Int J Hematol (2014) 100:457–463 DOI 10.1007/s12185-014-1659-y
ORIGINAL ARTICLE
Clinicopathological and molecular features of myeloid sarcoma as initial presentation of therapy-related myeloid neoplasms: a single institution experience Deniz Peker • Vishwas Parekh • Ravikumar Paluri • Taylor Deal • Uma Borate • Antonio Di Stasi • Shuko Harada • Emmanuel Agosto Arroyo Vishnu Reddy
•
Received: 29 June 2014 / Revised: 26 August 2014 / Accepted: 1 September 2014 / Published online: 11 September 2014 Ó The Japanese Society of Hematology 2014
Abstract Therapy-related myeloid neoplasms (t-MN) have a common origin in prior cytotoxic therapy and/or radiation. These neoplasms include therapy-related acute myeloid leukemia, myelodysplastic syndrome (t-MDS), and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN). Myeloid sarcoma (MS), on the other hand, is a rare disease manifesting as an extramedullary collection of immature cells of myeloid lineage. Rarer still is therapy-related MS (t-MS), which has not been adequately studied due to its rarity and its lack of recognition as a unique entity among other t-MN. Here, we report what is to our knowledge the first case series of t-MS, with the aim of investigating and establishing salient clinicopathological and molecular features of this entity. Keywords Therapy-related myeloid neoplasms Acute myeloid leukemia Myeloid sarcoma
Introduction Therapy-related myeloid neoplasms (t-MN) refer to secondary acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) that occur as a late complication of prior treatment with cytotoxic chemotherapeutic agents and/or radiation for various cancers [1–8]. t-MN account
up to 20 % of all cases of AML, MDS, and MDS/MPN [9– 11] and is generally associated with a poor prognosis [2]. Although molecular alterations are yet to be understood in these disease, BRAF mutation has been found in t-MN often associated with MLL gene re-arrangement [12]. Myeloid sarcoma (MS) is a rare myeloid neoplasm of immature myeloid precursors that occurs at various extramedullary sites, most frequently in skin (also known as leukemia cutis), but also lymph nodes, gastrointestinal tract, bone, and virtually every organ and tissue in the body [13–16]. MS can occur de novo [17] or concurrently with AML [18, 19], MDS [20, 21] or MDS/MPN [22, 23]. The prognostic factors and clinical behavior for these patients still remain unknown. Some studies have demonstrated a difference in the clinical behavior between patients with isolated MS and MS patients with concomitant AML or relapsed-AML [24]. Therapy-related myeloid sarcoma (t-MS) is an extremely rare entity with sporadic cases reported in the English literature [25, 26]. Due to the rare incidence, the clinical significance of t-MS, either de novo or with concurrent t-AML, is not yet determined. In this study, we report our experience t-MS, a subtype of MS, in patients with a history of prior cytotoxic treatment for malignant diseases. We present the clinicopathological, immunophenotypic, and molecular findings in nine t-MS cases and compare them with t-AML and conventional MS.
D. Peker (&) V. Parekh T. Deal S. Harada E. A. Arroyo V. Reddy Department of Pathology, University of Alabama, 1802 6th Ave South, NP 3552, Birmingham, AL 35233-7331, USA e-mail: [email protected]
Materials and methods
R. Paluri U. Borate A. Di Stasi Division of Hematology and Oncology, Department of Medicine, University of Alabama, Birmingham, AL, USA
A search of the electronic databases of the Department of Pathology at the University of Alabama at Birmingham
Study group
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was conducted to retrieve the cases of t-AML and MS between January 1, 2003 and December 31, 2013 following Institutional Review Board approval. The study was limited to include only adult patients at the age of 19 years and above. The clinicopathological data and archived hematoxylin–eosin, Wright–Giemsa, and immunohistochemically stained tissue sections were reviewed for each patient. The clinicopathological data collected included patient demographics (age and gender), site of MS, prior disease and treatment history, complete blood count and differential counts, peripheral blood and bone marrow blast counts, serum lactate dehydrogenase (LDH) level, bone marrow status, flow cytometry, karyotype, fluorescence in situ hybridization (FISH), molecular genetic testing results (when available), and clinical follow-up for each patient.
area on FFPE tissue sections and amplified by polymerase chain reaction with primers specific to exon 15 of the BRAF gene. The amplified product was purified, and direct gene sequencing was performed using capillary electrophoresis. Computer analysis of sequencing data was done to determine mutation presence or absence. Results were reported as ‘‘wild type’’ or ‘‘mutation positive’’ in exon 15 of the BRAF gene including codon 600.
Histology, immunohistochemistry, and flow cytometry
Results
Hematoxylin and eosin and immunohistochemically stained slides from formalin-fixed, paraffin-embedded (FFPE) tissue sections and Wright–Giemsa-stained peripheral blood and bone marrow aspirate smears were reviewed for each case to confirm the initial diagnosis. Immunohistochemical stains were performed on each MS case, which included the antibodies to CD45 (Dako North America, Carpentaria, CA, USA), CD43 (Ventana, Tuscan, AR, USA), CD3, CD117 (Biocare, Concord, AR, USA), CD33 (Leica-Novocastra, Buffalo Grove, IL, USA), CD68 (Thermo, Fremont, CA, USA), and myeloperoxidase (Ventana, Tuscan, AR, USA). The stains were performed on FFPE Sections (5 lm thickness) using two detection platforms—Dako AutostainerLink 48 and Ventana semiautostainer. Flow cytometry was performed using 4-color flow cytometry (Becton–Dickinson FACSort, San Jose, CA, USA).
Clinicopathological characteristics
Molecular studies Ancillary test results including conventional cytogenetics and FISH were available in the majority of the t-AML cases and MS cases which were performed on the subsequent bone marrow biopsy following the diagnosis of MS. AML FISH panel included -5/5q-: D5S630 [5p15.2]/ EGR1 [5q31], t(8;21): ETO [8q22]/AML1 [21q22], 11q23: 5’MLL/3’MLL, 16q22: 5’CBFb/3’CBFb, and -7/7q-: ELN [7q11.23]/D7S486 [7q31]. MDS FISH panel included -5/ 5q-: D5S630 [5p15.2]/EGR1 [5q31], -7/7q-: ELN [7q11.23]/D7S486 [7q31], ?8: 8cen (8p11.1q11.1), and 20q-: 20q12. FLT3-ITD and FLT3-TKD mutation assays were performed by multiplex PCR and capillary electrophoresis. For BRAF gene mutation analysis, tissue sections were reviewed by a pathologist and relevant tumor area was selected for analysis. DNA was extracted from tumor
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Statistics All statistical analysis was performed using SAS v9.4 software (Cary, NC, USA) and Kaplan–Meier survival analysis.
