hematoxylin
* Corresponding author: Ekta Aggarwal, MS, Vasan Eye Care, 3-6-611, Street No.8, Himayath Nagar, Hyderabad, India. E-mail address: [email protected] (E. Aggarwal). 0039-6257/$ e see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.survophthal.2013.06.004
s u r v e y o f o p h t h a l m o l o g y 5 9 ( 2 0 1 4 ) 2 3 2 e2 3 5
and eosin stained sections to assess morphological details. All 31 cases had immunostaining for MPO, CD34, CD117, CD45, CD43, CD20, CD3, pan-cytokeratin (panCK), CD30, neurone specific enolase (NSE), HMB45, epithelial membrvane antigen (EMA), synaptophysin, and Ki-67 (BioGenex, Freemont, CA).
2.
Results
The clinicopathological and immunohistochemical features of our patients with orbital GS are shown in Table 1. None of these had been previously diagnosed with a hematological malignancy. Bone marrow and peripheral blood examination done immediately upon diagnosis of orbital GS showed a concomitant hematological malignancy in 13 (41.9%) patients. Of the remaining 18 (59.1%) cases of isolated orbital GS, 13 (72.2%) patients developed AML within 3 to 21 months (median, 11.3 months). All presented with proptosisdbilateral in three patients. Other presenting findings were visual disturbances, ptosis, diplopia, and lid edema. An orbital mass was palpable in 22 (70.7%) (Fig. 1A and 1B). Motility was restricted to varying degrees in 16 (51.6%). Fundus examination showed disk edema in seven (22.5%), retinal hemorrhages in six (19.3%), and dilated vessels in two (6.4%). Computed
Table 1 e Clinicopathological and immunohistochemical features of orbital granulocytic sarcoma Total cases Sex distribution Males Females Age distribution Range (years) Children (<18 years) Adults (18 years) Laterality Right Left Presenting symptoms Proptosis Lid edema Diminution of vision Ptosis Diplopia Association with hematological malignancy Concomitant Diagnosed during follow-up Isolated granulocytic sarcoma Type of associated hematological malignancy AML with maturation (FAB, AML-M2) Acute myelomonocytic leukemia (FAB, AML-M4) Chronic myeloid leukemia (CML) Myelodysplastic syndrome Immunohistochemical features Myeloperoxidase (MPO) CD34 CD117 CD 45 CD 43
31 11 (35.5%) 20 (64.5%) 3e59 (median, 12) 23 (74.2%) 8 (25.8%) 13 (41.9%) 18 (58.1%) 31 4 3 2 1
(100%) (12.9%) (9.7%) (6.5%) (3.3%)
13 (41.9%) 13 (41.9%) 5 (16.2%) 17 (65.4%) 6 (23%) 2 (7.7%) 1 (3.8%) 31 31 31 22 31
(100%) (100%) (100%) (70.9%) (100%)
233
tomography revealed a diffuse orbital mass, mostly in the superomedial region, with globe indentation in eight (25.8%) (Fig. 1C). Gross examination of the biopsy showed a fleshy, solid cut surface. Microscopic examination in all cases revealed diffusely infiltrating, discohesive, round cells in sheets and trabeculae. These cells had scant to moderate cytoplasm and a large, vesicular nucleus with prominent nucleoli and minimal indentation of nuclear membrane in some (Fig. 1E). Immunostaining showed reactivity to MPO (Fig. 1F), CD34, CD43, and CD117 in all cases. CD45 (leucocyte common antigen) was positive in 22 (70.9%) patients. In all cases tumor cells were negative for CD20, CD3, EMA, panCK, NSE, CD30, synaptophysin, and HMB45. All were periodic acid Schiff negative. Ki-67 activity ranged from 56% to 89%. AML with maturation (WHO, AML-not otherwise specified) (FAB classification, AML-M2) was the most common associated hematological malignancy (17/26 patients, 65.4%) (Fig. 1D). This was followed by acute myelomonocytic leukemia (WHO, AML-not otherwise specified) (FAB classification, AML-M4) in six (23%) and chronic myeloid in two (7.7%). Five patients have not yet developed any hematological malignancy (mean follow-up, 18.6 months).
