Hematology Lesson 9

Plasma cell disorders

 Langerhans Cell Histiocytoses (Histiocytosis X)

Epidemiology
 Characteristics
a. Histiocytes are CD1 positive.
b. Cells contain Birbeck granules (tennis racket appearance; Fig. 14-11A).
• Only visible with electron microscopy
 2. Primarily occurs in children and young adults
 Types of histiocytoses

 Letterer-Siwe disease
 Hand-Schüller-Christian disease
 Eosinophilic granuloma
Letterer-Siwe disease

 Epidemiology
a. Malignant histiocytosis
b. Occurs in infants and children that are <2 years old
 Clinical findings
a. Diffuse eczematous rash (see Fig. 14-11B)
b. Multiple organ involvement
c. Lytic lesions in the skull, pelvis, and long bones
 Rapidly fatal
Hand-Schüller-Christian (HSC) disease

 Epidemiology
a. Malignant histiocytosis
b. Mainly affects children
 Clinical findings
a. General findings
 1) Fever
 2) Localized rash on the scalp and in the ear canals
b. Classic triad due to infiltrative disease
 1) Lytic lesions are present in the skull.
 2) Central diabetes insipidus (CDI), due to invasion of the posterior pituitary stalk
 3) Exophthalmos from infiltration of the orbit
 Intermediate prognosis
Eosinophilic granuloma

 Epidemiology
a. Benign histiocytosis
b. Occurs in adolescents and young adults
 Clinical findings
a. Unifocal lytic lesions are present in bone (skull, ribs, and femur).
b. Bone pain and pathologic fractures are common.
 Prognosis is excellent
Mast Cell Disorders

1. Epidemiology
• Localized (urticaria pigmentosa and solitary mastocytoma) or systemic
2. Signs and symptoms relate to mast cell release of histamine—pruritus and
swelling of tissue
 Urticaria pigmentosa (UP)
 Majority of persons with UP are children
• UP resolves spontaneously
 In adolescents and adults, UP is more likely to
persist.
Skin lesions
a. Multiple oval, red-brown, nonscaling macules
(flat lesions) or papules are present b. Scratching
of the lesions results in erythematous swelling and
pruritus.
• Called Darier sign
 Dermatographism • Dermal edema occurs
when apparently normal skin is stroked with a
pointed object.
 Lesions remain hyperpigmented when they
regress.
Urticaria pigmentosa (UP)

 Skin biopsy findings

• Mast cells have metachromatic granules that stain positive with toluidine blue
and Giemsa stain.
Pruritus and flushing are triggered by foods, alcohol, or drugs (e.g., codeine).
Other findings include:
a. Abdominal pain with diarrhea
b. Headaches with flushing of the skin
c. Anaphylactic reactions if envenomated by a bee, hornet, or wasp
 Treatment
 • H1 and H2 antihistamines decrease pruritus, flushing, and gastrointestinal
symptoms.
Plasma Cell Dyscrasias (Monoclonal
Gammopathies)
Overview of monoclonal gammopathies (MG; plasma cell dyscrasias)
 All are monoclonal B-cell disorders
• Definition—increase in a single immunoglobulin (M protein) and its
corresponding light chain
 Clinical significance of M proteins
a. Most MGs are due to an increase in IgG.
• All other plasma cell clones are immunologically suppressed.
b. Bence Jones (BJ) protein
1) Definition—free κ or λ light chains that are excreted in urine
2) Associated with plasma cell malignancies and Waldenström
macroglobulinemia
 Test used to detect MGs
 Serum protein electrophoresis (SPE; also
refer to Chapter 3)
1) Useful in quantitating the M protein and
shows a monoclonal spike (M protein)
2) Does not specify which M protein is
increased (e.g., IgG, IgA, IgM)
Serum immunofixation electrophoresis
1) 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)
2) Does not quantitate the M protein
 Test used to detect MGs
 Urine protein electrophoresis
1) Identifies BJ protein (free light chains) and quantitates the amount of light
chains in the urine
2) Does not specify whether the light chains are κ or λ
 Urine immunofixation electrophoresis
1) Characterizes whether BJ protein is κ or λ
2) More sensitive in detecting BJ protein than the standard urine protein
electrophoresis
 Serum for free light chains
1) Detects and quantitates κ and λ light chains in serum
2) More sensitive for detecting light chains than any of the urine
methodologies listed above
Classification

