Discussion
Extramedullary AML, also known as myeloid sarcoma, is characterized by
the infiltration of blast cells into normal tissues, as confirmed by
histological examination.1 Although it can occur at
any age, myeloid sarcoma predominantly presents in the pediatric
population.8 Myeloid sarcoma may develop either de
novo or concomitantly with systemic AML. In some cases, it may precede
the development of systemic disease by several months or serve as the
initial manifestation of relapsed AML.5 The most
commonly affected sites are other hematopoietic organs (such as the
liver, spleen, and lymph nodes), followed by skin and
gingivae.6 Localized bone involvement, particularly in
the temporal bone, is rare and has only been reported in a few case
studies. The underreporting of such cases could be a common issue that
may be attributed to the diagnostic challenges associated with
distinguishing myeloid sarcoma from other conditions, with misdiagnosis
rates reported as high as 47% in recent studies.9
In cases similar to the one presented, several factors can contribute to
an erroneous diagnosis. Patients with leukemia are prone to developing
otologic symptoms, and acute leukemia patients are particularly
susceptible to bacterial, fungal, or viral infections affecting the
external, middle, or inner ear.10 Less commonly,
thrombocytopenic hemorrhage or direct leukemic infiltration can lead to
thickening or bleeding in the external auditory canal and tympanic
membrane, skin lesions, acute otitis media or externa with effusions,
and various types of hearing loss, including sensorineural, conductive,
or mixed.11–14 Temporal bone involvement,
specifically, may often manifest as a triad of otalgia, hearing loss,
and facial paralysis due to facial nerve involvement; additional
symptoms may include retroauricular swelling and pain, ear fullness, and
vertigo.15–17 Finally, progressive disease can result
in extensive bone erosions, permanent damage, and bacterial
superinfections, contributing to the development of acute
otomastoiditis.11
In the presented case, the patient initially exhibited two of the three
symptoms of the aforementioned triad (otalgia and hearing loss), along
with fever, ear effusions, and narrowing of the left external auditory
canal. Still, these symptoms are non-specific. Considering the prolonged
hematologic remission with no signs of systemic disease or central
nervous system involvement, a provisional diagnosis of acute otitis
media and externa was made.
Unsurprisingly, the subsequent conservative treatment proved
ineffective. In some cases, a CT or magnetic resonance imaging (MRI)
scan can aid in establishing the diagnosis. Specifically, extramedullary
involvement could present as a well-defined, solid
mass.8 Imaging features are variable and
site-dependent: craniospinal lesions are mostly homogenous and
hyperdense on CT, iso- or hypointense on T1 and hyperintense on T2 MRI,
with frequent invasion of adjacent bony structures.7,8Nevertheless, these features may be indistinguishable from other, more
common malignancies, such as lymphoma.8 Imaging can
also demonstrate less specific findings, as was the case in our patient,
posing additional diagnostic challenges. Therefore, given a patient’s
history, even non-specific opacification should be considered as
potential evidence of neoplastic invasion mimicking a benign condition
(such as otomastoiditis). Although PET/CT has demonstrated high
sensitivity and specificity in identifying myeloid
sarcoma,18 it is costly and not widely available. Most
importantly, its results are heterogenous when it comes to concurrent
bone marrow involvement,18 and interpretation can be
even more challenging in cases of extramedullary bone disease and
inflammatory complications. As such, imaging features can be
insufficient for distinguishing not only between various neoplasms, but
also non-malignant disorders.
Hence, a biopsy of the lesion appears to be the only definitive method
for confirming a case of isolated extramedullary relapse or de novo
myeloid sarcoma. Despite this, invasive procedures are frequently avoided or not feasible owing to certain frequent comorbidities, such as thrombocytopenia. As mentioned, the reported frequency of myeloid sarcoma has varied from 2.5% to 9.1%.2 In contrast to this, a recent PET/CT-based study revealed a prevalence of 22%.18 Likewise, a large-scale study of newly diagnosed AML patients showed an overall incidence of extramedullary disease of 23.7% based on physical examination and imaging.6 Access to potentially affected sites (including the most typical ones, such as liver and spleen) may be challenging or life-threatening, and these are commonly not subjected to biopsy, which likely contributes to the underestimation of prevalence in previous reports, including the cases of temporal bone involvement. Finally, the
morphologic appearance of blasts in myeloid sarcoma can vary and depends
on the type of AML and characteristics of differentiation, presenting additional challenges. Nevertheless,
immunohistochemistry, flow cytometry, and genetic analysis can usually
resolve most issues when a tissue biopsy specimen is available.
