The M-Band

Monoclonal Gammopathy-02

Figure 1. Each plasma cell produces a different type of antibody. Normal γ globin band is depicted in the left column. The plasma cell numbers are normal and each produces an antibody with a different amino acid structure and electrophoretic mobility. Patients with monoclonal gammopathy have expansion (increase number) of a plasma cell clone (red in the diagram) resulting in the production of a disproportionate large amount of immunoglobulin from one type of plasma cell. This results in the M Band (see below). Patients with polyclonal gammopathy have an expansion (increased number) of plasma cells. This is usually occurs in response to infection/inflammation that result in production of a diversity of antibodies. The diversity is reflected in increase in the γ but as no one clone dominates the sharp M band is not seen.

What is an M-Band?

Immunoglobulins are antigen binding molecules secreted by plasma cells. Immunoglobulins bind antigens and play a role acquired immunity. Plasma cells develop from antigen exposed B-lymphocytes. The process of maturation of lymphocytes involves inducing mutations in region of the immunoglobulin gene that encodes for antigen binding regions, the hypervariable regions. This makes the DNA and consequently the amino acid sequence of the immunoglobulin secereted by a plasma cell unique. This is true even when two plasma cells make antibody against the same antigen or antigenic epitope (see figure 1).

Monoclonal Gammopathy-01

Figure 2. The serum protein separate into many bands on electrophoresis. The albumin is a dark band closest to the anode. This is followed by the α1, α2, β and γ bands. The immunoglobulin are mainly found in the γ globulin band but some may be found in the β globin band. The electrophoretic mobility of a molecule depends on the charge it carries which in turn depends on the amino acid sequence. Amino acid sequence determines the antigen specificity and differs between antibodies resulting in a slight variation in electrophoretic mobility of immunoglobulins and resulting in the γ region being a broad band.

The amino acid sequence determines the charge on the immunoglobulin. The electrophoretic mobility is determined by the charge. Majority of the immunoglobulins move to the γ-globulin fraction of serum proteins, some move with β-globulin. The γ-globulin band is a wide electrophoretic band reflecting the diversity in electrophoretic mobility of immunoglobulins arising from the diversity in amino acid sequences (figure 2).

Monoclonal Gammopathy-03

Figure 3. Patinets of monoclonal gammopathies have an expansion of one clone of plasma cells. This reflects in production of a disproportionally large amount of immunoglobulin with identical electrophoretic mobility resulting in a dense band with in γ globin region

Patients of monoclonal gammopathies have clonal expansion of plasma cells. The cells of a clone have identical DNA and produce identical immunoglobulin molecules. When the clone grows to level that it forms a significant proportion of the plasma cell pool the immunoglobulin it produces forms a significant proportion of the total serum immunoglobulins. The identical electrophoretic mobility of molecules produced by the clone results in a disproportionately large number of immunoglobulin concentrating to a point on electrophoresis forming a band.  This is known as the M band.  Lymphoma cells, notably those of lymphoplasmacytic lymphoma, can secrete immunoglobulin and are associated with an M band for similar reasons.

Diseases associated with an M-Band

The M-Band is a serum marker for plasma cell dycrasias and Waldenström macroglobulinemia. IgM and non-IgM (mainly IgG and IgA) monoclonal bands have differing clinical implications. The former is more commonly associated with lymphoproliferative disease and the latter with plasma cell dycrasias. The presence of an M band only indicates a clonal expansion of immunoglobulin producing cells. It does not indicate malignancy. The diagnosis of malignancy is made by features that suggest end organ damage. The absence of end organ damage indicates a premalignant disease including monoclonal gammopathy of uncertain significance (MGUS), soldering multiple myeloma or smoldering Waldenström macroglobulinemia.  The evidence of end-organ damage includes

  1. non-IgM Monoclonal Gammoathies: CRAB (elevated calcium, renal involvement, anaemia and osteolytic (bone) lesions) creatinine,
  2. IgM Monoclonal Gammapathies: Anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder if diagnosis is Waldenström macroglobulinemia or CRAB (elevated calcium, renal involvement, anaemia and osteolytic (bone) lesions) creatinine if the diagnosis of IgM myeloma

False positive M-Band

The presence of M band indicates presence of a clonal expansion of plasma cells. When end organ damage co-exists with M band a diagnosis of a malignancy (multiple myeloma or Waldenström macroglobulinemia) is made. In the absence of end organ damage the diagnosis of a premalignant disease is made. Proliferation a of plasma cells are seen in infections/inflammation. These are polyclonal and result in s polyclonal gammopath. They do not result in the presence of an M-band.



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.

Faggot Cells

The old/middle english term faggot means a bundle of sticks bound together as fuel (faggot is derived the latin term fascis which is also the root for the term fasiculus).  Patinets with acute promyelocytic leukemia have cells with bundles of auer rods. These are known as faggot cells and are virtually diagnostic of acute promyelocytic leukemia. faggot cells can be seen in more mature cells following treatment of acute promyelocytic leukemia with ATRA. The have rarely been reported in patients with other from of acute myeloid leukemia.