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.

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)

Electron micrograph showing racket-shaped Birbeck granules in a histiocyte

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)

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

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

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

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)

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

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

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

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)

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

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

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

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

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

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

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

Russell Bodies

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

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)

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

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)

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

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

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)

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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)

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

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

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)

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

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

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)

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