Aetiology
Categorisation of splenomegaly according to aetiology is outlined below. Splenomegaly of indeterminate aetiology is termed idiopathic. A non-haematologist clinician may initiate an assessment of splenomegaly and even determine its aetiology, but there should be a low threshold for referral to a haematologist.
Hepatic
Alcohol-induced liver disease causes portal hypertension with resultant retrograde pressure into the spleen and further splenomegaly.[4] Chronic exposure of hepatocytes to ethyl alcohol causes Mallory bodies to form within and leads to cell destruction. Fibrosis occurs within the liver parenchyma that then bridges from portal triad to portal triad. Eventually, extensive irreversible scarring occurs.
Many other liver diseases can also lead to cirrhosis. The underlying mechanisms of liver injury may differ, but the end result is the same: cirrhosis. Examples include primary biliary cholangitis, primary sclerosing cholangitis, viral hepatitis (B or C), non-alcoholic hepatic steatosis, and hereditary haemochromatosis.
In portal hypertension, the spleen enlarges due to increased retrograde pressure through the portal and then the splenic vein. The enlarged spleen clears all the cellular elements of the blood more rapidly than normal, and thus affected patients have varying degrees of leukopenia, anaemia, and thrombocytopenia. Patients can also develop varices where the portal and systemic circulations merge, especially in the distal oesophagus and the haemorrhoidal veins, which may present as oesophageal variceal rupture or haemorrhoidal bleeding. The umbilical veins are also affected but this does not lead to severe clinical consequences.
Neoplastic and myeloproliferative disease: lymphomas and splenic tumours
Lymphomas are divided into Hodgkin's disease and non-Hodgkin's lymphoma. Non-Hodgkin's lymphomas are divided into several subtypes based on histological criteria. Several affect the spleen and may cause splenomegaly. Updated guidance is available from the National Comprehensive Cancer Network (NCCN).[5][6][7]
Hodgkin's disease
Most splenic involvement by Hodgkin's disease is focal and multicentric. It may or may not lead to palpable splenomegaly, but if diagnosed late the spleen can become quite enlarged. Rarely, the spleen may be the only site of involvement in Hodgkin's disease.
Small lymphocytic lymphoma
A nodal and splenic-based malignancy of lymphocytes. Splenomegaly in this setting can be mild or severe. Peripheral blood may or may not be involved by the malignant cells.
Follicular non-Hodgkin's lymphoma[8]
Tends to be malignant in growth pattern and, despite the fact that the spleen can be large, may not necessitate any treatment for years.
Diffuse large B-cell lymphoma
One of the more common (up to 40%) non-Hodgkin's lymphomas.[9] Splenomegaly can be mild to severe. It can also involve the spleen diffusely or focally, with normal splenic elements adjacent to a large neoplastic area. Affected patients may have metabolic derangements (e.g., hyperuricaemia, hyperkalaemia). Because it is potentially curable with systemic chemotherapy and immunotherapy, patients are usually treated as soon as the diagnosis is established and are at risk of tumour lysis syndrome once treatment is initiated.
Burkitt's lymphoma and lymphoblastic lymphoma[10]
These are examples of high-grade lymphoma. Affected patients have the most rapidly growing lymphomas, with dramatic presentations. The spleen can be normal sized or massively enlarged. Often, abdominal or mediastinal nodal disease is the pre-eminent feature. Immediate attention to metabolic derangements and prevention of tumour lysis syndrome are very important diagnostic and treatment considerations.
Waldenström's macroglobulinaemia and lymphoplasmacytic lymphoma[11][12]
These are closely related malignancies involving an elevated IgM monoclonal paraprotein along with splenomegaly. Patients are often anaemic or thrombocytopenic due to bone marrow infiltration by malignant B cells. Elevated IgM levels can lead to hyperviscosity, which may have devastating neurological consequences requiring immediate attention. Splenomegaly and lymphadenopathy are seen at presentation in many patients with Waldenström's macroglobulinaemia.
