THE KURSK STATE MEDICAL UNIVERSITY
DEPARTMENT OF SURGICAL DISEASES № 1
SURGICAL DISEASES OF THE SPLEEN
Information for self-training of English-speaking students
The chair of surgical diseases N 1 (Chair-head - prof. S.V.Ivanov)
BY ASS. PROFESSOR I.S. IVANOV
KURSK-2010
THE SPLEEN
ANATOMY
Embryonic development of the spleen begins in the fifth week of gestation as a
small cluster of mesenchymal cells in the dorsal mesogastrium between the
stomach and pancreas. Mesenchymal remnants that do not fuse with the main
splenic mass account for the high incidence (15%–30%) of accessory spleens in
adjacent tissues.
The spleen is the second largest organ of the reticuloendothelial system. It is
located in the posterior left upper quadrant of the abdomen where its relationships
to the diaphragm, stomach, pancreas, left kidney, and splenic flexure of the colon
are maintained by suspensory ligaments. The splenophrenic, splenorenal, and
splenocolic ligaments are usually relatively avascular, except in patients with
portal hypertension, and their transection allows the spleen to be displaced
medially and anteriorly. The gastrosplenic ligament, which extends from the
greater curvature of the body and fundus of the stomach to the spleen, contains the
short gastric arteries and veins. Located in the most medial aspect of the
splenorenal ligament and attached to the spleen at the hilum, the splenic pedicle
contains the splenic artery and vein, lymphatic structures, and often the tail of the
pancreas .
The arterial supply to the spleen is derived from the celiac artery from both the
splenic artery and the short gastric arteries, which usually arise as branches of the
gastroepiploic or the splenic arteries . The splenic vein is formed by a coalescence
of polar veins in the splenic hilum and courses with the splenic artery along the
dorsal surface of the pancreas to enter the portal system.
The normal adult spleen is a slightly concave, solid, dark red organ that measures
approximately 3 × 8 × 14 cm., weighs between 100 and 175 gm., and frequently
has fetal lobulations on its anterior edge. A thin peritoneal capsule encloses the
deeper organ pulp and easily strips from it. In elderly individuals or in those with
prior splenic injury, irradiation, or recurrent infarction, the splenic capsule may
become firm and thickly scarred (“sugar coated”) and adherent to the diaphragm.
A trabecular connective tissue framework extends into the splenic pulp from the
internal capsular surface to subdivide the organ into small communicating
compartments. After entering the spleen at the hilum, arterial vessels branch into
the trabeculae to enter the pulp. Veins and lymphatics draining the pulp also pass
in the trabeculae to leave the spleen at the hilum. The splenic pulp is
conventionally divided into three areas: red pulp, white pulp, and an interfacing
marginal zone. The red pulp, so designated due to its gross appearance from the
presence of blood, is composed almost entirely of large, branching, thin-walled
blood vessels, called splenic sinuses or sinusoids, and thin plates or cords of
cellular tissue lying between the sinuses to form splenic cords. Within this cordal
meshwork, erythrocytes, platelets, and some granulocytes are crowded with
macrophages and plasma cells, with macrophages often being the predominant
cells. Lying within and surrounded by the red pulp are small gray-white zones of
lymphatic tissue consisting of lymphocytes, plasma cells, and macrophages, which
constitute the white pulp. The white pulp forms periarterial lymphatic sheaths and
lymphatic nodules, which, like those of lymph nodes, may contain germinal
centers. The marginal zone constitutes the interface between the red and white pulp
and is an ill-defined vascular space where many arterial vessels terminate.
Controversy has surrounded the exact nature of the splenic microcirculation for
300 years. Billroth is credited with the open circulation theory, in which either
arterioles empty blood directly into tissue spaces or arterial capillaries open into
pulp cords, with blood cells then passing through pores in the walls of splenic
sinusoids to enter the venous circulation. In the closed circulation theory, splenic
blood follows an endothelialized pathway throughout to flow directly into
sinusoids. Studies in rabbits using plastic microspheres too large to pass through
pores of the venous sinuses confirm the unique open splenic microcirculation.
Ninety percent of splenic arterial flow enters the open circulation of the red pulp,
with only 10% of the blood in arterial capillaries emptying directly into venous
sinuses. Blood cells and particles such as particulate antigens must circulate
through the meshwork of splenic cords before squeezing through 0.5 to 2.5 mm.
pores between endothelial cells of the sinuses to enter the venous circulation.
FUNCTION
During early fetal development, the spleen produces red and white blood cells. By
the fifth month of gestation, the spleen and other extramedullary sites of blood cell
production no longer have hematopoietic function but retain the capability
throughout life. As a result of a singular microcirculation, the spleen is a
sophisticated filter having both blood cell monitoring and management functions
and important immune functions. When the spleen is removed, these functions are
lost.
Normal red cells usually traverse the splenic circulation but may undergo repair by
having surface abnormalities such as pits or spurs removed. Reticulocytes pass
through the spleen more slowly than mature red cells and lose nuclear remnants
and excess membrane before entering the circulation as mature cells. In reducing
the membrane surface area, the spleen converts the red cell from a target
appearance to a biconcave disc. The spleen also removes high-molecular-weight
surface protein, Howell-Jolly bodies (nuclear remnant), Heinz bodies (denatured
hemoglobin), Pappenheimer bodies (iron granules), and spur cells. These cleaned
red cells, if they have the deformability to pass through the splenic circulation, reenter the bloodstream. Aged red cells (120 days) that have lost enzymatic activity
and membrane plasticity are trapped and destroyed in the spleen
The normal filtering function of the spleen also enables it to remove abnormal
blood cells. Morphologically abnormal erythrocytes, such as the spherocytes of
hereditary spherocytosis, fixed sickled cells, and rigid hemoglobin C cells, are
trapped by the splenic filter. Blood cells coated with IgG are destroyed by the
splenic monocytes, which have surface receptors for the Fc fragment of the IgG
coating the cells. Because the spleen removes cells coated with IgG or IgM, it is
the site of destruction in diseases such as autoimmune hemolytic anemia (AIHA),
immune thrombocytopenic purpura, and probably Felty's syndrome. Parasites with
intraerythrocytic habitation, such as malaria, can be pitted from the red cell by the
spleen. 8 Red cells that are unable to deform to pass into the splenic sinuses are
eventually destroyed by the histiocytes/macrophages of the red pulp.
In addition to blood cell morphology and surface characteristics, rate of blood flow
through the splenic microcirculation and alterations of splenic pulp pressure affect
the filtering function of the spleen. For example, patients with splenic vein
thrombosis have slow red cell passage through the splenic microcirculation due to
elevated portal-splenic pulp pressure, with resultant increased red cell
sequestration and destruction.
The spleen is involved in specific and nonspecific immune responses. Properdin
and tuftsin, which are synthesized in the spleen, are opsonins. Tuftsin binds to
granulocytes to promote phagocytosis, while properdin can initiate the alternative
pathway of complement activation to produce destruction of bacteria as well as
foreign and abnormal cells. Because these opsonic proteins are also produced in
other organs, the loss of the splenic contribution to their synthesis is probably
small. However, serum levels of both tuftsin and properdin are below normal after
splenectomy and in some diseases associated with hyposplenism.
The macrophages and histiocytes of the spleen remove bacteria and abnormal or
foreign cells and are especially effective in removing bacteria coated with antibody
or opsonic proteins. If bacteria for which the host lacks pre-existing antibody are
present in the bloodstream, the spleen's unique circulation makes it the major site
for clearance of these bacteria as well as the initial site for synthesis of IgM. When
radioactively labeled bacteria are administered to animals, the liver clears most of
the well-opsonized microorganisms while the spleen removes those that are poorly
opsonized. When specific antibody is lacking to facilitate bacterial removal by the
liver, the spleen becomes the primary site for clearance. Encapsulated bacteria,
which resist antibody binding, are less effectively removed in an asplenic
individual than in a normal host. 8
The role of the spleen in removing malignant tumor cells is probably
underestimated. Although large metastases to the spleen are uncommon,
micrometastases occur frequently, with one study reporting 50% of spleens from
patients with solid tumors containing neoplastic cells. Experimental evidence
suggests that intense destruction of malignant cells in the spleen limits the
incidence of clinically apparent metastases.
A third important immune function of the spleen is the production of specific
antibody, especially IgM. Particulate antigens, such as Salmonella flagella, lodge
in the splenic red pulp and are transported by macrophages into the germinal
centers where the IgM response is thought to occur. In asplenic individuals, IgM
levels fall and the antibody response to a blood-borne antigen diminishes. Because
of the anatomy of the splenic microcirculation, humoral and cellular antigens
remain in contact with macrophages and lymphocytes for longer periods than in
other areas of the reticuloendothelial system. The importance of an adequate time
period for interaction of these cells after antigen exposure is becoming apparent as
lymphocyte and macrophage subpopulations responsible for humoral and cellular
immunity are identified.
INDICATIONS FOR SPLENECTOMY
Two large series of studies illustrate the changing indications for splenectomy that
have accompanied improved diagnosis and therapy of hematologic diseases. In
one report of a 30-year experience, splenectomy was performed for primary and
secondary hypersplenism (41%), incidental to other operations (30%), for trauma
(10.5%), for diagnosis (9%), for Hodgkin's staging (8%), and for non-Hodgkin's
lymphoma (NHL) (1.5%). The more recent 5-year experience, at the University of
North Carolina, Chapel Hill, showed the indications for splenectomy in 473 cases
to be Hodgkin's staging (27%), incidental to other operations (20%),
hypersplenism (16%), trauma (14%), NHL (7%), and diagnosis (7%).
In a comparison between two series of splenectomies performed for hematologic
disorders between 1946 and 1962 and 1963 and 1982, 400 splenectomies (20 per
year) were performed between 1963 and 1982, compared with 94 (5.5 per year)
during the earlier interval. 50 A sharp decline occurred in the number of
splenectomies performed each year between 1974 and 1982. The evolution of the
staging laparotomy for lymphomas, particularly Hodgkin's disease, with the
decline in the average annual incidence of staging laparotomies since 1974 was the
major factor responsible. Contributing to the differences was an increase in the
total number of splenectomies for hereditary spherocytosis, idiopathic
hypersplenism, and myeloproliferative disorders. The average number of
splenectomies for immune thrombocytopenic purpura increased significantly
between the two time periods. Hairy cell leukemia (HCL) and Felty's syndrome
emerged as indications for splenectomy during the second time period. Of the 400
splenectomies performed for hematologic disorders between 1963 and 1982, the
indications were therapeutic splenectomy (57%), Hodgkin's staging (40%), and
diagnosis (3%).
An improved understanding of immune anemia, thrombocytopenia, and
neutrocytopenia has clarified the role of splenectomy in many hematologic
diseases. Some diseases, such as immune thrombocytopenic purpura, appear to be
increasing in incidence. Splenectomy as a means of staging Hodgkin's disease is no
longer such an important diagnostic test in the overall approach to that disease,
which now can be controlled in most patients using radiation therapy and
chemotherapy. Splenectomy for splenomegaly associated with selected leukemias
and NHLs is less commonly indicated because chemotherapy and radiation therapy
have become more effective. Hypersplenism, both primary and secondary, is now
diagnosed less commonly because of better definition and classification of diseases
that previously were labeled as hypersplenic syndromes. The most frequent
indications for splenectomy are now traumatic injury, immune thrombocytopenic
purpura, and hypersplenism.
In another report of splenectomy for hematologic disease, 81% of the patients
underwent splenectomy to control anemia, thrombocytopenia, neutropenia, or
discomfort from splenomegaly. 36 In 19%, splenectomy was performed for
diagnostic purposes, most commonly Hodgkin's disease staging. The morbidity
rate of 25% accurately reflects the frequency of complications that are related
primarily to bleeding and infection. Sepsis is the usual cause of death after
splenectomy for hematologic disease, and the mortality rate ranges from 5% to
27%
Splenic Trauma
The spleen is the most common intra-abdominal organ injured in blunt trauma and
is frequently injured in penetrating abdominal injury. Selected older reports reveal
mortality rates for splenic injury as high as 20%. Although some recent series
report no deaths from splenic trauma, others still show a mortality rate approaching
10% because of the frequent association of other major organ injuries.
Diagnosis. Injury to the spleen should be suspected in blunt upper abdominal
injuries, which commonly occur in motor vehicle or bicycle accidents. Splenic
injuries are often associated with fractured ribs of the left chest. The diagnosis and
clinical course of an isolated splenic injury is variable. The spleen receives
approximately 5% of the cardiac output, and a large laceration through the body of
the spleen can extend into the splenic pedicle, causing extensive and continued
hemorrhage, abdominal distention with hemoperitoneum, and shock. More
commonly, a laceration deep into the pulp occurs or an adhesion between the
spleen and its ligaments or diaphragm causes capsular avulsion with cessation of
hemorrhage after an initial blood loss of 500 to 750 ml. If the injury does not
involve the major splenic vasculature and is limited to the pulp or capsule, the
patient may remain hemodynamically stable. However, subcapsular hematomas
can form, which have the potential to rupture at a time remote from the injury,
accounting for the phenomenon of delayed rupture of the spleen. Alternatively,
some subcapsular hematomas evolve into splenic cysts while others resolve with
fibrosis and scarring . Unfortunately, in the acute setting of evaluating the stable
patient with splenic injury, it is difficult to identify which splenic injuries will
resolve without operative management.
If a splenic injury is suspected, admission to the hospital for monitoring is
mandatory. Although many useful measures are available to aid in the diagnosis of
splenic injury, their application requires a high index of clinical suspicion. A
careful history should be obtained to include delineation of pain and a mechanism
of injury consistent with splenic trauma. Usually injury to the left upper abdomen
associated with fractured ribs of the left anterior chest alerts the clinician to
proceed with evaluation by specific diagnostic tests. If the patient is in shock with
hemoperitoneum, the diagnosis of splenic injury is established at laparotomy.
The signs and symptoms of splenic trauma are those of hemoperitoneum.
Generalized and nonspecific abdominal pain in the left upper quadrant occurs in
approximately one third of patients with splenic injury. Pain referred to the tip of
the left shoulder (Kehr's sign) is inconstant, varying in incidence from 15% to
75%, and is unreliable for excluding splenic injury but is useful for enhancing the
diagnostic probability if present. Kehr's sign is elicited by bimanual compression
of the left upper quadrant after the patient has been in Trendelenburg's position for
several minutes preceding the maneuver. On rare occasions, patients with splenic
injury have a palpable tender mass in the left upper quadrant (Ballance's sign),
caused by an extracapsular or subcapsular hematoma with omentum adherent to
the injured spleen.
