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.

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Classification of Lymphoma


Lymphomas are a group of malignancies arising from lymphoid tissue. They have a diverse etiology, pathogenesis, clinical presentation, treatment and outcomes. Morphology alone is insufficient to classify lymphomas but for a long time a pathologist had little other than morphology for diagnosis. By the 1980s many advances that were instrumental in taking lymphoma classification beyond morphology had taken place. These advances included:

  1. Recognition of lymphocyte subtypes, T, B and NK cells and development of immunological and DNA based tests to identify these cells.
  2. Hybridoma technology that made available antibodies which were used initially for lymphoma diagnosis and then in lymphoma treatment
  3. Sanger sequencing made determining the sequence of genes possible
  4. Fluorescent in situ hybridisation (FISH) allowed study the mutations in cells in interphase
  5. Chemotherapy achieved cure in some lymphomas and control in others

These technologies were instrumental in generating information about lymphomas including pathogenesis, genetics, immunophenotype and clinical course. It became apparent that lymphomas are one of the most complex malignancies in terms of pathogeneis diagnosis and treatment. Such is the heterogeneity of lymphomas that one of the aggressive (Burkitts’s lymphoma) and one of the most indolent malignancies (small lymphocytic lymphoma/chronic lymphocytic leukaemia) are both lymphomas.

Historically several lymphoma classifications have came into use. Each specialist looked at lymphomas from a different  and his/her own perspective. To the pathologist it was about defining different histological entities and how these entities related to each other. To the clinician it was about defining entities with distinct treatments and outcomes. To complicate matters similar/same entities were referred to by different names by different groups. The confusion that prevailed highlighted the need for co-operation between experts in the field of lymphoma. The first such attempt of co-operation resulted in  the REAL (Revised European American Lymphoma) classification proposed in 1994 by a group of 19 haematopathologists, the International Lymphoma Study Group. This classification used all available information (including histology, genetics, immunophenotyping and clinical course) to define entities. This approach was adapted by the WHO classifications that followed the REAL classification. The most current classification of lymphomas is the 2008 WHO classification. The milestones in the classification of lymphomas are given in the table below.

Year Classifications Features
1941 Gall and Mallory
  1. First generally accepted classification of lymphoma, defined follicular lymphoma
1947 Jackson Parker
  1. First Classification of Hodgkin Lymphoma
1956 Rapaport (Non-Hodgkin Lymphoma)
  1. Classified lymphomas in to follicular and diffuse and within each category by cell morphology.
  2. Within each category nodular lymphomas had a better outcome.
  3. Continued to regard the origins of large cell lymphomas from non-lymphoid cells
1966 Luke and Buttler
  1. Proposed a classification of Hodgkin lymphoma which from the basis of modern classification.
  2. Recognised nodular sclerosis and mixed cellularity.
  3. Recognized the L&H cell
1974 Kiel Classification (Non-Hodgkin Lymphoma)
  1. Recognised that many lymphomas resemble normal germinal centre.
  2. Classified lymphomas according to lymphocytic differentiation as understood at the time. Suggested the putative normal counterparts of lymphomas.
  3. Classified lymphomas in B and T types
1982 Working Formulation (Non-Hodgkin Lymphoma)
  1. Studied 6 classification schemes in use at the time found none to be superior. Consenseus could not be reached because of lack of agreement between pathologists.
  2. Proposed a formulation to translate amongst schemes.
  3. Stratified outcomes based on outcome of trials conducted in the 1970s. Did not use immunophenotyping.
1994 REAL Classification
  1. Developed by a group of pathologists, international lymphoma study group, that made an attempt to overcome differences and focused on identification of “real” entities by incorporating all (morphology, genetics, immunophenotype and clinical course) knowledge available at the time.
  2. Formed the basis of the currently used WHO classification
2001 and 2008 WHO Classifications
  1. The 2008 WHO lymphoma classification is the current classification
  2. Based on pathology, genetics and clinical outcomes

