|Year : 2022 | Volume
| Issue : 3 | Page : 642-648
|A clinicopathological experience in acute myeloid leukemia: Effects of clinical data and status of FLT3, CEBPA and NPM1 on prognosis
Emre Yener1, Kerem Ozcan2, Şeniz Öngören3, Ayşe Salihoğlu3, Ahu Senem Demiröz2, Hilal Akı2
1 Department of Pathology, Mehmet Akif Inan Training and Research Hospital, University of Health Sciences, &xs#350;anlıurfa, Turkey
2 Department of Pathology, School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
3 Department of Internal Medicine, Division of Hematology, School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
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|Date of Submission||12-Oct-2021|
|Date of Decision||07-Nov-2021|
|Date of Acceptance||25-Nov-2021|
|Date of Web Publication||21-Jul-2022|
| Abstract|| |
Background: The purpose of the study was to analyze the expression of nucleophosmin (NPM1), CCAT/enhancer-binding protein alpha (CEBPA), and FMS-like tyrosine kinase 3 (FLT3) with immunohistochemistry and evaluate the relationship with clinicopathologic data with special emphasis on prognosis in bone marrow biopsy specimens diagnosed with acute myeloid leukemia (AML). Materials and Methods: Bone marrow biopsies of 104 patients who were diagnosed with AML were re-evaluated for diagnosis and subclassification. Immunohistochemically, anti-NPM1, anti-CEBPA, and anti-FLT3 antibodies were applied to slides prepared from formalin-fixed paraffin-embedded tissues. Sixty-three of these patients had their follow-up in our institutional hematology clinic and these patients' clinical, biochemical, and radiological data were obtained and analyzed from patient files. These data were analyzed with survival times statistically. Results: Except for age, no significant effect of clinical data on prognosis was detected. Immunohistochemical results were also statistically compared with clinical data. No correlation was found between overall survival and disease-free survival with the expression of anti-CEBPA or anti-NPM1 antibodies. However, immunohistochemical reactivity for anti-FLT3 antibody was found to be a poor prognostic factor and statistically significant. Also, when the expression of FLT3 was analyzed with that of NPM1 or CEBPA, a correlation (dependent on the expression of FLT3) was found with disease-free survival. Conclusions: FLT3 is an independent prognostic factor for AML. CEBPA and NPM1 should be considered as good prognostic factors only in the absence of FLT3 abnormalities.
Keywords: Acute myeloid leukemia, bone marrow, FMS-like tyrosine kinase 3, immunohistochemistry, survival
|How to cite this article:|
Yener E, Ozcan K, Öngören &, Salihoğlu A, Demiröz AS, Akı H. A clinicopathological experience in acute myeloid leukemia: Effects of clinical data and status of FLT3, CEBPA and NPM1 on prognosis. Indian J Pathol Microbiol 2022;65:642-8
|How to cite this URL:|
Yener E, Ozcan K, Öngören &, Salihoğlu A, Demiröz AS, Akı H. A clinicopathological experience in acute myeloid leukemia: Effects of clinical data and status of FLT3, CEBPA and NPM1 on prognosis. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Oct 3];65:642-8. Available from: https://www.ijpmonline.org/text.asp?2022/65/3/642/351587
| Introduction|| |
Acute myeloid leukemia (AML) is a disease characterized by early disruption in hematopoietic stem cells, which carry a myeloid, monocytic, erythroid, or megakaryocytic phenotype.,, To briefly understand the pathogenesis, clinical and hematological properties, and prognosis, the World Health Organization (WHO) classifies AML into four further major categories: AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, AML, NOS.
Gene mutations in AML, especially in those with normal karyotype have been subject to many studies. Type I mutations have an impact on prognosis without having any effect on differentiation, whereas type II mutations disrupt the differentiation of hematopoietic cells and apoptosis. Amongst type I mutations that are commonly used as prognostic markers, tyrosine kinase receptor mutation is the most frequent.
Activating mutations of FMS-like tyrosine kinase 3 (FLT3), causing proliferation and immortality of cells are widely used clinically; however, they do not represent a distinct subtype. They can be found in the majority of AMLs. FLT3 mutation has been found to have poor prognostic value regardless of the cytogenetic features.
sCCAT/enhancer-binding protein alpha (CEBPA) and nucleophosmin (NPM1) mutations are examples of type II mutations and these mutations tend to appear in AML patients with normal karyotype, 13% and 20%, respectively. In the absence of FLT3 abnormalities, these mutations are suggestive of a good prognosis.,,, These are included as subtypes of AML with recurrent genetic abnormalities in the latest WHO classification of tumors of hematopoietic and lymphoid tissues.
