Pembelajaran Jarak Jauh 2020

Patologi Sistem Limfoid

dr. Devy Ariany, M.Biomed
FK UIN Syarif Hidayatulah Jakarta
 Lymph Node

Lymph node germinal centre.

[A] Normal germinal centre showing distinct zoning. The
lower, darker-appearing half contains closely packed and
highly proliferative centroblasts while centrocytes
predominate in the paler, upper half.
Wheater’s Pathology, 6th ed, 2020 Underwood's Pathology, 7th ed, 2019
 Fig. 16.1
Reactive hyperplasia of lymph nodes.
(B) follicular hyperplasia
(C) paracortical hyperplasia
(D) sinus hyperplasia

Wheater’s Pathology, 6th ed, 2020

 Here is the normal appearance of a
benign reactive lymph node.
http://library.med.utah.edu/WebPath
• At the top is the capsule and just
under that a subcapsular sinus
where lymphatics enter that drain
tissues peripheral to the node.
• Beneath the capsule is the
paracortical zone with lymphoid
follicles having a pale germinal
center in which the immune
responses are often generated.
• Beneath this are sinusoids
extending to the center of the
node.
 At high magnification is seen a
lymph node follicle with a
germinal center containing
larger lymphocytes undergoing
activation.
B cell are activating to become
differentiated plasma cells
producing immunoglobulin
specific to the encountered
antigens. At the upper left is the
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mantle zone.
• This is a more pronounced reactive
change in a lymph node, with a larger
follicle and germinal center containing
'tingible body' macrophages.
• These large macrophages are involved
in phagocytosis of antigenic material
passed from follicular dendritic cells to
be processed into peptides
• In general, lymph nodes in a benign
reactive process are more likely to
enlarge quickly and become tender
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 [D] High-power view of a tingible-body
macrophage ( arrowed ) engulfing
apoptotic lymphoid cells. These highly
phagocytic macrophages are
concentrated in the proliferative ‘dark
zone’ of the germinal centre; they
remove lymphoid cells selected for
elimination by apoptosis due to poor
affinity or autoreactivity.

Underwood's Pathology, 7th ed, 2019

 Fig. 16.2
Metastatic colonic carcinoma in lymph
node
This micrograph shows a mesenteric
carcinoma cells invade into lymphatic
channels draining the primary tumour
and gain access to the regional lymph
nodes through the afferent lymphatic
channels .
These malignant cells enter the
subcapsular sinus (SS) of the lymph
node and may settle at this site where
they can proliferate to form a secondary
Wheater’s Pathology, 6th ed, 2020
tumour mass.
 Lymphoma
Non-Hodgkin's Lymphoma
1. Small Lymphocytic Lymphoma
2. Follicular Lymphoma
3. Diffuse Large B-cell Lymphoma
4. Burkitt Lymphoma
5. High-grade B-cell Lymphoma (small non-cleaved) Burkitt-like
Lymphoma
6. Precursor T or B-cell Lymphoblastic Lymphoma/Leukemia
(Lymphoblastic Lymphoma)
7. Mantle Cell Lymphoma
8. Marginal Zone Lymphoma
 Fig. 16.4
Follicular lymphoma. (A) H&E of lymph
node with follicular lymphoma
This is a common form of B cell lymphoma that
tends to occur in middle-aged and older adults
and presents as painless lymphadenopathy.
These tumours are derived from germinal
centre B cells and usually have a nodular
or follicular architecture (F) ( Fig. 16.4A )
The cells are a mixture of small centrocyte-like
cells and larger centroblast-like cells. Although
most tumours are low grade, an increasing
Wheater’s Pathology, 6th ed, 2020
proportion of centroblastic cells indicate more
aggressive behaviour. The tumour cells show a
similar pattern of immunopositivity to normal
germinal centre B cells.
Fig. 16.4. Follicular lymphoma. (B) immunohistochemical stain for bcl-2 in follicular lymphoma (LP); (C)
immunohistochemical stain for bcl-2 in normal reactive node (LP).
Most cases are characterised by a specific chromosomal abnormality, t(14;18), which
juxtaposes the immunoglobulin heavy chain (IGH) gene on chromosome 14 with the gene for
the anti-apoptotic protein BCL-2 on chromosome 18. Because IgH is expressed in normal
mature B cells, this chromosomal rearrangement results in over-expression of bcl-2 protein
within the tumour cells and so these cells effectively avoid the normal pathway of apoptotic
destruction. In normal reactive lymph nodes, the cells of the mantle zone (MZ) are bcl-2
positive but germinal centre cells (GC) are bcl-2 negative ( Fig. 16.4C ). In contrast, strong bcl-2
positivity is characteristically seen within the neoplastic follicles (F) in follicular lymphoma ( Fig.
16.4B ). Wheater’s Pathology, 6th ed, 2020
Burkitt lymphoma

A, At low power, numerous pale

tingible body macrophages are evident,
producing a "starry sky" appearance.

