Leukemoid reaction causing arterial thrombus in a patient with lung adenocarcinoma
- 1 Internal Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
- 2 Medical Oncology, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
- Correspondence to Dr Thejus Jayakrishnan; thejus.jayakrishnan@ahn.org
Abstract
A leukemoid reaction is typically defined as white blood cell (WBC) count >50×109/L, predominantly neutrophil precursors, that are not due to tumour involvement in the bone marrow and not derived from clones. Leukemoid reactions associated with malignancy, known as paraneoplastic leukemoid reactions, are less common and are most notably seen with non-small cell lung cancer. A 64-year-old woman presented with right leg painful ulceration. On examination, she had multiple venous stasis ulcers more severe on the right, with no palpable pulses in her lower extremities. Her WBC count was 124×109/L and platelets were 517×109/L. Arterial dopplers showed limb-threatening arterial insufficiency which prompted right femoral endarterectomy. Few months earlier she was diagnosed with metastatic lung adenocarcinoma to the bone and she had leukemoid reaction with WBC 43.920× 109/L with 90% neutrophils. Repeat imaging showed progression of her malignancy and she passed shortly after. Inflammation is a key element of carcinogenesis and cancer progression. Among the different tumours, lung cancer is a non-haematologic malignancy that is most closely associated with leucocytosis. Some studies have found that leucocytosis was significantly associated with metastasis and shorter survival irrespective of other factors such as age or sex. The mechanism remains unclear however elevated levels of granulocyte colony-stimulating factor (CSF), granulocyte macrophage-CSF and interleukin 6 have been linked to this phenomena. The degree of leucocytosis seen in our patient is suggestive of CSF production leading to a paraneoplastic leukemoid reaction.
Background
A leukemoid reaction is typically defined as white blood cell (WBC) count >50×109/L, predominantly neutrophil precursors, that are not due to tumour involvement in the bone marrow and not derived from clones. Mild leucocytosis occurs frequently with non-haematologic malignancies. However, leukemoid reactions associated with malignancy, known as paraneoplastic leukemoid reactions (PLR), are less common and are most notably seen with non-small cell lung cancer, especially large cell carcinoma.1
In our case, we present a severe PLR in a female patient with stage IV lung adenocarcinoma. We discuss the origin and progression of her leucocytosis and provide a complete haematologic and infectious investigation that was unremarkable and non-contributory to her condition. To our knowledge, this is the first case where the PLR is strongly attributed to peripheral arterial disease and causes detrimental effects on our patient.
Case presentation
We report a 64-year-old Caucasian woman with a history of hypertension. Our patient was a 40 pack-year smoker and presented to her primary care physician for management of invasive ductal carcinoma (IDC). In preparation for a lumpectomy, she had preoperative blood work that showed haemoglobin 11.5 g/L, WBC count 43.920×109/L and platelet count 584 ×109/L. Chest X-ray performed as part of her preoperative work-up revealed a mass-like consolidation involving the right upper lobe and a pulmonary nodule in the left upper lobe. Blood cultures were negative. Peripheral blood smear showed leucocytosis and thrombocytosis with no blasts. Flow cytometry for leukaemia/lymphoma panel, JAK-2 mutation and BCR ABL testing was negative. An ultrasound of the spleen was also normal. Bone marrow biopsy was done and revealed hypercellular bone marrow (60%–70%) with active trilineage haematopoiesis. Definitive features of a chronic myeloproliferative neoplasm were not identified. CT scan of the chest, abdomen and pelvis showed a 6.1×5.2 cm right upper lobe lung mass with 2×1.8 cm left upper pulmonary nodule suspicious for metastasis with no other evidence of metastasis. Biopsy of the left upper lobe mass showed poorly differentiated non-small cell carcinoma favouring pulmonary adenocarcinoma, programmed death-ligand-1: 70%. We performed a fluorodeoxyglucose positron emission tomography (PET)/CT scan for staging that revealed multiple hypermetabolic mediastinal lymph nodes, a hypermetabolic left hilar node, a large necrotic hypermetabolic right upper lobe pulmonary mass, a left upper lobe pulmonary mass and a rounded lytic focus in the anterolateral aspect of the left iliac bone that was also hypermetabolic. MRI of the brain showed no evidence of intracranial metastatic disease. She was diagnosed with stage IVA (cT4 cN3c M1b) adenocarcinoma of the lung. Due to poor prognosis of the disease and her concern for poor quality of life, she denied chemotherapy and was started on pembrolizumab for palliative therapy as well as anastrozole daily for IDC with no plans for surgery. At this time, her WBC count remained stable (around 40×109/L) with persistent thrombocytosis and mild anaemia. Follow-up PET-CT scan after three cycles of pembrolizumab showed mixed pattern of response with overall mild improvement. She developed painful ulceration of her right leg prompting a visit to the emergency room. On physical examination, she appeared cachectic and had multiple venous stasis ulcers more severe on the right, slow capillary refill and no palpable pulses in her lower extremities. Her WBC count at that time was 124.08×109/L and platelets were 517 ×109/L. Her blood cultures were positive for Escherichia coli from a urinary source. She was treated with 14 days of cefazolin. Follow-up blood cultures were negative however WBC count remained >140 ×109/L. Repeat bone marrow biopsy again showed hypercellular marrow with prominent granulocytic hyperplasia with no blasts and negative for leukaemic changes. Meanwhile, she was evaluated by vascular surgery and was started on therapeutic heparin drip. Arterial dopplers showed limb-threatening arterial insufficiency which was confirmed by CT angiography (figure 1). She underwent a right femoral endarterectomy. Given her increasing white count, decision was made to start leukopheresis as it was believed that the arterial insufficiency was likely secondary to hyperviscosity. Heparin-induced thrombocytopenia (HIT) was considered however the patient’s 4T score was low indicating a very low pretest probability of HIT. Another consideration in a case like our patient is paraneoplastic antiphospholipid syndrome. This was not tested; however, the patient was already on anticoagulation for ischaemia. Unfortunately, our patient developed acute hypoxic respiratory failure of unknown aetiology. She was placed on comfort measures as per her wishes and passed away 1 day later.