3.
Discussion
Rappaport introduced “granulocytic sarcoma” to describe tumors only of granulocytic origin.17 The term is now often applied to any tumor related to acute leukemia or myelodysplastic syndrome (MDS).1 GS has been reported in 2.5e9.1% of patients with AML, occurring concomitantly or prior to the onset of bone marrow leukemia.11,15,24 Only a few reports describe GS in the absence of leukemia, MDS, and a positive bone marrow biopsy.5 Though it may occur at any age, GS usually affects children and young adults. Our median age of patients at presentation was 12 years (range, 3e59 years). Previous studies by Zimmerman et al26 and Stockl et al21 found a median age of 7 years and 8.8 years at presentation, respectively. Reports on sex predilection have been variable. A male preponderance has been reported by Davis et al4 and Zimmerman et al,26 whereas a slight female predilection was seen in Murthy et al.14 We had a female preponderance (M:F, 1:1.8) in our series. Although skin, gums, and lymph nodes are common sites of involvement, GS is described at multiple sites.2 Various studies report orbital GS in 9.3e36% of children with AML.3,20 In Zimmerman et al’s series, 88% of orbital GS developed before the systemic leukemia.26 In isolated cases of orbital GS, systemic disease usually develop within a year.14 Zimmerman et al reported leukemia within 2 months in 12 of 29 patients.26 In our study, 13 patients (41.9%) had a concomitant hematological malignancy at presentation. Of the remaining 18, 13 (72.2%) developed AML within 3e21 months (median, 11.3 months) of diagnosis. Clinical and radiological features do not aid in diagnosis as these features are not specific for GS. Like Zimmerman et al, we found lymphoma to be the most common misdiagnosis in both adults and children.26 Immunohistochemistry is the mainstay of diagnosis. GS is immunoreactive for MPO, CD117,
234
s u r v e y o f o p h t h a l m o l o g y 5 9 ( 2 0 1 4 ) 2 3 2 e2 3 5
Fig. 1 e Granulocytic sarcoma presenting with abaxial proptosis due to a superolateral mass (A) and a diffuse superior orbital mass (B). Diffuse supero-orbital swelling in a 4-year-old child. Computed tomography (coronal section) showing a diffuse, nearly homogenous orbital mass with globe indentation (C ). Myeloid blasts with Auer rods seen in bone marrow aspirate (D, Giemsa 31,000). Round cells of granulocytic sarcoma with scant cytoplasm, vesicular nuclei and slightly indented nuclear membranes (E, hematoxylin and eosin 3400). Tumor cells exhibiting immunoreactivity for MPO (F, MPO 3400).
and CD68; CD43 is positive in most cases, and 75% are reactive for CD45.22 A variety of chromosomal abnormalities have been reported in patients with AML with extra-medullary involvement. t (8; 21) has been associated with orbital GS in children.18 Nucleophosmin (NPM) 1 mutations with consequent aberrant cytoplasmic expression of NPM represent the most common genetic abnormality in AML. NPM1 mutations in the absence of FLT3-ITD identify a subgroup of patients with favorable prognoses.7 Falini et al have suggested the addition of anti-NPM antibodies to the panel in immunohistochemical staining of granulocytic sarcomas as they predict NPM1 mutations and might help in prognostication of these tumors.6 We did not perform immunostaining with anti-NPM antibodies. A recent study describes a 12p-deletion in a FAB M1 orbital myeloid sarcoma.16 Data on prognostic significance of GS are limited. The Children’s Oncology Group concluded that patients with myeloid sarcoma (MS) involving orbital and central nervous system (CNS) sites had a significantly better survival than patients with non-CNS MS, with CNS leukemia, or without extra medullary leukemia.10 There are no consensus guidelines on how to treat GS. Delayed or inadequately treated isolated GS almost always progresses to AML.13 Therapy involving daunorubicin- and cytarabine-based chemotherapy for AML should be instituted promptly, including a two-partinduction phase to achieve complete remission and a consolidation phase to maintain this.1,9 Low-dose radiation therapy is an option in cases that require debulking or where chemotherapy has failed. In the present study, patients with GS and a concomitant hematological malignancy were treated with chemotherapy involving an induction phase, followed by a consolidation phase. The induction phase regimen comprised cytarabine and daunorubicin with cytarabine given
