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)

LANGERHANS CELL HISTIOCYTOSES (LCH)

3 distinctive clinicopathologic entities

1. Multisystem LCH (Letterer-Siwe disease)

2. Unifocal unisystem LCH (Eosinophilic granuloma)

3. 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 DISEASEHAND-SCHÜLLER-CHRISTIAN (HSC) DISEASE

Malignant histiocytosis mainly affecting children

Multiple bony masses that may extend into soft tissues

Hand-Schüller-Christian triad:1. Lytic lesions in Skull2. Diabetes Insipidus3. 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 featuresprominent nucleoli abnormal cytoplasmic inclusions

containing immunoglobulin

In terminal stages, a leukemic picture may

emerge

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)

DIAGNOSISClinically 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 • 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

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

Low or no serum and urine M proteinNo malignant plasma cells in the bone marrow

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

POEMS SYNDROME

Paraneoplastic syndrome including

PolyneuropathyOrganomegalyEndocrinopathyMonoclonal gammopathySkin changes

SPLENOMEGALY

Spleenfrequently involved in systemic diseaseresponds 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

SPLENECTOMY Increases the risk for infections

Hematologic findingsNucleated RBCsHJ bodiesTarget 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

THYMOMA Tumors of thymic epithelial cells

Classification:

1. Benign or encapsulated thymoma: cytologically and biologically benign

2. Malignant thymomaType I: cytologically benign but infiltrative and locally aggressiveType 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