Symposium on Surgery of the Liver, Spleen, and Pancreas
The Dilemma of Hypersplenism
Lawrence D. Ellis, M.D.,* and H. Lee Dameshek, M.D.**
The dilemma of hypersplenism has perplexed clinicians since the clinical syndrome was first recognized in 1866 by Gretsel as "splenic anemia."l1 Confusion and controversy have continued for over a century regarding definition of the syndrome, its pathogenesis and etiology, and indications for splenectomy. Jandl and Aster6 ' in 1967 stated that no expression in medicine is used by so many to describe such variegated phenomena as hypersplenism. Although there continue to be missing links in our understanding of the syndrome, increasing unanimity among hematologists and surgeons has grown with respect to the indications for and merits of splenectomy in this syndrome. Three essential features which characterize the syndrome of hypersplenism: (1) Splenomegaly. (2) Cytopenia(s) associated with hyperplasia of bone marrow. The reduction in circulating blood cells may involve red blood cells, granulocytes, and platelets either singly or in any combination. (3) Correction of the cytopenia(s) by splenectomy-the "sine qua non" of the diagnosis of this syndrome. While the dilemma regarding pathogenesis has remained unresolved for over a century, two views include: sequestration of blood cells which is enhanced by the enlarged spleen, and production by the spleen of a humoral substance which inhibits the production or release of blood cells by the bone marrow. There is increasing evidence that sequestration is primarily responsible for this syndrome, primarily from two studies. First, significant decreases in granulocyte and platelet counts can be demonstrated across the splenic circulation by sampiing arterial and venous bloodY Second, red blood cells or platelets tagged with chromium51 and injected into patients with hypersplenism results in increased radioactivity over the enlarged spleenY If this increased radioactivity, reflecting sequestration, has a greater than 2:1 ratio when compared with similar monitoring of the liver, it is more likely that splenectomy will be of therapeutic value. 'Clinical Associate Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania '*Clinical Assistant Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Evidence supporting the "humoral" theory is less convincing. There is no question, however, that some patients with aplastic or hypoplastic anemias occasionally respond to splenectomy. In addition, a significant number of patients with typical hypersplenism do not respond to splenectomy in spite of positive radioactive sequestration studies, suggesting that sequestration is not the only pathogenetic mechanism.
ETIOLOGY Hypersplenism is either a primary or idiopathic hematologic disorder or it is a syndrome induced by splenomegaly produced by a variety of diseases. The latter is referred to as secondary hypersplenism.
PRIMARY HYPERSPLENISM
This interesting syndrome formerly was termed splenic neutropenia. It has been recognized more frequently in recent years and is not confined to a cytopenia of only the white blood cells. On a clinical level the diagnosis is one of exclusion after a careful search for a cause of the hypersplenism has been unrewarding, and the pathology of the removed spleen is not diagnostic of any secondary underlying disease. Table 1 lists the criteria for the diagnosis of this specific hematologic syndrome. Dacie et al.a refer to this syndrome as "nontropical idiopathic splenomegaly" and have emphasized the value and safety of splenectomy in alleviating the cytopenia and abdominal discomfort from the splenomegaly. These authors also reported that 2 of their series of 10 patients who underwent splenectomy subsequently developed lymphosarcoma. This experience is in agreement with our own as well as that of others.!' 7 We followed 6 of 12 patients who fulfilled the criteria for the diagnosis of primary hypersplenism for 10 years. Three of the 6 patients developed chronic lymphatic leukemia or lymphosarcoma within 18 months of splenectomy. Others have reported a significant occurrence of acute leukemia in these patients after splenectomy.!' 7 It seems appropriate to consider primary hypersplenism as a relatively specific hematologic syndrome which responds favorably to splenectomy and then follows either a benign or a malignant course. In some patients it represents a pre-lymphoma or pre-leukemia state, which is recognized only when the malignancy develops at a point in time after the splenectomy.
Table 1. 1. 2. 3. 4. 5.