Primary splenic malignancies
Typically, non-Hodgkin's lymphomas that have a predilection to involve only the spleen (negative marrow examination, presence of splenomegaly, and often absence of circulating malignant cells). The most common is splenic marginal zone lymphoma. Often, the only way to confirm diagnosis is splenectomy, which can be therapeutic as well as diagnostic.
T-cell lymphoma
Much less common than B-cell lymphomas, there are many different types of T-cell lymphomas. Overlapping characteristics of these malignancies make diagnosis difficult; the differential diagnosis is broad. For example, T-cell prolymphocytic leukaemia features pronounced peripheral lymphocytosis, notable splenomegaly, and erythematous or papular skin lesions.[13] Adult T-cell leukaemia-lymphoma is caused by human T-cell lymphotropic virus type 1 (HTLV-1) and has a non-specific presentation with lymphadenopathy, pulmonary infiltrates, splenomegaly, and hepatomegaly. It involves the peripheral blood and bone marrow in most patients, and cerebrospinal fluid in about half.[14]
Splenic metastases
From other primary sites, particularly colon and breast cancer. Splenomegaly may result, but more commonly foci of disease appear on imaging studies.
Benign splenic tumours
Isolated incidental palpable or computed tomography-detected splenomegaly may occur, causing anxiety in patients and physicians.[15] The contribution of a radiologist may be helpful in identifying relevant benign conditions. A watch-and-wait approach may be advisable, as often some lesions do not grow. If splenectomy occurs (the only definitive test), histological analysis may reveal a benign condition. Splenic benign lesions include splenic hamartoma, littoral cell angioma (lesions that are benign growths of endothelial cells; may recur in other organs over time), haemangioma, and cysts.
Neoplastic and myeloproliferative disease: leukaemias and haematological cytopathologies
Leukaemias are divided into acute (myeloid, acute myeloid leukaemia, or acute lymphoblastic leukaemia [ALL]) and chronic (myeloid, chronic myeloid leukaemia [CML], or chronic lymphocytic leukaemia [CLL]).
The acute leukaemias (both acute myeloid leukaemia and ALL) are generally so devastating at presentation that spleen size is not the major clinical consideration. Exceptions do exist, and in some patients, perhaps more commonly in ALL, splenomegaly is a major clinical issue. Usually, however, the presence of malignant blast cells on peripheral smear and in bone marrow leads to diagnosis and treatment. An international standard (World Health Organization [WHO] Classification of Tumours) is available for differential diagnosis of the leukaemias and lymphomas.[16] Updated guidance is available from the National Comprehensive Cancer Network (NCCN).[5][17][18][19]
Acute myeloid leukaemia
Characterised by clonal expansion of myeloid blasts in the bone marrow, peripheral blood, or extramedullary tissues.
Acute lymphoblastic leukaemia (ALL)
Characterised by dysregulated proliferation and clonal expansion of lymphoid progenitor cells that replace the normal haematopoietic cells of the bone marrow and further infiltrate other body organs.
Chronic lymphocytic leukaemia (CLL)[20]
A neoplastic proliferation of CD5-positive B lymphocytes initially in blood, followed by lymph node and then liver and spleen involvement. Eventually, anaemia and thrombocytopenia may result from either immunological destruction or marrow overgrowth of the malignant cells. T-cell variants are rare. As the disease progresses, constitutional symptoms (fevers, night sweats, and weight loss) occur. In CLL the diagnosis is usually made based on lymphocytosis or enlargement of lymph nodes observed before hepatosplenomegaly manifests clinically. The spleen can become massively enlarged in CLL. The same considerations as seen in small lymphocytic lymphoma apply to patients with CLL.
Hairy cell leukaemia (HCL)
B lymphoid cells have characteristic circumferential hairy projections. Typical immunophenotype for classic HCL is CD5-, CD10-, CD11c+, CD20+(bright), CD22+, CD25+, CD103+, CD123+.[21] Splenomegaly is common at presentation along with pancytopenia. These patients have a predilection for unusual infections, such as atypical mycobacterial disease.
