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  • 1. April 8, • On this day, Buddhists celebrate the commemoration of the birth of Gautama Buddha, the founder of Buddhism, thought to have lived in India from 563 B.C. to 483 B.C. Actually, the Buddhist tradition that celebrates his birthday on April 8 originally placed his birth in the 11th century B.C., and it was not until the modern era that scholars determined that he was more likely born in the sixth century B.C., and possibly in May rather than April.
  • 2. Red Blood & Platelet Cell Deficiencies Anemia is present when the RBC count is less than 4.5 X 10↑5cells/ l in males (4.1in females) or hemoglobin (Hgb) is less than 13.5g/dl in males (11.5 in females). General features: result from inadequate supply of oxygen reaching the tissues (pallor, shortness of breath, fatigability). Classically categorized by microscopic examination of peripheral blood • Normocytic-normochromic –normal size & color of RBCs • Microcytic-hypochromic – small and less Hgb than normal • Macrocytic-hyperchromic – larger and more Hgb (no hole in the donut) • Mechanisms of anemia 1. Decreased production 2. Increased destruction 3. Blood loss (hemorrhage) Thrombocytopenia is a reduction in the number of functional platelets, although normally in the range of ~150,000-300,000/mm3 the number must dip below 10,000-20,000 before bleeding is clinically evident
  • 3. Red Blood Cell & Platelet Excesses Increased RBCs are associated with hypercellularity of the marrow • Polycythemia: ↑ RBC number/unit volume Primary: 1. Myeloid neoplasia involving hematopoietic precursor cells 2. Polycythemia vera – increased RBC precursor proliferation independent of erythropoietin (EPO levels are low). Anemia develops late due to marrow replacement by non-functional immature forms Secondary: 1. Due to increased erythropoietin: chronic hypoxia (altitude, smoking, lung disease, cyanotic heart disease). Tumors producing erythropoietin – renal cell, hepatocellular carcinoma 2. Due to loss of plasma (dehydration) Thrombocytosis • Increased coagulability requires platelet counts >~400,000, (>1,000,000 are common) often when the result of myeolproliferative disorders, the platelets are dysfunctional. The marrow has markedly increased numbers of megakaryocytes.
  • 4. Anemias caused by Decreased RBC Production Causes include: 1. Bone marrow failure 2. Inadequate supplies of components Aplastic anemia: Replacement of bone marrow by fats cells or metastatic disease resulting in anemia, neutropenia & thrombocytopenia; due to the failure or suppression of multipotent myeloid stem cells. • Cause: In 65% the cause is unknown. Drugs may cause anemia in a predictable, dose dependent and reversible fashion (chemotherapy agents, benzene, non-neoplastic drugs) or an idiosyncratic fashion (chloramphenicol, chlorpromazine). • The onset is usually insidious and symptoms are due to impaired oxygenation or defects in platelets or WBCs. • Treatment involves removing the offending agent and/or bone marrow transplantation.
  • 5. Iron deficiency anemia: this is the most common cause of anemia Causes: A negative iron balance 1. Inadequate iron intake or absorption: 20% in ingested heme iron (animal products) and only 1-2% of non-heme iron is absorbed in the duodenum, deficiency may result from inadequate intake of an iron source or inadequate absorption (duodenal disease, achlorohydria* (acidic environment needed to convert iron to absorbable from). 2. Excess iron loss: chronic blood loss GI, menstrual 3. Increased demand: pregnancy, lactation, infancy Pathologic Findings 1. Microcytic-hypochromic RBCs 2. Low marrow iron stores 3. Low iron levels in plasma (serum iron, ferritin and transferrin).
  • 6. Vitamin B12 & folate deficiency • These adversely affect DNA synthesis in hematopoietic cells and hinder maturation of precursors. This results in gigantic RBC precursors (megaloblasts) because granulocytes and platelets are also affected this often results in pancytopenia. B12 deficiency anemia is called pernicious anemia (megaloblastic anemia) Causes: 1. Malabsorption of B12: B12 is normally found in animal products and is absorbed in the distal ileum when combined with intrinsic factor which is produced by the gastric parietal cells. Gastritis, Crohn’s disease or parasitic infections of the small intestine can result in malabsorption. Achlohydria is associated with B12 malabsorption. Antibodies to intrinsic factor may be found. Autoimmune destruction of gastric parietal cells results in classic pernicious anemia.
