Evaluation of Splenomegaly


The spleen is a secondary lymphoid organ that lies in intraperitoneally in the left hypochondrium, abuting the diaphragm. It spans from the 9th to 11th rib and weighs between 150-200g. Spleen is supplied by the splenic artery and drains into portal circulation via the splenic vein. It is a part of reticuloendothelial system, immune system and is a site of in utero haematopoiesis. The spleen is enlarged in a diverse set of disease of the above mentioned  systems and in portal hypertension.

Normal Functions of the Spleen

The normal functions of the spleen include

  1. Reticuloendothelial functions: The spleen as a component of the reticuloendothelial system is involved in clearing the blood of ageing or damaged erythrocytes, antibody coated cells and opsonised bacteria. It also removes particles from red cells. The spleen ensures that the red cell in circulation have adequate deformability for passage through microcirculation.
  2. Immune Functions: The spleen is a part of the immune system and plays a role in mounting the immune response . Splenectomy increases the risk of infections particularly with capsulated organisms (see Overwhelming Post-Splenectomy Infection (OPSI)).
  3. Haematopoiesis: Spleen is the site for haematopoiesis in utero. In extrauterine life spleen can become a site of haematopoiesis in disease.

Palpating the Spleen

  1. Palpation of the spleen should start from the right iliac fossa. If this is not done there is a risk of missing a massively enlarged spleen.
  2. Move towards the left costal margin in a direction perpendicular to the margin. Move with each breath. At every position ask the patient to take a deep breath. The tip of the spleen will hit your palpating finger.
  3. If the spleen does not hit your finger move your palpating finger to a position closer to coastal margin, ask the patient to take a deep breath and repeat the procedure described above till your finger hits the costal margin.
  4. If the spleen is felt measure the perpendicular distance between the tip and the left coastal margin. Also note the texture and presence of tenderness.
  5. If the spleen is not felt repeat the procedure with patients lying on right side.
  6. Large spleen can rupture with aggressive palpation. The spleen lies directly under the anterior abdominal wall. One does not need to be aggressive.

Causes of Splenomegaly

The spleen enlarges from the left coastal margin in the direction of the umbilicus. It needs to enlarge 2-3 times before it is palpable. Splenomegaly may be caused be increase in portal venous pressure, infiltrative conditions or when the spleen function needs to increase. Clinically it is useful to classify splenomegaly by size. Massive splenomegaly is enlargement of the spleen beyond the umbilicus. The causes of massive splenomegaly include

  1. Malignant: Chronic myeloid leukaemia, Idiopathic myelofibrois, hairy cell leukaemia, splenic marginal zone lymphoma, chronic lymphocytic leukaemia, prolymphocytic leukaemia
  2. Infections: Tropical splenomegaly, AIDS with Mycobacterium avium complex infections, Kala-azar (visceral leishmaniasis)
  3. Others: β-Thalassaemia major and intermedia, Extrahepatic portal venous obstructions,megaloblastic anaemia, diffuse splenic haemagiosis

The causes of splenomegaly include the above and the following

  1. Portal Hypertension: Cirrhosis, Budd-Chairy syndrome, splenic vein thosmbosis, congestive heart failure, hepatic schistosomiasis
  2. Increased splenic function:
    1. Increased functional demands: Haemolytic anaemia commonly hereditary spherocytosis, autoimmune haemolytic anaemia, β-thalassaemia, early sickle cell anaemia, sickle cell β-thalassaemia,
    2. Infections:
      1. Bacterial: Septicaemia, bacterial endocarditis, splenic abscess, brucellosis, tuberculosis, AIDS with Mycobacterium avium complex infections, secondary syphilis
      2. Viral: Viral hepatitis, infectious mononucleosis, cytomegalovirus,
      3. Parasitic: Malaria , Kala-azar (visceral leishmaniasis), Trypanosomiasis,
      4. Fungal: Histoplasmosis
    3. Immune Disorders:
      1. Autoimmune diseases: Rhumatoid arthritis (Felty’s syndrome), systemic lupus erythrmatosis
      2. Other immune disorders: Immune haemolytic anaemia, immune neutropenia, drug reaction, serum sickness, sarcoidosis
      3. Haemophgocytic lymphohistiocytosis
  3. Infiltrations
    1. Haematological Malignancy:
      1. Myeloid: Chronic myeloid leukaemia, myeloproliferative disease, idiopathic myelofibrosis, polycythaemia vera
      2. Lymphoid: Acute lymphoblastic leukaemia, hairy cell leukaemia, chronic lymphocytic leukaemia, prolymphocytic leukaemia, splenic marginal zone lymphoma, angioimmnoblastic T cell lymphoma
      3. Other: Histiocytosis X, eosinophilic granuloma
    2. Storage disorders:Gaucher disease, Niemann-Pick, Tangier disease, mucopolysachroidosis
    3. Other Infiltrations: Amyloid
  4. Others: Iron deficiency anaemia