B, At high power, tumor cells have

multiple small nucleoli and high mitotic
index. The lack of significant variation
in nuclear shape and size lends a
monotonous appearance. (B, courtesy of Dr.
José Hernandez, Department of Pathology, University of
Texas Southwestern Medical School, Dallas, TX.)
 Diffuse large B-cell lymphoma (spleen)

The presence of an isolated large mass is typical. In contrast,

indolent B-cell lymphomas usually produce multifocal expansion of
white pulp (Courtesy of Dr. Mark Fleming, Department of Pathology, Brigham and
Women's Hospital, Boston, MA.)
Fig. 22.13
Underwood's Pathology, 7th ed, 2019
Diffuse large B-cell lymphoma.
The majority of the cells, growing in a diffuse pattern, are
centroblasts — large cells with nuclei containing multiple nucleoli
that are often peripherally located. Small cells with darkly stained
nuclei in the background are mainly reactive T cells.
 Hodgkin lymphoma
Hodgkin lymphoma (HL), formerly called Hodgkin disease (HD)
may respond well to therapy.
Thus, it is important to determine the stage of the disease and
the histologic type of HD in order to provide the most
appropriate therapy.
The first four types listed in the table below are "classical HL"
and have Reed-Sternberg cells that immunohistochemically are
positive for CD15 and CD30 but negative for CD45.

Nodular lymphocyte-predominant HL has RS cells that are

CD20 positive but CD15 and CD30 negative, like B cells.
http://library.med.utah.edu/WebPath
 Here is a 5 cm lymph node (obviously from a
patient with lymphadenopathy). The node
should normally be soft and pink and less than
1 cm in size.
This lymph node is involved with Hodgkin's
disease.

This is a liver that is involved with Hodgkin's

disease. The staging of Hodgkin's disease is very
important in determining therapy. Thus, it is
important to determine whether the patient has
only a single lymph node region involved,
multiple node regions, or extranodal
involvement.

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Nodular sclerosis (NSHL) and mixed cellularity classic Hodgkin lymphoma (MCHL).
These low-power images show the pale fibrosis and cellular nodules ( dark ) in
NSHL [A] in contrast with the diffusely cellular pattern in MCHL [B] . Note that the
capsule (upper border of tissue in each photomicrograph) is intact and sharply
demarcated in both cases. Underwood's Pathology, 7th ed, 2019
Fig. 22.8 Underwood's Pathology, 7th ed, 2019

Nodular sclerosing classic Hodgkin lymphoma (cHL).

[A] Cellular nodules are surrounded by thick collagen bands. [B] Lacunar cells (Reed–
Sternberg cell variants) that appear to be surrounded by a clear space, due to
retraction from adjacent tissue, are characteristic of nodular sclerosing cHL.
 Underwood's Pathology, 7th ed, 2019

Classic Hodgkin lymphoma (cHL).

[A] Reed–Sternberg cell with multiple nuclei containing prominent nucleoli. [B] Reed–
Sternberg cells identified by immunohistochemical staining for CD30, a cell surface antigen
expressed by some activated, reactive lymphoid cells but also characteristically expressed by
the neoplastic cells in cHL.
 Multiple myeloma
The skull demonstrates the characteristic rounded
"punched out" lesions of multiple myeloma.
The plasma cell proliferation results in bone lysis
to produce these lytic lesions.
Such lesions can produce bone pain and lead to
hypercalcemia

Round lesions filled with a soft reddish

material are indicative of foci of myeloma in
this section of vertebral bone.
Larger lesions may weaken the bone to cause
fracture with back pain.

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 At low power, the abnormal plasma cells of
multiple myeloma fill the marrow.

