Lecture 8 and 9
Lymphomas; Multiple Myeloma, Plasma cell disorders; Lipid storage
disease and Histiocytosis
Abdulkarim Aldosari
Objectives
List distinguishing features for nodular lymphocyte predominant, mixed cellularity,
lymphocyte rich, lymphocyte depletion and nodular sclerosis Hodgkin lymphoma
List distinguishing features for the four stages of Hodgkin lymphoma
Describe classification criteria, differential diagnosis, prognosis and treatment for
Hodgkin and non Hodgkin lymphomas
Describe and compare multiple myeloma and monoclonal gammopathy
Describe the workup of patients with plasma cell dyscrasia
Define and describe amyloidosis
Name and describe enzyme deficiencies seen in Gaucher’s disease, Niemann-Pick, and
Tay-Sachs disease
Describe clinical features and laboratory findings of Mucopolysaccharidoses and seablue histiocyte syndrome
Lymphomas
•
http://blausen.com/?Topic=9562
Lymphomas - Introduction
Malignant lymphomas are a heterogeneous group of diseases
From cells of the lymphoid tissue
•
Lymphocytes
•
Histiocytes
•
Reticulum cells
Two categories
•
Hodgkin disease/ Hodgkin lymphoma
•
Lymphocytic lymphoma/non-Hodgkin lymphomas (NHLs)
Introduction to the lymphomas
Difficulties involved in lymphoma diagnosis due to the many subcategories
Need to make distinction between:
•
Benign and malignant lymphoid proliferations
•
Hodgkin versus non-Hodgkin lymphoma
•
Subcategories of each type of lymphoma
Definitive diagnosis may not be possible
Introduction to Hodgkin Lymphoma
First described by Thomas Hodgkin in 1832
Samuel Wilks in 1865 applied the term Hodgkin disease
In 1898 Sternberg and in 1902 Reed described the histological features of Hodgkin
disease, the unusual cell that is characteristic of Hodgkin disease
= Reed-Sternberg cell
Two distinct clinical and pathological disease
•
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)
•
Classical Hodgkin lymphoma (CHL)
Etiology and pathogenesis
Possible viral etiology
•
Epstein-Barr virus (EBV)
 EBV nucleic acids demonstrated in 80% of all cases of Hodgkin lymphoma (HL)
 EBV antigens detected in 50% of the cases
•
CMV, Herpesvirus 6 also implicated
•
Mechanism is unclear
•
Possibly a preceding immunosuppression causing an abnormal immune response to
the infections
HL – malignant clonal proliferation
•
A small percentage of Reed-Sternberg cells and its variants
•
A larger percent of B cells
Pathology
Reed-Sternberg cell – cytological hallmark of HL
 Large cell ( up to 45 µm ) with abundant acidophilic cytoplasm
 Multinucleated or polylobed nucleus
 Gigantic, inclusion like nucleoli
 Halo effect around the nucleoli
 Not necessarily diagnostic because seen in a variety of other conditions
 Helpful in suggesting the possibility of HL or a subclassification of HL
Reed-Sternberg cells in the proper cellular, stromal and clinical setting in
conjunction with immunophenotyping → diagnosis of HL
Nodular lymphocyte predominant HL
•
5% of cases
•
Pathologically and clinically distinct from HL
•
Characterized by a nodular, and/or a diffuse
proliferation of scattered large neoplastic
cells known as L&H , popcorn cell, or
lymphocyte predominant cells (LP cells)
 L&H = lymphocyte histiocyte RS variant
 Popcorn cells are Reed Sternberg variants
•
Most of the lymphocytes found in the lymph nodes
are normal (not cancerous)
Nodular lymphocyte predominant HL
•
Occurs at any age with a peak incidence at 40yrs
•
Cervical and axillary lymph nodes are most frequently involved
•
Presents as an early stage disease; has slow progression and excellent outcome with
standard therapy
•
Recurrence is common and occurs in 21% of cases
•
The immunophenotype of the L&H cells is distinct from the cells of the classic
Hodgkin's lymphoma
•
Unlike classical Hodgkin Lymphoma, the LP cells show immunoreactivity with CD45
and CD20 and no staining with CD30 or CD15
•
There is consistent staining with CD20, CD22, and CD79a
•
http://www.universitypathologists.com/education/case-of-the-month/february-2011
Nodular lymphocyte predominant HL
•
Slightly higher incidence in the U.S. among blacks than whites, and a lower
incidence among Asians
•
3:1 male predominance
•
Shows a propensity toward peripheral (neck and/or axilla)
•
Nodal spread is dis-contiguous, compared with the contiguous nodal spread of
classical HL.
•
In 50%–60% of NLPHL cases, the time between the initial presentation of
lymphadenopathy and the diagnosis of NLPHL is 6–12 months or longer
http://theoncologist.alphamedpress.org/content/14/7/739.long
Nodular lymphocyte predominant HL
•
Prognosis is good - 90-100% remission rate with primary therapy
•
Relapse seen in 10-15% of patients and occurs on average 3-6 years after diagnosis
•
Overall 10 year survival rates are >90% in limited stage disease
Classic Hodgkin Lymphoma
Defined by the observation of classic Reed-Sternberg cells in the appropriate cellular
and stromal background
Background of the lesion determines the subclassification of CHL:
Nodular sclerosis HL
•
Most common subtype of HL; 60-80% of all cases of HL
•
The involved lymph nodes contain




R-S cells
Normal WBCs
Lacunar cells (grouped lacunars)- type of RS cells
Scar tissue (birefringent collagenous sclerosis)
•
The disease is more common in women than men
•
Usually affects adolescents and adults under 50
•
Most patients are cured with current treatments
Classic Hodgkin Lymphoma
Mixed-cellularity HL
•
Accounts for about 15-30% of all cases of HL
•
Found more commonly in men than women
•
Lymph nodes contain heterogeneous mix of cells; R-S cells in addition to several
other cell types
•
Primarily affects older adults
•
More advanced disease is usually present by the time this subtype is diagnosed
Classic Hodgkin Lymphoma
Lymphocyte-rich HL
•
< 5% of HL cases
•
The disease may be diffuse (spread out) or nodular (knot-like) in form
•
Characterized by the presence of numerous normal-appearing lymphocytes and
classical R-S cells.