 

History and Physical Examination

  1. Fever: Fever is a feature of splenomegaly due to infections, inflammations or malignancy, particularly haematological malignancy. Usually the fever is low grade. High grade fever suggests splenic abscess.
  2. Painful splenemegaly: The nature of pain associated with splenomegaly varies with the cause of splenomegaly.
    1. An enlargement spleen from any cause can cause a dragging pain in the left upper quadrant.
    2. Acute pain left upper quadrant pain is a feature of is a feature of splenic infarct and splenic abscess. Sickle Cell anaemia is associated with small fibrotic spleen because of repeated splenic infarcts. Early in disease the spleen enlarges. Patients may present with acute pain from splenic infarcts. Enlarged spleen from any cause is predisposed to infarction. Acute pain in the left upper quadrant is also a feature of acute splenic abscess.
    3. Splenic vein thrombosis can cause splenomegly and pain in left upper quadrant or epigastric region. It may also cause generalised abdominal pain.
    4. Pancreatitis presents with abdominal pain and can cause painful splenomegaly secondary to splenic vein thrombosis.
    5. Alcohol induced pain is an uncommon but unique feature of Hodgkin lymphoma. Spleen is a common site of involvement by Hodgkin lymphoma. Such patients may have alcohol induced pain in an enlarged spleen.
  3. Pallor: Pallor in a patient with splenomegaly suggests a diagnosis of haemolytic anaemia, haemolymphatic malignancy and infective endocarditis.
  4. Clubbing: Clubbing with splenomegaly is a feature of infective endocarditis and cirrhosis of the liver.
  5. Skin rash: Skin rash in a patient with splenomegaly is seen in systemic lupus erthomatosis, infective endocarditis, lymphoma (angioimmuniblastic T Cell lymphoma, mycosis fungiodes, skin involvement with lymphoma) and drug reaction.  Each of these conditions have a distinct type of rash.
  6. Skin Pigmentation: Hyperpigmantation suggests be seen in hemachromatosis or megaloblastic anaemia. The patients with megaloblastic anaemia may also have knuckle pigmentation.
  7. Jaundice: Jaundice with enlarged spleen is a feature of haemolytic anaemia. The jaundice is usually achloruric. Patients with haemolytic anaemia are predisposed to gallstones. Obstruction of the biliary system from a calculus dislodged from the gall bladder can cause obstructive jaundice with abdominal pain and signs of acute inflammation. Splenomegaly with jaundice is a feature of advanced cirrhosis. Patients with advanced cirrhosis almost always have ascites.
  8. Lymphadenopathy: The enlargement of lymph nodes and spleen is a feature of lymphoid malignancies or diseases that stimulate the lymphoid systems viz. infections and autoimmune diseases and lymphoid malignancy.
  9. Joint symptoms: Arthropathy with splenomegaly suggests the diagnosis of rheumatoid arthritis, systemic lypus erythrmatosis or haematochromatosis.
  10. Oral symptoms: infectious mononucleosis is charecterized by pharyngitis and generalised lymphadenopathy. Bleeding gums and/or gum hypertrophy suggests a diagnosis of leukaemia. Lymphoma can cause tomsillar enlargement. Amyloid is charectetized by macroglossia.
  11. Evidence of Portal Hypertension and Liver Cell Failure: Patients with portal hypertension often have history of haemetemesis. Examination may reveal periumbilical veins (capital medusae), anterior abdominal or flank veins. Patients with evidence liver cell failures with portal hypertension (e.g. jaundice, ascites, spider angiomas, asterxis etc. see Portal Hypertension) have cirrhosis. When the jugular venous pressure is high a diagnosis of congestive cardiac failure should be considered.

