Transcript Cutaneous Lymphomas - Abdel Hamid Derm Atlas

Cutaneous lymphomas
Abdel Hamid M. Abdel-Aziz
Professor of Dermatology & Venereology,
AL-Azhar University
WWW. Abdelhamiddermatlas . com
Primary cutaneous lymphomas
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Primary cutaneous lymphomas can originate from T, B or NK lymphocytes. To understand primary cutaneous
lymphomas, knowledge of the skin as an immune organ is necessary –it is a large organ and a barrier system
between the organism and the external environment, taking active part in the immune responses and inflammatory
reactions. The cell population involved in these responses consists mainly of keratinocytes, Langerhans cells,
dermal dendrocytes, T-lymphocytes, polymorphonuclear leukocytes, mast cells and endothelial cells. Tlymphocytes are produced in the bone marrow and undergo differentiation in the thymus. After maturation, they
constantly circulate in the naïve form (virgin, not exposed to antigens) in blood and peripheral lymphoid organs.
When T lymphocytes are presented, in the lymph nodes, to antigens coming from the skin (effector lymphocytes,
memory lymphocytes) they express markers on their surface, which turns them into "participants" of the immune
system of this organ. B-lymphocytes do not belong to the skin cell population under physiological conditions, but
they are produced and matured in the bone marrow, remaining in the peripheral lymphoid organs and tissues
(spleen, lymph nodes and mucosa), as well as in the bone marrow. In response to antigenic stimuli (at distance),
the B-lymphocytes can migrate to other organs.
To understand the lymphoproliferative disorders of the B-cells, it is important to know some concepts about the
differentiation of the B-lymphocytes. This process comprises an initial phase, named antigen-independent, which
occurs in the fetal liver and in the fetal and adult bone marrow, and an antigen-dependent phase, which takes
place in peripheral lymphoid organs. During the first stage (antigen-independent), the Ig genes undergo a gene
rearrangement V(D)J of the variable (V), diversity (D) and junction (J) segments, by means of somatic
recombination, producing immature B-cells that are able to migrate to the spleen. In the spleen, part of the
lymphocytes will constitute the native follicular B-cells, and another subpopulation will originate the cells of the
marginal zone. During the second maturation phase, the recognition of a "T-dependent antigen" triggers the
formation of a germinal center and the corresponding transition of naïve follicular B-cells to effector cells.
All cells express molecules (antigens) that identify them, either on their surface or inside. Many of these
molecules, named CD (cluster of differentiation), are identified by monoclonal or polyclonal antibodies. Based on
the development of antibodies to recognize these molecules, it was possible to study the role of the T/NK and Blymphocytes in both physiological and neoplastic processes, and to classify the lymphomas, which are clonal
proliferations of theses cells in their several stages of differentiation.
Basic B cell function: bind an antigen, receive help from a cognate helper T cell, and
differentiate into a plasma cell that secretes large amounts of antibodie
Early B cell development: from stem cell to immature B cell
Transitional B cell development: from immature B cell to MZ B cell or
mature (FO) B cell
B cell activation: from immature B cell to plasma cell or memory B cell
The B cell differentiation from the hematopoietic stem cell to the mature B cell, in the
bone marrow, is antigen independent. The final differentiation stages, from the mature B
cell to the plasma cell and memory B cell, in the germinal centers of the secondary
lymphoid organs, is antigen dependent, and generally requires a cooperation between B
and T cells.
Lymphomas
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Lymphomas are initially divided into two large groups: Hodgkin and non-Hodgkin. Hodgkin lymphomas affect
mainly cervical lymph nodes in adults. Their absolute incidence does not seem to have changed, as opposed to
the evident increased incidence of non-Hodgkin lymphomas. The latter are further divided into two groups: nodal
and extranodal. Nodal non-Hodgkin lymphomas affect primarily the lymph node. The primary cutaneous
lymphomas belong to the group of extranodal non-Hodgkin lymphomas, which primarily involve other sites,
different from the lymph nodes. Skin is the second location of extranodal involvement, corresponding to 25% of all
extranodal non-Hodgkin lymphomas, following the gastrointestinal tract. The primary cutaneous lymphomas differ
significantly from the equivalent nodal forms with regard to their clinical behavior and prognosis.