At medium power, the plasma cells of multiple

myeloma here are very similar to normal
plasma cells, but they may also be poorly
differentiated.
Usually, the plasma cells are differentiated
enough to retain the function of
immunoglobulin production.
Thus, myelomas can be detected by an
immunoglobulin "spike" on protein
electrophoresis, or the presence of Bence-
Jones proteins (light chains) in the urine.
Immunoelectrophroesis characterizes the type
of monoclonal immunoglobulin being
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produced.
 Type I hypersensitivity
Anaphylaxis: Prior sensitization has resulted in an immune response initially mediated
by CD4 lymphocytes (of the Th2 variety) that promote mast cell proliferation and
plasma cell production of IgE. The IgE becomes bound to mast cells in places such
as respiratory tract mucosa. Encountering the allergen again leads to mast cell
degranulation with release of primary mediators (such as histamine, serotonin) which
cause vasodilation, bronchoconstriction, etc. and release of secondary mediators
(such as leukotrienes, prostaglandin) which lead to inflammatory cell infiltrates.
There are two forms of anaphylaxis:
•Systemic anaphylaxis: In some individuals, a severe reaction occurs within
minutes, leading to symptomatology such as acute asthma, laryngeal edema,
diarrhea, urticaria, and shock. Classic examples are penicillin allergy and bee sting
allergy.
•Local anaphylaxis (atopy): About 10% of people have "atopy" and are easily
sensitized to allergens that cause a localized reaction when inhaled or ingested.
This can produce hay fever, hives, asthma, etc. Classic examples are food allergies
and hay fever to ragweed pollen.

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A form of localized anaphylaxis with type I
hypersensitivity occurs with "hay fever" when
allergens in plant pollens contact IgE bound to
mast cells, causing them to release their
granules containing mediators such as
histamine that promote vasodilation and
edema. Beneath the nasal mucosa at the left,
eosinophils have been attracted. The plasma
cells seen here have collected along with many
small blue lymphocytes due to the chronic
nature of the antigenic stimulation with
upregulation of the arachidonic acid pathway.
 The acute laryngeal edema seen here
that killed the patient was due to an
anaphylactic reaction to penicillin.
Such an allergy is a form of type I
hypersensitivity reaction in which
there is preformed IgE antibody on
mast cells that quickly reacts with an
antigen. The mast cells release
histamine and other mediators that
lead to the edema
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Type II Hypersensitivity
Complement dependent reactions: Antibody is directed against antigen
on cells (such as circulating red blood cells) or extracellular materials
(basement membrane). The resulting Ag-Ab complexes activate
complement (via the classic pathway), leading to cell lysis or
extracellular tissue damage.

Antibody is directed against acetylcholine receptors at the motor end plate of a

muscle, blocking the receptors and diminishing the muscular response. This is the
mechanism for muscle weakness in myasthenia gravis.
Diseases caused by this mechanism include:
•Myasthenia gravis: acetylcholine receptor antibody.
•Graves disease (thyrotoxicosis): anti-TSH receptor antibody
•Pernicious anemia: anti-parietal cell antibody.
A red blood cell has antigen fixed on its surface to which antibody
attaches. The attached antibody sets off the complement cascade,
which ends with the formation of the "membrane attack complex"
of C5-9 which causes lysis of the cell. Other complement
components may be generated, such as the opsonin C3b.
Diseases in this complement dependent category include:
•Transfusion reactions: incompatible RBC's or serum is transfused.
•Autoimmune hemolytic anemia: antibody is made against one's
own RBC's.
•Erythroblastosis fetalis: maternal IgG crosses the placenta and
attaches to fetal RBC's.
•Goodpasture's syndrome: glomerular basement membrane
antibody is present.
Antibody-dependent cell-mediated cytotoxicity (ADCC): Low
concentrations of IgG or IgE (in the case of parasites) coat target cells.
Inflammatory cells such as NK (natural killer) cells, monocytes, and
granulocytes then bind to the immunoglobulin Fc receptors and lyse, but
do not phagocytize, the target cells.
A macrophage with Fc receptors on its surface is able to recognize a
target cell coated with antibody via the Fc receptor portion of the
attached antibody. The macrophage can then demolish the targeted cell
by elaboration of proteases.
Examples of ADCC include:
•Transplant rejection
•Immune reactions against neoplasms
•Immune reactions against parasites
Antireceptor antibodies: IgG antibody is directed against receptors in
target cells, resulting in complement-mediated destruction of the
receptors.
 This is the linear pattern of
immunofluorescence with antibody
to IgG in a patient with Goodpasture
syndrome. The even linear pattern is
produced because the antibody is
directed against the entire
glomerular basement membrane
(antiglomerular basement membrane
antibody).

http://library.med.utah.edu/WebPath
 Type III Hypersensitivity

• This reaction is mediated by immune (Ag-Ab) complexes which

promote tissue damage primarily through complement activation
(alternate pathway). C3b as an opsonin attracts neutrophils, which
then release lysosomal enzymes. C5a as a chemoattractant brings
in neutrophils. Serum complement is reduced as it is used up in this
process.

