V.N. KARAZIN KHARKOV NATIONAL UNIVERSITY Kharkov Regional Centre of Cardiovascular surgery V.N. Karazin Kharkov National University Department of Internal Medicine Lymphomas Associate professor Abduyeva F.M., MD, PhD 2014 Classification of lymphomas Lymphomas are malignancies of the lymphoid cells Lymphomas Hodgkin’s lymphomas Non hodgkin’s lymphoma WHO classification of tumors of hematopoietic and lymphoid tissues 2008 1. Non-Hodgkin's lymphomas • B-cell lymphoma • account for about 85% of the diagnosed cases, and within Africa, Burkitt lymphoma is the most common B-cell tumour 2. Hodgkin's lymphoma • T-cell lymphoma • NK-cell lymphomas Hodgkin lymphoma Dr. Thomas Hodgkin (1798-1866) British physician, considered one of the most prominent pathologists of his time and a pioneer in preventive medicine. In 1832, Dr. Thomas Hodgkin, working at Guy’s Hospital in London, reported a series of seven cases of enlargement of the lymph nodes and spleen, which he speculated might represent a primary disorder of those tissues rather than reactive enlargement • The first descriptions of the microscopic appearance of the affected tissues appeared in the late 1800s. However, it was not until the seminal observations by Sternberg in 1898 and Reed in 19025 that widespread attention was drawn to the curious giant cell present in many such cases, which would later come to bear their names and which would soon become regarded as a morphologic hallmark of Hodgkin’s disease. Interestingly, neither Sternberg nor Reed felt that this disorder represented a neoplasm. Sternberg believed that it was a variant of tuberculosis, whereas Reed felt it to be an independent entity of inflammatory origin. Dr. Dorothy Reed Mendenhall Definition Hodgkin lymphoma (formerly, Hodgkin disease) is a potentially curable lymphoma with distinct histology, biologic behavior, and clinical characteristics. Classification WHO (2000) • Hodgkin lymphoma can be divided into two main types: Classical Hodgkin lymphomas Nodular lymphocytepredominant Hodgkin lymphoma 1. Nodular sclerosis 2. Mixed cellularity 3. lymphocytedepleted 4. Lymphocyte-rich PATHOGENESIS • In classic HD has been proven to be a malignant tumor of B-cell Origin • PCR studies have provided evidence to suggest that the RS cells of classic HD are derived from germinal center B cells that have undergone unusual “crippling” mutations of their immunoglobulin genes, rendering them nonfunctional—providing a fascinating clue as to why this B-cell neoplasm appears so different from all others. • During normal B-cell development, naïve B lymphocytes (which have few or no mutations in their immunoglobulin genes) enter germinal centers where, upon exposure to antigen, they undergo high rates of mutation of their immunoglobulin gene variable regions. This process, termed somatic hypermutation, is a key process in generating a diverse antibody repertoire and serves to increase the likelihood that high-affinity antibody is produced against a foreign antigen. Only B cells that are successful in creating immunoglobulin with high affinity for the antigen presented are permitted to leave the germinal center to become either plasma cells or memory B cells. • B cells that cannot make antibody undergo apoptosis and die. • Cells are “rescued” from apoptosis only if they produce high-affinity antibody; this rescue appears to involve activation of the bcl-2 anti-apoptosis gene. • Epstein-Barr virus subsequently has been found to latently infect the RS cells in the majority of cases of classic HD. Infection by EBV can cause up-regulation of the bcl-2 gene, thereby allowing the cell to avoid apoptosis PATHOGENESIS PATHOGENESIS transforming event(s) EBV? loss of apoptosis cytokines germinal centre B cell RS cell inflammatory response Clinical Presentation • Nontender lymph nodes enlargement ( localised ) – neck and supraclavicular area 60-80% – mediastinal adenopathy 50% – other ( abdominal, extranodal disease ) • systemic symptoms (B symptoms) 30% – fever – night sweats – unexplained weight loss (10% per 6 months) • other symptoms – – – – – – fatigue, weakness, pruritus cough , chest pain, shortness of breath, vena cava syndrome abdominal pain, bowel disturbances, ascites bone