Pathology of Therapy-Related Myeloid Neoplasms
- Author: Yuri Fedoriw, MD; Chief Editor: Cherie H Dunphy, MD more...
Therapy-related myeloid neoplasms (t-MN) are a heterogeneous group of clonal hematopoietic stem cell disorders that are directly related to previous cytotoxic chemotherapy and/or radiation therapy. Two predominant and clinically significant types of therapy-related myeloid neoplasms (t-MN) have been defined, those arising after treatment with alkylating chemotherapy and/or radiation therapy and those arising after therapy with topoisomerase II inhibitors. Other drug classes (ie, antimetabolites/immunosuppressants) have been implicated in the development of these neoplasms, but in these cases, the clinical course is less distinct. Therapy-related myeloid neoplasms (t-MN) include the following:
Myelodysplastic syndromes (t-MDS)
Acute myeloid leukemia (t-AML)
Myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN)
Therapy-related myeloid neoplasms (t-MN) are defined by the World Health Organization (WHO) as clonal hematopoietic stem cell disorders related to previous exposure to chemotherapy and/or radiation therapy. The therapy-related myeloid neoplasms (t-MN) category represents a heterogeneous group of myeloid neoplasms that share diagnostic features of conventionally defined myeloid malignancies, including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). However, the therapy-related neoplasms progress quickly regardless of their morphologic appearance at presentation and are considered to be a single diagnostic entity.
On the basis of clinical behavior and morphologic features, 2 groups of therapy-related myeloid neoplasms (t-MN) have been defined; these 2 groups are distinguished principally on the basis of the nature of cytotoxic therapy. Cases of therapy-related myeloid neoplasms (t-MN) that arise following therapy with alkylating agents (eg, cyclophosphamide, chlorambucil, cisplatin) and/or ionizing radiation have a relatively long latency period (5-10 y) after primary exposure. On bone marrow aspiration, the morphologic features are those of myelodysplasia. Patients who are exposed to topoisomerase II inhibitors (eg, etoposide, doxorubicin) tend to present with frank leukemia within 1 year of the time primary therapy was initiated (see the following image).
See also Pathology of Acute Myeloid Leukemia With Myelodysplasia-Related Features, Pathology of Other Myeloid Related Precursor Neoplasms, and Pathology of Acute Myeloid Leukemia Not Otherwise Categorized.
Epidemiology and Clinical Features
The incidence of therapy-related myeloid neoplasms (t-MN) is dependent on the type, dose, and intensity of therapeutic intervention and on the nature of the underlying primary malignancy/disease process. All age groups are affected; however, the risk of developing secondary myeloid neoplasms following alkylating chemotherapy or radiation therapy seems to increase with age. The risk of developing therapy-related myeloid neoplasms (t-MN) dramatically decreases after 10 years.
An extensive review and analysis of previously published data highlighted vague trends, with the greatest likelihood of developing therapy-related myeloid neoplasms (t-MN) following treatment of hematopoietic malignancies. However, significant variability between studies was also demonstrated, and the precise incidence is not clear. Approximately 30% of therapy-related myeloid neoplasms (t-MN) cases involve patients treated for non-neoplastic disorders, and those treated with high-dose chemotherapy followed by autologous stem cell transplantation.[4, 5] Significantly, cases of therapy-related myeloid neoplasms (t-MN) represent approximately 10-30% of all confirmed cases of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN).[3, 4]
The heritable risk factors predisposing to the development of therapy-related myeloid neoplasms (t-MN) are the topic of intense study. Defects in the RAS-BRAF signal-transduction pathway, point mutations of AML1 and p53, and polymorphisms affecting drug metabolism have been implicated.[6, 7]
The clinical presentation of therapy-related myeloid neoplasms (t-MN) is largely dependent on the nature of the antecedent therapeutic regimen. Patients treated with alkylating agents and/or radiation therapy typically present 5-10 years after exposure; the latency period for patients treated with topoisomerase inhibitors is on the order of 1-5 years. Despite the archetypal and often distinguishing morphologic features of these 2 groups, the clinical presentations are nonspecific and are related to the degree of bone marrow failure (see Morphologic Features). Clinical features are generally related to the corresponding cytopenia (eg, bleeding with thrombocytopenia; fatigue and exercise intolerance with anemia; fever and infection with neutropenia).
