Pediatr Blood Cancer 2015;62:12–15
Utility of Bone Marrow Aspiration and Biopsy in Initial Staging of Ewing Sarcoma Lisa M. Kopp,
DO,
1
* Chengcheng Hu, PhD,2 Beatriz Rozo, NP,3 Andrea White-Collins, NP,4 Winston W. Huh, Angela Yarborough, NP,3 Cynthia E. Herzog, MD,3 and Pooja Hingorani, MD4
Background. The current standard of care for initial staging of pediatric Ewing sarcoma (EWS) patients is to obtain a bilateral bone marrow aspiration and biopsy (BMAB). The incidence of bone marrow (BM) disease in patients deemed non-metastatic by conventional and metabolic imaging and the concordance of BM positivity with other clinical characteristics are not well established. Procedure. This study is a multi-institutional retrospective review of newly diagnosed EWS patients less than 40 years of age with initial staging that included imaging and BMAB. Results. A total of 116 patients were eligible with 85 patients considered non-metastatic and 31 considered metastatic by imaging. None of the 85 patients with non-metastatic disease were BMAB positive (0%; 95% CI: 0–4.2%);
MD,
3
13 of the 31 patients with metastases were BMAB positive (41.9%; 95% CI: 24.5–60.9%). Primary tumor size was significantly higher in patients with metastases (P ¼ 0.017). Bone metastasis by imaging had high correlation with BMAB positivity (P ¼ 0.0002). In addition, the number of bony metastatic sites was significantly higher in patients with a positive BMAB as compared to those with a negative BMAB (median 3.5 and 0.0, respectively; P < 0.001). Conclusions. BMAB may not be required for initial staging of pediatric and young adult EWS patients deemed non-metastatic by imaging. In patients with metastatic disease, there is a high correlation of BM involvement with multiple bone metastases. Pediatr Blood Cancer 2015;62:12–15. # 2014 Wiley Periodicals, Inc.
Key words: bone marrow aspiration; bone marrow biopsy; bone scan; Ewing sarcoma; pediatrics; staging
INTRODUCTION Ewing sarcoma (EWS) is the second most common bone tumor in children and adolescents [1]. The overall incidence of EWS is almost three cases per million individuals per year and occurs primarily in adolescents [1]. The pelvis, femur, and rib are the most common primary tumor sites, yet one quarter of tumors arise in soft tissue rather than bone. The most common locations for metastasis are the lungs and bone, however, disease can also be found in the bone marrow. Metastatic disease is found in approximately 25% of patients at diagnosis [1]. Staging for pediatric EWS usually includes imaging of the primary site with plain film radiographs and magnetic resonance imaging (MRI) scan, and evaluation of metastatic disease with a whole body bone scan, chest computed tomography (CT) scan, whole body positron emission tomographycomputed tomography (PET/CT) (optional), and bilateral bone marrow aspiration and biopsy (BMAB) [2,3]. Prognosis for patients with metastatic disease is poor with a five year disease free survival of less than 25% [1]. The worst prognosis is found in patients with a combination of pulmonary and bone/bone marrow metastasis. Patients with only pulmonary metastatic disease have a better prognosis than those with bone metastasis [1,4,5]. However, the usefulness of performing BMAB as part of the initial staging is not well defined. The Children’s Oncology Group (COG) does not comment on the necessity of a BMAB but does require this procedure for enrollment on the current EWS protocol for patients with non-metastatic disease (NCT01231906) [6]. The National Comprehensive Cancer Networks (NCCN) Guidelines on Bone Cancer recently updated their staging recommendations to give the choice of performing bilateral BMAB or screening MRI of the spine and pelvis [7]. In the majority of pediatric institutions in the United States, the Children’s Oncology Group’s protocols are utilized and it is standard to obtain a bilateral BMAB as part of the initial staging. This is a painful procedure, with potential complications including bleeding and infection. In the pediatric population, BMAB is usually performed under anesthesia or sedation to reduce the painful experience, yet both have potential complications as well, which greatly increases the anxiety and stress level for these patients and their parents [8]. C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25212 Published online 30 August 2014 in Wiley Online Library (wileyonlinelibrary.com).
In our current study we analyzed the concordance of positive BMAB results with positive or negative metastatic status by imaging criteria. We hypothesized that patients with localized disease by imaging in specific anatomic sites are unlikely to have bone marrow disease and therefore do not warrant a BMAB. We retrospectively evaluated the characteristics of children and young adults with EWS at initial staging through imaging and pathology reports including the quality of BMAB specimens. We also evaluated if patients with metastatic disease in specific locations are more likely to have positive bone marrow disease.