Patients with splenic trauma usually have hemoglobin/hematocrit values that are
10% to 30% below normal and a moderate leukocytosis. Diagnostic peritoneal
lavage is a useful and inexpensive maneuver, which may reveal gross blood or an
elevated red blood cell count diagnostic of intraperitoneal hemorrhage. When
intraperitoneal hemorrhage is diagnosed by peritoneal lavage, laparotomy is
performed to diagnose and treat all bleeding viscera, including the spleen.
A variety of imaging techniques are useful in the diagnosis of splenic injury.
Standard abdominal or contrast radiography may reveal depression of the splenic
flexure of the colon and medial displacement of the stomach in patients with an
injured spleen but are less reliable in establishing the diagnosis of splenic trauma
than isotope or scanning techniques. Splenic angiography can demonstrate a
variety of splenic injuries but is used infrequently because of the equal or greater
accuracy of diagnostic peritoneal lavage and less invasive imaging techniques.
Ultrasonography of the spleen can provide evidence of free blood and hematoma
surrounding the splenic capsule with reasonable accuracy. Isotope scans ( 99mTc
sulfur colloid) are popular in many centers for the acute diagnosis of splenic injury
with a diagnostic accuracy rate exceeding 90%. However, computed tomography
(CT) is probably the most accurate method available for diagnosing splenic injury .
Reports of imaging techniques reveal a high sensitivity and specificity (>90%) for
the diagnosis of splenic injury; however, considerable variation exists in the skill
and enthusiasm of different radiologic units performing the tests for suspected
splenic injury. Although CT and isotope imaging techniques are accurate methods
for establishing the diagnosis of an injured spleen, the accuracy in individual
instances is in large part dependent on the skill of the radiologist.
Changing Concepts in the Treatment of Ruptured Spleen. In recent years the
spleen's important role in cellular and humoral immunity has been clarified and the
danger of overwhelming bacterial infection in asplenic patients has been
established. Consequently, operative techniques for splenic preservation have been
developed, and a concept for nonoperative management of selected splenic injuries
is evolving. Although periodic reports of repairing injured spleens by use of suture
or cauterization have been available for many years, interest in partial splenectomy
has been rekindled since 1960. In animal and human studies, it has been shown
that segmental resection of the spleen is practical and safe. In addition to partial
splenectomy, splenorrhaphy, ligation of segmental vessels, and capsular repair are
useful techniques for splenic salvage. Splenic salvage operations have been greatly
aided by the development and use of topical hemostatic agents such as
microfibrillar collagen (Avitene) and a variety of absorbable envelopes to aid in
hemostasis from splenic injuries. 28 Although technically more difficult than
splenectomy, splenic repair can be performed with comparable transfusion
requirements, reoperation rates, and morbidity.
Conservatism in the management of splenic injury has extended beyond repairing
and preserving an injured spleen when possible. Because bleeding from splenic
trauma appears to be more self-limited in children than in adults, nonoperative
therapy may prove to be safe in selected pediatric patients. Nonoperative therapy
requires a stable patient who is found by diagnostic tests to have an isolated splenic
injury. At The Hospital for Sick Children (Toronto), where nonoperative
management of splenic injury has been pioneered, 75 children with splenic injury
were treated between 1981 and 1986. Ten (13%) required splenectomy or
splenorrhaphy, but the remaining 65 patients (87%) were successfully managed
nonoperatively. Of those patients treated nonoperatively, only 23% required blood
transfusions. In comparison to an earlier report, current guidelines for management
have resulted in an increased number of patients managed nonoperatively, a
reduction in the number of patients receiving blood transfusions, and a decrease in
the length of both hospital stay and time spent in the intensive care unit.
In one large series of injuries associated with splenic trauma an appropriate note of
caution was suggested before nonoperative management of splenic trauma is
adopted. 47 In 258 patients with splenic injury, concomitant injuries requiring
operative therapy were present in 36.5% of those with blunt trauma and 94% of
patients with penetrating injury. Children younger than the age of 16 had an
incidence of intra-abdominal injuries in addition to the spleen of 32.6% for blunt
trauma and 100% for penetrating trauma.
One pitfall of nonoperative management of splenic trauma lies in the significant
possibility of failing to diagnose and treat concomitant intra-abdominal injuries.
An additional concern is that most reported series of nonoperative management of
splenic injuries include patients with blood transfusion requirements substantial
enough to expect an incidence of transfusion-related hepatitis greater than the
statistical probability of postsplenectomy sepsis. In addition, hospital time is
usually longer for nonoperative management (13–16 days) compared with
operative management (7 days) with a longer period for convalescence.
The recommended management in adults with hemoperitoneum and demonstrated
splenic injury is laparotomy with the expectation that 30% to 50% of spleens may
be salvaged with sufficient (>50%) splenic pulp retained to preserve immune
function. In both children and adults with splenic injury secondary to penetrating
wounds, laparotomy should be performed because of the risk of significant injury
to other intra-abdominal organs. All patients in shock or with significant
transfusion requirement should have exploratory laparotomy for control of
hemorrhage from the spleen and management of any other injured structures.
Nonoperative treatment of splenic trauma in children is prudent only for the stable
patient who is being followed in an appropriate hospital area by surgeons
experienced in nonoperative management. There should be no hesitation to
proceed with laparotomy and splenic repair. Operation is well tolerated, and
splenic salvage techniques are probably more feasible in children than adults
because of the higher ratio of splenic capsule to pulp. Any mortality from
nonoperative management of splenic injury in children is unacceptable.
Delayed Rupture of the Spleen. As early as 1866, Evans suggested that the spleen
might bleed catastrophically at a time remote from injury. 43 It was postulated that
injury to the pulp of the spleen could not be contained indefinitely by the thin
splenic capsule under continuous arterial pressure. The usual interval between
injury and the onset of clinically apparent intra-abdominal hemorrhage (period de
latence, Baudet, 1907) is within 2 weeks, although longer intervals have been
reported. 43 Although the incidence of delayed rupture of the spleen has been
reported to be 15% to 30%, the criteria for diagnosis are variable and
unconvincing. 43 It is apparent from splenic injuries managed nonoperatively that
many heal by fibrosis and without sequelae. The entity of delayed rupture of the
spleen is more properly referred to as delayed diagnosis of splenic injury. As
imaging techniques for follow-up of suspected or proved splenic trauma become
commonplace, it is likely that delayed rupture of the spleen will cease to be an
entity with clinical meaning or application.
Splenosis and Splenic Implants. Splenosis is the autotransplantation of splenic
tissue after splenic trauma. Although fewer than 200 cases have been reported, the
true incidence of splenosis undoubtedly is more common because of the high
incidence of traumatic injury to the spleen. Appearing as sessile or pedunculated
dark red nodules, splenic implants vary from a few millimeters to several
centimeters in diameter. Splenic implants depend on a blood supply from small
arteries penetrating the capsule and usually remain small or outgrow their blood
supply and undergo infarction. Splenosis may occur anywhere in the peritoneal
cavity and has been reported on the pericardium and the pleura as well as in the
subcutaneous tissue of abdominal incisions. 10 Splenosis seldom causes symptoms
and is usually discovered as an incidental finding at reoperation years after splenic
trauma. Isolated reports have described splenosis producing intestinal obstruction
from adhesions, stomach masses simulating carcinoma, and pain, presumably from
torsion.
Recent interest in the postsplenectomy sepsis syndrome has heightened interest in
splenosis as potentially valuable for preservation of immune function by providing
splenic implants at the time of removal of an injured spleen. Splenosis can be
produced in a variety of animals by transplantation of splenic pulp. Von
Stubenrauch seeded crushed splenic pulp throughout the peritoneal cavity in dogs
and believed that splenoids arose de novo from the peritoneum. Perla described the
histologic sequence of splenic transplants in rats. After transplantation, splenic
implants underwent degeneration with only the reticulum cells at the periphery
remaining viable after 24 hours. Regeneration of splenic tissue appeared to
originate from the reticulum cell precursor. 10 Recently, investigators interested in
preserving the immune function of the spleen have injected splenic pulp into the
liver to avoid mechanical problems from adhesions that sometimes develop in
association with splenosis.
Splenosis, the born-again spleen, may provide the blood management functions of
the spleen. The absence of Howell-Jolly bodies, siderocytes, and other
postsplenectomy blood changes as well as the recurrence of the hematologic
disease for which splenectomy was performed should raise suspicion of splenosis
or the presence of accessory splenic tissue. Splenosis has been reported in
conjunction with the expected postsplenectomy blood changes, suggesting a
critical mass of splenic tissue is needed for recovery of splenic function. Residual
splenic tissue can be detected by isotope scanning using 99mTc sulfur colloid .
Splenic reticuloendothelial function has been investigated in a series of patients
previously undergoing total splenectomy, partial splenectomy and splenic repair,
and splenic autotransplantation. 48 Partial splenectomy and splenorrhaphy resulted
in normal splenic reticuloendothelial function that was indistinguishable from a
control group of patients sustaining trauma but who had intact spleens.
Extraperitoneal splenic autotransplantation resulted in the preservation of a small
amount of reticuloendothelial function. The subnormal reticuloendothelial function
achieved by splenic autotransplantation was clearly superior to that resulting from
total splenectomy without deliberate splenic autotransplantation. Splenic
autotransplantation, which in this study involved placing thin slices of spleen
weighing a total of 25 to 30 gm. into an anterolateral extraperitoneal pocket,
appeared to be safe and was not associated with increased postoperative
complications.
Although autotransplanted splenic tissue, accessory splenic tissue, and splenosis
can restore some of the spleen's blood management functions and antibody
synthesis, it is unclear how much splenic tissue is needed for protection against
overwhelming postsplenectomy sepsis. Studies have failed to identify reestablishment of resistance to postsplenectomy sepsis after autotransplantation of
splenic tissue. Death from postsplenectomy sepsis has occurred in children and
adults having a total mass of residual splenic tissue weighing 3 to 92 gm.
Although residual splenic tissue can restore some of the spleen's functions, a
critical amount of splenic tissue is required for full protection against
postsplenectomy sepsis.
Immune Thrombocytopenic Purpura
Immune thrombocytopenic purpura (ITP, previously called idiopathic
thrombocytopenic purpura) is a syndrome characterized by a persistently low
platelet count. The thrombocytopenia is caused by a circulating antiplatelet factor
that causes platelet destruction by the reticuloendothelial system. In most patients,
the antiplatelet factor is an immunoglobulin (IgG) antibody directed toward a
platelet-associated antigen. Circulating immune complexes may have a causal role
in some cases, but their precise role is unclear. Proof of autoimmunity is lacking.
31
The majority of patients with ITP are young women. In Schwartz's series, the
average age was 36 years and the duration of clinical symptoms before
splenectomy was 24 weeks, with an average preoperative platelet count of 33,000
per cu. mm. 41 ITP is increasing in frequency, and the disease is being diagnosed
more often now in men. This increase results in part from the association of
immune thrombocytopenia with the acquired immunodeficiency syndrome (AIDS)
and an increasing occurrence of ITP in three groups of patients at risk for
developing AIDS—homosexual men positive for human immunodeficiency virus
(HIV), parenteral drug abusers, and hemophiliacs receiving multiple transfusions.
The diagnosis of ITP is suggested by spontaneous and easy bruising, petechiae,
and mucosal bleeding. Menorrhagia is common, and prolonged bleeding after
shaving trauma may be an initial complaint in males. Intracranial hemorrhage is a
rare and usually fatal complication.
The propensity for hemorrhage is reflected by the level of thrombocytopenia. A
bleeding diathesis is unlikely with thrombocytopenia in the range of 50,000 to
100,000 per cu. mm. Bleeding with minor trauma or surgical procedure can be
expected with platelet counts in the range of 20,000 to 100,000 per cu. mm.
Spontaneous bleeding with purpura and petechiae, epistaxis, menorrhagia, gingival
bleeding, and so on, occurs commonly with platelet counts below 20,000 per cu.
mm. and especially below 5,000 per cu. mm.
Crosby has suggested classifying patients with thrombocytopenia into those with
dry purpura (petechiae and ecchymoses) and those with wet purpura (active
bleeding from mucosal surfaces). This distinction postulates that patients with wet
purpura are at increased risk for central nervous system bleeding and thus require
aggressive treatment.
Patients with easy bruisability or hemorrhage require a careful history with special
emphasis on recent exposure to quinine, quinidine, sulfonamides, and thiazides that
may produce drug-dependent antibodies and immune thrombocytopenia.
Isoantibodies against transfusion products can also cause thrombocytopenia.
Collagen disease such as systemic lupus erythematosus may be indistinguishable in
initial presentation from ITP. 26, 31 Pseudothrombocytopenia, a phenomenon in
which the platelet count is spuriously low, results when antibodies in the patient's
serum react with platelets in blood anticoagulated with ethylenediaminetetraacetic
acid (EDTA), causing agglutination. Platelet clumping results in a falsely low
platelet count that will be at variance with the estimated number of platelets
present on a peripheral blood smear obtained by fingertip puncture. EDTAdependent platelet antibodies have been detected in several patients erroneously
diagnosed as having ITP. Diagnosis of immune thrombocytopenia requires the
exclusion of drug-dependent antibodies, isoantibodies, collagen vascular disease,
lymphoproliferative disorders, thyroid disease, recent viral illness, and spurious
thrombocytopenia. Patients with classic ITP rarely have a palpable spleen (<2%),
whereas a palpable spleen that reflects mild to moderate enlargement and an
associated high incidence of generalized lymphadenopathy have been found in ITP
associated with AIDS.
ITP is diagnosed definitively only after exclusion of other illnesses or conditions
that cause or are associated with thrombocytopenia. Except for thrombocytopenia,
patients with ITP usually have normal blood cell counts. Antinuclear antibodies are
rarely present, but autoantibodies have been noted in some patients. A peripheral
blood smear shows thrombocytopenia, occasionally with an increased number of
large platelets. A bone marrow aspirate reveals normal granulocytic and
erythrocytic elements with an increased megakaryocyte count.