Laboratory Evaluation

Haemogram; The haemogram is the most important laboratory test in evaluating a patient with splenomegaly. The significance of findings on haemogram is described in the table below.

Haemogram Finding Conditions
Pancytopenia Hypersplenism, Lymphoma (splenic marginal zone lymphoma), Hairy cell leukaemia, Myelofibrosis, systemic lupus erythrmotosis
Neutrophilic Leucocytosis Acute infections, inflammation
Leucocytosis with premature white cells Chronic myeloid leumaemia, Myeloproliferative disease, Myeloproliferative/Myelodysplastic overlap, Acute lymphoblastic leukaemia
Leucoerythroblastic anaemia Idiopathic myelofibrosis, Bone marrow infiltration
Polycythaemia Polycythaemia vera
Atypical Lymphocytes Infectious mononucleosis
Thrombocytosis Myeloproliferative disease (Chronic myeloid leukaemia, idiopathic myelofibrosis, polycythaemia vera), chronic infections like tuberculosis
Parasites Malaria, bartonelosizs, babesiosis

Other investigations are dictated by the clinical presentations. Commonly performed investigations include biochemistry, microbiology, echocardiography, endoscopy and biopsy of any lymph node or any other mass. Other investigation may be performed as indicated

Imaging

Imaging is an important aspect of evaluation of the spleen but is beyond the scope of this article. Several good reviews exist e.g Singapore Med J 56(3):133-144.

From Hodgkin’s Disease to Hodgkin Lymphoma


Hodgkin lymphoma was described by Thomas Hodgkin in 1932. It was referred to as Hodgkin’s disease till the WHO classification proposed the use of the term Hodgkin Lymphoma. The journey from Hodgkin’s disease to Hodgkin Lymphoma was possible because of breakthroughs immunophonotyping, molecular biology and microdissection.

The difference between Hodgkin’s disease and Hodgkin lymphoma is not about semantics. The term lymphoma recognises the disorder to be malignant whereas the term “disease” was ambiguous. Unlike any other malignancy the bulk the tumour in patients with Hodgkin lymphoma is made of normal reactive cells, lymphocytes, neutrophils, eosinophils and plasma cells. Reed-Sternberg (RS) is the malignant cell of classical Hodgkin lymphoma (cHL) and the LP cell is the malignant cell of nodular lymphocytic predominant Hodgkin lymphoma (NLPHL). Both cells form a small minority of the tumour mass. The combination of a bizarre looking cell that are sparsely distributed in what looked like a chronic inflammatory infiltrate was unlike any other malignancy and was the cause of uncertainty about the malignant nature of Hodgkin lymphoma. The term Hodgkin’s diseases reflected this uncertainty.

Malignancy is driven by mutations in genes regulating growth and differentiation. Many mutations result from chromosomal defects that can be demonstrated by karyotyping. The RS cell and the LP cell from a small proportion of the tumour mass. A pure population of malignant cells was needed for karyotyping. Today it is possible to separate out these cells from tissue by laser micro dissection. Before this technology became available the only way to get a pure population of RS cells was by establishing cell lines from patients suffering from Hodgkin’s disease. Study of cell lines as well as laser dissected RS cells showed the cells to have karyotype anomalies confirming the disease was a malignancy.

