34: Spleen Flashcards

Question

Which has a worse prognosis: Hodgkin's or non-Hodgkin's lymphoma?

Answer 1

Non-Hodgkin's lymphoma has worse prognosis [90% of non-Hodgkin's lymphomas are B-cell lymphomas. Vast majority of non-Hodgkin's lymphomas are systemic by the time of diagnosis. Treatment is chemotherapy.] [UpToDate: The clinical presentation of non-Hodgkin lymphoma (NHL) varies tremendously depending upon the type of lymphoma and the areas of involvement. Common presentations include lymphadenopathy, hepatosplenomegaly, fever, weight loss, and night sweats. Less common presentations include rash or side effects related to extranodal involvement. Complications of NHL need to be considered during the initial workup. Prompt recognition and therapy is critical for these situations, which may be life-threatening, interfere with, and/or delay treatment of the underlying NHL. An excisional biopsy of an intact node consistently allows sufficient tissue for histologic, immunologic, and molecular biologic assessment by experienced hematopathologists. Fine needle aspiration (FNA) of a lymph node without evaluation of the architecture is usually insufficient for definitive NHL diagnosis. The importance of this evaluation for appropriate diagnostic, prognostic, and treatment purposes cannot be overemphasized. Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 30% of patients with NHL. It is an aggressive NHL in which survival without treatment is measured in months. For most patients with non-bulky limited stage DLBCL, we suggest treatment with abbreviated chemotherapy plus involved-field radiotherapy, rather than chemotherapy alone (Grade 2B). We administer three cycles of R-CHOP followed by 30 to 36 Gy of involved-field radiation. In cases where radiation may cause significant morbidity (eg, involvement of the oronasopharynx or pelvis), the dose of chemotherapy is maximized to allow delivery of a more tolerable radiation dose. Chemotherapy alone may be preferable, for example, in young women in whom the breast would otherwise have to be irradiated, in those for whom radiation to the salivary glands might lead to loss of teeth, or in patients who choose to defer radiation therapy.]

Answer 2

1. Mononucleosis 2. Malaria 3. Sepsis 4. Sarcoid 5. Leukemia 6. Polycythemia vera

Answer 3

* 85% * Removal of abnormalities in RBC membrane (Howell-Jolly bodies [nuclear remnants], Heinz bodies [hemoglobin]), and removal of less deformable RBCs.

Answer 4

The splenic hilum (20% of accessory spleens found here)

Answer 5

1. Intracerebral hemorrhage 2. Acute renal failure [UpToDate: Untreated, TTP typically follows a progressive course in which progressive neurologic deterioration, cardiac ischemia, irreversible renal failure, and death are common. The mortality rate prior to the 1980s, when effective therapy became available, was approximately 90%. Prompt, effective treatment is essential for survival.]

Answer 6

* Pyruvate kinase deficiency: **Yes** * Glucose-6-phosphate dehydrogenase deficiency (G6PD): **No** * Warm antibody-type acquired immune hemolytic anemia: **Yes** * Sickle cell anemia: **No** * Beta thalassemia: **Yes** (if splenomegaly present)

Answer 7

The spleen

Answer 8

Pyruvate kinase deficiency [Causes altered glucose metabolism. RBC survival is enhanced by splenectomy.] [UpToDate: Pyruvate kinase (PK) deficiency is the **most common cause of congenital non-spherocytic chronic hemolytic anemia** and is the result of an erythrocyte enzyme defect. It is an autosomal recessive condition caused by a deficiency of erythrocytic PK. Although the gene frequency for PK deficiency is far lower than that for glucose-6-phosphate dehydrogenase (G6PD) deficiency, the vast majority of patients inheriting G6PD deficiency never suffer acute or chronic hemolysis, whereas chronic hemolysis of variable severity is common in those with PK deficiency. The mechanism for hemolysis in PK deficiency is not clear. Although the defect in ATP generation contributes to hemolysis, it is not a sufficient explanation because ATP deficiency is difficult to demonstrate in some of the affected patients. In addition, other disorders with more severe degrees of ATP deficiency are not associated with significant hemolysis. It has been alleged that the mechanism of hemolysis in PK deficiency is similar to the as yet unexplained destruction of young red cells described in individuals descending from high altitude, a process termed "neocytolysis." It is possible that the impaired mitochondrial autophagy leading to increased production of reactive oxygen species (ROS) may be involved; however, this remains speculative at this time. Patients with hemolytic anemia who undergo splenectomy, with a resultant decrease in the hemolytic process and improvement of anemia, have a higher number of reticulocytes than they did before the splenectomy. This perplexing observation indicates that our knowledge of the regulation of erythropoiesis and reticulocyte kinetics remains incomplete. A significant interaction may occur between the spleen and PK-deficient young red blood cells, through an as yet unknown mechanism, which influences premature destruction of reticulocytes and young red cells in this organ, especially in patients with more severe PK deficiency. The metabolic disturbances in PK deficiency affect not only the survival of red cells but also the maturation of splenic erythroid progenitors, which results in their apoptosis (ie, ineffective erythropoiesis). This has been demonstrated in a splenectomized PK deficient patient as well as in a PK deficient mouse model. It remains to be established, however, whether apoptosis of erythroid progenitors in PK deficiency extends to marrow erythroblasts, if this observation accounts for the previously unexplained post-splenectomy reticulocytosis, and if PK activity has any role in the apoptotic pathway in general. The beneficial effect of **splenectomy** on hemolysis has been well documented. Typically, hemolysis and anemia are ameliorated but not entirely abated. In severe cases the transfusion requirement is generally, but not invariably, abolished. No reliable way to predict success of splenectomy exists. However, results of splenectomy in other family members may be of major guidance in this matter. Concomitant splenectomy should be strongly encouraged if the patient requires surgery for removal of pigment (bilirubin) gallstones; these procedures can at times be performed simultaneously using laparoscopic techniques. Even if the affected infant is transfusion-dependent, delaying splenectomy as long as possible is advisable, preferably after the age of three years, since the immune suppressive effect and high susceptibility to infectious agents following splenectomy declines after that age. A single report indicates failure of partial splenectomy (80%) to reduce the transfusion requirement of a four-year-old patient with PK deficiency. Six months later, she successfully underwent total splenectomy and became transfusion-independent.]

