acute myeloid leukemia ( aml ) may occur in a variety of extramedullary ( em ) tissues , with or without bone marrow disease .
two well - known em manifestations of aml are granulocytic sarcoma ( gs ) and leukemia cutis .
gs , also known as myeloid sarcoma or chloroma , is a rare em tumor of immature myeloid cells.1 the high expression of myeloperoxidase ( mpo ) makes these tumors appear green hence , the name  chloroma  ( from the greek  chloros ,  meaning green).2 gs can develop de novo or concurrently with aml , myeloproliferative neoplasms ( mpns ) or myelodysplastic syndromes ( mdss).1,36 isolated gs defined by the absence of a history of aml , mds , or mpn , and unremarkable blood and bone marrow analyses has been described , albeit sparsely.79 gs , most commonly see in the context of widespread and uncontrolled disease , may also be the first manifestation of aml , antedating it by months or years , or represent the initial manifestation of relapse in a patient previously treated for aml.10,11 the risk factors for gs include specific chromosomal abnormalities , such as translocations between chromosomes 8 and 21 ( t[8;21 ] ) and inversion of chromosome 16 ( inv ) , the expression of cell - surface markers ( cluster of differentiation [ cd]56 , cd2 , cd4 , and cd7 ) , and the french  american  british ( fab ) classification m2 , m4 , and m5 leukemia subtypes .
additional risk factors include poor nutritional status , cellular immune dysfunction , high presenting leukocyte count , and decreased blast auer rods.12 gs is slightly more common in men than in women ( male to female ratio , 1.42:1).13 while various body sites have been associated with gs , the most common locations include soft tissue , bone , periosteum and the lymph nodes.9,12 here , we describe the case of a female with gs manifesting as a nasopharyngeal mass that was treated with radiation therapy , after which aml manifested 12 months later .
we also review the literature of previously reported cases of nasopharyngeal gs and focus on the clinical presentation , diagnosis , and the treatment of this disorder .
a 63-year - old caucasian female sought evaluation in the otolaryngology clinic ( virginia mason medical center , seattle , wa , usa ) due to decreased hearing in her left ear and progressive nasal congestion . prior to that visit , she had been treated empirically for several months with various antibiotics and decongestants and briefly with intranasal steroids .
her chronic medical problems were notable for nonallergic rhinitis , hypertension , hyperlipidemia , and morbid obesity .
her general and cranial nerve exam were unremarkable , but she was identified as having conductive hearing loss due to a left middle ear effusion .
on sinonasal endoscopy , an excoriated mass was also identified , involving the posterior nasopharynx and nasal turbinates .
a biopsy of the mass revealed intermediate - sized blastic cells that stained positive for mpo , cd68 ( dim ) , cd99 , and cd117 ( dim ) , consistent with involvement by gs ( figure 1 ) .
the results of the laboratory studies included a normal complete blood count ( cbc ) as well as unremarkable serum chemistry and liver enzyme levels .
a flow cytometry study of the circulating white cells was also unremarkable , as were the polymerase chain reaction ( pcr ) studies of peripheral blood for the breakpoint cluster region ( bcr)-abelson ( abl ) gene rearrangements and janus kinase 2 ( jak-2 ) mutations .
a bone marrow biopsy showed no evidence of aml or features of an mpn ; normal trilineage hematopoiesis was present .
a chromosome analyses showed an xx karyotype . an integrated whole body positron emission tomography  computed tomography ( pet - ct ) scan showed only modest inflammation in the nasopharynx ( figure 2 ) . because of her age and comorbid medical conditions , we elected to treat her gs with involved - field radiation therapy to the nasopharynx , 30 gy delivered in 15 daily fractions .
she tolerated the radiation therapy well , with alopecia involving the vertex of her scalp and mild mucositis , fatigue , and dysgeusia .
subsequently , she was monitored closely , with exams of her nasopharynx coupled with blood studies every 2 to 3 months .
twelve months after her initial diagnosis of isolated gs , the patient presented to clinic with fever and cough of a week s duration and complained of recrudescent fatigue and dyspnea on exertion . on exam , she appeared acutely ill , dehydrated , febrile , and diaphoretic , and with diminished breath sounds and crackles at the left lung base .
