HENATOLYMPHOID SYSTEM THIRD YEAR MEDICAL STUDENTS- UNIVERSITY OF JORDAN AHMAD T. MANSOUR, MD. Part 1
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1 HENATOLYMPHOID SYSTEM THIRD YEAR MEDICAL STUDENTS- UNIVERSITY OF JORDAN AHMAD T. MANSOUR, MD Part 1 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 depend 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.
2 ! 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.
3 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
4 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 cell/microliter. However, in leukemoid reaction the rise may reach up to 40, ,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
5 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 only increase 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
6 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
7 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
8 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.
9 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 the reference range. o Causes:! The most important factor is HIV infection! Mediations such as steroids, chemotherapy and medications for HIV infection! Debilitative conditions such as advanced cancer, renal failure, aplastic anemia, autoimmune disorders and starvation! Infections: such as TB, influenza, typhoid fever! Abnormal lymphatic circulation: intestinal lymphangectasia, thoracic duct obstruction o Lab findings: decrease lymphocytic count with other findings depending on the underlying cause. o Complications: increased risk of infection by a wide variety of organisms including candida, viruses and bacteria.! Opportunistic infections: an infection that is caused by a pathogen that would not cause infection in normal conditions, and takes the opportunity of disrupted immune system to cause severe, and sometimes, fatal disease. o Monocytopenia: a decrease in the monocytic count in the peripheral blood below reference range. o Rare as an isolated finding.
10 o Causes:! Steroids, monocytes drop in the first few hours of receiving steroids.! Hairy cell leukemia: a form of B cell neoplasm. o Basopenia and eosinopenia are not a cause of clinical concern and will not be covered in this manuscript. Functional disorders: o Neutrophilic functional disorders: four disorders will be discussed! Chédiak- Higashi syndrome! Chronic granulomatous disease! Myeloperoxidase deficiency! Leukocyte adhesion deficiency o Chédiak- Higashi syndrome: autosomal recessive affecting the LYST gene (lysosomal trafficking regulator). This gene is involved in regulation of vesicular size, trafficking, and intracellular movement, such that vesicular migration and release are abnormal. o Clinically: recurrent pyogenic infection, albinism (affects vesicles that contain melanin pigment, neurologic manifestations and photophobia). Early death due to infections. o Morphology: large cytoplasmic granules in the neutrophils, monocytes and lymphocytes.
11 Note in this image the large basophilic cytoplasmic granules in the neutrophil, similar granules can be seen in lymphocytes and monocytes. o Chronic granulomatous disease: autosomal recessive (66%) or X- linked (33%) resulting in genetic defect affecting NADPH oxidase, this enzyme catalyzes the production of oxygen radical species that plays a vital role in killing microorganisms. This, in turn, results in inability of the cells to kill phagocytized bacteria. o Clinically: chronic, recurrent bacterial infections with frequent granulomatous lesions o Morphology: there is no morphologic change in the blood cells (normal appearance). o Myeloperoxidase deficiency: autosomal recessive disorder, resulting in qualitative or quantitative deficiency of MPO. o Most people with this deficiency are completely asymptomatic with increased risk of infection o In less than 5% of patients fungal infections by candida species can develop. o The neutrophils look absolutely normal. o Leukocyte adhesion molecules deficiency (LAD): rare disorder characterized by defective expression of the adhesion molecules on the neutrophils o Clinically, there is an increase risk of infection, neutrophilia and delayed separation of the umbilical cord. o There are no morphologic changes, the neutrophils look absolutely normal. ***Functional diseases of the lymphocytes will be covered in the immunology course and won t be discussed in this manuscript. NONEOPLASTIC LYMPH NODE DISEASES Lymphoid tissue (lymph nodes, mucosa associated lymphoid tissue, Peyer patches..etc.) are dynamic organs that undergo changes in response to antigenic stimulation. Lymphadenopathy refers to enlargement of the lymph nodes, readily notable in the superficial groups such as cervical, axillary and inguinal lymph nodes.
12 The following will be discussed 1. Acute lymphadenitis 2. Follicular and parafollicular hyperplasia. 3. Sarcoidosis. Acute nonspecific lymphadenitis: Occurs in the setting of infection in the vicinity of the lymph nodes. For example, infection of the tonsils or teeth abscess can result in cervical acute lymphadenitis. Infection of the breast can result in axillary lymphadenitis, and infection of the skin of the lower extremity causes inguinal lymph node enlargement. Some bacterial or viral infections can result in generalized lymphadenopathy. Acute mesenteric lymphadenitis can result as a complication to certain viral infections, and can mimic acute appendicitis clinically. Morphology: o Enlarged, sometimes tender, lymph nodes. o Large, variably sized follicles with necrotic germinal centers and neutrophilic infiltration. o
13 Note in the image that the center contains a large necrotic focus filled with dead tissue and neutrophilic infiltration. Follicular and parafollicular hyperplasia Remember that the lymph node contains areas for B- lymphocytes called the follicles or the cortex and areas for T- lymphocytes typically reside between the follicles in the parafollicular or paracortical area. The location of the of the hyperplasia (cortical or paracortical) depends the nature of the stimulating antigen, remember that B lymphocytes are involved in humoral (antibody producing) immune response while T lymphocytes are activated by stimuli that need T- cell mediated immune response. Follicular hyperplasia is defined as an increase in the number and size of follicles secondary to stimuli that need B cell response o Causes o Bacterial infection o Rheumatoid arthritis o Lupus o Early stages of HIV infection o Sometimes no known cause is found o Morphology o Numerous, variably sized secondary follicles (follicles with germinal centers) o Abundant tangible- body macrophages in the germinal centers o Frequent mitosis o Small mantle zones o
14 Note in the images the presence of follicles with different sized. In the second image note the presence of tigible- body macrophages that contain debris of apoptotic cells. o Differential diagnosis: the most important differential diagnosis is follicular lymphoma o In contrast to follicular lymphoma, follicular hyperplasia is characterized by! Variably sized follicles (in FL follicles are roughly the same size)! Tingible- body macrophages (FL does not have macrophages as it is composed only of neoplastic B cells)! Age of presentation, follicular hyperplasia typically affects young patients while FL is a is a disease of the people older that 50 years of age! BCL2 (an antiapoptotic protien) is typically negative in hyperplasia while positive in FL (see later discussion of follicular lymphoma) Paracortical hyperplasia is defined as an expansion of the paracortical areas by T lymphocytes in various stages of stimulation and maturation. o Caused usually by viral infection, medications and after vaccinations o Morphology: o Expansion of the paracortical areas with resulting atrophy of the follicles o The paracortical areas show the presence of immunoblasts (activated T lymphocytes that are three times larger than the normal T lymphocytes with fine chromatin and prominent nucleoli.
15 o
16 Note in the first image the presence of atrophic follicle in the upper half and an expanded paracortex in the lower half. In the second image, note the presence of large cells (immunoblasts, thick arrow), compare them to the mature lymphocyte (thin arrow). Sarcoidosis: Sarcoidosis is a systemic granulomatous disease of unknown cause that may involve many different tissues and organs. In the vast majority of cases the lung and hilar lymph nodes are involved. o Morphology: the lymph nodes are effaced by a large number of nonnecrotizing granulomas
17 o Note in the first image the presence of numerous granulomas. In the second image, notice that these granulomas do not contain necrosis and are composed of epithelioid histiocytes with a rim of lymphocytes.
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