Chronic myeloid leukaemia (CML)[22][23]
Some patients with newly diagnosed CML (Philadelphia chromosome positive, BCR-ABL gene rearrangement positive) complain of pain in the left upper quadrant or early satiety, and on physical examination have an enlarged spleen. When the bone marrow is occupied by a myeloproliferative disorder, the liver and spleen may attempt to recreate marrow function, termed 'extramedullary haematopoiesis' (EMH).
Myelofibrosis or agnogenic myeloid metaplasia (AMM)[24]
The marrow becomes scarred and filled with fibroblasts, collagen, and/or reticulin, and the spleen and liver have a marrow-like morphology. In these organs, EMH (which may occur in other sites, such as the gastrointestinal tract, epidural space, or brain) is never as efficient as the nascent marrow, and patients are usually cytopenic, though they may have high leukocyte or platelet counts at some point. The spleen may become massively enlarged. As the spleen grows, pain and early satiety become problematic. Areas of spleen can outgrow the blood supply, and infarction can occur, leading to acute exacerbation of pain, as well as fever and perisplenic fluid collection. Spontaneous spleen rupture may occur.
Polycythaemia vera
Typically presents with erythrocytosis. Thromboses, myocardial infarction, and stroke may occur. Post-bathing pruritus, perhaps secondary to basophil degranulation, is a very bothersome symptom for some patients. The JAK2 mutation V617F can be demonstrated in >90% of cases (it is present in 60% of the other myeloproliferative disorders, essential thrombocytosis, and myelofibrosis).[18] A palpable spleen has been reported in 36% of patients.[25] Patients with polycythaemia vera evolve into a 'spent phase' characterised by increasing marrow fibrosis, weight loss, fevers, night sweats, and cytopenias, especially anaemias. The natural history is evolution from requiring phlebotomies to needing transfusions. Many patients progress towards acute leukaemia.
Essential thrombocytosis
Patients predominantly have an elevated platelet count, which can be very high (in the order of millions per microlitre). Young people, particularly those aged <40 years, can tolerate elevated platelet counts better than older people, especially those aged >65 years. Symptoms include erythromelalgia (painful burning in palms or soles), headaches, or transient ischaemic attack. The platelets in these patients are dysfunctional, and there can be a bleeding diathesis.
Vascular occlusive
The veins draining the spleen towards the liver can become occluded by clots, leading to splenomegaly.
Splenic vein thrombosis can occur as a consequence of acute pancreatitis, because the splenic vein courses just superior and posterior to this organ. The onset of splenomegaly can be rapid and painful.
Portal vein thrombosis may be seen in myeloproliferative diseases (especially in young women with polycythaemia vera). Portal vein thrombosis may also occur in paroxysmal nocturnal haemoglobinuria (PNH), a clonal disorder in which erythrocytes are especially sensitive to lysis by complement, and hypercoagulable states, such as antiphospholipid antibody syndrome, or as an adverse effect of oral contraceptives. Collateral vessels may form around the portal vein, and re-establishment of blood flow through the portal vein may occur over time (cavernous transformation of the portal vein). Splenomegaly may be mild or severe. In patients with underlying myeloproliferative disorder with hypercoagulability leading to the portal vein thrombosis, there can be synergistic reasons for the splenomegaly.
Budd-Chiari syndrome is caused by thromboses in small vessels within the liver, with tracking of thrombosis towards the main hepatic veins. It can occur after high-dose chemotherapy (as a consequence of preparatory chemotherapy at the time of bone marrow transplant), in PNH, and in myeloproliferative disorders.
Immunological/inflammatory
Amyloidosis[26]
Amyloid is a deposition of part of the heavy and/or light chain from immunoglobulin molecules or other substances such as transthyretin. This can occur secondary to plasma cell dyscrasias. These substances can deposit anywhere but typically target the soft tissues, heart, liver, and spleen. Splenomegaly may be mild, moderate, or severe and can lead or contribute to cytopenias.