Classification of Lymphoma

The 2008 WHO classification was a result of international collaboration among pathologists, molecular biologists and clinicians interested in the hematological malignancies. Lymphomas are divided into three groups the

  1. B-cell neoplasm
  2. T and NK cell lymphomas

  3. Hodgkin’s lymphoma.

The non-Hodgkin lymphomas are further divided into into precursor neoplasm and peripheral/mature neoplasm. The peripheral lymphoid tissue have mature lymphocytes (peripheral lymphocytes). The precursor lymphoid cells mature in the bone marrow (B cells) and thymus (T Cells).

Lymphocyte development begins with the lymphoblast. A mature lymphocyte expresses a antigen receptor complex which consists of two parts, the antigen receptor and associated signal proteins. Immunoglobulins serve as antigen receptors of B cells. Immunoglobulins  have a constant and a variable region. The genome has many DNA segments encoding for the variable region. Antibodies have different antigen specificity because different segments are chosen to form the gene of the variable region. A wide array of antibody   specificity (millions) can be generated from combination of these DNA segments. Antibody specificity can be further diversified by a process known as somatic hypermutation referred to below. Cells that are undergoing antibody editing are precursor B cells. B cell maturation occurs when the process of antibody editing is complete. Mature B cells express a complete antigen receptor, IgD and IgM on the surface. Similarly a mature T cell is a cell that has completed the process of editing its T cell receptor.

Precursor Neoplasm

Precursor cells are cells that have not undergone the B or T cell receptor rearrangement. The malignancies of precursor lymphoid tissue incelude T and B cell lymphoblastic lymphomas and acute lymphoblastic leukaemia.

B lymphoblastic lymphoma/leukaemia is further classified into B-lymphoblastic leukaemia/lymphoma with recurrent genetic anomalies and B-lymphoblastic leukaemia/lymphoma that does not show these anomalies (B-lymphoblastic leukaemia/lymphoma NOS). The recurrent anomalies seen in B-lymphoblastic leukaemia/lymphoma are [gene rearrangements]

  1. t(9;22)(q34;q11.2) [BCR-ABL1]
  2. t(v;11q23) [MLL rearranged]
  3. t(12;21)(p13;q22) [TEL-AML1 (ETV6-RUNX1)]
  4. t(5;14)(q31;q32)[IL3-IGH]
  5. t(1;19)(q23;p13.3)[TCF3-PBX1]
  6. hyperdiploidy
  7. hypodiploidy

 

Neoplasm of the Mature (peripheral) Cells

Neoplasm of mature lymphocytes are classified into B cell neoplasms and T and NK cell neoplasms.

 

Mature B cell neoplasms

Mature B-cell neoplasm arise from B cells that have undergone B cell receptor rearrangement. Though these cells have their immunoglobulin or T cell receptors rearranged and are referred to as mature the process of maturation is not complete. They undergo a final phase of maturation on exposure to antigens that results in increased antibody avidity. This process takes place in the germinal centre. Antibody avidity is increased by inducing mutations in the DNA segments encoding for the variable regions. This process known as somatic hypermutation.  Somatic hypermutation is a considered to be an evidence of a cell that has passed through the germinal centre (and hence been exposed to antigen). Somatic hypermutations result in a spectrum of avidity (both higher and lower than the original cell). Cells producing highest affinity antibodies survive to form memory B cells or mature to antibody secreting plasma cells. The rest undergo apoptosis. Mutations and apoptosis are two phenomena central to malignant transformation. Germinal centre cells are subject to both. It is not surprising that the germinal centre is the site of the largest number of lymphomas. Diffuses large B Cell lymphoma, follicular lymphoma, Hodgkin’s lymphoma classical and nodular lymphocyte predominant and Burkitts’s lymphoma originate in the germinal centre. Together these constitute almost two third of the lymphomas. Most mantle cell lymphomas originate from cells that have yet to enter the germinal centre. Chronic lymphocytic leukaemia, marginal zone lymphomas, plasma cell neoplasms and lymphoplasmacytic lymphomas arise from cells that have passed through the germinal centre.

