Clinical Approach to Isolated Splenomegaly 441

Clinical Approach to

77 Isolated Splenomegaly

MANORANJAN MAHAPATRA, PRAVAS MISHRA, RAJAT KUMAR

Patients with splenomegaly may come to medical such as in chronic myeloid metaplasia; 5) infiltrative
attention for a variety of reasons. However, patients with such as in sarcoidosis and some neoplasms; and 6)
no obvious explanation for an enlarged spleen present neoplastic such as in chronic lymphocytic leukemia and
a difficult diagnostic problem. A detailed history taking, the lymphomas. Miscellaneous causes of splenomegaly
appropriate clinical examination and relevant include trauma, cysts, hemangiomas, and other
investigations is tool for a diagnosis of splenomegaly. malformations.
Appropriate investigations in most patients with
undiagnosed splenomegaly will yield a diagnosis. CLINICAL SIGNIFICANCE OF SPLENOMEGALY
Patients with undiagnosed splenomegaly, who are
It might be noted that spleen size is not a reliable
otherwise well and who have no evidence of systemic
guide to spleen function, because palpable spleens are
diseases, particularly if the spleen is minimally enlarged,
not always abnormal and hypersplenic spleens are not
may be followed with careful and regular observation.
always palpable. Patients with emphysema and low
diaphragms commonly have palpable but normal-sized
NORMAL FUNCTIONS OF SPLEEN
spleens. One study showed that 63 (3%) of 2200 healthy
In many instances the spleen enlarges as it performs college freshmen had palpable spleens2 and another
its normal functions. The four most important normal study showed that almost 5 percent of hospital patients
functions of the spleen are 1) clearance of micro- with normal spleens by scan were thought to have
organisms and particulate antigens from the blood palpable spleens by their physicians3. In contrast, clinical
stream; 2) synthesis of immunoglobulin and properdin splenomegaly rarely noted in immune thrombocyto-
factors; 3) destruction of effete or abnormal RBCs; and penic purpura, despite avid destruction of antibody-
4) embryonic hematopoiesis, which can reactivate as coated platelets by the spleen.
extra-medullary hematopoiesis in certain diseases. Although palpable splenomegaly can be detected in
only a few patients who do not have an obvious
MECHANISMS OF SPLENOMEGALY pathophysiologic disorder, the condition should be of
Many of the mechanisms of splenic enlargement are interest to the primary care physician because it is
exaggerated forms of normal spleen function1. While a generally this physician who detects the abnormality.
wide variety of diseases are associated with enlargement The presence of a palpably enlarged spleen must be
of the spleen, 6 etiologies of splenomegaly are considered considered a physical finding that demands further
primary, including 1) immune response work evaluation.
hypertrophy such as in subacute bacterial endocarditis Patients with splenomegaly may come to medical
or infectious mononucleosis; 2) RBC destruction work attention for a variety of reasons. Patients may complain
hypertrophy such as in hereditary spherocytosis or of left upper quadrant pain or fullness or of early satiety.
thalassemia major; 3) congestive such as in splenic vein A splenic infarct, which typically manifests with left
thrombosis or portal hypertension; 4) myeloproliferative upper quadrant pain that sometimes radiates to the left
442 Medicine Update