Autoimmune haemolytic anaemia
Direct antiglobulin tests reveal the presence of immunoglobulin on the surface of red cells (warm-type), which leads to clearance of these red cells by the reticuloendothelial system. Red cells become spherocytes, which are more prone to destruction. Splenomegaly can result in either warm- or cold-type haemolysis (associated with complement on the surface of red cells) because the splenic red pulp is so active in clearing these cells that it expands. Generally, this type of splenomegaly is mild.
Haemophagocytic lymphohistiocytosis (HLH)
HLH can be primary or secondary.
Primary HLH usually presents in childhood. It is caused by genetic mutations that impair the cytotoxic function of natural killer and cytotoxic T cells. Genetic mutations associated with HLH include PRF1, RAB27A, STX11, STXBP2, UNC13D, LYST, AP3B1, SH2D1A, XIAP, NLRC4, CDC42, the Epstein-Barr virus susceptibility diseases, and XLP.[27][28]
Secondary HLH can be seen in association with autoimmune conditions, immunodeficiency, infection, or malignancy; however, in some cases an associated illness is not identified.[29][30]
Several criteria have been developed to identify patients with syndromes that may represent HLH, including HLH-2004, and the HScore.[31][32][33] However, both lack sensitivity and specificity, therefore no single set of criteria is sufficient to diagnose a HLH across all populations.[31]
A EULAR/ACR (European Alliance of Associations for Rheumatology/American College of Rheumatology) task force recommends that clinical and laboratory abnormalities together should be used to recognise potentially life-threatening HLH.[31]
Rheumatological disorders
Rheumatological syndromes such as rheumatoid arthritis can cause splenomegaly as a result of expansion of the white pulp. This is due to a systemic expansion of immune cells. The degree of splenomegaly is usually mild to moderate.
Felty syndrome is a triad of rheumatoid arthritis, splenomegaly, and neutropenia. Neutropenia is mediated by an antibody response or, in some cases, by excessive large granular lymphocytes in the spleen or the systemic circulation.
Splenomegaly in systemic lupus erythematosus occurs by a similar mechanism to that in rheumatoid arthritis and generally is mild to moderate.
Sarcoidosis
A disease of unknown origin and mechanism, characterised by non-caseating granulomas, found mostly in the lungs and lymph nodes. The spleen can become quite enlarged in sarcoidosis, leading to symptoms of pain and inanition. Cytopenias can occur and may be exacerbated by the marrow being filled with non-caseating granulomas, decreasing marrow output of leukocytes, red blood cells, and platelets.
Lysosomal storage disorders
Gaucher's disease
The prototypical example of lysosomal storage disease-associated splenomegaly.[34] It is a common genetic disease, particularly among those of Ashkenazi Jewish descent.[35] Due to a deficiency of glucocerebrosidase, cells of the reticuloendothelial system accumulate glucocerebroside, which is a breakdown product of the metabolism of fatty acids. The cells become hypertrophic and cannot be removed from the spleen or liver. Hepatosplenomegaly can be severe. Cytopenias and bone pain (crises) are common presenting features.[35] Bone imaging reveals distinctive changes, such as the 'Erlenmeyer flask' sign in the distal femurs. Bone density is compromised.
Niemann-Pick disease
Caused by an abnormality, or a deficiency, of the sphingomyelinase gene.[36] Includes three types: type A is seen in infants and causes neuronal disorders; type B has a later onset of presentation and is non-neuronopathic; and type C, the most common form, is neuronopathic, showing a later onset and abnormal cholesterol transport. Type C disease affects Ashkenazi Jews in a disproportionate manner.