When present, extramedullary involvement, whether de novo or in the
context of relapse, is generally considered a negative prognostic
factor.2,19,20 In a study of newly diagnosed AML, CR
rate and OS were significantly reduced for patients with EM AML (median
OS of 14 months vs. 26.2 months), but event- and relapse-free survival
did not differ in patients with and without extramedullary
involvement.20 Still, up to 60% of adult patients
first present with EM AML during relapse, as was the case in the current
report.21 Expectedly, these patients show inferior
outcomes when compared to newly-diagnosed cases, with a median overall
survival (OS) of 11.6 months and 19.1 months,
respectively;21 however, the prognostic significance of EM AML in the context of relapse is still controversial. In a different study investigating
extramedullary relapses among AML patients, there was no difference in
survival between extramedullary and bone marrow
relapse.22 In contrast, another study showed
significantly better survival rates in patients with extramedullary
relapse (69% at 6 months) when compared to systemic or combined
relapses (27% and 8%, respectively).23 Overall,
data are limted and show significant heterogeneity and the independent
prognostic value of extramedullary disease is still debated. Despite
this, the site and pattern of leukemic involvement seem to be important
prognostic factors.6,21 For instance, patients with
leukemia cutis showed a significantly inferior OS when compared to other
sites of disease (median of 5.7 months vs. 21.9 months,
respectively).21,24 Interestingly, rare areas of
involvement, such as the bone, may be associated with better survival
rates.6 Furthermore, a recent review reported that
around 22% of temporal bone MS cases may harbor the prognostically
favorable t(8;21) translocation.17 Although genetic
profiling was unavailable at our center at the time of this case,
earlier data had also indicated at existing associations between myeloid
sarcoma and the favorable cytogenetic abnormalities t(8;21) and inv(16);
still, results are inconsistent, and several studies showed no
significant associations with these core-binding factor mutations, and
report a varying incidence of other molecular and genetic
abnormalities.5,20,21,25 In summary, both the prognostic
significance and the genetic profile of MS may be dependent on disease
site and other unexplored risk factors, and further studies are needed
to investigate this possibility.
Current management of AML in eligible patients involves standard
anthracycline-based multi-agent chemotherapy induction, followed by
consolidation, with the possible addition of targeted therapy based on
risk stratification and mutational profiling.3 There
is a lack of prospective clinical trials, and treatment of
extramedullary disease, specifically, remains controversial. However,
the onset of isolated extramedullary relapse frequently heralds a bone
marrow relapse with a mean interval of around 7
months.26 Accordingly, current recommendations for MS
are based mainly on existing AML protocols, with or without the addition
of radiation therapy and surgery.2,3 In the present
case, local treatment was attempted initially. Radiation therapy has
shown excellent response rates (91-97%) and local disease control, with
a median progression-free survival of 11 months, in one
study.27–29 Unsurprisingly, cases of isolated
temporal bone AML relapse with prolonged responses after radiation
therapy have previously been reported.15 Regardless,
survival is poor even among those achieving clinical remission with
local therapy, and the majority are likely to
relapse.30 In the current case, systemic relapse
occurred soon after the end of radiation therapy, possibly due to
delayed recognition of the local relapse. Regrettably, management
options for relapsed AML and targeted treatment are limited at our
center. Despite the late relapse increasing the odds of reinduction with
the previously successful regimen, subsequent chemotherapy failed to
achieve CR.
Improving management strategies and outcomes in myeloid sarcoma may
involve novel therapy and targeting specific molecular alterations,
similar to systemic acute myeloid leukemia. For instance, a recent analysis reported a
45% CR rate among EM AML patients treated with venetoclax and
hypomethylating agents, and 38% for patients in a relapsed
setting.31 However, genetic events underlying
extramedullary disease are still not well understood and remain
controversial.20 Potentially targetable mutations
commonly encountered in AML, such as those of NPM1, FLT3-ITD, IDH,
KMT2A, as well as the presence of KIT, TET1, ASXL1, EZH3, SF3B1, NRAS
alterations have been associated with extramedullary disease in several
recent next-generation sequencing (NGS) studies.20,21In line with this, a study by Ball et al. demonstrated a complete
response in three out of four patients treated with IDH inhibitors based
on on-site next-generation sequencing of the MS
tumor.21 Therefore, biopsy followed by mutational
analysis could be crucial for optimizing future therapy of EM AML.
Furthermore, significant discordance has been observed between the
molecular profiles of the myeloid sarcoma tumors and concurrent bone
marrow disease, suggesting the importance of molecular alterations in the pathogenesis of extramedullary disease.21,32 In one study, up to one third of
cases showed molecular discordance, with the majority revealing
discordance in prognostically important or potentially targetable
alterations.32 Importantly, patients presenting with
mutational discordance were shown to have an inferior overall survival,
underlining the significance of this clonal heterogeneity not only for
the pathogenesis, but also
prognostication and targetability of extramedullary AML.32 In practice, obtaining sufficient
material for cytogenetic and molecular analyses from MS biopsies, often
available only in the form of formalin-fixed-paraffin-embedded tissues,
can be challenging.33 Utilization of novel NGS-based
analyses in clinical practice may overcome this limitation, enabling
proper genetic risk assessment and precision-based
treatment.33 Nonetheless, due to the low prevalence
and varying presentation of myeloid sarcoma, our understanding of
optimal management strategies is limited, and more prospective trials
are necessary to evaluate the novel treatment approaches for
extramedullary AML.