Platelet Kinetics and the Immune System in ITP. Platelet kinetics in patients with
ITP are markedly altered with an increased platelet production (four to five times
normal) and an increased megakaryocyte mass being present in association with a
greatly shortened platelet survival. 31 In patients with ITP, body-surface counts
show primarily splenic sequestration of platelets with significant liver
sequestration occurring only in patients with severe disease. The amount of
platelet-associated antibody reflects the severity of the clinical disease and is
inversely correlated with the patient's platelet count and intravascular platelet life
span. The antiplatelet factor probably is an IgG antibody directed against a plateletassociated antigen. In some patients, the IgG antibody functions in combination
with IgM, IgA, or both. 31 Antiplatelet antibody assays are now routinely
available, and the value for platelet-associated IgG normally is less than 1200
gamma-globulin molecules per platelet.
The spleen is an important site of antibody production, and splenic cells from
patients with chronic ITP produce five to six times more IgG in culture than
control splenic cells. 31 The initial immune response to the platelet antigen
probably occurs in the spleen, or in the bone marrow where intramedullary
platelets and megakaryocytes share antigenic determinants and may trigger a
response. In its function as a monitor of the intravascular space, the spleen
probably is more important in the early response. Less involved initially, the
marrow assumes an important role as the immune response becomes generalized.
With development and recirculation of memory cells (both B and T lymphocytes),
the marrow becomes a major site of antibody production. The liver produces little
or no antiplatelet antibody, and the lymph nodes are not deeply involved in the
response to intravascular antigens.
Platelet destruction in ITP requires sufficient quantities of antigen (platelets),
antibody, and phagocytic cells in an environment that provides time for antibody
binding and subsequent platelet phagocytosis. 31 The spleen is ideally suited for
this function, and once platelet sensitization has occurred, phagocytosis is triggered
by the Fc portion of the IgG molecule or by complement activation with C3b
fixation to the platelet surface. The macrophage Fc receptor mechanism clearly is
important as increased platelet-bound IgG is present in essentially all patients with
ITP. Macrophage Fc and C3b receptors may act synergistically, resulting in a
greatly enhanced phagocytic efficiency.
Because 30% of the total circulating platelet mass is within the spleen at all times
as an exchangeable platelet pool, the spleen is the most active site of platelet
destruction. The stagnant blood flow in the splenic microcirculation allows
sensitized platelets to be readily removed by phagocytic cells lining the reticular
network of the red pulp. Having no resident platelet pool and possessing a rapid
microcirculation by contrast, the liver assumes a major role in platelet destruction
when severe disease and high antibody titers result in heavily sensitized platelets.
The bone marrow is the most likely source of antibody in patients who have
undergone splenectomy. 31 Intramedullary platelet destruction and inhibition of
thrombopoiesis may occur as a result of antiplatelet antibody binding to both
platelets and megakaryocytes, although the efficiency of the marrow
reticuloendothelial system is below that of the liver and the spleen.
A study investigating the mechanisms of increase in the platelet count after
treatment of ITP determined the survival time and localization of radiolabeled
autologous platelets and measured platelet-associated immunoglobulin levels
before and after prednisone therapy or splenectomy. 12 Prednisone therapy
produced an increased platelet count from increased platelet production. The
increased platelet count after splenectomy correlated with increased platelet
survival. The degree of radiolabeled platelet localization in the liver was normal in
patients in whom splenectomy was effective and was increased to above normal in
patients in whom splenectomy was ineffective. The conclusion that prednisone
improves platelet counts primarily by increasing platelet production requires
modification of the pathophysiologic concept of ITP to incorporate the hypothesis
that in some patients the predominant cause of thrombocytopenia is ineffective
marrow production of platelets rather than accelerated platelet removal.
In summary, thrombocytopenia in patients with ITP usually occurs from a
combination of intramedullary platelet removal by reticuloendothelial cells,
causing ineffective platelet production and decreased survival of circulating
platelets due to peripheral sequestration and destruction in the spleen and liver.
Successful therapy may produce an increase in the platelet count either by
increasing the effective production of platelets or by decreasing peripheral platelet
sequestration and destruction. Splenectomy appears to increase platelet survival by
removing a major organ of peripheral destruction. If the liver is the major site of
platelet destruction, splenectomy may not result in improvement in the platelet
count.
Treatment. The goal of therapy in chronic ITP is to obtain a complete and
sustained remission of the disease and to remove the patient from the risks of
hemorrhage. This can be achieved in 80% to 90% of patients.
When ITP is initially diagnosed, the patient should be hospitalized. A patient
having active bleeding should remain at bed rest and have specific therapy
instituted. Platelet transfusions provide immediate benefit and should be
administered as needed to control bleeding. Although transfused platelets rapidly
become coated with antibody and destroyed and provide only transient benefit,
they afford protection against life-threatening bleeding. High-dose intravenous
gamma-globulin is also useful but requires several days for a beneficial platelet
increase to occur.
Corticosteroid therapy (prednisone, 1 mg. per kg. per day or the therapeutic
equivalent) is instituted at the time of diagnosis. Most patients with ITP are
improved with administration of corticosteroids, with an increase in the platelet
count occurring within 3 to 7 days and reaching a maximum in several weeks. 31
Complete and sustained remission with corticosteroid therapy is rare, although
rates as high as 25% have been reported. 31 In most cases, even if the platelet
count becomes normal, the response is transient, and thrombocytopenia recurs as
the corticosteroid dose is tapered.
Splenectomy should be performed in patients with ITP that is refractory to
corticosteroid therapy. In the majority of patients, splenectomy is performed
electively. Emergent splenectomy is necessary in patients with ITP who have
evidence of central nervous system bleeding.
Complete remission after splenectomy is more likely in patients who have shown a
response to corticosteroids. Additional clinical features indicating the likelihood of
a favorable response to splenectomy include patients who are younger than 60
years old, who have disease of relatively short duration, and who exhibit a prompt
thrombocytosis with platelet counts reaching 500,000 per cu. mm. or more after
splenectomy. Most patients, however, are improved after splenectomy, even if
their platelet counts were not significantly increased by corticosteroid therapy.
Eighty-eight percent of Schwartz's patients responded to splenectomy and
developed normal platelet counts. Of those responding to splenectomy, 20% had
platelet counts exceeding 100,000 per cu. mm. by the third postoperative day, and
90% of them had normal platelet counts after 1 week. The remaining responders
developed normal platelet counts within 1 to 6 months postoperatively. In three
patients, thrombocytopenia recurred after a long interval and was attributed in one
patient to an accessory spleen.
The level of platelet-associated IgG falls to normal after a response to splenectomy
due to the removal of a large site of antiplatelet antibody production. 31 A
corticosteroid response is also accompanied by a decrease in platelet-associated
IgG. An increase in the platelet count often occurs before platelet-associated IgG
falls because of the corticosteroid influence on the reticuloendothelial system. A
response to immunosuppressants such as cyclophosphamide and vincristine is also
associated with a decrease in platelet-associated IgG.
ITP During Childhood. In children, particularly those younger than age 6, ITP
often appears after a viral upper respiratory tract infection. In contrast to the adult
form of the disease, childhood ITP usually undergoes spontaneous remission
without specific therapy. A short course of prednisone therapy is usually
prescribed; however, a clear benefit has not been demonstrated. 26
Intracranial hemorrhage is a life-threatening complication of childhood ITP and
occurs in 1% to 2% of cases. It is responsible for the majority of deaths from the
disease in this age group. The risk of intracranial hemorrhage is greatest during the
first month of the illness. Most reported cases appear to be spontaneous, but minor
head trauma may result in intracranial hemorrhage in patients with platelet counts
below 10,000 to 20,000 per cu. mm. 52 Development of intracranial hemorrhage in
ITP is an indication for emergency splenectomy.
Spontaneous and complete remission occurs in approximately 85% of children
with ITP. Those in whom spontaneous remission does not occur within 1 year are
considered to have chronic ITP and usually undergo elective splenectomy to avoid
the risks of chronic thrombocytopenia.
Splenectomy and Perioperative Therapy for ITP. Most patients are referred for
splenectomy after corticosteroid therapy has failed to achieve a complete and
sustained remission. A small group of patients have ITP diagnosed due to
abnormal bleeding during surgical procedures or after injury. A third group of
patients require emergent splenectomy for intracranial hemorrhage.
High-dose intravenous gamma-globulin is very effective in achieving an increase
in the platelet count preoperatively in patients who do not respond to
corticosteroids or are not candidates for corticosteroid therapy. It is postulated that
intravenous gamma-globulin therapy promotes a rise in the platelet count due to
temporarily reducing platelet destruction by saturating macrophage Fc receptors,
thus producing a transient blockade of the reticuloendothelial system. A
significantly improved platelet count (100,000–250,000/cu. mm.) occurs within 4
to 6 days and provides a therapeutic window for performance of splenectomy. 23,
51 In addition to affecting an increase in the platelet counts of patients failing to
respond to corticosteroids or who are not candidates for corticosteroid therapy,
high-dose gamma-globulin therapy is appropriate for the patient with ITP needing
urgent splenectomy in whom a trial of corticosteroids is not warranted and in the
pregnant patient with ITP late in the third trimester of pregnancy.
Immunizations with polyvalent pneumococcal vaccine , Haemophilus influenzae
vaccine, and Neisseria meningitidis vaccine should be administered as soon as it
becomes likely that splenectomy will be performed. Ideally these immunizations
should be carried out 10 to 14 days preoperatively. It is probable that patients
receiving corticosteroids have a suboptimal early response to these vaccines but
ultimately will develop protective antibody titers. The availability of blood and
platelets for transfusion should be ensured, although the need for blood transfusion
is rare. Intraoperative thrombocytopenic bleeding usually ceases after the splenic
artery is ligated. In Schwartz's series, platelets were not used preoperatively and
were administered intraoperatively or postoperatively in only 9 of 120 patients
having splenectomy for ITP. Although a nasogastric tube is advisable for
postoperative gastric decompression in most patients undergoing splenectomy,
some avoid use of a nasogastric tube in patients with ITP because of the potential
risk of precipitating hemorrhage from the nose or nasopharynx.
Splenectomy can be performed through a variety of abdominal incisions. The
midline incision is preferred in ITP because it allows entry into the peritoneal
cavity without transection of abdominal muscles and thus reduces the potential for
postoperative muscle hematoma. The spleen, usually of normal size, is assessed for
adhesions and the nature of its ligamentous attachments. Splenic ligaments vary
considerably in composition, being thin membranes affording easy dissection in
some patients and being thick and tendinous in others. The technique for
splenectomy is a matter of personal preference. The authors prefer the sequence of
initially incising the posterior splenic ligaments followed by mobilizing the spleen
and tail of the pancreas toward the midline for subsequent dissection of the splenic
vessels in the hilus. Caution is taken to avoid excessive traction or trauma to the
tail of the pancreas. Division of the gastrosplenic ligament is performed with suture
ligation of the gastric ends of the short gastric arteries. After removal of the spleen,
laparotomy pads are placed in the left upper quadrant while a search is made for
accessory splenic tissue. Approximately 20% of patients have an accessory spleen,
and common sites are the splenic hilus, adjacent to the splenic vessels and tail of
the pancreas, greater omentum, and gastrosplenic and gastrocolic ligaments. Rarely
has an accessory spleen been found in the intestinal mesentery, presacral, and
gonadal regions. The left upper quadrant is not drained routinely. Indications for
closed suction drainage are injury to the pancreas during hilar dissection and
incomplete hemostasis.
During the immediate postoperative period, corticosteroid therapy is continued
intravenously, and the platelet count is monitored. It usually is possible to begin
tapering the corticosteroid dose immediately, and in patients demonstrating a
satisfactory thrombocytosis, corticosteroids are gradually reduced over 4 to 6
weeks and discontinued.
The mortality rate for splenectomy in ITP is under 2% and occurs primarily in
patients with intracranial hemorrhage. In approximately 80% of adult patients who
have splenectomy for ITP, the platelet count returns to normal or above-normal
levels within the first 6 weeks after operation. 31 In approximately 15% there is
substantial improvement in the platelet count from preoperative levels, but it does
not reach a normal level. Only about 5% of patients remain severely
thrombocytopenic after splenectomy and require some form of chronic therapy. In
these patients with refractory ITP, therapy having the least side effects is chosen to
maintain the platelet count at a safe level (30,000 to 50,000/cu. mm.). Ingestion of
antiplatelet drugs, trauma, azotemia, fever, and infection increases the bleeding
tendency in thrombocytopenic patients. 31 Immunosuppressants such as
cyclophosphamide, Vinca alkaloids (vincristine and vinblastine), azathioprine, and
danazol, a modified androgen, have been used to treat patients with refractory ITP,
with variable results
.
Thrombotic Thrombocytopenic Purpura
Thrombotic thrombocytopenic purpura (TTP, Moschcowitz's syndrome) is a
syndrome characterized by thrombocytopenia, microangiopathic hemolytic
anemia, fluctuating neurologic abnormalities, progressive renal failure, and fever.
TTP is produced by widespread deposition of platelet microthrombi, and the
pentad of clinical manifestations results from occlusion of arterioles and capillaries
by subendothelial and intraluminal deposits of hyaline material composed of
aggregated platelets and fibrin. The etiology of TTP is unknown, and
approximately 90% of the cases of TTP are idiopathic. The pathologic response in
TTP may be initiated by various stimuli, including viral and bacterial infection,
pregnancy, drugs (oral contraceptives, mitomycin, and cyclosporine), and
nonspecified toxins. The syndrome has been associated with systemic lupus
erythematosus and other connective tissue disorders, malignancies, and more
recently with AIDS. TTP has a peak incidence in the third decade of life and
occurs more frequently in females than in males.
The differential diagnosis includes hemolytic-uremic syndrome, disseminated
intravascular coagulation, drug reaction, eclampsia, aplastic anemia, idiopathic
AIHA, ITP, leukemia, paroxysmal nocturnal hemoglobinuria, periarteritis nodosa,
infection, systemic lupus erythematosus, and exposure to toxins. The exact role of
the spleen in TTP is unclear, but approximately 20% of patients will have
splenomegaly.
Prognosis for untreated patients with TTP is very poor, with less than 10%
surviving beyond 1 year. 23 The current therapeutic regimen of infusions of freshfrozen plasma results in dramatic improvement for the majority of patients with
TTP. A combined therapeutic approach using plasma therapy, antiplatelet agents
(aspirin and dipyridamole) and high-dose corticosteroid therapy is instituted
immediately after the diagnosis is established. Plasma infusion or plasma exchange
using plasmapheresis and replacement with fresh-frozen plasma achieves response
rates between 70% and 90%. 23 It is speculated that plasma infusion or plasma
exchange replaces a deficient plasma component or removes some toxic substance.