pain cachexia, anemia, splenomegaly, hepatomegaly, jundice Rarely Pel-Ebstein fever is a rarely seen condition noted in patients with Hodgkin's lymphoma in which the patient experiences fevers which cyclicly increase then decrease over an average period of one or two weeks. A cyclic fever may also be associated with other conditions, but it is not called "PelEbstein fever" unless the fever is associated with Hodgkin's. Symptoms related lymph nodes enlargement I. Enlarged, painless, non-tender, superficial lymph nodes II.Alcohol-induced pain Rarely, patients with Hodgkin’s lymphoma complain of severe pain following alcohol ingestion. The pain typically occurs within a few minutes after the ingestion of even a small amount of alcohol. The mechanism is unknown. Symptoms related to mass 1. Mediastinal mass: retrosternal chest pain, cough, or shortness of breath. 2. Retroperitoneal lymphadenopathy discomfort and pain in the paravertebral or loin regions, particularly in the supine position. Cotswolds staging classification Ann Arbor classification (1971г) Stage I Stage II Stage III Stage IV Classical Hodgkin Lymphoma Hodgkin lymphoma generally involves contiguous nodes. Non-Hodgkin lymphoma is noncontiguous. Enlarged lymph nodes in the supraclavicular region in HL patients. Cervical lymphadenopathy in HL pruritus in HL 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 gross appearance could pass for a non-Hodgkin's lymphoma as well. Group of mediastinal lymph nodes. Note the anthracotic pigment in some lymph nodes. The specimen measured 12 cm. in greatest dimension. This is a liver that is involved with Hodgkin's disease. Staging evaluation for Hodgkin’s Disease (1) • Essential – – – – pathologic documentation by hemopathologist physical examination documentation of B symptoms laboratory evaluation • • • • complete blood count, ESR liver function tests renal function tests lactate dehydrogenase – – – – chest radiograph ultrasonography CT scan of chest, abdomen and pelvis bone marrow aspiration / biopsy (bilateral) Staging evaluation for Hodgkin’s Disease (2) • Essential under certain circumstances – – – – – – – liver biopsy gallium scan technetium bone scan bone radiographs MRI bipedal lymphangiogram staging laparotomy • Useful but not essential tests – cell-surface marker phenotypic analysis – gene rearrangement analysis Hodgkin's disease. This contrast-enhanced computed tomographic scan of the patient in Figure 2 better delineates the extensive anterior mediastinal adenopathy (large arrows) from the thymus (arrowhead) and aorta (A). >10 cm Bulky disease This 23 y/o female with left inguinal adenopathy was referred for gallium scan. Abdominal and pelvic CT scans were subsequently performed. Selected images from the gallium scan demonstrate abnormal uptake in the left inguinal region and the left side of the pelvis. The CT scan demonstrates heterogenous masses in these regions consistent with lymphadenopathy. In addition, there are multiple low attenuation lesions in the spleen. Lymphangiography Abdominal lymphangiogram X-ray of a patient with Hodgkin's disease, showing the organization of lymph nodes in the pelvis and the back of the abdomen. A lymphangiogram is conducted by injecting a radio-opaque liquid dye into the lymph system through the feet. The fluid travels through the lymph system and remains visible by X-ray Diagnosis To diagnose Hodgkin lymphoma a histologic evaluation is always required, and an excisional lymph node biopsy is recommended for this purpose. Comparison between two types Classical Hodgkin lymphomas Nodular lymphocyte-predominant Hodgkin lymphoma About 19 out of 20 people with Hodgkin lymphoma. Reed–Sternberg cell unique to this kind of Hodgkin lymphoma. •Only 1 in 20 people with Hodgkin lymphoma. Typically affects people aged 30– 50 and it is more common in men. •So called a ‘popcorn cell’ is unique to this kind of Hodgkin lymphoma. •It has a very good prognosis and over 90% of people go into remission after an excision biopsy and radiotherapy. •NLPHL can relapse later on and require another course of treatment and this can occur after as long as 10 years after treatment has finished. In some cases, the relapse takes the form of a non-Hodgkin