34: Spleen Flashcards Preview

Absite > 34: Spleen > Flashcards

Flashcards in 34: Spleen Deck (38):
1

Which organ serves as an antigen-processing center for macrophages?

The spleen

2

What are the following characteristics of Hodgkin's disease?

  • Subtype with best prognosis
  • Subtype with worst prognosis
  • Most common subtype
  • Treatment

  • Subtype with best prognosis: Lymphocyte predominant
  • Subtype with worst prognosis: Lymphocyte depleted
  • Most common subtype: Nodular sclerosing
  • Treatment: Chemotherapy

 

[UpToDate: Hodgkin lymphoma (HL), formerly called Hodgkin's disease, arises from germinal center or post-germinal center B cells. HL has a unique cellular composition, containing a minority of neoplastic cells (Reed-Sternberg cells and their variants) in an inflammatory background. It is separated from the other B cell lymphomas based on its unique clinicopathologic features, and can be divided into two major sub-groups, based on the appearance and immunophenotype of the tumor cells:

Classical HL – The tumor cells in this group are derived from germinal center B cells, but typically fail to express many of the genes and gene products that define normal germinal center B cells. Based on differences in the appearance of the tumor cells and the composition of the reactive background, classical HL is further divided into the following subtypes:

  • Nodular sclerosis classical HL (70%)
  • Mixed cellularity classical HL (20% to 25%)
  • Lymphocyte rich classical HL (5%)
  • Lymphocyte depleted classical HL (< 1%)

Nodular lymphocyte predominant HL – The tumor cells in this subtype retain the immunophenotypic features of germinal center B cells.

Patients with early stage disease (stage I-II) are usually treated with a combination of chemotherapy plus radiation therapy. The amount of chemotherapy and dose of radiation differs for patients with favorable and unfavorable prognosis disease. Chemotherapy alone is an acceptable alternative for patients with favorable disease characteristics at higher risk for complications from radiotherapy.

Combination chemotherapy is the main treatment for patients with advanced stage (stage III-IV) HL. Radiation therapy may be used for select patients as consolidation.

Patients with primary refractory (resistant) disease may attain durable responses and remissions with second line chemotherapy that incorporates drugs not used in initial treatment followed by high dose chemotherapy and autologous hematopoietic cell rescue. Patients with a second relapse or progressive, resistant disease are candidates for high dose chemotherapy and autologous hematopoietic cell transplantation as well.

Patients with early stage (stage I-II) HL have a high likelihood of achieving long-term complete remission.]

3

Post-splenectomy sepsis is most common in patients who have undergone splenectomy for which two indications?

  • Hemolytic disorders
  • Malignancy

 

[UpToDate: Asplenic individuals are at increased risk for overwhelming sepsis, a fulminant and rapidly fatal illness that complicates bacteremic infections due to encapsulated pathogens, which are normally cleared from the circulation by the spleen. The incidence of this syndrome is highest in children who undergo splenectomy in infancy and in splenectomized lymphoma patients who have received combined modality therapy.

Although underlying immunodeficiency and underlying malignancy are associated with an increased risk of postsplenectomy sepsis, asplenic sepsis can occur in otherwise healthy asplenic adults, and the risk of infection persists indefinitely. A report describing two episodes of overwhelming S. pneumoniae sepsis in asplenic mothers within one year of delivery may reflect increased exposure to S. pneumoniae in this population and calls attention to the importance of maintaining appropriate immunizations among women of childbearing age.

Patients who undergo posttraumatic splenectomy are thought to retain variable degrees of splenic function postoperatively and may have a reduced risk of subsequent sepsis. However, experimental studies suggest that regenerated splenic tissue is histologically and functionally abnormal, thus offering limited protection against sepsis. Splenic angioembolization is often utilized in the management of patients with moderate splenic injury to avoid splenectomy. Patients who have undergone this procedure may subsequently demonstrate Howell-Jolly bodies on peripheral blood smears, a sign of splenic hypofunction indicating an increased risk of asplenic sepsis.]

4

Which condition can result in hemolytic anemia in response to infection, certain medications, and fava beans?

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

 

[Splenectomy is not usually required.]