Criteria for Diagnosis of Primary Hypersplenism
Criteria for hypersplenism present (splenomegaly. cytopenia. hyperplastic marrow) No secondary etiology discovered clinically Pathology of spleen nondiagnostic Good response to splenectomy Possible lymphoma or leukemia after splenectomy
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Table 2. Causes of Secondary Hypersplenism Primary liver disease Cirrhosis (Laennec's and postnecrotic) Chronic hepatitis Wilson's disease Schistosomiaisis Extrahepatic portal or splenic vein obstruction Collagen-vascular disease Systemic lupus erythematosus Felty's syndrome Hematologic diseases Non-Hodgkin's lymphomas Hodgkin's disease Acute and chronic leukemias Idiopathic myelofibrosis Polycythemia vera Congenital hemolytic anemias (hemoglobinopathies, spherocytosis, P-K defiCiency) Infections Acute (infectious mononucleosis, SBE, psittacosis) Chronic (miliary tuberculosis, malaria, brucellosis, Kala-azar, syphilis, histoplasmosis) Miscellaneous infiltrative diseases of the spleen Sarcoidosis Reticuloendothelioses (Gaucher's disease) Amyloidosis
SECONDARY HYPERSPLENISM
The possible causes of secondary hypersplenism are multiple and diverse (Table 2). It is essential, however, that all possible causes be entertained both before and after splenectomy in order that appropriate treatment of the primary disease can be administered. A recommended clinical diagnostic approach to the patient who has the established diagnosis of the syndrome of hypersplenism is included in Table 3. Approximately 50 per cent of patients in whom the diagnOSis of the primary disease is unknown at the time of the appearance of hypersplenism will be discovered to have a specific disease with this type of complete clinical evaluation. Another 10 per cent will require examination of sections of the spleen, liver, or lymph nodes obtained at the time of splenectomy to establish the cause of the hypersplenism. The remaining patients will fall into the previously discussed category of "primary hypersplenism. "
THERAPY After the diagnosis of hypersplenism is established the therapeutic dilemma of splenectomy versus treatment of underlying disease and ob-
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LAWRENCE D. ELLIS AND
Table 3.
H. LEE DAMESHEK
Clinical Evaluation of Hypersplenism
1. Careful history and physical and routine laboratory studies
2. 3. 4. 5. 6. 7. 8.
Skin tests for tuberculosis, histoplasmosis, etc. Serologic tests for collagen diseases Immunoprotein studies Needle biopsy of liver and culture Bone marrow biopsy and culture Lymph node biopsy and culture (if adenopathy present) Angiography of hepatic and splenic circulation
servation of the hematologic picture must be resolved. In primary hypersplenism there is general agreement that splenectomy is indicated once the diagnosis is made on clinical grounds. Not only will the surgical removal of the spleen usually result in improvement, but it also may provide a specific diagnosis when the spleen sections are examined carefully by the pathologist. When there is a known cause for the hypersplenism (secondary) the indications for splenectomy are not as clear. The severity and prognosis of the primary disease process must be carefully evaluated and the risk of surgery weighed against the benefit achieved by relieving the hypersplenic state. There is an increasing tendency among hematologists to recommend splenectomy earlier in many of the diseases associated with hypersplenism even if one can expect only a decrease in transfusion requirements, decrease in number of infections, prevention of some hemorrhagic phenomena, or palliation of pain. Since the decision to proceed with splenectomy depends greatly upon the primary disease responsible for the splenomegaly, a discussion of each major disease category seems warranted.
PRIMARY LIVER DISEASE By far the most common cause of secondary hypersplenism in any hospital is primary liver disease. Laennec's or alcoholic cirrhosis and post-necrotic or post-hepatic cirrhosis are the liver diseases most often responsible for the development of secondary hypersplenism. The splenomegaly associated with these chronic liver diseases is clearly secondary to chronic splenic vein hypertension, which is usually associated with portal vein hypertension as well. When the syndrome of hypersplenism occurs in these patients it may be an isolated manifestation of splenic vein hypertension without the serious consequences associated with portal hypertension (e.g., esophageal and gastric varices and ascites). In these patients the indications for splenectomy would be the same as those for any patient with secondary hypersplenism (Table 4). However, when the clinical manifestations of portal hypertension are also present to a degree necessitating a portal-systemic-venous shunt operation, the indications for splenectomy as an additional surgical procedure are more difficult to establish. If the patient has a cytopenia(s) which is causing clinical dif-
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Table 4. Indications for Splenectomy in Hypersplenism 1. Primary Hypersplenism-Once diagnosis is established 2. Secondary Hypersplenism a. Dependent upon primary disease, medical status of patient, and prognosis b. Early splenectomy indicated in non-Hodgkin's lymphomas c. Common causes of secondary hypersplenism when following present: (1) Major hemolysis with symptomatic anemia and transfusion requirement (2) Neutropenia of marked degree « 1000 polymorphs per cu mm) with recurrent infections (3) Thrombocytopenia causing purpura or hemorrhage (4) Massive splenomegaly causing incapacitating symptoms
ficulties, splenectomy should be considered either at the time of the shunt procedure or as an independent operation before or after the shunt, depending upon the overall clinical status and the urgency for the shunt. For example, if a patient with marked neutropenia «1000 granulocytes per cu mm) secondary to hyersplenism also has had several hemorrhages from esophageal varices, the morbidity of the portocaval shunt may be reduced considerably by performing splenectomy first in order to alleviate the granulocytopenia and thus avoiding the risk of serious postoperative infection following the shunt procedure. Similarly, a significant thrombocytopenia clearly due to hyPersplenism (platelet count < 40,000 per cu mm) would be an indication for splenectomy prior to the shunt in order to prevent major operative and postoperative bleeding. If technically feasible and if the patient's general condition permits, combining splenectomy with a splenorenal shunt is ideal for patients with significant problems associated with both splenic and portal venous hypertension. A portocaval shunt alone may transiently or partially relieve splenic venous hypertension and its resultant congestive splenomegaly and thus favorably affect the hypersplenism. However, improvement in the cytopenias, if it occurs, is usually quite transient. In summary, splenectomy is indicated in patients with secondary hypersplenism of clinical significance due to cirrhosis of the liver. If there is associated portal hypertension of a degree requiring a venous shunt operation, the hypersplenism should then be treated by splenectomy first, in order to reduce the morbidity and mortality of the longer and more potentially serious portal-systemic venous shunt. If feasible, splenectomy and splenorenal shunt is an ideal operation for these patients.
