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Spleen
Splenectomy for Hematologic Disorders
INTRODUCTION
Splenectomy may be indicated in a wide variety of hematologic diseases that lead to hypersplenism. It may also be performed more generally to relieve the mass effect and symptoms of splenomegaly, to control infection or traumatic hemorrhage, and, finally, a surgeon may decide to remove the spleen to diagnose splenic pathology. Despite a broad range of disease processes affecting the spleen, the most common indications for elective splenectomy are hematologic autoimmune disorders such as idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), and malignancy. For the purposes of this chapter, which is focused primarily on hematologic disorders for which splenectomy may be used for cure or palliation, we divide the indications into the following categories: (1) benign conditions, including red blood cell disorders, hemoglobinopathies, and platelet disorders; (2) malignant conditions, including white blood cell disorders, myeloproliferative disorders, and tumors of the spleen; and (3) miscellaneous conditions. Although not an exhaustive list, we highlight the most common hematologic disorders of the spleen that are clinically relevant from a surgeon’s perspective. We also touch on perioperative considerations of the splenectomized patient, and finally we discuss current surgical techniques.
BENIGN CONDITIONS
Red Cell Disorders
Glucose-6-Phosphate Dehydrogenase Deficiency
The most common red blood cell enzyme deficiency is glucose-6-phosphate dehydrogenase (G6PD) deficiency. It is an X-linked genetic disease of the glutathione pathway. It is estimated that over 400 million people are affected worldwide. Clinical manifestations occur after oxidative stress (acute infections, trigger foods such as fava beans, and several medications) and vary in severity from acute and chronic intermittent hemolytic episodes to no hemolysis depending on the variant of G6PD deficiency. Transfusions are often required in cases of symptomatic anemia. Conventional wisdom suggests that the majority of patients with G6PD deficiency will not progress or benefit from splenectomy, however case series do exist supporting splenectomy for severe and refractory clinical presentations including massive splenomegaly, transfusion dependence, or medication side effects.
Hereditary Spherocytosis
Hereditary spherocytosis (HS) is the most common type of hemolytic anemia for which splenectomy is indicated and a common type of congenital hemolytic anemia. Its estimated prevalence in Western populations is roughly 1 in 2000. HS results from an autosomal dominant deficiency or dysfunction in one of the many erythrocyte membrane proteins (including but not limited to alpha or beta spectrin, ankyrin, or protein 4.2). This results in destabilization of the membrane lipid bilayer, and the red blood cell assumes a more spherical, less deformable shape causing sequestration and destruction in the spleen and resulting in hemolytic anemia. Common clinical manifestations include mild jaundice and palpable splenomegaly. Indications for splenectomy often include moderate to severe cases of symptomatic hemolytic anemia including growth retardation, skeletal changes, leg ulcers, and extramedullary hemopoietic tumors in young patients. Because HS can affect children, the timing of splenectomy is important and is aimed at reducing the possibility of post-splenectomy sepsis. Unless the anemia and hemolysis are rapidly accelerating, delaying splenectomy until 4 to 6 years of age is generally recommended, as is consideration for a near-total splenectomy in children. If gallstones coexist with spherocytosis, cholecystectomy should be strongly considered. Prophylactic cholecystectomy in this population without gallstones remains controversial.
Pyruvate Kinase Deficiency
Pyruvate kinase (PK) deficiency is the most common glycolytic defect causing congenital non-spherocytic hemolytic anemia. PK deficiency affects people worldwide, with a slight predisposition for those of Northern European or Asian descent. Its estimated prevalence in the Caucasian population is roughly 50 per 1 million. Clinical manifestations of the disease also vary widely, from severe transfusion-dependent anemia in early childhood to well-compensated mild to moderate anemia in adolescents or adults. Prenatal hydrops fetalis has also been reported. PK enzyme activity remains the gold standard for initial diagnostic testing (and a favorite among standardized tests). Splenomegaly is common, and in severe cases splenectomy is recommended to alleviate transfusion requirements. As with HS, splenectomy should be delayed in children, if possible, to at least 4 years of age to reduce the risk of post-splenectomy infection.
Warm-Antibody Autoimmune Hemolytic Anemia
AIHAs are characterized by the destruction of red blood cells, whose erythrocyte life span is diminished by autoantibodies. AIHA is classified as either primary or secondary , depending on whether the underlying cause, such as a disease or toxin, is clearly identified and either warm or cold based on the temperature at which the autoantibodies exert their effect. In cold-agglutinin disease, severe symptoms are uncommon, and splenectomy is almost never indicated. Warm-antibody AIHA has clinical manifestations with which the surgeon should be most familiar. Warm AIHA can affect individuals of all ages and both sexes but most commonly affects women in midlife. Clinical manifestations include mild jaundice, signs and symptoms of anemia, and roughly 30% to 50% of patients will have palpable splenomegaly on physical examination. Although the mainstay treatment of both primary and secondary AIHA remains long-term corticosteroid administration, newer therapies such as anti-CD20 antibody therapy exist and may be of benefit to specific subpopulations of patients. Splenectomy remains third-line therapy after failure of medical management. Notably, some unfortunate patients experience hemolytic episodes, even post-splenectomy.
