1. By: Dr Jeevan Divakaran. Presenter: Dr Abiodun Mark Akanmode.
langerhan cell disorders, plasma cell lesions, spleen & thymus lesions.
By: Dr Jeevan Divakaran. Presenter: Dr Abiodun Mark Akanmode.

2. Langerhans Cell
Langerhans cells: immature dendritic cells in the epidermis
Function: to capture antigens and display them to T cells
Express MHC class II antigens, CD1a, and Langerin.
The presence of Birbeck granules in the cytoplasm of langerhan cell is characteristics.
Birbeck granules.
Contain protein Langerin.
The Birbeck granules are pentalaminar rodlike tubular structures with a dilated terminal end.(“tennis racket” appearance)

3. Electron micrograph showing racket-shaped Birbeck granules in a histiocyte

4. Langerhans Cell Histiocytoses (LCH)
3 distinctive clinicopathologic entities
Multisystem LCH (Letterer-Siwe disease)
Unifocal unisystem LCH (Eosinophilic granuloma)
Multifocal unisystem LCH (Hand-Schüller-Christian disease)

5. Pathogenesis
Different clinical forms are frequently associated with an acquired mutation in the serine/threonine kinase BRAF (valine to glutamate substitution in residue 600) that leads to hyperactivity of the kinase
BRAF is a component of the Ras signaling pathway that drives cellular proliferation and survival

6. Multisystem Langerhans cell histiocytosis (Letterer-Siwe disease)
Children < 2 years
Multifocal cutaneous lesions
Hepatosplenomegaly, Lymphadenopathy, Pulmonary & Osteolytic Lesions
Marrow infiltration - pancytopenia
Rapidly fatal if untreated, but with intensive chemotherapy 50% of the patients survive 5 years

7. Letterer-Siwe disease - child with eczematous type rash over the body surface due to malignant histiocytes infiltrating the skin and dermis

8. Unisystem Langerhans cell histiocytosis
May be unifocal or multifocal
Expanding, erosive accumulations of Langerhans cells, within medullary cavities of bones or skin, lungs, stomach
Calvaria, ribs, and femur are most commonly affected
Langerhans cells are admixed with variable numbers of lymphocytes, plasma cells, neutrophils, and eosinophils (may be prominent)

9. Unifocal unisystem disease (Eosinophilic Granuloma)
Benign histiocytosis mainly in adolescents and young adults
Unifocal lytic lesions in bone (skull, ribs and femur)
Bone pain and fractures are common
Prognosis is excellent

10. Multifocal unisystem disease Hand-Schüller-Christian (HSC) disease
Malignant histiocytosis mainly affecting children
Multiple bony masses that may extend into soft tissues
Hand-Schüller-Christian triad:
Lytic lesions in Skull
Diabetes Insipidus
Exophthalmos

11. Plasma Cell Lesions Multiple Myeloma Solitary Plasmacytoma/myeloma.
Lympho-plasmacytic Lymphoma
Heavy-chain Disease
Primary Amyloidosis
MGUS

12. Multiple Myeloma Median age at diagnosis - 70 years
More common in males and in people of African origin
Principally involves bone marrow and associated with lytic lesions throughout the skeletal system
Evidence of end-organ damage includes Calcium elevation, Renal insufficiency, Anemia, and Bone lesions (CRAB)

13. Multiple Myeloma
Most frequent M protein is IgG (60%), followed by IgA (20% to 25%)
In 15 to 20% cases, the plasma cells produce only κ or λ light chains
Bence-Jones proteins: free κ or λ light chains that are excreted in the urine

15. Pathogenesis of Myeloma
Dysregulation of D cyclins is common.
IL-6 produced by fibroblasts, macrophages in the bone marrow stroma stimulates proliferation of myeloma cells.
IL-6 production is also induced by the myeloma cell themselves.
Myeloma Cells secrete IL-1β, TNF, IL-6 which stimulate production of RANK-ligand causing increased osteoclast activity leading to bone resorption

16. Pathogenesis of Myeloma
Immunosuppression: Although plasma contains increased immunoglobulin owing to M protein, the levels of functional antibodies are profoundly depressed, leaving patients at high risk for bacterial infections

17. Morphology
Multifocal destructive skeletal lesions, most commonly involving the VERTEBRAL COLUMN, ribs, skull, pelvis, femur, clavicle, and scapula
Punched-out defects 1 to 4 cm in diameter
Arise in medullary cavity, erode cancellous bone, and progressively destroy the cortical bone
Pathologic fractures, mostly in vertebra or femur

18. Multiple myeloma with multiple vertebral fractures at the thoracic and lumbar levels

19. Microscopic examination
Increased numbers of plasma cells > 30% of the cellularity
abnormal features
prominent nucleoli
abnormal cytoplasmic inclusions containing immunoglobulin
In terminal stages, a leukemic picture may emerge

21. Bone marrow aspirate showing replacement of normal marrow cells by plasma cells, including atypical forms with multiple nuclei, prominent nucleoli, and cytoplasmic droplets containing immunoglobulin A