•
Usually diagnosed at an early stage in adults and has a low relapse (returns after
treatment) rate
Lymphocyte depletion HL
•
Rarely diagnosed
•
Abundant R-S cells and few normal lymphocytes are present in the lymph nodes of
patients with this subtype
•
Aggressive and usually not diagnosed until it is widespread through the body
Classic Hodgkin Lymphoma
Hodgkin Lymphoma - Classification
Type
Histologic Features
Frequency
Prognosis
Nodular sclerosis
Bands of fibrosis, lacunar cells
Most frequent type (60-80%),
more common in women
Good, most are
stage I or II
Mixed cellularity
Composed of many different
cells
Most frequent in older
Fair, most are stage
persons, second most frequent
III
overall (15-30%)
Lymphocyte rich
Mostly reactive lymphocytes
Uncommon (5%). Older adults
and many Reed-Sternberg cells
Good to excellent
Lymphocyte depletion
Many Reed-Sternberg cells and
Rare (<1%)
variants
Poor, most are
stage III or IV
Lymphocyte predominance
Mostly B-cells and few ReedSternberg variant cells
Good, most are
stage I or II
Uncommon (5%)
Classic Hodgkin Lymphoma
Histologic progression
HL progresses from: Lymphocyte rich → mixed cellularity → lymphocyte depletion
lymphoma
Clinical features:
•
~9,000 new cases of HL are projected each year
•
Most commonly diagnosed in young adults 15-35yrs and in adults over 50
•
Most patients with HL present with swelling of the lymph nodes (which is often
but not always painless)
•
Fever, night sweats, unexplained weight loss, and lack of energy
Diagnosis and staging of HL
Clinical staging for patients with Hodgkin lymphoma (HL) includes
•
Careful history
•
Detailed physical examination
•
Laboratory studies (CBC, sedimentation rate, chemistry panel; liver, kidney, bone
profile)
•
Thoracic and abdominal/pelvic computerized tomographic (CT) scans
•
Positron emission tomography (PET) scans, gallium scans
•
Bone marrow biopsy if symptomatic, Cytopenia or advanced stage
Diagnosis and staging of HL
Most widely used staging scheme - Cotswold’s revision of the Ann Harbor classification
Stage I - Involvement of a single lymph node region (cervical, axillary, inguinal,
mediastinal) or lymphoid structure (spleen, thymus, or Waldeyer's ring)
Stage II - Involvement of two or more lymph node regions or structures on the same
side of the diaphragm. Hilar nodes should be considered to be "lateralized“. All nodal
disease within the mediastinum is considered to be a single lymph node region. The
number of anatomic regions should be indicated by a subscript (II-3).
Stage III – Involvement of lymph node regions or lymphoid structures on both sides of
the diaphragm.
III-1 with or without the involvement of the spleen, hilar, celiac or portal nodes; and stage
III-2 with involvement of the paraaortic, iliac, inguinal, or mesenteric nodes
Stage IV - Involvement of one or more extranodal organs or tissue beyond that
designated E, with or without associated lymph node involvement
Diagnosis and staging of HL
Subclassification of stage
Stages I, II, III, and IV adult HL can be sub classified into A and B categories:
B for those with defined general symptoms
A for those without B symptoms
The B designation is given to patients with any of the following symptoms:
•
Unexplained loss of more than 10% of body weight in the 6 months before diagnosis
•
Unexplained fever with temperatures above 38°C
•
Drenching night sweats
http://www.cancer.gov/cancertopics/pdq/treatment/adulthodgkins/HealthProfessional/p
age3
Stage1 of HL
Stage I adult nonHodgkin lymphoma.
Cancer is found in one
lymphatic area (lymph
nodes, tonsils, thymus,
or spleen). In stage IE
(not shown), cancer is
found in one organ or
area outside the
lymph nodes.
E: is used if the
disease is "extranodal"
(not in the lymph
nodes) or has spread
from lymph nodes to
adjacent tissue
Stage 11 of HL
Stage II: Cancer in
two or more lymph
node groups, and
both are either
above (a) or below
(b) the diaphragm
Stage IIE Cancer in
one or more lymph
node groups either
above or below the
diaphragm and
outside the lymph
nodes in an organ
or area on the same
side of the
diaphragm as the
lymph nodes with
cancer (a).
Stage 111 of HL
Stage III - in one or more
lymph node groups above and
below the diaphragm (a).
Stage IIIE - in lymph node
groups above and below the
diaphragm and outside the
lymph nodes in a nearby organ
or area (b).
Stage IIIS - in lymph node
groups above and below the
diaphragm (a) and in the
spleen (c).