COLLAGEN-VASCULAR DISEASE Hypersplenism with resultant cytopenias may occur in systeInic lupus erythematosus or in Felty's syndrome. In these disorders, there is also the possibility that the cytopenia may have an autoimmune basis and therefore may be favorably treated with steroids. The indications for
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splenectomy in these patients should be quite strict since one must carefully assess the patient's overall clinical status as well as his prognosis. For example, if the patient with systemic lupus erythematosus or Felty's syndrome has not had any infections, bleeding episodes, or symptoms from anemia, splenectomy for hypersplenism should not be performed. However, splenectomy is indicated for patients with significant neutropenia associated with recurrent infections, thrombocytopenic purpura, or symptomatic anemia requiring transfusions if it is determined the patient can tolerate surgery.
HEMATOLOGIC DISEASES Malignant Lymphomas Hypersplenism with resultant cytopenia(s) occurs not uncommonly both in the non-Hodgkin's lymphomas and in Hodgkin's disease. Recent reports by O'Brien et al.s and Yam and Crosby12 have demonstrated the value of early splenectomy in hypersplenism in the nonHodgkin's lymphomas, particularly the well-differentiated lymphocytic varieties (lymphosarcoma, chronic lymphocytic leukemia, and giant follicular lymphomas). Yam and Crosby emphasize the importance of early splenectomy once hypersplenism, however mild, develops in these lymphoproliferative disorders. Thirty-nine of their series of 50 patients had favorable responses to splenectomy. In 27 of these 39, responses lasted more than 6 months. Postoperative complications were infrequent. The effect of splenectomy on survival could not be determined because of lack of a control study. However, 6 patients were alive and well 5 years after splenectomy. Apparent curability of a group of patients with giant follicle lymphomas of the spleen has been emphasized by Hickling.4 In the current classification of the non-Hodgkin's lymphomas, the patients reported by Hickling fit the category of well-differentiated,nodular, lymphocytic non-Hodgkin's lymphomas. A specific type of non-Hodgkin's lymphomas termed leukemic reticuloendotheliosis or "hairy cell disease" has a most favorable response to splenectomy for early manifestations of hypersplenism. In fact, splenectomy is the only treatment recommended for this disorder. In contrast to the non-Hodgkin's lymphomas, hypersplenism occurs late in Hodgkin's disease when stage III-B or IV of the disease is present. The results of splenectomy have been poor and the morbidity and mortality quite high.s, 10 Leukemias Except for the chronic lymphocytic leukemia which is best considered with the non-Hodgkin's lymphomas, indications for splenectomy for hypersplenism in leukemia are few. In the acute leukemias, the morbidity and mortality are prohibitive, with little hope for any significant response. In chronic myelocytic leukemia the spleen may become huge with associated symptoms of pain and discomfort. Some degree of hypersplenism may develop but may be difficult to interpret, particularly
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if there is incipient or actual blast crisis. Splenectomy for chronic myelocytic leukemia is therefore rarely, if ever, indicated because of the poor prognosis and morbidity and mortality of the procedure.