23, 51 Immunosuppressive drugs (vincristine and azathioprine) are also beneficial
adjunctive agents in the present combined therapeutic approach for TTP. If
combined-modality therapy fails, splenectomy should be performed. Splenectomy
occasionally results in spectacular improvement, particularly when combined with
high-dose corticosteroid therapy and antiplatelet drugs. 23 Although a clear
physiologic explanation is lacking for this occasional response to splenectomy,
prior experience has documented that 70% of the long-term survivors with TTP
were patients who had undergone splenectomy.
Hypersplenism
Hypersplenism is a concept, probably first used by Chauffard in 1907, which refers
to a variety of ill effects resulting from increased splenic function that may be
improved by splenectomy. 23, 51 Criteria for diagnosis include: (1) anemia,
leukopenia, thrombocytopenia, or combinations thereof; (2) compensatory bone
marrow hyperplasia; (3) splenomegaly; and (4) improvement after splenectomy. 8,
23, 51 Hypersplenism is classified as primary when an underlying disease cannot
be identified to account for the exaggerated splenic function. Secondary
hypersplenism refers to those cases in which a specific or more-or-less welldefined disorder has been diagnosed. Because it now is possible to obtain more
specific diagnoses for many patients who previously would have been thought to
have primary hypersplenism, primary hypersplenism is now diagnosed much less
frequently than secondary hypersplenism.
Primary hypersplenism was initially described in 1939 by Doan and Wiseman as
an illness consisting of neutropenia and splenomegaly for which splenectomy was
curative. 40 The definition of the syndrome subsequently was broadened to include
patients with variable degrees of anemia, thrombocytopenia, or pancytopenia.
Subclassification of primary hypersplenism is used to describe splenic
hyperfunction producing depression of one or more of the formed elements of the
blood (red cells, white cells, and platelets). Primary splenic panhematopenia
(pancytopenia) refers to depression of all formed elements, whereas in primary
splenic neutropenia, depression of the white blood cells is the prominent feature.
Most patients with primary hypersplenism are women. Clinical manifestations are
dependent on the specific formed elements that are depressed and include pallor
and other signs of anemia, fever, recurrent infections, oral ulcerations, ecchymoses,
and petechiae. Splenomegaly is common. The peripheral blood smear shows
leukopenia or varying degrees of pancytopenia without evidence of leukemia or
myeloproliferative disorders. Pancellular hyperplasia is present in the bone
marrow.
Primary hypersplenism is a diagnosis of exclusion and should be accepted only
after an exhaustive search for a specific etiology of hypersplenism has been
unrewarding. Corticosteroids are seldom of benefit in primary hypersplenism.
Splenectomy is indicated when the diagnosis is established and usually results in
marked hematologic improvement for virtually all patients. Occasional patients
have subsequently developed reticulum cell sarcoma or histiocytic lymphoma.
Lymphoma having primary presentation in the spleen may present as
asymptomatic splenomegaly with or without hypersplenism. Radionuclide studies,
CT, and magnetic resonance imaging usually reveal nonspecific, featureless organ
enlargement. If parenchymal expansion secondary to tumor infiltration and
congestion becomes massive, splenic pooling and increased regional blood flow
may result in hypersplenism. Lymphoma with primary presentation in the spleen
may result in the diagnosis of idiopathic splenomegaly until splenectomy permits
accurate histopathologic diagnosis.
Secondary hypersplenism classically refers to a syndrome of pancytopenia
(anemia, thrombocytopenia, and leukopenia) associated with portal hypertension
from intrahepatic or extrahepatic portal or splenic vein obstruction. Hypersplenism
associated with portal hypertension secondary to cirrhosis seldom requires
splenectomy. Cytopenias commonly are improved after a shunt between the portal
and systemic circulations, presumably caused by relief of congestive
splenomegaly. Splenic vein thrombosis with bleeding from gastric varices should
be treated by splenectomy, which usually cures the gastric variceal bleeding and
any existing hypersplenism.
Secondary hypersplenism includes a number of diseases sharing the common
feature of splenomegaly. Rather than listing these, it is more appropriate to
consider the mechanisms producing splenic enlargement
8 Work hypertrophy from immune response and/or red blood cell destruction,
venous congestion, myeloproliferation, infiltration, and neoplastic proliferation
within the spleen produce variable degrees of splenomegaly. Diverse
pathophysiologic mechanisms are involved in the resulting hypersplenism . 8 In
both primary and secondary hypersplenism, the degree of splenomegaly does not
correlate closely with the severity of clinical symptoms or the degree of depression
of formed elements of the blood.
Hyposplenism
Hyposplenism is a potentially lethal syndrome characterized by diminished splenic
function. Hyposplenism was first described by Dameshek in 1955 in a patient with
sprue who had an asplenic peripheral blood picture with Howell-Jolly bodies and
target cells. 8 As in the asplenic patient, other peripheral blood findings that
suggest hyposplenism are the presence of acanthocytes and siderocytes, a longterm lymphocytosis and monocytosis, and a mild thrombocytosis. 8 Diagnosis of
hyposplenism is confirmed by an isotope scan ( 99mTc sulfur colloid) revealing an
atrophic spleen. Hyposplenism can occur in the presence of a normal sized or an
enlarged spleen .
The danger of hyposplenism is the risk of developing potentially lethal sepsis (see
The Problem of Overwhelming Postsplenectomy Sepsis). Sickle cell anemia is the
most common disease associated with hyposplenism. Children with sickle cell
anemia are vulnerable to overwhelming pneumococcal infection similar to that
seen in asplenic children. The child with sickle cell anemia is most vulnerable
when the spleen is enlarged. By the time the spleen becomes atrophic from
recurrent infarctions (autosplenectomy), the patient will have developed some
immunity from exposure to different pneumococcal strains.
The most common surgical disease associated with hyposplenism is chronic
ulcerative colitis, in which 40% or more of patients develop hyposplenism as the
pancolitis progresses. Other conditions associated with hyposplenism in which the
surgeon is commonly involved include thyrotoxicosis, corticosteroid
administration, and patients who have received Thorotrast (thorium dioxide) as a
radiocontrast agent. If a patient is suspected or proved to have hyposplenism, the
same precautions against sepsis recommended for asplenic patients should be
instituted.
Hodgkin's Disease
Described by Thomas Hodgkin in 1832, Hodgkin's disease is a malignant
lymphoma characterized by the presence of typical, multinucleate giant cells. The
unique cell, described by Sternberg and later Reed around the turn of the century,
is essential for diagnosis. Hodgkin's disease is relatively rare, with a bimodal ageincidence curve that peaks in the late 20s and declines to the mid 40s. After age 45,
the incidence of Hodgkin's disease increases with age. The disease is slightly more
common in men than women.
Most patients with Hodgkin's disease have asymptomatic lymphadenopathy at the
time of diagnosis. The site of initial nodal involvement is the cervical area in most
patients (65%–80%), followed by the axillary (10%–15%) and inguinal (6%–12%)
regions. Retroperitoneal lymph nodes may be involved but require
lymphangiography or CT for diagnosis. Mediastinal involvement occurs in 6% to
11% of patients at the time of diagnosis.
Constitutional symptoms (B symptoms) such as fever, night sweats, weight loss,
and pruritus are usually indicative of widespread involvement and are unfavorable
prognostic signs. They may appear simultaneously with lymph node enlargement
or may precede development of lymphadenopathy. A typical fever pattern is a high
temperature alternating for a few days with an afebrile period (Pel-Ebstein fever).
Less specific constitutional symptoms include localized acute discomfort in areas
of adenopathy after ingestion of alcoholic beverages, malaise, lethargy, easy
fatigability, generalized weakness, and anorexia.
Many patients have a mild normochromic normocytic anemia. One third have a
leukocytosis due to a neutrophil increase, and eosinophilia is present frequently.
Lymphopenia is common in the later stages of the disease. The platelet count is
normal initially but is frequently depressed in advanced disease. There is a
progressive loss of T-lymphocyte function with reduced cell-mediated immunity.
A classification of Hodgkin's disease was developed by the international
symposium held in Rye, New York, in 1965, at which time the earlier
classifications were simplified. In the Rye classification there are four
histopathologic subtypes of Hodgkin's disease: lymphocyte predominance, nodular
sclerosis, mixed cellularity, and lymphocyte depletion. Lymphocyte predominance
and nodular sclerosis subtypes have a more favorable prognosis than mixed
cellularity and lymphocyte depletion subtypes. However, the prognostic
implications of subtyping are becoming less useful because of the excellent results
of current aggressive treatment.
Hodgkin's disease metastasizes initially in a predictable, nonrandom pattern
through lymphatic channels to contiguous lymph node groups and organs with a
prominent lymphatic tissue component. The predictable mode of spread of
Hodgkin's disease provides the basis for irradiation of adjacent lymph node areas
in patients with apparently localized disease. 3 Treatment and ultimately survival
of the patients with Hodgkin's disease depend on the anatomic distribution of the
disease and the presence or absence of specific symptoms, the stage of the disease,
and the histopathologic subtype.
Histopathologic diagnosis is made by lymph node biopsy in which the largest and
most centrally placed node should be selected for excision. In a matted group or
cluster of nodes, a central node from the group should be excised or a generous
incisional biopsy specimen obtained. Nodes from the lower cervical or axillary
areas provide the most satisfactory tissue for histopathologic evaluation, because
nodes from the parotid, submandibular, and inguinal regions often show changes
due to previous inflammatory processes in their regions of drainage. When only
mediastinal adenopathy is present, biopsy is performed through mediastinoscopy
or thoracotomy, as indicated. Laparotomy is seldom required to obtain the initial
diagnosis in Hodgkin's disease.
Since the concept of staging was introduced approximately 30 years ago, the
staging process has undergone continued modification with the intent of accurately
defining the anatomic sites of involvement and thus improving patient selection for
the most appropriate type and amount of therapy. Stage I disease indicates nodal
involvement in only one lymph node region. Stage II disease is limited to two or
more lymph node regions on the same side of the diaphragm. Stage III refers to
disease involving lymph node regions on both sides of the diaphragm (the spleen is
considered a lymph node). Stage IV disease encompasses diffuse or disseminated
involvement of one or more distant extranodal organs with or without associated
lymph node involvement. Stage IV is further classified as A (absence) or B
(presence) with regard to fever, night sweats, weight loss, and pruritus. The
subscript E is used to classify selected patients having localized extranodal disease
in Stages I to III (e.g., lung, muscle, bone, skin) contiguous to involved nodes. In
general, the E designation is reserved for patients having extralymphatic disease so
limited in extent and/or location that it is amenable to definitive treatment by
radiotherapy. The S subscript indicates splenic involvement. Anatomic substages
of Stage IIIA disease have been designated to differentiate between upper
abdominal disease (III 1) and lower abdominal disease (III 2). A biologic
difference or prognostic significance has not been clearly shown with respect to 5year survival or disease-free survival between upper and lower abdominal
involvement. 42 Both a clinical stage designation and a pathologic stage
designation are implied by the Ann Arbor staging classification.
Clinical stage is dependent on history and physical examination, the initial
diagnostic biopsy, laboratory tests, and the results of radiographic and imaging
studies. Pathologic stage is more accurate than the clinical stage because
histopathologic data from the bone marrow, liver, spleen, intra-abdominal lymph
nodes, and other involved tissues (e.g. bone, skin, lung) provide precise knowledge
of the extent of the disease.
Lymphangiography and abdominal CT are reliable and complementary tests to
evaluate retroperitoneal and abdominal nodal involvement. Lymphangiography has
an overall accuracy of 80% to 90% with high sensitivity and specificity and can
detect disease in nodes that are not significantly enlarged. Shortcomings include
the need for bipedal incisions and a failure to adequately visualize the celiac,
splenic hilar, and portal nodes. These and other enlarged lymph nodes can be
detected by CT, which has lower overall accuracy, sensitivity, and specificity than
lymphangiography. 42 CT is not helpful in detecting splenic involvement unless
extensive splenic disease exists. 24, 25 When the lymphangiogram is positive,
involvement of retroperitoneal nodes by Hodgkin's disease is confirmed by staging
laparotomy in 80% to 90% of cases. 24, 42 Additionally, approximately 40% of
patients with abnormal lymphangiograms have another site of Hodgkin's disease
within the abdomen, most commonly the spleen. 24 A normal lymphangiogram
usually indicates that the retroperitoneal lymph nodes are uninvolved (10%–15%
incidence of false-negative results) but does not exclude other abdominal sites of
occult disease. Approximately 20% of patients with negative lymphangiograms
have intra-abdominal disease, usually in the spleen.
Subdiaphragmatic Hodgkin's disease is frequently confined to the spleen and
splenic hilar lymph nodes. The probability of subdiaphragmatic Hodgkin's disease
is related closely to histopathologic subtype, with mixed cellularity and
lymphocyte depletion subtypes having greater likelihood of subdiaphragmatic
extension than lymphocyte predominance and nodular sclerosis subtypes. The
probability of splenic involvement increases with increasing spleen size and is
almost always present in spleens weighing more than 400 gm. The absence of
splenomegaly does not exclude splenic involvement. Hodgkin's disease involving
the spleen is commonly apparent on gross examination as grayish white nodules
ranging from several millimeters to several centimeters. Liver involvement with
Hodgkin's disease rarely occurs in the absence of splenic disease. Hepatic disease,
in contrast to splenic disease, may not be apparent from inspection and palpation.
In a report of the Stanford experience, the spleen was found to be involved with
Hodgkin's disease in 39% of patients undergoing staging laparotomy. 42 In 50% of
these, the spleen was the only site of intra-abdominal disease detected by staging
laparotomy. Splenic involvement consisted of fewer than five nodules in 27%, with
all of the nodules being too small to have been detected by CT or found on random
biopsy. All positive liver and accessory spleen specimens were associated with
positive splenic involvement, suggesting that the spleen is the trigger for visceral
dissemination.
Staging laparotomy, which in the past was frequently employed for pathologic
staging of Hodgkin's disease, is now being used less frequently. Its use as a
diagnostic test has been based on the following:
1. Hodgkin's disease generally begins in a single area and spreads initially in a
predictable and nonrandom manner through lymphatic channels to contiguous
lymph node areas and organs having a prominent lymphatic tissue component.
2. Selection of therapy is dependent on pathologic stage.
3. Assignment of stage using clinical criteria alone is often inaccurate. Twentyfive to 30% of clinically staged patients will have their stage of disease increased
(upstaged), and 10% to 15% will be downstaged after laparotomy for a total
alteration in stage of approximately 40%. (Patients with AIDS who develop
Hodgkin's disease have great likelihood of being upstaged by laparotomy.)