Stage IIIE plus S,- in lymph
node groups above and below
the diaphragm, outside the
lymph nodes in a nearby organ
or area (b), and in the spleen
(c).
Stage 1V of HL
Stage IV: Cancer found
throughout one or more organs
that are not part of a
lymphatic area (lymph nodes,
tonsils, thymus, or spleen) (a);
or in one organ that is not part
of a lymphatic area and has
spread to lymph nodes far
away from that organ (b); or
cerebrospinal fluid (not
shown), the liver, bone
marrow, or lungs.
Treatment and prognosis
•
Based on staging evaluation
•
Multiagent chemotherapy
•
10 year survival for stage 1 and 11 > 80%
•
10 year survival for stages 111 and 1V improved with aggressive chemotherapy
~70%
Non-Hodgkin Lymphoma
•
Any of a large group of cancers of lymphocytes
•
Can occur at any age
•
Marked by lymph nodes that are larger than normal, fever, and weight loss
•
Many different types divided into aggressive (fast-growing) and indolent (slowgrowing) types
•
Can be formed from either B-cells or T-cells
•
Estimated new cases and deaths from non-Hodgkin lymphoma in the United States
in 2013:
 New cases: 69,740
 Deaths: 19,020
http://www.cancer.gov/cancertopics/types/non-hodgkin
Non-Hodgkin Lymphoma
B-cell non-Hodgkin lymphomas
•
Burkitt lymphoma
•
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
•
Diffuse large B-cell lymphoma
•
Follicular lymphoma
•
Immunoblastic large cell lymphoma
•
Precursor B-lymphoblastic lymphoma
•
Mantle cell lymphoma
Non-Hodgkin Lymphoma
T-cell non-Hodgkin lymphomas
•
Mycosis fungoides
•
Anaplastic large cell lymphoma
•
Precursor T-lymphoblastic lymphoma
Lymphomas that occur after bone marrow or stem cell transplantation are usually Bcell non-Hodgkin lymphomas
Prognosis and treatment depend on the stage and type of disease.
Etiology and pathogenesis
•
Damage to region of the genetic code that regulate growth and reproduction of
immune cells
•
May be due to chemicals, ionizing radiation, viruses (EBV)
•
Genetic damage associated with numeric and/or structural alterations in
chromosomes
•
Chromosomal abnormalities demonstrated in 60% of NHL cases
•
Mainly translocations in chromosomes 2,8,14,22
•
Chromosomal regions relates to function of the genetic material
 t(11;14) = BCL1-IgH; t(14;18) = IgH- BCL2; t(3;14) = BCL6-IgH
Etiology and pathogenesis
Best example
 Burkitt’s lymphoma – in
90% of cases – c-myc
proto-oncogene located
at region q24 of chr 8
translocated to IgH
chain 14q32
 Also in 40% of large-cell
lymphomas
Pathology of NHL
Classification schemes based on:
•
Growth pattern: nodular or diffuse
•
Cytological features of malignant cells
Historically the most widely used in USA: Working formulation for clinical usage
Working Formulation has become outdated and less useful to clinicians and
pathologists
European and American pathologists proposed a new classification
•
The Revised European American Lymphoma (REAL) classification
Pathology of NHL
Since 1995, members of the European and American Hematopathology societies have
been collaborating on a new World Health Organization (WHO) classification
•
Represents an updated version of the REAL system
•
Utilizes clinical, morphological, immunophenotypic and genotypic features
•
Requires an understanding of the morphology of the lymph nodes and the maturation
of normal lymphocytes
Pathology of NHL
The WHO modification of the REAL classification identifies three major categories of
lymphoid malignancies based on morphology and cell lineage:
•
B-cell neoplasms
•
T-cell/natural killer (NK)-cell neoplasms
•
Hodgkin lymphoma
Both lymphomas and lymphoid leukemias are included in this classification because
both solid and circulating phases are present in many lymphoid neoplasms and
distinction between them is artificial.
•
B-cell chronic lymphocytic leukemia and B-cell small lymphocytic lymphoma are
different manifestations of the same neoplasm
•
Also lymphoblastic lymphomas and acute lymphocytic leukemias
Within B-cell and T-cell categories, two subdivisions:
•
Precursor neoplasms = earliest stages of differentiation
•
Mature neoplasms
Lymph nodes
Three major anatomical regions
Cortex – populated by B cells,
plasma cells, reticular cells
B cell organized into nodules - 1o or
2o follicles
1o follicles → 2o follicles containing
a germinal center
Germinal center surrounded by
mantle zone (crescent of B cells)
Germinal center contains –
centrocytes, centroblasts, dendritic
cells, histiocytes/macrophages
Lymph nodes
Paracortex – occupied by Tcells
Medulla – contains T cells, B
cells, macrophages, plasma cells
NHL arise from any of these
normal cellular counterparts
B cell – most common 85-90%
T/NK – 10-15%
Histiocytes and dendritic cells -
< 1%
Follicular B-cell lymphoma
•
The most common of the indolent non-Hodgkin's lymphomas = 40% of adult NHL
•
The second-most-common form of non-Hodgkin's lymphomas overall
•
It is a lymphoma of follicle center B-cells (centrocytes and centroblasts) with at least
partial follicular growth pattern
 Follicular growth should be included in the pathologic assessment
•
Positive for the B-cell markers CD10, CD19, CD20, and CD22 but almost always
negative for CD5
•
A translocation between chromosome 14 and 18 results in the overexpression of the
bcl-2 gene
Follicular B-cell lymphoma
According to the WHO criteria, the disease is morphologically graded into
•
grade 1 (<5 centroblasts per high-power field (hpf))
•
grade 2 (6–15 centroblasts/hpf)
•
grade 3 (>15 centroblasts/hpf)
 grade 3A (centrocytes still present)
 grade 3B (the follicles consist almost entirely of centroblasts
 More aggressive than grades 1 and 2
Progression from follicular to more aggressive diffuse large cell lymphoma – 40% of
cases
Male: female – 1:1
Survival rate at 5yrs >60%
Mantle cell lymphoma
Characterized by
•
small-to-medium sized lymphocytes with pale staining cytoplasm
•
Irregular nucleus
•
Inconspicuous nucleoli
•
Cells express CD5, Cd34
•
t(11;l4)
•
A disease of older adults
•
Male: female – 3:1
•
Disease widespread at diagnosis
•
Lymph nodes and spleen as most common sites of involvement
•
One of the rarest of the NHL
Mucosal-associated lymphoid tissue
•
Marginal zone- poorly defined anatomical compartment of the lymph nodes
•
Small cleaved cell (centrocytes-like)
•
Lymphomas related to marginal zone cells – referred to as lymphomas of the
mucosa-associated lymphoid tissue (MALT)
•
Frequently of the stomach, but virtually any mucosal site can be afflicted.
