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Monocytosis And Patient Risk Of Malignancy And Mortality

Monocytosis And Patient Risk Of Malignancy And Mortality

Monocytosis is a common occurrence in primary care, but its significance is not always clear. In adults, monocytosis is defined as having a higher-than-normal count of monocytes (a type of white blood cell) in the peripheral blood, specifically above 0.8 x 10^9/L. Monocytosis is a key feature of certain conditions like chronic myelomonocytic leukemia (CMML), where diagnostic criteria include clonality and monocytosis of at least 0.5 x 10^9/L comprising more than 10% of the total white blood cell count (WBC). However, monocytosis can also be present in other myeloid diseases such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and acute myeloid leukemia (AML), as well as benign conditions. When a persistent and unexplained monocytosis of at least 1.0 x 10^9/L is observed, it is generally recommended, according to guidelines from organizations like the World Health Organization (WHO), to refer the patient to a hematologist for further evaluation.

In a hematological specialist clinic, the cause of monocytosis is typically investigated through blood samples, abdominal ultrasound, and bone marrow biopsy for assessing cytogenetics and morphology. Next-generation sequencing (NGS) can be used to analyze genetic mutations in both bone marrow and peripheral blood samples. Many cases of CMML exhibit specific molecular abnormalities detectable through these methods. In cases where the diagnosis remains uncertain, flow cytometry has been introduced as a diagnostic tool to differentiate secondary monocytosis from CMML, as an increased fraction of classic monocytes is indicative of malignancy.

Despite these investigations, some patients referred from primary care to hematologists due to monocytosis do not receive a clear diagnosis and are eventually sent back to primary care. To better understand the risk associated with unexplained monocytosis, the study aims to describe the predictive value of monocytosis in primary care. The researchers identified a group of patients with monocytosis in one or more complete blood cell counts (CBC) over a 15-year period using data from the Copenhagen Primary Care Laboratory (CopLab) Database. The study evaluates the occurrence of hematological malignant diseases and overall mortality in these patients during a 3-year follow-up to provide estimates of the associated risks.

Study Methods 

In the region of Copenhagen, which encompasses both the Copenhagen Municipality and the former Copenhagen County, a sole laboratory handled all laboratory analyses for a population of 1.3 million inhabitants. This facility, known as the Copenhagen General Practitioners’ Laboratory (CGPL), was responsible for conducting a wide array of tests on blood, urine, and semen samples. Additionally, it carried out various clinical physiological, cardiac, and lung function assessments. The CGPL served both general practitioners (GPs), who accounted for 85% of the laboratory’s workload, and practicing specialists (15%) from the year 2000 to 2015. 

The laboratory outcomes, including a diverse range of numerical results (totaling 112 million), were documented in the CopLab Database, as previously outlined in comprehensive detail. For this current study, our analysis focused on individuals who had at least one complete blood cell count (CBC) recorded in the CopLab database between October 2000 and the conclusion of 2015, while also confirming their Danish residency by January 1st of the corresponding measurement year. CBCs collected before July 1, 2000, were excluded due to internal validation results suggesting potential data issues.

Results 

In a study encompassing 663,184 individuals, 4.6% (30,582) exhibited monocytosis in randomly selected samples. Monocytosis was more common in older individuals and males, while socioeconomic factors showed uniform distribution across monocyte ranges. Hematological malignancy occurrence was 170 cases per 100,000 person-years. 

Prominent diagnoses included M-component-related diseases and non-Hodgkin lymphoma. Subgroups with monocytosis displayed frequent non-Hodgkin lymphoma and myeloproliferative neoplasms (e.g., polycythemia vera, chronic myeloid leukemia) diagnoses. Among those with monocytosis, 1.8% (551) were diagnosed with malignant hematological conditions within three years of complete blood cell count (CBC) measurement. Manifest monocytosis exhibited an elevated risk of hematological malignancy (OR 5.97), linked to increased mortality (ORs 1.66 for subclinical, 2.23 for manifest monocytosis).

Chronic myelomonocytic leukemia (CMML) occurred in only 21 cases within the CopLab population over a three-year follow-up, with 15 showing manifest monocytosis in the initial CBC. CMML risk was substantially elevated (OR 105.22) compared to the normal range but remained rare. Risk notably escalated with sustained monocytosis (OR 144.36). The risks of myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML) were heightened with manifest monocytosis (ORs 5.85, 10.21, and 14.44 respectively). Subclinical monocytosis raised MPN risk (OR 2.61), while MDS and AML risk showed no increase. Sustained monocytosis magnified all risks.

Both subclinical and manifest monocytosis correlated with various lymphoproliferative neoplasms. Over three years, 381 individuals developed chronic lymphocytic leukemia (CLL), with manifest monocytosis linked to over twelvefold increased risk (OR 12.20), 103 individuals with monocytosis and subsequent CLL also exhibited lymphocytosis in their CBC. Sustained monocytosis increased CLL risk sixfold (OR 29.49). Risks for non-Hodgkin lymphoma, Hodgkin lymphoma, and M-component diseases more than doubled with manifest monocytosis. Subclinical monocytosis raised Hodgkin lymphoma risk, while sustained monocytosis increased the risk of plasma cell dyscrasia fivefold and Hodgkin lymphoma tenfold.

Conclusion 

In a study involving a substantial cohort of 663,184 patients within the realm of primary care, researchers identified peripheral monocytosis in 4.6% of complete blood cell counts (CBCs), highlighting the relatively frequent occurrence of monocytosis in this clinical context. After measuring manifest monocytosis, the most frequently observed hematological malignancies were myeloproliferative neoplasms (MPNs) and non-Hodgkin lymphoma. However, the highest estimated relative risk was associated with manifest monocytosis and chronic myelomonocytic leukemia (CMML), revealing an odds ratio (OR) exceeding 100. Moreover, sustained monocytosis further intensified the risk, reaching an OR surpassing 140. Notably, even with sustained monocytosis, CMML remained a rare finding within the primary care sample.

Approximately 20% of newly diagnosed acute myeloid leukemia (AML) cases demonstrated manifest monocytosis upon initial CBC assessment, consistent with the distribution of acute myelomonocytic leukemia and acute monoblastic/monocytic leukemia cases in the cohort. In the context of MPNs, the presence of both manifest and subclinical monocytosis correlated well with the underlying disease pathophysiology, where the malignant clone typically generates mature cells of the myeloid lineage at progressively increasing rates. This pattern encompasses both subclinical and manifest monocytosis, representing only a fraction of the overall disease profile and often affecting a single compromised cell line.

In summary, within a significant primary care patient population devoid of established hematological malignancy, monocyte counts surpassing 1.0 x 10^9/L was associated with an elevated three-year risk of diverse myeloid and lymphoproliferative neoplasms, in addition to heightened all-cause mortality. Despite the substantial relative risk for CMML in the presence of monocytosis, the actual incidence of hematological malignancy remained low. The substantial augmentation of malignancy risk with sustained monocytosis underscores the importance of repeated measurements when uncertainty arises regarding the underlying cause of monocytosis. Although challenges persist in ensuring appropriate referrals from primary care, these findings support the consideration of hematological malignancy suspicions when monocytosis persists or when clinical presentation aligns with such conditions. Future analyses could potentially encompass comprehensive CBC variables to enhance precision in risk assessment.

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