Diffuse large B cell lymphoma (DLBCL) is a lymphoma composed of B cells where the size of malignant cells is equal to or exceeds the size of a macrophage nucleus. DLBCL is the most common lymphoma across the world. All DLBCLs are aggressive lymphomas. The commonest form of DLBCL lacks any special features and is known as DLBCL NOS (not otherwise specified). There four DLBCL subtypes. EBV positive DLBCL of the elderly is a provisional entity in the 2008 WHO classification.

  1. T Cell/histiocyte rich DLBCL (THRLBCL): THRLBCL is a rare variant of DLBCL that is characterised by scattered large B cells that comprise about 10% of the cells in reactive infiltrate that is abundant in T cells with frequent histiocytes.  It resembles Hodgkin’s lymphoma in having a paucity of malignant cells and an abundance of infiltrate. Some TCRLBCL may be arising from progression of nodular lymphocytic predominant Hodgkin’s lymphoma.
  2. Primary CNS DLBCL: Primary CNS DLBCL forms about 90% of primary CNS lymphomas.
  3. Primary cutaneous DLBCL, leg type: Primary cutaneous DLBCL, leg type is a cutaneous lymphoma most commonly arising in the leg. Unlike other DLBCL women are affected more often than men.
  4. EBV positive DLBCL of the elderly

Other forms of DLBCL include those having special anatomical sites (primary mediastinal B cell lymphoma, intravascular lymphoma), histological features (ALK positive large B cell lymphoma, de novo CD5+ large B cell lymphoma) and pathogenesis (large B cell lymphoma arising out of HHV-8 associated Castleman’s disease, pleural effusion lymphoma)

Follicular lymphomas (FL) arise from germinal centres. They have follicle centre (centerocytes/small cell) and large (centroblasts/transformed) arranged at least in a partially follicular pattern. Eighty percent of the patients have the t(14;18)(q32;q21) translocation that results in fusion of immunoglobulin heavy chain gene with BCL2. FL is divided into three categories according to the number of centrblasts. Grade 1-2 FL have 0-15 centroblasts per high power field, Grade 3A FL has >15 centeroblasts per high power field and 3B FL shows solid sheets of centroblasts. Grade 1-2 and Grade 3A FL are indolent lymphomas and Grade 3B is an aggressive lymphoma to be treated as DLBCL.

Small lymphocytic lymphoma (SLL) is a lymphoma that consists small lymphocytes that co-express CD19 and Cd5. It is the nodal counterpart of chronic lymphocytic leukaemia (CLL) and the entity is referred to as CLL/SLL. Patients having lymph node involvement and <5 X 109/L lymphocytes are classified as SLL. Patients with ≥5 X109/L lymphocytes are said to have CLL. The normal counterpart of SLL is the antigen experienced B cell.

Marginal zone lymphomas (MZL) are indolent lymphomas. They are of three types, nodal MZL, extranodal lymphomas of the mucosa associated lymphoid tissue (MALT) and splenic marginal zone lymphomas (SMZL). They arise from post-germinal memory B lymphocytes in the marginal zone of the germinal follicles. About one third of the patients of SMZL do not have somatic hypermutation of the variable regions of the immunoglobulins. The cell of origin is in these SMZL is not known. MZL are peculiar amongst lymphomas in being related to infection. Gastric MALT lymphomas are associated with H. pylori infection, ocular adnexal MALT lymphoma is associated with Chlaymydia psittaci, immunoproliferative small intestinal disease (IPSID) with Campylobacter jejuni, and cutaneous MALT lymphoma with Borrelia burgdorferi. Hepatitis C infection is associated with splenic marginal zone lymphoma.