METHODS Patients This retrospective study included patients less than 40 years of age with newly diagnosed EWS at the University of Arizona Medical Center, Phoenix Children’s Hospital, and the University of Texas MD Anderson Cancer Center between January 1, 2000 and December 31, 2012. Patients with incomplete initial staging imaging reports or pathology reports of BMAB were excluded from the study. After obtaining local institutional review board approval at all sites, we performed a comprehensive review of each patient’s medical record including all diagnostic imaging and BMAB evaluations to determine if metastasis was present. Information was
1
Department of Pediatrics, Division of Hematology/Oncology/BMT University of Arizona, Tucson, Arizona; 2Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health University of Arizona, Tucson, Arizona; 3Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas; 4 Division of Hematology and Oncology, Phoenix Children’s Hospital, University of Arizona Phoenix, Arizona Conflict of interest: Nothing to declare.
Correspondence to: Lisa M. Kopp, University of Arizona, Department of Pediatrics, 1501 N. Campbell Ave., PO Box 245073, Tucson, AZ 85724-5073. E-mail: [email protected] Received 30 June 2014; Accepted 9 July 2014
Bone Marrow Aspiration and Biopsy in EWS collected on each patient’s age at diagnosis, sex, primary tumor site, tumor size, metastatic sites by imaging and BMAB results. We categorized primary tumor site as pelvic or non-pelvic and categorized metastatic sites by lung alone, bone alone, bone marrow alone or multiple sites (more than one organ system). For those patients with bone metastasis, the number of bony sites involved was recorded if available.
Imaging For each patient we reviewed the diagnostic imaging reports of the primary tumor using MRI scans. The longest dimension of the primary tumor was recorded in centimeters for tumor size as threedimensional measurements were not available for all cases to calculate tumor volume. The diagnosis of metastasis for each patient was determined by the final imaging report at each institution, including chest CT for pulmonary metastasis and wholebody bone scans for bone metastasis. We recorded if metastatic disease was lung alone, bone alone, bone marrow alone, or multiple sites and which of these sites (lung, bone, bone marrow or other) were involved.
Bone Marrow Sampling All BMAB samples were obtained from the iliac crest either bilaterally or unilaterally. Bone marrow disease status was determined by reviewing the pathology reports individually for the right and left BMAB results on each patient. We recorded if an aspirate or biopsy was completed and if the samples were adequate as well as whether the sample was obtained from the right, left, or bilateral iliac crests. A bone marrow was considered positive if the pathologist’s report indicated EWS tumor cells present in the aspirate or core biopsy either on H&E stain or by immunohistochemistry.
Statistical Analysis For the estimate of any proportion, the 95% Clopper-Pearson confidence interval (CI) was also calculated. Fisher’s exact test was used to compare proportions between two groups. For the comparison of continuous or ordinal variables between two groups
13
the Wilcoxon rank-sum test was used. All tests were two-sided alpha with 0.05 significance level.
RESULTS Patient Characteristics Our data set included 116 eligible patients, 85 with nonmetastatic disease and 31 with metastatic disease by imaging at initial diagnosis (Table I). There was a male preponderance consistent with historical data. The median age at diagnosis was younger (13 years) with a range of 1–38 years for non-metastatic disease versus metastatic disease (16 years) with a range of 3–25 years. This difference in age was not found to be statistically significant. Pelvic primary tumors were found more frequently in patients with metastatic disease at presentation (P ¼ 0.0038). The primary tumor size was significantly larger in patients with metastatic disease compared to those with non-metastatic disease at presentation (P ¼ 0.017). Patients with metastatic disease most often had involvement of multiple metastatic sites (52%) at initial presentation as opposed to lung (42%), bone (6%), or bone marrow (0.0%) alone. Of the multiple metastatic sites, the most common site of metastasis was bone.
Imaging and Bone Marrow Aspiration and Biopsy Results None of the 85 patients with non-metastatic disease determined by imaging had a positive BMAB. Of the patients with a pelvic primary, 21% had bone marrow disease whereas 9% of patients without a pelvic primary had bone marrow disease. Having a pelvic primary did not correlate with having bone marrow disease (P ¼ 0.189) (Table II). Of the patients with metastatic disease by imaging, 42% had a positive BMAB. Patients who were found to have bone metastasis had a high correlation of a positive BMAB (P ¼ 0.002) whereas patients having lung metastasis had a low correlation with a positive BMAB (P ¼ 0.017) (Table III). Patients with a positive BMAB had significantly increased number of bony metastatic sites versus patients with a negative BMAB, 3.5 bone metastasis versus 0.0 (P < 0.001).