Answer 9

Warm antibody-type acquired immune hemolytic anemia [Warm agglutinins are IgG mediated. Cold agglutinins are IgM mediated.] [UpToDate: The most common form of autoimmune hemolytic anemia (AIHA) is that due to IgG antibody able to react with its antigen at core body temperature, the so-called "warm agglutinins". These account for more than 80% of all cases of AIHA. Characteristics of the antibodies — Warm antibodies are always polyclonal, even when they occur in diseases characterized by monoclonal accumulation or proliferation of lymphocytes. The distribution of subtypes varies from patient to patient and does not necessarily reflect the distribution of subtypes in the IgG in the plasma. The subisotypes are one of the characteristics that determine the rate of destruction; IgG3 and IgG1 antibodies are the more destructive due perhaps to their greater ability to fix complement. The antibodies in AIHA appear to react only to protein structures on the RBC surface. These antibodies probably persist because of continued antigenic stimulation from the autoantigens. Protein antigens are nearly always processed into the T-cell memory system. Thus, after the primary immunization, subsequent antibody production (as in an anamnestic antibody response), is derived from cells that have undergone the second Ig rearrangement to result in IgG antibodies. In cases in which the antigen is not continuously available (eg, certain forms of drug-related immune hemolytic anemia), antibody production will stop fairly abruptly, but is readily reinitiated when the antigen (drug) is reintroduced. Indications for treatment – Most patients with AIHA present with an acute onset of severe hemolysis with symptomatic anemia, requiring immediate treatment. In patients with underlying cardiac disease, AIHA can present as a medical emergency, requiring immediate packed red cell transfusion. Initial treatment – Once the diagnosis of symptomatic warm agglutinin AIHA is confirmed, we recommend immediate institution of **treatment with glucocorticoids over splenectomy, rituximab, or other immunosuppressive agents** (Grade 1B). Poorly responsive, severe, or resistant disease: * Second-line treatment – **For symptomatic patients not responding to glucocorticoids, or for those who require large doses to maintain their response (eg, \>15 mg/day), we suggest either elective splenectomy or rituximab** over the use of immunosuppressive or cytotoxic agents (Grade 2B). **For adults, we prefer splenectomy over rituximab** as it is the only modality with potential for long-term cure, while rituximab is the treatment of choice for adults who either are not surgical candidates or refuse surgery. For children, rituximab has become the preferred treatment for those who do not respond to treatment with glucocorticoids, and is generally suggested before resorting to splenectomy. * Third-line treatment – **For those who have failed treatment with both splenectomy and rituximab, we suggest the institution of immunosuppressive or cytotoxic agents** (eg, azathioprine, cyclophosphamide, cyclosporine) (Grade 2C). There is insufficient information to choose one of these agents over another.]

Answer 10

1. Decrease in circulating erythrocytes and/or platelets and/or leukocytes 2. Normal compensatory hematopoietic responses present in bone marrow 3. Correction of cytopenia by splenectomy [These can occur with or without splenomegaly.]