•
Originate from B cells in the marginal zone of the MALT
•
Also called extranodal marginal zone B cell lymphoma
Non-Hodgkin's Lymphomas
Type
Histologic Features
Immunogenetics
Small Lymphocytic
Lymphoma
Small and well-differentiated
B lymphocytes, with diffuse
effacement of nodal
architecture and no follicles
CD19, 5; Bcl-2 and Bcl-6
expression
Follicular Lymphoma
Nodal architecture is effaced CD19, 20, 79a; t(14:18); Bcl-2
(predominantly small cell) by monotonous, crowded
expression
follicles composed of
monomorphous small cleaved
B-lymphocytes
Clinical Features
Seen in older adults, it is
essentially the solid tissue
(lymph nodal) component
of chronic lymphocytic
leukemia; disease tends to be
generalized but with indolent
course and prolonged
survival; some may transform
to more aggressive
lymphomas
Most common type, seen in
adults, often involves multiple
lymph nodes, course is
indolent, with prolonged
survival, though some may
transform to a large cell
lymphoma
Diffuse Large B-cell
Lymphoma
Cells are large, with
prominent nucleoli and
abundant cytoplasm and
many mitoses. Most are Bcell, but 20% are T-cell
phenotype
CD19, 20, 79a; some have
t(14;18); some have Bcl-2 and
Bcl-6 expression; linked to
EBV infection; negative TdT
Though often localized, they
tend to be aggressive
extranodal masses; seen in
adults and children, can be
seen in HIV infection
Burkitt Lymphoma
Intermediate sized Blymphocytes (smallnoncleaved cells)
CD10, 19, 20, 79a; t(8:14) is
characteristic; African
form linked to EBV
infection; negative TdT,
Bcl-2, CD5, CD23; surface
IgM+
Endemic in Africa with
mandibular and abdominal
involvement; sporadic
elsewhere with abdominal
involvement; affects mainly
children and young adults
High-grade B-cell
Lymphoma (small noncleaved) Burkitt-like
Lymphoma
Intermediate sized BCD19, 20
lymphocytes (small non-cleaved
cells)
Sporadic; may be seen with
HIV infection
Precursor T or B-cell
Lymphoblastic
Lymphoma/Leukemia
(Lymphoblastic
Lymphoma)
Intermediate sized lymphocytes B-cells are CD19, 20,
Seen in children and
in a diffuse pattern
sometimes CD10; T-cells are
adolescents; T-cell type often in
CD3 and 8; all are TdT positive mediastinum; very aggressive
and can progress to acute
lymphocytic leukemia
Mantle Cell Lymphoma Small to medium sized B cells
CD 19, 20, 43; t(11;14); Bcl-1
(Cyclin D1) expression
Seen in adults in middle age;
often advanced at diagnosis
and may be extranodal,
including multifocal
submucosal nodules in bowel
Marginal Zone
Lymphoma
CD19, 20, 79a; negative CD5
and 10
Seen in middle aged adults;
typically arises in areas of
immune activation (Hashimoto
thyroiditis, Sjogren syndrome,
Helicobacter pylori gastritis);
similar lesions associated
with mucosal lymphoid
tissue are called MALTomas
(mucosa-associated
lymphoid tissue tumors); may
transform to diffuse large B-cell
lymphoma
Small to medium sized B cells
T-cell and NK cell lymphomas
•
T-cell lymphomas account for ~15% of all NHLs in the USA
•
NK cell shares many features with T-cells
•
When NK cells become cancerous, the cancer is called NK or NK/T-cell lymphoma
•
Many different forms of T-cell lymphomas, some of which are extremely rare
•
T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing)
T-cell and NK cell lymphomas
•
Peripheral T-cell lymphoma (PTCL) - entire group of mature or "post-thymic" T-cell
lymphomas (arise from mature T-cells)
 distinguishes them from the immature T-cell lymphomas such as acute lymphocytic
leukemia (ALL) or lymphoblastic lymphoma.
