Abstract
The complete blood count (CBC) is the most requested medical test in the world and it is used for various clinical purposes. Due to its characteristic of quantifying red blood cells, white blood cells, and platelets, it assesses bone marrow function, where most leukemias originate. Therefore, the test has the potential to unintentionally detect different types of leukemia. Screening refers to the application of a diagnostic test to a population without signs or symptoms of the disease. Although the request of a CBC in clinical practice does not necessarily constitute screening, the premise that early detection allows more effective treatment, preventing deaths and allowing patients to live longer, may also apply to leukemias. In this article, leukemias and the CBC are used as a didactic platform to explain some aspects regarding potential benefits, harms, and limitations of incidental detection of diseases in asymptomatic individuals and its implications for the primary care clinician.
- Cancer
- Complete Blood Count
- Diagnostic Tests
- Hematology
- Incidental Findings
- Leukemia
- Overtreatment
- Primary Health Care
- Screening
Introduction
The complete blood count (CBC) is the most requested medical test in the world1 and it is used for various clinical purposes. Due to its characteristic of quantifying red blood cells, white blood cells, and platelets, it assesses bone marrow function, where some hematologic cancers originate, especially leukemias. Therefore, the test has the potential to unintentionally detected different leukemia types.
A CBC request in clinical practice does not necessarily constitute screening, but it shares many similarities. Screening refers to the application of a diagnostic test to a population without signs or symptoms of the disease. The premise is that early detection allows more effective treatment, preventing deaths and allowing patients to live longer.2 Although it makes sense, when it comes to cancer screening, things are not so simple. The widespread use of screening often results in complex decisions regarding interventions due to false-positive results and the identification of inconsequential findings (incidentalomas). Moreover, counterintuitive concepts, such as overdiagnosis and overtreatment, and semantic issues, such as confusing advanced disease with late diagnosis and initial disease with early diagnosis, contribute to the complexity and misinterpretation of the subject.
In this article, leukemias and the CBC are used as a didactic platform to explain some aspects regarding potential benefits, harms, and limitations of incidental detection of diseases in asymptomatic individuals and its implications for clinical practice.
Chronic Myeloid Leukemia (CML)
In about 50% of patients, CML is detected incidentally in the asymptomatic phase when a CBC is requested for an unrelated reason. The characteristic finding in the CBC is leukocytosis with left shift, displaying the entire spectrum of granulocytic differentiation. Basophilia is a typical finding.3 The diagnosis is confirmed by the detection of the Philadelphia chromosome by genetic or molecular methods.4
Evolution in CML treatment represents one of the greatest successes in oncohematology history. Imatinib has transformed a disease fatal within a few years (except for the few patients who underwent and survived an allogeneic bone marrow transplant) into a chronic condition with life expectancy and quality of life similar to the general population.5 Early treatment reduces the likelihood that the leukemic clone acquires additional genetic changes responsible for disease progression. Hence, once diagnosed, guidelines recommend immediate treatment, regardless of symptoms.
This situation illustrates the main benefit of screening, when diagnosis and treatment of asymptomatic disease likely decrease mortality. Although no randomized clinical trials compared immediate treatment in asymptomatic patients with deferring treatment until symptoms are seen, the progression of the disease is inexorable and related to time-dependent genetic changes that confer therapeutic resistance. Conducting such a study would be unethical. The consensus is that, if untreated, all patients (including asymptomatic) will inevitably progress and die.6 Therefore, the natural history of this disease reduces the likelihood of overdiagnosis and overtreatment.
Chronic Lymphoid Leukemia (CLL)
Most CLL cases are also initially detected in asymptomatic patients by the CBC. The characteristic finding in the CBC is leukocytosis with lymphocytosis. Diagnosis is usually confirmed by immunophenotyping of peripheral blood. A significant proportion of these asymptomatic patients will never progress to symptomatic disease and will die from unrelated causes.7 This presents a challenging consultation: explaining to an individual who has always heard that early cancer diagnosis is crucial for survival that despite being diagnosed with leukemia, the best course of action is “only” watchful waiting.
The diagnosis of CLL in some asymptomatic patients fits the definition of overdiagnosis: diagnosing a condition that would have not caused symptoms or death. The most pernicious consequence of overdiagnosis is overtreatment: treating a cancer that would have not harmed the patient, who is exposed to the risks of unnecessary surgery, radiotherapy, chemotherapy, or other treatments.8 Since it is unknown at diagnosis which patients will progress to symptomatic disease and it has been shown that treating asymptomatic patients does not improve survival, although increasing toxicity, the recommended approach is watchful waiting, reserving treatment for patients who develop specific indications, such as signs of bone marrow failure (anemia, thrombocytopenia), significant lymph node enlargement, symptomatic splenomegaly, among others.7
Acute Leukemias
The development of de novo acute myeloid or lymphoid leukemia (outside the context of a previous hematologic disease or predisposing condition) is unpredictable. The usual scenario involves an acutely ill patient with severe cytopenias and symptoms of marrow failure that developed over a short period of time, with normal tests and no complaints a few weeks prior. Typical CBC findings are leukocytosis (normal white blood cell count or leukopenia can also occur) with immature cells (blasts) in the peripheral blood associated with anemia and thrombocytopenia. The diagnosis is made through a combination of immunophenotyping and genetic/molecular tests performed on bone marrow and/or peripheral blood.