 Monoclonal gammopathy of undetermined significance (MGUS)

 Multiple myeloma
 Light chain amyloidosis
 Solitary plasmacytoma
 Waldenström macroglobulinemia
 Heavy chain disease
Multiple myeloma (MM)

 Accounts for 10% of all hematologic malignancies

 Two times more common in blacks than whites
 Median age at onset is 66 years
• Rare under 40 years of age
 Increased risk with radiation or benzene exposure
Multiple myeloma (MM)

 M-spike occurs in 80% to 90% of cases

 1) IgGκ myeloma (60% of cases) followed by IgA (20% of cases) and pure
light chain myeloma (20% of cases)
 Serum M protein is >3g/dL.
2) Urinalysis for BJ protein is positive in 60% to 80% of cases.
 Evidence of end-organ damage includes calcium elevation, renal
insufficiency, anemia, and bone lesions (CRAB).
Nonsecretory multiple myeloma

 Accounts for 1% to 3% of all cases

 No serum or urine M protein
 Bone marrow plasma cells are >10%
 CRAB present
Pathogenesis

 Chromosome abnormalities (deletions, translocations)

• Detected with fluorescence in-situ hybridization (FISH) and have prognostic
significance for detecting high-risk patients
 Possible evolution from normal plasma cells → MGUS → multiple myeloma
 Pathologic findings
 Sheets of malignant plasma cells are
present in a bone marrow
aspirate/biopsy (Fig. 14-14A).
 Malignant plasma cells account for
>10% of cells in the aspirate.
 Malignant plasma cells in multiple
myeloma. The majority of malignant
plasma cells show a dark blue
cytoplasm, peripherally located
nuclei, and perinuclear clearing.
Occasional cells have vacuoles
containing immunoglobulin.
Skeletal system findings

 Bone pain occurs in ∼60% of cases.

1) “Punched out” lytic lesions occur in the bone (see Fig. 14-14B and C).
 Myeloma cells produce an inhibitor of osteoblast differentiation (DKK1).
 Myeloma cells release interleukin-1 (osteoclast activating factor), which
activates osteoclasts.
2) Vertebrae are the most common sites of bone involvement.
3) Other sites include ribs, skull, femur, and pelvis.
4) Pain commonly presents with pathologic fractures, particularly if rib lesions
are present.
 Hypercalcemia (25% of cases)
 Radiograph
 skull showing multiple “punched out” lytic
lesions in multiple myeloma.
 Multiple lytic lesions in the femur and pelvis in
multiple myeloma.
Renal findings

 1. Renal failure (30%–50% of cases)

 2. Proteinaceous tubular casts
a) Casts are composed of BJ protein.
b) BJ protein is nephrotoxic and damages tubular epithelium.
c) Biopsy reveals an intratubular multinucleated giant cell reaction.
 3. Nephrocalcinosis
a) Hypercalcemia leads to metastatic calcification of the tubular basement
membranes in the collecting ducts (refer to Chapter 2).
b) Calcium deposits are a common cause of acute renal failure in multiple
myeloma.
Renal findings

 3. Metastatic disease to interstitial tissue

 4. Primary amyloidosis (10% of cases)
• Light chains are converted into amyloid (refer to Chapter 4 and produce a
nephrotic syndrome (refer to Chapters 4 and 20).
 Hematologic findings
 Normocytic anemia with rouleaux (Fig. 3-19)
 Markedly increased erythrocyte sedimentation rate (ESR)
 Prolonged bleeding time
1) Defect in platelet aggregation
2) Dialysis restores the bleeding time to normal.
Other findings

 Radiculopathy may occur from bone compression and vertebral fractures.