Another area of confusion was the cell of origin of Hodgkin lymphoma. The cells that had been suggested to be giving rise to RS cell included B-lymphocyte, T-lymphocyte, reticulum cell, dendritic cell and histiocyte/macrophage. Molecular studies have shown that the RS cell originates from the pre-apoptotic germinal centre B cell and the LP cell originates from the antigen selected germinal centre B cell. The former does not express the classical B cell markers the latter does. There are multiple reasons for the lack of expression of B cell markers and these include expression of inhibitors of B-cell molecules, down-regulation of B-cell transcription factors and the epigenetic silencing of B-cell genes.

Hodgkin lymphoma is a malignancy of germinal B cell origin and the term lymphoma describes the disease more accurately than the word disease. WHO classification of lymphoid malignancies refers to the disorder as Hodgkin Lymphoma in recognition of this fact.

Manifestations of Lymphoma


Lymphomas are the most prevalent haematological malignancies. They are highly curable particularly in the early stage. As is the case with all cancers, there are no symptoms typical of lymphoma. The manifestations of lymphoma include:

Lymphadenopathy

Lymph node may be classified into superficial or deep group.

  1. Superficial Nodes: Superficial nodes include occupital, cervical, supraclavicular, epitrochlear, axillary, inguinal node.
    1. Cervical Nodes: Enlargement of cervical nodes is common. Children may have palpable cervical nodes that regress with age. These nodes are usually soft and small. Large, firm to hard, matted or enlarging cervical nodes need evaluation. The commonest cause of enlargement of cervical nodes is infection of upper repiratory tract. Patients with cervical lymphadenopathy associated with an upper respiratory tract infection need to be followed up till the lymph node regress. Nodes that do not regress after the infection subsides need evaluation.
    2. Occipital Nodes: Occipital nodes may be enlarged in patients with lice infestations. It is unusual to find occipital node engagement in disease.
    3. Axillary Nodes: Enlargement of axillary nodes usually indicates a disease in the draining areas – upper limbs, breast, lungs. Patients with recurrent trauma of the upper limbs may have enlarged axillary nodes.
    4. Inguinal Nodes: Inguinal lymphadenopathy is a feature of disease of the lower limb and the anogenital region. Recurrent trauma to the lower limbs can cause inguinal lymphadenopathy.
    5. Epitrochlear Nodes: Enlarged epitrochlear or popleteal nodes always indicates a disease, usually one causing a diffuse lymphadenopathy.
  2. Deep Nodes: The deep nodes include the mediastinal, hilar, intra-abdominal and pelvic nodes. Enlargement of these nodes causes pressure symptoms and is . Enlargement of  these nodes indicates disease.

Almost all Hodgkin’s lymphomas and majority of non-Hodgkin’s lymphoma present with enlargement of lymph nodes. Lymphadenopathy is a common symptom. It may be a result of  infection, inflammation or malignancy.

  1. Lymphadenopathy of Acute Infection/Inflammation: Patients with acute inflammation can be differentiated from lymphoma as they have painful and tender nodes often with erythema of the overlying skin. These node can suppurate. The area drained by the node has a inflammatory lesion, usually an infection.
  2. Lymphadenopathy of Chronic Infection/Inflammation: Lymphadenopathy of chronic inflammation has lacks erythema, pain and do not suppurate. The node enlarge at a slower rate. Differentiation of lymphadenopathy caused by chronic inflammatory disorders and malignancy can only be made by pathological examination of the nodes. The differentiation between tuberculous lymphadenitis and lymphoma (particularly Hodgkin’s lymphoma) can be challenging as regions of the world that have high prevalence of tuberculosis also have a resource constrain.

 

Tuberculosis lymphadenitis is common in resource constrained regions of the world. It is the practice in these regions to initiate anti-tuberculous therapy for patients with matted cervical nodes either on clinical grounds or following a fine needle aspiration cytology. While this can not be justified scientifically, proponents of this practice point to the lack of healthcare infrastructure to justify this practice. If one is choosing this path one must follow the patient to confirm regression and be aware of the existence of paradoxical response in tuberculosis. Paradoxical response is characterised by increase in constitutional symptoms and lymph node size on initiation of anti-tuberculous treatment. It is seen in about 10-15% patients.