In the past, cutaneous lymphomas were not recognized as a condition, but rather as a secondary skin involvement
by nodal lymphoma. Initially, only mycosis fungoides, a cutaneous T-cell lymphoma, was recognized as a primary
form of cutaneous lymphoma. Recently, the World Health Organization –WHO and the European Organization for
Research and Treatment of Cancer –EORTC proposed a consensus classification for cutaneous lymphomas,
encompassing histopathological, immunohistochemical, molecular and clinical aspects.
The diagnostic confirmation of cutaneous lymphoma is not easy. The tests considered as the "golden standard"
are histopathology and immunohistochemistry. The diagnosis of this neoplasm is usually suggested by
experienced pathologists by means of cytomorphological evaluation and by the disposition of the infiltrate
architectural arrangement. Currently, to classify lymphomas it is indispensable to perform an immunohistochemical
study, with an antibody panel that is rationalized according to the histological findings. On rare occasions, the
immunohistochemical study has diagnostic power. It is also important to distinguish between the phenotypes of the
cells of interest (neoplastic cells) and those of the reactive infiltrate (reactive inflammatory cells). The panel used
to mark the T-cells consists mainly of anti-CD3 and CD45RO antibodies; for NK cells, anti-CD16 and CD56; and,
for B cells, anti-CD19, CD20, CD79a and CD10. T-lymphocytes are CD3+ and, when they are memory cells, they
are also CD45RO+. NK lymphocytes are CD3-, CD16+ and CD56+. B-lymphocytes are CD3-, CD19+, CD20+and
CD79a+. The B-lymphocytes of the germinal center are CD19+, CD20+, CD79a+ and CD10+, whereas the Blymphocytes of the marginal zone are CD19+, CD20+, CD79a+ and CD10-. The plasma cells are usually CD19-,
CD20- and CD79a+. Other complementary markers are important aids for diagnosis or classification, such as
CD21, CD23, ALK, EMA, CD4, CD8, besides the molecules related to apoptosis, such as bcl-2, bcl-6, and the cell
proliferation marker Ki-67
WHO classification 2OO8 for malignant lymphomas with primary
cutaneous manifestations
Differences Between Hodgkin’s and Non-Hodgkin’s Lymphomas
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Differences Between Hodgkin’s and Non-Hodgkin’s Lymphomas
Both Hodgkin and non-Hodgkin lymphoma are malignancies of a family of white blood cells known as
lymphocytes, which help the body fight off infections and other diseases. Hodgkin lymphoma is marked by the
presence of Reed-Sternberg cells, which are mature B cells that have become malignant, are unusually large, and
carry more than one nucleus. The first sign of the disease is often the appearance of enlarged lymph nodes. NonHodgkin lymphoma, by contrast, can be derived from B cells or T cells and can arise in the lymph nodes as well as
other organs. (B cells and T cells play different roles in the body’s immune response to disease.) there are many
subtypes of each disease, with more than 50 subtypes of non-Hodgkin lymphoma alone
There are a few distinct differences between HL and NHL including how the disease spreads, where tumors are
most commonly found in the body and variances in symptomology experienced by individuals. Additionally,
treatment protocols are very different. HL is not as common as NHL and the age of onset for HL occurs in a
bimodal (2 age time points) distribution with the average age of onset at 28 years and a less substantive peak
after age 55, whereas it is less common to see cases of NHL in people under age 50 (National Cancer Institute
2007a). For both HL and NHL the most common location of the tumors is in the lymph nodes and occurs above
the collarbone (National Cancer Institute 2010).