The aim of this study was to evaluate NPM1, FLT3, and CEBPA expression and its relationship with clinicopathologic data regarding special emphasis on prognosis in AML patients.
| Materials and Methods|| |
This study was approved by the ethics committee with a waiver of obtaining informed consent and was carried out in conformity with the ethical principles of the Helsinki Declaration.
The study included 104 patients who were diagnosed with AML in our department and followed up by our institutional hematology clinic. Cases were selected blinded to any clinical data and re-evaluated pathologically. After re-evaluation of bone marrow biopsies, the diagnosis was further supported by clinical data and flow cytometric analysis.
Histological evaluation was based on formalin-fixed, paraffin-embedded (FFPE) tissue sections and aspiration materials. The clinical and follow-up data of 63 patients were retrieved from the Department of Internal Medicine, Division of Hematology of our institution. For 41 patients, no clinical data were available. Relevant clinical, biochemical, and radiological data were obtained and analyzed from patient files.
Immunostaining of FFPE tissue sections by avidin-biotin-peroxidase complex technique is used for anti-NPM1 (polyclonal, Cell Signaling Technology), anti-CEBPA (D56F10, Cell Signaling Technology), anti-FLT3 (polyclonal, Acris Antibodies) antibodies and was performed using autostainer (BenchMark XT IHK/ISH Staining Module, Ventana Medical Systems Inc., Medical Systems, Tucson, AZ, USA). Tonsil tissue, colonic adenocarcinoma, and reactive lymph node were used as positive controls for CEBPA, NPM1, and FLT3, respectively.
Evaluation of hematoxylin & eosin (H&E) and immunohistochemistry stained slides were made by two pathologists, blinded to clinical data as well as original pathology reports. After finalizing the reports, the results of two pathologists were compared and when a discrepancy between the results was present, a consensus was established.
IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY) was used for statistical calculations.
Pearson Chi-square test and Fisher's Chi-square test were used to compare the obtained clinical parameters and immunohistochemical findings. Regarding the expression of antibodies and prognosis; Kaplan–Meier analysis and log-rank test were used. The 95% confidence interval and P < 0.05 significance level, were considered significant.
| Results|| |
Out of 104 cases, 55 were men (52.9%) and 49 were women (47.1%). The average age was 47.9 (1–84). Clinical, biochemical, radiological, and demographic data are summarized in [Table 1].
Clinical follow-up data were available for 63 patients of which survival ranged between 15 days and 180 months with an average survival of 34.81 ± 5.06 months.
The median overall survival time of death was 16 months and the median disease-free survival was 12 months. The age at the time of diagnosis and survival analysis showed significantly lower mortality rates among patients lower than 50 years. Thirty-one patients were over 50 years and of these patients, 27 died (87.1%), whereas, of the 32 patients who were below 50 years of age, 20 died (62.5%) (P = 0.025). Apart from age, no clinical or demographic data were found to be statistically significant.
Nuclear staining for CEBPA was observed in 35 cases (33.7%), of which 19 were evaluated as weak positive and 16 were strongly positive [Figure 1]. During immunohistochemical evaluation for NPM1, 39 cases (37.5%) were found to be reactive, 21 cases showed weak [Figure 2], and 18 cases showed strong reactivity. FLT3 was found to show the highest reactivity among all 104 cases with 55 cases (52.9%), which showed weak or strong positivity [Figure 3] for 23 and 32 cases, respectively.
The relationship between immunohistochemical results and clinical, biochemical, radiological, and demographic data were evaluated statistically.
Fifty patients were under 50 years and of these patients, 25 (50%) were positive with NPM-1 (immunohistochemically), whereas of 54 patients who were over 50 years of age, only 14 (26%) were positive. Accordingly, it was observed that the staining intensity with NPM-1 was statistically significantly higher in cases under 50 years of age (P = 0.026).
No correlation was found between overall survival and disease-free survival with the expression for anti-CEBPA or anti-NPM1 antibodies (P = 0.576 and P = 0.369 respectively). However, for FLT3, the expression of this antibody and its intensity were found to be a poor prognostic factor and statistically significant (P = 0.007).