Idiopathic Myelofibrosis with Myeloid Metaplasia Agnogenic myeloid metaplasia is usually associated with myelofibrosis, massive splenomegaly, and a leukoerythroblastic peripheral blood smear. A small group of patients with myeloid metaplasia have a cellular marrow. Hypersplenism, massive symptomatic splenomegaly, splenic infarctions, a tenninal "blast crisis" plus portal hypertension are the major complications of this disorder. Hypersplenism is usually manifested by significant hemolytic anemia or severe thrombocytopenic purpura. The resultant cytopenias are especially severe because of the associated impaired blood cell production due to the myelofibrosis. Splenectomy for hypersplenism in this disorder has been associated with a high morbidity and mortality in the past.!O Recent series,!1 especially the Mayo experience, have demonstrated an acceptable morbidity and mortality from splenectomy when the indications are restricted. Silverstein and Reminel l believe the procedure is indicated in those patients who have: (1) major hemolysis not relieved by medical management, (2) life-threatening thrombocytopenia, (3) progressive and massive splenomegaly leading to severe incapacitating discomfort, or (4) portal hypertension. Their results in 29 patients who underwent splenectomy demonstrated 3 immediate postoperative deaths and 11 serious postoperative complications. However, those who survived the procedure also survived longer than those treated medically for major hemolysis and massive splenomegaly. These authors emphasized an apparent advantage for females in terms of postoperative complications and survival. The indications for splenectomy in this serious myeloproliferative disorder must be rigid and individualized because of the persistent high morbidity and mortality. Polycythemia Vera It is a rare patient with polycythemia vera who manifests hypersplenism. When it occurs, there most likely has been a transformation of the myeloproliferative syndrome to myelofibrosis with myeloid metaplasia and the preceding remarks are applicable. Congenital Hemolytic Anemias Although hypersplenism per se is not the basic or primary reason for hemolysis in the hemoglobinopathies, thalassemias, or congenital nonspherocytic hemolytic anemias, it may playa contributory role as the splenomegaly becomes progressive. Congenital spherocytic hemolytic anemia (hereditary spherocytosis) is a unique example of a specific hypersplenic syndrome in which splenectomy is curable 100 per cent of the time.
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LEE DAMESHEK
Increased sequestration in the spleen should be demonstrated by investigative studies prior to considering splenectomy for improving the anemia in all of the congenital hemolytic anemias. In most instances, the transfusion requirement may be decreased and the anemia only partially improved even when splenectomy is successful.
Infections Hypersplenism may occur with a variety of acute and chronic infections, some of which are listed in Table 2. Usually, appropriate antimicrobial treatment of the primary infectious disease alleviates the splenomegaly and therefore the hypersplenism is relieved. It is possible in some instances, especially with chronic granulomatous infections, that the splenomegaly and resultant hypersplenism will persist after the completion of an adequate course of antibiotics. If this occurs, splenectomy is indicated. We have seen two patients in this category with subacute bacterial endocarditis. They both had persistent splenomegaly with a significant cytopenia long after adequate courses of intravenous antibiotic therapy. Splenectomy was curative in both cases. Infiltrative Diseases of the Spleen Many disorders of varying etiology may produce splenomegaly and hypersplenism as a result of infiltration and replacement of splenic tissue. In these diseases, splenectomy is indicated for palliation if the hypersplenism is significant and more threatening to life than the primary disease itself.
SUMMARY While the dilemma of hypersplenism has not yet been resolved, we do have a clearer understanding of the pathogenesis of this syndrome. Once hypersplenism is established in a patient, the indications for splenectomy are dependent upon the primary disease process and the associated prognosis. There is an increasing tendency for early splenectomy in primary hypersplenism and in secondary hypersplenism associated with the non-Hodgkin's lymphomas of the well-differentiated lymphocytic variety. Each patient with the syndrome of hypersplenism must be evaluated individually and the decision for splenectomy made only after careful hematologic and medical investigation and an informed dialogue between the surgeon and the hematologist.
REFERENCES 1. Block, M., Jacobson, L. 0., and Bethard, W. F.: Preleukemic acute human leukemia.
J.A.M.A., 152:1018,1953. 2. Dacie, J. V., et al.: Non-tropical idiopathic splenomegaly (primary hypersplenism): A review of ten cases and their relationship to malignant lymphomas. Brit. J. Haemat., 17:317,1969.
