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Cutaneous lymphomas Abdel Hamid M. Abdel-Aziz Professor of Dermatology & Venereology, AL-Azhar University WWW. Abdelhamiddermatlas . com Primary cutaneous lymphomas • • • 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 • • • 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 • • • • • 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 • • • • • • • • • • • • • • • 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 • • • • • • • • • • • • 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 • 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 • Subcutaneous panniculitis like T cell lymphoma • Sezary syndrome • 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 • • • • • • • • 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 • • • • • • • • 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, • Multiple lymphomatous masses affecting both kidneys. • CT scan with dural masses • CT scan of chest: white arrow: right paratracheal nodes; Black arrow : left internal mammary nodes • C T scan to the gut Spleen, non-Hodgkin lymphoma. This spleen exhibits uniform multicentric involvement of the white pulp by a malignant lymphoma