Answer 11

* Cause: Many etiologies (Drugs, viruses, etc.) * Pathophysiology: **Anti-platelet antibodies** bind platelets (results in decreased platelets) * Signs/symptoms: **Petechiae**, **gingival bleeding**, **bruising**, soft tissue **ecchymosis** * Treatment: **Steroids** (primary therapy), **gammaglobulin** if steroid resistant, **splenectomy** for those who fail steroids (removes IgG production and source of phagocytosis; 80% respond after splenectomy) [UpToDate: **Primary immune thrombocytopenia (ITP)** is an acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is one of the more common causes of thrombocytopenia in otherwise asymptomatic adults. Major diagnostic concerns in an adult with suspected ITP are distinguishing ITP from other causes of thrombocytopenia, which often have a similar presentation but may require completely different management approaches, and determining whether the ITP is primary or secondary to an underlying condition that might also benefit from treatment. The goal of immune thrombocytopenia (ITP) therapy is to provide a safe platelet count to prevent clinically important bleeding, rather than to normalize the platelet count. For many patients, we tolerate a lower platelet count before initiating second-line therapy (ie, \<20,000/microL rather than 30,000/microL that is used for first-line therapy). For all patients with persistent ITP who have experienced clinically important bleeding despite **first-line therapy with glucocorticoid**s, we recommend proceeding to **second-line therapy with splenectomy or rituximab** rather than observation or chronic glucocorticoid administration (Grade 1B). We also suggest ITP-specific therapy for patients with a platelet count \<20,000/microL despite initial therapy, even in the absence of bleeding (Grade 2B). The importance of proceeding to second-line therapy is greater for patients with a higher risk of bleeding due to other comorbidities (eg, renal insufficiency) or athletic activities. Patients who are less concerned about bleeding and more concerned about side effects of therapy may choose to defer second-line therapy at lower platelet counts. Splenectomy and rituximab are both associated with durable remissions off treatment. Balancing the risks and benefits of these therapies is challenging because their benefits, side effects, and toxicity profiles differ greatly (table 1). The relative efficacy of splenectomy versus rituximab has not been evaluated in a randomized trial; however, reported response rates with splenectomy are higher and last longer. Thus, for patients who require additional treatment after glucocorticoids or IVIG, we suggest splenectomy, provided the patient can tolerate surgery (Grade 2B). Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. It is characterized by small-vessel platelet-rich thrombi that cause thrombocytopenia, microangiopathic hemolytic anemia, and sometimes organ damage. TTP is a medical emergency that is almost always fatal if appropriate treatment is not initiated promptly. With appropriate treatment, survival rates of up to 90% are possible.]

Answer 12

* Medical treatment includes blood transfusions and iron chelators (deferoxamine, deferiprone) * Splenectomy [Symptoms of beta thalassemia include pallor, retarded body growth, head enlargement. Most die in teens secondary to hemosiderosis.] [UpToDate: Beta thalassemia is caused by one or more mutations in the beta globin gene that result in an imbalanced ratio of alpha to beta globin. The specific gene mutations involved and their mechanism of affecting beta globin production are discussed separately. This imbalance in turn leads to impaired red blood cell (RBC) maturation and destruction of developing RBC precursors in the bone marrow, called ineffective erythropoiesis or intramedullary hemolysis; as well as hemolysis, with reduced RBC survival in the peripheral blood. The severe anemia can result in extramedullary hematopoiesis and increased iron absorption, which can lead to excess iron stores even in the absence of transfusions. Beta thalassemia minor (trait) – Subjects with beta thalassemia minor (beta thalassemia trait) require no specific therapy. Transfusions may be required in pregnant women with symptomatic "physiologic" anemia of pregnancy. Beta thalassemia major – Subjects with beta thalassemia major are severely affected and will die of their disease unless given appropriate medical attention. * We recommend that all children with beta thalassemia major receive treatment with a **hypertransfusion protocol along with iron chelation therapy** (Grade 1A). Such treatment should be instituted once the stigmata of the disease become evident and should be rigorously followed. * Appropriately selected subjects (eg, younger age, availability of HLA-matched donor, presence or absence of hepatomegaly/hepatic fibrosis, quality of iron chelation therapy) should be considered for potentially curative **hematopoietic cell transplantation**. Beta thalassemia intermedia – Subjects with beta thalassemia intermedia have clinical complications less severe than those seen in beta thalassemia major, and may not develop the need for any treatment until later in life. Accordingly, all patients should be carefully monitored for development of symptomatic anemia, abnormalities in growth and development, symptomatic splenomegaly, iron overload, and cardiopulmonary complications. * We suggest institution of **red cell transfusions and/or a hypertransfusion/chelation regimen** in subjects with disease-related complications (eg, activity limitations, delayed growth and development, early appearance of skeletal changes, progressive marrow expansion) (Grade 2C). * We suggest that splenectomy be avoided in these patients if at all possible; **splenectomy should be considered only in those with severe disease-related complications such as growth retardation, poor health, leukopenia, thrombocytopenia, increased transfusion need, or symptomatic splenomegaly** (Grade 2C).]

Answer 13

* Tuftsin: An opsonin that facilitates phagocytosis * Properdin: An activator of the alternate complement pathway [UpToDate: Patients without a spleen or with hypofunction of the spleen are at increased risk for infection due to defects in antibody production, decreased ability to remove bacteria from the blood, and decreased production of important opsonin-associated proteins like tuftsin. Properdin, released from granules upon neutrophil activation, can bind activated C3 to form a C3 convertase. Properdin likely also serves as a platform for efficient C3 activation by the alternative pathway.]

Answer 14

* Vaccinate at least 10-14 days prior to splenectomy if possible * If splenectomy is urgent, wait until at least 14 days postprocedure to vaccinate