4. Prognosis is related primarily to the pathologic stage of the disease.
The role of staging laparotomy continues to be re-evaluated as a routine staging
procedure for Hodgkin's disease. Diagnostic advantages and contributions of
staging laparotomy have helped to significantly change the understanding and
therapeutic management of patients with Hodgkin's disease, and the current
success and widespread use of combination chemotherapy has challenged the need
to know the precise anatomic extent of the disease required for treatment by
radiation therapy. 31 Staging laparotomy is not applicable to all patients with
Hodgkin's disease and should be performed only in patients in whom the results
may change management decisions and plans for therapy. Patients with advanced
disease, clinical Stage IIIB or Stage IV, do not benefit from staging laparotomy
because treatment employs combination chemotherapy. (If splenomegaly is present
or develops in these advanced stages of Hodgkin's disease, splenectomy may be of
value to control cytopenias and reduce tumor burden.) Staging laparotomy has
been restricted by the recognition of the limitations of radiation therapy for patients
with extensive mediastinal presentation or with multiple extranodal sites. The
success of combination chemotherapy in treating minimal or occult disease and for
controlling recurrent disease after radiation therapy is a major consideration in
further restricting the use of staging laparotomy. 31 Splenectomy in Hodgkin's
staging has been shown to be a predisposing risk factor for acute leukemia in
patients older than 40 years of age who have received combination chemotherapy
(MOPP—mechlorethamine, vincristine, procarbazine, and prednisone). This
surprising association suggests that staging laparotomy with splenectomy should
not be done in patients of this age group who may eventually require MOPP-like
chemotherapy.
Controversy continues regarding the role of staging laparotomy, and improved
noninvasive diagnostic tests and the introduction of more effective and less toxic
chemotherapy continue to reduce the indications for this procedure. Currently,
staging laparotomy is appropriate for selected patients with Hodgkin's disease of
low clinical stage (Stage IA, IIA, and IIIA) in whom the results will have major
influence on therapeutic management.
Staging laparotomy is based on a systematic abdominal exploration with an
organized approach to tissue sampling and consists of splenectomy, liver biopsy,
and selective excision of abdominal and retroperitoneal lymph nodes based on CT,
lymphangiographic, and operative findings. The operation is performed through a
midline incision. The liver is examined initially, and if no gross evidence of
disease is identified, a 2-cm. wedge of tissue is excised from the left hepatic lobe,
and deep biopsy samples are obtained from the right and left lobes with a Trucut
needle. Splenectomy is then performed with biopsy of splenic hilar lymph nodes
and placement of identifying metal clips on the splenic pedicle. Partial
splenectomy does not provide an adequate degree of accuracy in staging to justify
its use as an alternative to splenectomy. The lesser omentum is incised, and a
lymph node is removed from the celiac axis region. The hilum of the liver, cystic
duct, and distal common duct areas are inspected, and representative lymph nodes
are removed. Representative nodes are excised from the small intestinal mesentery
and mesocolon. Exposure of the para-aortic, paracaval, and iliac lymph nodes is
necessary to adequately examine these areas. If any abnormal or suspicious
retroperitoneal nodes were demonstrated on the lymphangiogram, the nodes are
excised and the sites are marked with metal clips. Confirmation that the specific
node or nodes have been excised can be obtained by comparing an intraoperative
abdominal radiograph with the lymphangiogram. Ten to 15% of patients with
normal lymphangiograms will have involvement of the retroperitoneal lymph
nodes by Hodgkin's disease (false-negative), and representative nodes should be
excised even if the lymphangiogram is normal. A bone marrow biopsy should be
obtained from the iliac crest to conclude the staging aspects of the operation.
Preoperative bone marrow biopsy has a false-negative rate of 2% to 3% and would
constitute a significant treatment error if not corrected by staging laparotomy
findings.
Oophoropexy (ovarian translocation) is advisable in the premenopausal woman in
whom radiation therapy using an inverted Y port is likely. Both ovaries should be
moved from the potential field of radiation and identified with metal clips. Lead
shielding is an important adjunct to the protective effects offered by oophoropexy,
and menstrual function is retained in approximately 55% of women receiving
pelvic irradiation for Hodgkin's disease after oophoropexy and lead shielding.
Ancillary procedures such as appendectomy or cholecystectomy add an
unnecessary risk to the staging laparotomy and are not recommended.
Staging laparotomy has minimal morbidity, and the mortality rate is less than
0.5%. The risk of developing postsplenectomy sepsis in patients with Hodgkin's
disease is 10% or higher.
Current treatment of Hodgkin's disease integrates radiation therapy and
combination chemotherapy to achieve the maximum potential for cure. The
success of combination chemotherapy in controlling and even curing Hodgkin's
disease in patients demonstrating recurrence after radiation therapy has been a
major therapeutic advance. In the Stanford experience from 1974 to 1980 for
patients at all stages of Hodgkin's disease, survival was 86%, and freedom from
progression (FFP) was 77% in surgically staged patients. 42 For patients with
Stage IA and IIA disease being treated by irradiation only, survival and FFP were
91% and 82%, respectively, with no advantage being shown by adding
chemotherapy (usually MOPP). Adding chemotherapy to radiation improved
survival from 65% to 92% and FFP from 70% to 82% in patients with Stage IIIA
disease. Patients with Stage IIIB disease had a generally poorer prognosis even
with combination therapy, but alternating chemotherapy and radiation therapy has
yielded significantly improved survival. Extensive extranodal disease (Stages IIE,
IIIE, IV) has a poor survival (approximately 60% at 5 years), whether irradiation or
combined therapy is used.
Most patients with Hodgkin's disease present with Stage II or III disease. Ten to
15% present with Stage I or IV. Untreated Hodgkin's disease has a 5-year survival
rate of 5%. Current survival rates for Hodgkin's disease, however, approximate
85% for all stages. The gold standard for the management of Stage I and IIA
Hodgkin's disease is external-beam radiation. The potential contribution of
adjuvant radiation therapy to the management of advanced-stage Hodgkin's disease
remains controversial. The cornerstone of therapy for advanced Hodgkin's disease
is combination chemotherapy. It is the staging between IIA and IIIA that might
make some difference.
There are subsets of patients in whom the likelihood of any staging change that
would alter therapy is remote. The risk of having abdominal involvement is less
than 10% in women with clinical Stage I disease, in men with clinical Stage I
disease with lymphocyte predominance, and in women with clinical Stage II
disease who are younger than 27 years of age with three different sites of
involvement. Alternatively, the patient with Stage I disease who has a large
mediastinal mass now usually requires chemotherapy in addition to external-beam
radiation, because of recurrence outside the radiation ports and the fact of cardiac,
especially pericardial, complications from radiation. Patients with Stage IIIB
disease require no staging, nor do ones with multiple E, IIA 2. Another
contraindication or reason for the decline in staging has been the appearance in
significant numbers of patients of acute myeloid leukemia in patients who have
had MOPP therapy and have received staging laparotomy with splenectomy.
The approximate results of different stages of Hodgkin's disease, then, are as
follows: Stages I and IIA treated by external-beam radiation alone have an 80%
FFP (free from progression) and a 90% regression-free survival; Stage IIIA has a
94% relapse-free survival at 10 years with MOPP; and Stage IVA with alternating
MOPP and ABD has an 80% remission. The potential of bone marrow
transplantation adding to the treatment is an additional therapeutic maneuver.
The reason, then, that staging laparotomies are less frequently done currently is not
entirely due to the ability to better stage the disease by noninvasive means (e.g.,
CT, laparoscopic surgery). It in part results from the effectiveness of the various
therapeutic modalities available. Salvage after recurrence is quite possible with
most patients with Hodgkin's disease, making it less important that the small
differential that would be changed from a staging process at the present time would
make much difference in overall survival.
Non-Hodgkin's Lymphomas
Non-Hodgkin's lymphomas constitute a diverse group of primary malignancies of
lymphoreticular tissue. The clinical course and natural history of NHL are more
variable than those of Hodgkin's disease, the pattern of spread is irregular, and
more patients have leukemic features.
Current histologic classifications
incorporate the nomenclature based on light and electron microscopic morphology,
histochemical studies, and selected cell-surface antigens. For prognostic and
therapeutic purposes, NHL is classified according to nodular (favorable) and
diffuse (unfavorable) types.
In contrast to Hodgkin's disease, only about two thirds of patients with NHL
initially have asymptomatic lymphadenopathy. In 20% to 35% of patients, the
onset of NHL occurs in an extranodal site. 3 In addition to peripheral and
mediastinal lymphadenopathy, NHL is commonly found initially as an abdominal
mass (retroperitoneal or mesenteric) or as hepatic and/or splenic enlargement.
Constitutional symptoms such as fever, weight loss, and night sweats are
frequently present. Occasionally the first manifestation of NHL is an oncologic
emergency such as superior vena caval syndrome, spinal cord compression, or
ureteral obstruction.
In NHL the mode of spread generally is unpredictable, and most patients have
disseminated disease at the time of presentation.
In patients with initial nodal involvement, early spread may be limited to
contiguous lymphatic sites or adjacent extranodal sites. More often, NHL spreads
rapidly to distant nodal and extranodal sites through the bloodstream. Progression
of NHL arising in extranodal areas may be through (1) local invasion of adjacent
structures, (2) extension to regional lymph nodes, and/or (3) dissemination to
noncontiguous lymph nodes and/or distant extranodal sites. The extranodal spread
of NHL is comparable to the pattern of metastasis observed in carcinoma. 3
The median age at the time of diagnosis is 50 years, without sex preference.
Patients younger than age 35 and older than 65 are more likely to have diffuse
histology. The majority of NHLs are monoclonal B-cell tumors that are sometimes
associated with an IgM or IgG protein. In some patients, particularly children with
a mediastinal mass, the disease is thymic.
As with Hodgkin's disease, chemotherapy and/or radiation therapy are the primary
forms of treatment. Therapeutic considerations are based on the histopathologic
type of lymphoma and the stage (extent) of disease. Because the majority of
patients with NHL have disseminated disease at the time of presentation, staging
laparotomy is seldom required and is indicated only for the patient with limited
disease in whom laparotomy findings may influence selection of therapy.
NHL having primary presentation in the spleen may present as asymptomatic
splenomegaly, with or without hypersplenism. Radionuclide scanning, CT, and
magnetic resonance imaging usually reveal nonspecific, featureless organ
enlargement. If parenchymal expansion secondary to tumor infiltration and
congestion becomes massive, splenic pooling and increased regional blood flow
may result in hypersplenism. NHL with primary presentation in the spleen may
result in the diagnosis of idiopathic splenomegaly until splenectomy permits
accurate histopathologic diagnosis.
Splenectomy in NHL is also performed for hematologic depression secondary to
hypersplenism or to relieve symptomatic splenomegaly or discomfort from
recurrent splenic infarctions. Hypersplenism may produce symptomatic anemia
requiring red blood cell transfusions, dangerous levels of thrombocytopenia, and
leukopenia with recurrent infections. The severity of the cytopenia may require
withholding of chemotherapy and radiation therapy. Immunohemolysis or AIHA
occasionally contributes to the anemia in NHL and is diagnosed by a positive
Coombs test.
The bone marrow typically has significant infiltration by neoplastic cells and
additionally shows erythroid hypoplasia and decreased megakaryocytes. Because
most patients with NHL have received chemotherapy or radiation therapy before
becoming candidates for splenectomy, the splenic contribution to the pancytopenia
can only be determined by the response to splenectomy. 13 Almost all patients
with NHL undergoing splenectomy for hypersplenism require red cell and platelet
transfusions preoperatively.
Significant therapeutic benefit can be achieved by splenectomy in 80% to 90% of
patients with advanced lymphomas (including Hodgkin's disease). Although
patients with both NHLs and Hodgkin's disease may develop remission with
reinstituted chemotherapy after correction of cytopenias, the eventual outcome of
the underlying disease is unchanged. Most patients with well-differentiated
lymphocytic lymphoma survive for 5 years, and many live 10 years after the
diagnosis is made. The prognosis is more favorable for the nodular than for the
diffuse forms of NHL.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative abnormality that
occurs primarily in the elderly (sixth decade of life or older), with a male
predominance (2:1). Proliferation and accumulation of abnormal lymphocytes in
lymphatic tissues result in the major signs of lymphadenopathy, splenomegaly, and
lymphocytosis in the peripheral blood. The most constant abnormality on physical
examination is lymph node enlargement, which frequently is found either by the
patient or on routine physical examination. Splenomegaly is present in most
patients and is progressive during the course of the disease. Hepatomegaly is a
frequent finding, and lymphocytic infiltration of the skin and gastrointestinal and
respiratory tracts occurs as the disease progresses. The diagnosis is based on the
increase in the total leukocyte count due to a large number of abnormal, small,
immature lymphocytes. Bone marrow examination demonstrates a variable and
progressive degree of infiltration by abnormal lymphocytes. 23, 51
Therapy for CLL incorporates the judicious use of chemotherapeutic agents,
corticosteroids, irradiation, and splenectomy. Although CLL is not cured by
available therapeutic modalities, effective palliation is achieved in most patients,
and many lead relatively normal lives. The disease progresses over 5 to 10 years
with gradual increases in lymphadenopathy, splenomegaly, and hepatomegaly and
development of weakness, weight loss, anemia, and thrombocytopenia. CLL is
frequently complicated by development of immune hemolysis (AIHA), in which
the hemolytic anemia is nearly always Coombs positive. If hemolysis becomes
severe and cannot be controlled by medical therapy, splenectomy is useful to
ameliorate the hemolytic process. As in NHL, splenectomy in chronic lymphocytic
leukemia is performed primarily for hematologic depression secondary to
hypersplenism and for palliation of symptomatic splenomegaly (Fig. 36–11 Fig.
36–11). Significant hematologic improvement occurs after splenectomy in 80% to
90% of patients, but the natural course of CLL is unchanged. Unless another
illness supervenes, death usually occurs from hemorrhage or infection.
Chronic Myeloid Leukemia
Chronic myeloid (granulocytic, myelocytic) leukemia (CML, CGL) is a
myeloproliferative abnormality characterized by marked elevation of the leukocyte
count from myeloid cells in all stages of maturation and by neoplastic overgrowth
of granulocytes in the bone marrow. The incidence of CML increases with age and
is more frequent in males than in females (ratio 3:2). Splenomegaly is the most
common physical finding, and sternal tenderness, lymphadenopathy, and
hepatomegaly are frequently present. A unique chromosomal abnormality
designated the Philadelphia chromosome (Ph) occurs in 90% of patients with
CML. Patients who are Ph-negative have an atypical course and a poorer prognosis
than patients with CML who have the Ph chromosome.