as a continuous intravenous (IV) infusion on 7 consecutive days and daunorubicin given as IV-push on 3 consecutive days. The consolidation phase comprised five cycles of cytarabine. Six patients with isolated orbital GS received highdose methyl prednisolone treatment (3 days 30 mg/kg/day and 4 days 20 mg/kg/day) administered initially, followed by the Acute Myeloid Leukaemia-Berlin Frankfurt Mu¨nster 2004 treatment protocol. Two (33.3%) of these patients later developed AML. Twelve patients with isolated GS received only external beam radiotherapy. Eleven of these (91.7%) developed AML during the follow-up period. Median survival of patients with GS without AML is about 36 months, and those progressing to AML have a poor prognosis, with median survival between 6 and 14 months.25 Our patients with isolated orbital GS and those who progressed to AML survived an average of 43 months and 9.2 months, respectively. Targeted therapies use tyrosine-kinase inhibitors such as imantib, C-kit inhibitors, and monoclonal antibodies. Studies suggest a combination of new drugs and conventional chemotherapy to be more effective.8
4.
Conclusion
GS in the orbit poses a diagnostic challenge, especially in patients with no prior history of a hematological malignancy. Patients diagnosed with orbital GS should be thoroughly assessed for a concomitant hematological malignancy and should be monitored carefully for progression to leukemia. Early diagnosis and rapid institution of therapy using surgery, chemotherapy, and radiotherapydeither alone or in combinationdconfers a better prognosis as delay often leads to progression to AML.
s u r v e y o f o p h t h a l m o l o g y 5 9 ( 2 0 1 4 ) 2 3 2 e2 3 5
5.
Disclosure
The authors report no conflict of interest in this work.
references
1. Bakst RL, Tallman MS, Douer D, et al. How do I treat extramedullary acute myeloid leukemia. Blood. 2011;118:3785e93 2. Byrd JC, Edenfield WJ, Shields DJ, et al. Extramedullary myeloid cell tumours in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol. 1995;13:1800e16 3. Cavdar AO, Babacan E, Gozdasoglu S, et al. Ocular granulocytic sarcoma (chloroma) with acute myelomonocytic leukemia in Turkish children. Cancer. 1978;41:1606e9 4. Davis JL, Park DW II, Font RL. Granulocytic sarcoma of the orbit. A histopathologic study. Ophthalmol. 1985;92:1758e62 5. Eshghabadi M, Shojania AM, Carr I. Isolated granulocytic sarcoma: report of a case and review of literature. J Clin Oncol. 1986;4:912e7 6. Falini B, Lenze D, Hasserjian R, et al. Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas. Leukemia. 2007;21:1566e70 7. Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMcþ AML): biologic and clinical features. Blood. 2007;109:874e85 8. Ferara F. New agents for acute myeloid leukemia: is it time for targeted therapies? Expert Opin Investig Drugs. 2012;21:179e89 9. Ghafoor T, Zaidi A, Al Nassir J. Granulocytic sarcoma of the small intestine: an unusual presentation of acute myelogenous leukemia. J Pakistan Med Association. 2010;60:133e5 10. Johnston DL, Alonzo TA, Gerbing RB, et al. Superior outcome of pediatric acute myeloid leukemia patients with orbital and CNS myeloid sarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2012;58:519e24 11. Liu PI, Ishimaru T, McGregor DH, et al. Autopsy study of granulocytic sarcoma (chloroma) in patients with myelogenous leukemia, HiroshimaeNagasaki 1949e1969. Cancer. 1973;31:948e55
235
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