"Neutrophilia" TUMOR TIDBITS, A BIWEEKLY VETERINARY ONCOLOGY E-LETTER Volume 3; Number 21; June 14, 2002. Editor: Kevin A. Hahn, DVM, PhD, Dipl - ACVIM (Oncology) & Overall Nice Guy! ANNOUNCEMENTS **Visit our web site at www.gcvs.com/oncology for the latest information. **Beginning July 8th, we're in Sugar Land and San Antonio 2 days per week. **One clinical trial for lymphoma is completed, one is still ongoing - call us for details. THIS WEEK'S TUMOR TIDBIT: Neutrophilia OVERVIEW  Neutrophilia is an increase in absolute numbers of circulating neutrophils. In adult dogs and cats, neutrophil counts exceed 12,000-13,000/5l.  Neutrophils are produced in the bone marrow, released into the blood, circulate briefly, and migrate into tissue spaces and onto epithelial surfaces. Injury or bacterial invasion of tissue causes production and release of colony- stimulating factors, which increase proliferation and maturation of neutrophilic progenitor cells in the bone marrow. Other mediators of inflammation stimulate bone marrow release and promote margination and adhesion of neutrophils to vascular endothelium at the site of inflammation. Transit time for bone marrow granulopoiesis is approximately 4-6 days. Neutrophils circulate for about 10 hours and are compartmentalized into a circulating neutrophil pool (CNP) and a marginal neutrophil pool (MNP). Neutrophils in the CNP circulate with other blood cells and are measured in the CBC. The MNP consists of neutrophils that are intermittently adherent to endothelium, especially in small veins and capillaries. Migration of neutrophils into tissues occurs randomly and is unidirectional. Neutrophils are destroyed in the spleen, liver, and bone marrow. Numbers of circulating neutrophils are affected by the rate of bone marrow production and release, the rate of exchange between CNP and MNP, and the rate of migration into tissue. Neutrophilia results when one or more of the following occurs: 1) the rate of marrow production and release increases, 2) neutrophils demarginate from the MNP into the CNP, 3) tissue demand for neutrophils increases, 4) neoplasia of granulopoiesis develops. CAUSES  Physiologic Neutrophilia: Fear, excitement, and vigorous exercise cause epinephrine release. Neutrophils demarginate from MNP into CNP, resulting in a transient (1 hour), mature neutrophilia. In cats, severe lymphocytosis (6,000-15,000/5l) occurs concurrently.  Corticosteroid- or Stress-Induced Neutrophilia: Corticosteriods cause increased bone marrow release of mature neutrophils, demargination into the CNP, and decreased tissue migration. Leukocytosis (15,000-35,000/5l) and neutrophilia occur 4-8 hours after administration and return to normal 1-3 days after treatment. Lymphopenia, eosinopenia, and monocytosis (dogs) occur concurrently. Pain, traumatic injury, boarding, transport, and other stressful conditions are common causes.  Neutrophilia of Acute Inflammation: Inflammation, sepsis, necrosis, and immune-mediated disease cause increased tissue demand and increased bone marrow release of segmented and band neutrophils. Leukocytosis (15,000-30,000/5l), neutrophilia with a left shift, toxic neutrophils, lymphopenia, eosinopenia, and variable monocytosis are usual responses. Surgical removal or drainage of a septic focus may increase neutrophilia.  Neutrophilia of Chronic Inflammation: Chronic suppuration (e.g., pyometra, abscesses, pyothorax, and pyoderma) and some neoplasms cause granulocytic hyperplasia that results in severe leukocytosis (50,000-120,000/5l), neutrophilia with a left shift, variable numbers of toxic neutrophils, monocytosis, and hyperglobulinemia. Anemia associated with chronic disease may be present. Leukemoid response is a term used to describe inflammatory neutrophilia with WBC count >100,000/5l because of its similarity to chronic granulocytic leukemia.  Hemolytic or Hemorrhagic Anemia: Neutrophilia with a left shift is common in dogs with immune-mediated hemolytic anemia. Mature neutrophilia develops 3 hours after acute hemorrhage.  