Extramedullary myeloid sarcoma (MS, also known as granulocytic sarcoma, myeloblastoma
or chloroma) is a rare form (<1%) of extramedullary acute myeloid leukemia (AML) presenting
without bone marrow involvement.
1
Due to the rarity of this disease, contemporary clinical data are mostly limited to
small case series.
2, 3, 4, 5
The prognostic factors and outcomes of extramedullary MS are unclear. Similar to AML,
the current National Comprehensive Cancer Network guidelines recommend initial treatment
with induction chemotherapy for all patients diagnosed with extramedullary MS.
6
In this study, we utilized the National Cancer Database (NCDB) to describe the clinical
features, prognostic factors and early treatment outcomes in extramedullary MS.
We identified patients with a histologically confirmed diagnosis of extramedullary
MS from 2004 to 2013 using International Classification of Diseases for Oncology version
3 (ICD-O-3) code 9930 from the NCDB. The NCDB is a joint program of the Commission
on Cancer of the American College of Surgeons and the American Cancer Society that
collects outcomes data for over 1500 Commission-accredited cancer programs in the
nation, and accounts for >70% of new cancer diagnoses.
7
Primary site codes were used to group extramedullary MS patients by location. We excluded
patients whose primary site code was bone marrow. We analyzed overall survival (OS)
using Kaplan–Meier estimates and their differences between race and sex using log-rank
tests. To allow for ⩾1 year of follow-up, we excluded patients diagnosed in 2013 from
OS analysis. To ascertain accuracy of follow-up, the OS analysis also excluded patients
whose treatment decisions were made at a facility outside of the reporting facility.
Multivariate analysis was performed adjusting for age, sex, race and disease location.
Because NCDB records only the initial treatment and not subsequent therapies, we performed
a landmark OS analysis among those patients who survived ⩾1 month according to treatments
received during the first month after diagnosis. We investigated the effect of early
chemotherapy, surgery and radiation on survival using Cox regression models. This
analysis was done separately for patients older and younger than 70-years of age.
A total of 94 185 cases of AML were reported from 2004 to 2013. During this time period,
there were 746 patients diagnosed with extramedullary MS and comprised 0.8% of all
AML diagnoses. The median age was 59 years (range, 41–73), and 56.1% were male. The
distribution by race was 80.2% White, 9.1% Black, 2.9% Asian, and 7.8% others/unknown.
Primary site was divided into 11 categories based on organ involved at presentation
of extramedullary MS (Table 1). The three most common sites of presentation were connective/soft
tissues (31.3%), skin/breast (12.3%) and digestive system (10.3%). The median OS for
the entire cohort was 12.8 months. According to OS, we categorized the patients into
three prognostic groups: good (OS >30 months: reproductive and digestive systems),
intermediate (OS 15–30 months: head/neck, skin/breast and kidney/bladder/retroperitoneum/adrenal)
and poor (OS <15 months: nervous system, connective/soft tissue, lymph nodes/spleen,
cardiac/mediastinal and bones/joints). Compared to other races, Blacks were more likely
to have extramedullary MS involving lymph nodes/spleen (4.4 vs 13.1%, P=0.03). Asians
were more likely to have cardiopulmonary/mediastinal disease as compared to other
races (13.6 vs 4.0%, P=0.02). Although both age groups had a similar proportion of
poor prognosis sites (60.0%), younger (<70 years) patients were more likely to have
good prognosis sites as compared to older patients (⩾70 years; 19.0 vs 10.9%, P=0.005).
On multivariate analysis, factors affecting OS were age (P<0.0001), sex (P=0.0195),
race (P=0.0009), as well as disease location (P=0.0027). Median OS was worse among
males (HR 1.26; 95% CI 1.03–1.54), elderly (HR 2.42; 1.97–2.97), Blacks (HR 1.66;
95% CI 1.22–2.23) and those involving poor prognosis sites (HR 1.44; 95% CI 1.03–2.06)
as compared to their counterparts.
We included 533 patients in the landmark analysis based on early treatment. Chemotherapy
was administered to 37.7% of the patients, while 25.3% had surgery or radiation therapy
only. The remaining (37%) patients did not undergo any treatment within 30 days of
diagnosis. A very small proportion of patients underwent a hematopoietic stem cell
transplant (3.4%), although the exact nature of conditioning regimen and donor source
was unavailable. Early chemotherapy had no effect on OS in younger patients (HR=0.93;
95% CI=0.68–1.28). Among older patients, receiving early chemotherapy was associated
with higher mortality (HR=2.59; 95% CI=1.54–4.36) (Figures 1a and b). It is worthwhile
to note that a substantial proportion (19.9%) of patients underwent chemotherapy after
30 days of diagnosis (Supplementary Figure S1). Of this latter group, 25% underwent
surgery and 14% underwent radiation therapy before receiving systemic chemotherapy.