shoulder, can be the first clue to the existence of an Table 1: Diagnostic approach to isolated splenomegaly
enlarged spleen. Rarely, splenomegaly can initially 1. Does the patient have a known illness that causes spleno-
manifest with the catastrophic symptoms of splenic megaly*?
rupture. Some patients are found to have splenomegaly • Infections: e.g. malaria, kala-azar, infectious mononucleosis
as a result of evaluation for unexplained cytopenias. etc
Splenomegaly can be discovered incidentally on • Hematological: e.g. hemolytic anemias, hemoglobinopathis,
physical examination. In recent years, splenomegaly has malignancies, myeloproliferative disorders, etc.
been frequently discovered on imaging studies of the • Hepatic: e.g. portal hypertension, splenic or portal vein
abdomen performed for other purposes. thrombosis
Treat and monitor for resolution.
CLINICAL EVALUATION OF SPLENOMEGALY 2. Search for an occult disease**.
• Infections: e.g. infective endocarditis
Physical examination is the most practical and cost
effective method of evaluation of splenomegaly4. The • Hematological: e.g. hereditary spherocytosis, polycythemia
vera
presence of an enlarged spleen can be more precisely
• Hepatic: e.g. cryptogenic cirrhosis
determined, if necessary, by liver-spleen radionuclide
scan, CT, MRI, or ultrasonography. The latter technique • Autoimmune: e.g. systemic lupus erythematosus
is the current procedure of choice for routine assessment • Storage disease: e.g. Gaucher’s disease
of spleen size (normal = a maximum cephalocaudal • Miscellaneous: e.g. sarcoidosis, amyloidosis, tropical
diameter of 13 cm) because it has high sensitivity and splenomegaly, splenic cysts
specificity and is safe, noninvasive, quick, mobile, and If found manage appropriately.
less costly. CT will frequently give a better view of the 3. Diagnostic splenectomy if
consistency of the spleen and can identify splenic tumors • Systemic symptoms are present and suggests malignancy
or abscesses that would otherwise be missed. • Focal replacement of the spleen on imaging studies
Radionuclide scans such as gallium scans can identify • No other sites are available biopsy
active lymphoma or infections. The technetium liver- 4. Monitor closely and repeat studies until the splenomegaly
spleen scan can be important in identifying liver disease resolves or a diagnosis is apparent if
as the cause of splenomegaly; in patients with • Otherwise well and no evidence of systemic diseases
cryptogenic cirrhosis, a technetium liver-spleen scan that • Spleen is minimally enlarged
shows higher activity in the spleen than the liver might
* Varies with age, associated features and geographical area
be the initial hint of liver disease. None of these
** If patient is asymptomatic look for the causes listed in Table 4
techniques is very reliable in the detection of patchy
infiltration e.g., Hodgkin’s disease5. Because of the
malignancies, congestive splenomegaly and anemias.
spleen’s location and its propensity to bleed, needle
Splenomegaly is a multi-disciplinary problem. The
aspiration or cutting needle biopsy of the spleen is rarely
common conditions that result in isolated splenomegaly
performed. In general, a splenic “biopsy” involves
can be divided into different diagnostic groups i.e.
splenectomy, which can be performed at the time of
hematological, hepatic, infective, primary splenic
laparotomy or with laparoscopy.
conditions 6. Indian data on splenomegaly are very
sparse, however, western literature 6 showed the
APPROACH TO ISOLATED SPLENOMEGALY
prevalence of different diagnostic groups resulting in
Splenomegaly may represent a manifestation pri- splenomegaly were hematological: 25-66%, hepatic:
mary disease or of associated disease or probably due 12-46%, infective: 13-25%, primary splenic: 2-5% and
to the previous illness not recognized4. The approach to others: 8-21%.
the patient with undiagnosed splenomegaly must be Proper history taking, appropriate clinical exami-
individualized. The list of causes of splenomegaly is nation and relevant investigations are tool for a diagnosis
formidable; the possibilities are, however, greatly redu- of splenomegaly. A detailed history (i.e. geographical
ced by appropriate clinical evaluation and investigation. area of the residence, duration of splenomegaly,
The approach to a patient with an enlarged spleen progressively enlarged splenomegaly, associated signs
should focus initially on excluding a systemic illness that and symptoms i.e. fever, jaundice, pain abdomen, joint
could explain the splenomegaly (Table 1). A wide variety pain etc, history of alcoholism, family history) is essential
of diseases can lead to splenic enlargement; common in for splenomegaly evaluation. The differential diagnosis
our country are malaria, leishmaniasis, hematological of splenomegaly differs with the splenic size at presen-
 Clinical Approach to Isolated Splenomegaly 443

