Heavy Chain Diseases and POEMS Syndrome

Heavy Chain Diseases

The heavy chain diseases are rare lymphoplasmacytic malignancies.  Clinical manifestations vary depending upon isotype. 

• Light chain & Heavy chain 
• Absence of light chains 
• Secretion of defective heavy chains that usually has:
  • Intact Fc fragment 
  • A deletion in Fd region (portion of Fab)  

Types:

Gamma (γ), alpha (α), and mu (μ) heavy chain diseases. No reports of Delta (δ)/ Epsilon (ε) heavy chain diseases. 

Molecular biological analysis revealed the presence of structural genetic defects. (Reason for aberrant chain secreted)

Gamma Heavy Chain Disease (Franklin’s Disease)

Different age groups are affected.  Characteristics features:

• Lymphadenopathy 
• Fever 
• Anemia 
• Malaise 
• Hepatosplenomegaly 
• Weakness 

Associated with auto immune diseases & rheumatoid arthritis.  The most distinctive symptom is Palatal edema.

• Palatal edema results from involvement of lymph nodes in Waldeyer’ ring. 
• Due to palatal edema, these individuals will have respiratory compromise. 

Diagnosis depends on the demonstration of anomalous serum M-component → reacts with anti-IgG 

• M-component 

It is an abnormal immunoglobulin/ paraprotein. Typically present in urine & serum. Most para proteins are of γ-1 sub class. (subclass of immunoglobulin IgG)

The patients may have: 

• Thrombocytopenia 
• Eosinophilia 
• Non-diagnostic bone marrow: ↑ number of lymphocytes/ plasma cells → do not stain for light chains.  

Patients have a rapid downhill course. 

• Immunoglobulins produced are abnormal → patients die of infections.
• Some patients have survived 5 years with chemotherapy. 

Treatment 

• All the symptomatic patients to be treated.
• Involve chemotherapeutic combinations used in low grade lymphoma. 
• Rituximab: reported to show efficacy.

Alpha Heavy Chain Disease (Seligmann’s Disease) M/c heavy chain diseases. Closely related to Mediterranean lymphoma. Affects young people.Disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated α-chains. Demonstrating alpha heavy chains is difficult: 

• α-chains tend to polymerize & appear as smears, instead of a sharp spike on electrophoretic profiles. 
• Hyperviscosity is not common in alpha heavy chain disease. 

Without J chain: 

• Facilitated dimerization 
• Viscosity does not increase 

Light chains are absent in the serum & urine. Patients present with:  

• Chronic diarrhea 
• Weight loss 
• Malabsorption 
• Extensive mesenteric & paraaortic adenopathy 
• Respiratory tract involvement is rare 
• Some patients may have diffused aggressive histologies of malignant lymphoma 

Treatment 

• Chemotherapy → Long term remission 
• Antibiotic treatment: Some patients showed response.
• Chemotherapy + Antibiotics > Chemotherapy alone 

IPSID (Immunoproliferative Small Intestine Disease)

IPSID is recognized as an infectious pathogen associated with human lymphoma with Campylobacter jejuni. Involves mainly the proximal small intestine, resulting in:

• Malabsorption 
• Diarrhea 
• Abdominal pain 

Associated with excessive plasma cell differentiation & produces truncated α heavy chains.  Early stage IPSID: Respond to antibiotics Most untreated IPSID patients: 

• Progress to lymphoplasmacytic and immunoblastic lymphoma.  
• Patients not responding to antibiotic treatment → Combination chemotherapy. 

Mu Heavy Chain Disease Isolated μ heavy chains secretion into serum occurs in rare subset of patients with CLL. The only features that may distinguish patients with μ heavy chain disease are: 

• Presence of vacuoles in malignant lymphocytes. 
• Excretion of κ- light chains in urine. 

Diagnosis requires: 

• Ultra centrifugation/ gel filtration → To confirm non-reactivity of para proteins with light chain reagents.

Tumor cells seem to have a defect in assembly of light chains & heavy chains because they appear to have both in their cytoplasm. In normal immunoglobulin, heavy chain gets paired with light chain.  In μ heavy chain disease, paraproteins lacks associated light chains

POEMS Syndrome        

Features include: 

• P: Polyneuropathy 
• O: Organomegaly 
• E: Endocrinopathy 
• M: M-Protein 
• S: Skin changes 

4 Important Criteria

• All 4 criteria should be present
• Includes
  • Presence of polyneuropathy
  • Monoclonal plasma cell proliferative disorder
  • Any one of the following:
    • Sclerotic bone lesions or 
    • Castleman disease or 
    • ↑ VEGF levels
  • Any one of the following: 
    • Extravascular volume overload
    • Organomegaly
    • Endocrinopathy
    • Skin changes
    • Papilledema
    • Thrombocytosis or 
    • Polycythaemia

Patients usually have a severe progressive sensory motor neuropathy.

• Associated with sclerotic bone lesions from myeloma. 
• Polyneuropathies occur in 1.4% of patients with myeloma. 

Unlike typical myeloma: 

• In 2/3^rd of patients with POEMS syndrome → Hepatomegaly, Lymphadenopathy 
• In 1/3^rd of patients → Splenomegaly 

Lymphadenopathy frequently resembles Castleman’s disease histologically. 

• Castleman’s disease → Linked to IL-6 over production. 
• Endocrine manifestations include: 
  • Amenorrhea in women 
  • Impotency & Gynecomastia in males 
    • Because of hyperprolactinemia 
  • Development of type 2 diabetes mellitus occurs in about 1/3^rd of patients. 
  • Hypothyroidism / adrenal insufficiency 
• CNS manifestations include 
  • Papilledema and elevated CSF pressure & proteins 
• Skin changes are diverse: 
  • Hyperpigmentation/ Hypertrichosis/ Skin thickening and Digital clubbing 
• Other manifestations include: 
  • Peripheral edema 
  • Ascites 
  • Pleural effusion 
  • Fever 
  • Thrombocytosis 

Pathogenesis

• The pathogenesis of the disease is unclear: 
  • High circulatory levels of pro-inflammatory cytokines 
    • IL-1 
    • IL-6 
    • VEGF 
    • TNF 

Treatment

Treatment of myeloma may result in improvement in other disease manifestations. Plasmapheresis does not have any benefit.Treatment: Similar to Multiple myeloma Patients presenting with isolated sclerotic lesions: 

Resolution of neuropathic symptoms after local therapy for plasmacytoma with radiotherapy. Similar to 

multiple myeloma novel agents and high dose therapy with Autologous stem cell transplantation → Associated with prolonged progression free survival.

Hope you found this blog helpful for your NEET SS hematology preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs. 

Propel your NEET SS Medicine Preparation! Access conceptual video lectures, QBank, Mock Tests, and premium study resources on the PrepLadder App. Download the PrepLadder app now to access high-yield content with 24-hr Free Trial.