lymphoma (this process of a lymphoma coming back in a different form is known as ‘transformation’). Nodular LPHL and Classical HL Morphologic and Immunophenotypic Features. Characteristic Pattern Tumour Cells Background Fibrosis CD15 CD30 CD20 CD45 Epithelial Membrane Antigen Nuclear BCL 6 ( PTN in R-S cells ) EBV ( in R-S ) cells Background Lymphocytes CD57 T-cells Ig genes CHL Diffuse, Interfollicular, Nodular R-S Mononuclear or Lacunar Lymphocytes ,histiocytes, eosinophils, plasma. Common + ( 85% ) + ( > 95% ) (- / +) (-) (-) (-) + ( 50% ) T -cells > B-cells (-) Rearranged, Clonal, Mutated, “Crippled” NLPHL Nodular, at least in part Lymphomcytic/Histiocytic or Popcorn Lymphocytic, Histiocytic. Rare (-) (-) (+) (+) (+) (+) (-) B-cells > T-cells (+) Rearranged, Clonal, Mutated, Ongoing Types of cells in HL classic RS cell (mixed cellularity) lacunar cell (nodular sclerosis) popcorn cell (lymphocyte predominance) Nodular lymphocytepredominant Hodgkin lymphoma Nodular lymphocyte-predominant Hodgkin lymphoma • • These cells have also been referred to as “popcorn” cells, but the WHO classification of 2008 recommended the use of the term “LP cell.” In comparison with classical HRS cells, the nucleoli of the LP cells are smaller, multiple, and basophilic. A close-up of L&H cell (popcorn cell) in a case of Nodular Lymphocyte-predominant Hodgkin Lymphoma. It has a http://www.webpathology. com/image.asp?case=38 large, multilobed, folded nucleus and is surrounded by 8&n=16 small lymphocytes. L&H cells are of B-cell lineage and express pan-B-cell markers. Classical Hodgkin lymphomas Reed-Sternberg cell • Diagnostic RS-cells are large cells (20-50 Mm) in diameter or more with abundant weakly acidophilic or amphophilic cytoplasm, which may appear homogenous or granular and lacks a pale zone in the Golgi area , The nucleus is bilobed or polylobed . • The nuclear membrane is thick and sharply defined. The nuclear pattern is usually vesicular but with some coarse chromatin clumps scattered throughout .There is very large ,variously shaped, but usually rounded, highly acidophilic central inclusion like nucleolus surrounded by a clear halo. When the two lobes face each other (mirror image) owl eye appearance results. • Cells with this set of features but lacking nuclear lobation are referred to as mononuclear variant of RS cells or H-cells (Hodgkin's cells). Reed-Sternberg cell Malignant REED-STERNBERG ( RS) Cell: Bi-nucleate cell with a prominent nucleolus. Derived from B cell, at an early stage of differentiation. Classical RS cells Nodular sclerosis • • 70% of all CHL - is the most frequent subtype In most cases, NSHL has at least a partially nodular pattern, with fibrosious bands separating the nodules. The disease affects primarily young adults and is less often observed in the elderly. Female predominance. In 80% of patients with NSCHL the mediastinum is involved and 50% of patients with NSCHL present with bulky disease. • • • Mixed cellularity Hodgkin’s disease • The appearance is usually diffuse or vaguely nodular, without bands forming sclerosis. The overall prognosis is also worse than in LP or NS HD but varies with stage, and the disease can be cured in many patients. At low power, the involved tissue appears diffusely effaced by a mixed cellular infiltrate consisting of scattered diagnostic RS cells and varying proportions of mature small lymphocytes, large lymphocytes, histiocytes, eosinophils, and plasma cells • • Lymphocyte Rich • Some cases of the CHL with RScells of the classical type or lacunar type may have a background infiltrate that consist predominantly of lymphocytes, with rare or no eosinophils, the term lymphocyte rich CHL was proposed. •The frequency of <10% •It is more common in young men •Usually found in stage I and progresses slowly •The prognosis is very good Lymphocyte depleted • Is the least common subtype of CHL •The pattern in LDHL is diffuse and often appears hypocellular ,due to the presence of fibrosis , necrosis, and a paucity of inflammatory cells. •Large number of classical RS-cells are present with a bizarre pleomorphic sarcomatous variants. •Approximately 70% of patients present at an advanced stage and most (80%) have B symptoms. • IMMUNOHISTOCHEMISTRY