tation in addition to the age of the patient, clinical Table 2: Causes of asymptomatic splenomegaly
features, associated hepatomegaly and lymphadeno- 1. Liver disease with portal hypertension
pathy. As the prevalence of splenomegaly and relative 2. Splenic vein thrombosis
incidence of diseases associated with it are subject to
3. Agnogenic myeloid metaplasia
geographical variation, a clinician while evaluating a
4. Gaucher’s disease
patient with palpable spleen should keep this factor in
5. Splenic cysts
mind.
6. Sarcoidosis
In one study, Swaroop, et al6 studied 317 patients
7. Amyloidosis
with splenomegaly over a period of 8 years and analyzed
8. Mild hereditary spherocytosis
the association of several clinical and laboratory features
9. Early stages of polycythemia vera
with different diagnostic groups. Hematological diseases
had significant positive associations with massive
splenomegaly, lymphadenopathy and blood cytosis i.e. show a focal abnormality, are sometimes indications for
erythrocytosis, leucocytosis or thrombocytosis. Hepatic splenectomy8. It is particularly important to avoid
diseases had highly significant positive association with splenectomy in a patient with occult liver disease and
hepatomegaly, abnormal liver function tests and blood portal hypertension.
cytopnia (as a part of hypersplenism). Infectious diseases
showed a positive association with fever. Left upper DIAGNOSTIC SPLENECTOMY
abdominal pain had significantly positive association Appropriate investigation in most patients with
with hematological and primary splenic diseases. None undiagnosed splenomegaly will yield a diagnosis.
of the patients with hepatic disease with splenomegaly Patients with undiagnosed splenomegaly, who are
had lymphadenopathy. otherwise well and who have no evidence of systemic
The differential diagnostic possibilities are much diseases, particularly if the spleen is minimally enlarged,
fewer when the spleen is “massively enlarged,” that is; may be followed with careful and regular observation
it is palpable more than 8 cm below the left costal margin at monthly interval. If the spleen size remains
or its drained weight is 1000 g. The vast majority of such unchanged, the patient may be followed up at progres-
patients will have a hematological diseases i.e. non- sively longer intervals. In patients who are unwell or
Hodgkin’s lymphoma, chronic lymphocytic leukemia, who have evidence of systemic diseases, in which
hairy cell leukemia, chronic myelogenous leukemia, appropriate investigations (Table 3) have not yielded a
myelofibrosis with myeloid metaplasia, or polycythemia
vera 7 . Other conditions like Gaucher’s disease,
Table 3: Essential investigations in patients with undiagnosed
Sarcoidosis, Diffuse splenic hemangiomatosis, kala azar, splenomegaly before diagnostic splenectomy
tropical splenomegaly syndrome can result in massive
splenomegaly. 1. Radiology:
Chest X-ray
Patients with no obvious explanation for an enlarged
spleen present a difficult diagnostic problem. Careful CT/MRI Chest/Abdomen

follow-up of these patients sometimes reveals occult 2. Procedures:

liver disease or an autoimmune process that initially Liver Biopsy**
defied diagnosis. Rarely splenomegaly may be the only Bone Marrow Aspirate
sign of portal hypertension. Patients with congestive Bone Marrow Biopsy
splenomegaly from liver disease or from splenic vein Lymph Node Biopsy*
thrombosis can be asymptomatic 7. Other common Broncho-Alveolar Lavage**
causes of asymptomatic splenomegaly are agnogenic Upper GI Endoscopy
myeloid metaplasia, Gaucher’s disease and splenic cysts 3. Blood:
(Table 2). Splenic aspiration is sometimes helpful for the Rheumatoid factor
diagnosis of isolated splenomegaly. Splenic aspiration
Anti-nuclear factor
can detect abnormal cells i.e. LD bodies, malaria
Coomb’s test
parasites, hairy cells, villous lymphocytes and metastatic
Blood cultures
deposits. Concerns about malignancy, particularly in
Serology for HIV, hepatitis and other infections
patients with systemic symptoms such as fever, sweats,
or weight loss or in patients in whom imaging studies * If lymph node palpable. ** If clinically indicated.
444 Medicine Update