•
Under this broad meaning, almost all types of T-cell lymphoma fall under the
category of PTCL
•
Cells characteristically express CD3, the T-cell receptor (TCR) αβ or γδ chains, and
either CD4 or CD8
•
Natural killer (NK) cells share the same ontogeny with T cells
 + NK-cell markers CD56
T-cell and NK cell lymphomas
Because of morphological phenotypic and genotypic complexity of T/NK cells clinical
features are necessary in classification of the lymphomas
Three patterns of clinical presentation of mature T/NK cell lymphoma
1.
Nodal
2.
Extranodal
3.
Leukemic/disseminated
T-cell and NK cell lymphomas
Nodal group most common in western countries
 Peripheral T-cell lymphoma, unspecified
 Anaplastic large cell lymphoma
 Angioimmunoblastic T-cell lymphoma
Peripheral T-cell lymphoma, unspecified (PTCL)
•
Most common of all the T-cell lymphomas
•
Involves the lymph nodes, other sites such as the liver, bone marrow,
gastrointestinal tract, and skin, may also be involved.
•
PTCLs is aggressive and requires combination chemotherapy upon diagnosis
•
Usually Tdt-, CD3+, CD4+, CD8-
T-cell and NK cell lymphomas
Anaplastic large cell lymphoma
•
Accounts for ~12-15% of all T-cell lymphomas in
adults and 10-30% of all lymphomas in children.
•
Can be divided into three types:
 2 systemic (presents in lymph nodes or organs) subtypes
 1 non-systemic subtype – appears only on the skin - not to
be confused with primary cutaneous anaplastic large cell
lymphoma
 The systemic types are usually fast-growing, while the
skin-only type is usually more slow-growing
•
Characterized by large cell with kidney-shaped
nuclei and eosinophilic inclusion-like region adjacent
to the nucleus
Unusual in that it responds to therapy
Overall survival – 80% at 5yrs
T-cell and NK cell lymphomas
Angioimmunoblastic T-cell lymphoma
•
Fast-growing; accounting for 1-2% of all T-cell lymphomas in the United States
•
Initial symptoms often include swollen lymph nodes and systemic symptoms such as
fever and rash.
•
It is generally treated like other fast-growing T-cell lymphomas, but can be managed
with milder therapies in certain circumstances
•
Affected lymph nodes contain mixture of atypical lymphoid cells, follicular dendritic
cells, thick-walled high endothelial venules
•
CD4+, CD21+
•
Usually follows an aggressive clinical course
T-cell and NK cell lymphomas
Primary Cutaneous T-cell Lymphoma (PCTL)
•
Extranodal presentation
•
Accounts for 2-3% of all NHL cases and usually affects adults.
•
A group of typically slow-growing cancers that appear on and are most often confined
to the skin
 Mycosis fungoides, which appears as skin patches or plaques, is the most common type of
cutaneous T-cell lymphoma
 Less common forms include: Sézary syndrome
 Primary cutaneous anaplastic large cell lymphoma
 Lymphomatoid papulosis
T-cell and NK cell lymphomas
Require thin sections of fixed paraffin-embedded material to observe the peculiar
cerebriform nucleus of malignant T-cells
90% exhibit pan-T+, CD4+, CD810% exhibit pan-T+, CD4-, CD8+
Different from systemic anaplastic large-cell lymphoma
 Both CD30+, but PCTLs are epithelial membrane antigen (EMA)- negative;
 T(2;5) translocation (+) for systemic anaplastic large-cell lymphoma (-) for PCTL
PCTL is indolent, incurable versus the aggressive curable systemic anaplastic
lymphoma
T-cell and NK cell lymphomas
Staging is similar to that of HD
Treatment and prognosis
Based on two categories
1.
Indolent
 relatively long median survival without therapy (7-9 yrs)
 Can be treated with radiotherapy
 90% present at stage 111 or 1V- sensitive to radiation and chemo, but incurable with standard
Multiagent chemo
2.
Aggressive
 Rapidly fatal if untreated
 Potentially curable with aggressive treatment strategies
•
Adults > 45yrs have longer survival than younger patients
•
Median survival more favorable for B-cell than for T-cell lymphoblastic lymphoma
Multiple myeloma and related plasma cell disorders
Multiple myeloma is a disorder characterized by:
•
Proliferation of abnormal plasma cells in the BM
•
Tumor of plasma cells – plasmacytoma
•
Monoclonal gammopathy – over production of an antibody in the serum
•
Secretion of Bence-Jones proteins in the urine
•
Symptoms of bone destruction, hypercalcemia, kidney failure, hyperviscosity,
pancytopenia, anemia, bleeding episodes, increased susceptibility to infections
Plasma cell development
B cells develop from multipotential stem cells present in BM. Following encounter with Ag, naïve B cells can
differentiate into short-lived plasmablasts, secreting predominantly IgM- first line of defense against
infection. Alternatively, activated naïve B cells can seed a GC, where affinity maturation and differentiation
into long-lived memory and plasma cells occur. Following their generation, memory cells and PCs can then
migrate into niches in distinct sites (MALT, BM, splenic red pulp) where they receive survival cues from
neighboring cells.