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3. Dameshek, W.: The spleen; facts and fancies. Bull. New Eng. Med. Cent., 3:304,1941. 4. Hickling, R. A.: Giant follicle lymphoma of the spleen. Brit. Med. J., 2:787,1964. 5. Jandl, J. H., and Aster, R. H.: Increased splenic pooling and the pathogenesis of hypersplenism. Amer. J. Med. Sci., 253 :383, 1967. 6. Meacham, G. C., and Weisberger, A. S.: Early atypical manifestations of leukemia. Ann. Intern. Med., 41 :780, 1954. 7. O'Brien, P. H., Hartz, W. H., Derlack, D., et al.: Splenectomy for hypersplenism in malignant lymphoma. Arch. Surg., 101 :348, 1970. 8. Schultz, J. C., Denny, W. F., and Ross, S. W.: Splenectomy in leukemia and lymphoma: Report of 24 cases. Amer. J. Med. Sci., 247:64130, 1964. 9. Schwartz, S. 1., et aL: Splenectomy for hematologic disorders. Arch. Surg., 101 :338, 1970. 10. Silverstein, M. N., and Remine, W. H.: Sex, splenectomy, and myeloid metaplasia. J.A.M.A., 27:424,1974. 11. Williams, W. J., et aL: Hematology. New York, McGraw-Hill Book Co., 1972. 12. Yam, L. T., and Crosby, W. H.: Early splenectomy in lymphoproliferative disorders. Arch. Intern. Med., 133:270,1974. 3515 Fifth Avenue Pittsburgh, Pennsylvania 15213
The Dilemma of Hypersplenism
Lawrence D. Ellis, M.D.,* and H. Lee Dameshek, M.D.**
The dilemma of hypersplenism has perplexed clinicians since the clinical syndrome was first recognized in 1866 by Gretsel as "splenic anemia."l1 Confusion and controversy have continued for over a century regarding definition of the syndrome, its pathogenesis and etiology, and indications for splenectomy. Jandl and Aster6 ' in 1967 stated that no expression in medicine is used by so many to describe such variegated phenomena as hypersplenism. Although there continue to be missing links in our understanding of the syndrome, increasing unanimity among hematologists and surgeons has grown with respect to the indications for and merits of splenectomy in this syndrome. Three essential features which characterize the syndrome of hypersplenism: (1) Splenomegaly. (2) Cytopenia(s) associated with hyperplasia of bone marrow. The reduction in circulating blood cells may involve red blood cells, granulocytes, and platelets either singly or in any combination. (3) Correction of the cytopenia(s) by splenectomy-the "sine qua non" of the diagnosis of this syndrome. While the dilemma regarding pathogenesis has remained unresolved for over a century, two views include: sequestration of blood cells which is enhanced by the enlarged spleen, and production by the spleen of a humoral substance which inhibits the production or release of blood cells by the bone marrow. There is increasing evidence that sequestration is primarily responsible for this syndrome, primarily from two studies. First, significant decreases in granulocyte and platelet counts can be demonstrated across the splenic circulation by sampiing arterial and venous bloodY Second, red blood cells or platelets tagged with chromium51 and injected into patients with hypersplenism results in increased radioactivity over the enlarged spleenY If this increased radioactivity, reflecting sequestration, has a greater than 2:1 ratio when compared with similar monitoring of the liver, it is more likely that splenectomy will be of therapeutic value. 'Clinical Associate Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania '*Clinical Assistant Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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LEE DAMESHEK
Evidence supporting the "humoral" theory is less convincing. There is no question, however, that some patients with aplastic or hypoplastic anemias occasionally respond to splenectomy. In addition, a significant number of patients with typical hypersplenism do not respond to splenectomy in spite of positive radioactive sequestration studies, suggesting that sequestration is not the only pathogenetic mechanism.
ETIOLOGY Hypersplenism is either a primary or idiopathic hematologic disorder or it is a syndrome induced by splenomegaly produced by a variety of diseases. The latter is referred to as secondary hypersplenism.
PRIMARY HYPERSPLENISM
This interesting syndrome formerly was termed splenic neutropenia. It has been recognized more frequently in recent years and is not confined to a cytopenia of only the white blood cells. On a clinical level the diagnosis is one of exclusion after a careful search for a cause of the hypersplenism has been unrewarding, and the pathology of the removed spleen is not diagnostic of any secondary underlying disease. Table 1 lists the criteria for the diagnosis of this specific hematologic syndrome. Dacie et al.a refer to this syndrome as "nontropical idiopathic splenomegaly" and have emphasized the value and safety of splenectomy in alleviating the cytopenia and abdominal discomfort from the splenomegaly. These authors also reported that 2 of their series of 10 patients who underwent splenectomy subsequently developed lymphosarcoma. This experience is in agreement with our own as well as that of others.!' 7 We followed 6 of 12 patients who fulfilled the criteria for the diagnosis of primary hypersplenism for 10 years. Three of the 6 patients developed chronic lymphatic leukemia or lymphosarcoma within 18 months of splenectomy. Others have reported a significant occurrence of acute leukemia in these patients after splenectomy.!' 7 It seems appropriate to consider primary hypersplenism as a relatively specific hematologic syndrome which responds favorably to splenectomy and then follows either a benign or a malignant course. In some patients it represents a pre-lymphoma or pre-leukemia state, which is recognized only when the malignancy develops at a point in time after the splenectomy.
Table 1. 1. 2. 3. 4. 5.