diagnosis, resort to surgical removal of the enlarged Table 4: Etiology of Hypersplenism in different conditions
spleen may be required9. In many instances, splenec- Disease Most likely mechanism
tomy is also therapeutic, providing relief from the
consequences of splenomegaly in addition to possibly Hairy cell leukemia Retention of hairy cells in red pulp
forming part of definitive therapy of the underlying Cirrhosis; splenic Increased pooling of blood
Vein thrombosis cells
condition.
Gaucher’s disease Increased pooling and
In one study10, 122 of the 1280 patients underwent dilutional anemia
splenectomy for diagnosis and in 116 patients a specific Felty syndrome Immune system work hypertrophy
disease was identified histologically that explained the
Thalassemia major RE system work hypertrophy
splenomegaly/splenic mass. Malignancy was the most
cause of unexplained splenomegaly or splenic mass,
though benign neoplasms and reactive disorders were
documented in 25% of cases. In anther study 11 , a TROPICAL SPLENOMEGALY SYNDROME
definitive histological diagnosis was established in 9 out
of 10 diagnostic splenectomies; seven of whom had This condition has recently been termed (more
lymphoma. The weight of the excised spleen in all appropriately) as hyperreactive malarial syndrome
patients with lymphoma exceeded 1kg; in all those with (HMS). This is one of the important conditions associated
a diagnosis other than lymphoma, the spleen weighed with isolated splenomegaly14. Evidence linking HMS to
less than 1 kg. malaria is reasonably convincing, although parasitemia
is not demonstrated in these patients. Certain diagnostic
In another study from India12, 41 splenectomies were
criteria must be fulfilled to make a definitive and
carried out for diagnostic purposes. Histopathology of
accurate diagnosis of HMS. The defining criteria include
the spleen showed lymphoma in 15 (37%), tuberculosis
the following:
in five (12%) and other lesions in five (12%) patients.
Sixteen (39%) patients had only congestive spleno- 1. Residence of malaria endemic area.
megaly. In our experience in last 2 years, out of 12 2. Chronic splenomegaly, often massive.
diagnostic splenectomies, 8 had lymphoma, 3 patients 3. Serum IgM at least 2 standard deviations (SD) above
had congestive splenomegaly and another 1 showed local mean.
extramedullary hematopoiesis. One out of three patients
4. High malarial antibody titer.
with congestive splenomegaly subsequently developed
to malignant lymphoma after one and half years. 5. Hepatic sinusoidal lymphocytosis.
Patients with splenomegaly in whom diagnosis is not 6. Clinical and immunological response to antimalarial
reached preoperatively utilizing conventional investi- prophylaxis.
gations are likely to have a lymphomatous process,
particularly if the spleen is grossly enlarged. Pathophysiology
Although the exact mechanism is unknown,
HYPERSPLENISM
evidence suggests that exposure to malaria elicits an
Splenomegaly is often accompanied by hypersple- exaggerated stimulation of polyclonal B-lymphocytes,
nism. This is a complication of splenomegaly and not a leading to excessive and partially uncontrolled
diagnosis13. The specific cause of the splenomegaly must production of immunoglobulin M (IgM) as the initiating
be determined. Classically it refers to 1) splenomegaly; event. IgM is polyclonal and not specific for any one
2) any combination of anemia, leukopenia and/or particular malaria species. Defective immunoregulatory
thrombocytopenia; 3) compensatory bone marrow control of B-lymphocytes by suppressor or cytotoxic T
hyperplasia; and 4) improvement after splenectomy. lymphocytes causes an increase in B lymphocytes and a
Within this framework, however, different diseases may decrease in T lymphocytes in the peripheral blood. This
cause different forms of hypersplenism due to diverse is accompanied by T cell infiltration of the hepatic and
pathophysiological mechanisms (Table 4). Furthermore, splenic sinusoids. An increase occurs in serum
an enlarged spleen can cause problems for the patient cryoglobulin levels, autoantibody levels, and high–
without meeting the aforementioned definition of molecular-weight immune complexes. This leads to
hypersplenism. Thus perhaps hypersplenism could be anemia, deposition of large immune complexes in
redefined to mean that the spleen in question has become Kupffer cells in liver and spleen, reticuloendothelial cell
more harmful than beneficial. hyperplasia, and hepatosplenomegaly.
 Clinical Approach to Isolated Splenomegaly 445

Clinical Manifestations dramatically to splenectomy. Histologically, the spleen

reveals lymphoid hyperplasia with prominent germinal
HMS is most frequently observed in young and
centers throughout parenchyma, which are not found in
middle-aged adults and uncommon in children younger
the normal spleen. The etiology of this condition remains
than 8 years. Abdominal swelling and pain generally
obscure. There is no evidence to support an infectious
chronic, and a dragging sensation are the most common
origin such as in the tropical splenomegaly syndrome,
presenting symptoms of HMS. Patients may rarely have
which is due to chronic malarial infection. The possibility
intermittent fever, but the presence of fever should raise
of prelymphoma was raised by dacie et al after the
questions regarding an alternative diagnosis. Spleno-
observation that 40% of patients they treated, malignant
megaly, usually moderate to massive, is the hallmark of
lymphomas subsequently developed. Review of
HMS. Most patients have accompanying hepatomegaly.
literature16 reveals that in 20% of patients with massive
Hematologic manifestations include the following:
splenomegaly of unknown origin reported from
1. Anemia (normocytic normochromic) is almost nontropical countries have subsequently had malignant
always present and is related to the degree of lymphoma.
splenomegaly. Several factors contribute to its
etiology, including pooling of red cells in the spleen, REFERENCES
hypersplenism, and increased red cell destruction
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and turnover, but the major factor is increased
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5. Fritscher-Ravens A, Mylonaki M, Pantes A, et al. Endoscopic
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