Mantle cell lymphomas are lymphomas small to medium sized cells that arise form peripheral B cells of the inner mantle zone. It is associated with the t(11;14)(q13;q32) translocation that results in the formation of the IGH@-CCND1 (Cyclin D1) fusion gene. Cyclin D1 can be detected on almost all mantle cell lymphomas by immunohostochemistry.

Burkitts lymphoma (BL) is a lymphoma composed of medium sized cells (nuclei similar to or smaller than histiocytes) that show a diffuse monotonous pattern. The tumour has a very high proliferation index and shows many mitotic figures and a high fraction of apoptosis. It is characterised by translocation that dysregulate the oncogene MYC. These include the t(8;14)(q24;q32) translocation that IGH@ (immunoglobulin heavy chain locus)  to MYC and is the commonest translocation in Burkitt’s lymphoma, the t(2;8)(p12;q24) that translocates the IGK@ (kappa light chain locus) to MYC and t(8;22)(q24;q11) that translocates IGL@ (lambda light chain locus) to MYC. There are two forms of Burkitt’s lymphoma. The Endemic BL occurs in equatorial Africa, affects children and has the EBV genome in majority of the neoplastic cells. The sporadic BL is seen in other parts of the world, is most common in young adults and shows EBV genome only in about 30% of the patients. Sporadic BL is a immunosuppression related malignancy seen in HIV and other forms of immunosuppression.

Lymphoplasmacytic lymphoma is a mature B cell lymphoma that is made of small B lymphocytes and plasmacytoid lymphocytes. These lymphocytes often secret IgM resulting in the syndrome Waldenström macroglobulinaemia. IgM Secretion however in not essential for diagnosis. The normal counterpart of lymphoplasmacytic lymphoma is the post germinal B cell that differentiates into a plasma cell.

Other rarer lymphomas have been described elsewhere (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues)

 

Mature T-cell and NK neoplasm

The differentiation of T lymphocytes is not understood as well as that of the B lymphomas.  Clinical picture plays a more important role in the diagnosis of T cell/NK cell lymphomas. T cells carry a more diverse set of function than B lymphocytes. These include cytotoxic functions, aiding other cells of the immune system and regulation of immunity. Many subtypes of T cells are recognised. Like B cells, the T cells have a antigen receptor complex. This consists of and antigen receptor and associated signal proteins. The T cell receptor is made of a pair of chains. There are four T cell receptor chains, α, β, δ and γ. These give rise to two types of T cell receptor the αβ  and δγ. Ninty five percent of the T lymphocytes have the αβ receptors and about 5% of the at T cells have δγ receptors. The δγ T cells and NK cells are a part of the innate immune system. Malignancies of these cells are common children and young adults. These include aggressive NK cell leukaemia, systemic EBV positive lymphoproliferative disease of the childhood, most hepatosplenic T cell lymphomas and δγ-T cell lymphoma.

T cells of the adaptive immune system include naive T cells, helper/regulatory T cells, cytotoxic T cells and memory T cells. Regulatory  cells express CD4. Depending on the cytokine secreting profile these cells are of two types Th1 and Th2. Th1 cells produce IL2 and INFγ that mainly help T cells and macrophages. Th2 cells secrete IL-4, IL-5, IL-6 and IL-10 and mainly help B cell. Follicular helper T cells are T cells that help the germinal centre reaction. In addition to the T cell markers they express germinal centre markers BCL6 and CD10. They also express CD57 and PD-1. Regulatory T cells are cells that suppress immune response. They express CD25.

Lymphomas of the T cells of the adaptive immune system are nodal and occur in adults.

Peripheral T cell lymphoma not otherwise specified (PTCL NOS) is a heterogenous group of malignancies of the peripheral T cells. Its is a basket entity that includes peripheral T cell lymphomas that lack any specific features (unlike the ones listed below). It is the commonest peripheral T cell lymphoma. Gene expression profiling has identified two subtypes of PTCL NOS. Lymphomas arising from the Th1 cells and those arising from Th2 cells.