Immunoglobulin
•
Igs have two identical
light chains (25kD), two
identical heavy chains
(50kD)
•
Held together by
disulfide bonds
•
Antibody produced by
each plasma cell has only
one type of light chain
and one type of heavy
chain
•
5 types of heavy chains;γ,
α, μ,δ, ε
 IgG1-4, IgA1,2
•
2 types of light chains; κ,
λ
Immunoglobulins
•
IgG, IgA, IgM, IgD, IgE
•
IgM does not cross the placenta
 Transient antibody produced in response to infection
 Unmeasurable within 2wks after initiation
•
IgG next to respond
 Remains until antigenic stimulus is removed
•
IgG and IgA form dimers
 IgA provides protection of epithelial surfaces in GI tract and airways
•
IgE – allergic/hypersensitivity reactions
•
IgD – role unclear
•
Overproduction of Igs is the hallmark of plasma cell disorders
Laboratory recognition and measurement
Electrophoresis (SPEP)
•
Total protein in serum measured in routine chemistry
•
Includes albumin, Igs, α1-antitrypsin, α2-macroglobulin, transferrin, β-lipoprotein
•
Total albumin also measured
•
Total protein – albumin = ~Ig fraction
•
Need to differentiate between polyclonal and monoclonal
 Polyclonal – in infections
 Monoclonal – plasma cell disorders
•
Then perform Immunofixation to investigate abnormal spike on SPEP
Electrophoresis
Normal pattern
Monoclonal spike
Polyclonal production
IgM M spike
Hypogammaglobulinemia
Immunofixation (IFE)
Proteins separated by electrophoresis
Mono-specific antibody added
Precipitation of proteins occur → washing →
staining of remaining immunoprecipitate
Example of identification of a monoclonal
serum protein by immunofixation
electrophoresis
The first track is serum protein electrophoresis
(ELP).
The next tracks are IgG, IgA, IgM, κ light
chains and λ light chains (L)
The arrow indicates the position of the
monoclonal protein.
The second track identifies the protein as IgG
after reaction with IgG antibody and protein
staining.
The sixth track identifies the light chain as λ.
Laboratory recognition and measurement
Quantitative Igs
•
By measuring decree of turbidity by light scatter caused by Ag-Ab complexes
•
Mix patient sample with specific Ab reagent
•
Use nephelometer
•
Clonality to be determined by SPEP and IFE
Free serum light chains (FLC)
•
Detect monoclonal FLC not detected by SPEP or IFE
•
Automated immunoassay
•
For diagnosis of and monitoring of myelomas and Amyloid light chain amyloidosis
Laboratory recognition and measurement
Bence-Jones proteinuria
•
Imbalanced Ig production yields an excess of free light chains (κ/λ)
•
Rapidly metabolized by blood → increased production of FLC being filtered into
urine
•
Proteins precipitate at 40-60oC, dissolve at 100oC, re-precipitate on cooling
•
Need 24-hr urine collection
•
FLC can be deposited in kidneys → leakage of protein into urine and kidney
failure
Clinical consequences of increased monoclonal Ig
Hyperviscosity syndrome
•
Viscous blood → decreased blood flow to vital organs → increased workload on the
heart → headaches, dementia, stroke, coma, congestive heart failure
•
Most cases seen with IgM, IgA, IgG3 – higher molecular weights
•
Plasmapheresis – plasma exchange in symptomatic patients
Decreased production of normal Igs
•
Abnormal Ig suppresses plasma cell production of other Igs → increased
susceptibility to infections (main cause of death of multiple myeloma patients)
•
May require intravenous infusion of Ig
Clinical consequences of increased monoclonal Ig
Cryoglobulinemic syndrome
•
Due to the presence of abnormal Igs called cryoglobulins in the blood
•
Cryoglobulins become thick or gel-like in cold temperatures → block blood vessels
throughout the body
•
On exposure to cold, patients experience painful extremities, palpable purpura
•
Can lead to complications ranging from skin rashes to kidney failure
Clinical consequences of increased monoclonal Ig
Cryoglobulinemic syndrome
Three main types, depending on the type of antibody that is produced:
•
Cryoglobulinemia type I Monoclonal Ig (IgG or IgM)
 Waldenstrom’s macroglobulinemia and/or multiple myeloma
•
Cryoglobulinemia type II
 Mixed polyclonal Ig
 Patients with viral infections; HCV, HIV
•
Cryoglobulinemia type III
 Mixed Igs
 Secondary to connective tissue disease
Monoclonal gammopathy of undetermined significance
(MGUS) – benign monoclonal gammopathy
Evident when patient has small M spike
Urine light chain of < 1g/24hrs
No lytic bone lesions
< 10% plasma cells in BM
No end organ damage from monoclonal Ig overproduction
20% develop multiple myeloma, NHL, CLL
Multiple myeloma
•
Most common plasma cell dyscrasia
•
Affects terminally differentiated B cells
•
Multi step process
•
Incurable but responsive to various therapies
•
Survival ranges from <1yr – 15yrs
•
Characterized by triad:
 Abnormal proliferation of plasma cells in BM
 Over production of monoclonal Ig
 Lytic/destructive bone disease
•
Disease manifestations of triad:
 Life threatening end-organ damage
 Renal insufficiency
 Anemia, immunosuppression, infections
Multiple myeloma
Most devastating feature
Osteolytic lesions → bone pain, pathologic fractures, spinal cord compression, hypercalcemia
•
Accounts for 10% of all hematological malignancies; 1% of all cancers
•
Median age of presentation – 67yrs
•
Higher in men than women
•
Only hematological malignancy that is higher among Blacks, lowest in Asians
•
Unknown cause – but associated with chronic stimulation of immune system
Diagnostic work up of Multiple myeloma