 

[UpToDate: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited disorder caused by a genetic defect in the red blood cell (RBC) enzyme G6PD, which generates NADPH and protects RBCs from oxidative injury. G6PD deficiency is the most common enzymatic disorder of RBCs.

The severity of hemolytic anemia varies among individuals with G6PD deficiency, making diagnosis more challenging in some cases. Identification of G6PD deficiency and patient education regarding safe and unsafe medications and foods is critical to preventing future episodes of hemolysis.

Some individuals with G6PD deficiency have episodes of acute hemolysis in the setting of oxidant injury from medications, acute illnesses, and certain foods. Once patients are diagnosed and are able to reduce oxidant stress exposures through medication avoidance, the frequency of hemolysis may decline dramatically. Episodes of acute hemolysis are more common in individuals with G6PD Mediterranean, which has a half-life measured in hours, than with G6PD A-, which has a half-life measured in days.

The cornerstone of management of G6PD deficiency is the avoidance of oxidative stress to red blood cells (RBCs). This is usually straightforward once the diagnosis is known. However, there may be instances in which an oxidant drug is absolutely required, or cases in which oxidative stress comes from an infection or other acute medical condition that cannot be avoided. In these settings, management depends on the severity of hemolysis and anemia and the patient's age and comorbidities.]

5

What effect does splenectomy have on on the following lab values?

  • RBC
  • WBC
  • Platelets

 

  • RBC: Increased
  • WBC: Increased
  • Platelets: Increased

 

[If platelets > 1,000,000 then give ASA.]

6

Which type of hemoglobin is replaced with HgbS in sickle cell anemia?

HgbA

 

[Spleen usually autoinfarcts so splenectomy is not required.]

 

[UpToDate: Hemoglobin normally is soluble in the erythrocyte and does not polymerize. Hemoglobin is a tetramer of two alpha globins and two beta globins. Hemoglobin S (HbS) is an abnormal hemoglobin that results from a point mutation in the beta globin gene that causes the substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain. The resulting hemoglobin tetramer (alpha2/beta S2) becomes poorly soluble when deoxygenated.

The pathological polymerization of deoxygenated HbS is essential to vasoocclusive phenomena. The polymer assumes the form of an elongated rope-like fiber, which usually aligns with other fibers, resulting in distortion of erythrocytes into the classic crescent or sickle shape and a marked decrease in red cell deformability.]

7

What is the most common congenital hemolytic anemia requiring splenectomy?

Spherocytosis

 

[UpToDate: Hereditary spherocytosis (HS) is the most common hemolytic anemia due to a red cell membrane defect. It is a result of heterogeneous alterations in one of six genes (most often the ankyrin gene) that encode for proteins involved in vertical associations that tie the membrane skeleton to the lipid bilayer.

The clinical features, diagnosis, and treatment of HS will be reviewed here. Red blood cell membrane function is discussed separately.

The incidence of hereditary spherocytosis (HS) is approximately 200 to 300 per million in northern European populations, but this is likely to be an underestimate as mild cases are often not diagnosed. In other parts of the world, the disease is thought to be less common although comprehensive population survey data are unavailable. Family studies indicate autosomal dominant inheritance in approximately 75% of patients, with recessive inheritance occurring in most of the remaining patients. However, a significant number of patients with hematologically normal parents and presumed recessive disease prove to harbor de novo mutations that will exhibit dominant inheritance in subsequent generations.

Decisions regarding splenectomy must take into account the severity of hemolysis, age of the patient, and the various associated risks. We are more likely to advise splenectomy for individuals with more severe hemolysis and/or greater symptoms, and we typically defer splenectomy in children until at least six years of age due to the risk of sepsis.]

8

Where does hematopoiesis occur prior to birth?

The spleen

 

[Hematopoiesis also occurs in the spleen in conditions such as myeloid dysplasia.]

 

[UpToDate: The relative red (active) marrow space of a child is much greater than that of an adult, presumably because the high requirements for red blood cell production during neonatal life. While vertebrae and pelvic bones remain active sites of hematopoiesis through life, during postnatal life red blood cell demand and therefore production is reduced, and much of the marrow space is slowly and progressively filled with fat, in particular, the marrow in the facial bones as well as the diaphyses of long bones such as the radius, ulna, femur, and fibula. Hematopoiesis becomes restricted to the skull, vertebrae, pelvis, and metaphyseal areas of long bones in adults. In certain disease states that are usually associated with anemia (eg, primary myelofibrosis, infiltrative diseases of the bone marrow such as granulomas or metastatic cancer, or diseases characterized by ineffective erythropoiesis such as thalassemia major), hematopoiesis may return to its former sites in the liver, spleen, and lymph nodes and may also be found in the adrenal glands, cartilage, adipose tissue, thoracic paravertebral gutters, and even in the kidneys.]

