• Cytosis: O Neutrophilia: Defined As an Increase in the Neutrophilic Count in the Peripheral Blood Above Reference Range for Age
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HENATOLYMPHOID SYSTEM THIRD YEAR MEDICAL STUDENTS-UNIVERSITY OF JORDAN AHMAD T. MANSOUR, MD NONNEOPLASTIC DISEASES OF THE WHITE BLOOD CELLS • There are five major types of WBCs in the blood: neutrophils, lymphocytes, eosinophils, basophils and monocytes. • The normal function of the white blood cells depends on a tight regulation of their count and their function. Therefore, disease develops if there is a derangement of the cells count or function, it takes one of the following forms: o Cytosis: increase in the number of circulating cells above reference range. (Note: leukocytosis means an increase in the WBC count, neutrophilia means increase in the neutrophilic count, lymphocytosis means increase in the lymphocytic count, monocytosis means increase in the monocytic count, basophilia means increase in the basophilic count and eosinophilia means in crease in the eosinophilic count). o Cytopenia: decrease in the number of circulating cells below reference range. (Note: neutropenia means decreased neutrophils, lymphocytopenia, or simply lymphopenia, means decrease in lymphocytes, monocytopenia means decrease in monocytes, eosinopenia means decrease in eosinophils, and basopenia means decrease in basophils). o Abnormal or absent function • Cytosis: o Neutrophilia: defined as an increase in the neutrophilic count in the peripheral blood above reference range for age. o Causes: bacterial infection is the most common and most important etiology. Tissue necrosis in cases of burns or trauma and medications such as epinephrine and corticosteroids are also additional causes for neutrophilia. § Some physiologic conditions can lead to neutrophilia such as stress, smoking and pregnancy. o Pathophysiology: neutrophils are present in the blood in two populations: circulating and marginal (meaning neutrophils stuck to the vessel wall). The normal neutrophil count reflects only the circulating population and NOT the marginal one. § Normally, there is a balance between neutrophils produced in the bone marrow and the ones removed from the blood; therefore, the count is normally kept in a normal range. § If this balance is broken; due to infection, necrosis…etc., there will be an increase in the number in the peripheral blood. There are two mechanisms for this increase: • Demarginalization: the cells move from the vessel wall to the circulation without an actual increase in the bone marrow production: this is seen in the setting of stress, exercise and epinephrine injection. All these conditions have in common an increase in epinephrine in the body, which increases the production of cAMP that, in turn, mobilizes the cells from the vessel wall to the circulation. This condition is termed pseudoneutrohilia as there is no actual increase in bone marrow production. • An increase in the bone marrow production: this is seen in tissue necrosis, bacterial infection and steroid administration. Several mediators (interleukins and cytokines) affect the bone marrow directly and increase the proliferation and release of neutrophils into the blood. Morphology: • There is an increase in the number of neutrophils in the peripheral blood • There is a “left shift”, which means in increase in the number of more immature granulocytic cells such as bands and metamyelocytes. • Toxic changes: this is most notable with severe bacterial sepsis and is composed of o Coarse cytoplasmic granules which are abnormal primary granules o Döhle bodies: sky-blue patches of expanded endoplasmic reticulum o Cytoplasmic vacuoles Differentiation between reactive and neoplastic granulocytosis is usually straightforward, however confusion can arise in one setting, the so-called LEUKEMOID REACTION. Leukemoid reaction is a reactive granulocytic proliferation secondary to bacterial infection that results in extreme elevation in the neutrophilic count and extreme left shift. Please remember, in typical bacterial infections the WBC count rises up to 15000-20000 cell/microliter. However, in leukemoid reaction the rise may reach up to 40,000-100,000cell/microliter, which overlaps with the numbers seen in the more ominous neoplasm Chronic Myeloid Leukemia (CML). The pathogenesis of leukemoid reaction involves outpouring of high quantities of interleukins and cytokines (such as IL1 and TNFa) that induces proliferation of granulocytes in the bone marrow and subsequently in the peripheral blood. There are different methods to differentiate between the leukemoid reaction and CML: 1- History of bacterial infection favors leukemoid reaction over CML 2- Leukocyte alkaline phosphatase (the amount of alkaline phosphatase in the WBCs) is low in CML while normal or high in leukemoid reaction 3- The