  • 7. 2. Inadequate folate or B12 as a result of inadequate intake, this requires chronic malnutrition because of large reserves of both components. 1.Increased demand for folate during pregnancy 2.Drug treatments may interfere with folate function, especially methotrexate. Pathology 1. RBCs are macrocytic & hypersegmented (immature forms). PMNs are hypersegmented 2. Marrow shows megaloblasts 3. Decreased platelet counts 4. B12 & folate levels are decreased. 5. B12 deficiency is associated with demyelination of the dorsal & lateral spinal cord tracts which results in a spastic paresis and sensory ataxia. This is absent in anemia due to folate deficiency.
  • 8. • Bone marrow biopsy from patient with megaloblastic anemia. Arrowheads point to megaloblasts and arrow to RBC undergoing apoptosis.
  • 9. Anemias caused by Increased RBC Destruction • Hemolytic Anemias: characterized by premature RBC destruction, accumulation of Hgb metabolites (bilirubin) and increased erythropoiesis. Intracorpuscular: Hemolysis results from intrinsic RBC abnormalities such as those affecting RBC structural proteins (spectrin, ankyrin), the globin portion of Hgb or RBC enzymes (glucose-6-phosphate dehydrogenase). • Hereditary spherocytosis is an autosomal dominant condition most often related to spectrin deficiency. RBCs lacking spectrin are less deformable resulting in increased fragility which results in fragmentation and subsequent phagocytosis by splenic components.
  • 10. Thalassemia is a term describing a set of anemias due to defective synthesis of Hgb (a tetramer composed of 2 α chains & 2 β chains). The α-chain is coded for by 2 separate genes on chromosome 16 the β chain is coded for by 1 gene on chromosome 11. Two factors account for the anemia seen in thalassemia • 1. Decreased concentration of normal hemoglobin • 2. Accumulations of Hgb chains due to the defective production of the other Hgb chain result in increased RBC destruction.
  • 11. Types of Thalassemia: • β- Thalassemias: the most common form, related to a mutation in one or both β-globin genes resulting in decreased β globin production. The excess α globin forms unstable aggregates that damage RBC membranes resulting in destruction in the marrow or by splenic phagocytes. 1. Thalassemia major - individuals homozygous for the defective β-globin gene develop hemolysis, splenomegaly bone marrow hyperplasia and bony deformities. Without transfusions these people die early. The failure of transition of fetal α2γ2 to α2β2results in persistent fetal hemoglobin. 2. Thalassemia minor – individuals have 1 defective gene and have mild symptoms.
  • 12. α-Thalassemia: related to the depletion of α-globin, free β- globin forms tetramers that damage RBC membranes. There are 4 types depending on the number of defective genes an individual possess. 1. One defective gene- silent carrier 2. Two defective genes - α-Thalassemia trait, minor symptoms 3. Three defective genes Hemoglobin H disease – increased production of β-globin tetramers that damage RBCs and result in destruction. 4. Four defective genes – hydrops fetalis, a complete lack of α-globin, excess fetal Hgb (γ globin) forms tetramers which do not release bound oxygen easily leading to fetal demise.
  • 13. Sickle Cell Anemia Sickle Cell Anemia, a hemoglobinopathy affecting 8% of African-Americans, is a defect in β-globin resulting in the formation of HgbS which results in sickling of RBCs under low oxygen conditions. The presentation depends on the amount of HgbS; 40% in heterozygotes to 100% in homozygotes. Symptoms are due to chronic hemolysis, the average lifespan of an RBC is reduced from 120 to 20 days, and bilirubin is elevated. Microvascular occlusion results in tissue hypoxia, mico-infarcts in bones, lungs, liver and brain. Aplastic crisis may be induced by viral infection on a stressed hematopoietic system.