The electronic database search revealed a total of 9 patients with a diagnosis of myeloid sarcoma that had a prior history of cytotoxic chemotherapy and/or radiation therapy. The characteristics of t-MS patients are summarized in Table 1. The median age for this group was 51 (range 37–88 years). Among these patients, there were three men (33 %) and six women (67 %), with a male to female ratio of 0.5. Seven of the nine patients did not have bone marrow disease at the time of diagnosis (78 %), one patient had concurrent AML (11 %), and one patient did not have a bone marrow biopsy performed due to patient’s refusal for further work-up and treatment. Four of the seven patients who did not have marrow involvement at the time of t-MS diagnosis developed AML during the course of the disease. The most common prior cancer was breast cancer (56 %, n = 5), followed by lymphomas including follicular lymphoma and classical Hodgkin lymphoma (22 %, n = 1 for each), AML with t(8, 21) (11 %, n = 1), and laryngeal carcinoma (11 %, n = 1). The patient who had prior diagnosis and treatment of AML with t(8, 21), RUNX1RUNZ1T1 did not have bone marrow involvement at the time of t-MS diagnosis; however, subsequent biopsies demonstrated AML with myelodysplasia related changes and no evidence of t(8, 21). The median time interval between the last cytotoxic treatment and diagnosis of t-MS was 29 months, ranging 5–84 months (both breast cancer cases). The most common location of t-MS lesion was skin (67 %, n = 6), followed by lymph node, bone, and larynx (33 %, n = 1 for each). With regards to treatment, seven of the nine patients received a form of chemotherapy, radiation therapy or both; one patient also received hematopoietic stem cell transplant (HSCT); one patient declined any treatment; and one patient could not be started on any
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Table 1 Clinical characteristics of patients with therapy-related myeloid sarcoma (t-MS) Age/ Sex
Prior cancer
Prior treatment
Time to MS (month)
Location of MS
AML at diagnosis
Therapy for MS
1
51/F
Invasive breast carcinoma
Chemotherapya and radiation
29
L3 vertebra
Nob
Cytarabine
6
Expired
2
45/F
Invasive breast carcinoma
Chemotherapya
22
Skin, abdomen
Nob
Cytarabine
10
Expired
3
81/F
Invasive breast carcinoma
Radiation
84
Skin, upper arm
No
RT
8
Lost f/u
4
43/F
Invasive breast carcinoma
Chemotherapya and radiation
11
Skin, chest
Nob
Cytarabine and MEC
7
Expired
5
44/F
Invasive breast carcinoma
Chemotherapya and radiation
5
Skin, chest
No
Cytarabine and MEC
3
Expired
6
63/M
AML with t(8, 21)
Chemotherapya
41
Vocal cord
Nob
MEC and RT
32
Expired
7
65/M
Follicular Lymphoma
Chemotherapy (R-CHOP) and HSCT
63
Skin, chest
No
None
1
Expired
8
37/F
Classical Hodgkin Lymphoma
Chemotherapy (ABVD) and Radiation
Skin, abdomen
Present
Cytarabine, FLAG, HSCT
6
Expired
9
88/M
Laryngeal carcinoma
Radiation
Lymph node
N/A
None
10
Expired
9 79
Overall survival (month)
Current status
MS Myeloid sarcoma, AML acute myeloid leukemia, MEC Mitoxantrone, etoposide, and cytarabine, FLAG Fludarabine, cytarabine, and granulocyte colony-stimulating factor, R-CHOP Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, ABVD Doxorubicin, bleomycin, vinblastine, and darcarbacine, RT Radiation therapy, HSCT hematopoietic stem cell transplant, f/u follow-up, N/A not available a
Patients 1, 2, 4, and 5 received neo-adjuvant chemotherapy
b
Patient 1 developed acute leukemia after 3 months with complex cytogenetics, patient 2 after 7 months, patient 4 after 3 months, and patient 6 after 30 months of the diagnosis of myeloid sarcoma
cytotoxic treatment due to his serious comorbidities, and he survived for only 1 month after the diagnosis of MS. The treatment was decidedly unsuccessful in all treated patients—all seven patients had refractory MS and four of the nine patients (cases 1, 2, 4 and 6) developed acute leukemia at various time intervals, which was also refractory to treatment (Table 1). The group of t-AML without extramedullary involvement included 62 patients with or without preceding MDS. The median age for this group was 59 years (range 21–86 years). Among these patients, 20 were men (32 %) and 42 were women (68 %), with a male to female ratio of 0.5. The most common prior cancer in the patients with t-AML was breast cancer (31 %, n = 19), followed by Hodgkin and non-Hodgkin lymphoma (27 %, n = 17) and other hematological and solid cancers. The median time interval between the last cytotoxic treatment and diagnosis of t-AML was 50 months, ranging 3 months (small cell carcinoma of lung) to 240 months (follicular lymphoma). The MS group without prior treatment history included 58 patients with a median age of 55 years (range 22–92 years) and male to female ratio of 1.9 (66 % male, n = 38 and 34 % female, n = 20). Of the 58 cases, 35 (60 %) also had bone marrow disease at the time of the diagnosis, AML being the most common (n = 33) followed by CMML-2 and RAEB-2 (n = 1 each). The salient
clinicopathological features of each group of patients are summarized in Table 2. Survival analysis was performed on all three patient groups. The mean survival was 9 months for t-MS group, 18 months for t-AML group, and 24 months for the MS group. There was no significant difference between t-MS and t-AML groups (p = 0.360). The overall survival was significantly worse in t-MS group compared with MS group with a p value of 0.047 (Fig. 1a, b). If we exclude the patients treated with HSCT from the analysis, the mean survival for the resulting t-MS (n = 8) and MS (n = 54) groups showed a similar trend toward poorer survival, but statistically not significant (8.5 and 16 months, respectively, p = 0.4). Phenotypic characteristics Immunohistochemical studies were performed on the FFPE tissue sections from each t-MS case for diagnostic purposes (Table 3). Five cases had myeloid type of differentiation, while the remaining four cases had partial or complete monocytic differentiation. Six cases had expression of CD33, while the remaining three cases were remarkably weak or negative. CD56 was detected in three of the nine cases. Flow cytometric analysis was not available on the MS tissue samples. Patient 8 with concurrent AML had