• Antigen-antibody complexes are circulating and becoming trapped

beneath the basement membrane of a small blood vessel, setting off the
complement cascade and generating components that attract PMN's to
generate an ongoing inflammatory response.
• Immune complexes can be deposited systemically or locally
• Systemic immune complex disease: Ag-Ab complexes form in the
circulatory system and are deposited in tissues, typically near
basement membranes in places such as blood vessels, glomeruli,
skin, joints, pleura, and pericardium. Larger immune complexes
are quickly phagocytized by macrophages and removed, but small
to intermediate complexes formed with antigen excess may
escape removal leading to:
1. Glomerulonephritis
2. Serum sickness
3. Vasculitis

• Local immune complex disease: Also called an "Arthus"

reaction, it occurs with local injection of the antigen and
leads to focal vasculitis. This kind of immune reaction also
plays a role in the development of hypersensitivity
pneumonitis (so-called "farmer's lung").

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If immunofluorescence microscopy using
an antibody to complement or
immunoglobulin is performed, then one
can see the brightly fluorescing band
along the dermal epidermal junction that
indicates immune complex deposits are
present.
A variety of immunoglobulins can be
present, usually IgG, and the immune
complexes trigger the "classic"
complement cascade so that
components such as C3 are present
 If immunofluorescence is
performed, here with antibody to
IgG, then a granular pattern of
immunofluorescence is seen,
indicative of deposition of immune
complexes in the basement
membranes of the glomerular
capillary loops. [Image contributed by
Elizabeth Hammond, MD, University of
Utah]
http://library.med.utah.edu/WebPath
 Type IV Hypersensitivity
This reaction is called "delayed hypersensitivity" because it is mediated by sensitized
CD4+ T lymphocytes which process antigens in association with class II HLA molecules
and release lymphokines. The lymphokines promote a reaction (especially mediated
through macrophages) beginning in hours but reaching a peak in 2 to 3 days.

This diagram above illustrates a sequence of events in granuloma formation in

response to Mycobacterium tuberculosis (MTB). The key cell in the process is the
epithelioid macrophage.
Hypersensitivity reactions with this mode of action include:
•Granulomatous diseases (mycobacteria, fungi)
•Tuberculin skin reactions
•Transplant rejection
•Contact dermatitis
Cytotoxic T lymphocyte (CTL) mediated responses: CD8+ T cells are generated
and lyse specific cells. Class I HLA molecules play a role. Reactions with this mode
include:
•Neoplastic cell lysis
•Transplant rejection
•Virus-infected cell lysis
 This is contact dermatitis, a form of
type IV hypersensitivity in which pre-
sensitized lymphocytes led to this
inflammatory reaction a couple of
days after contact with the offending
plant material. Antigens such as those
in poison oak and poison ivy are most
often responsible for this appearance.

http://library.med.utah.edu/WebPath
 Autoimmune Diseases
"The fancier the plumbing, the easier it is to stop up the drain" -- The human immune system is very
complex and, hence, there are numerous ways it can malfunction. There are a number of diseases
that can result, and many of these have similarities. It is sometimes difficult to separate them. They
are also often called "connective tissue" disorders because many of them are manifested in a variety
of tissues.
Hypersensitivity reactions involved in autoimmunity are primarily types II and III, though type IV
reactions can also be present.