  • 14. Extracorpuscular hemolytic anemia: abnormality outside the RBC (usually involving antibodies or splenomegaly) Autoimmune hemolytic anemias – anti RBC antibodies, 2 types 1. Warm antibody type: The most common form is related to the deposition of IgG antibodies on the RBC surface resulting in opsonization without complement activation. This type of hemolytic anemia associated with SLE. Drug induced hemolytic anemias result from the formation of novel antigens when certain drugs bind to the RBC surface (common with penicillins). 2. Cold antibody type: This is mediated by IgM antibodies; these antibodies activate complement in addition to opsonization. They are especially effective in colder regions of the body (extremities) and can result in small vessel thrombotic events. This may occur as an acute process after viral mononucleosis or chronically in lymphoma patients. These antibodies have their optimal activity at ~30Cº. Hemolytic episodes are associated with cold exposure and occur in the extremities. Pathologic findings in hemolytic anemia include compensatory marrow hyperplasia, reticulocytosis and hemosiderin deposits (due to RBC destruction). Clinical features include jaundice, splenomegaly and hepatomegaly.
  • 15. • Anemia of renal failure: due to inadequate production of erythropoietin by the kidney, treatment with EPO improves RBC production. • Anemia of chronic disease: Increased chronic inflammatory mediators causes a sequestration of iron stores from the erythroid organs (mainly bone marrow) so serum iron is low but total iron binding capacity (TIBC) is low while ferritin levels are high (there’s lots of iron it’s just not available for RBC synthesis. Also erythropoietin production is reduced. TIBC measures the available binding sites on transferrin
  • 16. Bleeding Disorders • These disorders may be congenital or acquired and result from abnormalities in vessel walls, platelets or clotting factors. • The anemia of acute blood loss results in a compensatory reticulocytosis in 4-5 days following the hemorrhage. Thrombocytopenia is defined as a platelet count of <100,000 platelets/microliter. Spontaneous bleeding does not occur until counts reach <20,000, this presents as petechial bleeding of the skin and mucous membranes. Causes: 1. Decreased production as a result of marrow failure 2. Decreased survival by to sequestration (hypersplenism) or destruction: due to drugs (heparin, quinidine, alpha-methyldopa) or viral infection related immune-mediated destruction 3. HIV infection 4. Dilution: In patients receiving transfusions without platelet supplementation; storage of blood at 4°C fro 24 hours results in rapid hepatic sequestration of platelets.
  • 17. A Model of Immune mediated Thrombocytopenia IgG antibodies form a complex with heparin and PF4 in the bloodstream. The tail of the antibody then binds to an Fc receptor on the surface of the platelet. This results in platelet activation and the formation of platelet micro-aggregates, which initiate the formation of clots; the platelet count falls as a result (hypercoaguable with thrombocytopenia).
  • 18. Idiopathic thrombocytopenia purpura (ITP) is an autoimmune disorders caused by antibodies to platelets, megakaryocytes or both. Opsonized platelets are sequestered by the spleen & liver. 1. Acute ITP is a self-limited disease usually related to a viral infection (rubella, hepatitis, mononucleosis) affecting children. 2. Chronic ITP affects women 20-40 years of age; platelet depletion is mediated by antibodies to particular platelet surface antigens. It may be treated (75- 80% success) with splenectomy
  • 19. Thrombotic Microangiopathic Purpura is a term used to describe several conditions characterized by the formation of platelet-fibrin thrombi in small vessels leading to small vessel occlusion and a consumptive- coagulopathy. 1. Thrombotic thrombocytopenic purpura (TTP) typically affects women; features include renal failure, fever, neurologic symptoms, hemolytic anemia and thrombocytopenia. 2. Hemolytic-uremic Syndrome is similar to TTP but occurs in children and lacks neurologic symptoms. It is caused by an infection with an enterhemorrhagic E. coli, this bacteria produces a toxin that injuries endothelial cells which promotes platelet activation & aggregation.
  • 20. Clotting Factor Deficiencies These may be acquired (liver disease, vitamin K deficiency, DIC) or congenital (hemophilia, von Willebrand disease). These disorders present with ecchymoses, hematomas, prolonged bleeding after laceration, GI & GU hemorrhage and hemearthrosis in weight bearing joints. Acquired defects result from vitamin K deficiency which results in deficiencies in factors II, VII, IX, X and protein C production (all produced by the liver). This may also be acquired through liver failure or a consumptive coagulopathy.