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Table 2 Summary of clinicopathological features of three groups: median values and ranges are shown T-MS n = 9
t-AML n = 62
MS n = 58
Age
51 (37–88 years)
59 (21–86 years)
55 (22–92 years)
Sex (M:F)
3:6
20:42
38:20
BM involvement at diagnosis
1 (11 %)
62 (100 %)
35 (60 %)
Time between prior treatment and t-MN diagnosis
29 months (9–132 months)
50 months (3–240 months)
N/A
Overall survival
9 months (1–32 months)
18 months (1–84 months)
24 months (2–72 months)
t-MS therapy-related myeloid sarcoma, t-AML therapy-related acute myeloid leukemia, MS myeloid sarcoma, BM bone marrow, N/A not applicable
detected by FISH. One of these patients (patient 2) was detected to have this abnormality on follow-up bone marrow with evolved AML later in the course. Although patient 6 had a prior diagnosis of AML with t(8, 21), he was included in the t-MS group following the development of MS. This patient developed AML with myelodysplasiarelated changes approximately 3 months after the diagnosis of t-MS and did not have recurrent cytogenetic abnormality via cytogenetics or FISH performed on the bone marrow with AML. One patient had deletion of chromosome 5q detected by cytogenetics performed on his morphologically normal corresponding bone marrow biopsy (patient 7). We assume this patient might have underlying evolving AML but due to the extremely short survival (1 month) no follow-up was possible to confirm. FLT3 mutation analysis was available and negative in two cases. BRAF exon 15 mutation analysis including codon 600 was performed on six cases, and all cases were found to be wild type.
A
Overall survival (%)
B
100
T-MS T-AML
50
P=0.360
Discussion
0 0
20
40
60
80
100
Time (months)
Fig. 1 Overall survival. a Overall survival in t-MS (n = 9) and MS (n = 58) cohorts: significantly shorter median OS in t-MS compared with MS (9 vs 24 months, respectively, p = 0.047). b Overall survival in t-MS (n = 9) and t-AML (n = 62) cohorts: no statistical significance between two groups (9 vs. 18 months, respectively, p = 0.360). t-MS therapy-related myeloid sarcoma, MS myeloid sarcoma, t-AML therapy-related acute myeloid leukemia
flow cytometric analysis on the bone marrow biopsy, which showed a myelomonocytic phenotype. Molecular and genetic findings Cytogenetic study results with or without FISH and mutational analysis were available in six of the nine t-MS cases (Table 3). Three of these six patients had abnormal karyotype. Two patients, one with normal karyotype and another with t(9, 11), had MLL gene rearrangement
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Therapy-related myeloid neoplasm (t-MN) is a well-known complication of cytotoxic chemotherapy and radiation therapy used to treat various malignant and rarely some benign diseases [2–8, 27]. t-MN often presents as acute myeloid leukemia (AML) followed in frequency of occurrence by myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/ MPN). Majority of the patients carry an abnormal karyotype including unbalanced chromosomal aberrations, particularly entire or partial loss of chromosomes 5 and/or 7, as well as additional abnormalities in the setting of a complex karyotype [1]. The prognosis is poor regardless of myeloid neoplasm subtype in these patients [2, 28, 29]; however, karyotype appears to be a factor predicting the survival [30]. Myeloid sarcoma (MS), also known as granulocytic sarcoma, is a diagnostic term for extramedullary proliferation of blasts of various phenotypes forming a soft tissue mass or involving skin [12–15]. Due to the rarity of this
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Table 3 Phenotypic, cytogenetic and molecular features in patients with therapy-related myeloid sarcoma Case
Phenotype of MS tumor cells
Cytogenetics at diagnosis (BM)
FISH for AML/MDS at diagnosis (BM)
FLT3 mutation status at diagnosis (BM)
BRAF exon 15 (PCR)
1
CD117?, CD33?, MPO?, CD43?, CD34-, CD56-
Normala
Negative
Negative
Wild type
2
CD33?, MPO? (partial), CD4? (partial), CD45?, CD34-, CD56-
Normal
MLL gene re-arrangement
N/A
Wild type
3
CD68, CD14?, CD34-, CD117-
Normal
N/A
N/A
Wild type
4
CD33?, CD4?, CD56?, CD45?, CD34-, CD123-
Normal
N/A
N/A
Wild type
5
CD33?, CD15?, CD56?, CD4?, CD123-
N/A
N/A
N/A
N/A
6
CD117?, CD33?, CD56?, CD4? (partial), CD34-b
Normal
Negative
N/A
Wild type
7
CD68?, CD4?, CD117-, CD34-
Deletion of 5q
Deletion of 5q
Negative
N/A
8
CD14?, CD68?, CD34-
t(9, 11)
MLL gene re-arrangement
Negative
N/A
9
CD33?, CD56?, CD34-
N/A
N/A
N/A
Wild type
MS Myeloid sarcoma, BM bone marrow, AML acute myeloid leukemia, MDS myelodysplastic syndrome, PCR polymerase chain reaction a
Patient 1 developed AML later in the course with complex cytogenetics
b
The phenotype of blasts in prior AML with t [8, 21] is as follows: CD34?, CD117?, CD15?, CD33?, MPO?, CD13-, CD56-, CD14-, CD64-
