Clinical and laboratory features of leukemias at the time of diagnosis: An analysis of 1,004 consecutive patients
Authors: Zdenek Racil, Lucie Buresova, Martin Brejcha, Jirina Prochazkova, Rene Zounar, Shira Timilsina, Filip Razga, Martina Toskova, Petr Cetkovsky, Jiri Mayer
Journal: American Journal of Hematology (2011)

To determine the major presenting features of the most frequent leukemias and to describe the period from the first symptoms to the final diagnosis, we analyzed the records of 1,004 consecutive patients with acute (AL) and chronic (CL) leukemias diagnosed between 2004 and 2009. In 24% of AL and 63% of CL, the diagnosis was made incidentally. In contrast to the frequency of the symptoms, their spectrum did not differ from historical studies, and fatigue and weakness were the most frequent symptoms observed [with the exception of acute promyelocytic leukemia (APL) where bleeding predominated]. More profound cytopenia was found in AL compared to CL. The median time from the first symptoms to final diagnosis was 3 weeks in AL and 4 weeks in CL. APL had the shortest time to a definitive diagnosis (2weeks); however, a very short duration of symptoms was also observed in CML (3 weeks). This study is the largest series reported to date on symptoms in leukemia patients at the time of diagnosis, and the first such report that reflects on clinical practice in the new millennium. Despite the availability of new diagnostic tools, clinical signs and symptoms as well as abnormalities in basic hematological examination still represent critical criteria for the initial diagnosis of leukemia. Although textbooks and reviews have described several different signs and symptoms of the various types of leukemia [1-8], the real incidence of these findings has not been described. Only a few studies specifically address this issue [9] and are usually several decades old [10, 11]. In an attempt to determine the major subjective and objective features of the most frequent acute and chronic leukemias that occurred during the first decade of the 21st century, and to describe the duration from initial symptoms to final diagnosis, we have reviewed the records of 1,004 patients that were referred to three hematological centers in the Czech Republic over the past 5 years. The baseline characteristics are shown in Table I. Three quarters of AL patients and one third of chronic leukemia (CL) patients were diagnosed due to the presence of any symptom of the disease. Interestingly, one quarter of AL patients and more than half of CL patients were incidentally diagnosed (Table I). The percentage of symptomatic patients before diagnosis increased slightly when a medical history was obtained during the first medical visit (Table I). At the time of diagnosis, AL patients had more symptoms of the disease compared to CL patients (83% vs. 47%; P < 0.001). The most frequent symptoms in AL patients were fatigue and weakness, followed by pain and dyspnea (Table I). Forty-six percent of AL patients with pain had musculoskeletal pain, and 27% had oral, throat, and dental pain. The majority of CL patients were asymptomatic at the time of diagnosis. The most frequent symptoms at the time of diagnosis were fatigue and weakness, B symptoms, and infection. Pain was documented in 12.5% of CL patients, and similar to AL patients, the majority reported musculoskeletal pain (35%). However, abdominal pain occurred at the same frequency. During the first medical visit all of the patients received a physical examination (data were not available for 0.2% of the patients). Moreover, some of these patients had blood tests (76.7%), biochemical analyses (54.4%), imaging studies (29%), or other tests (28%) performed. An abnormality during physical examination was found in 68.9% of the patients and occurred more frequently in AL compared to CL patients (79.7% vs. 56.0%; P < 0.001) (Table I). The highest frequency occurred in APL patients (P = 0.002). The most frequent findings in AL patients were clinically documented infections, followed by bleeding and labored breathing. CL patients had fewer objective findings than AL patients during the first medical visit, and no differences in the frequency of these findings were observed among the different types of CL (P = 0.134). An abnormality in the blood count was found in almost all patients (99.7%) regardless of AL or CL diagnosis (99.5% vs. 100%; P = 0.097) (see Fig. 1). Biochemical analyses showed an abnormality in 37.7% of the patients in whom the analyses were carried out, and occurred more frequently in AL cases (45.7% vs. 28.5%; P < 0.001). If an imaging study was performed, an abnormality was observed in 57.6% of the patients regardless of an AL and CL diagnosis (54.6% vs. 61.4%; P = 0.286). Median, 25–75 quartile interval, and min-max of total leukocytes (LEU), hemoglobin level (HB), platelets (PLT), and Neutrophils (NEU) counts in different leukemias. ALL—acute lymphoblastic leukemia, AML—acute myeloid leukemia, APL—acute promyelocytic leukemia, CLL—chronic lymphocytic leukemia, CML—chronic myelogenous leukemia, HCL—hairy cell leukemia. The correlation of presence of symptoms with blood count parameters was performed. WBC count was significantly different (lower) only in patients complaining of dyspnea (P = 0.003). Any