9

What are the staging criteria for Hodgkin's lymphoma?

  • Stage I
  • Stage II
  • Stage III
  • Stage IV

  • Stage I: 1 area or 2 contiguous areas on the same side of diaphragm
  • Stage II: 2 non-contiguous areas on the same side of the diaphragm
  • Stage III: Involved on each side of diaphragm
  • Stage IV: Liver, bone, lung, or any other non-lymphoid tissue except spleen

 

[UpToDate: The Ann Arbor staging system with Cotswolds modifications is the current staging system used for patients with HL. While further revisions have been proposed at a meeting in Lugano (ie, the Lugano classification), the proposed revisions are controversial and not widely accepted. Patients are staged using information from a clinical examination and imaging studies. They are placed into one of four stages, based upon the sites of involvement, and are assigned numbers and letters that designate the number of lymph node regions involved and the presence or absence of systemic symptoms or of bulky or extended disease. For these purposes, the tonsils, Waldeyer's ring, and spleen are considered nodal tissue.

  • Stage I – Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE) without nodal involvement. A single lymph node region can include one node or a group of adjacent nodes.
  • Stage II – Involvement of two or more lymph node regions on the same side of the diaphragm alone (II) or with involvement of limited, contiguous extralymphatic organ or tissue (IIE).
  • Stage III – Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm.
  • Stage IV – Additional noncontiguous extralymphatic involvement, with or without associated lymphatic involvement.

All cases are subclassified to indicate the absence (A) or presence (B) of one or more of the following three systemic symptoms: unexplained fevers to more than 101°F (38.3°C), drenching night sweats, or unexplained weight loss exceeding 10% of body weight during the six months prior to diagnosis. Fatigue, pruritus, and alcohol-induced pain are not considered B symptoms but should be noted.

The subscript "X" is used if bulky disease is present and the size of the bulky disease should be noted. No subscripts are used in the absence of bulk. Criteria for bulky disease used for treatment purposes are discussed in more detail below.

The subscript "E" is used if limited extranodal extension is documented. More extensive extranodal disease is designated stage IV.

Patients with stage III or stage IV disease are considered to have advanced stage disease. Patients with stage I or stage II disease are considered to have early (limited) stage disease and are then further stratified for treatment purposes into favorable and unfavorable prognosis disease based upon the presence or absence of certain clinical features, such as age, B symptoms, and large mediastinal adenopathy.]

10

Which is more commonly an indication for splenectomy: Idiopathic thrombocytopenic purpura (ITP) or Thrombotic thrombocytopenic purpura (TTP)?

Idiopathic thrombocytopenic purpura (ITP)

 

[ITP is the most common nontraumatic condition requiring splenectomy. Give platelets 1 hour before surgery.]

11

In which condition are Reed-Sternberg cells seen?

Hodgkin's disease

12

Where is the splenic vein in relation to the splenic artery?

Posterior and inferior to the splenic artery

13

What is the most common cause of chylous ascites?

Lymphoma

14

What are the following characteristics of thrombotic thrombocytopenic purpura (TTP)?

  • Cause
  • Pathophysiology
  • Signs/symptoms
  • Treatment

  • Cause: Medications, infection, inflammation, autoimmune disease
  • Pathophysiology: Loss of platelet inhibition leading to thrombosis and infarction (profound thrombocytopenia)
  • Signs/symptoms: Purpura, fever, mental status changes, renal dysfunction, hematuria, hemolytic anemia
  • Treatment: Plasmapheresis (primary), immunosuppression; 80% respond to medical therapy

 

[Splenectomy is rarely indicated.]

 

[UpToDate: 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.