Specific to HL, malignancies are also found in the chest area, whereas in NHL tumors in the abdomen are more
common. Similarly, in HL as few as 4% of cases demonstrate cancer outside the lymph nodes, which differs
significantly in NHL where nearly one quarter of all patients have confirmed lymphoma outside the lymph nodes. In
terms of the symptoms of both HL and NHL, they are quite similar; however, approximately 40% of individuals with
HL will show symptoms that apply to the whole body or systemic symptoms such as weight loss, night sweats
and/or fevers. In NHL systemic symptoms are not as common.
An important difference between both lymphomas surrounds the progression of disease. In HL, the progression is
often quite orderly spreading in a downward pattern from the initial site to each lymph node and rarely diagnosed
in stage IV. Additionally, when HL first presents below the diaphragm it most frequently progresses to the spleen.
Conversely, in NHL nearly 40% of diagnosed cases are at stage IV, which are more likely to spread and not as
predictable in terms of their progression.
B lymphocyte development & neoplastic equivalent
From bone marrow to lymph node stage
Lymphomas
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Lymphomas can be classified into:
1. Hodgkin’s Lymphomas: ( 15%)
2. Non Hodgkin's lymphomas (85%)
Hodgkin’s lymphomas
Key structure:
A. Reed Sternberg cells : May be T or B lymphocytes
B. Failure of T cell function. N.B. : another disease with failure of T cell function is
HIV.
Stages:
I. Presence of enlarged node
II Presence of 2 or more nodes on the same side of diaphragm
III. Presence of 2 nodes on the different side of the diaphragm.
IV. Presence of more nodes in any site of the body.
Another classification of staging of Hodgkin’s lymphoma is
A. : No symptoms
B: There are symptoms (lymph node enlargement, itchy skin, night sweats, weight
loss, splenomegaly, hepatomegaly, cyclical fever )
Stages of Hodgkin’s lymphoma
Stage 1 Hodgkin's lymphoma
Stage 2 Hodgkin's lymphoma
Stage 3 Hodgkin's lymphoma
Stage 4 Hodgkin's lymphoma
Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie);
Stage II is involvement of two or more lymph node regions on the same side of the diaphragm (II) or of one lymph node region
and a contiguous extralymphatic site (IIe);
Stage III is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) and/or limited
contiguous extralymphatic organ or site (IIIe, IIIes);
Stage IV is disseminated involvement of one or more extralymphatic organs.
Types of Hodgkin’s lymphoma
Name
Lymphocytic
predominant
Mixed cells
Lymphocyte deleted
Mixed sclerosis
Prevalence
5%
3O%
5%
6O%
Age
Young
Middle
Old
Young females
Reed Sternberg cells
Few
Moderate
Large
Variable with
collagen & clear
spaces around Reed
sternberg cells
Position of lymph
nodes
Cervical &
inguinal
Cervical, chest &
abdomen
Visceral
Cervical & chest
Cure rate
9O%
75%
45%
85%
Reed Sternberg cell
Large multinucleated or have bilobed nucleus (resemble an “owl eye” ) with prominent inclusion like
nucleus. They are negative for CD 2O & CD 45
Popcorn cell , a variant of Reed Sternberg Hodgkin cells, seen in
nodular lymphocyte predominant Hodgkin ‘s lymphoma
Hodgkin's lymphoma –Nodular sclerosis (Reed Sternberg cell)
The infiltrate consist of lymphocyte, eosinophil, histiocyte, plasma cell & moderate fibrosis/ The
infiltrate lacks the monomrphic appearance of non-Hodgkin’s lymphoma
Lymph node biopsy from Hodgkin’s lymphoma showing
mixed cellularity type
Hodgkin’s Lymphoma
Hodgkin’s lymphoma
X- ray chest
Non Hodgkin’s lymphoma
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This can be classified into:
1. B cells:
@ CD 19
@ 8O% : out of these i. 4O% follicle like ii. 4O% diffuse i.e. more primitive
2. T cells
@ CD 4 , CD 8
@ 2O% Diffuse
3. Dendritic Langerhans cell :
@ S 1OO @ Characteristic racquet shape bodies
Characteristics of lymphoma which is important in prognosis.