Splenomegaly and Hepatomegaly

Spleen is a lymphoid organ. Lymphomas can originate in the spleen of the spleen can be secondarily involved by lymphoma. Primary splenic lymphomas, defined as splenic involvement without lymph node involvement forms about 6% of all lymphomas (Blood 2010; 117:2585). The symptoms of splenic lymphomas include abdominal discomfort and early satiety due to splenomegaly, constitutional symptoms like fever, weight loss and night sweats due to underlying lymphomatous process.  Patients with splenic lymphomas may have alterations in blood counts. Important history includes that of infections hepatitis C, hepatitis B, autoimmune disorders, treatment with anti-TNF agents.

Bone Marrow and Peripheral Blood

All lymphomas may involve the bone marrow and spread into the blood. Bone marrow and peripheral involvement is common in two groups of lymphoma the very high grade lymphomas like lymphoblastic lymphoma and Burkitt’s lymphoma and low grade lymphomas like small lymphocytic lymphoma. Bone marrow involvement in lymphoblastic lymphoma and Burkitt’s lymphoma manifests as acute lymphoblastic leukaemia is destructive. It manifests as leucocytosis and bone marrow failure (anaemia, neutropenia, thrombocytopenia). Leucocytosis is also a feature of bone marrow involvement with low grade lymphomas. These cells are mature. The growth is accommodative and cytopenias occurs late in the disease, if at all.

Extranodal Lymphomas

It is exceptional to have an extra-nodal Hodgkin’s lymphoma. The proportion of extra nodal non-Hodgkin lymphoma varies across the world.

  1. Gastrointestinal Tract: The commonest site of extranodal involvement is the gastrointestinal tract. Within the gastrointestinal tract, stomach is the commonest site for extranodal lymphomas of the gastrointestinal tract followed by small intestine, colon and oesophagus. The most common manifestation of gastrointestinal lymphoma is nonspecific symptoms like abdominal dyscomfort and pain. Anaemia is a feature of gastric and colonic lymphoma. High grade small intestinal lymphoma may present with intussusception.
  2. Skin Involvement: Cutaneous lymphomas are a distinct entity. Unlike other sites many cutaneous lymphomas are of T cell origin. They present with macules, papules and nodules.
  3. Central Nervous System: Central nervous system may manifest with global symptoms like comfusion, headache and altered consciousness, may have foaly neurolohical deficiit, seizures or multiple cranial nerve involvement because lymphomatous meningitis
  4. Primary testicular lymphoma presents as a unilateral painless swelling of the testis in an elderly male (see Primary Testicular Lymphoma). Hydrocele is present in about 40% of the patients.

Presentation Peculiar to Some Lymphomas

  1. Lymphoplasmacytic lymphoma is unlike other lymphomas in that symptoms of fatigue, weakness and breathlessness dominate. Splenomegaly and lymphoadenopathy are uncommon. Patinets may develop symptoms of hyper viscosity including headache, blurring, eipstasix.
  2. Nasal NK/T cell lymphoma presents with obstructive and destructive mass in the upper aerodigestive tract. It is reported most commonly in patients from the far east.
  3. Hepatosplenic γδ-T cell lymphoma presents with hepatosplenomegaly, no adenopathy, B symptoms and cytopenias. Patinets may have history of anti-TNF therapy for Crohn’s disease.
  4. Intravascular diffuse Large B Cell lymphoma is characterized by disseminated intravascular proliferations of B cells most commonly in the vessels of the CNS, kidney and lungs. Patinets present with symptoms secondary to vascular occlusion. The diagnosis is usually difficult.

Paraneoplastic Syndromes

Paraneoplastic syndromes associated with lymphomas include hypercalcaemia, syndrome of inappropriate ADH secretion, paraneoplastic ceribellar degeneration, motor neuron disease, acute polyradiculopathy, polyneuropathy of paraproteinaemia, neuropathy due to paraneoplastic vasculitis, neuromuscular junction disorders, sweets syndrome and minimal change nephrotic syndrome (see paraneoplastic syndromes associated with lymphoma for more conditions and a detailed discussion).