Most commonly, the morphologic features of alkylating agent/radiotherapy–related therapy-related myeloid neoplasms (t-MN) are those of myelodysplasia, in particular, refractory cytopenia with multilineage dysplasia (RCMD). Evaluation of the peripheral blood smear demonstrates 1 or more cytopenias, often including a macrocytic anemia. Platelets may show nonspecific variation in size; giant forms may be present. Dysplasia of the granulocyte lineage may be assessed on the peripheral blood smear; hypolobated nuclei and hypogranularity are common features.
The bone marrow is most frequently normocellular to hypercellular with a variable blast percentage. The erythroid series may show the full breadth of dysplasia, including nuclear and cytoplasmic atypia (see the first image below), as well as megaloblastoid features. Ring sideroblasts are often present and may be identified with iron stains (eg, Prussian blue) (see the second image below).
Megakaryocyte dysplasia is manifest as hypolobate or hyperlobate forms, megakaryocytes with nuclear segregation (see the first image below), and/or microcytic forms with abnormal paratrabecular localization and clustering (see the second and third images below). As with peripheral blood, the bone marrow granulocyte lineage may show variation and abnormalities of granulation and nuclear hypolobation of the mature forms (ie, pseudo–Pelger-Huet anomaly) (see the fourth image below).
Cases of therapy-related myeloid neoplasms (t-MN) related to treatment with topoisomerase II inhibitors typically present as overt acute myeloid leukemia (see the following image). Morphologic features are not unique in therapy-related cases. Although monocytic and monoblastic differentiation is often present, the appearance may be that of de novo cases, including those with recurrent cytogenetic abnormalities. Cases of therapy-related acute lymphoblastic leukemia (ALL) have also been described.
Importantly, the 2 treatment-related groups cannot always be distinguished on the basis of histologic findings; a complete clinical history, in addition to cytogenetic studies, is necessary to accurately diagnose and prognosticate these neoplasms. The morphologic findings are not entirely specific and are rarely distinguishable from those of de novo cases of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or myelodysplastic/myeloproliferative neoplasms (MDS/MPN). In contrast to de novo myeloid neoplasms, however, there is no significant clinical or prognostic benefit to further subclassification.
Immunophenotypic studies are not used to distinguish therapy-related myeloid neoplasms (t-MN) from de novo cases of myeloid neoplasms but rather to clarify abnormal populations. The myeloblasts are characteristically CD34-positive; their distribution and burden may be demonstrated with CD34 immunohistochemical studies.
Flow cytometric analysis may be helpful in assessing the proportion of myeloid blasts, as well as aberrant antigenic expression. Aberrant expression of CD7 (a T-cell–associated antigen), CD56 (a natural killer [NK]-cell–associated antigen), and/or CD19 (a B-cell–associated antigen) may be seen in therapy-related myeloid neoplasms (t-MN) blasts. The relevance of such findings and of associated cytogenetic changes is similar to that in de novo cases. Immunophenotypic maturation patterns of the myeloid and erythroid lineages may also be evaluated; they may be particularly helpful when morphologic and cytogenetic evaluations of the bone marrow are inconclusive (see Morphologic Features and Cytogenetic Features).[10, 11]
Therapeutic advances have dramatically influenced the clinical course of numerous malignant, reactive, and autoimmune disorders. However, the therapies themselves can be mutagenic.
Cytogenetic abnormalities are present in the majority of cases of therapy-related myeloid neoplasms (t-MN) and are related to the therapeutic regimen.[4, 5] Conventional cytogenetic analysis (ie, karyotype) and fluorescence in situ hybridization (FISH) studies for specific abnormalities may be helpful in the diagnosis and prognostication of disease.
Alkylating agents and radiation therapy
Cases of therapy-related myeloid neoplasms (t-MN) due to treatment with alkylating agents and radiation characteristically show unbalanced translocations and partial or complete loss of chromosomes 7 and/or 5. Monosomy 7 is the most common finding associated with alkylating agents; loss of the long arm of chromosome 5 (5q-) is the most common finding associated with ionizing radiation. Additional chromosomal abnormalities are common, yielding a complex karyotype.