entity, there are no large studies analyzing prognostic factors in these patients [24]. Extramedullary presentation of t-MN in the form of t-MS has been reported in only rare cases [25, 26]. Due to such anecdotal reporting, it is unclear if extramedullary involvement in t-MN has any impact on the already poor prognosis in these patients. In the current study, we report the first-ever case series including nine cases of t-MS with or without concurrent bone marrow involvement. Our results suggest that t-MS is indeed a rare entity with distinct clinicopathological features. The leading prior cancer type was breast carcinoma, followed by hematologic malignancies. Only 1 of 8 patients (12.5 %) who underwent bone marrow biopsy at t-MS diagnosis had concurrent bone marrow disease, whereas in the MS group without prior treatment history, 35 of the 58 cases (60 %) had bone marrow disease at the time of the diagnosis. Thus, an absence of bone marrow disease at the time of presentation appears to be a particularly significant feature, which may potentially preclude accurate cytogenetic testing, as it is often performed on the blood or bone marrow specimens. The biopsy materials from most of our cases were initially managed as possible metastasis from the prior malignancy, and in the absence of hematologic manifestations, no leukemia-focused molecular analysis was performed on the fresh biopsy specimens. This indicates a need to perform such genetic testing on fresh soft tissue biopsy samples from patients who have a prior chemo-/radiotherapy history. Additionally mutations in the RAS-BRAF signaling pathway were found to be associated with t-AML [31] and might be significant for future targeted therapies. In our
series, BRAF mutation was not present in any of the cases tested. Interestingly, our results show that t-MS patients have a strikingly shorter survival compared to conventional MS and t-AML patients. The difference in survival rates is statistically significant between t-MS and MS groups (Fig. 1). The issue of clinical management of t-MS patients becomes even more confounding when there is no consensus for the treatment of conventional MS. Considering the rare and aggressive nature of this neoplasm, a multidisciplinary approach involving hematology, pathology, and stem cell transplant team is critical in management. Due to rarity of this disease, there are no established consensus guidelines or randomized controlled studies on the optimal therapeutic strategies. There have been high rates of relapse or progression to acute leukemia especially in patients who are treated with localized methods such as radiation therapy or surgery alone [32]. Moderate doses of radiation therapy have been used in conjunction with systemic treatments for local disease control and palliation of symptoms without causing significant toxicity [33]. However, this did not translate into significant impact on progression free and overall survival. Surgery alone is not an effective treatment strategy and can be considered before the systemic treatment in acute situations requiring rapid debulking and symptomatic relief [34]. Currently, the AML-like treatment regimens containing cytosine arabinoside and anthracycline have been commonly used based on previous retrospective studies and case reports [35]. Yamauchi and Yasuda [36] reported prolonged disease-free survival in isolated MS patients
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when treated with cytarabine-based systemic chemotherapy. Imrie et al. showed that systemic chemotherapy administration at the time of diagnosis significantly increased overall survival (OS) compared with those initially not treated with chemotherapy. In this study, surgical resection or local radiotherapy at diagnosis had no impact on overall survival [37]. Therefore, treatment with systemic chemotherapies should be initiated as soon as the diagnosis is confirmed [32]. HSCT effectiveness has been studied retrospectively. Pileri and colleagues [13] reported a significant impact on long-term OS after HSCT compared to the ones who did not receive HSCT. Additionally, Avni et al. showed that HSCT had a significant impact on OS in a 19-patient study. A larger scale study on 99 patients with MS who underwent HSCT, including 30 patients with isolated MS, showed that HSCT was an effective treatment for MS; however, there was no significant difference in outcomes between isolated and leukemic MS [38]. Therefore, HSCT can be considered in patients who are in first remission and also in relapsed disease [39]. Indeed, in our comparison of t-MS patients with conventional MS patients, the t-MS patients have a significantly poorer survival, but if we were to exclude the patients treated with HSCT, the new cohorts, while showing a similar trend, do not show statistically significant difference in survival, suggesting an important impact of HSCT upon survival. In the era of personalized medicine and accumulating molecular data on AML and MDS, the targeted treatments are promising with reported successful treatment options. Humanized anti-CD33 monoclonal antibody conjugated to calicheamicin has been used in CD33-positive AML and MS patients with significant complete remission (CR) rates [40]. FLT3 inhibitors [41], DNA methyltransferase inhibitors [42], and farnesyl-transferase inhibitors [43] are still under investigation as potential targeted therapies in AML, promising less toxic and more effective regimens in the near future. Newer modalities appear important because none of the treated patients in our case series benefitted from the conventional treatment and the disease persisted.
Conclusion In summary, we report that t-MS is a secondary disease with a very poor prognosis and has a distinct overall survival compared with conventional MS and possibly t-AML. From our experience, we contend that it is worth keeping a high degree of suspicion for t-MS and performing leukemia-focused genetic testing on any potential neoplastic lesion when managing a patient with a prior chemo-/radiotherapy history. We additionally recommend recognizing t-MS as a unique entity among t-MN and as being distinct from conventional MS, for better patient
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stratification. Clearly, large-scale multi-institute studies are warranted to further elucidate the pathophysiology, genetics, prognostication, and optimal treatment for this rare but highly aggressive disease. Conflict of interest of interest.