Chemotherapy (busulfan, hydroxyurea), irradiation, radioactive phosphorus, and
extracorporeal irradiation of the blood can control symptoms and most physical
and laboratory abnormalities of CML during the chronic or treatable phase, which
lasts from 1 to 4 years. 23, 51 Development of myeloblastic crisis appears to be an
intrinsic feature of CML and indicates an accelerated or acute stage of the disease,
which results in death from infection or hemorrhage within 3 to 6 months.
Splenectomy may be of benefit in selected patients during the chronic stage of
CML to palliate severe thrombocytopenia and/or anemia and to relieve pain from
splenic infarctions or massive splenomegaly. Splenectomy offers no benefit in
delaying the onset of blastic transformation, improving the quality of life after the
development of blastic crisis, or in prolonging survival. 32
Hairy Cell Leukemia
Hairy cell leukemia (leukemic reticuloendotheliosis) is an uncommon form of
leukemia characterized by pancytopenia, splenomegaly without significant
lymphadenopathy, and characteristic mononuclear cells in the blood and bone
marrow. The disease is more common in males (ratio 4:1). The typical patient is a
middle-aged man with moderate splenomegaly, absence of significant peripheral
adenopathy, and variable hepatomegaly.
Initial complaints among symptomatic patients are abdominal fullness or
discomfort due to splenomegaly, nonspecific symptoms of fatigue, weakness, and
weight loss, easy bruising from thrombocytopenia, or recurrent infections
associated with leukopenia. In approximately 25% of patients, splenomegaly and
cytopenias are detected during a routine examination or during evaluation for an
unrelated illness.
HCL is characterized by the presence of malignant cells that have irregular,
filamentous cytoplasmic projections on light microscopy that give the cells a hairy
appearance. The surface projections are demonstrable by electron microscopy as
broad-based, undulating ruffles and patches of short, blunt microvilli.
A pancytopenia of moderate severity is present in approximately two thirds of
patients at the time of diagnosis. Hairy cells are frequently present in the peripheral
blood and often account for a large proportion of the total white cell count.
Demonstration in the hairy cells of tartrate-resistant acid phosphatase (TRAP)
isoenzyme activity as a red reaction product is helpful supporting evidence for
diagnosis. Although not required for diagnosis, the TRAP positive reaction product
occurs in 90% to 95% of patients with HCL. Bone marrow biopsy permits
definitive diagnosis of HCL from characteristic morphology.
Ten to 15% of patients with HCL have an indolent course with a nearly normal life
expectancy and require no specific therapy. These are usually elderly men who
have minimal splenomegaly, relatively few hairy cells in the blood, and
asymptomatic neutropenia. The remaining 85% to 90% require treatment because
of one or more cytopenias resulting in symptomatic anemia requiring transfusions,
thrombocytopenic bleeding, and repeated infections attributable to neutropenia.
Pancytopenia develops from concurrent splenic pooling secondary to infiltrative
splenomegaly and bone marrow replacement with hairy cells. Symptomatic
splenomegaly and recurring splenic infarctions are other indications for therapy.
For the majority of patients who require some form of therapy shortly after
diagnosis, splenectomy continues to be an early consideration. Splenectomy is
most appropriate for those patients with severe cytopenias, a large spleen, and
patchy bone marrow infiltration. It results in rapid palliation, and almost all
patients have hematologic improvement. Blood cell counts return to normal in 40%
to 50% of patients, with the response lasting for many years and almost half the
patients requiring no further therapy.
Patients with HCL having diffuse infiltration of the bone marrow, minimal
splenomegaly, and severe cytopenias gain only minor or short-term benefit from
splenectomy and require additional therapy. In the past 5 years interferon alfa and
pentostatin have been found to be highly effective systemic therapy for HCL.
Randomized trials of interferon alfa versus pentostatin are in progress, both for
newly diagnosed HCL patients and those patients previously having had
splenectomy. Presently, interferon alfa remains the systemic therapy of choice,
with pentostatin being indicated for patients with HCL that is refractory to
interferon alfa. Splenectomy likely will continue to have a place in the sequential
treatment of those patients with HCL requiring therapy.
SPLENECTOMY FOR ANEMIA
Hemolytic anemia results from an increase in the rate of red blood cell destruction.
The adult bone marrow can produce red cells at six to eight times the normal rate,
and hemolysis must be reasonably severe before laboratory or clinical evidence of
anemia occurs. Diagnostic evaluation should include a detailed family history
because many hemolytic anemias that improve after splenectomy have a hereditary
basis. Congenital hemolytic anemias have a defect intrinsic to the red blood cell
that may involve the cell membrane (hereditary spherocytosis), cellular
metabolism (pyruvate kinase deficiency, glucose-6-phosphate dehydrogenase
deficiency), hemoglobin structure (sickle cell anemia), or hemoglobin chain
synthesis rates (thalassemia). Acquired hemolytic anemias have an
extracorpuscular factor that affects normal red cells. Chromium-51–labeled red cell
survival studies are sometimes useful to confirm hemolysis and a shortened red
cell life span and to determine sites of red cell destruction.
Clinical features include variable pallor related to the degree of anemia, mild,
fluctuating jaundice, and splenomegaly. Pigment gallstones are common after
childhood and may produce biliary tract symptoms. Valuable laboratory studies
include serum direct and total bilirubin and haptoglobin levels. Jaundice associated
with hyperbilirubinemia resulting from hemolysis is caused by an excess of
unconjugated (free) bilirubin and is measured by an increase in the indirect
reacting fraction of bilirubin. The unconjugated bilirubin that is bound to albumin
does not enter the urine, and indirect hyperbilirubinemia thus is not associated with
biliuria. Reticulocytosis and bone marrow erythroid hyperplasia reflect increased
red cell production. Red cell morphology is often abnormal, as is osmotic fragility.
Red cells tagged with chromium-51 demonstrate a shortened red cell survival.
Hereditary Spherocytosis
Hereditary spherocytosis is a relatively common, genetically determined red blood
cell membrane disorder that results in hemolytic anemia. The erythrocyte
membrane defect results from a deficiency in spectrin, a major component of the
membrane skeleton that is thought to be responsible for the shape, strength, and
reversible deformability of the red blood cell.
The membrane abnormality leads to a gradual loss of red cell surface area, so that
instead of remaining a flexible biconcave disc, the red cell becomes small and
spherical. Lacking adequate deformability to traverse the splenic microcirculation,
spherocytes are trapped in the splenic red pulp and are eventually destroyed by
reticuloendothelial cells.
Hereditary spherocytosis occurs primarily by autosomal dominant inheritance with
variable expression. Twenty to 25% of the cases appear sporadically. The severity
of the anemia and other clinical manifestations are variable. The disease may be so
severe that repeated blood transfusions are required to maintain a functional
hemoglobin level, or it may be so mild as to go unnoticed in childhood, becoming
manifest in adult life with development of symptomatic cholelithiasis. Aplastic
crisis, which usually is precipitated by a viral illness such as human parvovirus,
may produce a rapidly worsening anemia that may be life threatening. Fluctuating
jaundice due to hemolysis is common, and pigment gallstones are frequent, with
the incidence being directly related to the severity of the hemolysis and patient age.
Cholelithiasis develops in 20% to 55% of patients with hereditary spherocytosis
but is uncommon before age 10. Moderate splenomegaly is a characteristic
physical finding.
Diagnosis is established by the presence of spherocytes in the peripheral blood,
reticulocytosis (usually 5%–20%), an increased osmotic fragility, and a negative
Coombs test.
Splenectomy is indicated in virtually all patients. In children, splenectomy is
usually performed after age 6 but can be done at a younger age if warranted by the
severity of the anemia and the need for frequent transfusions. After splenectomy,
hemolysis is alleviated, and clinical cure of the anemia is achieved in most
patients. The intrinsic red cell membrane defect is unaltered by splenectomy, but
red cell survival becomes normal. With resolution of hemolysis, jaundice
disappears, and the increased risk of calculous biliary tract disease is removed.
Gallbladder ultrasonography is advisable before splenectomy in anticipation of
combining cholecystectomy with splenectomy if gallstones are demonstrated.
Hereditary Elliptocytosis
Hereditary elliptocytosis is a relatively common heterogeneous red blood cell
membrane disorder characterized by an abundance of elliptical red cells. The
abnormality usually produces a mild anemia, and most patients remain
asymptomatic throughout their lives. Like hereditary spherocytosis, hereditary
elliptocytosis is caused by an abnormal erythrocyte membrane skeleton. Several
defects in the red cell membrane skeleton have been identified in hereditary
elliptocytosis and include impaired association of spectrin chains and a quantitative
deficiency of protein 4.1. Symptomatic individuals have a mild hemolytic anemia
with clinical and laboratory features similar to those of hereditary spherocytosis
except for the elliptical appearance of the erythrocytes. Splenectomy is indicated in
symptomatic patients, and results are uniformly good, although the abnormal
erythrocyte morphology persists.
Hereditary Pyropoikilocytosis
Hereditary pyropoikilocytosis (HPP) is a rare congenital hemolytic anemia that is
catalogued along with hereditary elliptocytosis because of certain molecular and
morphologic similarities. Distinguished from hereditary elliptocytosis (and
hereditary spherocytosis) by marked alterations in red cell morphology and by the
pattern of inheritance, this severe hemolytic disorder occurs most commonly in
blacks. Erythrocytes in HPP are severely deformed, and virtually all red cells are
poikilocytic, fragmented, spherocytic, or elliptocytic. Osmotic fragility is
increased, and red cells in HPP exhibit increased susceptibility to thermal injury.
The decision for splenectomy in HPP is deferred until the natural course of the
disease has been established. In some newborns, HPP gradually evolves into a
morphologic picture characteristic of hereditary elliptocytosis. True HPP persists
as a severe hemolytic anemia that usually requires early splenectomy, which
greatly reduces hemolysis.
Hereditary Nonspherocytic Hemolytic Anemia
A number of erythrocyte enzyme deficiencies associated with hemolytic
syndromes constitute this group of hemolytic anemias. Pyruvate kinase (PK)
deficiency is the prototype of the enzymopathies involving the Embden-Meyerhof
pathway of anaerobic glycolysis in the red cell. PK deficiency is inherited as an
autosomal recessive trait and affects both sexes equally. An unusually high
incidence exists among the Pennsylvania Amish. A discrepancy between red cell
energy needs and adenosine triphosphate–generating capacity produces irreversible
membrane injury with cellular distortion, rigidity, dehydration, and premature
destruction of the red cells by the spleen. 23, 51 The severity of the anemia is
variable. Splenectomy results in improvement, but hemolysis is not abolished, and
mild anemia persists. After splenectomy, transfusion requirements are reduced,
young children experience a period of rapid catch-up growth, and the danger from
aplastic crises is reduced.
It is important to differentiate between pyruvate kinase deficiency and other
erythrocyte enzymopathies that cause hemolytic anemia such as G-6-PD deficiency
and its variants. Specific enzyme assays are employed for this purpose. In G-6-PD
deficiency, hemolysis is precipitated by infection and other acute illness, certain
drugs, and fava beans. Splenic enlargement is rare, in contrast to frequent
splenomegaly with pyruvate kinase deficiency, and splenectomy is not indicated
for patients with G-6-PD deficiency. A role for splenectomy in other erythrocyte
enzyme deficiency states has not been established.
Sickle Cell Anemia
Sickle cell anemia is a hereditary hemolytic anemia occurring in blacks who are
homozygous for the sickle hemoglobin (HbS) gene. Sickle hemoglobin (HbS)
differs from normal adult hemoglobin (HbA) only in the substitution of valine for
glutamic acid in the sixth position of the beta chain. HbS, which results from this
single amino acid substitution, imparts the sickle shape to deoxygenated red blood
cells and is responsible for the wide spectrum of clinical features that characterize
sickle cell anemia. The highest incidence of HbS occurs among black Africans and
descendants of emigrants from equatorial Africa. Sickle cell anemia (homozygous
state for HbS) occurs in approximately 0.5% of the black population, and sickle
cell trait (heterozygous state for HbS) is present in approximately 8% of African
Americans. In the homozygous state, HbA is totally lacking and the red cells
contain predominantly HbS. The red cells of individuals with sickle cell trait
contain both HbA and HbS, with the relative amount of HbS ranging between 35%
and 45%. A combination of two variant hemoglobin genes or a combination of a
variant hemoglobin and an interacting thalassemia gene results in doubly
heterozygous states designated by both aberrant gene products (e.g., HbS/C,
HbS/beta thalassemia).
Under conditions of reduced oxygen availability, red cells containing HbS acquire
the sickle-shaped deformity due to the intracellular polymerization of the HbS
molecules. Sickling of erythrocytes containing HbS occurs more readily with a
reduced pH, higher intracellular concentration of HbS, low intracellular
concentrations of HbF (fetal hemoglobin), and conditions favoring hemoglobin
deoxygenation. Increased blood viscosity due to the sickled cells and an increased
adhesion of sickled cells to vascular endothelium result in circulatory stasis and
stagnation that leads to further reduction in oxygen tension, further sickling, and a
vicious cycle of erythrostasis. The consequent thrombosis, ischemia, necrosis, and
organ fibrosis result in the clinical features of sickle cell anemia.
Patients with sickle cell anemia characteristically are without symptoms until the
second half of the first year of life due to an initial sufficiency of HbF that limits
clinically significant sickling. Clinical features of sickle cell anemia, which are
both acute and episodic (crises) and chronic and progressive, are more a
consequence of the rheologic properties of the sickle cells than of the anemia itself.
Patients with sickle cell crisis often have severe abdominal pain and signs of
peritoneal irritation similar to those of acute surgical illnesses such as acute
cholecystitis and appendicitis. Clinical features of abdominal crises in patients with
sickle cell anemia tend to be similar for a given individual, and deviation from
previous patterns may be an important differentiating feature of an acute surgical
illness in patients with sickle cell anemia. 27 Chronic features of sickle cell anemia
include retarded growth and development after the first decade; bone and joint
disease; cardiovascular, pulmonary, hepatobiliary, genitourinary, and neurologic
manifestations; hematuria; priapism; and ulcerations over the malleoli and distal
portions of the legs. The incidence of pigment gallstones in patients with sickle cell
anemia increases with age. Calculi appear first in childhood (2–4 years of age) and
are present in approximately 70% of adult patients.