Criteria for Diagnosis of Primary Hypersplenism
Criteria for hypersplenism present (splenomegaly. cytopenia. hyperplastic marrow) No secondary etiology discovered clinically Pathology of spleen nondiagnostic Good response to splenectomy Possible lymphoma or leukemia after splenectomy
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Table 2. Causes of Secondary Hypersplenism Primary liver disease Cirrhosis (Laennec's and postnecrotic) Chronic hepatitis Wilson's disease Schistosomiaisis Extrahepatic portal or splenic vein obstruction Collagen-vascular disease Systemic lupus erythematosus Felty's syndrome Hematologic diseases Non-Hodgkin's lymphomas Hodgkin's disease Acute and chronic leukemias Idiopathic myelofibrosis Polycythemia vera Congenital hemolytic anemias (hemoglobinopathies, spherocytosis, P-K defiCiency) Infections Acute (infectious mononucleosis, SBE, psittacosis) Chronic (miliary tuberculosis, malaria, brucellosis, Kala-azar, syphilis, histoplasmosis) Miscellaneous infiltrative diseases of the spleen Sarcoidosis Reticuloendothelioses (Gaucher's disease) Amyloidosis
SECONDARY HYPERSPLENISM
The possible causes of secondary hypersplenism are multiple and diverse (Table 2). It is essential, however, that all possible causes be entertained both before and after splenectomy in order that appropriate treatment of the primary disease can be administered. A recommended clinical diagnostic approach to the patient who has the established diagnosis of the syndrome of hypersplenism is included in Table 3. Approximately 50 per cent of patients in whom the diagnOSis of the primary disease is unknown at the time of the appearance of hypersplenism will be discovered to have a specific disease with this type of complete clinical evaluation. Another 10 per cent will require examination of sections of the spleen, liver, or lymph nodes obtained at the time of splenectomy to establish the cause of the hypersplenism. The remaining patients will fall into the previously discussed category of "primary hypersplenism. "
THERAPY After the diagnosis of hypersplenism is established the therapeutic dilemma of splenectomy versus treatment of underlying disease and ob-
280
LAWRENCE D. ELLIS AND
Table 3.
H. LEE DAMESHEK
Clinical Evaluation of Hypersplenism
1. Careful history and physical and routine laboratory studies
2. 3. 4. 5. 6. 7. 8.
Skin tests for tuberculosis, histoplasmosis, etc. Serologic tests for collagen diseases Immunoprotein studies Needle biopsy of liver and culture Bone marrow biopsy and culture Lymph node biopsy and culture (if adenopathy present) Angiography of hepatic and splenic circulation
servation of the hematologic picture must be resolved. In primary hypersplenism there is general agreement that splenectomy is indicated once the diagnosis is made on clinical grounds. Not only will the surgical removal of the spleen usually result in improvement, but it also may provide a specific diagnosis when the spleen sections are examined carefully by the pathologist. When there is a known cause for the hypersplenism (secondary) the indications for splenectomy are not as clear. The severity and prognosis of the primary disease process must be carefully evaluated and the risk of surgery weighed against the benefit achieved by relieving the hypersplenic state. There is an increasing tendency among hematologists to recommend splenectomy earlier in many of the diseases associated with hypersplenism even if one can expect only a decrease in transfusion requirements, decrease in number of infections, prevention of some hemorrhagic phenomena, or palliation of pain. Since the decision to proceed with splenectomy depends greatly upon the primary disease responsible for the splenomegaly, a discussion of each major disease category seems warranted.
PRIMARY LIVER DISEASE By far the most common cause of secondary hypersplenism in any hospital is primary liver disease. Laennec's or alcoholic cirrhosis and post-necrotic or post-hepatic cirrhosis are the liver diseases most often responsible for the development of secondary hypersplenism. The splenomegaly associated with these chronic liver diseases is clearly secondary to chronic splenic vein hypertension, which is usually associated with portal vein hypertension as well. When the syndrome of hypersplenism occurs in these patients it may be an isolated manifestation of splenic vein hypertension without the serious consequences associated with portal hypertension (e.g., esophageal and gastric varices and ascites). In these patients the indications for splenectomy would be the same as those for any patient with secondary hypersplenism (Table 4). However, when the clinical manifestations of portal hypertension are also present to a degree necessitating a portal-systemic-venous shunt operation, the indications for splenectomy as an additional surgical procedure are more difficult to establish. If the patient has a cytopenia(s) which is causing clinical dif-
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Table 4. Indications for Splenectomy in Hypersplenism 1. Primary Hypersplenism-Once diagnosis is established 2. Secondary Hypersplenism a. Dependent upon primary disease, medical status of patient, and prognosis b. Early splenectomy indicated in non-Hodgkin's lymphomas c. Common causes of secondary hypersplenism when following present: (1) Major hemolysis with symptomatic anemia and transfusion requirement (2) Neutropenia of marked degree « 1000 polymorphs per cu mm) with recurrent infections (3) Thrombocytopenia causing purpura or hemorrhage (4) Massive splenomegaly causing incapacitating symptoms
ficulties, splenectomy should be considered either at the time of the shunt procedure or as an independent operation before or after the shunt, depending upon the overall clinical status and the urgency for the shunt. For example, if a patient with marked neutropenia «1000 granulocytes per cu mm) secondary to hyersplenism also has had several hemorrhages from esophageal varices, the morbidity of the portocaval shunt may be reduced considerably by performing splenectomy first in order to alleviate the granulocytopenia and thus avoiding the risk of serious postoperative infection following the shunt procedure. Similarly, a significant thrombocytopenia clearly due to hyPersplenism (platelet count < 40,000 per cu mm) would be an indication for splenectomy prior to the shunt in order to prevent major operative and postoperative bleeding. If technically feasible and if the patient's general condition permits, combining splenectomy with a splenorenal shunt is ideal for patients with significant problems associated with both splenic and portal venous hypertension. A portocaval shunt alone may transiently or partially relieve splenic venous hypertension and its resultant congestive splenomegaly and thus favorably affect the hypersplenism. However, improvement in the cytopenias, if it occurs, is usually quite transient. In summary, splenectomy is indicated in patients with secondary hypersplenism of clinical significance due to cirrhosis of the liver. If there is associated portal hypertension of a degree requiring a venous shunt operation, the hypersplenism should then be treated by splenectomy first, in order to reduce the morbidity and mortality of the longer and more potentially serious portal-systemic venous shunt. If feasible, splenectomy and splenorenal shunt is an ideal operation for these patients.
