Pathology Lecture 7 PDF

7 Mahde sabbagh Mahde sabbagh  Non-neoplastic WBC disorders Topics that will be discussed today: *These are modified slides that contain a lot of extra information for understanding purposes, original slide...

7 Mahde sabbagh Mahde sabbagh  Non-neoplastic WBC disorders Topics that will be discussed today: *These are modified slides that contain a lot of extra information for understanding purposes, original slide notes are bold, other than that, everything is extra. 1. An overview 2. Neutropenia/Agranulocytosis 3. Reactive leukocytosis: HLH and cat- scratch disease. WHITE BLOOD CELL DISORDERS Disorders are primarily associated with the count of white blood cells and include deficiency (leukopenia) and proliferation (leukocytosis). Leukocytosis is more common than leukopenia (whereas in RBCs, anemia is more common than polycythemia). Leukocytosis: increased number of WBC in peripheral blood (any cause). Leukocytosis can be benign or neoplastic. if benign, it is called reactive leukocytosis, which happens in response to a primary, often microbial, disease (common). Neoplastic disorders (autonomous production, called leukemia), although less common, are more serious. Leukemia: increased number of WBC in peripheral blood secondary to neoplastic disease. Reactive leukocytosis is more common than leukemia. Next are brief descriptions of some non-neoplastic conditions (this lecture), followed by more detailed considerations of the malignant proliferations of white cells (lectures 8,9,10): Non-neoplastic WBC disorders: 1. Neutropenia/ Agranulocytosis: A reduction in the number of granulocytes (mainly neutrophiles) in blood is known as neutropenia or, when severe, agranulocytosis. Patients become susceptible to infections (namely bacterial and fungal). If neutrophil count drops below 500 cells/uL (severe), spontaneous infection becomes a risk (Infection arising internally, often from gut bacteria, without external cause). Pathogenesis of neutropenia: 1. Decreased production (caused mostly by disorders that result in pancytopenia, we discussed most of them in the previous lectures):aplastic anemia, Myelophthisic anemia, myelodysplastic syndrome, advanced megaloblastic anemia, chemotherapy, drugs (anti-epileptic, antihyperthyroidism). 2. Increased destruction: This can be seen in immune mediated injury (seen in SLE), anything that causes splenomegaly (leads to the sequestration and accelerated removal of neutrophils), overwhelming bacterial, fungal or rickettsial infections (increased peripheral use and destruction). 2. Reactive leukocytosis: An increase in any type of white blood cell (WBC) leads to a higher overall WBC count, known as leukocytosis. Since neutrophils are the most abundant leukocytes in peripheral blood, leukocytosis is most commonly due to an increase in neutrophils (neutrophilia), resulting in a higher total WBC count The types of leukocytosis, from most to least common, include: 1. Neutrophilia: caused by infections or even sterile inflammations (tissue necrosis, as seen in burns). 2. Lymphocytosis: viral infections, Bordetella pertussis infection (bacteria), chronic infections (TB, brucellosis). In children, it can be more common than neutrophilia. 3. Monocytosis: mostly in chronic infections and chronic inflammations (rheumatologic diseases, a chronic autoimmune disorder, and inflammatory bowel disease) 4. Eosinophilia: asthma, allergic diseases, drug sensitivity, parasitic and helminthic infections, and some neoplasms as in Hodgkin lymphoma. 5. Basophilia: rare, seen in myeloproliferative neoplasms (like polycythemia vera and chronic myeloid leukemia) 3. Reactive Lymphadenitis: A benign proliferation, secondary to a stimulus. Infections and nonmicrobial inflammatory stimuli often activate immune cells residing in lymph nodes, which act as defensive barriers. Any antigenic stimulation in lymph nodes can lead to lymph node enlargement (lymphadenopathy). Lymphadenopathy is an enlargement of the lymph node regardless of the cause (benign or malignant). It can be localized to a specific area of the body, such as the neck or armpit, or it can be generalized throughout the body. A. ACUTE NON-SPECIFIC LYMPHADENITIS: This form of lymphadenitis usually follows acute infections, as lymph nodes work to drain the infection, resulting in swollen, enlarged and painful lymph nodes. The nerves around the lymph nodes stretch and cause pain due to the rapid enlargement of the lymph node. In contrast, chronic lymphadenitis is painless because the enlargement occurs gradually. Overlying skin is red and may develop a sinus tract (tunnel-like passageway that extends from the surface of the lymph node to an underlying or area of infection), the germinal centers in the lymph node are enlarged (high mitotic activity). With severe infection, liquefactive necrosis develops and may enlarge to form an abscess. In severe cases, two key indications are: Liquefactive necrosis: necrosis in which tissue turns into a liquid mass, often due to bacterial or fungal infections or chemical burns. Hydrolytic enzymes digest the cells, resulting in a soft lesion filled with pus and necrotic fluid Abscess formation: a tissue mass usually in severe infection, containing bacteria, dead cells, and inflammatory cells, resulting in pus-filled cavity. B. CHRONIC NON-SPECIFIC LYMPHADENITIS: Chronic (benign) enlargement of lymph node, painless. Depending on the causative agent, chronic nonspecific lymphadenitis can assume one of three patterns: 1-Follicular hyperplasia (activated B cells, migrate into B cell follicles and create the follicular reaction): chronic proliferation of B-lymphocytes, seen in rheumatologic diseases, toxoplasmosis and HIV infection (even though HIV is viral infection, only B cell proliferation is seen since HIV directly reduces T cell count). 