Diagnosis is established by the presence of characteristic sickle cells on blood
smear, hemoglobin electrophoresis demonstrating predominantly HbS, variable
amounts of HbF (5%–15%) and no HbA, and the presence of the sickle cell trait in
both parents. Treatment is palliative and is directed toward minimizing
complications of the disease. Many patients die during childhood from infections,
renal failure, and heart failure. Rarely will a patient with sickle cell anemia have a
relatively normal life span.
The role of the spleen in sickle cell anemia is unclear. Sequestration crisis
characterized by sudden trapping of blood in the spleen is a complication that
occurs almost exclusively in infants and young children whose spleens are
chronically enlarged. Further enlargement of the spleen occurs rapidly at the
expense of the blood volume, and hypovolemic shock and death may occur within
hours. Splenomegaly first becomes apparent after 6 months of age and
characteristically persists throughout childhood. Despite splenomegaly, splenic
hypofunction may be documented as early as 5 months of age, and the risk of
overwhelming infection exists in a child with sickle cell anemia by age 1 year. By
adolescence or early adult life, recurrent infarctions have resulted in splenic
atrophy and functional asplenia (hyposplenism). (See Hyposplenism and The
Problem of Overwhelming Postsplenectomy Sepsis.) Splenectomy may be
beneficial to the occasional child with sickle cell anemia in whom excessive red
cell sequestration occurs in an enlarged spleen. The beneficial effect of
splenectomy clearly is related to spleen size and is most effective in children with
large spleens.
Sickle cell trait is rarely associated with significant clinical or hematologic
manifestations, although splenic infarction has occurred in patients flying at high
altitudes in unpressurized aircraft.
Thalassemia (Thalassemia Syndromes)
These hereditary hemolytic anemias result from a defect in hemoglobin synthesis
in which one of the hemoglobin polypeptide chains is synthesized at a markedly
reduced rate. Specific pairs of genes are responsible for synthesis of the alpha,
beta, gamma, and delta chains of the hemoglobin molecule, and a deficiency in
synthesis of one of these subunits may lead to one of the thalassemia syndromes.
Thalassemia is classified by the deficient peptide chain. Beta-thalassemia, in
which there is a quantitative reduction in the rate of beta chain synthesis, is the
most common type of thalassemia. When the abnormal gene is inherited from both
parents (homozygous), severe anemia, termed thalassemia major, results.
Heterozygous patients have a mild anemia termed thalassemia minor. The term
thalassemia intermedia is used to describe some homozygous patients who have a
milder than usual course and some heterozygous patients who have a more severe
course than usual. In thalassemia major, the reduction in the rate of beta chain
synthesis produces a marked decrease in the amount of normal adult hemoglobin
(HbA) with a compensatory increase in fetal hemoglobin (HbF). Homozygous
alpha-thalassemia is incompatible with life, and these infants are stillborn or die
shortly after birth. Patients with heterozygous alpha-thalassemia have a mild form
of anemia similar to that in heterozygous beta-thalassemia.
The pathogenesis of hemolysis in thalassemia lies in the unbalanced synthesis of
the polypeptide chains. Because of the absence of the complementary polypeptide
chain with which to bind, the overproduced normal chains form aggregates that
precipitate within the red cell cytoplasm and lead to premature cell destruction. In
homozygous beta-thalassemia (thalassemia major), the deficiency of beta chain
synthesis causes a relative overproduction of alpha chains, which undergo
aggregation to form insoluble inclusions in bone marrow erythroid precursors.
Ineffective erythropoiesis occurs because of the death of many of these cells.
Additionally, the inclusion-bearing red cells are detained in the spleen, where they
sustain mechanical and metabolic injury that facilitates their ultimate destruction.
Thalassemia major results in a severe anemia and clinical manifestations, usually
within the first year of life. Pallor, retarded growth, and enlargement of the head
with thalassemic facies are present, along with splenomegaly and hepatomegaly.
The intense erythroid hyperplasia in the bone marrow causes expansion of the
medullary cavities and attenuation of the cortex, producing bony abnormalities and
a predisposition to fractures. Iron overload due to defective iron utilization coupled
with increased iron absorption and frequent blood transfusions is a common
complication.
The peripheral blood smear in thalassemia major shows a microcytic hypochromic
anemia with a severe degree of poikilocytosis, anisocytosis, and
polychromatophilia. Nucleated red cells are invariably present and may outnumber
the leukocytes. Reticulocytosis and leukocytosis are characteristic, but the platelet
count is generally normal. Hemoglobin electrophoresis in thalassemia major
reveals absence or almost complete absence of HbA with the presence of large
amounts of HbF.
Treatment consists of transfusion therapy and iron chelation, and splenectomy is
effective in selected patients. Although the basic hematologic disease is not
influenced, splenectomy decreases blood transfusion requirements and relieves
discomfort from splenomegaly. Most patients with thalassemia major die during
the second decade of life from complications of iron excess with myocardial
hemosiderosis. Patients with alpha-thalassemia minor and beta-thalassemia minor
rarely need treatment, and an important therapeutic consideration for patients with
thalassemia minor is avoidance of therapeutic iron to minimize the risk of iron
overload.
Autoimmune Hemolytic Anemia
Autoimmune hemolytic anemia is an acquired hemolytic anemia resulting from
antibodies that are produced by the body against its own red cells. Patients with
AIHA have the usual manifestations of hemolysis with anemia, reticulocytosis, a
shortened erythrocyte survival time, fluctuating jaundice, and splenomegaly. The
blood smear in AIHA shows spherocytes and microspherocytes in numbers
exceeded only in hereditary spherocytosis. The distinguishing feature of AIHA is a
positive direct Coombs test, which identifies antibody on the red cell surface. The
type of antibody attached to the red cell determines the mechanism of hemolysis as
well as the site for primary destruction of the sensitized cells. Anti–red cell
antibodies are classified as warm reactive or cold reactive, depending on whether
they bind to red cells most avidly at 37º C or have progressively greater affinity for
erythrocytes as the temperature approaches 0º C.
Warm-reactive antibodies usually are IgG (less commonly IgM, IgA, or a
combination) and facilitate sequestration and destruction of sensitized erythrocytes
in the spleen. When IgG-coated red cells become attached to splenic macrophages,
which have receptors for the Fc portion of the IgG molecule, portions of the red
cell membrane are removed, rendering the erythrocyte more spherical and more
susceptible to sequestration and premature destruction. Red cells coated by both
IgG and complement are destroyed by the reticuloendothelial system generally and
not primarily by the spleen. Cold-reactive antibodies usually are IgM (rarely IgG
or IgA) and bind to red cells mainly in the peripheral circulation where the blood
temperature is cooled. Cold-reactive antibodies may cause either immediate
intravascular hemolysis by complement-mediated mechanisms or sequestration and
destruction of sensitized red cells by the liver. These patients usually have chronic
hemolysis that is acutely worsened by cold exposure and often demonstrate
acrocyanosis (Raynaud's phenomenon) due to intracapillary red cell agglutination.
The designation autoimmune in AIHA must not obscure the fact that in many cases
the hemolytic process is associated with or related to a drug or a reversible disease
that can be eliminated. Drugs associated with AIHA include penicillin,
cephalothin, streptomycin, methyldopa (Aldomet), quinidine, quinine, phenacetin,
p-aminosalicylic acid, and several sulfonamides.
AIHA may occur in association with another disease, such as mycoplasmal
pneumonia, viral infections, chronic lymphocytic leukemia, lymphoma, Hodgkin's
disease, systemic lupus erythematosus, infectious mononucleosis, and AIDS.
When a drug exposure or an underlying disease is identified, AIHA is termed
secondary. When no other etiologic association is demonstrable, AIHA is
classified as primary or idiopathic. AIHA occurs at any age and in both sexes but is
more common in women older than age 50. Pallor and splenomegaly are the main
physical findings in idiopathic AIHA, whereas in secondary AIHA additional
clinical features of the underlying disease are present. The severity and duration of
the hemolytic anemia may vary, and in some patients the course is rapid and
fulminating. Severe hemolysis may produce hemoglobinuria and acute tubular
necrosis. When AIHA follows mycoplasmal pneumonia, the disease may be acute
and self-limited over several weeks and require no therapy. More often the disease
is chronic, with varying degrees of severity over months or years.
Treatment is directed toward the hemolytic anemia and any underlying disease.
Blood transfusions, corticosteroid therapy, and splenectomy are important aspects
of treatment for the anemia. Splenectomy is usually performed in patients with
AIHA in whom either corticosteroids are ineffective or an excessive corticosteroid
dose is required, or when complications preclude corticosteroid use. Chromium51–labeled red cell studies are useful to measure the degree of splenic
sequestration and to serve as a guide for selecting patients who are most likely to
respond to splenectomy. Splenectomy results in a favorable response, with
complete hematologic remission in approximately 80% of patients demonstrating
significant splenic sequestration. Lack of significant red cell sequestration by the
spleen does not preclude a good response to splenectomy. Splenectomy is more
likely to induce a complete and sustained remission in primary (idiopathic) AIHA
in which only IgG (warm-reactive) antibodies coat the red cells. In addition to
removing the primary site for destruction of the sensitized red cells, splenectomy
can be expected to significantly reduce production of anti-red cell antibody,
because the spleen is a major site for IgG antibody production. The prognosis for
patients with secondary AIHA depends mainly on the underlying disease and is
generally favorable when the hemolytic anemia follows a viral illness or is related
to a drug exposure. Prognosis is poor when AIHA is associated with an underlying
malignancy or one of the collagen diseases. The presence of complement indicates
greater likelihood of association with an underlying disease than the presence of
IgG alone coating the red cells. AIHA due to cold-reactive antibodies is usually not
benefited by splenectomy, and treatment for these patients consists of avoiding
cold temperatures, treating any underlying disease, suppression of antibody
production, and employing plasmapheresis in acutely ill patients.
Hereditary Hydrocytosis and Xerocytosis
Hereditary hydrocytosis and xerocytosis are rare forms of hemolytic anemia that
result from a primary alteration in red cell membrane monovalent cation
permeability. If the major effect involves membrane permeability to sodium,
sodium gain exceeds potassium loss with an increase in total intracellular cation
content and water movement into the red cell. The water-distended red cells
(hydrocytes) have increased fragility, a low mean corpuscular hemoglobin
concentration and an elevated mean corpuscular volume, and a characteristic fishmouth (stomatocyte) appearance on peripheral blood smear. When the
permeability disorder allows potassium loss to exceed sodium gain, total
intracellular cation content decreases, with resulting loss of water and cell
dehydration. The dehydrated red cells (xerocytes) have a low mean corpuscular
volume, an elevated mean corpuscular hemoglobin concentration, and a dense
appearance on blood smear. Xerocytosis is differentiated from hereditary
spherocytosis, elliptocytosis, or other conditions where the mean corpuscular
hemoglobin concentration is elevated by red cell morphology and resistance of the
cells to osmotic lysis.
Splenectomy is effective in hydrocytosis by reducing hemolysis and eliminating
the need for transfusion and the potential risk for life-threatening aplastic crises. In
contrast to hereditary spherocytosis, mild hemolysis persists after splenectomy, and
the risk of pigment gallstone formation continues. Splenectomy is seldom required
for xerocytosis because the hemolysis is usually not severe.
MISCELLANEOUS
ANEMIAS
SOMETIMES
BENEFITTED
BY
SPLENECTOMY
Splenectomy is occasionally performed for rare disorders such as acquired
idiopathic sideroblastic anemia, congenital dyserythropoietic anemia, and
porphyria erythropoietica. In these syndromes, splenectomy may offer significant
benefits by improving the hemolytic anemia and reducing transfusion
requirements.
Myeloid Metaplasia (Agnogenic Myeloid Metaplasia, Myelofibrosis,
Myelosclerosis)
Myeloid metaplasia is an unusual illness with numerous names but no known
cause. There is gradual and progressive impairment of normal hematopoiesis due
to continued fibroblastic proliferation, which ultimately produces sclerosis of the
bone marrow and myelofibrosis. 5, 23, 51 The panproliferative process produces
increased connective tissue proliferation, also in the liver, spleen, and lymph
nodes, and concomitant proliferation of hematopoietic elements in the spleen, liver,
and long bones. Myeloid metaplasia is closely related to polycythemia vera,
myelocytic (myelogenous) leukemia, and essential (idiopathic) thrombocytosis and
with these conditions constitutes a disease spectrum termed myeloproliferative
disorders. Characteristic features of myeloid metaplasia are (1) progressive fibrosis
of the bone marrow, (2) extramedullary hematopoiesis, (3) presence in the
peripheral blood of immature erythroid and granulocyte precursors (leukoerythroid
response), and (4) massive splenomegaly. In some patients the enlarged spleen
provides an expanded vascular space with an associated increase in plasma
volume. By serving as a shunt, the enlarged spleen may result in a decreased
peripheral vascular resistance and an increased cardiac workload. Portal
hypertension with varices and ascites may develop in some patients from hepatic
fibrosis, increased forward blood flow through the splenoportal system, or a
combination of these factors.
Most patients are middle-aged or older and have symptoms related to anemia and
splenomegaly. Malaise, dyspnea, and weight loss are common, and symptoms due
to splenomegaly include abdominal fullness and discomfort, early satiety, and
intermittent pain from splenic infarction. Less common symptoms include episodes
of spontaneous bleeding, recurrent infections, bone pain, pruritus, and
complications of hyperuricemia. Splenomegaly due primarily to extramedullary
hematopoiesis is invariably present, and myeloid metaplasia (myelofibrosis) has
been responsible for some of the largest spleens the authors have encountered (Fig.
36–12 Fig. 36–12). Hepatomegaly is present in 50% to 75% of the patients.
The peripheral blood smear characteristically shows immature red cells,
anisocytosis, poikilocytosis, and numerous teardrop and elongated shapes. Most
patients have a mild normochromic anemia that worsens as myelofibrosis
progresses. The white blood cell count is usually depressed but may reach levels of
50,000 per cu. mm. or higher. Immature granulocyte forms are present, and these,
along with the red cell abnormalities, constitute a leukoerythroblastic anemia. A
normal platelet count is present in 25% of patients, and thrombocytopenia occurs
in approximately one third. Thrombocytosis of over 1 million per cu. mm. occurs
in 25% of the patients. The leukocyte alkaline phosphatase score is usually normal
or high. Hyperuricemia is present frequently and should be anticipated to avoid
episodes of gouty arthritis and renal calculi. Bone marrow biopsy reveals varying
degrees of fibrosis with scattered foci of hematopoietic elements.