Anaplastic large cell lymphoma (ALCL) is the second most common T peripheral T cell lymphoma. The normal counterpart of ALCL is not known. ALCL has two subtypes depending on the expression of the anaplastic lymphoma kinase (ALK), ALK+ ALCL and ALK -ve ALCL. These have distinct clinical picture.

Angioimmunoblastic T cell lymphoma (AITL) arises from follicular helper T cells. It usually disseminated at presentation.  It is characterised by generalised lymphadenopathy, systemic symptoms and polyclonal hypergammaglobulinaemia. The patients have immune phenomena including circulating immune complexes, cold agglutinins with haemolytic anaemia, rheumatoid factor and anti-smooth muscle antibodies. These are attributed to polyclonal proliferation of B lymphocytes (which are not the malignant lymphocytes).

Adult T cell Leukaemia/lymphoma is a lymphoma composed of highly pleomorphic lymphoid cells. It is seen in Southwest Japan, Caribbean and parts of Central Africa and is caused by the retrovirus HTLV-I. The clinical types include acute, lymphomatous, chronic and smoldering. Patients often have hypercalcaemia and often have immunodeficiency.

Skin unlike other organs has a higher proportions of T cell lymphomas than B cell lymphomas. These include Mycosis fungoides, Sezary syndrome and the primary cutaneous CD30+ T cell lymphoproliferative disorder, primary cutaneous T cell lymphomas, subcutaneous panniculitis like T cell lymphoma.

Other rare T cell lymphomas include T cell prolymphocytic leukaemia, T-cell Large Granular lymphocytic leukaemia, Extranodal NK/T cell lymphoma, nasal type, enteropathy associated T cell lymphoma and hepasplenic T-Cell lymphoma. A complete list is given elsewhere (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues)

 

Hodgkin lymphoma

Hodgkin’s lymphoma is of two types classical and modular lymphocytic predominant. The uncertainty that surrounded the cell of origin of Hodgkin’s lymphoma was ended when microdissected Reed-Sternberg cells were shown to be of B cell origin. The classical Hodgkin’s lymphoma is further divided into lymphocyte rich, nodular sclerosis, mixed cellularity and lymphocyte depletion types.

 

References

  1. Elaine S. Jaffe, Nancy Lee Harris, Harald Stein, and Peter G. Isaacson. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood. 2008 Dec 1; 112(12): 4384–4399.
  2. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

 

Primary Cutaneous DLBCL – Leg Type


The first description of a primary cutaneous diffuse large B cell lymphoma was by Willemze et al in 1987 who described a group of elderly women with cutaneous large cell lymphomas with tumours in the legs and a worse prognosis ( Am J Pathol. Feb 1987; 126(2): 325–333).

Primary cutaneous diffuse large B cell lymphoma, leg type is a type of high grade cutaneous B cell lymphomas that was included as a separate entity in the WHO 2008 lymphoma classification. It forms about 20% of all cutaneous B cell lymphomas and about 4% of all cutaneous lymphomas. It is more common in women and the median age of occurrence is the 7th decade.

Pathology

Primary cutaneous large B cell lymphoma is characterized by a monotonous, diffuse, non-epidermotrophic infiltrate that is CD 20 and CD79a positive. and almost always express BCL2, IRF4/MUM1 and FOX-P1. The latter three markers are not expressed in in the primary cutaneous follicular centre cell lymphoma  another type of primary cutaneous B cell lymphoma. BCL6 is usually expressed but CD10 is not. 

Clinical Features

DLBCL-LT is a disease of elderly women (M:F:12-4, median age 70 years). Though called leg type, only 85-90% of the primary cutaneous DLBCL, leg type occur in the legs. The remaining occur at other sites. Patients present with a rapidly growing red or reddish blue nodule on one or both the legs. Patients may have ulceration and may be confused with venous ulcer. Unlike other cutaneous lymphomas primary cutaneous DLBCL, leg type disseminates to non-cutaneous sites.