Chronic Granulocytic Leukemia: Hematologic response in dogs is similar to neutrophilia associated with chronic inflammation. Severe neutrophilic leukocytosis (> 80,000/5l), disordered left shift, and variable degrees of thrombocytopenia and anemia are observed. Splenomegaly and hepatomegaly may be pronounced. DIFFERENTIAL DIAGNOSES  Animals with inflammatory neutrophilia usually have historical or clinical evidence of septic or nonseptic inflammatory disease such as pyrexia, weight loss, loss of appetite, and specific organ system involvement.  Stress neutrophilia commonly develops in dogs and cats examined because of noninflammatory disorders.  Physiologic neutrophilia affects young healthy animals, especially cats. LABORATORY FINDINGS  Corticosteroid administration causes stress leukogram. Neutrophilia subsides with long term therapy but lymphopenia persists.  Electronic WBC counts can be falsely high because of large platelets, platelet clumps, and Heinz bodies. Leukocyte clumping causes a false decrease in the count. Some human laboratories overestimate the number of band cells at the expense of mature neutrophils. Clinically normal animals will appear to have left shifts.  Assessment of sequential leukograms is important because numbers of segmented and band neutrophils can change dramatically in a few hours. Trends that are persistent, increasing, or decreasing are important in diagnosis and prognosis.  Toxic neutrophils are observed in animals with inflammation, especially when associated with toxemia. Toxic neutrophils are observed in blood and bone marrow and are characterized by diffuse cytoplasmic basophilia, foamy vacuolated cytoplasm, Dvhle's bodies, and giant forms with bizarre nuclear shapes. OTHER DIAGNOSTIC TESTS TO CONSIDER  Blood culture  Bacterial or fungal culture of urine, tissue samples, and body fluids  Serologic tests for fungi, protozoa, and rickettsia. Genera of special interest include Blastomyces, Histoplasma, Coccidioides, Actinomyces, Nocardia, Toxoplasma, Hepatozoon, and Rickettsia.  Coombs' test, antinuclear antibody test, or rheumatoid factor test indicated if immune-mediated disease is suspected  Radiography and ultrasonography of abdomen, thorax, soft tissue, or skeleton to detect inflammatory or neoplastic lesions (e.g., abscesses, granulomatous lesions, effusions, foreign bodies, and organomegaly) TREATMENT OPTIONS  Treatment varies with the identity and severity of underlying cause.  Animals with acute sepsis or hemolytic anemia require aggressive intervention.  Those with chronic granulocytic leukemia require chemotherapy.  Those with inflammatory neutrophilia may require surgical intervention to remove or drain sites of sepsis. MEDICATIONS  Appropriate antimicrobial therapy for septic inflammation after identification of causative agent and sensitivity testing  Corticosteroids should be avoided if fungal or protozoal infection is suspected. FOLLOW-UP  Animals with inflammatory neutrophilia, especially of acute onset, may require daily or twice-daily hematologic assessment.  Animals with acute inflammatory neutrophilia may become neutropenic if migration into the inflammed tissue exceeds the bone marrow production rate. If neutropenia develops, prognosis is grave. ABBREVIATIONS  CNP = circulating neutrophil pool  MNP = marginal neutrophil pool WHAT DO WE DO AT GULF COAST?  Following hemogram evaluation and the above diagnostics, a bone marrow aspirate and bone marrow core biopsy might be considered; evaluation of an underlying mass that might include cancer (we are oncologists so there must be a mass) would include images of the chest and abdomen and the consideration of an ultrasound of the abdomen (prostate if male). Don't hesitate to call or email us at Gulf Coast Veterinary Oncology! Kevin Kevin A. Hahn, DVM, PhD Diplomate American College of Veterinary Internal Medicine (Oncology) & Overall Nice Guy Gulf Coast Veterinary Diagnostic Imaging & Oncology 1111 West Loop South, Suite 150, Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 W: http://www.gcvs.com Email: mailto:drhahn@gcvs.com