The authors declare that they have no conflict
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463 28. Michels SD, McKenna RW, Arthur DC, Brunning RD. Therapyrelated acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases. Blood. 1985;65(6): 1364–72 Epub 1985/06/01. 29. Singh ZN, Huo D, Anastasi J, Smith SM, Karrison T, Le Beau MM, et al. Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant. Am J Clin Pathol. 2007;127(2):197–205 Epub 2007/01/11. 30. Kern W, Haferlach T, Schnittger S, Hiddemann W, Schoch C. Prognosis in therapy-related acute myeloid leukemia and impact of karyotype. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(12):2510–1 Epub 2004/06/16. 31. Czader M, Orazi A. Therapy-related myeloid neoplasms. Am J Clin Pathol. 2009;132(3):410–25 Epub 2009/08/19. 32. Bakst RL, Tallman MS, Douer D, Yahalom J. How I treat extramedullary acute myeloid leukemia. Blood. 2011;118(14): 3785–93 Epub 2011/07/29. 33. Chen WY, Wang CW, Chang CH, Liu HH, Lan KH, Tang JL, et al. Clinicopathologic features and responses to radiotherapy of myeloid sarcoma. Radiat Oncol. 2013;8:245 Epub 2013/10/24. 34. Yilmaz AF, Saydam G, Sahin F, Baran Y. Granulocytic sarcoma: a systematic review. Am J Blood Res. 2013;3(4):265–70 Epub 2014/01/08. 35. Sakai T, Tamura S, Miyoshi T, Nesumi N, Nagai K, Oshima K. Development of myeloid sarcoma after long-term methotrexate use for rheumatoid arthritis. Int J Hematol. 2014;99(4):493–8 Epub 2014/02/08. 36. Yamauchi K, Yasuda M. Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and a review of 72 cases in the literature. Cancer. 2002;94(6):1739–46 Epub 2002/03/29. 37. Imrie KR, Kovacs MJ, Selby D, Lipton J, Patterson BJ, Pantalony D, et al. Isolated chloroma: the effect of early antileukemic therapy. Ann Intern Med. 1995;123(5):351–3 Epub 1995/09/01. 38. Chevallier P, Labopin M, Cornelissen J, Socie G, Rocha V, Mohty M, et al. Allogeneic hematopoietic stem cell transplantation for isolated and leukemic myeloid sarcoma in adults: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation. Haematologica. 2011;96(9):1391–4 Epub 2011/06/21. 39. Antic D, Elezovic I, Milic N, Suvajdzic N, Vidovic A, Perunicic M, et al. Is there a ‘‘gold’’ standard treatment for patients with isolated myeloid sarcoma? Biomed Pharmacother. 2013;67(1): 72–7 Epub 2012/12/12. 40. Piccaluga PP, Martinelli G, Rondoni M, Malagola M, Gaitani S, Isidori A, et al. Gemtuzumab ozogamicin for relapsed and refractory acute myeloid leukemia and myeloid sarcomas. Leukemia Lymphoma. 2004;45(9):1791–5 Epub 2004/06/30. 41. Knapper S. The clinical development of FLT3 inhibitors in acute myeloid leukemia. Expert Opin Investig Drugs. 2011;20(10): 1377–95 Epub 2011/09/08. 42. Yu J, Peng Y, Wu LC, Xie Z, Deng Y, Hughes T, et al. Curcumin down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in acute myeloid leukemia. PloS one. 2013;8(2):e55934. Epub 2013/03/05. 43. Medeiros BC, Landau HJ, Morrow M, Lockerbie RO, Pitts T, Eckhardt SG. The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines. Leukemia. 2007;21(4):739–46 Epub 2007/02/03.
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ORIGINAL ARTICLE
Clinicopathological and molecular features of myeloid sarcoma as initial presentation of therapy-related myeloid neoplasms: a single institution experience Deniz Peker • Vishwas Parekh • Ravikumar Paluri • Taylor Deal • Uma Borate • Antonio Di Stasi • Shuko Harada • Emmanuel Agosto Arroyo Vishnu Reddy
•
Received: 29 June 2014 / Revised: 26 August 2014 / Accepted: 1 September 2014 / Published online: 11 September 2014 Ó The Japanese Society of Hematology 2014
Abstract Therapy-related myeloid neoplasms (t-MN) have a common origin in prior cytotoxic therapy and/or radiation. These neoplasms include therapy-related acute myeloid leukemia, myelodysplastic syndrome (t-MDS), and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN). Myeloid sarcoma (MS), on the other hand, is a rare disease manifesting as an extramedullary collection of immature cells of myeloid lineage. Rarer still is therapy-related MS (t-MS), which has not been adequately studied due to its rarity and its lack of recognition as a unique entity among other t-MN. Here, we report what is to our knowledge the first case series of t-MS, with the aim of investigating and establishing salient clinicopathological and molecular features of this entity. Keywords Therapy-related myeloid neoplasms Acute myeloid leukemia Myeloid sarcoma
Introduction Therapy-related myeloid neoplasms (t-MN) refer to secondary acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) that occur as a late complication of prior treatment with cytotoxic chemotherapeutic agents and/or radiation for various cancers [1–8]. t-MN account
up to 20 % of all cases of AML, MDS, and MDS/MPN [9– 11] and is generally associated with a poor prognosis [2]. Although molecular alterations are yet to be understood in these disease, BRAF mutation has been found in t-MN often associated with MLL gene re-arrangement [12]. Myeloid sarcoma (MS) is a rare myeloid neoplasm of immature myeloid precursors that occurs at various extramedullary sites, most frequently in skin (also known as leukemia cutis), but also lymph nodes, gastrointestinal tract, bone, and virtually every organ and tissue in the body [13–16]. MS can occur de novo [17] or concurrently with AML [18, 19], MDS [20, 21] or MDS/MPN [22, 23]. The prognostic factors and clinical behavior for these patients still remain unknown. Some studies have demonstrated a difference in the clinical behavior between patients with isolated MS and MS patients with concomitant AML or relapsed-AML [24]. Therapy-related myeloid sarcoma (t-MS) is an extremely rare entity with sporadic cases reported in the English literature [25, 26]. Due to the rare incidence, the clinical significance of t-MS, either de novo or with concurrent t-AML, is not yet determined. In this study, we report our experience t-MS, a subtype of MS, in patients with a history of prior cytotoxic treatment for malignant diseases. We present the clinicopathological, immunophenotypic, and molecular findings in nine t-MS cases and compare them with t-AML and conventional MS.
D. Peker (&) V. Parekh T. Deal S. Harada E. A. Arroyo V. Reddy Department of Pathology, University of Alabama, 1802 6th Ave South, NP 3552, Birmingham, AL 35233-7331, USA e-mail: [email protected]
Materials and methods
R. Paluri U. Borate A. Di Stasi Division of Hematology and Oncology, Department of Medicine, University of Alabama, Birmingham, AL, USA
A search of the electronic databases of the Department of Pathology at the University of Alabama at Birmingham
Study group
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was conducted to retrieve the cases of t-AML and MS between January 1, 2003 and December 31, 2013 following Institutional Review Board approval. The study was limited to include only adult patients at the age of 19 years and above. The clinicopathological data and archived hematoxylin–eosin, Wright–Giemsa, and immunohistochemically stained tissue sections were reviewed for each patient. The clinicopathological data collected included patient demographics (age and gender), site of MS, prior disease and treatment history, complete blood count and differential counts, peripheral blood and bone marrow blast counts, serum lactate dehydrogenase (LDH) level, bone marrow status, flow cytometry, karyotype, fluorescence in situ hybridization (FISH), molecular genetic testing results (when available), and clinical follow-up for each patient.
area on FFPE tissue sections and amplified by polymerase chain reaction with primers specific to exon 15 of the BRAF gene. The amplified product was purified, and direct gene sequencing was performed using capillary electrophoresis. Computer analysis of sequencing data was done to determine mutation presence or absence. Results were reported as ‘‘wild type’’ or ‘‘mutation positive’’ in exon 15 of the BRAF gene including codon 600.
