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LYMPHOMAS. INTRODUCTION. Lymphomas are cancers that begin by the malignant transformation of a lymphocyte in the lymphatic system. the prefix " lymph -" indicates their origination in the malignant change of a lymphocyte and the suffix "- oma " is derived from the Greek word meaning "tumor.".
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INTRODUCTION • Lymphomas are cancers that begin by the malignant transformation of a lymphocyte in the lymphatic system. • the prefix "lymph-" indicates their origination in the malignant change of a lymphocyte and • the suffix "-oma" is derived from the Greek word meaning "tumor."
INTRODUCTION • Lymphoma encompasses 2 large groups of neoplasms, namely non-Hodgkin lymphoma (NHL) and Hodgkin disease. • NHL includes many clinicopathologic subtypes, each with distinct epidemiologies; etiologies; morphologic, immunophenotypic, genetic, and clinical features; and responses to therapy.
Hodgkin’s Disease • Hodgkin disease (HD) is a potentially curable malignant lymphoma with distinct histology, biologic behavior, and clinical characteristics. • Histologically, the picture is unique, with 1-2% of neoplastic cells (Reed-Sternberg [RS] cells) in a background of a variety of reactive mixed inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes
Hodgkin’s Disease - In the Beginning • First described in 1832 by Dr. Thomas Hodgkin • Neoplasm of B lymphocytes – large pleomorphic prominent nucleolus in a halo - Hodgkin cells • Reed-Sternberg cell – binucleate Hodgkin cell with owl eye appearance • Classification: • Classical Hodgkin’s • Nodular sclerosis – low grade • Mixed cellularity • Lymphocyte rich classical • Lymphocyte depleted. – high grade • Nodular lymphocyte-rich Hodgkin’s 1798-1866
Hodgkin’s Disease - Epidemiology Accounts for ~ 30% of all malignant lymphomas Socioeconomic class is associated with a higher risk of HD. Composed of two different disease entities: Lymphocyte-predominant Hodgkin’s (LPHD), making up ~ 5% of cases Classical HD, representing ~ 95% of all HDs. A common factor of both HD types is that neoplastic cells constitute only a small minority of the cells in the affected tissue, often corresponding to < 2% of the total tumor
Hodgkin’s Disease - Epidemiology • Bimodal age distribution • first peak between 2nd - 3rd decade of life • second peak between 5th - 6th decade of life • Male: Female 2:1 in kids, adults almost equal M:F • Mixed cellularity (MC) Hodgkin’s Disease is more common at younger ages • More common in immune deficiency patients
Fatal disease with 90% of untreated patients dying within 2 to 3 years With chemotherapy, >80% of patients suffering from HD are cured. Pathogenesis of HD is still largely unknown. HD nearly always arises and disseminates in lymph nodes Hodgkin’s Disease - Epidemiology
H D – Etiology • The etiology of HD is unknown. • Infectious agents, especially the Epstein-Barr virus (EBV), may be involved in the pathogenesis of HD. • Patients with HIV infection have a higher incidence of HD compared to the population without HIV infection. • Genetic predisposition may play a role in the pathogenesis of HD. • Approximately 1% of patients with HD have a family history of the disease. • Siblings of an affected individual have a 3- to 7-fold increased risk for developing HD. • This risk is higher in monozygotic twins.
H D - Pathophysiology • The RS cells represent a clonal proliferation of B lymphocytes that derive from the germinal centers of lymph nodes and that have lost their ability to express their antibodies. • The RS cell is chracterised by its large size and classic binucleated structure with large eosiniphilic nucleoli. • They consistently express CD15 (Leu-M1) and CD30 (Ki-1) antigens. • Some of the clinical manifestations of HD (eg, eosinophilia) are attributed to the production of cytokines.
H D - History • Asymptomatic lymphadenopathy may be present (above the diaphragm in 80% of patients). • Constitutional symptoms (eg, unexplained weight loss, fever, night sweats) are present in 40% of patients. • Chest pain, cough, and/or shortness of breath may be present due to a large mediastinal mass or lung involvement. Rarely, hemoptysis is observed.
H D - History • Patients may present with pruritus. • Alcohol-induced pain at sites of nodal disease is specific for HD and occurs in less than 10% of patients. • Intermittent fever is observed in approximately 25% of cases. Infrequently, the classic Pel-Ebstein fever (high fever for 1-2 wk followed by an afebrile period of 1-2 wk) is observed. • Back or bone pain occurs rarely.
H D - Physical • Palpable painless lymphadenopathy occurs in the : • cervical area (60-80%), • axilla (6-20%), and, less commonly, • inguinal area (6-20%). • It is described as : • asymmetrical, discrete • painless, non-tender • elastic character on palpation ( rubbery) • not adherent to skin • fluctuate in size • Involvement of the Waldeyer ring or occipital or epitrochlear areas is observed infrequently. • Splenomegaly may be present.