 Recurrent infection is a common cause of death.
• Sepsis is commonly due to Haemophilus influenzae or Streptococcus
pneumoniae.
Treatment and Prognosis

 Treatment
High-dose chemotherapy
Autologous stem cell transplantation
• Dramatically improved survival
 Prognosis
• Median survival after diagnosis is 3 years.
Spleen Disorders

 Clinical anatomy and physiology

 Red pulp of spleen
• Contains the cords of Billroth with fixed macrophages and sinusoids
 White pulp of spleen
• Contains B and T cells
Important functions

 Blood filtration; macrophages remove:

1) Hematopoietic elements (e.g., senescent red blood cells)
2) Intraerythrocytic parasites (e.g., malaria)
3) Encapsulated bacteria (e.g., S. pneumoniae)
 Antigen trapping and processing in macrophages
 Reservoir for one third of the peripheral blood platelet pool
 Site for extramedullary hematopoiesis (EMH)
Splenomegaly
 Basic mechanisms and causes
a. Immune response work hypertrophy; examples include:
• Infectious mononucleosis, subacute bacterial endocarditis, and malaria
b. Congestion; examples include:
• Splenic vein thrombosis and portal hypertension
c. RBC destruction work hypertrophy; examples include:
• Hereditary spherocytosis, pyruvate kinase deficiency, and β-thalassemia major
d. Myeloproliferative disease; examples include:
• Polycythemia vera, myelofibrosis and myeloid metaplasia, and essential
thrombocythemia
e. Neoplastic disease; examples include:
• Acute and chronic leukemias, and malignant lymphoma
Splenomegaly

 Infiltrative disease; examples include:

1) Primary and secondary amyloidosis, sarcoidosis, Gaucher disease, and Niemann-
Pick disease.
2) Gaucher disease
 Autosomal recessive lysosomal storage disease with a deficiency of
glucocerebrosidase and lysosomal accumulation of glucocerebrosides
 Macrophages with a fibrillary appearance (Fig. 14-15A)
3) Niemann-Pick disease
 Autosomal recessive lysosomal storage disease with a deficiency of
sphingomyelinase and lysosomal accumulation of sphingomyelin
 Macrophages with a soap bubble appearance
Gaucher vs. Niemann-Pick
Clinical findings of splenomegaly

 Left upper quadrant pain

• Pain may be due to splenic infarctions causing friction rubs and a left-sided
pleural effusion.
 Hypersplenism (see later discussion)
 Spleen in portal hypertension (PH)
 Gross findings
• Spleen is covered by a thickened (“sugar-
coated”) capsule from perisplenitis
 Microscopic findings
• Calcium and iron concretions called
Gamna-Gandy bodies are deposited in
collagen.
 Hypersplenism
 Normal splenic function is exaggerated.
 RBCs, WBCs, and platelets, either singly or in combination, are sequestered
and destroyed.
 Most common cause is PH associated with cirrhosis
Clinical findings
 Splenomegaly
 Peripheral blood cytopenias • Anemia, thrombocytopenia, and
neutropenia, alone or in combination
 Compensatory reactive bone marrow hyperplasia • Attempt by the
marrow to replace lost hematopoietic cells
 Correction of cytopenias with splenectomy
Splenic dysfunction and splenectomy

 Signs of splenic dysfunction

 Howell-Jolly (HJ) bodies (nuclear remnants) in the peripheral blood RBCs
(Fig. 12-24C)
• With a functioning spleen, macrophages would have removed RBCs with HJ
bodies.
Predisposition to infections by encapsulated
pathogens
 Infections include septicemia, peritonitis, and osteomyelitis.
a) Pathogens include S. pneumoniae (most common), Haemophilus influenzae,
Salmonella, and Neisseria meningitidis.
b) Immunization helps prevent infectious complications of splenic dysfunction.
 Mechanisms causing infections by the pathogens just listed
a) Concentration of IgM drops, leading to a decrease in complement system
activation (less C3b for opsonization).
• Spleen is a site for IgM synthesis.
b) Splenic macrophages are not present in sufficient numbers to phagocytose the
opsonized encapsulated pathogens.
c) Tuftsin, which is normally synthesized in the spleen, is lost.
• Tuftsin activates receptors on macrophages to increase their phagocytic
activity.
Splenectomy

 Increases the risk for infections (see previous discussion)

 Hematologic findings
1) Nucleated RBCs
2) HJ bodies
3) Target cells (excess membrane cannot be removed)
4) Thrombocytosis
 Platelets normally sequestered in the spleen are now circulating