A. Less proliferate Cleaved Small Mature Follicle
B. More proliferate Non cleaved
Large Immature Diffuse
Grades of non Hodgkin's lymphoma
Low grade
Intermediate grade
High grade
1.
1.
Lymphoblastic lymphoma: leukemia T cell
4O% of childhood lymphoma which
can affect skin & C.N.S.
Adult T cell lymphoma or leukemia
caused by HTLV1 (virus). More
common in Japan & Caribbean.
There is hypercalcemia
Sezary’s syndrome: T cell lymphoma
(Mycosis fungoides)
Small non cleaved lymphoma:
Burkett’s lymphoma There is stary
star trasnslocation at C myc gene
which makes immunoglobulin.
Instead of making Ig, it divides. It is
due to Epstein Bar virus.
Immunoblast lymphoma T or B
lymphocyte
2.
3.
4.
5.
6.
B cell, diffuse, mature,
small
2.Mycosis fungoides
Small lymphocytic
lymphoma: CLL,
macroglobulinemia
T cell, small, cleaved.
3.Follicular lymphoma:
85% translocation (14,
18) of BCL-2 , epiptosis (
instead of cell death, it
becomes larger & diffuse)
4. Extranodal lymphoma
MALT, small
lymphocytes.
2.
Follicular large cell
lymphoma
2. Diffuse
lymphoma: B cells
or T cells mixed
lymphoma.
Non Hodgkin's lymphoma types
Another classification
Update on classification of lymphoma
Sabharawal, R. et al. Dental Hypotheses 4: 4, 2O13
Mycosis fungoides
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Folliculotropic mycosis fungoides
Lymphoproliferative process of the skin. Part 2 : Cutaneous T cell& NK
cell lymphoma
Sanches, J. ,A. et al An. Bras. Dermatol. 81 : (1) , 2OO6
T cell lymphoma
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Subcutaneous panniculitis like T cell
lymphoma
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Sezary syndrome
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Sezary syndrome : Sezary cell
Primary cutaneous CD 4 + small size pleomorphic T cell lymphoma
Cutaneous anaplastic large cell lymphoma
Extra nodal NK/T - cell lymphoma
© positive CD 8 (d) positive TT-1
Primary cutaneous B cell lymphoma
Anais Brasileiras Dermatologia 8O : (5) 2OO5
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Diagnostic aspects
Clinical history and physical examination collaborate in the diagnosis of primary cutaneous B-cell lymphomas.
Confirmation, however, is obtained essentially by the histological and immunohistochemical studies Both the
histological and the immunohistochemical studies are performed on a fragment of skin biopsy. Currently, the
immunohistochemical examination may be done in formaldehyde-fixed and paraffin-embedded specimens, due to
the development of antibodies and techniques capable of revealing antigens present in tissues processed in this
manner. The search for a rearrangement of the immunoglobulin heavy chain gene and for genetic alterations by
means of molecular biology techniques has been described as an important aid in the diagnosis of
lymphoproliferative processes. The search for a rearrangement in the immunoglobulin gene is currently also
performed in formaldehyde-fixed and paraffin-embedded specimens.
Clinical aspects
By and large, the primary cutaneous B-cell lymphomas clinically present as papules, plaques or nodules.35 Their
coloration can vary from erythematous to purple. The lesions could be solitary or multiple, disseminated or
grouped in a region of the body, rarely presenting ulceration or necrosis As for their localization, they may affect
any region of the skin, although some subtypes show areas of predilection presents a list of the main clinical
characteristics of primary cutaneous B-cell lymphomas, according to the recent WHO-EORTC classification of
primary cutaneous lymphomas
Histological aspects
A histological study using hematoxylin-eosin (HE) staining enables identifying neoplastic lymphocyte proliferation.