Despite being statistically insignificant, the overall survival times of the positive cases with NPM1 and CEBPA, which are known as good prognostic factors, were higher than the negative ones (59 and 48.66 months for NPM1; 61.13 and 44.09 months for CEBPA). Although NPM1 and CEBPA reactivity are good prognostic factors and their expression is associated with longer survival times when evaluated alone. If FLT3 positivity is also present, the overall and disease-free survival times are significantly shorter (33.71 and 12.64 months for NPM1; 25.33 and 9.13 months for CEBPA). Although being insignificant for overall survival, this situation was found to be statistically significant for disease-free survival [Table 2] and [Table 3].
|Table 2: The combined effect of FLT3 and NPM1 on overall and disease-free survival|
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|Table 3: The combined effect of FLT3 and CEBPA on overall and disease-free survival|
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Twenty-seven patients survived less than 12 months. When immunohistochemical features were analyzed, intensity for expression of CEBPA was found to be weak for 5 cases (18.5%) and strong for 3 cases (11.1%), whereas 19 cases (70.4%) were completely negative. Immunohistochemical NPM1 expression was found to be weak in 3 cases (11.1%), and strong in 5 cases (18.5%); 19 cases (70.4%) were negative. FLT3 had more expression than the other two markers immunohistochemically amongst these 27 patients, where 5 cases (18.5%) were found to be weak positive and 11 cases (40.7%) strong positive; 11 cases (40.7%) were completely negative.
When the remaining 36 patients who survived more than 12 months were categorized according to immunohistochemical staining intensity, 24 cases (66.7%), 25 cases (69.4%), and 20 cases (55.6%) were negative for CEBPA, NPM1, and FLT3, respectively. Seven cases (19.4%), 6 cases (16.7%), and 13 cases (36.1%) showed weak expression, whereas 5 cases (13.9%), 5 cases (13.9%), and 3 cases (8.3%) showed strong expression for CEBPA, NPM1, and FLT3, respectively.
When immunohistochemical results were analyzed statistically, no significance was found between the expression of anti-CEBPA and anti-NPM1 antibodies with survival when 12 months was accepted as a cut-off value (P = 0.936 and P = 0.762, respectively). Also, co-expression or negativity of these two markers did not have any effect on prognosis. However, FLT3 expression was found to be statistically significant showing a reverse correlation with prognosis (P = 0.008).
| Discussion|| |
In acute leukemias, morbidity and mortality continue to be a major problem due to its high incidence, despite all promising developments. Age remains one of the major independent prognostic factors for acute leukemias.,, Juliusson et al. has suggested 50 years as a cut-off value as an indicator of prognosis and in patients over 50 years, prognosis has been shown to be significantly worse. In our study, patients below 50 years had a statistically significant better prognosis, and age showed a reverse correlation with prognosis, which is consistent with the literature.
Internal tandem duplication in FLT3 in AML patients is associated with a worse outcome, whereas in the absence of FLT3 mutations, NPM1 and CEBPA mutations are indicative of a better prognosis.,
Immunohistochemical evaluation of NPM1 expression is documented to be a substitute for molecular methods.,,, In a large study by Falini et al., 200 cases, shown to carry NPM1 mutations by polymerase chain reaction (PCR), demonstrated the expression of cytoplasmic NPM1 with immunohistochemistry. However, in a study by Pasqualucci et al., about 40% of the discrepancy between PCR and immunohistochemistry was noted due to technical errors. NPM1 mutation, demonstrated by molecular methods or immunohistochemistry, is related to a better prognosis.,,,,, In patients carrying this mutation, disease-free survival and overall survival have been found to be significantly better and after standard induction chemotherapy, complete remission is more likely.,,, In our study, diversely with the literature data, we found no correlation of NPM1 expression with survival or remission status. This discrepancy may be due to our limited patient population or analyses of this mutation by only immunohistochemical methods.
The prevalence of NPM1 mutations varies within the literature. According to two major studies by Thiede et al. and Port et al., NPM1 mutations are found to occur in 27.5% and 45 to 64% of AML patients, respectively. The prevalence of NPM1 mutation was 37.5% in our study.
In Brown et al.'s study, the prevalence of NPM1 mutation was found to increase with age, in women, in AML patients with FLT3 mutation, and in patients with normal karyotype, whereas many other studies did not find statistical relevance between NPM1 mutation and gender,,, yet slightly higher rates of expression were observed in women.,, Rau et al. also concluded that NPM1 mutations were observed to a lesser extent; 7.5% in the pediatric population. Thiede et al. reported higher rates of NPM1 reactivity with a higher blast ratio, white blood cell (WBC) and platelet count, especially in the presence of concomitant FLT3 mutations. Also, some studies revealed that (Lit et al.) in patients with FLT3 mutations, NPM1 mutation was found more frequently.