If clinical symptoms (anemia, renal insufficiency, bone pain, neuropathy, high protein
levels) suggests MM then perform confirmatory testing to establish stage and
prognosis
Diagnostic criteria
1. Biopsy proven plasmacytoma
11. BM Plasmacytosis
111. Monoclonal protein- M spike
CRAB:
Calcium; >11mg/dL
Renal insufficiency; creatinine >2 mg/dL
Anemia; Hgb <10g/dL
Bony lesions; lytic lesions, osteoporosis
Diagnostic work up of Multiple myeloma
Blood count and PB smear
•
CBC – normocytic normochromic anemia
•
PB smear – rouleaux formation of RBC due to ↑ Igs in blood
•
↑ Sedimentation rate blood test
 measures how quickly RBCs settle in a test tube in one hour. The more red cells that fall to
the bottom of the test tube in one hour, the higher the sed rate
Diagnostic work up of Multiple myeloma
Chemistry studies
•
↑ BUN, creatinine (kidney function affected by MM)
•
↑ Calcium – calcium is usually bound to albumin, unbound or free calcium major
cause of symptoms;
•
↓ albumin- prognostic criterion in MM
•
Β2- Microglobulin – most useful predictor of tumor load and ↓ activity – predicts the
prognosis for MM
•
C-reactive protein
Diagnostic work up of Multiple myeloma
Bone marrow examination
•
↑ plasma cells – forms sheets with
immature, bi-nucleated, large cells plasmacytoma
•
Flame cells – large intensely
staining (IgA)
•
Plasmacytosis 10-100%
•
CD38,CD56,CD138 (+)
•
sIg, pan-B-cell antigen CD19 (-)
•
± CD20, CD52
Diagnostic work up of Multiple myeloma
X-rays, CT scans
•
A series of X-rays are taken to find out whether there is any bone damage. Any sign
of bone damage will appear as dark areas in X-ray pictures
•
If the doctor requires more detailed images an MRI (magnetic resonance imaging) or
CT (computerized tomography) scan may be ordered
Cytogenetics
•
Slow to be recognized and implemented
•
Chromosomal abnormalities found in 30-40% of patients
•
Monosomy 13, 13q14 deletion and hypodiploidy have worst prognosis
•
Chromosomal translocations
•
Gene expression profiling – emerging technology to id subgroups
Treatment
Waldenström's macroglobulinemia
•
Lymphoplasmacytic lymphoma
•
Type of lymphoproliferative disease - shares clinical characteristics with the
indolent non-Hodgkin lymphomas
•
Overproduction of the IgM antibody → hyperviscosity
 makes it harder for blood to flow through small blood vessels
•
1,400 people in the United States are diagnosed every year
•
Most people with this condition are over age 65, however, it may occur in younger
people
•
The average survival ~ 6.5 years. Some people live more than 10 years
•
In some people, the disorder may produce few symptoms and progress slowly
Waldenström's macroglobulinemia
•
Physical examination - a swollen spleen, liver, and lymph nodes. An eye exam may show
enlarged veins in the retina or retinal bleeding (hemorrhages)
•
Cryoglobulinemic purpura
•
CBC - ↓ RBCs and platelets
 Bleeding of gums and nose
 Prolonged bleeding time
•
Blood chemistry – evidence of kidney disease
•
A serum viscosity test can tell if the blood has become thick
 Symptoms usually occur when the blood is four times thicker than normal
•
SPEP shows ↑ of the IgM antibody
 Levels seen are generally greater than 3 g/dL
Waldenström's macroglobulinemia
Chemotherapy - primary treatment
Alkylators
Rituximab – monoclonal Ab against CD20
Amyloidosis
•
Protein conformation disorder
•
Protein becomes insoluble → deposition in extracellular matrix of organs
•
Most common precursor protein that result in amyloidosis – protein derived from Ig light
chain fragments (λ secretions) – source plasma cell
•
Less common – AA amyloidosis – associated with inflammation
•
Rare and potentially fatal when deposited insoluble proteins impair organ functions
•
Causes progressive loss of organ function
•
Chemotherapy or stem cell transplantation and plasmapheresis to eliminate the plasma
cell
•
Similar to Light chain deposition on disease ( LCDD)
 LCDD do not form amyloid fibrils, and is usually related to κ secretions
Lipid storage disease and histiocytosis
Lipid storage diseases, lipidoses, lysosomal storage disease
•
Group of autosomal inherited metabolic disorders
•
Harmful amounts of fatty materials (lipids) accumulate in various cells and tissues
in the body
•
Caused by enzyme deficiencies - either do not produce enough of one of the enzymes
needed to metabolize lipids or have enzyme defects
•
Over time excessive storage of fats → permanent cellular and tissue damage
particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow
Lipid storage disease
Most widely known:
1.
Gaucher’s disease
2.
Niemann-Pick disease
3.
Tay-Sach’s disease
4.
Mucopolysaccharidose – rare
Increased incidence of Gaucher’s and Tay-Sach’s in Ashkenazi Jews
Wide clinical expression- from asymptomatic to fatal
Prenatal detection is the aim of control
Enzyme replacement – current effective therapy
Gaucher disease
Most common of the lipid storage diseases
Caused by a deficiency of the enzyme βglucocerebrosidase
Mutations in the GBA gene greatly reduce or eliminate
the activity of beta-glucocerebrosidase → Accumulation
of unmetabolized substrate glucocerebroside in cells
•
Mainly in the monocyte-macrophage system
•
Produces the distinctive Gaucher’s cells – histiocytes
20-100µm in diameter with displaced nucleus
Clinical Triad
•
Hepatoslenomegaly
•
Gaucher’s cells in BM
•
↑ serum acid phosphatase
Gaucher disease
Fatty material can collect in the spleen, liver, kidneys, lungs, brain, and bone
marrow.