Mechanisms proposed for development of autoimmunity include:

Bypass of CD4+ T-cell tolerance of "self" antigens by:
•complex of antigen with a hapten (such as a drug or infectious agent) or infectious degradation of an
antigen
•cross-reaction with a hapten on an infectious agent that is similar to tissue proteins--classic for
poststreptoccocal glomerulonephritis and rheumatic heart disease
•direct activation of B-cells via bacterial endotoxin and via Epstein-Barr virus receptors on B-cells
Idiotype bypass through ligand mimicry, as seen in antireceptor antibody mediated disease, and
cross-reactivity with infectious agents:
•T-suppressor/helper imbalance
•emergence of a sequestered antigen through tissue trauma or inflammatory destruction. Examples
include: lens crystalline of eye, spermatozoa in testis, and myelin in CNS
Antinuclear Antibodies
Many autoimmune diseases have serologic evidence for antibodies directed at components of "self"
cell nuclei. Though these antibodies may not be the direct cause of, or evidence for, tissue injury, they
are very useful for diagnosis and categorization of autoimmune diseases. The types include:
ANA (antinuclear antibody): seen in many autoimmune diseases and not diagnostic of any. In general,
the higher the titer, the worse the disease. There are some characteristic fluorescent staining patterns
for ANA:
•homogenous (diffuse) - not very specific for anything
•rim - may be indicative of anti-double stranded DNA, seen in SLE
•speckled - indicative of antibody to extractable nuclear antigens, often seen in MCTD
•nucleolar - antibody to nucleolar RNA, seen often in PSS
•centromere - antibody to centromeric protein, seen in CREST syndrome

Sometimes when performing the ANA test, the

substrate cells demonstrate particular patterns of
staining. This is the so-called "rim" pattern that is
more characteristic of systemic lupus erythematosus
(SLE) than other autoimmune diseases.
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 This young woman has a malar rash (the so-
called "butterfly" rash because of the shape
across the cheeks). Such a rash suggests lupus.
Discoid lupus erythematosus (DLE) involves
mainly just the skin and is, therefore, relatively
benign compared to systemic lupus
erythematosus (SLE). In either case, sunlight
exposure accentuates this erythematous rash
("photosensitivity"). A small number (5 to 10%)
of DLE patients go on to develop SLE (usually
the DLE patients with a positive ANA). [Image
contributed by Elizabeth Hammond, MD, University of Utah

http://library.med.utah.edu/WebPath

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Histologically, the skin of a patient
with SLE may demonstrate a
vasculitis and dermal chronic
inflammatory infiltrates, as seen
here. Vasculitis with autoimmune
disease (often related to deposition
of antigen-antibody complexes) can
occur in many different organs and
can lead to the often confusing signs
and symptoms of patients with
rheumatic diseases. [Image contributed
by Elizabeth Hammond, MD, University of Utah]
 Here is another immunofluorescence
staining pattern with antibody to IgG
showing evidence for immune
complexes at the dermal-epidermal
junction. If such a pattern is seen only
in skin involved by a rash, then the
pattern is more characteristic for DLE,
but if this pattern appears even in skin
uninvolved by a rash, then SLE may
underlie this phenomenon
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 The periarteriolar fibrosis ("onion
skinning") seen in the spleen in
patients with SLE at autopsy is
quite striking, though of no major
clinical consequence. This
results from vasculitis.

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 Here is a glomerulus with thickened
pink capillary loops, the so-called "wire
loops", in a patient with lupus nephritis.
The surrounding renal tubules are
unremarkable.

Here is another granular pattern of

immunofluorescence in the glomerulus, this
time with antibody to C1q complement,
which is more specific for SLE. [Image
contributed by Elizabeth Hammond, MD, University of
Utah]

http://library.med.utah.edu/WebPath
 Here is a patient with the taut and shiny
skin typical of sclerodactyly. The skin
becomes inelastic and it is hard to move
the fingers. If sclerodactyly is seen along
with calcinosis, Raynaud phenomenon,
esophageal dysmotility, and telangietasias,
then the best diagnosis is CREST
syndrome ("limited" scleroderma). [Image
contributed by Elizabeth Hammond, MD, University
of Utah]

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 At low magnification, there is a
greater amount and depth of
dermal collagen, leading to the
decrease in elasticity. Though
scleroderma (systemic
sclerosis) is an autoimmune
disease, the main microscopic
feature is fibrosis, and chronic
inflammatory cell infiltrates are
sparse, unlike SLE.
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 A serious consequence of the "R" in
the CREST syndrome (limited
scleroderma) is seen here. The
fingertips are blackened and
additional portions of the hand
purplish with early gangrenous
necrosis from vasospasm with the
Raynaud phenomenon.

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Underwood's Pathology, 7th ed, 2019
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Fig. 9.28 Fig. 9.29
Anorectal herpes simplex infection in a Kaposi’s sarcoma. A disseminated tumour caused by
homosexual man with AIDS human herpes virus type 8 in an immunocompromised
Underwood's Pathology, 7th ed, 2019 host.