However, analyzing OS at later landmarks (60 and 90 days) yielded similar results
for survival between chemotherapy and no chemotherapy subgroups.
Ours is the largest study of extramedullary MS in the United States. A previous study
included 345 patients with extramedullary MS from the surveillance, epidemiology and
end results (SEER) database from 1973 to 2010 and demonstrated superior median OS
for extramedullary MS as compared to AML without MS (8 vs 5 months).
8
This study also showed improved survival for pelvic/genitourinary, gastrointestinal
mucosa, gonads/eye as compared to nervous system, soft tissue and lymph node/hematopoietic
tissue. In contrast, a study from Toronto evaluated 90 patients with extramedullary
MS and did not find any correlation between the site of disease and outcomes.
9
The reason for the difference in OS among various disease sites is unclear. The initial
treatment received was similar among the sites involved (Table 1). Reproductive and
digestive system MS may have a better prognosis due to early symptom onset and detection,
while poorer survival in bone MS may indicate early onset marrow involvement. Upon
reviewing these findings, one may hypothesize that extramedullary MS involving the
poor prognosis sites may benefit from early chemotherapy.
Previous institutional studies have shown that the median time to develop AML from
extramedullary MS ranged from 5 to 12 months. Hence most experts recommend treating
extramedullary MS with induction chemotherapy.
10
A case series of 15 patients with extramedullary MS and 46 AML patients with MS showed
that 87% (13/15) of extramedullary MS cases developed AML.
2
The entire cohort consisted of a higher proportion of poor prognosis sites (bone and
lymph node) than ours. In a subsequent series of 16 patients with extramedullary MS,
only 7 (44%) developed AML.
11
Six out of these seven patients died within 5 weeks to 16 months after diagnosis,
despite systemic chemotherapy in five of those six patients. The disease sites for
patients who progressed were nervous system (2), skin/subcutaneous tissue (2) and
one each of uterine, ileal and nasal fossa.
11
It is to be noted that four of the nine patients who did not progress to AML (intermediate/good
prognosis sites) were alive without evidence of disease at 3.5–16 years of initial
presentation and had received systemic chemotherapy.
11
These findings, along with our study, suggest prognostic differences based on site
of involvement of extramedullary MS, and median OS for some of the disease sites like
reproductive and digestive system is perhaps better than AML in general.
We showed a disparity in OS according to sex and race. As seen in prior studies of
AML, Blacks had a worse survival as compared to Whites.
12
Both these differences in sex and race were not seen in prior MS series, likely due
to smaller sample size.
8
The racial disparity in survival could be ascribed to higher frequency of the poor
prognosis sites (lymph nodes/spleen) in Blacks as shown in our study, or due to disease
heterogeneity.
In our study, only 37% of the patients received systemic chemotherapy within the first
30 days. A similar proportion of patients did not receive any treatment during the
same time period, with no difference in outcomes as compared to early systemic or
local therapies in younger patients. Of note, NCDB does not contain information whether
any of these patients received second line chemotherapy. Hence, our focus was on the
role of early treatment. In our study, early systemic chemotherapy was associated
with worse outcomes in older patients (>70 years) as compared to early radiation/surgery
or no treatment. This may be explained by a lower frequency of good prognosis sites
in older patients, thereby suffering from the combined impact of worse disease biology
and chemotherapy-related toxicities.
The primary limitations of our study are those related to its derivation from a database.
It does not give us information about the patients who progressed to AML and the exact
treatment regimens received. Nevertheless, it is the largest database for malignant
diseases in the United States and is especially helpful in assessing prognosis in
rare diseases like extramedullary MS, where traditional clinical studies are limited
by sample size.
Our study demonstrates that extramedullary MS has a diverse anatomic clinical presentation
and the OS varied significantly according to age, sex, race and sites of presentation.
Randomized trials analyzing optimal treatment strategy for extramedullary MS would
be challenging to conduct due the rarity of the condition. Hence the results of our
study may aid the prognostication of patients for treatment planning and in the understanding
of the biological differences by anatomic sites of presentation.