TABLE I. Patient Characteristics Metastatica
P-value
85 13 (1, 38)
31 16 (3, 25)
— 0.1614
38 (44.7%) 47 (55.3%) 85 (100.0%)
13 (41.9%) 18 (58.1%) 31 (100.0%)
0.8352
Non-metastatica Number of subjects Age at diagnosis Sex Female Male Total Site UE LE Pelvis Spine Other Total Tumor size (cm)
21 21 19 6 18 85 7.5 a
(24.7%) (24.7%) (22.4%) (7.1%) (21.2%) (100.0%) (1.3, 26.0)
4 8 14 1 4 31 11.2
(12.9%) (25.8%) (45.2%) (3.2%) (12.9%) (100.0%) (3.5, 35)
0.017
UE, upper extremity; LE, lower extremity. Median (min, max) for continuous variables and count (percentage) for categorical variables. Fisher’s exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. Pediatr Blood Cancer DOI 10.1002/pbc
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Kopp et al.
TABLE II. Correlation of Patients With a Positive BMAB Versus a Negative BMAB to Pelvic and Non-Pelvic Primary Sites
BMAB positive BMAB negative
Pelvic primary
Non-pelvic primary
6 27
7 76
TABLE III. Correlation of BMAB Results and Metastasis by Imaging Bone
0.189
A positive pelvic primary site was not correlated with a positive bone marrow.
BMAB results
Yes
No
Yes
No
Positive Negative P-value for association
12 4
1 14
6 16
7 2
Concordance of BoneMarrow Aspirate and Biopsy Specimens Of the 116 patients, 111 had bilateral BMAB results. Of the patients who did not have bilateral results, three had pelvic tumors, one had a chest wall tumor and one had a hand tumor. For the concordance of bone marrow aspirate and biopsy from the left side, 114 of the 116 patients (98.3%; 95% CI: 93.9–99.8%) had the same results, and the two patients with discordant results both had positive biopsy but negative aspirate. For the concordance of bone marrow aspirate and biopsy from the right side, 115 of the 116 patients (99.1%; 95% CI: 95.3–100.0%) had the same results, and the patient with discordant results had negative biopsy but the result of the aspirate was not available.
DISCUSSION In this study, we aimed to better define the necessity of BMAB in the initial staging of pediatric and young adult patients with Ewing sarcoma. The current standard of care for pediatric and young adult patients is to perform BMAB in all patients as part of the initial staging evaluation, even if it has been determined by imaging that the patient only has localized disease. However, in adult patients a BMAB is not routinely performed, and the current NCCN guidelines recommend an MRI of the spine and pelvis as an alternative to BMAB [7]. More recently, imaging modalities including PET/CT are becoming increasingly used in the initial staging of adult and pediatric patients with EWS and other sarcomas [6,7]. Recent reviews evaluating the use of PET/CT in EWS and rhabdomyosarcoma (RMS) have demonstrated that it has a high sensitivity and specificity for detection of metastasis, specifically bone metastases when compared to bone scan and MRI [9–11]. Also, multiple studies have been published which demonstrate the ability of PET/ CT to detect bone marrow metastasis in Hodgkin’s and NonHodgkin’s Lymphoma just as effectively as bone marrow biopsy [10,12,13]. We did not include PET/CT in our analysis, as it was not utilized consistently until the last few years of our study period. But our results using bone scan were similar to those published using PET scans in terms of correlation of bone metastasis with positive BMAB. Newman et al. published a review evaluating PET/CT as well as BMAB in EWS. In 91 newly diagnosed pediatric patients with EWS, all patients without metastases by PET/CT scan also had negative BMAB [11].Weiss et al. recently published their findings in a large cohort of childhood RMS patients evaluating the necessity of BMAB for these patients. They found that RMS patients who had T1 tumors (tumors less than 5 cm and localized disease) had a low Pediatr Blood Cancer DOI 10.1002/pbc
Lung
P-value
0.0002
0.017
Fisher’s exact test was used to evaluate association.