The presence of the normal collagen band in the superficial dermis, called Grenz zone, separating the epidermis
from the dermal lymphoid infiltrate, is a common finding in cutaneous B-cell lymphomas.1Epidermotropism, the
migration of lymphocytes to the epidermis, frequent in T-cell lymphomas, is rare in B-cell lymphomas.2,17 The
lymphocytic infiltrate described in cutaneous B-cell lymphomas is usually dense, asymmetric, nodular or diffuse,
and often tends to be more intense in the deep dermis, called the "bottom-heavy pattern". Lesions at early stages
of cutaneous B-cell lymphomas tend to present irregular or nodular perivascular and periadnexal infiltrates in the
superficial reticular dermis , whereas old lesions tend to present a more diffuse cell infiltrate, from the dermis to the
subcutaneous tissue, with or without the presence of reactive lymphoid follicles. Reactive T-lymphocytes are
observed in the periphery or among the neoplastic B-cells, mainly in initial lesions. Mitosis figures can also be
found in great amounts. presents the main histological characteristics of primary cutaneous B-cell lymphomas
Immunohistochemical aspects
The immunohistochemical study is designed to identify the cell line and the differentiation stage of the lymphocyte
population, as well as other cells present in the cell infiltrate under study. The main B-lymphocyte markers used in
paraffin-embedded tissues are: anti-immunoglobulin k and l light-chain antibodies, CD20, CD79a, CD10 and CD5
(marking a subpopulation of B-lymphocytes from the mantle zone) . In the study of cutaneous B-cell lymphomas, it
is also necessary to investigate the presence of T-cells. The main T-lymphocyte markers used in paraffinembedded tissues are: CD3 and CD45RO. The anti (bcl-2, bcl-6, CD21, CD23 and Ki-67) antibodies are also
helpful in diagnosing B-cell lymphoproliferative processes
Primary cutaneous B cell lymphoma
Anais Brasileiras Dermatologia 8O : (5) 2OO5
Non-Hodgkin lymphoma
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Cancer starts when cells in the body begin to grow out of control. Cells in nearly any
part of the body can become cancer, and can spread to other areas of the body.
Non-Hodgkin lymphoma (also known as non-Hodgkin’s lymphoma, NHL, or
sometimes just lymphoma) is a cancer that starts in cells called lymphocytes, which
are part of the body’s immune system. Lymphocytes are in the lymph nodes and
other lymphoid tissues (such as the spleen and bone marrow).
Some other types of cancer – lung or colon cancers, for example – can spread to
lymph tissue such as the lymph nodes. But cancers that start in these places and
then spread to the lymph tissue are not lymphomas.
The main types of lymphomas are:
Hodgkin lymphoma (also known as Hodgkin’s lymphoma, Hodgkin disease, or
Hodgkin’s disease),
Non-Hodgkin lymphoma
These different types of lymphomas behave, spread, and respond to treatment
differently.
Doctors can usually tell the difference between them by looking at the cancer cells
under a microscope. In some cases, sensitive lab tests may be needed to tell them
apart.
Lymphatic system
Non Hodgkin’s Lymphoma
Non Hodgkin’s Lymphoma
Non Hodgkin’s Lymphoma
Dermatological manifestations of HIV as follicular lymphoma
Moreira, E. et al. Dermatology on line journal 14 (7), 2OO8
Generalized B cell non Hodgkin’s lymphoma
Cardinali, C et al Dermatology on line J. 12 (3) 15
Non Hodgkin lymphoma
MALT lymphoma of the foreskin
It is a cancer from the mucosal regional zone originating from B cells of the MALT ( mucosa associated
lymphoid tissue)
Haque ,S et al: Leukemia lymphoma 45: 699, 2OO4
Burkitt’s lymphoma
It is a cancer of lymphatic system particularly B lymphocyte
C T scan to Non Hodgkin masses,
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Multiple lymphomatous masses affecting both
kidneys.
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CT scan with dural masses
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CT scan of chest: white arrow: right paratracheal
nodes; Black arrow : left internal mammary nodes
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C T scan to the gut
Spleen, non-Hodgkin lymphoma. This spleen exhibits uniform
multicentric involvement of the white pulp by a malignant lymphoma