Thrombotic thrombocytopenic purpura (TTP) is a medical emergency that is almost always fatal if appropriate treatment is not initiated promptly. For patients with a presumptive diagnosis of TTP (eg, thrombocytopenia and microangiopathic hemolytic anemia [MAHA] without an obvious underlying cause), we recommend prompt initiation of plasma exchange (PEX) therapy rather than plasma infusion and/or immunosuppressive therapy alone (Grade 1B). Therapy should not be delayed while awaiting the results of ADAMTS13 activity levels. Early involvement of the consulting specialist is advised to assist in decision making, testing, and facilitating urgent initiation of PEX.

PEX is performed daily. The choice of replacement plasma (eg, Fresh Frozen Plasma [FFP], Solvent/Detergent [S/D] Plasma) is determined by the physicians overseeing the procedure. PEX therapy almost always requires a central venous catheter with a large bore and two lumens.

Plasma infusion is not an adequate substitute for PEX in the initial treatment of TTP, and plasma infusion should not delay initiation of PEX. However, we use plasma infusion as a temporizing measure if an unavoidable delay in PEX is expected.

For all patients with a presumptive diagnosis of acquired TTP, we suggest administration of a glucocorticoid (Grade 2C). A typical regimen is prednisone, 1 mg/kg per day orally or intravenous methylprednisolone 125 mg two to four times daily intravenously. For most patients, we suggest not administering rituximab for the initial treatment of acquired TTP (Grade 2C). However, for patients with severe disease (eg, major neurologic complications) we suggest adding rituximab unless the patient has a prompt response to PEX and glucocorticoids (Grade 2C).]

15

What are the following characteristics of the spleen?

  • #1 overall splenic tumor
  • #1 malignant splenic tumor

  • #1 overall splenic tumor: Hemangioma
  • #1 malignant splenic tumor: Non-Hodgkin's lymphoma

 

[Treatment for symptomatic hemangioma is splenectomy.]

16

In which age group does idiopathic thrombocytopenic purpura (ITP) usually resolve spontaneously?

In children < 10 years of age

 

[Avoid splenectomy in children.]

17

Which condition is characterized by rheumatoid arthritis, hepatomegaly, and splenomegaly, and what is the treatment?

 

[According to UpToDate the triad is severe subset of seropositive rheumatoid arthritis (RA) complicated by neutropenia and splenomegaly.]

  • Felty's syndrome
  • Treatment is splenectomy for symptomatic splenomegaly

 

[UpToDate: The cause of Felty’s syndrome (FS), which occurs within a subset of patients with rheumatoid arthritis (RA), is unknown. Its presence primarily in patients with longstanding active disease who test positive for rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA), and for human leukocyte antigen (HLA)-DR4, suggests important roles for chronic inflammation in a genetically predisposed individual.

Neutropenia in patients with FS results from an imbalance between granulocyte production and granulocyte removal from the circulating pool. One or more of the following can contribute to the development of neutropenia:

  • Autoantibodies to deiminated histones (predominantly histone H3) and other components of neutrophil extracellular chromatin traps (NETs) that bind to activated neutrophils, which are then sequestered in the spleen and depleted.
  • Autoantibodies that bind and neutralize granulocyte colony-stimulating factor (G-CSF).
  • Cytotoxic lymphocytes, which infiltrate the bone marrow and inhibit myelopoiesis. Bone marrow abnormalities most commonly include a maturation arrest of the granulocyte cell line. Overall bone marrow cellularity either is normal or reveals myeloid hyperplasia.
  • Increased white blood cell margination.

Major features — Felty described a syndrome characterized by the triad of rheumatoid arthritis (RA), neutropenia, and splenomegaly, with the following features:

  • Rheumatoid arthritis – The arthritis is typically severe, erosive, and seropositive for rheumatoid factor (RF) and/or anti-citrullinated peptide antibodies (ACPA).
  • Neutropenia – Neutropenia is present in all patients, with absolute neutrophil counts below 2000/microL.
  • Splenomegaly – Splenomegaly is present in most patients, although infrequently splenomegaly is undetectable in RA despite marked neutropenia; spleen size does not correlate with the degree of neutropenia or clinical course.

Splenectomy is generally indicated in the patient with Felty’s syndrome (FS) with recurrent or severe infections despite nonpharmacologic efforts to reduce risk of infection and use of medical therapies, including the nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs) used for patients with FS and granulocyte colony-stimulating factor (G-CSF). Patients with recurrent or severe infections usually have severe granulocytopenia (<1000 cells/microL).