Treatment

Radiotherapy

As DLBCL-LT has a tendency to disseminate to extra-cutaneous sites than other cutaneous lymphomas radiation is less effective in this disease. . A complete response rate of 88%  with a high (58%) relapse rate has been reported. relapses are in the in field and extra-cutaneous.

Chemotherapy

R-CHOP is the standard first line therapy. Dose reduction may be needed in elderly. Single agent rituximab is also an option but is associated with a high rate of recurrences. Linelidomide has been used in patients with relapse.

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).

Bendamustine


Bendamustine is a mechlorethamine derivative synthesised by Ozegowski and Krebs from the former East Germany in 1963. The  molecule has three parts,

  1. The alkylator mechloethamine,
  2. Benzimidazole ring that mimics purines
  3. Butyric acid side chain.

Each of these part has potential anti-malignacy action but only the alkylating actions are of clinical significance.

Mechanism of Action

Bendamustine acts as a classical chlorethyl alkylating agent. It causes inter and intrastrand DNA cross links that result in DNA strand breaks. The number of DNA strand breaks caused by bendamustine is grater than those caused by cyclophosphamide or melphalan. In addition the breaks are repaired slowly. This is probably because of the bulky structure of bendamustine. It has a partial cross sensitivity against other alkylating agents.

The benzimidazole side chain mimics purines and butyric acid side chain can react with membranes and proteins.  These actions do not contribute to the anti-tumour effect of bendamustine.

Mechanisms of Resistance

Resistance to bendaustime may develop because  of

Increased activity of DNA repair enzymes

Increased expression of sulfhydryl proteins, e.g. glutathione and glutathione-related enzymes

Bendamustine is partially cross-resistance with other alkylators.

Pharmacokinetics

  1. Absorption and Distribution: Bendamustine has a high oral bioavailability of 90% but no oral preparation is available. It is tightly (94%-96%) bound to human serum plasma proteins. Protein binding is not affected by hypoalbuminaemia.  It does not appear to displace other drugs or be displaced by other drugs. It is mainly distributed in the extracellular space and has a steady state volume of distribution of 25 L.
  2. Elimination: It is metabolised by hydrolysis. Active metabolites are formed as a result of drugs metabolism but theses have little clinical significance.  The half-life after a 30 minute infusion is 40 minutes with clearance of 700ml/min.
  3. Effect of Renal Impairment: Renal impairment with creatinine clearance unto 40 ml/min does not affect the elimination of bendamiustine. The effect of more severe renal failure is not studied.
  4. Effect of Hepatic Impairment: Mild Hepatic impairment does not have an effect on bendamustine elimination. The effect of moderate and severe liver impairment is unknown.

Toxicity

  1. Myelosupression: The main toxicity is myelosupression with about half the patients having grade 3 or 4 neutropenia. The incidence of febrile neutropenia is about 7%. Grade 3  to 4 thromboctopenia is about 24%. Anaemia is less common.
  2. Nausea and vomiting is usually mild to moderate
  3. Infusion reactions: infusion reaction is characterised by fevers, hypotension, back and muscle pain, chills, and rigours and may be seen within the 24 hours of infusion. It may be seen unto the third cycle. Steroids may help in patients getting infection reactions.
  4. Skin Toxicity: Skin rash and bullous exanthema
  5. Tumour lysis syndrome
  6. Carcinogenicity: Bendamustine has been associated with myelodysplastic syndrome and acute leukaemia.