rate of metastasis at all sites. Specifically none of their 614 patients (36% of their cohort) who were found to have T1 tumors had metastatic disease. This led them to conclude that in this specific group of RMS patients a BMAB was unnecessary [14]. In our retrospective review of 116 patients with newly diagnosed EWS, none of 85 patients with local disease by imaging had a positive bone marrow aspiration or bone marrow biopsy, similar to studies by Weiss and Newman [11,14]. Of the 64 patients for whom we had tumor size available, we did not find a correlation between tumor size and a positive BMAB as Weiss et al. did in their cohort; however, we had a smaller sample size so the finding might be different with a larger cohort of EWS patients. Our patients with metastatic disease were most commonly found to have multiple sites of metastasis rather than solely one organ/location of metastasis. The second most common sites of metastasis were pulmonary alone followed by bone alone. None of our patients with metastases had bone marrow metastasis as the sole site of metastatic disease. When evaluating our population with only pelvic disease, we found that having a pelvic primary was not correlated with bone marrow disease. However, it is possible that our cohort size was too small to adequately analyze the association between pelvic primary tumor site and positive bone marrow disease. One argument that BMAB is necessary for EWS patients is that there is a need to monitor bone marrow status for those patients that may have myeloablative chemotherapy with autologous stem cell rescue (MC-ASCR). The effectiveness of this treatment is controversial as the results are mixed regarding improved survival [15–17]. The only prospective trial to evaluate MC-ASCR was the EURO-EWING 99 trial for newly diagnosed patients with metastatic EWS. This arm of the study was not randomized, therefore definitive conclusions on superiority of this treatment cannot be made [18]. Patients with multiple bone metastases should have a BMAB if they are being considered for a MC-ASCR in their future treatment. The evaluation for minimal residual disease (MRD) in bone marrow though reverse transcriptase polymerase chain reaction (RT-PCR) may be another argument for BMAB in EWS patients. Greater than 95% of EWS cells have a chromosomal translocation between chromosome 22 and 11, or less frequently between chromosome 22 and chromosome 21, 7, 17, or 2 [19]. These translocations can be detected through RT-PCR. Schleiermacher et al. performed RT-PCR on blood and bone marrow specimens in 172 Ewing’s sarcoma patients, and they found that patients with localized disease who had RT-PCR positivity of their bone marrow had a poorer outcome than those with a negative RT-PCR [20]. Also, patients with localized disease found to have circulating tumor cells via RT-PCR had a poorer outcome compared to those
Bone Marrow Aspiration and Biopsy in EWS without circulating tumor cells [20]. Therefore, one could argue that evaluating a peripheral blood sample is much less invasive than BMAB; however, there is currently no study to date able to conclude whether peripheral blood RT-PCR or BMAB is most accurate. Wagner et al. recently published a review on molecular techniques utilizing RT-PCR as well as flow cytometry and fluorescent in situ hybridization for evaluation of minimal residual disease (MRD) of EWS [21]. As the utilization of these techniques continues to be developed, it will require large clinical trials to determine the most sensitive method for detecting MRD. Limitations of our study include the retrospective nature of the study as well as the small cohort size. In addition, we did not perform centralized imaging or pathology analysis of all cases. However, since EWS is a rare tumor, re-evaluation of our results should be done in the context of a prospective collaborative group study. Strengths of our study include its multi-institutional design and diverse patient population. In conclusion our study demonstrates that in pediatric and young adult patients with non-metastatic EWS as determined by imaging studies, BMAB may potentially be eliminated as part of the initial staging evaluation. However, our findings need to be validated in a larger cohort. Future studies should attempt to prospectively correlate imaging studies such as PET/CT scan with bone marrow positivity and also to correlate primary tumor site such as pelvic tumors with bone marrow involvement.
REFERENCES 1. Esiashvili N, Goodman M, Marcus RB Jr. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance epidemiology and end results data. J Pediatr Hematol Oncol 2008;30:425–430. 2. Arndt CA, Rose PS, Folpe AL, et al. Common musculoskeletal tumors of childhood and adolescence. Mayo Clin Proc 2012;87:475–487.
Pediatr Blood Cancer DOI 10.1002/pbc