H D - Physical • Patients may have hepatomegaly. • Superior vena cava syndrome resulting from massive mediastinal lymphadenopathy is observed rarely. • Central nervous system (CNS) symptoms or signs may be due to paraneoplastic syndromes, including cerebellar degeneration, neuropathy, Guillain-Barré syndrome, or multifocal leuko-encephalopathy.
H D – Lab studies • CBP : Anemia (normochromic/normocytic), eosinophilia, neutrophilia, lymphopenia • ESR -raised • LFT- (liver infil / obs at porta hepatis) • RFT- prior to treatment • Urate , Ca, • LDH - adverse prognosis • CXR- mediastinal mass • CT thorax / abdomen / pelvis-for staging • Other: Gallium scan, PET, Lymphangiography , Laporotomy
H D – Lab studies • Erythrocyte sedimentation rate (ESR) may be elevated. • Complete blood count (CBC) should be performed. • anemia usually is due to anemia of chronic disease, but it may be due to bone marrow involvement or the presence of an autoantibody • Cytopenias are common in advanced disease. • Platelet counts can be increased or decreased.
H D – Lab studies • Lactate dehydrogenase (LDH) may be increased. LDH may correlate with the bulk of disease. • Rarely, HD is associated with nephrotic syndrome. • Alkaline phosphatase may be increased due to the presence of liver or bone involvement. • Other uncommon laboratory findings include hypercalcemia, hypernatremia, and hypoglycemia (due to the presence of insulin autoantibodies). • Beta-2-microglobulin correlate with tumor burden, systemic symptoms, and prognosis.
H D – Imaging studies • Chest radiography • CT scans of the chest, abdomen, and pelvis • Possible abnormal findings include enlarged lymph nodes, hepatomegaly and/or splenomegaly with or without focal parenchymal abnormalities, lung nodules or infiltrates, and pleural effusions. • A mediastinal mass, representing mediastinal lymphadenopathy, is a very common finding. • Gallium-67 scan or positron emission tomography (PET) scan may be used as a baseline test to assess response to therapy.
H D – Imaging studies • Lymphangiography • It is used infrequently because it is technically challenging. • Lymphangiography may demonstrate abnormalities, even in normal-sized lymph nodes. • One additional advantage of this technique is that residual dye may be present in the lymph nodes for months to years, and the size of affected lymph nodes can be followed easily with plain radiographs.
H D – Diagnosis • A histological diagnosis always is required. • Because the lymph node architecture is important for histological classification, an excisional lymph node biopsy is recommended. • Staging laparotomy includes splenectomy, needle and wedge biopsy of the liver, and biopsies of the paraaortic, mesenteric, portal, and splenic hilar lymph nodes. • Bilateral bone marrow biopsies - because HD is seen as patchy infiltrates in the bone marrow, bilateral bone marrow biopsies are advised.
H D – Histologic Findings • According to the recent World Health Organization (WHO) classification, the first 4 subtypes are referred to as classic HD. • Nodular sclerosis Hodgkin disease - 60-80% • Mixed-cellularity Hodgkin disease - 15-30% • Lymphocyte-depleted Hodgkin disease - Less than 1% • Lymphocyte-rich classic Hodgkin disease - 5%
H D – Histologic Findings • Nodular sclerosis Hodgkin disease • The morphology shows a nodular pattern. The broad bands of fibrosis divide the node into "nodules." The capsule is thickened. The characteristic cell is the lacunar-type RS cell, which has a monolobated or multilobated nucleus and a small nucleolus with abundant and pale cytoplasm. • NS frequently is observed in adolescents and young adults and usually involves the mediastinum and other supradiaphragmaticsites.
H D – Histologic Findings • Mixed-cellularity Hodgkin disease • Histologically, the infiltrate usually is diffuse. RS cells are of the classic type (large, with bilobate, double or multiple nuclei, and a large eosinophilic inclusionlike nucleolus). • It commonly affects the abdominal lymph nodes and spleen. • Patients with this histology typically have advanced-stage disease with systemic symptoms and immunodeficiency.
H D – Histologic Findings • Lymphocyte-depleted Hodgkin disease • The infiltrate in lymphocyte-depleted Hodgkin disease (LDHD) is diffuse and often appears hypocellular. Large numbers of RS cells and bizarre sarcomatous variants are present. • It is associated with older age and HIV positivity. • Patients usually present with advanced-stage disease. • EBV proteins are expressed in many of these tumors. • Many cases of LDHD diagnosed in the past actually were non-Hodgkin lymphomas, often of the anaplastic large-cell type.
H D – Histologic Findings • Lymphocyte-rich classic Hodgkin disease • In this type of HD, RS cells of the classic or lacunar type are observed, with a background infiltrate of lymphocytes. • It requires immunohistochemical diagnosis. • Some cases may have a nodular pattern. • Clinically, the presentation and survival patterns are similar to those for MCHD.