Prophylactic splenectomy is not justified in patients who do not become infected, even in the presence of marked granulocytopenia. The decision to perform splenectomy may also be influenced by the frequency and severity of infections, the degree and nature of comorbid conditions, and the patient’s overall medical status.]

18

What is the most common cause of splenic artery or splenic vein thrombosis?

Pancreatitis

19

What age should one try to allow a child to reach prior to performing a splenectomy?

Age 5 years

 

[This allows for antibody formation; the child can get fully immunized. Children have an increased risk of post-splenectomy sepsis and death from post-splenectomy sepsis. Some say that children < 10 years of age should be given prophylactic antibiotics for 6 months (this is controversial).]

20

Vaccinations for which organisms should be given to a patient prior to splenectomy?

  • Pneumococcus
  • Meningococcus
  • H. Influenzae

21

What are the following characteristics of spherocytosis?

  • Pathophysiology
  • Signs/symptoms
  • Treatment

  • Pathophysiology: Spectrin (membrane protein) deficit that deforms RBCs and leads to splenic sequestration (hypersplenism)
  • Signs/symptoms: Hemolytic anemia, pigmented stones, anemia, reticulocytosis, jaundice, splenomegaly
  • Treatment: Splenectomy and cholecystectomy (Try to delay splenectomy until after age 5 years. Give immunizations prior to splenectomy)

 

[Elliptocytosis is a separate condition with similar symptoms and a similar mechanism (Spectrin and protein 4.1 deficits).]

 

[UpToDate: Hereditary spherocytosis (HS) is a result of heterogeneous alterations in genes that encode for proteins involved in the vertical associations that tie the red cell's inner membrane skeleton to its outer lipid bilayer. The resistance and elastic deformability of red cells are due to a cytoskeleton that underlies the lipid bilayer and to proteins that provide vertical association of the cytoskeleton with the bilayer. A number of interconnected proteins are involved in the coupling of the cytoskeleton to the lipid bilayer.

  • Spectrin (composed of alpha, beta heterodimers)
  • Ankyrin
  • Band 4.2 (previously called pallidin)
  • Band 4.1 (protein 4.1)
  • Band 3 protein (the anion exchanger, AE1)
  • RhAG (the Rh-associated glycoprotein)

Spectrin deficiency is often present in HS. This is true even if the primary mutation is in a nonspectrin protein, because alterations in these proteins adversely affect the assembly of spectrin onto the membrane skeleton. The clinical severity of the disorder correlates well with the degree of spectrin deficiency. Spherocyte formation and subsequent hemolysis is due to red cell membrane instability and conditioning by the spleen. Often more than one red cell membrane protein is deficient in HS. As shown in HS mouse models, aberrant protein sorting during erythroid enucleation, a consequence of the primary red blood cell (RBC) membrane defect, appears to be an important explanation for these secondary deficiencies. For example, in ankyrin deficient mice, band 3, RhAG, and GPA all show increased sorting to the extruded nucleus, thus explaining their deficiency in reticulocytes and mature RBC.]

22

What percent of the spleen is composed of white pulp and what is its function?

  • 15%
  • Immunologic function; contains lymphocytes and macrophages

 

[The white pulp is the major site of bacterial clearance that lacks preexisting antibodies. It is the site of removal of poorly opsonized bacteria, particles, and cellular debris. It is the site of antigen processing with interaction between macrophages and helper T cells.]

23

When is post-splenectomy sepsis most likely to occur?

Within the first 2 years of splenectomy

 

[UpToDate: Asplenic individuals are at increased risk for overwhelming sepsis, a fulminant and rapidly fatal illness that complicates bacteremic infections due to encapsulated pathogens, which are normally cleared from the circulation by the spleen. The incidence of this syndrome is highest in children who undergo splenectomy in infancy and in splenectomized lymphoma patients who have received combined modality therapy.