The disease is almost never detected by the CBC before symptoms are seen. Even in this unlikely scenario, prognosis is primarily determined by the biological characteristics of the disease (genetic and molecular alterations) and patients’ clinical characteristics (performance status, comorbidities), rather than early diagnosis.9,10
This situation illustrates one of the main limitations of screening: the inability to detect very aggressive cancers that grow fast enough to cause symptoms between tests. Not detecting a cancer with these characteristics does not mean a health care system failure. This issue is more related to tumor biology than absent or insufficient screening. In these cases, the best approach is to raise awareness among the population and primary care doctors about signs and symptoms and ensure the health care system is prepared for efficient diagnostic investigation and therapeutic intervention.
Discussion
Although there are no formal recommendations for systematic screening in hematology, a similar situation occurs for leukemias every time a CBC is requested. In this article, we used this well-known laboratory test and this set of diseases in a simplified attempt to explain some of the main (and often misunderstood) aspects of the topic.
Cancer is a heterogenous disease, even within the same class like leukemias. A useful way to understand the heterogeneity of cancer and its relationship with screening or incidental detection is the barnyard pen analogy.1 We aim to catch cancers before they surpass a certain threshold at which treatment would be less effective. Different cancers behave like different animals, such as birds, rabbits, and turtles (Figure 1). Birds represent very aggressive cancers, like acute leukemias, that are already advanced by the time they are detectable. They are not captured by screening. Even so, treatment still might work. Incidental detection helps with rabbits, more slowly progressive cancers that will cause harm if untreated. Rabbits can be caught early, and immediate treatment is indicated, as in the case of CML.
Leukemias and their detection by the complete blood count (CBC). Acute leukemias (AL) exhibit rapid tumor growth and are usually not detected during the short asymptomatic period by CBC. They represent the birds, which usually are not incidentally detected. Chronic myeloid leukemia (CML) are always rabbits, as they can be detected during the asymptomatic period by CBC and will progress to symptomatic disease if left untreated. Chronic lymphocytic leukemia (CLL) can also be detected during the asymptomatic period by CBC. However, not all patients will progress to symptomatic disease (turtles) and it is not possible to know, at the moment of diagnosis, who will progress (rabbits). Diagnosing these cases that represent the turtles is an example of overdiagnosis. Adapted from Overdiagnosis, by National Cancer Institute, 2019 (Available at: https://visualsonline.cancer.gov/details.cfm?imageid=12720).
In asymptomatic CLL, the issue is more complex, because it is unknown who will progress and require treatment (rabbits) and who will remain stable or progress so slowly, that they will not be harmed by the cancer during their lifetime (turtles). There is no need to catch the turtles, as they will not cross the “harm threshold.” Therefore, monitoring disease progression and reserving treatment for symptomatic cases is the best approach, avoiding overtreatment.
A similar situation arises in screen-detected prostate cancer, for example. At diagnosis, there is often insufficient information to determine which cases will benefit more from early treatment.11 However, most screen-detected prostate cancer patients are treated as if they were rabbits, suffering significant harms from overtreatment, such as erectile dysfunction and urinary incontinence, without having their lives extended.11 In prostate cancer, one of the main strategies to reduce screening harms is using decision aids for shared decision-making for men requesting screening and, once diagnosed, using active surveillance and watchful waiting protocols in selected cases, similar to asymptomatic CLL cases.
Semantic issues related to screening or incidental detection can cause confusion. Diagnosing advanced disease is not synonymous with late diagnosis. Advanced disease means having a high tumor burden, which can occur in a short period of time in aggressive cancers. Similarly, diagnosing limited disease is not synonymous with early diagnosis. If a disease that has existed for a long time without causing problems is detected, the diagnosis was not early. The test detected a long-lasting indolent, clinically irrelevant disease.
We believe the relationship between leukemias and CBC serves as a didactic model to help doctors understand these counterintuitive aspects of cancer screening and incidental detection. It highlights general lessons that can be extrapolated to solid tumors screening, which occurs more systematically for some diseases, but it still leaves many questions regarding potential risks, benefits, and limitations. In Figure 2, we propose a decision aid to facilitate communication and the shared clinical decision-making process regarding leukemias detected in primary care.
Decision aid to facilitate communication about leukemias natural history and treatment recommendations to patients. Abbreviations: CBC, complete blood count; CML, chronic myeloid leukemia; CLL, chronic lymphoid leukemia; AL, acute leukemias.
Conclusion
While the CBC is indispensable in general medical practice, its role in the incidental detection of leukemias offers crucial insights into cancer screening in general. It underscores the complex balance between the benefits of early detection and the challenges of avoiding overdiagnosis and overtreatment. It emphasizes the importance of nuanced clinical judgment and tailored patient management strategies, highlighting the need for ongoing education and dialog between generalists and specialists. Navigating these complexities, this model serves as a reminder of broader implications for cancer screening practices in primary care, urging careful consideration of potential harms, benefits, and limitations in the pursuit of improving patient outcomes.
Notes
This article was externally peer reviewed.
Funding: None.
Conflict of interest: None.
To see this article online, please go to: http://jabfm.org/content/38/2/355.full.
- Received for publication July 21, 2024.
- Revision received September 26, 2024.
- Revision received October 8, 2024.
- Accepted for publication October 14, 2024.
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