Topoisomerase II inhibitors
Cases of therapy-related myeloid neoplasms (t-MN) arising after use of topoisomerase II inhibitors are associated with a short latency to presentation. Balanced translocations are also seen in these cases. Frequent rearrangements of 11q23(MLL) and 21q22(AML1) are identified. Balanced translocations seen in de novo cases of acute myeloid leukemia (AML) are also present, including t(15;17)(q22;q21), inv(16)(p13.q22), and t(8;21)(q22;q22), although they are less common than in de novo cases.[4, 5]
Although therapy-related myelodysplastic syndromes (t-MDS), acute myeloid leukemia (t-AML), and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN) have morphologically disparate phases, rapid progression and shortened survival are common in all cases, irrespective of subclassification. Overall survival is poor (< 10% at 5 y).[1, 12]
As with other myeloid neoplasms, the cytogenetic features of therapy-related myeloid neoplasms (t-MN) are predictive of outcome. However, despite the morphologic and cytogenetic similarities of some therapy-related myeloid neoplasms (t-MN) and de novo myeloid neoplasms, therapy-induced disease typically carries a worse prognosis than its de novo counterpart. Balanced translocations are associated with a relatively better prognosis, whereas loss of the entire or partial chromosomes 5 or 7 is associated with a particularly dismal prognosis.
As seen in de novo cases of AML, favorable cytogenetic findings, including t(15;17)(q22;q12) and inv(16)(p13.1q22), confer a relatively better prognosis; however, this is not universal. A study that compared t(8;21) t-AML to de novo t(8;21) AML demonstrated that despite virtually indistinguishable morphologic, immunophenotypic, and cytogenetic features, the median overall survival was dramatically worse in therapy-related cases.
Vardiman JW, Arber DA, Brunning RD, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissue. Swerdlow SH, Campo E, Harris NL, et al, eds. Vardiman JW, Arber DA, Brunning RD, et al. 4th ed. Lyon, France: IARC Press; 2008. chapter 6.
Leone G, Pagano L, Ben-Yehuda D, Voso MT. Therapy-related leukemia and myelodysplasia: susceptibility and incidence. Haematologica. 2007 Oct. 92(10):1389-98. [Medline].
Leone G, Mele L, Pulsoni A, Equitani F, Pagano L. The incidence of secondary leukemias. Haematologica. 1999 Oct. 84(10):937-45. [Medline].
Mauritzson N, Albin M, Rylander L, et al. Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. Leukemia. 2002 Dec. 16(12):2366-78. [Medline].
Smith SM, Le Beau MM, Huo D, et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood. 2003 Jul 1. 102(1):43-52. [Medline].
Rund D, Krichevsky S, Bar-Cohen S, et al. Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients. Leukemia. 2005 Nov. 19(11):1919-28. [Medline].
Pedersen-Bjergaard J, Andersen MK, Andersen MT, Christiansen DH. Genetics of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2008 Feb. 22(2):240-8. [Medline].
Ishizawa S, Slovak ML, Popplewell L, et al. High frequency of pro-B acute lymphoblastic leukemia in adults with secondary leukemia with 11q23 abnormalities. Leukemia. 2003 Jun. 17(6):1091-5. [Medline].
Singh ZN, Huo D, Anastasi J, et al. Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant. Am J Clin Pathol. 2007 Feb. 127(2):197-205. [Medline].
Wood BL. Myeloid malignancies: myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia. Clin Lab Med. 2007 Sep. 27(3):551-75, vii. [Medline].
Truong F, Smith BR, Stachurski D, et al. The utility of flow cytometric immunophenotyping in cytopenic patients with a non-diagnostic bone marrow: a prospective study. Leuk Res. 2009 Aug. 33(8):1039-46. [Medline].
Schoch C, Kern W, Schnittger S, Hiddemann W, Haferlach T. Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML. Leukemia. 2004 Jan. 18(1):120-5. [Medline].
Michels SD, McKenna RW, Arthur DC, Brunning RD. Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases. Blood. 1985 Jun. 65(6):1364-72. [Medline].
Gustafson SA, Lin P, Chen SS, et al. Therapy-related acute myeloid leukemia with t(8;21) (q22;q22) shares many features with de novo acute myeloid leukemia with t(8;21)(q22;q22) but does not have a favorable outcome. Am J Clin Pathol. 2009 May. 131(5):647-55. [Medline].