OF HODGKIN’S LYMPHOMA The diagnosis of Hodgkin’s lymphoma is primarily based on the recognition of the typical tumor cells, either HRS cells or LP cells, in the appropriate environment. In addition immunophenotypic and molecular markers help to classify the disease into the various tumor subtypes. In nearly all cases of CHL, HRS cells are positive for CD30. In addition, the majority of HRS cells (85%) also express CD15 LP cells are usually negative for both CD15 and CD30. The B-cell markers CD20 and CD79a are positive in nearly all cases of NLPHL. • • • Reed-Sternberg cells and most Hodgkin variants express the monoclonal antigens Treatment of Hodgkin Disesae With appropriate treatment about 85% of patients with Hodgkin disease are curable • I A,B: radiation therapy • II A : combination chemotherapy ( ABVD Adriamycin, Bleomycin, Vinblastine and Dacarbazine) + radiotherapy • IIB IIIA,B IVA,B : combination chemotherapy (+/radiotherapy) Irradiation fields used in Hodgkin’s Lymphoma Outcomes of HL In assessing the long-term 20-year results of treatment it has been established: 1.During the first 5-8 years after the end of treatment, the patients mostly die from Hodgkin's disease progression. 2.After 15-20 years of follow-leading cause of death of patients are late complications of treatment: • secondary tumors and leukemias (10-30%) • myocardial infarction (7-16%) • infection (4-10%) • serious damage to the lung tissue after mediastinal irradiation, particularly when combined with bleomycin (6-7%) Causes of Death among 2733 Patients with Hodgkin’s Disease/Lymphoma Hodgkin lymphoma Secondary cancers Cardiovascular Pulmonary Infection 383 200 148 41 35 41.2% 21.5% 15.9% 4.4% 3.8% Trauma/Suicide MDS Other/Unknown Total 16 11 96 930 1.7% 1.2% 10.3% 100.0% Stanford, Hoppe et al Prognosis • Hodgkin� ' s disease is considered one of the most curable forms of cancer, especially if it is diagnosed and treated early. • Unlike other cancers, Hodgkin's disease is even potentially curable in late stages • Five-year survival rates for patients diagnosed with stage I or stage II Hodgkin� ' s disease are 90 - 95%. • With advances in treatment, recent studies have indicated that even patients with advanced Hodgkin� ' s disease have 5-year survival rates of 90%, although it is not yet certain if their cancer will return. Patients who survive 15 years after treatment are more likely to later die from other causes than Hodgkin� ' s disease. Non-Hodgkin lymphomas Definition • Non-Hodgkin’s lymphoma (NHL) is a heterogeneous group of lymphoproliferative malignancies. More than 30 different subtypes of NHL have been identified and categorized according to several prognostic factors, including size, growth rate, and anatomic site. Epidemiology: - annual incidence: 5-10 new cases per 100 000 persons, - age distribution: middle-age patients and the elderly, - males are affected more often than females (1.5:1.0). Risk Factors • Most cases of NHL occur in patients who are 60 years of age or older. • NHL occurs more frequently in men than in women. • Exposure to chemicals such as benzene and herbicides has been linked to an increased risk of NHL. • People with a weakened immune system and certain infections, such as HIV, are also at an increased risk for NHL. Non-Hodgkin’s Lymphoma Rappaport Classification Nodular (follicular) Diffuse Indolent Aggressive Small cell Large cell The two most often encountered patterns of growth are 1) follicular (sometimes referred to as nodular) in which the lymphoma mimics follicular center structures and 2) diffuse in which the lymphoid cells proliferate in an apparently unorganized fashion. Occasionally lymphoma will be distributed within lymph node sinuses. Histological comparison of normal lymph node and the lymph node affected by lymphoma Normal lymph node Follicular lymphoma WHO Classification: B-Cell Malignancies Precursor B-cell neoplasm • Precursor B-lymphoblastic leukemia/lymphoma Mature (peripheral) B-cell neoplasms • B-cell chronic lymphocytic leukemia/ small lymphocytic lymphoma • B-cell prolymphocytic leukemia • Lymphoplasmacytic lymphoma • Hairy cell leukemia • Plasma-cell myeloma/ plasmacytoma • Follicular lymphoma • Splenic marginal-zone B-cell lymphoma • Nodal marginal-zone lymphoma • Extranodal marginal-zone B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) type • Mantle-cell lymphoma • Diffuse large B-cell lymphoma (DLBCL) • Burkitt's lymphoma/Burkitt's cell leukemia • Blastic NK-cell leukemia Harris NL et al. J Clin Oncol. 