Occluded right common femoral artery.
Outcome and follow-up
The patient was followed during her entire hospitalisation by the oncology team. Unfortunately, the patient passed away from acute hypoxic respiratory failure during the same hospital encounter.
Discussion
Lung cancer remains the leading cause of cancer death in men and the second leading cause of cancer deaths in women worldwide.2 Classically, patients with lung cancer present with respiratory symptoms such as cough, dyspnoea and haemoptysis. Constitutional symptoms, such as anorexia, fatigue and weight loss, are also common however, symptoms often precede the diagnosis.3 Thromboembolic events occur in approximately 20% of patients with cancer. This high risk is related to both the underlying malignancy and numerous cancer therapy used. There is much attention devoted to venous thromboembolism as compared with arterial despite the worse prognosis.4
Inflammation is a key element of carcinogenesis and cancer progression. The development of leucocytosis, although rare, has been an area of interest for the past several decades. Some studies have even suggested that PLR be used as a marker for tumour progression and poor outcomes.5 Among the different tumours, lung cancer is a non-haematologic malignancy that is most closely associated with leucocytosis. Although neutrophils are not usually present in lung tissue, it is possible that pulmonary malignancies create a local environment that allows for neutrophil recruitment from peripheral blood.6
Shoenfeld et al 7 first studied leucocytosis as a possible tumour-associated marker in 1986. Out of 252 patients 77 had leucocytosis, most mild (>10 000) and few (8/77 patients) had marked leucocytosis (>15 000). Most of these patients had lung cancer as their primary malignancy. Interestingly, they found that leucocytosis was significantly associated with metastasis and shorter survival irrespective of other factors such as age or sex. Furthermore, the presence of metastasis showed a higher incidence of neutrophilia although the leucocytosis was the focus of that study rather than its differentiation. Asano et al 8 transplanted lung tissue from a patient with poorly differentiated squamous cell carcinoma and mild, persistent neutrophilia into nude mice. It was hypothesised that the increase in granulocytic colonies in vivo was secondary to colony-stimulating activity by the tumour cells. This was evident by the neutrophilia developed by the mice that paralleled tumour growth even after controlling for the response by the native’s neutrophils to the transplanted tissue. Once it became evident that there is a link between leucocytosis, tumour burden and worse outcome, the question became, what about neutrophils or neutrophil granulocytes promote tumour progression? Tumor-infiltrating neutrophils not only play a role in angiogenesis and tumour migration, but also release chemoattractants that promote further neutrophil recruitment.9 These neutrophil chemoattractants can also be produced by the tumour itself and contribute to tumour progression and survival by releasing pro-tumoural factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) and/or tumour necrosis factor alpha in the tumour microenvironment. The mechanism remains unclear, however once these factors were identified as possible assailants, it became possible to better study patients with tumour-related leucocytosis. Kasuga et al 10 examined 33 patients with leucocytosis, believed to be tumour-related. In these patients, granulocyte-CSF, GM-CSF and interleukin 6 were measured. Most patients had at least one of these factors elevated while only 4/33 had no detectable levels. These patients all had non-small cell lung cancer (NSCLC) and showed an overall poor prognosis leading to their conclusion that tumour-related leucocytosis is a phenomenon most often seen in NSCLC and is a sign of poor prognosis. It is important to note that previously mentioned studies have not described an arterial ischaemic event related to leucocytosis such as the case of our patient. Elevated WBC count is a marker of inflammation and less likely associated with arterial thrombi than thrombocytosis.11 Potential mechanisms by which leucocytes may contribute to acute ischaemic vascular events are related to the pro-thrombotic and vascular effect of leucocytosis, many of which are a result of the tissue factors and their properties described above.12
The degree of leucocytosis present in our patient, despite having an infection that was treated with antibiotics and cleared, is suggestive of CSF production leading to a paraneoplastic leukemoid reaction. The role of hyperleucocytosis in venous and arterial events and whether it is linked to specific mutations is unclear. Similar to previous studies, the clinical outcome of our patient was poor. However, this is the first report to our knowledge of leucocytosis causing peripheral arterial disease in a patient with no history of arterial disease. We have found several case reports of patients with severe paraneoplastic leucocytosis.13 14 However, most poor outcomes reported were due to tumour burden, not deleterious effects of the leucocytosis itself.
Learning points
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Paraneoplastic leukemoid reaction is a rare complication seen in non-small cell lung cancer and is associated with poor prognosis. In our patient, it manifested as peripheral arterial disease and was associated with poor outcome.
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We are far from understanding the mechanism that drives paraneoplastic leukemoid reactions and in fact not much knowledge is present about the factors that may be involved. While studies mentioned earlier have found that colony-stimulating activity may have a role to play in leucocytosis, not all cytokines that may be involved are identified.
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Learning more about this process may lead to treatments that target neutrophils and lead to effective paraneoplastic treatment.
Footnotes
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Contributors ZC and YS conceived the presented idea. ZC prepared the manuscript draft with important intellectual input from TJ and YS. DM supervised the findings of this work and provided editorial support. All authors discussed the case and approved the final manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Next of kin consent obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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