her cbc consisted of a white blood count ( wbc ) of 11.8  10/l with 62% myeloid blasts , hematocrit of 23% , and platelets of 117  10/l .
the flow cytometric analysis of peripheral blood revealed an abnormal population of blasts ( cd45-dim ) that expressed cd117 ( moderate ) and bright uniform cd33 ; this population comprised approximately 80% of the circulating wbcs .
the tumor cells were negative for human leukocyte antigen ( hla)-dr , cd34 , cd13 , cd14 , cd15 , cd16 , cd64 , cd2 , cd3 , cd4 , cd5 , cd7 , cd56 , cd71 , and cd38 .
the phenotype was similar to the phenotype of the myeloid blasts identified in her prior nasopharyngeal biopsy .
band karyotyping of the peripheral blood blasts showed normal ( 46 , xx ) cytogenetics .
induction chemotherapy was prescribed , consisting of cytarabine ( 100 mg / m / day , days 17 ) and idarubicin ( 13 mg / m / day , days 13).14 her clinical course was notable for mild mucositis , fluctuating blood sugars , and culture - negative neutropenic fever .
a bone marrow aspirate and biopsy obtained on day 14 was markedly hypocellular ; a repeat bone marrow biopsy on day 28 was normocellular , with maturing trilineage hematopoiesis and no residual leukemia .
she went on to receive an additional three cycles of consolidation therapy , with continuous infusion cytarabine and bolus idarubicin ( 5 + 2 regimen).14 she remains in remission , with a normal cbc at the 18-month follow - up visit .
it is reported in about 2.5%9.1% of patients with aml.1517 while it can be solitary or multifocal , most cases manifest as isolated single lesions.1 the most common sites of em involvement of aml include the skin ( leukemia cutis ) , lymph node , and bone , but other sites , including the female reproductive tract , breast , gut , and testis have been reported . in the head and neck region
, gs will usually involve the orbits , and only rarely will it affect the nasopharynx.18 utilizing a medline/pubmed search , with the key words 
chloroma ,   nasopharynx ,  and  acute myeloid leukemia  and restricting our search to the english language reports between the years 20002013 , we identified 13 additional patients between the ages of 1 to 81 years ( median age of 37 years ) with gs involving the nasopharynx ( table 1).4,1930 the male to female ratio within the group was 1:1 . sinonasal congestion or
the longest reported disease - free interval from diagnosis was 36 months.4,22 among the seven cases where the disease - free interval was reported , the median was 18 months ( range , 4 to 36 months ) . in the absence of circulating myeloblasts ,
gs is seldom considered in the initial differential diagnosis of a soft tissue mass.10,12 its similarity , both radiographically and histopathologically , to other small round cell tumors , such as lymphoblastic leukemia , melanoma , ewing sarcoma , blastic plasmacytoid dendritic cell neoplasm , as well as certain forms of non - hodgkin lymphoma and benign em hematopoiesis means that there may be a delay in diagnosis while the clinician waits for supportive diagnostic tests from the pathologist.31 gs typically consists of a diffuse and infiltrative population of myeloblasts and granulocytic cell types .
infrequently , tumors can occur in the setting of trilineage hematopoiesis or erythroid or megakaryocytic precursors , particularly in cases of transformation from mpn .
immunohistochemistry is useful for establishing the diagnosis of gs and can be easier to perform than flow cytometry , which requires fresh tissue.32 immunohistochemical markers , such as cd68 , mpo , lysozyme , and cd43 , can assist in differentiating between myeloid and nonmyeloid cells.1 myelocytic differentiation may also be confirmed by leder stain ( chloroacetate esterase).17 cd117 , cd34 , and terminal deoxynucleotidyl transferase ( tdt ) are useful as markers of immaturity .
when gs is found in an em location and in the absence of circulating blasts , a bone marrow biopsy is necessary to rule out concurrent marrow involvement .