Histology, immunohistochemistry, and flow cytometry
Results
Hematoxylin and eosin and immunohistochemically stained slides from formalin-fixed, paraffin-embedded (FFPE) tissue sections and Wright–Giemsa-stained peripheral blood and bone marrow aspirate smears were reviewed for each case to confirm the initial diagnosis. Immunohistochemical stains were performed on each MS case, which included the antibodies to CD45 (Dako North America, Carpentaria, CA, USA), CD43 (Ventana, Tuscan, AR, USA), CD3, CD117 (Biocare, Concord, AR, USA), CD33 (Leica-Novocastra, Buffalo Grove, IL, USA), CD68 (Thermo, Fremont, CA, USA), and myeloperoxidase (Ventana, Tuscan, AR, USA). The stains were performed on FFPE Sections (5 lm thickness) using two detection platforms—Dako AutostainerLink 48 and Ventana semiautostainer. Flow cytometry was performed using 4-color flow cytometry (Becton–Dickinson FACSort, San Jose, CA, USA).
Clinicopathological characteristics
Molecular studies Ancillary test results including conventional cytogenetics and FISH were available in the majority of the t-AML cases and MS cases which were performed on the subsequent bone marrow biopsy following the diagnosis of MS. AML FISH panel included -5/5q-: D5S630 [5p15.2]/ EGR1 [5q31], t(8;21): ETO [8q22]/AML1 [21q22], 11q23: 5’MLL/3’MLL, 16q22: 5’CBFb/3’CBFb, and -7/7q-: ELN [7q11.23]/D7S486 [7q31]. MDS FISH panel included -5/ 5q-: D5S630 [5p15.2]/EGR1 [5q31], -7/7q-: ELN [7q11.23]/D7S486 [7q31], ?8: 8cen (8p11.1q11.1), and 20q-: 20q12. FLT3-ITD and FLT3-TKD mutation assays were performed by multiplex PCR and capillary electrophoresis. For BRAF gene mutation analysis, tissue sections were reviewed by a pathologist and relevant tumor area was selected for analysis. DNA was extracted from tumor
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Statistics All statistical analysis was performed using SAS v9.4 software (Cary, NC, USA) and Kaplan–Meier survival analysis.
The electronic database search revealed a total of 9 patients with a diagnosis of myeloid sarcoma that had a prior history of cytotoxic chemotherapy and/or radiation therapy. The characteristics of t-MS patients are summarized in Table 1. The median age for this group was 51 (range 37–88 years). Among these patients, there were three men (33 %) and six women (67 %), with a male to female ratio of 0.5. Seven of the nine patients did not have bone marrow disease at the time of diagnosis (78 %), one patient had concurrent AML (11 %), and one patient did not have a bone marrow biopsy performed due to patient’s refusal for further work-up and treatment. Four of the seven patients who did not have marrow involvement at the time of t-MS diagnosis developed AML during the course of the disease. The most common prior cancer was breast cancer (56 %, n = 5), followed by lymphomas including follicular lymphoma and classical Hodgkin lymphoma (22 %, n = 1 for each), AML with t(8, 21) (11 %, n = 1), and laryngeal carcinoma (11 %, n = 1). The patient who had prior diagnosis and treatment of AML with t(8, 21), RUNX1RUNZ1T1 did not have bone marrow involvement at the time of t-MS diagnosis; however, subsequent biopsies demonstrated AML with myelodysplasia related changes and no evidence of t(8, 21). The median time interval between the last cytotoxic treatment and diagnosis of t-MS was 29 months, ranging 5–84 months (both breast cancer cases). The most common location of t-MS lesion was skin (67 %, n = 6), followed by lymph node, bone, and larynx (33 %, n = 1 for each). With regards to treatment, seven of the nine patients received a form of chemotherapy, radiation therapy or both; one patient also received hematopoietic stem cell transplant (HSCT); one patient declined any treatment; and one patient could not be started on any
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Table 1 Clinical characteristics of patients with therapy-related myeloid sarcoma (t-MS) Age/ Sex
Prior cancer
Prior treatment
Time to MS (month)
Location of MS
AML at diagnosis
Therapy for MS
1
51/F
Invasive breast carcinoma
Chemotherapya and radiation
29
L3 vertebra
Nob
Cytarabine
6
Expired
2
45/F
Invasive breast carcinoma
Chemotherapya
22
Skin, abdomen
Nob
Cytarabine
10
Expired
3
81/F
Invasive breast carcinoma
Radiation
84
Skin, upper arm
No
RT
8
Lost f/u
4
43/F
Invasive breast carcinoma
Chemotherapya and radiation
11
Skin, chest
Nob
Cytarabine and MEC
7
Expired
5
44/F
Invasive breast carcinoma
Chemotherapya and radiation
5
Skin, chest
No
Cytarabine and MEC
3
Expired
6
63/M
AML with t(8, 21)
Chemotherapya
41
Vocal cord
Nob
MEC and RT
32
Expired
7
65/M
Follicular Lymphoma
Chemotherapy (R-CHOP) and HSCT
63
Skin, chest
No
None
1
Expired
8
37/F
Classical Hodgkin Lymphoma
Chemotherapy (ABVD) and Radiation
Skin, abdomen
Present
Cytarabine, FLAG, HSCT
6
Expired
9
88/M
Laryngeal carcinoma
Radiation
Lymph node
N/A
None
10
Expired
9 79
Overall survival (month)
Current status
MS Myeloid sarcoma, AML acute myeloid leukemia, MEC Mitoxantrone, etoposide, and cytarabine, FLAG Fludarabine, cytarabine, and granulocyte colony-stimulating factor, R-CHOP Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, ABVD Doxorubicin, bleomycin, vinblastine, and darcarbacine, RT Radiation therapy, HSCT hematopoietic stem cell transplant, f/u follow-up, N/A not available a
Patients 1, 2, 4, and 5 received neo-adjuvant chemotherapy
b
Patient 1 developed acute leukemia after 3 months with complex cytogenetics, patient 2 after 7 months, patient 4 after 3 months, and patient 6 after 30 months of the diagnosis of myeloid sarcoma
cytotoxic treatment due to his serious comorbidities, and he survived for only 1 month after the diagnosis of MS. The treatment was decidedly unsuccessful in all treated patients—all seven patients had refractory MS and four of the nine patients (cases 1, 2, 4 and 6) developed acute leukemia at various time intervals, which was also refractory to treatment (Table 1). The group of t-AML without extramedullary involvement included 62 patients with or without preceding MDS. The median age for this group was 59 years (range 21–86 years). Among these patients, 20 were men (32 %) and 42 were women (68 %), with a male to female ratio of 0.5. The most common prior cancer in the patients with t-AML was breast cancer (31 %, n = 19), followed by Hodgkin and non-Hodgkin lymphoma (27 %, n = 17) and other hematological and solid cancers. The median time interval between the last cytotoxic treatment and diagnosis of t-AML was 50 months, ranging 3 months (small cell carcinoma of lung) to 240 months (follicular lymphoma). The MS group without prior treatment history included 58 patients with a median age of 55 years (range 22–92 years) and male to female ratio of 1.9 (66 % male, n = 38 and 34 % female, n = 20). Of the 58 cases, 35 (60 %) also had bone marrow disease at the time of the diagnosis, AML being the most common (n = 33) followed by CMML-2 and RAEB-2 (n = 1 each). The salient