COLLAGEN-VASCULAR DISEASE Hypersplenism with resultant cytopenias may occur in systeInic lupus erythematosus or in Felty's syndrome. In these disorders, there is also the possibility that the cytopenia may have an autoimmune basis and therefore may be favorably treated with steroids. The indications for
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splenectomy in these patients should be quite strict since one must carefully assess the patient's overall clinical status as well as his prognosis. For example, if the patient with systemic lupus erythematosus or Felty's syndrome has not had any infections, bleeding episodes, or symptoms from anemia, splenectomy for hypersplenism should not be performed. However, splenectomy is indicated for patients with significant neutropenia associated with recurrent infections, thrombocytopenic purpura, or symptomatic anemia requiring transfusions if it is determined the patient can tolerate surgery.
HEMATOLOGIC DISEASES Malignant Lymphomas Hypersplenism with resultant cytopenia(s) occurs not uncommonly both in the non-Hodgkin's lymphomas and in Hodgkin's disease. Recent reports by O'Brien et al.s and Yam and Crosby12 have demonstrated the value of early splenectomy in hypersplenism in the nonHodgkin's lymphomas, particularly the well-differentiated lymphocytic varieties (lymphosarcoma, chronic lymphocytic leukemia, and giant follicular lymphomas). Yam and Crosby emphasize the importance of early splenectomy once hypersplenism, however mild, develops in these lymphoproliferative disorders. Thirty-nine of their series of 50 patients had favorable responses to splenectomy. In 27 of these 39, responses lasted more than 6 months. Postoperative complications were infrequent. The effect of splenectomy on survival could not be determined because of lack of a control study. However, 6 patients were alive and well 5 years after splenectomy. Apparent curability of a group of patients with giant follicle lymphomas of the spleen has been emphasized by Hickling.4 In the current classification of the non-Hodgkin's lymphomas, the patients reported by Hickling fit the category of well-differentiated,nodular, lymphocytic non-Hodgkin's lymphomas. A specific type of non-Hodgkin's lymphomas termed leukemic reticuloendotheliosis or "hairy cell disease" has a most favorable response to splenectomy for early manifestations of hypersplenism. In fact, splenectomy is the only treatment recommended for this disorder. In contrast to the non-Hodgkin's lymphomas, hypersplenism occurs late in Hodgkin's disease when stage III-B or IV of the disease is present. The results of splenectomy have been poor and the morbidity and mortality quite high.s, 10 Leukemias Except for the chronic lymphocytic leukemia which is best considered with the non-Hodgkin's lymphomas, indications for splenectomy for hypersplenism in leukemia are few. In the acute leukemias, the morbidity and mortality are prohibitive, with little hope for any significant response. In chronic myelocytic leukemia the spleen may become huge with associated symptoms of pain and discomfort. Some degree of hypersplenism may develop but may be difficult to interpret, particularly
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if there is incipient or actual blast crisis. Splenectomy for chronic myelocytic leukemia is therefore rarely, if ever, indicated because of the poor prognosis and morbidity and mortality of the procedure.