Treatment of patients with myeloid metaplasia is directed toward the anemia,
thrombocytosis, and splenomegaly and includes blood transfusions, corticosteroid
and androgen therapy, chemotherapy (busulfan, hydroxyurea), and splenic
irradiation. Hydroxyurea is of great value in rapidly reducing and controlling the
marked thrombocytosis associated with this disease. In addition, hydroxyurea may
be beneficial in slowing development of splenomegaly.
Splenectomy is effective in controlling anemia and thrombocytopenia and relieving
symptoms due to painful or massive splenomegaly. 51 Splenectomy should be
performed early rather than late in the course of the illness, because the risk of
complications after splenectomy increases with progression of the disease.
Indications for splenectomy are (1) an increasing transfusion requirement, (2)
thrombocytopenic bleeding episodes, (3) symptomatic splenomegaly, (4) high
output cardiac failure, and (5) portal hypertension with bleeding varices. 23, 42,
51 Although the course of myeloid metaplasia is not altered by splenectomy,
certain prognostic factors are associated with favorable long-term survival. These
include a hemoglobin level greater than 10 gm. per 100 ml., a platelet count greater
than 100,000 per cu. mm., a normal leukocyte alkaline phosphatase score, and a
spleen weighing less than 3,000 gm.
Loss of the spleen as a major site of extramedullary hematopoiesis rarely has an
adverse influence on the hematologic status of patients with myeloid metaplasia.
Morbidity and mortality rates after splenectomy, however, are significantly higher
for patients with myeloid metaplasia than for patients with other hematologic
disorders. In advanced disease, the patients are in poor general condition, and the
risk of postoperative hemorrhage and infection is great. Additionally, after
splenectomy many of these patients have a marked thrombocytosis that is
associated with an increased risk of thromboembolic complications that include
thrombosis of the portal vein and major mesenteric veins. Specific antiplatelet
therapy may be needed in the preoperative preparation and postoperative care of
patients undergoing splenectomy for myeloid metaplasia. The spectrum of
antiplatelet therapy includes administration of aspirin, dipyridamole, heparin,
dextran, hydroxyurea, and busulfan. Hydroxyurea is especially valuable in
reducing and controlling the marked thrombocytosis that can occur after
splenectomy. A rapid reduction in the platelet count can be achieved by
plateletpheresis (thrombocytopheresis) in patients who have thrombohemorrhagic
manifestations and severe thrombocythemia.
In some patients with myeloid metaplasia, there is transition to another form of
myeloproliferative disorder, and in approximately 10% of patients, acute myeloid
leukemic transformation occurs. The median survival after diagnosis of myeloid
metaplasia is 5 years, but many patients live longer. Death usually results from
hemorrhage, infection, or cardiac or renal failure.
Felty's Syndrome
Felty's syndrome consists of the triad of severe rheumatoid arthritis,
granulocytopenia, and splenomegaly. It usually occurs in patients with a long
history of rheumatoid arthritis. Patients with Felty's syndrome fail to show a
substantial granulocytosis in response to infection, and severe, persistent, and
recurrent infections are characteristic. Antibody directed against granulocytes is
demonstrable in most patients. Mild anemia and thrombocytopenia are present in
some cases. Moderate splenomegaly is common and is caused by the expansion of
the red pulp.
Splenectomy is effective in most patients with Felty's syndrome and should be
performed in those having significant recurrent infections and chronic leg ulcers.
The granulocyte response is immediate, and most patients will have resolution or
significant improvement of granulocytopenia within 48 to 72 hours after
splenectomy. Long-term correction of the granulocytopenia is achieved in the
majority of patients with a marked reduction in the incidence of infections and
healing of leg ulcerations. Controversy exists regarding the advisability of
splenectomy for patients with Felty's syndrome who have severe granulocytopenia
(less than 500 granulocytes/cu. mm.) but have not yet developed severe or
recurrent infections.
Gaucher's Disease
Gaucher's disease is a disorder of lipid metabolism that may result in massive
splenomegaly and hypersplenism. Genetically transmitted as an autosomal
recessive trait, the disease is most commonly found in Ashkenazi Jews. Caused by
a deficiency of beta-glucocerebrosidase, an enzyme responsible for breaking down
certain lipid complexes, Gaucher's disease ultimately leads to retention of
glucocerebroside in macrophages, especially those of the spleen, liver, bone
marrow, and lungs.
Diagnosis is made by finding the typical Gaucher cells in biopsied tissues. These
large-diameter (20–80 mm.) cells, which contain dense fibrillar deposits of
glucocerebroside in the cytoplasm, may be found in any tissue having a fixed
macrophage population (e.g., bone marrow, spleen, and liver).
The appearance of clinical manifestations is earliest and progression of disease is
most rapid in patients having the least glucocerebrosidase activity. Of the three
clinical forms of the disease, the adult form is most common. Splenomegaly, which
may be massive, is usually the presenting feature and may be discovered
accidentally or as a result of symptoms of early satiety, abdominal fullness, or
painful infarctions. Bone pain is common due to bone destruction, which may
result in collapse of vertebral bodies, pathologic fractures, and crippling. Central
nervous system abnormalities are absent in the adult form of Gaucher's disease.
Thrombocytopenia causes recurrent bleeding from the nose and gums, purpura,
and petechiae.
The infantile form, in which the central nervous system is the major site of
involvement, is a much less common form of Gaucher's disease. Retarded
development, early appearance of neurologic signs, seizures, hepatosplenomegaly,
and cachexia are followed by death, usually before 3 years of age. The juvenile
form appears during childhood and usually becomes apparent due to splenomegaly.
In contrast to the adult form of Gaucher's disease, there is progressive neuronal
damage and development of central nervous system abnormalities.
Moderate to severe thrombocytopenia is present in most patients and is the most
troublesome hematologic manifestation. Moderate normocytic anemia and
leukopenia are common. Splenectomy is almost uniformly effective in correcting
the cytopenias and relieves symptoms due to splenomegaly and recurring splenic
infarction, although there is no evidence that splenectomy influences other aspects
of the disease.
Subtotal splenectomy has been performed for patients with the adult form of
Gaucher's disease who have developed massive splenomegaly and hypersplenism.
20 Hypersplenism was controlled, and dramatic improvement occurred in appetite
and general feeling of well being, after resection of approximately 85% of the
spleen. Functioning residual splenic tissue was demonstrable postoperatively. In
addition to controlling cytopenias and eliminating symptoms related to
splenomegaly, subtotal splenectomy in Gaucher's disease may provide a splenic
remnant large enough to afford protection against overwhelming sepsis.
Cysts and Tumors of the Spleen
The differential diagnosis of splenomegaly and isolated splenic masses includes
cysts and primary tumors of the spleen other than systemic neoplasms of lymphoid
tissue and the reticuloendothelial system. Splenic cysts and primary tumors are rare
but must be considered in the differential diagnosis of a left upper quadrant mass.
Cystic lesions of the spleen comprise parasitic and nonparasitic cysts. Parasitic
cysts are due almost exclusively to echinococcal disease and account for 60% to
70% of splenic cysts in countries where hydatid disease is endemic (South
America, Australia, and Greece). Because echinococcal disease is rare in the
United States, nonparasitic cysts are encountered much more frequently in this
country. Nonparasitic cysts are classified as primary or true cysts, which have an
epithelial lining, and pseudocysts. Pseudocysts are much more common and
probably result from liquefaction of old hematomas or areas of infarction and
inflammation. True cysts of the spleen are very rare and include epidermoid and
dermoid cysts, cystic hemangiomas, and cystic lymphangiomas.
Symptoms of splenic cysts are vague and are caused primarily by mass effect,
compression of adjacent viscera, and diaphragmatic irritation. Although selected
nonparasitic cysts may be effectively managed by aspiration, splenectomy should
be performed for all large cysts and those with uncertain diagnosis. In some
patients a splenic cyst may be suitably located for excision by partial splenectomy.
Intraoperative drainage may facilitate dissection and splenectomy for very large
cysts. External drainage and marsupialization have an unacceptable incidence of
infection, bleeding, and cyst reaccumulation and are inappropriate techniques for
management of splenic cysts.
Malignant and benign primary tumors of the spleen are rare. Most primary
malignant tumors are angiosarcomas, although primary splenic lymphoma may
occur. Before primary parenchymal lymphoma is diagnosed in the spleen, the bone
marrow, nodal regions, liver, and other areas must be evaluated and found to be
free of disease. Benign splenic tumors include hamartomas, lymphangiomas,
hemangiomas, and lipomas.
Except for involvement with Hodgkin's disease and NHLs, metastatic disease to
the spleen is diagnosed infrequently. The spleen's effective filtering mechanism
and high blood flow suggest that the spleen would develop metastatic lesions more
often. Although spleens from patients dying of metastatic tumors frequently reveal
malignant cells, metastatic deposits are rare. Studies in rodents have confirmed that
metastatic tumors rarely develop in the spleen after injection of tumor cells into the
splenic artery. It is probable that the splenic immune mechanisms that so
efficiently destroy abnormal red cells also eliminate the majority of metastatic
tumor cells that are trapped in the red pulp.
Splenic Vein Thrombosis
Since the pathophysiology of splenic vein thrombosis was first elucidated 50 years
ago, this uncommon cause of upper gastrointestinal variceal hemorrhage has been
found to be eminently curable by splenectomy. 6 Pancreatitis is the cause of
splenic vein thrombosis in more than half of the reported cases. Other causes
include pancreatic carcinoma, pancreatic pseudocyst, penetrating gastric ulcer,
retroperitoneal fibrosis, and myeloproliferative disorders. 6 The underlying disease
produces thrombosis of the splenic vein with subsequent development of venous
collateral channels. Because the collateral pathways are usually the short gastric
veins to the submucosal venous plexus of the gastric cardia and fundus, gastric
varices develop.
Splenic vein thrombosis should be suspected in a patient with upper
gastrointestinal hemorrhage, isolated gastric varices on endoscopy, and a history of
pancreatitis or pancreatic cancer. Splenomegaly is variable, and if present it is not
associated with other stigmata of cirrhosis. Anemia is usually present, but tests of
liver function are normal. Definitive diagnosis is made by celiac angiography,
which demonstrates absence of the splenic vein. Splenomegaly may be noted along
with venous collaterals in the splenic hilus.
Splenectomy is curative and eliminates the increased blood flow through
collaterals to the gastric venous plexuses. Although there are no studies that have
followed the course of asymptomatic patients with splenic vein thrombosis, it
seems prudent to consider splenectomy if this diagnosis is made.
RARE SPLENIC DISORDERS
Wandering (Ectopic) Spleen. Congenital deficiency or acquired laxity of the
suspensory ligaments of the spleen may cause extreme splenic mobility. This rare
condition, which is termed wandering or ectopic spleen, permits a normal-sized
spleen to be palpable in the lower abdomen or in the pelvis. The majority of cases
of wandering spleen have occurred in young and middle-aged women in whom
multiparity and laxity of the abdominal wall and splenic ligaments due to the
hormonal effects of pregnancy have been cited as predisposing causes. A
wandering spleen may be an incidental finding on physical or radiographic
examination. An elongated splenic pedicle predisposes a wandering spleen to
torsion, leading either to development of acute symptoms due to splenic volvulus
and infarction or to chronic and intermittent abdominal discomfort due to
spontaneous torsion and detorsion. Useful diagnostic tests in the patient who is
asymptomatic or has chronic and recurring symptoms include abdominal CT or
ultrasonography, a splenic radionuclide scan, and visceral arteriography. Splenic
volvulus with infarction requires emergency splenectomy. Selected asymptomatic
patients and those with chronic and recurring symptoms may sometimes be
managed successfully by splenopexy, which preserves splenic function and avoids
the potential danger of postsplenectomy sepsis.
Splenic Artery Aneurysm. Aneurysms of the splenic artery are rare and occur more
frequently in females, in whom the most common etiology is medial dysplasia of
the arterial wall. Atherosclerosis accounts for the majority of splenic artery
aneurysms in males. Additional causes include focal arterial injury due to
pancreatitis, trauma or arteritis due to septic emboli, portal hypertension with
splenomegaly, and an ill-defined pathogenesis associated with multiparity. Most
splenic artery aneurysms are asymptomatic, and characteristic eggshell
calcification of an arteriosclerotic aneurysm may be an incidental finding on an
abdominal radiograph. When symptoms are present, they are variable and consist
primarily of vague left upper quadrant discomfort. Aneurysmal rupture may occur,
and the rupture initially may be contained within the lesser sac. Initial aneurysmal
rupture into the peritoneal cavity or delayed rupture from the lesser sac are
associated with findings of hemoperitoneum and exsanguinating hemorrhage.
Rarely, a splenic artery aneurysm ruptures into the gastrointestinal tract, pancreatic
duct, or splenic vein. The mortality with a ruptured splenic artery aneurysm
remains high. Excision of the aneurysm is advisable for symptomatic aneurysms
and for asymptomatic aneurysms in patients who are acceptable operative risks.
This is especially important for women of childbearing age who have an increased
propensity for aneurysmal rupture during pregnancy. Elective operation has a low
risk of mortality and minimal morbidity. In the treatment of splenic artery
aneurysm, the spleen should be preserved if possible.
Splenic Abscess. Splenic abscess occurs rarely and usually results from (1)
bacteremia associated with a primary septic focus such as bacterial endocarditis or
lung abscess or (2) secondary infection in an area of the spleen damaged by
infarction (sickle cell anemia or leukemia), trauma, or parasitic infestation. Clinical
features of splenic abscess are those of left subphrenic suppuration and include
fever, chills, left upper quadrant tenderness, and often splenomegaly. Imaging
techniques (ultrasonography and radionuclide and CT scans) are useful in
differentiating splenic abscess from left subphrenic abscess and in determining
whether there is a single abscess or multiple abscesses within the spleen. CT is
probably the most direct way of evaluating the spleen and establishing an early
diagnosis.
Splenectomy has been the preferred treatment for most patients in the past and
remains a standard means of safe and rapid management. Splenotomy and abscess
drainage may be advisable for selected patients with a single abscess and extensive
adhesions between the spleen and adjacent structures. Image-guided percutaneous
drainage may be appropriate in the management of some patients with splenic
abscess. Percutaneous drainage is most likely to be successful, if the abscess is
unilocular and if the abscess contents are amenable to complete evacuation by an
in-dwelling suction catheter.