clinicopathological features of each group of patients are summarized in Table 2. Survival analysis was performed on all three patient groups. The mean survival was 9 months for t-MS group, 18 months for t-AML group, and 24 months for the MS group. There was no significant difference between t-MS and t-AML groups (p = 0.360). The overall survival was significantly worse in t-MS group compared with MS group with a p value of 0.047 (Fig. 1a, b). If we exclude the patients treated with HSCT from the analysis, the mean survival for the resulting t-MS (n = 8) and MS (n = 54) groups showed a similar trend toward poorer survival, but statistically not significant (8.5 and 16 months, respectively, p = 0.4). Phenotypic characteristics Immunohistochemical studies were performed on the FFPE tissue sections from each t-MS case for diagnostic purposes (Table 3). Five cases had myeloid type of differentiation, while the remaining four cases had partial or complete monocytic differentiation. Six cases had expression of CD33, while the remaining three cases were remarkably weak or negative. CD56 was detected in three of the nine cases. Flow cytometric analysis was not available on the MS tissue samples. Patient 8 with concurrent AML had
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Table 2 Summary of clinicopathological features of three groups: median values and ranges are shown T-MS n = 9
t-AML n = 62
MS n = 58
Age
51 (37–88 years)
59 (21–86 years)
55 (22–92 years)
Sex (M:F)
3:6
20:42
38:20
BM involvement at diagnosis
1 (11 %)
62 (100 %)
35 (60 %)
Time between prior treatment and t-MN diagnosis
29 months (9–132 months)
50 months (3–240 months)
N/A
Overall survival
9 months (1–32 months)
18 months (1–84 months)
24 months (2–72 months)
t-MS therapy-related myeloid sarcoma, t-AML therapy-related acute myeloid leukemia, MS myeloid sarcoma, BM bone marrow, N/A not applicable
detected by FISH. One of these patients (patient 2) was detected to have this abnormality on follow-up bone marrow with evolved AML later in the course. Although patient 6 had a prior diagnosis of AML with t(8, 21), he was included in the t-MS group following the development of MS. This patient developed AML with myelodysplasiarelated changes approximately 3 months after the diagnosis of t-MS and did not have recurrent cytogenetic abnormality via cytogenetics or FISH performed on the bone marrow with AML. One patient had deletion of chromosome 5q detected by cytogenetics performed on his morphologically normal corresponding bone marrow biopsy (patient 7). We assume this patient might have underlying evolving AML but due to the extremely short survival (1 month) no follow-up was possible to confirm. FLT3 mutation analysis was available and negative in two cases. BRAF exon 15 mutation analysis including codon 600 was performed on six cases, and all cases were found to be wild type.
A
Overall survival (%)
B
100
T-MS T-AML
50
P=0.360
Discussion
0 0
20
40
60
80
100
Time (months)
Fig. 1 Overall survival. a Overall survival in t-MS (n = 9) and MS (n = 58) cohorts: significantly shorter median OS in t-MS compared with MS (9 vs 24 months, respectively, p = 0.047). b Overall survival in t-MS (n = 9) and t-AML (n = 62) cohorts: no statistical significance between two groups (9 vs. 18 months, respectively, p = 0.360). t-MS therapy-related myeloid sarcoma, MS myeloid sarcoma, t-AML therapy-related acute myeloid leukemia
flow cytometric analysis on the bone marrow biopsy, which showed a myelomonocytic phenotype. Molecular and genetic findings Cytogenetic study results with or without FISH and mutational analysis were available in six of the nine t-MS cases (Table 3). Three of these six patients had abnormal karyotype. Two patients, one with normal karyotype and another with t(9, 11), had MLL gene rearrangement
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Therapy-related myeloid neoplasm (t-MN) is a well-known complication of cytotoxic chemotherapy and radiation therapy used to treat various malignant and rarely some benign diseases [2–8, 27]. t-MN often presents as acute myeloid leukemia (AML) followed in frequency of occurrence by myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/ MPN). Majority of the patients carry an abnormal karyotype including unbalanced chromosomal aberrations, particularly entire or partial loss of chromosomes 5 and/or 7, as well as additional abnormalities in the setting of a complex karyotype [1]. The prognosis is poor regardless of myeloid neoplasm subtype in these patients [2, 28, 29]; however, karyotype appears to be a factor predicting the survival [30]. Myeloid sarcoma (MS), also known as granulocytic sarcoma, is a diagnostic term for extramedullary proliferation of blasts of various phenotypes forming a soft tissue mass or involving skin [12–15]. Due to the rarity of this
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Table 3 Phenotypic, cytogenetic and molecular features in patients with therapy-related myeloid sarcoma Case
Phenotype of MS tumor cells
Cytogenetics at diagnosis (BM)
FISH for AML/MDS at diagnosis (BM)
FLT3 mutation status at diagnosis (BM)
BRAF exon 15 (PCR)
1
CD117?, CD33?, MPO?, CD43?, CD34-, CD56-
Normala
Negative
Negative
Wild type
2
CD33?, MPO? (partial), CD4? (partial), CD45?, CD34-, CD56-
Normal
MLL gene re-arrangement
N/A
Wild type
3
CD68, CD14?, CD34-, CD117-
Normal
N/A
N/A
Wild type
4
CD33?, CD4?, CD56?, CD45?, CD34-, CD123-
Normal
N/A
N/A
Wild type
5
CD33?, CD15?, CD56?, CD4?, CD123-
N/A
N/A
N/A
N/A
6
CD117?, CD33?, CD56?, CD4? (partial), CD34-b
Normal
Negative
N/A
Wild type
7
CD68?, CD4?, CD117-, CD34-
Deletion of 5q
Deletion of 5q
Negative
N/A
8
CD14?, CD68?, CD34-
t(9, 11)
MLL gene re-arrangement
Negative
N/A
9
CD33?, CD56?, CD34-
N/A
N/A
N/A
Wild type
MS Myeloid sarcoma, BM bone marrow, AML acute myeloid leukemia, MDS myelodysplastic syndrome, PCR polymerase chain reaction a
Patient 1 developed AML later in the course with complex cytogenetics
b
The phenotype of blasts in prior AML with t [8, 21] is as follows: CD34?, CD117?, CD15?, CD33?, MPO?, CD13-, CD56-, CD14-, CD64-