Infectious
Malaria
A major health problem in anopheles mosquito-affected parts of the world. It is most commonly caused by four protozoan parasites: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.[37]
Transmission to humans occurs through the bite of the anopheles mosquito. The parasite has various life-cycle stages but primarily infects the red blood cells, causing lysis. The spleen enlarges partly through the overactivity of the red pulp in clearing these lysed red cells.[38]
Hyper-reactive malarial splenomegaly (HMS) is caused by an inappropriate immune response to chronic malarial parasite exposure. It is one of the leading causes of massive splenomegaly in malaria-endemic regions.[39]
Epstein-Barr virus (EBV)
Causes infectious mononucleosis. Infection manifests as fever, pharyngitis, posterior cervical adenopathy, and splenomegaly. Splenomegaly is usually mild but can be substantial under unusual circumstances. Generally, once the infection is cleared, the spleen reverts to normal size. Chronic EBV infections can occur in immunocompromised patients and can lead to generalised adenopathy and more prominent hepatosplenomegaly. EBV may be responsible for a complication of solid organ transplant recipients, an entity called post-transplant lymphoproliferative disease, in which splenomegaly may be a feature.
Dengue
Characterised by fever, malaise, headache, asthenia, and less commonly, bleeding, plasma leakage and organ impairment (e.g., hepatosplenomegaly).[40]
Approximately 1 in 10 people with severe dengue have secondary haemophagocytic lymphohistiocytosis (HLH), which has a high mortality rate.[41] Patients with dengue-associated HLH have fever, thrombocytopenia, splenomegaly, anaemia, and hepatomegaly, and raised serum ferritin.[42]
Hepatitis viruses
Chronic ongoing infection of the liver by hepatitis B or C viruses can lead to cirrhosis and resultant splenomegaly.
Endocarditis
Caused by many different types of bacteria and other organisms. May cause splenomegaly because the entire immune system is expanded in an attempt to clear the organisms from the circulation. Additionally, the spleen can become a seeding ground for the invading organism, and splenic abscesses can appear. Splenic abscesses can become quite large, with liquefaction necrosis within, leading to splenomegaly.
Splenic abscesses secondary to sepsis
Splenic abscesses can occur as a consequence of seeding from septicaemia unrelated to endocarditis. Bacteria or fungi can be the culprits. Splenomegaly can be mild to moderate.
Inherent red blood cell abnormalities
Cytoskeletal defects
Can lead to abnormal deformability of red blood cells, which get trapped in the red pulp of the spleen, causing splenomegaly.[43] Spectrin abnormalities are the most common type of cytoskeletal defect and result in hereditary spherocytosis. Hereditary elliptocytosis is another example of a cytoskeletal defect.
Haemoglobinopathies
Can be divided into thalassaemias and structural defects (amino acid substitutions) in alpha- or beta-globin.[44]
In homozygous sickle cell anaemia, repeated infarctions in the spleen lead to a self-destructive process by which the spleen is reduced to a small fibrotic nubbin. However, in some sickle cell variants, such as sickle C (HbSC) disease, the spleen can become enlarged. In children, there can be sudden enlargement and pooling of red cells within the spleen, known as sequestration crisis. Hypotension and cardiovascular collapse can occur.
Thalassaemias result from an improper amount of alpha- or beta-globin being produced. Clinically, thalassaemias are divided into three categories.
Thalassaemia major: severe anaemia with anisocytosis and poikilocytosis, with severe microcytosis. Liver and spleen can be massively enlarged.
Thalassaemia intermedia: less severe thalassaemia. Spleen is usually mildly enlarged.
Thalassaemia minor: hypochromic microcytic anaemia may be present. Spleen can be normal sized or slightly enlarged.
Trauma
Spleen can be ruptured, with tears in the splenic capsule and intraperitoneal bleeding necessitating emergency splenectomy. Rarely, trauma can lead to bleeding within the splenic capsule, and a subcapsular haematoma may result.
Drug-related
Granulocyte colony-stimulating factor treatment can cause splenomegaly.[45] In very rare cases, splenic rupture may result. High-dose chemotherapy can lead to Budd-Chiari syndrome. Prior or current treatment with oral contraceptives raises the possibility of portal vein thrombosis.
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