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3. Balamuth NJ, Womer RB. Ewing’s sarcoma. Lancet Oncol 2010;11:184–192. 4. Bacci G, Balladelli A, Forni C, et al. Ewing’s sarcoma family tumours. Differences in clinicopathological characteristics at presentation between localised and metastatic tumours. J Bone Joint Surg Br 2007;89:1229–1233. 5. Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing’s tumor of bone: Analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 2000;18:3108–3114. 6. Meyer JS, Nadel HR, Marina N, et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: A report from the Children’s Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 2008;51:163–170. 7. NCCN. NCCN Clinical Practice Guidelines in Oncology: Bone Cancer. NCCN Clinical Practice Guidelines in Oncology 2013; http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. Accessed March 2, 2013. 8. Hockenberry MJ, McCarthy K, Taylor O, et al. Managing painful procedures in children with cancer. J Pediatr Hematol Oncol 2011;33:119–127. 9. Eugene T, Corradini N, Carlier T, et al. (1)(8)F-FDG-PET/CT in initial staging and assessment of early response to chemotherapy of pediatric rhabdomyosarcomas. Nucl Med Commun 2012;33:1089– 1095. 10. Treglia G, Salsano M, Stefanelli A, et al. Diagnostic accuracy of (1)(8)F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours: A systematic review and a meta-analysis. Skeletal Radiol 2012;41:249–256. 11. Newman EN, Jones RL, Hawkins DS. An evaluation of [F-18]-fluorodeoxy-D-glucose positron emission tomography, bone scan, and bone marrow aspiration/biopsy as staging investigations in Ewing sarcoma. Pediatr Blood Cancer 2013;60:1113–1117. 12. Muzahir S, Mian M, Munir I, et al. Clinical utility of (1)(8)F FDG-PET/CT in the detection of bone marrow disease in Hodgkin’s lymphoma. Br J Radiol 2012;85:e490–496. 13. Moulin-Romsee G, Hindie E, Cuenca X, et al. (18)F-FDG PET/CT bone/bone marrow findings in Hodgkin’s lymphoma may circumvent the use of bone marrow trephine biopsy at diagnosis staging. Eur J Nucl Med 2010;37:1095–1105. 14. Weiss AR, Lyden ER, Anderson JR, et al. Histologic and clinical characteristics can guide staging evaluations for children and adolescents with Rhabdomyosarcoma: A report from the Children’s Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol 2013;12:3226–3232. 15. Fraser CJ, Weigel BJ, Perentesis JP, et al. Autologous stem cell transplantation for high-risk Ewing’s sarcoma and other pediatric solid tumors. Bone Marrow Transplant 2006;37:175–181. 16. Paulussen M, Ahrens S, Burdach S, et al. Primary metastatic (stage IV) Ewing tumor: Survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 1998;9:275–281. 17. Meyers PA, Krailo MD, Ladanyi M, et al. High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing’s sarcoma does not improve prognosis. J Clin Oncol 2001;19:2812–2820. 18. Ladenstein R, Potschger U, Le Deley MC, et al. Primary disseminated multifocal Ewing sarcoma: Results of the Euro-EWING 99 trial. J Clin Oncol 2010;28:3284–3291. 19. Delattre O, Zucman J, Melot T, et al. The Ewing family of tumors–a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 1994;331:294–299. 20. Schleiermacher G, Peter M, Oberlin O, et al. Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J Clin Oncol 2003;21: 85–91. 21. Wagner LM, Smolarek TA, Sumegi J, et al. Assessment of minimal residual disease in ewing sarcoma. Sarcoma 2012;2012:8. Article ID: 780129.
Utility of Bone Marrow Aspiration and Biopsy in Initial Staging of Ewing Sarcoma Lisa M. Kopp,
DO,
1
* Chengcheng Hu, PhD,2 Beatriz Rozo, NP,3 Andrea White-Collins, NP,4 Winston W. Huh, Angela Yarborough, NP,3 Cynthia E. Herzog, MD,3 and Pooja Hingorani, MD4
Background. The current standard of care for initial staging of pediatric Ewing sarcoma (EWS) patients is to obtain a bilateral bone marrow aspiration and biopsy (BMAB). The incidence of bone marrow (BM) disease in patients deemed non-metastatic by conventional and metabolic imaging and the concordance of BM positivity with other clinical characteristics are not well established. Procedure. This study is a multi-institutional retrospective review of newly diagnosed EWS patients less than 40 years of age with initial staging that included imaging and BMAB. Results. A total of 116 patients were eligible with 85 patients considered non-metastatic and 31 considered metastatic by imaging. None of the 85 patients with non-metastatic disease were BMAB positive (0%; 95% CI: 0–4.2%);
MD,
3
13 of the 31 patients with metastases were BMAB positive (41.9%; 95% CI: 24.5–60.9%). Primary tumor size was significantly higher in patients with metastases (P ¼ 0.017). Bone metastasis by imaging had high correlation with BMAB positivity (P ¼ 0.0002). In addition, the number of bony metastatic sites was significantly higher in patients with a positive BMAB as compared to those with a negative BMAB (median 3.5 and 0.0, respectively; P < 0.001). Conclusions. BMAB may not be required for initial staging of pediatric and young adult EWS patients deemed non-metastatic by imaging. In patients with metastatic disease, there is a high correlation of BM involvement with multiple bone metastases. Pediatr Blood Cancer 2015;62:12–15. # 2014 Wiley Periodicals, Inc.