22. Russell Bodies

23. Clinical Features Pathologic fractures Bone Pain
Vertebral fracture may lead to spinal cord impingement
Hypercalcemia from bone resorption
Neurologic manifestations (confusion, lethargy)
Renal dysfunction
Symptoms related to hyperviscosity
Anemia: due to marrow replacement by tumor cells and suppression of hematopoiesis
Recurrent infections with bacteria
(S. aureus, S.pneumoniae, and E. coli) resulting from the marked suppression of normal humoral immunity
Common cause of death

25. Renal findings Renal insufficiency (in 50% of patients)
Proteinaceous tubular casts
Casts are composed of BJ protein, which is nephrotoxic and damages tubular epithelium
Biopsy reveals an intratubular multinucleated giant cell reaction
Nephrocalcinosis
Hypercalcemia leads to metastatic calcification of the tubular basement membranes in the collecting ducts
Calcium deposits are a common cause of acute renal failure in multiple myeloma
AL-type amyloidosis (5% to 10% of patients)

27. Diagnosis
Clinically suspected when focal, punched-out skeletal defects are present - especially in vertebrae or calvaria
Electrophoresis of the serum and urine - monoclonal complete immunoglobulin or monoclonal free immunoglobulin light chain
Examination of bone marrow: to confirm plasma cell proliferation

28. SERUM PROTEIN ELECTROPHORESIS
Serum protein electrophoresis (SPE) showing a schematic of a monoclonal gammopathy
SERUM PROTEIN ELECTROPHORESIS
Useful in quantitating the M protein and shows a monoclonal spike
Does not specify which M protein is increased (e.g., IgG, IgA, IgM)

29. Other tests Serum immunofixation electrophoresis
More sensitive than SPE and provides a characterization of the M protein (heavy and light chain subclass; e.g., IgGκ or IgGλ; IgMκ or IgMλ)
Does not quantitate the M protein
Urine protein electrophoresis
Identifies BJ protein (free light chains) and quantitates the amount of light chains in the urine
Does not specify whether the light chains are κ or λ
Urine immunofixation electrophoresis
Characterizes whether BJ protein is κ or λ
More sensitive in detecting BJ protein than the standard urine protein electrophoresis
Serum for free light chains
Detects and quantitates κ and λ light chains in serum
More sensitive for detecting light chains than any of the urine methodologies listed above

30. Non-secretory multiple myeloma
In 1 to 3% cases, monoclonal free immunoglobulins can only be detected within the plasma cells
No serum or urine M protein
Bone marrow plasma cells are >10%
CRAB present

31. Treatment and Prognosis
Progressive disease, median survival of around 4 to 6 years
Not curable
Autologous stem cell transplantation - dramatically improved survival
New therapies
Proteasome inhibitors (induce plasma cell apoptosis)
Thalidomide analogues (alter the marrow microenvironment to inhibit myeloma cell growth and survival)

32. Solitary Plasmacytoma/myeloma
Low or no serum and urine M protein
No malignant plasma cells in the bone marrow
Skeletal Plasmacytoma
Occurs in same locations as multiple myeloma
Progresses to full-blown multiple myeloma over 5 to 10 years
Soft tissue Plasmacytoma
Most often in upper respiratory tract
Spreads infrequently, cured by local resection

33. Lymphoplasmacytic Lymphoma (Waldenström macroglobulinemia)
Affects older persons; peak incidence between 6 -7th decades
Tumor cells secrete an M protein (commonly IgM)
Mixture of B cells ranging from small lymphocytes to plasmacytic lymphocytes to plasma cells
Behaves like indolent B cell lymphoma, involves lymph nodes, bone marrow, and spleen at presentation

34. Lymphoplasmacytic Lymphoma
↑IgM causes viscous blood - Waldenström Macroglobulinemia
No free light chains or Bence Jones proteinuria
No lytic bone lesions
Renal disease and amyloidosis are rare

35. Waldenström Macroglobulinemia
Visual impairment: tortuosity and distention of retinal veins; retinal hemorrhages and exudates
Neurologic problems - headaches, dizziness, tinnitus, deafness, and stupor, (from sluggish blood flow and sludging)
Bleeding - formation of complexes between macroglobulins and clotting factors as well as interference with platelet function
Cryoglobulinemia - precipitation of macroglobulins at low temperatures - Raynaud phenomenon and cold urticaria

36. Heavy-Chain Disease Not a specific entity
Proliferations in which only heavy chains are produced
IgA heavy-chain disease: more common, has a predilection for lymphoid tissues in which IgA normally is produced (Small intestine, Respiratory tract)
IgG heavy-chain disease: diffuse lymphadenopathy and hepatosplenomegaly

37. Primary Amyloidosis
Monoclonal proliferation of plasma cells that secrete free light chains underlies primary amyloidosis
Amyloid deposits (of AL type) consist of partially degraded light chains