cytogenetic abnormalities are seen in roughly 50% of cases and include monosomy 7 , trisomy 8 , inv(16 ) , t(9;11 ) , deletion ( del)(16q ) , t(8;16 ) , and t(1;11).1,3237nucleophosmin ( npm1 ) mutations have been reported in 15% and fms - related tyrosine kinase 3 ( flt 3 ) gene mutations in 20%30% of gs cases;38,39 however , the clinical significance of npm1 and flt3 mutation in this clinical context remains uncertain.38,39 a ct scan is best for evaluating soft tissue gs , and magnetic resonance imaging ( mri ) with gadolinium is preferred when gs involves the central nervous system.40,41 a pet scan may be helpful for detecting additional sites of em aml and also for planning local ( eg , radiotherapy ) treatment and/or systemic chemotherapy.42 it can also be used for monitoring the response to treatment.32 for patients who achieve a complete remission with treatment , the role of routine monitoring with radiographs has not been established.32 the treatment of gs depends upon patient and disease characteristics .
the patient s age , associated medical comorbidities , clinical symptoms , tumor karyotype , stage , and the extent of disease are important factors to be considered before planning treatment .
there are no randomized studies to help guide the treatment choices , and the gs location does not appear to impact survival .
chemotherapy ( both systemic and intrathecal ) , radiation therapy , surgical extirpation , or any combination of these interventions have all been employed ( table 2 ) .
remission - induction chemotherapy similar to that used for aml is favored for either isolated gs or gs presenting with concomitant aml.43,44 significantly longer disease - free intervals without leukemia have been achieved in patients with isolated gs who received systemic chemotherapy rather than surgery or radiation therapy , belying the fact that this is inevitably the first manifestation of a systematic disease.45,46 surgery is generally reserved for cases with acute symptoms ( eg , pain , acute nerve compression ) , and at times , to obtain an adequate tissue sample following a nondiagnostic fine - needle aspiration .
the role of allogeneic hematopoietic stem cell transplantation ( ahsct ) in patients with gs has not been studied prospectively , but improved outcomes with ahsct have been reported in repeated retrospective analyses.1,47 in a retrospective study of 51 patients with gs , either isolated or associated with aml , the 5-year overall survival was 48% , with no significant differences in outcomes between the two presentations.48 for those patients with gs and graft - versus - host disease , there was a trend toward improved overall survival .
patients with a history of gs are at risk for relapse , and careful assessments at follow - up appointments are needed as early isolated gs can be asymptomatic.49 a biopsy of any new or suspicious soft tissue or skin abnormality should be performed , and if no circulating blasts are present , a bone marrow biopsy is necessary.32 for patients who relapse after chemotherapy , reinduction chemotherapy may be an option if there has been a long disease - free interval after the initial treatment . for those individuals who are deemed hardy enough and who have an identified hla match , ahsct is the preferred consolidative approach .
when bone marrow and em relapse occurs synchronously after ahsct , survival is very poor and no standard treatment has proven effective , although donor lymphocyte infusions , tapering of immunosuppression , or investigational agents may be considered.50,51
 granulocytic sarcoma ( gs ) is a rare extramedullary manifestation of acute myeloid leukemia ( aml ) 
 . it may also represent blastic transformation of myelodysplastic syndromes or myeloproliferative neoplasms . 
 although usually seen in the context of advanced and poorly controlled disease , it may also present as the first manifestation of illness , without concurrent bone marrow or blood involvement . in the medical literature , chloroma and gs are terms that have been used interchangeably with myeloid sarcoma . 
 gs usually manifests as soft tissue or bony masses in several extracranial sites , such as bone , periosteum , and lymph nodes ; involvement of the head and neck region is uncommon . 
 we report a case of a woman with insidious onset of progressive nasal congestion and diminished hearing who was diagnosed with an isolated gs of the nasopharynx . with involved field radiotherapy , she achieved a complete remission of 12-months duration before being diagnosed with overt aml . 
 she has remained disease - free for greater than 18 months following induction and consolidation chemotherapy . through a medline/pubmed search we identified an additional 13 cases of nasopharyngeal gs . 
 the median age was 37 years ( range 1 to 81 years ) . 
 the cases were equally distributed among the sexes . 
 the most common presenting symptoms were conductive hearing loss and sinonasal congestion . 
 isolated gs was identified in six cases , and the median time from diagnosis of gs to aml was 12 months ( range 3 to 48 months ) . 
 the treatment varied , but responses were seen in all the patients who received chemotherapy with or without radiotherapy . 
Introduction
Case report
Discussion and literature review