  • 21. Congenital Defects 1. Hemophilia A is due to a decreased amount and activity of factor VIII, levels of <1% of normal are required for spontaneous bleeding to occur. This is a classic X-linked disorder. 2. Hemophilia B (Christmas disease) is due to an X-linked defect in factor IX activity. Its presentation is identical to type A, only clotting studies can differentiate them. 3. Von Willebrand disease is characterized by a deficiency of von Willebrand factor which stabilizes factor VIII and participates in platelet adhesion to endothelial surfaces. This is the most common hereditary bleeding disorder, it usually results from an autosomal dominant but some recessive disorders have been identified. It presents with menorrhagia, excessive bleeding from minor wounds or spontaneous bleeding from the gums and mucous membranes. Lab evaluation reveals abnormal platelet function and coagulation. There are three basic types: 1. Type 1: low level of vWF ± decreased Factor VIII levels (most common, least severe, autosomal dominant). 2. Type 2: Defective vWF (4 sub-types, autosomal dominant) 3. Type 3: vWF absent & decreased Factor VIII (most severe, recessive)
  • 22. White Blood Cell Neoplasia
  • 23. Leukocytosis
  • 24. Mechanisms of bone marrow neoplasia • Blast cells (malignant) overpopulate the bone marrow and replace the normal cells causing bony destruction and/or blood or lymphoid cell deficiencies. • Malignant cells or their descendents may appear in the peripheral blood (leukemia), in extramedullary sites such as the spleen and liver (hepatosplenomegaly) and in lymph nodes (lymphadenopathy). • Bone marrow malignancy may be accompanied by myelofibrosis (the extensive deposition of collagen by non-neoplastic fibroblasts). • Types of bone marrow neoplasia: Malignant transformation of hematopoietic and lymphoid cell precursors may occur at any point in their maturation. Malignant cells are classified as myeloid, lymphoid, or plasmacytic. The characteristic behavior of particular malignant stem cells determines the presentation of the disease. There are four major groups:
  • 25. Types of bone marrow neoplasia 1. Myeloproliferative disorders: Characterized by the malignant transformation of developmentally pluripotent myeloid stem cells and their linage-restricted descendants. 2. Myelodysplastic syndromes: Characterized by ineffective hematopoiesis and pancytopenia. 3. Leukemia: Characterized by the appearance of neoplastic WBCs in the peripheral circulation. 4. Plasma cell disorders: Characterized by the monoclonal proliferation of neoplastic plasma cells and plasmacytoid lymphocytes usually in the bone marrow
  • 26. Myeloproliferative Disorders These disorders include polycythemia rubra vera (proliferation of RBC precursors), essential thrombocytemia (proliferation of platelet precursors) chronic myelocytic leukemia (proliferation of neutrophil precursors) and myelofibrosis (proliferation of fibroblasts). These entities are interrelated and may transform one into another or into acute myeloblastic leukemia (AML). Features common to all myeloproliferative disorders: 1. Peak incidence in 40-70 years of age 2. Marrow hypercellularity, except myelofibrosis which is dominated by fibrosis 3. Splenomegaly due to extramedullary hematopoiesis 4. Peripheral blood abnormalities and hyperviscosity, except for myelofibrosis
  • 27. Myelodysplastic syndromes • Myelodysplastic syndromes (MDS, formerly known as "preleukemia") are a diverse collection of hematological conditions united by ineffective production of blood cells and varying risks of transformation to acute myelogenous leukemia (AML). Anemia requiring chronic blood transfusion is frequently present. • Myelodysplastic syndromes (MDS) are bone marrow stem cell disorders resulting in disorderly and ineffective hematopoiesis manifested by irreversible quantitative and qualitative defects in hematopoietic cells. In a majority of cases, the course of disease is chronic with gradually worsening cytopenias due to progressive bone marrow failure. • Approximately one-third of patients with MDS progress to AML within months to a few years. • The median age at diagnosis of a MDS is between 60 and 75 years; a few patients are less than 50; MDS are rare in children. Males are slightly more commonly affected than females. Signs and symptoms are nonspecific and generally related to the blood cytopenias (anemia, neutropenia, thrombocytopenia). • A significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML but rather from the cytopenias seen in all MDS patients. Anemia is most common and responds to transfusion, patients often suffer from iron overload. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells).