entity, there are no large studies analyzing prognostic factors in these patients [24]. Extramedullary presentation of t-MN in the form of t-MS has been reported in only rare cases [25, 26]. Due to such anecdotal reporting, it is unclear if extramedullary involvement in t-MN has any impact on the already poor prognosis in these patients. In the current study, we report the first-ever case series including nine cases of t-MS with or without concurrent bone marrow involvement. Our results suggest that t-MS is indeed a rare entity with distinct clinicopathological features. The leading prior cancer type was breast carcinoma, followed by hematologic malignancies. Only 1 of 8 patients (12.5 %) who underwent bone marrow biopsy at t-MS diagnosis had concurrent bone marrow disease, whereas in the MS group without prior treatment history, 35 of the 58 cases (60 %) had bone marrow disease at the time of the diagnosis. Thus, an absence of bone marrow disease at the time of presentation appears to be a particularly significant feature, which may potentially preclude accurate cytogenetic testing, as it is often performed on the blood or bone marrow specimens. The biopsy materials from most of our cases were initially managed as possible metastasis from the prior malignancy, and in the absence of hematologic manifestations, no leukemia-focused molecular analysis was performed on the fresh biopsy specimens. This indicates a need to perform such genetic testing on fresh soft tissue biopsy samples from patients who have a prior chemo-/radiotherapy history. Additionally mutations in the RAS-BRAF signaling pathway were found to be associated with t-AML [31] and might be significant for future targeted therapies. In our
series, BRAF mutation was not present in any of the cases tested. Interestingly, our results show that t-MS patients have a strikingly shorter survival compared to conventional MS and t-AML patients. The difference in survival rates is statistically significant between t-MS and MS groups (Fig. 1). The issue of clinical management of t-MS patients becomes even more confounding when there is no consensus for the treatment of conventional MS. Considering the rare and aggressive nature of this neoplasm, a multidisciplinary approach involving hematology, pathology, and stem cell transplant team is critical in management. Due to rarity of this disease, there are no established consensus guidelines or randomized controlled studies on the optimal therapeutic strategies. There have been high rates of relapse or progression to acute leukemia especially in patients who are treated with localized methods such as radiation therapy or surgery alone [32]. Moderate doses of radiation therapy have been used in conjunction with systemic treatments for local disease control and palliation of symptoms without causing significant toxicity [33]. However, this did not translate into significant impact on progression free and overall survival. Surgery alone is not an effective treatment strategy and can be considered before the systemic treatment in acute situations requiring rapid debulking and symptomatic relief [34]. Currently, the AML-like treatment regimens containing cytosine arabinoside and anthracycline have been commonly used based on previous retrospective studies and case reports [35]. Yamauchi and Yasuda [36] reported prolonged disease-free survival in isolated MS patients
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when treated with cytarabine-based systemic chemotherapy. Imrie et al. showed that systemic chemotherapy administration at the time of diagnosis significantly increased overall survival (OS) compared with those initially not treated with chemotherapy. In this study, surgical resection or local radiotherapy at diagnosis had no impact on overall survival [37]. Therefore, treatment with systemic chemotherapies should be initiated as soon as the diagnosis is confirmed [32]. HSCT effectiveness has been studied retrospectively. Pileri and colleagues [13] reported a significant impact on long-term OS after HSCT compared to the ones who did not receive HSCT. Additionally, Avni et al. showed that HSCT had a significant impact on OS in a 19-patient study. A larger scale study on 99 patients with MS who underwent HSCT, including 30 patients with isolated MS, showed that HSCT was an effective treatment for MS; however, there was no significant difference in outcomes between isolated and leukemic MS [38]. Therefore, HSCT can be considered in patients who are in first remission and also in relapsed disease [39]. Indeed, in our comparison of t-MS patients with conventional MS patients, the t-MS patients have a significantly poorer survival, but if we were to exclude the patients treated with HSCT, the new cohorts, while showing a similar trend, do not show statistically significant difference in survival, suggesting an important impact of HSCT upon survival. In the era of personalized medicine and accumulating molecular data on AML and MDS, the targeted treatments are promising with reported successful treatment options. Humanized anti-CD33 monoclonal antibody conjugated to calicheamicin has been used in CD33-positive AML and MS patients with significant complete remission (CR) rates [40]. FLT3 inhibitors [41], DNA methyltransferase inhibitors [42], and farnesyl-transferase inhibitors [43] are still under investigation as potential targeted therapies in AML, promising less toxic and more effective regimens in the near future. Newer modalities appear important because none of the treated patients in our case series benefitted from the conventional treatment and the disease persisted.
Conclusion In summary, we report that t-MS is a secondary disease with a very poor prognosis and has a distinct overall survival compared with conventional MS and possibly t-AML. From our experience, we contend that it is worth keeping a high degree of suspicion for t-MS and performing leukemia-focused genetic testing on any potential neoplastic lesion when managing a patient with a prior chemo-/radiotherapy history. We additionally recommend recognizing t-MS as a unique entity among t-MN and as being distinct from conventional MS, for better patient
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stratification. Clearly, large-scale multi-institute studies are warranted to further elucidate the pathophysiology, genetics, prognostication, and optimal treatment for this rare but highly aggressive disease. Conflict of interest of interest.
The authors declare that they have no conflict
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