Key words: bone marrow aspiration; bone marrow biopsy; bone scan; Ewing sarcoma; pediatrics; staging
INTRODUCTION Ewing sarcoma (EWS) is the second most common bone tumor in children and adolescents [1]. The overall incidence of EWS is almost three cases per million individuals per year and occurs primarily in adolescents [1]. The pelvis, femur, and rib are the most common primary tumor sites, yet one quarter of tumors arise in soft tissue rather than bone. The most common locations for metastasis are the lungs and bone, however, disease can also be found in the bone marrow. Metastatic disease is found in approximately 25% of patients at diagnosis [1]. Staging for pediatric EWS usually includes imaging of the primary site with plain film radiographs and magnetic resonance imaging (MRI) scan, and evaluation of metastatic disease with a whole body bone scan, chest computed tomography (CT) scan, whole body positron emission tomographycomputed tomography (PET/CT) (optional), and bilateral bone marrow aspiration and biopsy (BMAB) [2,3]. Prognosis for patients with metastatic disease is poor with a five year disease free survival of less than 25% [1]. The worst prognosis is found in patients with a combination of pulmonary and bone/bone marrow metastasis. Patients with only pulmonary metastatic disease have a better prognosis than those with bone metastasis [1,4,5]. However, the usefulness of performing BMAB as part of the initial staging is not well defined. The Children’s Oncology Group (COG) does not comment on the necessity of a BMAB but does require this procedure for enrollment on the current EWS protocol for patients with non-metastatic disease (NCT01231906) [6]. The National Comprehensive Cancer Networks (NCCN) Guidelines on Bone Cancer recently updated their staging recommendations to give the choice of performing bilateral BMAB or screening MRI of the spine and pelvis [7]. In the majority of pediatric institutions in the United States, the Children’s Oncology Group’s protocols are utilized and it is standard to obtain a bilateral BMAB as part of the initial staging. This is a painful procedure, with potential complications including bleeding and infection. In the pediatric population, BMAB is usually performed under anesthesia or sedation to reduce the painful experience, yet both have potential complications as well, which greatly increases the anxiety and stress level for these patients and their parents [8]. C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25212 Published online 30 August 2014 in Wiley Online Library (wileyonlinelibrary.com).
In our current study we analyzed the concordance of positive BMAB results with positive or negative metastatic status by imaging criteria. We hypothesized that patients with localized disease by imaging in specific anatomic sites are unlikely to have bone marrow disease and therefore do not warrant a BMAB. We retrospectively evaluated the characteristics of children and young adults with EWS at initial staging through imaging and pathology reports including the quality of BMAB specimens. We also evaluated if patients with metastatic disease in specific locations are more likely to have positive bone marrow disease.
METHODS Patients This retrospective study included patients less than 40 years of age with newly diagnosed EWS at the University of Arizona Medical Center, Phoenix Children’s Hospital, and the University of Texas MD Anderson Cancer Center between January 1, 2000 and December 31, 2012. Patients with incomplete initial staging imaging reports or pathology reports of BMAB were excluded from the study. After obtaining local institutional review board approval at all sites, we performed a comprehensive review of each patient’s medical record including all diagnostic imaging and BMAB evaluations to determine if metastasis was present. Information was
1
Department of Pediatrics, Division of Hematology/Oncology/BMT University of Arizona, Tucson, Arizona; 2Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health University of Arizona, Tucson, Arizona; 3Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas; 4 Division of Hematology and Oncology, Phoenix Children’s Hospital, University of Arizona Phoenix, Arizona Conflict of interest: Nothing to declare.
Correspondence to: Lisa M. Kopp, University of Arizona, Department of Pediatrics, 1501 N. Campbell Ave., PO Box 245073, Tucson, AZ 85724-5073. E-mail: [email protected] Received 30 June 2014; Accepted 9 July 2014
Bone Marrow Aspiration and Biopsy in EWS collected on each patient’s age at diagnosis, sex, primary tumor site, tumor size, metastatic sites by imaging and BMAB results. We categorized primary tumor site as pelvic or non-pelvic and categorized metastatic sites by lung alone, bone alone, bone marrow alone or multiple sites (more than one organ system). For those patients with bone metastasis, the number of bony sites involved was recorded if available.
Imaging For each patient we reviewed the diagnostic imaging reports of the primary tumor using MRI scans. The longest dimension of the primary tumor was recorded in centimeters for tumor size as threedimensional measurements were not available for all cases to calculate tumor volume. The diagnosis of metastasis for each patient was determined by the final imaging report at each institution, including chest CT for pulmonary metastasis and wholebody bone scans for bone metastasis. We recorded if metastatic disease was lung alone, bone alone, bone marrow alone, or multiple sites and which of these sites (lung, bone, bone marrow or other) were involved.
Bone Marrow Sampling All BMAB samples were obtained from the iliac crest either bilaterally or unilaterally. Bone marrow disease status was determined by reviewing the pathology reports individually for the right and left BMAB results on each patient. We recorded if an aspirate or biopsy was completed and if the samples were adequate as well as whether the sample was obtained from the right, left, or bilateral iliac crests. A bone marrow was considered positive if the pathologist’s report indicated EWS tumor cells present in the aspirate or core biopsy either on H&E stain or by immunohistochemistry.
Statistical Analysis For the estimate of any proportion, the 95% Clopper-Pearson confidence interval (CI) was also calculated. Fisher’s exact test was used to compare proportions between two groups. For the comparison of continuous or ordinal variables between two groups
13
the Wilcoxon rank-sum test was used. All tests were two-sided alpha with 0.05 significance level.