  • 28. Leukemias These are composed of two major groups: myeloid (granulocytic) and lymphoid. Causes: The cause is unknown but some predisposing factors have been recognized: 1. Myelodysplastic syndromes precede the onset of leukemia 2. Genetic factors may play a role, chromosomal syndromes (Downs, etc.) are associated with increased risk of leukemias. 3. Ionizing radiation; there is increased incidence in those exposed to radiation for treatment or otherwise. 4. Alkylating agents used in chemotherapy are associated with increased risk 5. Viruses: Human T-cell lymphocytic virus-1 (HTLV-1) is an RNA oncogenic virus that causes T-cell leukemias 6. Endogenous oncogenes play a role and are associated with chromosomal breaks, translocations or deletions. The Philadelphia chromosome (translocation of fragments of chromosomes 9 & 22) is associated with the formation of an oncogene and are associated with the development of CML.
  • 29. Types of Leukemias 1. Acute Lymphoblastic leukemia (ALL) ~30% of all leukemias, the most common among children under 5 years old. The marrow contains more than 30% lymphoblasts. The prognosis is inversely proportional to age. 2. Acute myelogenous leukemia (AML) ~80% of acute leukemias in adults. Marrow has >20% myeloblasts. Overall prognosis is poor with relapse after chemotherapy and most do not survive more than 5 years after diagnosis. Two forms; acute denovo AML or as an end-stage of CML and myelofibrosis. AML ALL
  • 30. Types of Leukemias 3. Chronic lymphocytic leukemia (CLL) Peak incidence is in elderly males >60years old. Bone marrow has >40% lymphoid cells, peripheral blood has >15 X10↑6. Neoplastic cells resemble B- lymphocytes. CLL has an indolent course over 7-10 years, it responds poorly to chemotherapy. It is closely related to small cell lymphoma and lymphadenopathy is common. 4. Chronic myelogenous leukemias (CML) Peak incidence is ~60years old. Symptoms are related to loss of normal marrow functioning; anemia, bleeding & infection. Peripheral WBC counts in the 20-50,000 range with large component of myeloid precursors. Frequently terminates in a “blast” crisis with peripheral WBCs of >100,000 with immature myeloid cells. Prognosis is poor despite chemotherapy.
  • 31. Plasma cell disorders Main types – Multiple myeloma – Waldenstrom macroglobulinemia: A malignancy of plasmacytoid lymphocytes that secrete IgM resulting in a hyperviscosity syndrome with renal, retinal and cerebral ischemia as a result of microvascular occlusion. – Monoclonal gammopathy of unknown significance: often diagnosed in asymptomatic elderly patients. It is present in ~1% of patients over 60 years old and 3% of patients over 70. There is a 1% risk of developing multiple myeloma. Clinical features – Tend to occur in those >45 years old. – Neoplastic plasma cells produce a monoclonal immunoglobulin component that can be identified by serum electrophoresis – Deposition of light chain immunoglobulin may form amyloid deposits in the kidneys, vessels and other organs.
  • 32. Multiple Myeloma • A neoplasm of mature plasma cells that respond poorly to chemotherapy and usually survive ~3 years after diagnosis. Renal damage due to protein deposition is the most common cause of death. Infection, systemic amyloidosis, anemia, hyperviscosity and metabolic disorders contribute to the poor outcome.
  • 33. Multiple Myeloma Clinical Presentation: - Pts present in their middle fifties or older (60-70 yr) - Constitutional symptoms, anemia, thrombocytopenia, and renal failure; - Approx 80% of pts have chief complaint of bone pain w/ diffuse bone tenderness, particularly over the sternum and pelvis. - Pathological fracture of spine or femur may be heralding event; - Symptoms range in duration from as short as few wks to as long as 2 yrs.
  • 34. • Neoplastic cells secrete a monoclonal immunoglobulin: IgG 60%, IgA 20% and IgD, IgE or the heavy or light chain 20%. Normal immunoglobulins are suppressed increasing the risk of infection. • Multiple bone lesions are composed of nests of neoplastic cells and appear as “punch” lesions in bones. Bony lesions may cause symptomatic hypercalcemia, metastatic calcification also occurs. • Excess immunoglobulin may be deposited in peripheral tissue forming amyloid. They may be secreted in the urine as Bence-Jones proteins, occasionally proteins obstruct renal tubules resulting in renal failure.