other correlation between WBC count and frequency of symptoms was not found. Moreover, we did not detect any relationship between neutrophil count and frequency of infection (P = 0.119) or fever (P = 0.067). In contrast, patients with lower hemoglobin and platelet levels had significantly higher frequency of all analyzed symptoms except lymphadenopathy (fatigue and weakness—P < 0.001 and P = 0.001, pain—P < 0.001 and P < 0.001, infection—P = 0.019 and P = 0.054, dyspnea—P < 0.001 and P < 0.001, B symptoms—P < 0.001 and P = 0.018, bleeding—P < 0.001 and P < 0.001, fever—p = 0.001 and P < 0.001). The median time from the first symptom to diagnosis was 22 days, however the range was extremely wide (0–370 days). This period was shorter in AL patients compared to CL patients (21 days vs. 27 days; Table II; P = 0.004). There was no significant difference in this period among patients with CLs. The shortest duration from the first symptom to the time of diagnosis among AL patients was observed in patients with APL (P < 0.001). The median time from the first medical visit to a definitive diagnosis was 8 days, however the range was again substantial (0–355 days). In addition, this period was shorter in AL patients compared to CL patients (7 days vs. 10 days; P < 0.001). Within both groups, the fastest diagnosis was established in patients with APL (P = 0.008) and CML (P < 0.001) (Table II). The first physician visited by patients with leukemia was a general practitioner (GP) in 48.6%, internist in 21.6%, hematologist in 7.3%, and another type of practitioner in 22.5% of the cases. The first physician visited by leukemia patients referred 64% of the patients directly to a hematologist or to the hematology department, excluding patients where the hematologist was the first physician visited. Thirty-six percent of the patients visited one specialist and 9.8% of the patients visited two or more specialists before referral to a hematologist. Interestingly, patients with AL visited a higher number of specialists than the other patient groups before referral to a hematologist (P < 0.001). Forty-eight percent of patients (57.8% of AL patients and 35.9% of CL patients; P < 0.001) were admitted to different medical wards with difficulties related to leukemia before the final diagnosis was established. Moreover, 5.1% were admitted to more than one. Greater awareness of hematological malignancies among clinicians, progress in medical care with a wide availability of economical blood count tests, and regular preventive medical examination have led to a dramatic change in the frequency of symptoms and findings at the time of leukemia diagnosis. Incidental diagnosis is still considered to be rare in patients with ALs, even in recent textbooks [12]. However, our analysis showed that almost one quarter of all AL patients were diagnosed based on abnormalities found in a random blood count that was frequently performed for preventive reasons or before a planned surgical procedure. An incidental diagnosis was reported more frequently in chronic leukemias [9, 13]. However, in this study we found an important shift with the biggest change detected in CML patients. While in the 1970s, symptoms were present at the time of diagnosis in all patients with CML [14], in the 1980s and 1990s, symptoms were present at the time of diagnosis in 80% of the patients [9]. However, in our study more than half of the patients with CML were incidentally diagnosed. Unlike the frequency of symptoms, the spectrum of symptoms did not differ from historical studies [2, 7-9, 15, 16]. Similarly, the spectrum of findings during physical examination at the time of diagnosis did not differ from published data; however the incidence was again notably lower. For example, only 10, 23, and 22% of patients with chronic lymphocytic leukemia (CLL), CML and hairy cell leukemia (HCL), respectively, had a palpable spleen compared to 78, 97, and 96% of these patients in previous analyses, respectively [10, 11]. APL again represents the only exception, where the frequency of bleeding, which is a typical finding during physical examination, is still currently very high in these patients (77%). Our analysis of blood counts at the time of diagnosis for individual types of leukemia roughly corresponded to findings in previously published studies [9, 11, 17-22]. Nevertheless, it is important to note that even though the total leukocyte (LEU) counts were highest in CML cases (median 93 × 109/l), these values only represent 40–50% of the median LEU counts in the analyses published two to four decades ago [9, 20]. It is very difficult to find studies analyzing the natural history of leukemias that report the duration of symptoms. In most cases, reviews are limited to a general statement of the duration of symptoms as “several weeks” in AL patients and “several months” in CL patients [1]. Our analysis has shown that although an extremely wide range was observed, the median time from the first symptom to a final diagnosis of leukemia was only 3 weeks in ALs and 4 weeks in CLs. The high frequency of bleeding symptoms in APL patients is most likely the reason for the shortest time to a definitive diagnosis (2 weeks) among all of the groups. However, we noticed that this period was surprisingly short in CML