38. Monoclonal Gammopathy of Undetermined Significance
Asymptomatic monoclonal gammopathy
Serum M proteins in 1 to 3% of healthy persons > 50 years
< 3 g/dL of monoclonal protein in serum
No Bence Jones proteinuria
Precursor lesion with a tendency to evolve to multiple myeloma (rate of 1% per year)
Diagnosis made only after careful exclusion of other monoclonal gammopathies, particularly multiple myeloma
The clonal plasma cells in MGUS contain the same chromosomal translocations found in full-blown multiple myeloma

39. POEMS syndrome Paraneoplastic syndrome including Polyneuropathy
Organomegaly
Endocrinopathy
Monoclonal gammopathy
Skin changes

40. Splenomegaly Spleen frequently involved in systemic disease
responds by enlarging (splenomegaly)

41. Massive splenomegaly (> 1000 g)
Myeloproliferative disorders (CML, Primary Myelofibrosis)
Chronic lymphocytic leukemia and hairy cell leukemia
Lymphomas
Malaria
Gaucher disease
Primary tumors of the spleen (rare)

42. Moderate splenomegaly (weight 500 to 1000 g)
Chronic congestive splenomegaly (portal hypertension or splenic vein obstruction)
Acute leukemias (variable)
Hemolytic Anemias (Hereditary spherocytosis, Thalassemia major, Autoimmune hemolytic anemia)
Amyloidosis
Niemann-Pick disease
Chronic Splenitis (especially with infective endocarditis)
Tuberculosis, Sarcoidosis, Typhoid
Metastatic carcinoma or sarcoma

43. Mild splenomegaly (<500 g)
Acute splenitis
Acute splenic congestion
Infectious mononucleosis
Miscellaneous: Septicemia, SLE and intra-abdominal infections

44. Hypersplenism
Chronically enlarged spleen removes excessive numbers of one or more of the formed elements of blood, resulting in anemia, leukopenia, or thrombocytopenia
Most common cause is Portal Hypertension associated with cirrhosis
Platelets are particularly susceptible to sequestration in the interstices of the red pulp

45. Splenic dysfunction Howell-Jolly bodies in the peripheral blood RBCs
Predisposition to infections by encapsulated pathogens (septicemia, peritonitis, and osteomyelitis)
S. pneumoniae (most common), Haemophilus influenzae, Salmonella, and Neisseria meningitidis
↓IgM, ↓tuftsin, ↓splenic macrophages
Spleen is a site for IgM synthesis
Tuftsin, normally synthesized in the spleen activates receptors on macrophages to increase their phagocytic activity

46. Splenectomy Increases the risk for infections Hematologic findings
Nucleated RBCs
HJ bodies
Target cells (excess membrane cannot be removed)
Thrombocytosis (platelets normally sequestered in the spleen are now circulating)

47. Thymic Hyperplasia
Presence of lymphoid follicles/germinal centers in the medulla
Thymic follicular hyperplasia is found in most patients with myasthenia gravis
In other autoimmune diseases – SLE, Rheumatoid arthritis
Removal of hyperplastic thymus is beneficial early in the disease
The germinal centers contain reactive B cells, which are only present in small numbers in normal thymus

48. Thymoma Tumors of thymic epithelial cells Classification:
Benign or encapsulated thymoma: cytologically and biologically benign
Malignant thymoma
Type I: cytologically benign but infiltrative and locally aggressive
Type II (Thymic carcinoma): cytologically and biologically malignant

49. Morphology Lobulated, firm, gray-white masses up to 20 cm
Most appear encapsulated, but in 20% to 25%, penetration of the capsule and infiltration of perithymic tissues and structures are seen
Microscopic: mixture of epithelial tumor cells and non- neoplastic thymocytes (immature T cells)

50. Benign Thymoma 60-70% of Thymomas
Medullary Thymoma: epithelial cells are spindled or elongated and resemble those that normally populate the medulla
Mixed Thymoma: admixture of the plumper, rounder, cortical-type epithelial cells

51. Malignant Thymoma Type I
20% to 25% of all thymomas
Cytologically benign but locally invasive
Occasionally metastasize
Varying proportions of epithelial cells and reactive thymocytes
Penetration of the capsule with the invasion of surrounding structures

52. Malignant Thymoma Type II (Thymic carcinoma)
5% of thymomas
Fleshy, invasive masses, often metastasize (lungs)
Microscopic:
most resemble Squamous Cell Carcinoma
next most common is Lymphoepithelioma-like carcinoma (more in Asian populations and sometimes contain the EBV genome)

53. Clinical Features Rare Mostly in middle-aged adults
30% asymptomatic
30% to 40% produced local manifestations (cough, dyspnea, and superior vena cava syndrome)
30% associated with a systemic disease
most commonly myasthenia gravis (Thymoma in 15 to 20% patients)
Additional associations: Hypogammaglobulinemia, Systemic Lupus Erythematosus, Pure Red Cell Aplasia and Non-Thymic Cancers
Removal of the tumor often leads to improvement of the neuromuscular disorder