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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 and some ; and 6) no obvious explanation for an enlarged present neoplastic such as in chronic lymphocytic and a difficult diagnostic problem. A detailed history taking, the . Miscellaneous causes of splenomegaly appropriate clinical examination and relevant include trauma, , , 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 are , 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 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 Patients with splenomegaly may come to medical or ; 2) RBC destruction work attention for a variety of reasons. Patients may complain hypertrophy such as in hereditary or of left upper quadrant pain or fullness or of early satiety. major; 3) congestive such as in splenic vein A splenic infarct, which typically manifests with left thrombosis or ; 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. , kala-azar, infectious mononucleosis as a result of evaluation for unexplained cytopenias. etc Splenomegaly can be discovered incidentally on • Hematological: e.g. hemolytic , hemoglobinopathis, . 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 performed for other purposes. thrombosis Treat and monitor for resolution. CLINICAL EVALUATION OF SPLENOMEGALY 2. Search for an occult **. Physical examination is the most practical and cost • Infections: e.g. effective method of evaluation of splenomegaly4. The • Hematological: e.g. , vera presence of an enlarged spleen can be more precisely determined, if necessary, by -spleen radionuclide • Hepatic: e.g. cryptogenic scan, CT, MRI, or ultrasonography. The latter technique • Autoimmune: e.g. systemic 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, , 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 if consistency of the spleen and can identify splenic tumors • Systemic symptoms are present and suggests malignancy or 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 or infections. The technetium liver- 4. Monitor closely and repeat studies until the splenomegaly spleen scan can be important in identifying 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 be the initial hint of liver disease. None of these * Varies with age, associated features and geographical area ** 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. conditions6. Indian data on splenomegaly are very sparse, however, western literature6 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, , 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, , 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 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 with different diagnostic groups. Hematological diseases 9. Early stages of polycythemia vera had significant positive associations with massive splenomegaly, 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 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 , chronic myelogenous leukemia, appropriate investigations (Table 3) have not yielded a myelofibrosis with myeloid metaplasia, or polycythemia vera7. 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 Biopsy* 7 thrombosis can be asymptomatic . 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 patients with systemic symptoms such as fever, sweats, Serology for HIV, and other infections 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 9 spleen may be required . 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 condition. Vein thrombosis cells 10 Gaucher’s disease Increased pooling and In one study , 122 of the 1280 patients underwent dilutional 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 11 documented in 25% of cases. In anther study , 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 14 a diagnosis other than lymphoma, the spleen weighed with isolated splenomegaly . 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%), 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 . 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

HYPERSPLENISM Although the exact mechanism is unknown, 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 ; 3) compensatory bone marrow control of B-lymphocytes by suppressor or cytotoxic T ; 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 . 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 and turnover, but the major factor is increased 1. Eichner ER. Splenic function: normal, too much and too little. American Journal of Medicine 1979;66:311-20. plasma volume. The reticulocyte count is increased, 2. McIntyre OR, Ebauch FG Jr. Palpable spleens in college reflecting erythroid hyperplasia. freshmen. Ann Intern Med 1967;66:301. 2. Leukopenia is common and sometimes associated 3. Sullivan S, Williams R. Reliability of clinical techniques for with lymphocytosis. detecting splenic enlargement. BMJ 1976;4:1043. 3. Thrombocytopenia is generally mild. Both neutro- 4. Bruckstein AH. Splenomegaly: When and how to treat. penia and thrombocytopenia are due to splenic Postgrad Med J 1986;79(5):289-96. pooling. 5. Fritscher-Ravens A, Mylonaki M, Pantes A, et al. Endoscopic -guided biopsy for the diagnosis of focal lesions of 4. Peripheral smear examination does not reveal the the spleen. Am J Gastroenterol 2003;98:1022-7. presence of malarial parasite in most cases. 6. Swaoop J, O’Reily RA. Splenomegaly at a University Hospital compared to a nearby county hospital in 317 patients. Acta Treatment Haematol 1999;102:83-8. 7. Eichner ER, Whitfield CL. Splenomegaly: An algorithmic Antimalarial drugs are effective therapy for HMS. approach to diagnosis. JAMA 1981;246(24):2858-61. The treatment should be continued regularly for a 8. Grover SA, Barkun AN, Sackett DL. Does this patient have prolonged period to be effective. Months may pass before splenomegaly? JAMA 1993;270:2218-21. response is noticed, and relapses may occur when 9. Deodhar M, Kakkar N. An audit of splenectomies in a teaching therapy is discontinued. No documented studies address hospital in north India. Are postsplenectomy guidelines being the duration of adequate treatment, and no studies complied with? J Clin Pathol 2004;57:407-10. compare the different antimalarial medications. The role 10. Kraus MD, Fleming MD, Vonderheide RH. The spleen as a diagnostic specimen. 2001;91(11):2001-9. of lifelong prophylaxis for individuals residing in 11. Cronin CC, Brady MP, Murphy C, et al. Splenectomy in endemic areas is also not clear. Treatment may have to patients with undiagnosed splenomegaly. Postgrad Med J 1994; be continued for more than a year, sometimes even 70:288-91. longer. Response to therapy is guided by the splenic size, 12. Pottakkat B, Kashyap R, Kumar A, et al. Redefining the role of decrease in serum IgM levels, improvement of anemia, splenectomy in patients with idiopathic splenomegaly. ANZ J and general improvement in the well being of the patient. Surg 2006;76(8):679-82. 13. Coetzee T. Clinical anatomy and physiology of spleen. S Afr Nontropical Idiopathic Splenomegaly Med J 1982;61:737-46. 14. Gupta OP, Bajaj S, Gupta SC. A study on tropical splenomegaly In nontropical countries isolated splenomegaly is syndrome and chloroquine prophylaxis. J Assoc Physicians usually due to lymphoma, myeloid metaplasia or India 1989;37(9):570-5. collagen vascular diseases. Massive splenomegaly of 15. Dacie JV, Brain MC, Harrison CV. Nontropical Idiopathic unknown cause is also known as primary hypersplenism Splenomegaly (primary hypersplenism): A review of ten cases 15 and their relationship to malignant lymphomas. Br J Haematol or Dacie’s syndrome . The syndrome as described by 1969;17:317-33. Dacie, et al, is characterized by splenomegaly and pan- 16. 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