  • 35. Lymphomas Neoplasms of lymphoid cells may be divided into two major groups: • Non-Hodgkin’s lymphoma ~70% • Hodgkins lymphoma ~30% Predisposing factors 1. Oncogenes, both lymphomas & leukemias may share the same oncogenes. 2. Radiation increases the risk of lymphomas particularly radiation therapy for neoplastic disorders. 3. Environmental factors, Burkitt lymphoma is related to EBV infection. 4. Immunodeficiency states (congenital or acquired) are associated with an increased incidence of lymphomas; HIV is associated with CNS lymphoma.
  • 36. Non-Hodgkin lymphomas Non-Hodgkin lymphomas are a heterogeneous group of neoplasms arising from both T and B cells and their precursor cells. • 85% of non-Hodgkins are of B-cell origin and involve marrow, lymph nodes, spleen and extranodal lymphoid tissue. Approximately 2/3rds of cases begin in lymph nodes, the remaining begin in extranodal lymphoid tissue. Multiple nodes are usually involved. Four general categories have been identified based on cell origin, level of differentiation, genetic abnormality and clinical presentation. 1. Precursor B-cell neoplasms: present as acute lymphoblastic leukemia/lymphoma. ALL/L of infancy and childhood and is often curable. Adult ALL/L usually responds but tends to recur and is rarely cured. 2. Precursor T-cell neoplasms ALL/L involving the mediastinum, lymph nodes and spleen. These respond less well than B-cell precursor types.
  • 37. Non-Hodgkin lymphomas 3. Peripheral B-cell neoplasms occur in several forms and affects adults. B-cell types are the most malignant. The most important are 1. Small cell lymphocytic lymphoma, the lymphoma equivalent of CLL. This tends to have a protracted course surviving 7-10 years after diagnosis 2. Follicular lymphoma affects elderly patients responsible for ~45% of lymphomas. Like CLL this disorder has an indolent course lasting 7-10 years. 3. Mantle cell lymphoma responds to chemotherapy but relapses are common and most survive only 3-4 years after diagnosis. 4. Diffuse B-cell lymphomas account for ~20% of all lymphomas, but represent 70% of all aggressive lymphomas in adults and are the most common rapidly proliferating lymphomas. Despite its aggressive nature ~50% are cured by chemotherapy. 5. Hairy cell leukemia is a low grade lymphoma associated with splenomegaly. The proliferation of characteristic “hairy cells” results in their appearance in peripheral blood (hence the description as leukemia).
  • 38. Non-Hodgkin lymphomas 4. Burkitt lymphoma is a rapidly growing B-cell lymphoma affecting children and adults. It is related to EB virus infection. Solid tumors are often located in extranodal tissue. Response to chemotherapy is inversely related to age.
  • 39. Hodgkin’s disease comprise several closely related neoplastic lymph node disorders that resemble lymphoma Areas of involvement: This usually involves a neoplastic process in contiguous lymph nodes usually in the neck and mediastinum. Extranodal involvement and disease above and below the diaphragm portend poor prognosis.
  • 40. Pathologic findings Affected nodes show an inflammatory response to tumor cells and contain infiltrates of lymphocytes, plasma cells and eosinophils Reed-Sternberg cells (large binucleate cells (owl eyes)) surround other cells that identify five types: • Nodular sclerosis the most common type • Lymphocyte predominant • Lymphocyte depletion • Mixed cellularity • Lymphocyte-rich Clinical features include fever, sweating, weight loss, etc., (characteristic of an inflammatory process). Prognosis depends on the stage of disease at the time of diagnosis; histological type has little influence on outcome. 5-years survival is 75%, Relapse after initial treatment has ~50% survival rate.
  • 41. Clinical Differences Between Hodgkin and Non-Hodgkin Lymphomas Hodgkin Lymphoma Non-Hodgkin Lymphoma More often localized to a single axial group of nodes (cervical, mediastinal, para-aortic) More frequent involvement of multiple peripheral nodes Orderly spread by contiguity Noncontiguous spread Mesenteric nodes and Waldeyer ring rarely involved Waldeyer ring and mesenteric nodes commonly involved Extranodal involvement uncommon Extranodal involvement common