1999;17:3835-3849. Antigen Expression in B-Cell Lineage ALL MCL, CLL Burkitts, FL, DLBCL WM MM Stem cell Pre-B Early B Mature B Activated B Plasmacytoid B Plasma Germinal center Type of B cell lymphoma is a function of: 1) 2) Where the cell was in development/maturation when it went “bad” What molecular derangement occurred Jaffe. In: Non-Hodgkin’s Lymphoma. 1997:84. WHO Classification: T-Cell Malignancies Precursor T-cell neoplasm • Precursor T-lymphoblastic leukemia/lymphoma Mature (peripheral) T-cell neoplasms • T-cell prolymphocytic leukemia • T-cell granular lymphocytic leukemia • Aggressive NK-cell leukemia • Adult T-cell lymphoma/leukemia (HTLV1+) • Extranodal NK/T-cell lymphoma, nasal type • Enteropathy-type T-cell lymphoma • Hepatosplenic gamma-delta T-cell lymphoma • Subcutaneous panniculitis-like T-cell lymphoma • Mycosis fungoides/Sézary syndrome • Primary cutaneous anaplastic large cell lymphoma, T/null cell • Peripheral T-cell lymphoma, unspecified • Angioimmunoblastic T-cell lymphoma • Primary systemic anaplastic large cell lymphoma, T/null cell • Blastic NK lymphoma Harris NL et al. J Clin Oncol. 1999;17:3835-3849. Non-Hodgkin’s Lymphoma Working Classification • Low Grade – Small Lymphocytic – Follicular small-cleaved cell – Follicular mixed small-cleaved and large cell • Intermediate Grade – – – – Follicular large cell Diffuse small cleaved cell Diffuse mixed small and large cell Diffuse large cell • High Grade – Large cell immunoblastic – Lymphoblastic – Small non-cleaved cell (Burkitt's and non-Burkitt's type) Lymphoma Biology • Aggressive NHL – short natural history (patients die within months if untreated) – disease of rapid cellular proliferation – Potentially curable with chemotherapy • Indolent NHL – long natural history (patients can live for many years untreated) – disease of slow cellular accumulation – Generally incurable with chemotherapy Non Hodgkin Lymphoma Indolent B cell Follicular SLL/CLL Marginal zone LP (WM) T/NK cell Mycosis fungoides Sezary syndrome Primary cut ALCL Aggressive B cell DLBCL FLg3 and tFL Mantle cell Primary effusion T/NK cell ALCL Angioimmunoblastic Subq panniculitis-like Blastic NK Extnanodal NK/T nasal Enteropathy-type Hepatosplenic PTCL nos Highly Aggressive B cell Pre-B lymphoblastic Burkitt T/NK cell Pre-T lymphoblastic Follicular Lymphoma Diffuse Large B Cell Lymphoma Non-Hodgkin’s Lymphoma Splenic Lymphoma Burkitt’s Lymhoma Starry, Starry Night Clinical Presentation • Patients with lymphoma may present with the following symptoms: •Lympadenopathy similar to tuberculosis •Mediastinal mass • Aggressive NHL •Pleural effusion – Patients likely to •Splenomegaly present with •Maxillary mass (Burkitt lymphoma) symptoms •Right iliac fossa mass • Indolent NHL •Intussusception – Patients likely to •Bowel obstruction present with •Bowel perforation painless •Fever, weight loss, night sweats adenopathy Denis Parsons Burkitt (28 February 1911 – 23 March 1993) Nodular nonHodgkin's lymphoma in a patient with AIDS В-клеточная неходжкинская лимфома с поражением илеоцекального угла. Non-Hodgkin Lymphoma Diagnosis Lymph node biopsy • • • • • • Biopsy of lymph node is the main method of diagnosis of lymphoma. Material for morphological study lymph node can be obtained by using: aspiration biopsy (suspension cells) needle biopsy (tissue column) open incisional biopsy (a fragment of the lymph nodes) open excisional biopsy (the entire lymph node or conglomerate lymph nodes). Non-Hodgkin’s Lymphoma Immunophenotyping • Immunohistochemistry • Immunofluorescence • Flow cytometry • Identification of CD’s (cluster determinants) – CD5 = T cell type – CD20 = B cell type Immunohistochemistry Extranodal NK / T-cell lymphoma, nasal type stain on CD3 Treatment approach • Approach dictated mainly by histology – reliable hematopathology crucial • Aggressive NHL – Cure is often the goal • Indolent NHL – Cure is rarely the goal – Control is the goal