In our study, in spite of being statistically insignificant, NPM1 reactivity was found to be slightly higher in women than in men (38.8% vs. 36.4%). When the pediatric population in our study was considered, NPM1 expression was found in 5 of 11 patients (45.5%), which is higher than that reported in the literature. This difference was considered to be due to limited number of pediatric patients in our cohort. Our study revealed no correlation between NPM1 expression and clinical or biochemical values; yet, the age below 50 years was found to show a correlation with expression of this antibody (P = 0.026). Despite being statistically insignificant, NPM1 expression was slightly higher in FLT3-positive cases than in FLT3-negative cases.
Also, 40% of patients carrying the NPM1 mutation had FLT3 mutations and these patients' outcome was considerably poor. Among these two markers, the best prognostic combination was seen in NPM1 (+)/FLT3 (–)., In our study, similarly, we found that NPM1 (+)/FLT3 (–) patients had an average overall survival of 71.5 months and disease-free survival of 67 months, whereas, in NPM1 (+)/FLT3 (+) patients, the overall survival of 33.7 months and disease-free survival of 12.6 months were observed. Regarding these data, we conclude that the effect of NPM1 on prognosis depends on the presence of FLT3 mutations.
Another marker, which can be used to assess prognosis is CEBPA that has a similar outcome with patients carrying NPM1 mutations in the absence of FLT3 mutations. In studies by Pabst et al. and Wouters et al., heterogeneity in prognosis is noted in patients carrying CEBPA mutations; with an only biallelic double mutation in CEBPA, showing a correlation with a better prognosis, which brings, CEBPA mutations being dependent on FLT3 mutations on prognosis to the mind. In our study, cases that showed CEBPA expression had an overall survival of 61 months and disease-free survival of 22.1 months. When FLT3 was considered, CEBPA (+)/FLT3 (–) cases had significantly higher overall survival and disease-free survival (96 months and 72.3 months, respectively) when compared to CEBPA (+)/FLT3 (+) cases (25.3 months for overall survival and 9.1 months for disease-free survival). Considering these data, we conclude that the effect of CEBPA on prognosis is also dependent on FLT3 mutations, like NPM1.
The incidence of CEBPA mutations in our study, with expression in 35 patients (33.7%) was higher than the data reported in the literature. In a study by Lin et al., CEBPA incidence was found to be 15%. A potential explanation to clarify this difference is that CEBPA incidence shows geographical variability, with a low level of evidence.
When AML is further classified according to the French-American-British (FAB) classification, CEBPA is most prevalent in AML FAB M1 or M2 subtypes.,, The results of our study were consistent with the literature, with a 47.4% rate for AML FAB M1 and 30.6% for AML FAB M2.
In various researches, studying the effect of CEBPA on prognosis, no consensus was established and the discrepancy was present between different studies. Apart from studies suggesting CEBPA as a good prognostic factor,,, many studies did not find any correlation between CEBPA and prognosis. A convenient study by Leroy et al. suggested that CEBPA mutation can only be suggestive of a good prognosis in the absence of other bad prognostic factors. We did not find any correlation between CEBPA expression and clinical, biochemical, and radiological data including prognosis.
The prevalence of FLT3 tandem mutation showed variation between different studies and the presence of this mutation showed a strong relation with karyotype. Thiede et al. reported a 20.4% prevalence and Illmer et al. reported a slightly higher prevalence (30–35%)., In cytogenetically normal adult AML patients, FLT3 internal tandem duplication is the most frequent molecular abnormality, indicative of a very poor prognosis. The overall survival in patients with FLT3 mutations has been shown to be as low as 8 months, which is also supported in the study by Port et al.,
In our study, 55 of 104 cases (52.9%) showed expression with FLT3. Similar to literature data, the median overall survival of patients carrying the FLT3 mutation was 13 months. Another important point is that in cases showing strong expression with this marker, the median overall survival decreased to 6 months (P = 0.007).
Our study showed that the immunohistochemical expression of FLT3 is a poor prognostic factor for AML patients, which is consistent with the literature. The other two markers, CEBPA and NPM1, showed no statistically significant effect on prognosis. Our study suggests that the expression of FLT3 is an independent prognostic factor. This marker did not show any correlation with other demographic, clinical, biochemical, or radiological data.
| Conclusion|| |
FLT3 is an independent prognostic factor for AML. CEBPA and NPM1 should be considered as good prognostic factors only in the absence of FLT3 abnormalities. These markers can also be investigated by immunohistochemical methods as an alternative to molecular methods.
Financial support and sponsorship
Scientific Research Projects Coordination Unit of İstanbul University-Cerrahpasa. Project number: 47063.
Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, Mehmet Akif Inan Training and Research Hospital, Esentepe – 63040, Sanliurfa
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]