H D – Staging • The Ann Arbor classification (1971) is used most commonly. • Clinical staging involves assessment of disease extent by clinical examination and imaging techniques. • When staging laparotomies are used as part of staging, disease extent is designated pathologic staging.
Hodgkin’s Disease – Staging Stage Definition I Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE) II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE) III Involvement of lymph node regions on both sides of the diaphragm (III) which may be accompanied by involvement of the spleen (IIIS) or by localized involvement of an extralymphatic organ or site (IIIE) or both (IIISE) IV Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues with or without associated lymph node involvement B symptoms: fever > 38ºC for three consecutive days, drenching night sweats or unexplained loss 10% or more of weight the preceding 6 months
Hodgkin’s Disease – Staging • The stage of HD correlates with prognosis. • Also, the bulk of nodal disease and the extent of subdiaphragmatic involvement have been found to correlate with prognosis. • Approximately one third of new patients have splenic involvement based on laparotomy data. • Spread in HD takes place via the lymphatics, hematogenous routes, and direct extension. • Contiguous involvement of extranodal sites, eg, involvement of the lung parenchyma due to direct extension of large mediastinal lymphadenopathy, is not considered stage IV disease.
H D – Prognosis • Early stages (I-IIA) - Early-stage disease is considered unfavorable when at least 1 of the following poor prognostic factors is present: • Bulky disease (defined as a mass >5-10 cm or a mediastinal mass larger than one third of the chest diameter) • Elevated ESR • B-symptoms • Multiple lymph node sites (>3) or extranodal disease
H D – Prognosis • Advanced stages (IIB-IV) • The International Prognostic Factors Project on Advanced Hodgkin's Disease has developed a prognostic score based on 7 adverse factors in advanced HD. These factors are • (1) an albumin level of less than 4 g/dL, • (2) a hemoglobin level of less than 10.5 g/dL, • (3) male sex, • (4) age older than 45 years, • (5) stage IV disease, • (6) a WBC count of higher than 15,000/mm3, and • (7) an absolute lymphocyte count of less than 600/mm3 or a lymphocyte count of less than 8% of the total WBC count.
H D – Treatment • Radiation therapy - is the use of high-energy x-rays (or sometimes other radiation) to kill cancer cells and shrink tumors. • The involved field encompasses the involved lymph node area plus one contiguous region. • Extended fields are the mantle (encompassing the cervical, axillary, and mediastinal nodes) or the inverted Y (encompassing the paraaortic, pelvic, and inguinal nodes). • Subtotal nodal irradiation involves the mantle plus the paraaortic field. The dose is 40-45 Gy when given alone or lower (usually 30 Gy) when used in combination with chemotherapy. • The mantle field is shaped accordingly in order to reduce radiation to the heart and lungs. • Careful avoidance of the spinal cord prevents myelitis. Shielding the testes and oophoropexy are important during the reproductive years. If these cannot be ensured, sperm and ova banking may be advisable.
H D – Chemotherapy • Conventional chemotherapy : • MOPP • ABVD • Alternating regimens – MOPP/ABVD • Hybrid regimens – MOPP/ABV • Stanford V • BEACOPP • High-dose chemotherapy with transplantation • High-dose chemotherapy (HDC) at doses that ablate the bone marrow is feasible with reinfusion of the patient's previously collected hematopoietic stem cells (autologous transplantation) or infusion of stem cells from a donor source (allogeneic transplantation).
H D – Response Assesment • The goal of treatment is to induce a complete response (CR). • Any other outcome is considered a treatment failure. • In assessing response, note that residual masses do not always represent active disease. • Gallium and PET scans are useful in this setting because they can differentiate active and inactive residual masses.
H D – Treatment Guidelines • The treatment of early-stage favorable - options include the following: • Extended-field radiotherapy, if pathologically staged (20% will be upstaged upon laparotomy) • Subtotal nodal irradiation, if clinically staged (approximately 20% will relapse, usually at nonirradiated sites) • Combined modality therapy - usually represents chemotherapy (ABVD) for 2-4 cycles, followed by radiotherapy of the involved field • ABVD alone without radiation, which may be adequate therapy for early-stage disease (under investigation).
H D – Treatment Guidelines • Treatment for early-stage unfavorable disease is as follows: • Combined modality therapy, which is chemotherapy (ABVD) for 4-6 cycles followed by involved-field radiotherapy, is used. • Approximately 80% of patients are cured, and treatment fails in 20%. Of these, 5% progress during treatment and 15% relapse. • The use of more aggressive chemotherapy for the treatment of unfavorable early-stage HD is being explored.
H D – Treatment Guidelines • Treatment for special presentations includes the following: • For patients with clinical stage IA disease with neck involvement and NLPHD histology, radiotherapy alone is adequate therapy. • For patients with clinical stage IA disease that is nonbulky and involves the mediastinum with NS histology, mantle irradiation alone may be adequate therapy.