Indications

  1. Chronic Lymphocytic leukaemia
  2. Low grade non-Hodgkin lymphoma
  3. Other disease wherebendamustine is used but the role is not established:
    1. Multiple Myeloma
    2. Acute Leukaemia
    3. Solid Tumours – breast cancer, small cell lung cancer, germ cell tumour

Dose

  1. Chronic Lymphocytic leukaemia:
    1. Single Agent: 100mg/m2 day 1 and 2 every 4 weeks
    2. With rituximab: 90mg/m2 day 1 and 2 when used with rituximab
  2. Non-Hodgkin Lymphoma:
    1. Single Agent: 120mg/m2 day 1 day 2 of a 21 day cycle.
    2. With Rituximab:  90mg/m2 o day 1 and day 2 of a 28 day cycle

Dosing in Special Populations

  1. Pregnancy:  Bendamustine is mutagenic.
  2. Paediatric Patients: Safety of bendamustine in paediatric population is not established
  3. Renal Failure: Bendamustine should not be used in patients with creatine clearance of less than 40ml/min
  4. Hepatic failure: Bendamustine should not be used in patients with moderate or severe hepatic impairment (bilirubin >3 X upper limit of normal or bilirubin 1.5-3 X upper limit of normal with AST or ALT 2.5-10X normal)

 

Low Grade Lymphomas In Children


Low grade lymphomas are rare in children but two entities have been described in the WHO classification paediatric follicular lymphoma and paediatric nodal marginal zone lymphoma.

Paediatric Follicular Lymphoma
Paediatric follicular lymphoma is distinct from the common adult variety genetically and clinically. The differences include

  • Patients of the paediatric folliculr lymphoma lack the t(14;18)(q32;q21) translocation and the bcl-2 activation that is the genetic hallmark of the adult follicular lymphoma. Expression of bcl2 in pediatric follicular lymphoma is associated with a poor outcome (Blood March 15, 2002vol. 99 no. 6 1959-1964)
  • Paediatric follicular lymphoma is a localized disease adult follicular lymphoma is disseminated at presentation
  • Paediatric follicular laymphomas have a better outcome than adult follicular lymphoma. This is despite the fact that pediatric patients have higher morphological grade (predominantly grade 3A). They may have a associated diffuse components but this dies not affect the outcome of treatment. Patients may be cured by local excision.

 

Paediatric Nodal Marginal Zone Lymphoma (pNMZL)
Peadiatric nodal marginal zone lymphoma presents with asymtomatic localized (usually stage I) disease usually in the neck region in males (M:F 20:1). The histology and immunophenotype is similar to that of adults. The outcome of pNMZL is excellent and relapses are exceedingly rare. Two adults with pNMZL have recently been described (Leuk Lymphoma. 2010 January; 51(1): 89–94).

Other B and T low grade lymphomas have been described in children. These are very rare and the natural history does not appear to be different from adults.

Paraneoplastic syndromes Associated with Lymphoma


Paraneoplastic synromes are non-metastatic distant manifestation of a cancer. The paraneoplastic manufestations of lymphoma aredescribed below.

Endocrine Manifestations
Hypecalcaemia: About 4% of Hodgkin’s Lymphoma and about 1% of the patinets with non-Hodgkin’s lymphoma (NHL) have hypercalcaemia. The  NHLs associated with high prevelance hypercalcaemia include high grade B-cell neoplasms and adult T cell lymphoma/leukaemia. Paraneoplastic hypercalcaemia may be caused by PTHrP or 1, 25-dihydroxy vitamin D3. Hypercalcaemia in almost all the patients of HL results from overproduction in 1,25-dihydroxy vitamin D. This mechanism is analogous of hypercalcaemia of tuberculosis and sarcoidosis, is believed to be a result of increased activity of 1α-hydroxylase in macrophages and is responsive to corticosteroids.

Among the HNLs the lymphoma with the highest incidence of hypecalcaemia is adult T-cell leukaemia/lymphoma. About one fifth to half thr patirnts have hypercalcaemia. Both PTHrP and calcetrol have been associated with hypercalcaemia.

Syndrome of Inappropriate ADH Secertion (SIADH): Paraneoplastic SIADH is most commonly associated with small cell lung cancer but has been described in patients with lymphoma. When the syndrome developes in patients with lymphoma on treatment vinca alkaloids may be the culprit.