Hemoglobinopathies
Sickle Cell Disease
Sickle cell disease (SCD) is an autosomal dominant disorder causing chronic hemolytic anemia that results from a mutant sickle cell hemoglobin S (HbS) within the red blood cell. Those who inherit an HbS gene from one parent are heterozygous carriers, and those who inherit HbS genes from both parents are homozygous and have sickle cell anemia. Deoxygenated HbS is insoluble and becomes polymerized and sickled. The lack of deformability of the red blood cell results in microvascular congestion, which may lead to thrombosis, ischemia, and tissue necrosis that manifest clinically as painful intermittent episodes. Abnormal red cell sequestration occurs within the spleen, and splenomegaly can result early in the disease course. In a large percentage of patients, infarction of the spleen and autosplenectomy will occur. The most common indications for splenectomy are recurrent acute sequestration “crises,” hypersplenism, and splenic abscess. Transfusions are often indicated for anemia and for moderate to severe episodes of acute chest syndrome, which include new infiltrate on chest radiograph associated with new symptoms of fever, cough with sputum production, or hypoxia. The occurrence of just one major acute sequestration crisis, which is characterized by rapid painful enlargement of the spleen and circulatory collapse, is generally considered sufficient to strongly consider splenectomy. Although both partial and total splenectomy have been shown as viable options in children, partial splenectomy may not be sufficient to control hematologic abnormalities. Preoperative preparation should include special attention to adequate hydration and avoidance of hypothermia.
Thalassemia
Thalassemias are a group of inherited disorders of hemoglobin synthesis found in all populations, but they appear to be most prevalent among individuals of Mediterranean descent and those from the Arabian Peninsula, Turkey, Iran, India, and southeastern Asia. In these populations the prevalence appears to be 2.5% to 15% of the population. Collectively, thalassemias are the most common genetic diseases that arise from a single gene defect. They are classified according to the hemoglobin chain (alpha, beta, or gamma) affected, with both underproduction of hemoglobin and excessive production of unpaired hemoglobin subunits leading to clinical manifestations. In all forms of thalassemia, the primary defect is reduced or completely absent hemoglobin chains causing reduced function of hemoglobin tetramers (which leads to hypochromia and microcytosis) and unbalanced biosynthesis of the individual alpha or beta subunits, resulting in insoluble red blood cells that cannot release oxygen normally and may increase cell aging. The clinical presentation of thalassemia varies, with heterozygous carriers usually asymptomatic and homozygous individuals usually presenting before 2 years of age with pallor, growth retardation, jaundice, and hepatosplenomegaly. Thalassemia major, a severe form of the disorder, may also present with intractable leg ulcers, head enlargement, frequent infections, and dependence on blood transfusions. Although blood transfusions and parenteral chelation therapy with deferoxamine are mainstays of treatment, splenectomy is indicated for patients requiring excessive transfusions, with splenomegaly or splenic infarction. Notably and unexplainably, thalassemia patients are at risk for pulmonary hypertension following splenectomy, which mandates careful and thorough preoperative discussion. As with other disorders that may require pediatric splenectomy, it should be delayed, if possible, until 4 years of age and consideration for partial splenectomy has also been explored.
PLATELET DISORDERS
Idiopathic Thrombocytopenic Purpura
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet count leading to mucocutaneous and petechial bleeding. It is one of the most common indications for elective splenectomy (and a favorite question on many standardized tests). ITP carries an estimated incidence of 100 persons per 1 million annually, of which 50% are children. Premature removal of circulating platelets opsonized by antiplatelet immunoglobulin G (IgG) autoantibodies produced in the spleen results in the disorder’s characteristic thrombocytopenia. The severity of bleeding frequently, and not unexpectedly, corresponds to the platelet count level. Levels > 50,000 mm 3 usually have mild bleeding, and levels < 10,000 mm 3 put patients at the greatest risk for major internal bleeding. Interestingly, children often present at around the 5 years of age with sudden onset of petechiae or purpura several days or weeks after an infectious illness. In contrast, adults seem to experience a more insidious and chronic form. Notably, splenomegaly is generally regarded as uncommon in ITP for both children and adults. Its presence warrants alternative diagnoses to be explored. The medical workup for ITP and symptomatic thrombocytopenia is quite extensive and should include the exclusion of other common disease processes such as systemic lupus erythematosus (SLE), antiphospholipid syndrome, human immunodeficiency virus (HIV), and hepatitis C (Hep C), to name a few. Although the first-line therapy for ITP is oral prednisone, there still remains no good consensus on the duration of therapy. However, on average most responders, which account for 50% to 75% of patients, will see dramatic improvements within 3 weeks. For severe cases with confirmed or presumed internal bleeding, intravenous immunoglobulin is indicated. Splenectomy is indicated in failure of medical management including prolonged steroid use with undesired effects, relapse after treatment to maintain platelet count levels >30,000 mm 3 , and in rare cases for life-threatening acute bleeding. Splenectomy in children with ITP remains controversial as their clinical courses are usually self-limited, and complete remission is seen in more than 70% of children regardless of medical therapy selected.