patients. Savage et al. [9] reported 3 months as the median duration of symptoms in patients with CML diagnosed in the 1970s and 1980s. In our study that analyzed cases occurring in the first decade of the 21st century, if the patient was symptomatic, then the time to final diagnosis was only 3 weeks. In our report, the majority (64%) of patients were referred by the first physician visited (generally a GP) directly to the hematologist or hematology department. Therefore, the time from the first medical visit to the final diagnosis was again short—∼1 week—despite the broad range of time. Thus, any possible influence of diagnostic procedure delays on patient prognosis was extremely rare. As expected from other analyses of this study, the shortest period from the first medical visit to final diagnosis occurred in the APL patient group. It is very likely that this was due to the high frequency of bleeding symptoms in APL patients, which are generally very alarming and suggest a hematological disorder. Surprisingly, a very short duration from the first medical visit to final diagnosis also occurred for patients with CML (median of 6 days). One explanation could be the occurrence of the highest leukocytosis of all of the subgroups; even though the majority of the patients were asymptomatic (53% of CML cases had an incidental diagnosis). A finding of leukocytosis immediately triggers a referral to a hematologist. The availability of rapid molecular tests for the detection of the BCR-ABL fusion gene in peripheral blood leukocytes leads to a final diagnosis of CML within a few days or even a few hours. Thus, CML represents the hematological malignancy where the most important steps toward very early diagnosis have been performed during the last several decades In summary, our unique study is the largest series to date that has analyzed the symptoms, physical signs, blood count at diagnosis, and the length of period to final diagnosis of patients with the major types of leukemias, despite being retrospective and limited to patients referred to tertiary care hospitals. Moreover, this is the first such report that reflects clinical practice in the new millennium. The medical history, medical records from referral physicians, and the first available blood count results were collected for all consecutive patients referred to three hematological centers in the Czech Republic between January 2004 and June 2009 with a final diagnosis of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL). Seventy-seven percent of patients in the study proceeded from Department of Internal Medicine—Hematology and Oncology, Masaryk University and University Hospital Brno; 17% from Institute of Hematology and Blood Transfusion, Prague; and 6% from Department of Hematology, Cancer Center Novy Jicin. While spectrum of leukemias analyzed in first two centers was roughly similar, Cancer Center Novy Jicin provided data only on patients with CLL. The diagnosis was defined according to the 2008 WHO classification of tumors of hematopoietic and lymphoid tissues [23]. The day of the diagnosis represented the date of obtaining the sample essential for the definitive diagnosis of the disease according to the aforementioned WHO criteria (usually the day of bone marrow sampling or the day of obtaining peripheral blood sample for flow cytometric analysis—in the case of CLL). For the analysis of percentage of patients diagnosed due to presence of symptoms we calculated only patients that visited a physician due to the presence of symptoms. However, for the description of frequency of the symptoms among different leukemias we have also added patients that were diagnosed incidentally, but had symptoms during anamnesis. For the calculation of the period from the onset of the first symptoms to the final diagnosis, the information from patient's anamnesis was used. In the cases where the exact date of the start of the symptoms was not known, the first day of the week when the symptoms started was used for calculation. If only the information about the month when the symptoms started was available, then the first day of that month was used as the first day of the onset of symptoms. Data were only rarely incomplete. In this analysis, the denominator used to calculate the percentage represents the number of cases for which information was available. Statistical methods included the M-L chi-square test for the comparison of the frequency of categorical variables, and the Mann-Whitney U test for the comparison of quantitative variables. A two-sided P value <0.05 was considered statistically significant. For all statistical analysis, the software Statistica, version 9.1 (StatSoft) was used. Zdenek Racil zracil@fnbrno.cz*, Lucie Buresova , Martin Brejcha , Jirina Prochazkova*, Rene Zounar§, Shira Timilsina*, Filip Razga*, Martina Toskova*, Petr Cetkovsky§, Jiri Mayer* ¶, * Department of Internal Medicine—Hematology and OncologyMasaryk University and University Hospital Brno, Brno, Czech Republic, Institute of Biostatistics and Analyses, Masaryk University, BrnoCzech Republic, Department of Hematology, Cancer Center Novy JicinNovy Jicin, Czech Republic, § Institute of Hematology and Blood TransfusionPrague, Czech Republic, ¶ CEITEC—Central European Institute of Technology, Brno, Czech Republic.