RESULTS Patient Characteristics Our data set included 116 eligible patients, 85 with nonmetastatic disease and 31 with metastatic disease by imaging at initial diagnosis (Table I). There was a male preponderance consistent with historical data. The median age at diagnosis was younger (13 years) with a range of 1–38 years for non-metastatic disease versus metastatic disease (16 years) with a range of 3–25 years. This difference in age was not found to be statistically significant. Pelvic primary tumors were found more frequently in patients with metastatic disease at presentation (P ¼ 0.0038). The primary tumor size was significantly larger in patients with metastatic disease compared to those with non-metastatic disease at presentation (P ¼ 0.017). Patients with metastatic disease most often had involvement of multiple metastatic sites (52%) at initial presentation as opposed to lung (42%), bone (6%), or bone marrow (0.0%) alone. Of the multiple metastatic sites, the most common site of metastasis was bone.
Imaging and Bone Marrow Aspiration and Biopsy Results None of the 85 patients with non-metastatic disease determined by imaging had a positive BMAB. Of the patients with a pelvic primary, 21% had bone marrow disease whereas 9% of patients without a pelvic primary had bone marrow disease. Having a pelvic primary did not correlate with having bone marrow disease (P ¼ 0.189) (Table II). Of the patients with metastatic disease by imaging, 42% had a positive BMAB. Patients who were found to have bone metastasis had a high correlation of a positive BMAB (P ¼ 0.002) whereas patients having lung metastasis had a low correlation with a positive BMAB (P ¼ 0.017) (Table III). Patients with a positive BMAB had significantly increased number of bony metastatic sites versus patients with a negative BMAB, 3.5 bone metastasis versus 0.0 (P < 0.001).
TABLE I. Patient Characteristics Metastatica
P-value
85 13 (1, 38)
31 16 (3, 25)
— 0.1614
38 (44.7%) 47 (55.3%) 85 (100.0%)
13 (41.9%) 18 (58.1%) 31 (100.0%)
0.8352
Non-metastatica Number of subjects Age at diagnosis Sex Female Male Total Site UE LE Pelvis Spine Other Total Tumor size (cm)
21 21 19 6 18 85 7.5 a
(24.7%) (24.7%) (22.4%) (7.1%) (21.2%) (100.0%) (1.3, 26.0)
4 8 14 1 4 31 11.2
(12.9%) (25.8%) (45.2%) (3.2%) (12.9%) (100.0%) (3.5, 35)
0.017
UE, upper extremity; LE, lower extremity. Median (min, max) for continuous variables and count (percentage) for categorical variables. Fisher’s exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. Pediatr Blood Cancer DOI 10.1002/pbc
14
Kopp et al.
TABLE II. Correlation of Patients With a Positive BMAB Versus a Negative BMAB to Pelvic and Non-Pelvic Primary Sites
BMAB positive BMAB negative
Pelvic primary
Non-pelvic primary
6 27
7 76
TABLE III. Correlation of BMAB Results and Metastasis by Imaging Bone
0.189
A positive pelvic primary site was not correlated with a positive bone marrow.
BMAB results
Yes
No
Yes
No
Positive Negative P-value for association
12 4
1 14
6 16
7 2
Concordance of BoneMarrow Aspirate and Biopsy Specimens Of the 116 patients, 111 had bilateral BMAB results. Of the patients who did not have bilateral results, three had pelvic tumors, one had a chest wall tumor and one had a hand tumor. For the concordance of bone marrow aspirate and biopsy from the left side, 114 of the 116 patients (98.3%; 95% CI: 93.9–99.8%) had the same results, and the two patients with discordant results both had positive biopsy but negative aspirate. For the concordance of bone marrow aspirate and biopsy from the right side, 115 of the 116 patients (99.1%; 95% CI: 95.3–100.0%) had the same results, and the patient with discordant results had negative biopsy but the result of the aspirate was not available.