Idiopathic Myelofibrosis with Myeloid Metaplasia Agnogenic myeloid metaplasia is usually associated with myelofibrosis, massive splenomegaly, and a leukoerythroblastic peripheral blood smear. A small group of patients with myeloid metaplasia have a cellular marrow. Hypersplenism, massive symptomatic splenomegaly, splenic infarctions, a tenninal "blast crisis" plus portal hypertension are the major complications of this disorder. Hypersplenism is usually manifested by significant hemolytic anemia or severe thrombocytopenic purpura. The resultant cytopenias are especially severe because of the associated impaired blood cell production due to the myelofibrosis. Splenectomy for hypersplenism in this disorder has been associated with a high morbidity and mortality in the past.!O Recent series,!1 especially the Mayo experience, have demonstrated an acceptable morbidity and mortality from splenectomy when the indications are restricted. Silverstein and Reminel l believe the procedure is indicated in those patients who have: (1) major hemolysis not relieved by medical management, (2) life-threatening thrombocytopenia, (3) progressive and massive splenomegaly leading to severe incapacitating discomfort, or (4) portal hypertension. Their results in 29 patients who underwent splenectomy demonstrated 3 immediate postoperative deaths and 11 serious postoperative complications. However, those who survived the procedure also survived longer than those treated medically for major hemolysis and massive splenomegaly. These authors emphasized an apparent advantage for females in terms of postoperative complications and survival. The indications for splenectomy in this serious myeloproliferative disorder must be rigid and individualized because of the persistent high morbidity and mortality. Polycythemia Vera It is a rare patient with polycythemia vera who manifests hypersplenism. When it occurs, there most likely has been a transformation of the myeloproliferative syndrome to myelofibrosis with myeloid metaplasia and the preceding remarks are applicable. Congenital Hemolytic Anemias Although hypersplenism per se is not the basic or primary reason for hemolysis in the hemoglobinopathies, thalassemias, or congenital nonspherocytic hemolytic anemias, it may playa contributory role as the splenomegaly becomes progressive. Congenital spherocytic hemolytic anemia (hereditary spherocytosis) is a unique example of a specific hypersplenic syndrome in which splenectomy is curable 100 per cent of the time.
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Increased sequestration in the spleen should be demonstrated by investigative studies prior to considering splenectomy for improving the anemia in all of the congenital hemolytic anemias. In most instances, the transfusion requirement may be decreased and the anemia only partially improved even when splenectomy is successful.
Infections Hypersplenism may occur with a variety of acute and chronic infections, some of which are listed in Table 2. Usually, appropriate antimicrobial treatment of the primary infectious disease alleviates the splenomegaly and therefore the hypersplenism is relieved. It is possible in some instances, especially with chronic granulomatous infections, that the splenomegaly and resultant hypersplenism will persist after the completion of an adequate course of antibiotics. If this occurs, splenectomy is indicated. We have seen two patients in this category with subacute bacterial endocarditis. They both had persistent splenomegaly with a significant cytopenia long after adequate courses of intravenous antibiotic therapy. Splenectomy was curative in both cases. Infiltrative Diseases of the Spleen Many disorders of varying etiology may produce splenomegaly and hypersplenism as a result of infiltration and replacement of splenic tissue. In these diseases, splenectomy is indicated for palliation if the hypersplenism is significant and more threatening to life than the primary disease itself.
SUMMARY While the dilemma of hypersplenism has not yet been resolved, we do have a clearer understanding of the pathogenesis of this syndrome. Once hypersplenism is established in a patient, the indications for splenectomy are dependent upon the primary disease process and the associated prognosis. There is an increasing tendency for early splenectomy in primary hypersplenism and in secondary hypersplenism associated with the non-Hodgkin's lymphomas of the well-differentiated lymphocytic variety. Each patient with the syndrome of hypersplenism must be evaluated individually and the decision for splenectomy made only after careful hematologic and medical investigation and an informed dialogue between the surgeon and the hematologist.
REFERENCES 1. Block, M., Jacobson, L. 0., and Bethard, W. F.: Preleukemic acute human leukemia.
J.A.M.A., 152:1018,1953. 2. Dacie, J. V., et al.: Non-tropical idiopathic splenomegaly (primary hypersplenism): A review of ten cases and their relationship to malignant lymphomas. Brit. J. Haemat., 17:317,1969.
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3. Dameshek, W.: The spleen; facts and fancies. Bull. New Eng. Med. Cent., 3:304,1941. 4. Hickling, R. A.: Giant follicle lymphoma of the spleen. Brit. Med. J., 2:787,1964. 5. Jandl, J. H., and Aster, R. H.: Increased splenic pooling and the pathogenesis of hypersplenism. Amer. J. Med. Sci., 253 :383, 1967. 6. Meacham, G. C., and Weisberger, A. S.: Early atypical manifestations of leukemia. Ann. Intern. Med., 41 :780, 1954. 7. O'Brien, P. H., Hartz, W. H., Derlack, D., et al.: Splenectomy for hypersplenism in malignant lymphoma. Arch. Surg., 101 :348, 1970. 8. Schultz, J. C., Denny, W. F., and Ross, S. W.: Splenectomy in leukemia and lymphoma: Report of 24 cases. Amer. J. Med. Sci., 247:64130, 1964. 9. Schwartz, S. 1., et aL: Splenectomy for hematologic disorders. Arch. Surg., 101 :338, 1970. 10. Silverstein, M. N., and Remine, W. H.: Sex, splenectomy, and myeloid metaplasia. J.A.M.A., 27:424,1974. 11. Williams, W. J., et aL: Hematology. New York, McGraw-Hill Book Co., 1972. 12. Yam, L. T., and Crosby, W. H.: Early splenectomy in lymphoproliferative disorders. Arch. Intern. Med., 133:270,1974. 3515 Fifth Avenue Pittsburgh, Pennsylvania 15213