2-Paracortical hyperplasia: proliferation of T-lymphocytes, seen in viral infections (example EBV), after vaccination and in some immune reactions triggered by drugs (a drug can cause eosinophilia when it reacts in peripheral blood, leading to an increased number of eosinophils. When it reacts in lymph nodes, it can cause paracortical hyperplasia, but still, it all depends on the drug itself and its interactions). 3-Sinus histiocytosis: proliferation of macrophages in lymph node sinuses, seen in adjacent cancer. Sinus histiocytosis is distention and prominence of the lymphatic sinusoids, owing to a marked hypertrophy of lining endothelial cells and an infiltrate of macrophages (histiocytes). It is often encountered in lymph nodes draining cancers and may represent an immune response to the tumor or its products (so, the lymphadenopathy is not malignant, but rather a reaction to an adjacent cancer, for ex: breast carcinoma causes enlargement of the axillary lymph nodes due to histiocytosis). This histologic diagram of reactive lymphadenitis shows: Left side: Numerous, large, and crowded lymphoid follicles, indicating follicular hyperplasia. Right side: A significant decrease in the number of follicles with expanded areas between them filled with T lymphocytes from the paracortex, indicating paracortical hyperplasia. Bottom right: Presence of sinus histiocytosis. Now, we will discuss some diseases that can cause Lymphadenitis: 1. CAT-SCRATCH DISEASE: A bacterial infection caused by Bartonella henselae. Transmitted from cats (bite, scratch or exposure to infected saliva). Most seen in children (disease of childhood). Causes acute lymphadenitis (so, it's painless) in neck/axilla area (upper body), and symptoms appear after two weeks of infection (incubation period). Bacteria causes liquefactive necrosis and necrotizing granulomas (remember, also seen in TB) in lymph nodes. Mostly self-limited in 2-4 months, rarely can disseminate into visceral organs. 2. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH disease): Hemophagocytic: phagocytosis of RBCs, thus, anemia. Lymphohistiocytosis: high number of lymphocytes and histiocytes. HLH is an uncommon disease in which Viral infection or other inflammatory agents severely activate macrophages (histiocytes) throughout body to engulf normal blood cells and their precursors in bone marrow. Patients have defective genes related to the function of cytotoxic T cells (CD8+) and natural killer cells Inherited defects in several genes that regulate the function of immune cells are associated with a greatly elevated risk of HLH. Patients have defective genes related to the function of cytotoxic T cells and natural killer cells; thus, they are unable to kill their targets (virus-infected cells) and are engaged with them for a long period, releasing excess interferon-γ that activates macrophages. Activated macrophages release TNF and IL-6 that causes systemic symptoms of inflammation and sepsis, leading to the systemic inflammatory response syndrome “SIRS”. HLH-TYPES: 1. Infants and young children: Homozygous defects in gene PRF1 (perforin1) that encodes perforin, an essential enzyme in cytotoxic T- lymphocytes and natural killer cells. In this setting the trigger may be some normally trivial childhood viral infection. 2. Adolescents and adults: X-linked lymphoproliferative disorder (males), in which the trigger is EBV infection. Those affected have a defective Signaling lymphocyte activation molecule (SLAM)-associated protein, leading to inefficient killing of EBV-infected B-lymphocyte 3. May be associated with systemic inflammatory disorders: HLH also may complicate other non-infectious systemic inflammatory disorders such as rheumatologic diseases (autoimmune). Patients have heterozygous genetic defects in genes required for cytotoxic T-cells, creating a genetic background that increases the likelihood of HLH, but the exact defect is still unknown. 4. T-cell Lymphomas: Finally, HLH may be seen as a secondary phenomenon in patients with peripheral T cell lymphomas, as Malignant T-cells produce aberrant cytokines leading to dysregulation of normal cytotoxic T-cells. Symptoms of HLH: 1.Fever (caused by the inflammation) Splenomegaly and hepatomegaly (due to macrocytic infiltration), pancytopenia (since macrophages destroy RBCS, WBCs, platelets, and even progenitor cells). 2.High ferritin (an inflammatory marker, acute phase protein). 3.High triglyceridemia (most likely due to hepatic dysfunction caused by hepatomegaly, which impairs lipid metabolism. Leading to an accumulation of triglycerides in the blood). 4.High serum IL-2 (an inflammatory marker). 5.Low level of blood cytotoxic T-cells and natural killer cells (although the primary issue is their activity, their prolonged engagement with inflammation localizes most of them in tissues). 6.BM biopsy: numerous macrophages engulfing RBCs, platelets and granulocytes.