DISCUSSION In this study, we aimed to better define the necessity of BMAB in the initial staging of pediatric and young adult patients with Ewing sarcoma. The current standard of care for pediatric and young adult patients is to perform BMAB in all patients as part of the initial staging evaluation, even if it has been determined by imaging that the patient only has localized disease. However, in adult patients a BMAB is not routinely performed, and the current NCCN guidelines recommend an MRI of the spine and pelvis as an alternative to BMAB [7]. More recently, imaging modalities including PET/CT are becoming increasingly used in the initial staging of adult and pediatric patients with EWS and other sarcomas [6,7]. Recent reviews evaluating the use of PET/CT in EWS and rhabdomyosarcoma (RMS) have demonstrated that it has a high sensitivity and specificity for detection of metastasis, specifically bone metastases when compared to bone scan and MRI [9–11]. Also, multiple studies have been published which demonstrate the ability of PET/ CT to detect bone marrow metastasis in Hodgkin’s and NonHodgkin’s Lymphoma just as effectively as bone marrow biopsy [10,12,13]. We did not include PET/CT in our analysis, as it was not utilized consistently until the last few years of our study period. But our results using bone scan were similar to those published using PET scans in terms of correlation of bone metastasis with positive BMAB. Newman et al. published a review evaluating PET/CT as well as BMAB in EWS. In 91 newly diagnosed pediatric patients with EWS, all patients without metastases by PET/CT scan also had negative BMAB [11].Weiss et al. recently published their findings in a large cohort of childhood RMS patients evaluating the necessity of BMAB for these patients. They found that RMS patients who had T1 tumors (tumors less than 5 cm and localized disease) had a low Pediatr Blood Cancer DOI 10.1002/pbc
Lung
P-value
0.0002
0.017
Fisher’s exact test was used to evaluate association.
rate of metastasis at all sites. Specifically none of their 614 patients (36% of their cohort) who were found to have T1 tumors had metastatic disease. This led them to conclude that in this specific group of RMS patients a BMAB was unnecessary [14]. In our retrospective review of 116 patients with newly diagnosed EWS, none of 85 patients with local disease by imaging had a positive bone marrow aspiration or bone marrow biopsy, similar to studies by Weiss and Newman [11,14]. Of the 64 patients for whom we had tumor size available, we did not find a correlation between tumor size and a positive BMAB as Weiss et al. did in their cohort; however, we had a smaller sample size so the finding might be different with a larger cohort of EWS patients. Our patients with metastatic disease were most commonly found to have multiple sites of metastasis rather than solely one organ/location of metastasis. The second most common sites of metastasis were pulmonary alone followed by bone alone. None of our patients with metastases had bone marrow metastasis as the sole site of metastatic disease. When evaluating our population with only pelvic disease, we found that having a pelvic primary was not correlated with bone marrow disease. However, it is possible that our cohort size was too small to adequately analyze the association between pelvic primary tumor site and positive bone marrow disease. One argument that BMAB is necessary for EWS patients is that there is a need to monitor bone marrow status for those patients that may have myeloablative chemotherapy with autologous stem cell rescue (MC-ASCR). The effectiveness of this treatment is controversial as the results are mixed regarding improved survival [15–17]. The only prospective trial to evaluate MC-ASCR was the EURO-EWING 99 trial for newly diagnosed patients with metastatic EWS. This arm of the study was not randomized, therefore definitive conclusions on superiority of this treatment cannot be made [18]. Patients with multiple bone metastases should have a BMAB if they are being considered for a MC-ASCR in their future treatment. The evaluation for minimal residual disease (MRD) in bone marrow though reverse transcriptase polymerase chain reaction (RT-PCR) may be another argument for BMAB in EWS patients. Greater than 95% of EWS cells have a chromosomal translocation between chromosome 22 and 11, or less frequently between chromosome 22 and chromosome 21, 7, 17, or 2 [19]. These translocations can be detected through RT-PCR. Schleiermacher et al. performed RT-PCR on blood and bone marrow specimens in 172 Ewing’s sarcoma patients, and they found that patients with localized disease who had RT-PCR positivity of their bone marrow had a poorer outcome than those with a negative RT-PCR [20]. Also, patients with localized disease found to have circulating tumor cells via RT-PCR had a poorer outcome compared to those
Bone Marrow Aspiration and Biopsy in EWS without circulating tumor cells [20]. Therefore, one could argue that evaluating a peripheral blood sample is much less invasive than BMAB; however, there is currently no study to date able to conclude whether peripheral blood RT-PCR or BMAB is most accurate. Wagner et al. recently published a review on molecular techniques utilizing RT-PCR as well as flow cytometry and fluorescent in situ hybridization for evaluation of minimal residual disease (MRD) of EWS [21]. As the utilization of these techniques continues to be developed, it will require large clinical trials to determine the most sensitive method for detecting MRD. Limitations of our study include the retrospective nature of the study as well as the small cohort size. In addition, we did not perform centralized imaging or pathology analysis of all cases. However, since EWS is a rare tumor, re-evaluation of our results should be done in the context of a prospective collaborative group study. Strengths of our study include its multi-institutional design and diverse patient population. In conclusion our study demonstrates that in pediatric and young adult patients with non-metastatic EWS as determined by imaging studies, BMAB may potentially be eliminated as part of the initial staging evaluation. However, our findings need to be validated in a larger cohort. Future studies should attempt to prospectively correlate imaging studies such as PET/CT scan with bone marrow positivity and also to correlate primary tumor site such as pelvic tumors with bone marrow involvement.
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