Symptoms may include:
•
enlarged spleen and liver
•
liver malfunction
•
skeletal disorders and bone lesions that may cause pain and fractures
•
severe neurologic complications
•
swelling of lymph nodes and (occasionally) adjacent joints
•
distended abdomen
•
a brownish tint to the skin, anemia
•
low blood platelets, and yellow spots in the eyes
•
Persons affected most seriously may also be more susceptible to infection
Gaucher disease
Type 1- most common
10-25% of patients
No treatment needed
Hepatoslenomegaly
Type 2 – more
uniform presentation
than type 1
Type 3 – two distinct
subtypes, a and b
Gaucher’s disease treatment
Enzyme replacement treatment given intravenously every two weeks can
dramatically decrease liver and spleen size, reduce skeletal abnormalities, and
reverse other manifestations.
Successful bone marrow transplantation cures the non-neurological
manifestations of the disease – high risk therapy, rarely performed for Gaucher’s
disease
Niemann-Pick disease
Heterogeneous group of disorders
Increased incidence in Jewish population
This disorder is divided into five main types
based on the genetic cause and the signs and
symptoms (A,B,C,D,E)
Clinical manifestation
•
Retardation
•
Hepatoslenomegaly
•
Lymphadenopathy
•
Pigmentation
•
Impaired neurologic function
•
Niemann-Pick cells – lipid-laden giant foam
cells found in affected tissues
Niemann-Pick disease
Niemann-Pick disease type A
Deficiency of the sphingomyelinase enzyme
→ accumulation of unmetabolized sphingomyelin
Sphingomyelin – sphingophospholipd - constituent of the cell membrane
•
Known as infantile or classic Niemann Pick
•
Appears during infancy
•
Characterized by Hepatoslenomegaly
•
Failure to thrive
•
Progressive deterioration of the nervous system.
•
Known as the neurological type.
•
Children affected by this condition generally do not survive past early childhood
Niemann-Pick disease
Niemann-Pick disease type B
•
Deficiency of the sphingomyelinase enzyme
•
Chronic or adult form
•
Features include Hepatoslenomegaly
•
Growth retardation
•
Problems with lung function including frequent lung infections.
•
Decreased platelets
•
Niemann-Pick disease type B is also known as the non-neurological type because the
nervous system is not usually affected
•
Live longer than type A – Type B usually survive into adulthood
Niemann-Pick disease
Niemann-Pick disease type C
•
Mutations in either the NPC1 or NPC2 gene
•
The NPC1 gene involve with cholesterol transport within cells
 Cholesterol and sphingomyelin accumulates
•
Most common form with onset in early childhood
•
Severe liver disease
•
Breathing difficulties
•
Developmental delay
•
Neurologic abnormalities
•
Can survive into adulthood
•
Types C1 and C2, caused by NPC1 and NPC2, respectively
 Infantile or juvenile and Adolescent or adult form
Niemann-Pick disease
No effective treatment for Niemann-Pick
allogeneic BM transplant done for type B with encouraging results
Splenectomy rarely required – death usually occurs before
Prognosis of type A – very poor
Type B – may survive into childhood or adult life
Type C – die usually in second decade of life
Tay-Sachs disease
•
Also known as GM2 gangliosidosis
•
Rare autosomal recessive sphingolipidosis as a result of hexosaminidase A
deficiency
•
Most common variant - infantile Tay–Sachs disease
•
Causes a progressive deterioration of nerve cells and of mental and physical abilities
•
Starts at ~ 6mths of age
•
Results in death by the age of four
•
Accumulation of harmful quantities of gangliosides in almost all tissues → the
premature death
 Affects central nervous system and eye
 Cherry red spot in macula of each eye
 Macrocephaly
•
1in 30 carrier rate in the Ashkenazi Jewish population
Tay-Sachs disease
Diagnosis
•
Peripheral blood contains vacuolated lymphocytes
•
Prenatal detection
•
Detection of hexosaminidase A levels in serum, plasma, leukocytes and cultured
fibroblasts of infants
•
Mass screening of adults
Prognosis and treatment
•
Fatal before age 4
•
Attempting enzyme replacement, results not yet known
•
Supportive treatment – manage hydration, infections, seizures
Mucopolysaccharidoses (MPS)
•
Rare disorder
•
Caused by the absence or malfunctioning of lysosomal enzymes needed to break
down mucopolysaccharides –
 long chains of sugar carbohydrates in each of our cells that help build bone, cartilage,
tendons, corneas, skin and connective tissue.
•
Mucopolysaccharides (also called glycosaminoglycans) are also found in the joint
fluid
•
Deficiency of one of the enzymes involved in mucopolysaccharide metabolism
•
Glycosaminoglycans collect in the cells, blood and connective tissues
 → permanent, progressive cellular damage which affects appearance, physical abilities,
organ and system functioning, and, in most cases, mental development
•
Arranged into seven categories
Mucopolysaccharidoses (MPS)
Histiocytosis
Abnormal proliferation and accumulation of
mature histiocytes or Langerhans's cells
Sea blue histiocyte syndrome
Striking blue color of histiocytes after
staining with Wright’s stain
Isolated in young adults with enlarged
spleen
Abnormalities of the eye, skin, nervous
system, lung
Laboratory findings confined to the blood
Thrombocytopenia
Most have normal life spans