The highest risk of sepsis occurs during the first few years following splenectomy but has been documented as late as 20 years after splenectomy. In a population-based cohort study, the risk of infection requiring hospital contact was highest during the 90 days following splenectomy, occurring in 10% of individuals who had undergone splenectomy compared with 0.6% in the general population (adjusted odds ratio 18.1, 95% CI 14.8 to 22.1). In comparison, hazard of infection was 4.6-fold higher from 91 to 365 days following splenectomy and 2.5-fold higher >365 days following splenectomy compared with the general population. The fraction of bacteremic episodes due to pneumococci in splenectomized patients, most of whom were adults with a high burden of comorbid conditions, was surprisingly low (<5%); the frequency of fulminant sepsis complicating bacteremia due to nonencapsulated pathogens was not reported.

Similar risks of postsplenectomy infection were noted in a review of 288 patients who had undergone splenectomy: one-third of first infections occurred within the first year of surgery and just over half within two years. One-third of all pneumococcal infections occurred at least five years after splenectomy. Among survivors of an initial episode of severe sepsis in another series, the risk of subsequent severe infection was increased more than sixfold, and the risk of a third episode among survivors of two severe infections was further increased more than twofold.]

24

What is the risk of post-splenectomy sepsis and what is the the cause?

  • 0.1% risk after splenectomy (risk increased in children)
  • Strep pneumoniae (#1), H. influenzae, N. Meningitidis

 

[It occurs secondary to lack of immunity (immunoglobulin, IgM) to encapsulated bacteria. The spleen is the largest producer of IgM.]

 

[UpToDate: Asplenic individuals are at increased risk for overwhelming sepsis, a fulminant and rapidly fatal illness that complicates bacteremic infections due to encapsulated pathogens, which are normally cleared from the circulation by the spleen. The incidence of this syndrome is highest in children who undergo splenectomy in infancy and in splenectomized lymphoma patients who have received combined modality therapy.

Although underlying immunodeficiency and underlying malignancy are associated with an increased risk of postsplenectomy sepsis, asplenic sepsis can occur in otherwise healthy asplenic adults, and the risk of infection persists indefinitely. A report describing two episodes of overwhelming S. pneumoniae sepsis in asplenic mothers within one year of delivery may reflect increased exposure to S. pneumoniae in this population and calls attention to the importance of maintaining appropriate immunizations among women of childbearing age.

The highest risk of sepsis occurs during the first few years following splenectomy but has been documented as late as 20 years after splenectomy. In a population-based cohort study, the risk of infection requiring hospital contact was highest during the 90 days following splenectomy, occurring in 10% of individuals who had undergone splenectomy compared with 0.6% in the general population (adjusted odds ratio 18.1, 95% CI 14.8 to 22.1). In comparison, hazard of infection was 4.6-fold higher from 91 to 365 days following splenectomy and 2.5-fold higher >365 days following splenectomy compared with the general population. The fraction of bacteremic episodes due to pneumococci in splenectomized patients, most of whom were adults with a high burden of comorbid conditions, was surprisingly low (<5%); the frequency of fulminant sepsis complicating bacteremia due to nonencapsulated pathogens was not reported.]

25

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

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.]

26

In which 6 conditions can spontaneous splenic rupture occur?

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

27

What percent of the spleen is composed of red pulp and what is its function?

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

28

What is the most common location of an accessory spleen?

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

29

What are the two most common causes of death in thombotic thrombocytopenic purpura (TTP)?

  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.]

30

In which of the following conditions is splenectomy usually required?

  • Pyruvate kinase deficiency
  • Glucose-6-phosphate dehydrogenase deficiency (G6PD)
  • Warm antibody-type acquired immune hemolytic anemia
  • Sickle cell anemia
  • Beta thalassemia

  • 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)

31

Which organ is the largest producer of IgM?

The spleen

32

What is the most common congenital hemolytic anemia requiring splenectomy that does not involve a membrane protein?

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.]

33

What is the most common form of autoimmune hemolytic anemia (AIHA)?

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.]

34

What are the 3 criteria for a diagnosis of hypersplenism?

  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.]

35

What are the following characteristics of Idiopathic thrombocytopenic purpura (ITP)?

  • Cause
  • Pathophysiology
  • Signs/symptoms
  • Treatment

  • 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 glucocorticoids, 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.]

36

What is the treatment for beta thalassemia?

  • 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).]

37

What is the function of the following products made in the spleen?

  • Tuftsin
  • Properdin

  • 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.]

38

What is the recommendation on timing of splenectomy vaccines?

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