Thrombotic Thrombocytopenic Purpura
Thrombotic thrombocytopenic purpura (TTP) is a serious medical condition characterized by thrombocytopenia, microangiopathic hemolytic anemia, and neurologic, renal, or cardiac complications. Its incidence is reported to be approximately 4 individuals per 1 million. Abnormal clotting of platelets occurs in arterioles and capillary beds, predisposing the patient to microvascular thrombotic events. The reduction in lumen size caused by clumping of platelets also leads to deformation of red blood cells, which are then subjected to hemolysis by the spleen. Clinical manifestations of TTP are hallmarked by petechial hemorrhages in the lower extremities, fever, neurologic symptoms (from generalized headaches to altered mental status or seizures), renal failure, and infrequently heart failure or cardiac arrythmia. Patients may also demonstrate flulike symptoms, malaise, or fatigue, making its differential diagnosis often broad. The diagnosis is confirmed by peripheral blood smear, which shows classic schistocytes, nucleated red blood cells, and basophilic stippling. In conjunction with thrombocytopenia and a negative Coombs test, the diagnosis of TTP is however often easy to make. Although plasma exchange is the first-line therapy for TTP, splenectomy should be considered in patients who experience a relapse or who require multiple plasma exchange therapies to control severe symptoms.
MALIGNANT CONDITIONS
White Cell Disorders
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is considered a subtype of NHL highlighted by progressive accumulation of old and nonfunctioning lymphocytes. Although the most common presentation of CLL includes lymphadenopathy, clinical presentations of CLL can be nonspecific and include weakness, fatigue, fever, and night sweats, along with frequent bacterial and viral infections. Splenomegaly may be present, and if massive, splenectomy may be indicated to also help improve cytopenias and facilitate chemotherapy in patients whose cell counts are prohibitively low.
Hairy Cell Leukemia
Hairy cell leukemia (HCL) is an uncommon white cell disorder representing only 2% of all adult leukemias. HCL is characterized by pancytopenia, a large number of abnormal lymphocytes in the bone marrow, and splenomegaly. These lymphocytes contain irregular hairlike cytoplasmic projections, as the name implies. Splenectomy for HCL was historically performed as a palliative procedure (especially in pregnancy), alleviating symptoms of splenomegaly and normalizing peripheral blood counts, but it may not lead to morphologic bone marrow remissions. Asymptomatic patients with HCL require no specific therapy.
Hodgkin’s Lymphoma
Hodgkin’s lymphoma (HL) is a disorder of the lymphoid system characterized by the presence of Reed-Sternberg cells. More than 90% of patients with HL present with lymphadenopathy above the diaphragm. Massive lymphadenopathy within the mediastinum can lead to shortness of breath, cough, and pneumonia. Lymphadenopathy below the diaphragm is uncommon but often suggests advanced disease. Although the spleen is often an occult site, massive splenomegaly with HL is uncommon, and therefore the role of splenectomy may be limited.
Non-Hodgkin’s Lymphoma
Non-Hodgkin’s lymphoma (NHL) encompasses all malignancies derived from the lymphoid system except classic HL. A proliferation of any one of the three predominant lymph cell types (natural killer cells, T cells, or B cells) may be included in the category of NHL. Because of the varied cell types, the clinical subtypes also vary, including but not limited to nodal versus extranodal, indolent versus aggressive, and very aggressive types. Clinical presentations may include mild lymphadenopathy or no symptoms to more aggressive symptoms such as pain, fever, and night sweats. Splenomegaly also exists in some, but not all forms of NHL. Although splenectomy does not alter the natural history of disease in NHL, it is indicated in cases in which a diagnosis cannot be established in peripheral tissue or for the management of an enlarged spleen.
MYELOPROLIFERATIVE DISORDERS
Acute Myeloid Leukemia
Acute myeloid leukemia (AML) involves abnormal growth of stem cells in the bone marrow with a rapid and dramatic presentation. The incidence of AML in the United States is approximately 10,000 new cases each year and accounts for just over 1% of all cancer deaths. Death from AML may be seen within weeks to months if untreated. Presenting symptoms are nonspecific and include viral-like illness with fever, malaise, and bone pain caused by expansion into the medullary space. Standard treatment includes systemic therapy and stem cell transplantation. Because of concerns of post-splenectomy infection in neutropenic patients on chemotherapy, splenectomy may be considered in AML only when massive splenomegaly leads to left upper quadrant abdominal pain and/or early satiety from mass effect.
Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) involves abnormal growth of the primitive pluripotent stem cells in the bone marrow that result in significant increases in erythroid, megakaryotic, and pluripotent progenitors on peripheral blood smear. It has a much more indolent course compared with AML and is hallmarked by transposition between the BCR gene on chromosome 9 and the ABL gene on chromosome 22. CML accounts for roughly 15% of all leukemias, with an incidence in the United States of 1.5 per 100,000. Although often asymptomatic, CML can cause fatigue, anorexia, left upper quadrant pain, and early satiety. Roughly one-half of patients will have splenomegaly, with splenectomy indicated to relieve symptoms associated with mass effect. Notably, splenectomy has no impact on blast crises and does not alter disease progression.
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