Neurological Manifestations
Paraneoplastic Cerebellar Degeration (PCD): PCD has been reported in HL as well as NHL but the syndrome associated with HL is better characterized as HL is one of the commonest malignancies associated with PCD. HL associated PCD may occur even when the patient is in remission and there appers to be no relation of PCD and stage of HL. PCD is an immune disease that is associated with anti-Hu in cases of PCD associated with small cell lung cancer and anti-Yo antibodies in gynecological cancers. PCD associated with HL is charcterized by the presence of anti-TR antibodies that are distinct from the antibodies mentioned above. PCD associated with HL appeares to have a better outcome. Spontaneous recovery has been reported in 15% of patients and recovery following therapy has been reported. Immunosupressive therapy has not been shown to be of benefit.

Other Central Nervous System Manifestations: Limbic encephalitis that reverses with treatment, a chloroform disorders, a paraneoplastic myelopathy have been described with HL.

Motor Neuron Disease (MND): Paraneoplastic MND associated with lymphoma is charcterized by upper and lower motor neuron involvement. These patients often have paraproteinaemia. They may may benefit from chemotherapy but the benefit of immunotherapy and plasmapheresis is less clear.

Peripheral Nerve Involvement
Acute polyradiculoneuropathy (APN): APN resembles Guillian-Barre syndrome and is seen with HL. No specific antibodies have been associated with this syndrome. Treatment of HL does not appear to alter it’s course. Plasmaphersis and intravenous gamma globin may control the manifestations. Patients with relapsing and remiting forms have been described.
Polyneuropathy of Paraproteinaemia: Lymphplasmacytic lymphoma is associated with a peripheral neuropathy (sensory, motor or both) in 5-10% of the patients. The pathogenesis of these neuropathies is diverse and include

  1. Demyelination resulting from IgM monoclonal band being directed against neuronal components
  2. Axonopathies due to endoneural granulofibrilar IgM diposits lacking activity against neuronal components.
  3. Rarely amyloid deposition may cause neuropathy

Neuropathy due to Paraneoplatic Vasculitis: painful mononeuritis multiplex may occur in patinets with lymphoma. In some of these patinets the vasculitis may be limited to the nerves. Patients may respond to treatment if the primary, immunosupression or plasmapheresis.

Neuromuscular Dysfunction: Rarely patients with lymphoma may develop Eaton-Lambert stndrome or myasthenia gravis

Cutaneous Paraneoplastic Syndromes
The cutaneous paraneoplastic syndromes associated with lymphoma include acanthosis nigracans, Sweet’s syndrome (neutrophila, fever, papular rash), paraneoplastic pemphigus (most commonly asociated with CLL and NHL) and lichen planus with low grade lymphomas.

Haematological Paraneoplastic Syndromes
Sixty three pecent of the patients of lymphoma have an abnormal haemoram. Anaemia is the commonest abnormality. Warm antibody type autoimmune haemolytic anaemia has been described NHL particularly angioimmunoblastic T cell lymphoma and chronic lymphocytic leukaemia (CLL). AIHA occurs with an incidence of 2-3% in other NHLs and HL. Immune thrombocytopenia is less common than AIHA. It is most commonly seen in CLL but may be seen with other lymphomas. Low grad B cell lymphomas may be associated with cold antibody type of AIHA. Pure red cell aplasia may be seen with T cell lymphomas. Eosinophila is more common in HL and T cell lymphomas but may be seen in B cell lymphomas. Lymphoma may be a cause of secondary thrombocytosis.

Renal Paraneoplastic Syndrome
About 10% patinets with idiopathic nephrotic syndrome have an underlying maligancy. Most of these patinets have membranoproliferative glomerulonephritis. HL is associated with minimal change disease. Membranous and membranoproliferative glomerulonephritis may be seen with CLL and other NHLs. A few patients with NHLs have been reported to have minimal change disease.