In cancer patients with severe leukocytosis, iatrogenic factors such as steroid treatment and growth factors must be considered as causes. If these possible causes are excluded, a paraneoplastic genesis should also be considered, as the medical history of a 72-year-old man shows, about which Dr. Josef Heusinger and his colleagues from the Schwarzwald-Baar-Klinikum in Villingen-Schwenningen report in the journal «Internal Medicine».
The patient and his history
The 73-year-old man came according to the authors because of four weeks persistent cough, fatigue and loss of appetite in the Emergency room of the clinic.According to the heavy smoker (40 «pack years»), the cough was bloody once. He had denied fever.
The findings
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Slim patient in reduced general condition, fully oriented
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Heart rate 98 beats per min, normal blood pressure values,
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Respiratory rate 15 breaths per min
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Auscultation of the lungs: right apically attenuated breathing sound, otherwise inconspicuous findings, none Rattling noises
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Significantly increased value of C-reactive protein (up to 143mg/l, normal value <5mg/l) with normal procalcitonin
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Throat swab: no infection with SARS-CoV-2, influenza A and B and respiratory syncytial virus (RSV)
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Blood cultures sterile
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Blood count: pronounced leukocytosis (91/nl), pre-occurring neutrophilia
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Blood smear: left shift without detection of blasts
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Thrombocytosis (554/nl) and mild normocytic anaemia
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X-ray diagnostics and computed tomography of the thorax: triangular consolidation zone in the right upper lobe with positive Bronchoaerogram
Slim patient in reduced general condition, fully oriented
Heart rate 98 beats per min, normal blood pressure values,
Respiratory rate 15 breaths per min
Auscultation of the lungs: right apically attenuated breathing sound, otherwise inconspicuous findings, none Rattling noises
Significantly increased value of C-reactive protein (up to 143mg/l, normal value <5mg/l) with normal procalcitonin
Throat swab: no infection with SARS-CoV-2, influenza A and B and respiratory syncytial virus (RSV)
Blood cultures sterile
Blood count: pronounced leukocytosis (91/nl), pre-occurring neutrophilia
Blood smear: left shift without detection of blasts
Thrombocytosis (554/nl) and mild normocytic anaemia
X-ray diagnostics and computed tomography of the thorax: triangular consolidation zone in the right upper lobe with positive Bronchoaerogram
Suspected diagnosis, therapy and course
The authors’ suspected diagnosis was: community-acquired pneumonia.After hospitalization, the man therefore received ampicillin/sulbactam intravenously; then followed the escalation of antibiotic therapy due to persistently high infection parameters, first to piperacillin/tazobactam with clarithromycin, then to meropenem with clarithromycin; however, the therapy was ineffective, so that further diagnostics were required:
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Pathogen diagnostics for legionella antigen in urine and serologies for atypical pneumonia pathogens: negative.
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Bronchial lavage: no germs detectable
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PCR test on Viruses, bacteria and fungi negative
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Because of the possibility of occult carcinoma: bronchoscopy with bronchoalveolar lavage and biopsy;
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Bronchoscopy findings: moderate chronic atrophic bronchitis with swollen mucosa and narrow ostia in the right upper lobe
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Histological analysis of tissue taken transbronchially: poorly differentiated, solid and diffusely growing adenocarcinoma (Primarius)
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Immunohistochemical negativity for melan A (Exclusion of metastasis of a history of melanoma)
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40 % of tumor cells PD-L1-positv (programmed cell death 1 ligand 1)
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No therapy-relevant driver mutations in BRAF, EGFR (Epidermal Growth Factor Receptor), ALK (anaplastic lymphoma kinase) and ROS1
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Bone scintigraphy, CT of thorax/abdomen and contrast sonography of the liver: without detection of distant metastases
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Magnetic resonance imaging of the Skull: cerebral micrometastases without clinical correlate
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Bone marrow biopsy: granulopoiesis with normal maturation without signs of dysplasia; no bone marrow carcinosis
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As the authors further report, die Leukocytes continued to increase despite broad antibiotic therapy (maximum after four weeks approx.178,000/μl).
Pathogen diagnostics for legionella antigen in urine and serologies for atypical pneumonia pathogens: negative.
Bronchial lavage: no germs detectable
PCR test on Viruses, bacteria and fungi negative
Because of the possibility of occult carcinoma: bronchoscopy with bronchoalveolar lavage and biopsy;
Bronchoscopy findings: moderate chronic atrophic bronchitis with swollen mucosa and narrow ostia in the right upper lobe
Histological analysis of tissue taken transbronchially: poorly differentiated, solid and diffusely growing adenocarcinoma (Primarius)
Immunohistochemical negativity for melan A (Exclusion of metastasis of a history of melanoma)
40 % of tumor cells PD-L1-positv (programmed cell death 1 ligand 1)
No therapy-relevant driver mutations in BRAF, EGFR (Epidermal Growth Factor Receptor), ALK (anaplastic lymphoma kinase) and ROS1
Bone scintigraphy, CT of thorax/abdomen and contrast sonography of the liver: without detection of distant metastases
Magnetic resonance imaging of the Skull: cerebral micrometastases without clinical correlate
Bone marrow biopsy: granulopoiesis with normal maturation without signs of dysplasia; no bone marrow carcinosis
As the authors further report, die Leukocytes continued to increase despite broad antibiotic therapy (maximum after four weeks approx.178,000/μl).
Diagnosis by Heusinger and his colleagues: paraneoplastic hyperleukocytosis in newly diagnosed adenocarcinoma of the lungs. Due to the malignant tumor, the man received chemotherapy. However, he died after the second cycle of chemotherapy.
Discussion
In patients with carcinomas and unclear leukocytosis, the authors conclude, paraneoplastic genesis should also be considered. In a retrospective study, 758 patients with solid tumors and leukocytosis -_gt; 40,000/μl. At ten percent, it was a paraneoplastic genesis. The most common tumor entity is non-small cell lung carcinoma; former. According to the authors, paraneoplastic leukocytosis correlates with faster tumor growth, poorer response to therapy and significantly poorer survival. It is believed that G-CSF produced by the tumor mediates the mobilization of CD11bGr1myeloid cells, which in turn favor tumor angiogenesis, metastasis and suppression of the T cell response.
There is currently no evidence on the management of secondary G-CSF administration in therapy-induced neutropenia after paraneoplastic leukocytosis.In the case of the 73-year-old man, it had come after iatrogenic G-CSF administration in the nadir quickly to a renewed excessive leukocytosis. Since an additional stimulating effect on the CD11bGr1myeloid cells by the growth factor cannot be ruled out, the treatment should be critically questioned.
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