presence of BCR/ABL gene fusion is only present in CML and absent in leukemoid reaction 4- Leukemoid reaction usually subsides with treatment of the underlying infection, while CML has persistent elevation in the WBC counts. o LympHocytosis: an increase in the number of lymphocytes in the peripheral blood above the reference range for age. o Causes: viral infection, chronic bacterial infection such as tuberculosis, brucellosis and, in children, pertussis o Pathophysiology: activation of cellular immune response in response to virally infected cells and the surge in antibodies that accompany that infection. In pertussis: changes in the surface proteins in the lymphocytes favor their mobilization into the blood and preventing their going back to the lymphoid tissue. Morphology: Depends on the etiology -In lymphocytosis caused by certain viruses such as coxacki, adenovirus and echo virus there will be lymphocytosis in which lymphocytes have normal, mature morphology (similar to normal lymphocytes but increased in number) - In EBV infectious mononucleosis: reactive lymphocytes are noted: these are lymphocytes with abundant cytoplasm that have cytoplasmic extensions that wrap around RBCs (please remember that EBV infects B lymphocytes but the reactive lymphocytes are T cell) -In pertussis: the lymphocytes have cleaved nuclei similar to the ones you see in cases of follicular lymphoma ***Here are the major differences between follicular lymphoma and pertussis -Age of presentation: FL is a disease of people above the age of 50, pertussis chiefly affects children -Clinical presentation: Whooping cough in pertussis and lymphadenopathy in FL -The cells in FL are monoclonal (express either kappa or lambda light chains but not both, cells in pertussis are polyclonal) - BCL2 is positive in FL and negative in reactive follicular hyperplasia Figure: peripheral blood from a patient with pertussis, notice lymphocytes with cleaved nuclei (similar finding can be seen in follicular lymphoma) Figure: peripheral blood from a patient with infectious mononucleosis (EBV), notice reactive lymphocytes with abundant cytoplasm and cytoplasmic extensions wrapping around RBCs o EosinopHilia: an increase in the number of eosinophils in the peripheral blood above reference range o Causes: o Allergic disorders: asthma, hay fever, urticaria o Parasitic infections: trichinosis, filarial...etc. o Nonparasitic infections: systemic fungal infection, scarlet fever, chlamydia o Certain medications such as pilocarpine, physostigmine, digitalis, p- aminosalicylic acid, sulfonamides, chlorpromazine, and phenytoin o Pathophysiology: the common feature to all conditions causing eosinophilia is the release of IL-5, which recruits eosinophils and increases their proliferation and release form bone marrow. o Morphology: normal morphology but increase in number o BasopHilia: an increase in the number of basophils in the peripheral blood above reference range o Causes: o Rarely as a reactive condition in cases of allergy, postsplenectomy and inflammatory bowel disease o Association with underlying hematolymphoid malignancy, most commonly chronic myeloid leukemia. o Morphology: normal in morphology, just increase in number o Monocytosis: an increase in the number of monocytes in the peripheral blood above reference range o Causes: o Infections: tuberculosis, protozoal infections, subacute bacterial endocarditis, syphilis o Recovery from neutropenia o Collagen vascular disorders such as myositis, temporal arteritis, and polyarteritis. o Certain leukemias o Morphology: in reactive conditions, monocytes have normal morphology with increase in numbers, however, in malignant conditions such as leukemia, the chromatin is fine with prominent nucleoli. **The first image represents reactive monocytosis and the second represents acute leukemia with monocytic differentiation (malignant monocytes). Note in the first image that the monocytes have normal morphology with folded nuclei and coarse chromatin and in the second image the nuclei are round with fine chromatin and prominent nucleoli. • Cytopenia: o Neutropenia: a decrease in the number of neutrophils in the peripheral blood below reference range. o Causes § Decrease production • Marrow hypoplasia in patients who receive chemotherapy or radiation therapy • Leukemia or other tumors replacing the marrow • Medications • Certain types of neoplastic lymphocytic proliferations such as large granular leukemia (LGL) § Increased peripheral use • Autoimmune destruction • Overwhelming bacterial, fungal or rickettsia infection • Splenomegaly o Lab findings: decrease neutrophilic count with other findings depending on the underlying cause. o Complications: increase risk of infection, especially bacterial infections. o Lymphocytopenia, or simply, lymphopenia, is a decrease in the lymphocytic count in the peripheral blood below